<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>Emission during coal
gasification
Evaluation of the carcinogenicity and genotoxicity
To: the State Secretary of Social Affairs and Employment
No. 2019/07, The Hague, May 20, 2019
                                                         2 2
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<pre> Contents                                                                                Emission during coal gasification | page 2 of 57
 contents
      Samenvatting                                           4 03 International classification                                      13
                                                                   3.1  European Commission                                           14
      Executive summary                                      6    3.2  IARC                                                          14
                                                                   3.3  The Health Council of the Netherlands                         14
 01 Scope8
      1.1  Background                                        9 04 Monitoring                                                        15
      1.2  Committee and procedure                           9    4.1  Environmental exposure monitoring                             16
      1.3  Data                                              9    4.2  Biological exposure monitoring                                16
      1.4  Criteria for classification                       9
      1.5  Quality assessment                               10 05 Manufacture and uses                                              17
                                                                   5.1  Manufacture                                                   18
 02 Identity of the substance                               11    5.2  Identified uses                                               18
      2.1  Name and other identifications                   12
      2.2  Composition of the emission of coal gasification 12 06 Summary of toxicokinetics                                         19
      2.3  Physicochemical properties                       12    6.1  Absorption, distribution and elimination                      20
                                                                   6.2  Toxicokinetics                                                20
1       Health Council of the Netherlands | No. 2019/07                                                 2                               3
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<pre> Contents                                                                                                  Emission during coal gasification | page 3 of 57
 07 Germ cell mutagenicity                                                     21  Literature                                                         32
      7.1  Summary and relevance of the provided information on (germ cell)
                                                                                    Annexes                                                            35
           mutagenicity22
                                                                                    A    IARC evaluation and conclusion                                 36
      7.2  Comparison with the CLP-criteria                                     25
                                                                                    B    Details epidemiological studies                                38
      7.3  Conclusion on classification and labelling for germ cell mutagenicity26
                                                                                    C    Details animal carcinogenicity studies                         45
                                                                                    D    EU Classification criteria on germ cell mutagenicity           49
 08 Carcinogenicity                                                            27
                                                                                    E    Classification system on carcinogenicity                       52
      8.1  Summary and relevance of the provided information
                                                                                    F    Reliability testing of animal and in vitro studies             53
           on carcinogenicity                                                   28
                                                                                    G    Reliability testing of epidemiological studies                 54
      8.2  Classification for carcinogenicity                                   30
      8.3  Conclusion on classification and labelling for carcinogenicity       31
2       Health Council of the Netherlands | No. 2019/07                                                                  2                                4
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<pre> Samenvatting                                                                                            Emission during coal gasification | page 4 of 57
 samenvatting                                                                                          het erfelijk materiaal in de cel blijvend verand-
                                                                                                       eren (mutatie of genafwijking). Hierdoor kunnen
                                                                                                       zij kankerverwekkend zijn. Aan de hand van de
 Op verzoek van de Minister van Sociale Zaken         waar kolenvergassing plaats vindt, kunnen        bewijskracht doet de commissie vervolgens
 en Werkgelegenheid heeft de Gezondheidsraad          blootstaan aan allerlei stoffen die als gevolg   voorstellen om de stof of proces te classificeren
 beoordeeld of de emissie die vrijkomt tijdens        van incomplete kolenvergassing vrij kunnen       in gevarencategorieën: één die aangeeft hoe
 kolenvergassing een genotoxisch effect heeft en      komen, zoal koolteer. Koolteer bevat verschil-   groot de bewijskracht is voor mutageniteit in
 tot kanker kan leiden, en op basis daarvan een       lende polycyclische aromatische koolwaterst-     geslachtscellen, en één die aangeeft hoe groot
 classificatievoorstel opgesteld. Dit advies is tot   offen, waarvan sommige – zoals benzo(a)          de bewijskracht is voor kankerverwekkend. De
 stand gekomen in de Subcommissie Classifi-           pyreen – kankerverwekkend zijn. In dit advies    categorieën zijn gebaseerd op EU-verordening
 catie carcinogene stoffen van de commissie           wordt de beroepsmatige blootstelling aan de      (EG) 1272/2008.
 Gezondheid en beroepsmatige blootstelling aan        emissie die vrijkomt tijdens kolenvergassing als
 stoffen. Op www.gezondheidsraad.nl staat infor-      geheel in ogenschouw genomen. De individuele     De commissie is van oordeel dat er voldoende
 matie over de taken van de subcommissie van          stoffen die in die emissie kunnen voorkomen      bewijs is voor een associatie tussen
 de Gezondheidsraad. De samenstelling van de          worden niet afzonderlijk beoordeeld.             beroepsmatige blootstelling aan de emissie die
 subcommissie is te vinden achterin dit advies.                                                        vrijkomt tijdens kolenvergassing en een
                                                      Beoordeling genotoxische en                      toegenomen risico op sterfte door in het
 Kolenvergassing                                      kankerverwekkende eigenschappen                  bijzonder longkanker. Dierexperimenten, waarbij
 Kolenvergassing is een proces waarbij bruin- of      De commissie beoordeelt aan de hand van de       dieren langdurig blootstonden aan monsters van
 steenkool bij hoge temperaturen en druk wordt        beschikbare wetenschappelijk literatuur of er    de emissie van kolenvergassing, ondersteunen
 vergast tot synthesegas. Het synthesegas wordt       aanwijzingen zijn dat een stof of een proces     de bevinding in mensen.
 gebruikt voor energieopwekking en voor de            genotoxisch en kankerverwekkend is en hoe
 productie van bijvoorbeeld kunststoffen, zoals       groot de bewijskracht daarvoor is. Genotoxische
 kunstmest. Mensen die in fabrieken werken            stoffen met mutagene eigenschappen kunnen
3        Health Council of the Netherlands | No. 2019/07                                                              2                                  5
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<pre> Samenvatting                                            Emission during coal gasification | page 5 of 57
 Advies aan de minister
 Op basis van beperkte gegevens adviseert de
 commissie om de emissie die vrijkomt tijdens
 kolenvergassing te classificeren als mutageen in
 geslachtscellen in categorie 2 (“reden tot
 bezorgdheid voor de mens omdat het mogelijk
 erfelijke mutaties in de geslachtscellen van
 mensen veroorzaakt”).
 De commissie concludeert verder dat
 de emissie die vrijkomt tijdens kolenvergassing
 kankerverwekkend is voor de mens, en adviseert
 deze emissie te classificeren in categorie 1A
 (“bekend dat het kankerverwekkend is voor de
 mens”). De kanker wordt veroorzaakt door een
 stochastisch genotoxisch werkingsmechanisme.
4        Health Council of the Netherlands | No. 2019/07            2                                   6
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<pre> Executive summary                                                                                        Emission during coal gasification | page 6 of 57
 executive summary                                                                                      process in question. The Subcommittee
                                                                                                        recommends classifying the substance or
                                                                                                        process in two hazard categories, which
 At request of the Minister of Social Affairs and     syngas or synthesis gas is used as fuel for       represent the grade of evidence for mutagenicity
 Employment, the Health Council of the                electricity generation, and as intermediate in    in germ cells (a measure for genotoxicity), and
 Netherlands assessed whether the emission,           manufacturing chemicals, such as chemical         for carcinogenicity. The categories are based on
 which is formed during coal gasification may         fertilizers. Workers who are involved in coal     the hazard categories set by the European
 induce genotoxic effects and may cause cancer,       gasification, can be exposed to the emission,     Commission (EU-guideline (EG) 1272/2008).
 and on this basis, submitted a proposal for a        which is formed during coal gasification. The
 classification. The advice is made by the            emission exists of a mixture of substances, for   The Committee is of the opinion that there is
 Subcommittee on Classifying carcinogenic             instance as a result of incomplete combustion     sufficient evidence of an association between
 substances of the Dutch Expert Committee on          (e.g., coal tar). In the present advisory report, occupational exposure to the emission, which is
 Occupational Safety. On www.healthcouncil.nl,        the evaluation accounts for the emission as a     formed during coal gasification and increased
 information can be found on the tasks of the         whole. Individual substances that can be found    cancer mortality, in particular lung cancer
 Subcommittee. The membership of the                  in the emission of coal gasification are not      mortality. In addition, support for the
 Subcommittee is given on the last page of this       considered.                                       carcinogenic properties comes from animal
 advisory report.                                                                                       experiments in which animals were chronically
                                                      Assessment of the genotoxicity and                exposed to coal gasification samples.
 Coal gasification                                    carcinogenicity
 Coal gasification is a process in which lignite      Based on the available scientific literature, the Recommendation
 and black coal is turned into combustible gas        Committee assesses the potential genotoxic and    Based on limited evidence, the Committee
 under high temperatures and pressure. The            carcinogenic properties of the substance or       recommends classifying the emission, which is
5        Health Council of the Netherlands | No. 2019/07                                                               2                                 7
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<pre> Executive summary                                       Emission during coal gasification | page 7 of 57
 formed during gasification, as a germ cell
 mutagen in category 2 (“concern for humans
 owing to the possibility that it may induce herit-
 able mutations in the germ cells of humans”).
 Furthermore, the Committee recommends
 classifying the emission, which is formed during
 coal gasification, in category 1A (“known to be
 carcinogenic to humans”). The carcinogenicity is
 caused by a stochastic genotoxic mechanism.
6        Health Council of the Netherlands | No. 2019/07            2                                   8
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<pre> chapter 01 | Scope                                    Emission during coal gasification | page 8 of 57
 01
 scope
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<pre> chapter 01 | Scope                                                                                        Emission during coal gasification | page 9 of 57
 1.1 Background                                                               replies by the committee, can be found on the website of the Health
 In the Netherlands a special policy is in force with respect to occupational Council.
 use and exposure to carcinogenic substances and processes. Regarding
 this policy, the Minister of Social Affairs and Employment has asked the     1.3 Data
 Health Council of the Netherlands to assess the genotoxic and carcino-       The committee’s recommendation is based on scientific data, which are
 genic properties of substances and processes, and to propose a classifi-     publicly available. The starting points of the committees’ reports are, if
 cation.                                                                      possible, the monographs of the International Agency for Research on
                                                                              Cancer (IARC). This means that the original sources of the studies, which
 This report contains the assessment of the genotoxic and carcinogenic        are mentioned in the IARC-monograph, are reviewed only by the
 properties of the emission, which is formed during (industrial) coal         committee when these are considered most relevant in assessing the
 gasification processes. The evaluation accounts for the exposure to the      carcinogenicity and genotoxicity of the substance in question. In the case
 emission as a whole; evaluation of individual substances, which can be       of coal gasification, such an IARC-monograph is available, of which the
 present in the emission, and to which workers can be exposed during coal     summary and conclusion is inserted in Annex A.
 gasification, is not considered.
                                                                              Relevant data, which are published after the (latest) publication of the
 1.2 Committee and procedure                                                  IARC Monograph, were retrieved from the online databases Medline,
 The evaluation is performed by the Subcommittee on Classifying Carcino-      Toxline, Chemical Abstracts, and RTECS. The last updated online search
 genic Substances of the Dutch Expert Committee on Occupational Safety        was in March 2019. The literature search was based on the following key
 of the Health Council, hereafter called the committee. The membership of     words: “coal gasification”, “manufactured gas plant residue” and “coal tar
 the Committee is listed on the last page of this advisory report.            from gas works”.
 In 2018, the President of the Health Council released a draft of the report
 for public review. The committee has taken these comments into account       1.4 Criteria for classification
 in deciding on the final version of the report. The comments, and the        For the classification on mutagenicity in germ cells the Committee uses
                                                                              standardly the criteria set by the European Parliament and Council on
8        Health Council of the Netherlands | No. 2019/07                                                                2                                 10
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<pre> chapter 01 | Scope                                                                                     Emission during coal gasification | page 10 of 57
 classification, labelling and packaging (CLP) of substances (Regulation    1.5 Quality assessment
 EC No. 1272/2008). Section 3.5 in Annex I of the regulation describes the  The Committee evaluates the available data on relevance and quality by
 classification and labelling requirements for  individual mutagenic        using criteria set by others to assess reliability, and by expert judgment. For
 substances and defined mixtures (see Annex D). In exceptional cases,       animal experiments and in vitro assays, the reliability criteria set by Klimisch
 such as in assessing the mutagenic potential of emissions, which are       et al. (1997) are used.27 For epidemiological studies, the reliability criteria
 unintentionally produced during work processes, the Committee bases its    set by Money et al. (2013) are used.28 A summary of the reliability criteria is
 recommendation on the criteria of the regulation, in combination with      given in Annex F and G, respectively. In addition, for the assessment of the
 expert judgement.                                                          carcinogenicity, the Committee used four categories of evidence. These
                                                                            categories are described in the Guideline to the classification of carcino-
 In 2010, the Health Council published a Guideline to the classification of genic compounds (Health Council, 2010, Chapter 6).26
 carcinogenic compounds, for classifying substances in terms of their
 carcinogenic properties, and for assessing the genotoxic mode of action.26
 The classification on carcinogenic properties is based on the Globally
 Harmonized System, which is also used by the European Union for the
 classification, labelling and packaging of substances and mixtures
 (Regulation EC 1272/2008, Section 3.6 Carcinogenicity).25 Annex E shows
 the classification system for carcinogenic substances, as used by the
 Committee.
 The proposal for a classification is expressed in standard sentences,
 combined with a category number.
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<pre> chapter 02 | Identity of the substance                Emission during coal gasification | page 11 of 57
 02
 identity of the
 substance
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<pre> chapter 02 | Identity of the substance                                                                       Emission during coal gasification | page 12 of 57
 2.1 Name and other identifications                                              Coal tar is a waste product that is produced in large quantities during coal
 Coal gasification is part of a process to produce combustible gas (mixture      gasification. In coal tar, a number of polynuclear aromatic compounds has
 of mainly hydrogen and carbon monoxide), also mentioned syngas or               been identified, some of which are known for its carcinogenic properties
 synthesis gas. See Section 5.1 for further explanation.                         (e.g., benzo(a)pyrene).1-3 In the scientific literature coal tar from coal
                                                                                 gasification is denoted as manufactured gas plant residue (MGP), coal tar
 2.2 Composition of the emission of coal gasification                            pitch volatiles, or coal gasification tar residue (CGTR).1-3
 During coal gasification, workers may be exposed to hydrogen and carbon
 monoxide, and to waste or by-products, as a result of incomplete combus-        2.3 Physicochemical properties
 tion of the coal. The emitted waste or by-products include: gases (e.g.,        Since the emission of coal gasification is a complex mixture of
 hydrogen sulphide, ammonia, hydrogen cyanide); hydrocarbon containing           substances, no physicochemical properties are specified.
 gases, aerosols and residues (e.g., polynuclear aromatic compounds, coal
 tar), and: mineral particulate residues (ash) and wastes. The type and
 amount of these waste and by-products emitted in the workplace air
 during coal gasification vary, due to variations in feed stocks (type of coal),
 operating temperatures, pressures and residence times.
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<pre> chapter 03 | International classification             Emission during coal gasification | page 13 of 57
 03
 international
 classification
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<pre> chapter 03 | International classification                                       Emission during coal gasification | page 14 of 57
 3.1 European Commission
 Not evaluated.
 3.2 IARC
 IARC evaluated the genotoxicity and carcinogenicity of exposure during
 coal gasification several times, the latest in 2012.1-3 It concluded that occu-
 pational exposure during coal gasification is carcinogenic to humans. Also
 there is sufficient evidence in experimental animals for the carcinogenicity
 of coal-tars from gas-works and manufactured gas plant residues. Further-
 more, IARC stated that there is strong evidence of a genotoxic mecha-
 nism for coal gasification samples based on experiments. IARC considers
 it highly likely that genotoxicity is the mechanism for the carcinogenic
 effects of coal gasification emissions, predominantly due to the presence
 of mutagenic polycyclic aromatic hydrocarbons. Therefore, IARC classi-
 fied coal gasification in Group 1 (“sufficient evidence in humans for the
 carcinogenicity of occupational exposure during coal gasification”). A
 summary of the latest evaluation and conclusion by IARC is given in
 Annex A.
 3.3 The Health Council of the Netherlands
 Not evaluated.
13       Health Council of the Netherlands | No. 2019/07                                      2                                  15
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<pre> chapter 04 | Monitoring                               Emission during coal gasification | page 15 of 57
 04
 monitoring
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<pre> chapter 04 | Monitoring                                                      Emission during coal gasification | page 16 of 57
 4.1 Environmental exposure monitoring
 Since exposure to the emission of coal gasification implies exposure to a
 complex mixture, a variety of markers may be applied for the measure-
 ment of exposure in workplaces. Overall, in the literature no preference for
 a certain exposure marker is identified. However, in human studies on the
 carcinogenic potential of occupational exposure during coal gasification,
 concentrations of single components (benzo(a)pyrene or other polycyclic
 aromatic hydrocarbons), total hydrocarbons, coal tar pitch volatiles, and
 total amount or mass of particles, have been used to estimate exposure.
 These exposure markers are chosen because of their association with
 cancer development.
 4.2 Biological exposure monitoring
 Not specified.
15      Health Council of the Netherlands | No. 2019/07                                    2                                  17
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<pre> chapter 05 | Manufacture and uses                     Emission during coal gasification | page 17 of 57
 05
 manufacture and
 uses
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<pre> chapter 05 | Manufacture and uses                                                                          Emission during coal gasification | page 18 of 57
 5.1 Manufacture                                                                turbine process, fluidised bed and entrained flow processes are particularly
 The information given below is abstracted from the IARC monographs.1,3         suitable, in which gasification occurs at high pressure (at least 25 - 30 bar).
                                                                                Entrained flow gasification takes place at considerably higher temperatures
 Several coal gasification systems have been developed, which can be            above the ash fusion point.
 classified by the heating value of the gas produced, and by the type of
 gasification reactor. The majority of the gasification systems consists of     5.2 Identified uses
 four operations: coal pretreatment, coal gasification, raw gas cleaning,       Syngas or synthesis gas is mainly used as fuel for electricity generation.
 and gas beneficiation. In this report, only the genotoxic and carcinogenic     In addition, the gas is used as intermediate resource in manufacturing of
 properties of the emission during coal gasification (step two) is evaluated.   chemicals, such as chemical fertilizers.
 Generally, any coal can be gasified if properly pretreated. Pretreatment
 operations include drying, partial oxidation, crushing, sizing, and
 briquetting of fines for feed to fixed bed gasifiers. The coal feed is
 pulverized for fluid or entrained bed gasifiers. After pretreatment, the coal
 enters the gasification reactor where it reacts with oxygen and steam to
 produce a combustible gas. Air is used as the oxygen source for making
 gas with a lower caloric value (so-called low-Btu gas, where Btu stands for
 British thermal units; one Btu is the heat required to raise the temperature
 of one pound of water by one degree Fahrenheit). Pure oxygen is used in
 making gas with higher value (medium- and high-Btu gas), as inert
 nitrogen in the air dilutes the heating value of the product. For gasification
 of coals, fixed bed, fluidised bed, and entrained flow reactors are used.3
 The choice of the appropriate process depends mainly on the fuel used
 and on the desired gas utilization. If the gas is utilised in a gas and steam
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<pre> chapter 06 | Summary of toxicokinetics                Emission during coal gasification | page 19 of 57
 06
 summary of
 toxicokinetics
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<pre> chapter 06 | Summary of toxicokinetics                                    Emission during coal gasification | page 20 of 57
 6.1 Absorption, distribution and elimination
 Data are available on certain individual substances that can be found in
 the emission of coal gasification, but no such data are available for the
 emission as a whole. Since in the present report only the emission as a
 whole is evaluated, this topic is not further discussed.
 6.2 Toxicokinetics
 The same applies for toxicokinetics.
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<pre> chapter 07 | Germ cell mutagenicity                   Emission during coal gasification | page 21 of 57
 07
 germ cell
 mutagenicity
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<pre> chapter 07 | Germ cell mutagenicity                                                                           Emission during coal gasification | page 22 of 57
 7.1 Summary and relevance of the provided information on                      Conclusion on genotoxicity
       (germ cell) mutagenicity                                                The number of studies on mutagenic and genotoxic activities of coal gasi-
                                                                               fication samples (e.g., MGP) is limited. The results of an in vitro reverse
 7.1.1 Summary of genotoxicity tests in vitro                                  mutation study indicate that MGP has mutagenic properties. No data are
 No studies are available on germ cell genotoxicity.                           available that address in vitro clastogenic or aneugenic activities of whole
                                                                               coal gasification samples.
 Mutagenicity
                                                                               Table 1. Mutations
 Cizmas et al. (2004) determined mutagenic activity of seven fractions of a     Reference     Method   Cell type    Concentration range      Results           Remarks and
 MGP residue in Salmonella typhimurium strain TA98.4 MGP residue was                                                                                           reliability
                                                                                Cizmas et al. Reverse  Salmonella   MGP fractions:           Positive (more    Only one
 provided by a single site of the Electric Power Research Institute (Palo       20044         mutation typhimurium  Total PAH (µg/mg         than doubling of  strain tested;
                                                                                              (Ames    strain TA98  fraction):               number of         no data on
 Alto, USA). The fractions were obtained by chromatographic fractionation                     test)                 F1 (197), F2 (295), F3   revertants/plate  cytotoxicity; no
 of the MGP residue. The residue and its fractions differed in the presence                                         (185), F4 (72), F5 (20), compared to       positive
                                                                                                                    F6 (12), and F7 (31)     solvent control): controls used
 and the composition of polycyclic aromatic hydrocarbons (PAH). Without                                             Carcinogenic PAH (µg/    • without
                                                                                                                    mg fraction; sum of        metabolic       Reliability 2
 metabolic activation, 4 of the 6 fractions tested showed mutagenic activity                                        benz[a]anthracene,         activation      (see Annex F)
                                                                                                                    benzo[b]fluoranthene,      (S9): F2, F3,
 (see Table 1; fraction F6 not tested). In the presence of metabolic activa-
                                                                                                                    benzo[k]fluoranthene,      F4, F5 (F6 not
 tion, mutagenic activity was observed in 6 of 7 fractions.                                                         benzo(a)pyrene,            tested)
                                                                                                                    chrysene, dibenzo[a,h]   • with metabolic
                                                                                                                    anthracene,and             activation
                                                                                                                    indeno[1,2,3-c,d]          (S9): in 6 of
 Clastogenic and aneugenic effects                                                                                  pyrene): F1 (0.18), F2     the 7 fractions
 Currently, no publications are available that address in vitro clastogenic or                                      (40.16), F3 (89,77), F4    (dose-related)
                                                                                                                    (39.48), F5 (11.03), F6
 aneugenic effects (chromosomal aberrations, formation micronuclei, sister                                          (2.18) and F7 (0.56)
 chromatid exchanges) of coal gasification samples.                                                                 Amount of fraction
                                                                                                                    applied per plate: 0.05,
                                                                                                                    0.5 and 1.0 mg
                                                                                                                    (solvent dimethyl
                                                                                                                    sulphoxide served as
                                                                                                                    negative control)
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<pre> chapter 07 | Germ cell mutagenicity                                                                                                       Emission during coal gasification | page 23 of 57
 7.1.2 Summary of human data relevant for germ cell mutagenicity                                       increase in DNA-adducts in the lung, the liver, and the forestomach in
 No data available.                                                                                    mice, which were given MGP in various concentrations in the diet.
                                                                                                       Analyses of the MGP showed the presence of several types of PAH,
 7.1.3 Summary of genotoxicity tests in mammalian somatic or germ                                      among which PAHs with well-known genotoxic and carcinogenic potential.
          cells in vivo                                                                                Animal experiments indicate that not only the well-known carcinogenic
 No in vivo studies are available, in which the mutagenic, clastogenic or                              PAH, but also other constituents in MGP may have induced part of the
 aneugenic effects of coal gasification samples were tested.                                           DNA-adducts. Since it is unknown to which extent the detected DNA
                                                                                                       adducts interfere with DNA replication or are subject to DNA repair
 DNA-adducts                                                                                           activities, the mere presence of DNA adducts cannot be taken as
 In Table 2 results on DNA-adduct formation are summarized. These                                      evidence for mutagenicity.
 studies show that crude MGP or fractions of MGP cause a dose-related
 Table 2. Formation of DNA-adducts in animals exposed to MGP
  Reference              Study design                                  Data on exposure                   Results                                              Remarks and reliability (Annex F)
  Culp and Beland 1994 5
                         Oral administration in diet for 28 days; male 0, 0.1, 0.25, 0.5, 1 or 2% MGP     DNA-adduct formation increased with increasing       Well-documented experimental set-up;
                         B6C3F1 mice; N = 8/group                      in diet (corresponds with 0 to     dose, adducts/mg DNA):                               proper use of controls; relevance for mode-
                                                                       52.5 mg MGP/day);                  Lung: 22 up to > 6,776                               of-action; well-performed study
                                                                       B[a]P) served as positive          Liver: 65 up to 3,121
                                                                       control (applied in diet at doses  Forestomach: 112 up to ± 1,792                       No statistical analyses
                                                                       of 2.5 - 50 mg/kg diet)
                                                                                                          Lower intake of diet found in animals given higher   Reliability 2
                                                                       DNA-adducts: 32P-postlabeling      doses of MGP; body weights in higher dose groups
                                                                       assay                              were lower compared to no and low-dosed animals.
                                                                                                          Data are corrected for food consumption
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<pre> chapter 07 | Germ cell mutagenicity                                                                                                      Emission during coal gasification | page 24 of 57
  Reference             Study design                                    Data on exposure                Results                                                 Remarks and reliability (Annex F)
  Weyand et al. 1994  6
                        Oral administration using a gel diet system for 0, 0.05, 0.25 or 0.5% MGP in    Dose-related increase in DNA-adduct formation in        Well-documented experimental set-up;
                        91 or 185 days; male and female B6C3F1          diet (corresponding with 0.5 g, the lung and forestomach cells; adduct levels lung      proper use of controls; relevance for mode-
                        mice; N = 2 male and 2 females/group            2,5 or 5 g MGP per kg diet);    higher than in the forestomach.                         of-action; well-performed study
                                                                        B[a]P) served as positive
                                                                        control                                                                                 No statistical analyses
                                                                        DNA-adducts: 32P-postlabeling                                                           Reliability 2
                                                                        technique
  Weyand et al. 19957   Oral administration using a gel diet system for Diets contained 0.25% MGP       MGP induced DNA adducts in isolated lung (± 1.8         Well-documented experimental set-up study
                        14 days; female A/J mice; N = 10/group          (corresponds to 5.9 mg MGP/     pmol adducts/mg DNA) and to a lesser extent in          (none-guideline study, not GLP); relevance
                                                                        day/ mouse);                    forestomach cells (±0.15 pmol adducts/mg DNA)           for mode-of-action
                                                                        B[a]P as positive control
                                                                                                                                                                No statistical analyses; no negative controls
                                                                        DNA-adducts: 32P-postlabeling
                                                                        assay combined with TLC and                                                             Reliability 2
                                                                        HPLC
  Koganti et al. 20018  Oral administration in basal gel diet for 14    0.25% MGP in diet               DNA adduct formation found in lung cells                Well-documented experimental set-up study
                        days; female A/J mice; no data on group size    (corresponds with 2.5 g MGP                                                             (none-guideline study, not GLP); proper use
                                                                        per kg diet);                   In MGP samples various PAH were found.                  of controls;
                                                                        ethylene chloride soil extracts                                                         relevance for mode-of-action; well-
                                                                        served as positive control      No statistical analyses                                 performed study
                                                                                                        performed
                                                                        DNA-adducts: 32P-postlabeling                                                           Reliability 2
                                                                        assay
  Cizmas et al. 20044   Single dermal application (topical; skin area 4 Crude MGP residue and seven     A dose-related increase in amount of DNA adducts        Well-documented experimental set-up
                        cm2; at back of mouse); female ICR mice; N =    MGP fractions, doses applied    found in isolated lung and skin (application site)      (none-guideline study, not GLP); proper use
                        3/group                                         0.48, 1.2, or 3.0 mg/mouse      cells                                                   of controls;
                                                                                                                                                                relevance for mode-of-action; well-
                                                                        7H-benzo[c]fluorene (PAH        Larger effects found in skin cells than in lung cells   performed study
                                                                        component) served as positive
                                                                        control                                                                                 Reliability 2
                                                                        DNA-adducts: 32P-postlabeling
                                                                        assay (cells were harvested 24
                                                                        hours after dermal application)
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<pre> chapter 07 | Germ cell mutagenicity                                                                       Emission during coal gasification | page 25 of 57
 7.2 Comparison with the CLP-criteria                                         mutagenicity or other genotoxicity tests have been performed on coal
 The CLP-criteria (Regulation (EC) 1272/2008, Section 3.5, see Annex D)       gasification samples.
 applies only for individual substances and defined mixtures, and not for
 emissions, which can be formed during work processes. However, to keep       If substances do not meet the criteria for classification in category 1, they
 close to the method of CLP in assessing genotoxic properties, the            may be classified in category 2 if there is “positive evidence from
 Committee based its present recommendation on these criteria, in combi-      experiments in mammals and/or in some cases from in vitro experiments
 nation with expert judgement.                                                obtained from a) somatic cell mutagenicity tests in vivo, in mammals”, or
                                                                              b) “other in vivo somatic cell genotoxicity tests, which are supported by
 According to the criteria in Annex I of the European regulation No.          positive results from in vitro mutagenicity assays”. Moreover, “substances
 1272/2008, classification as a mutagen in category 1 is warranted when       which are positive in in vitro mammalian mutagenicity tests, and which
 positive evidence of in vivo heritable germ cell mutagenicity in humans      also show chemical structure activity relationship to known germ cell
 (1A) or mammals (1B) has been reported. For exposure during coal             mutagens, shall be considered for classification as category 2 mutagens”.
 gasification, no data have been found on in vivo mutagenicity in human or    There is limited evidence that coal gasification emission samples are
 animal germ cells. Therefore, the committee concludes that there is a lack   mutagenic in vitro. However, in the emission of coal gasification,
 of evidence to classify the emission during coal gasification in category 1. substances may be found with known mutagenic properties (e.g., coal tar
                                                                              and benzo(a)pyrene). Taking into account these findings, the committee is
 In addition, substances may be categorized in 1B if there are “positive      of the opinion that the emission during coal gasification should be
 results from in vivo somatic cell mutagenicity tests in mammals, in          classified in category 2. Most likely the mutagenic activity is caused by a
 combination with some evidence that the substance has potential to cause     stochastic genotoxic mechanism of action, since coal gas emission
 mutations to germ cells”. The latter may be based on a) “supporting          samples showed mutagenic activity.
 evidence from mutagenicity or genotoxicity tests in germ cells in vivo”, or
 b) “by demonstrating the ability of the substance or its metabolites to
 interact with the genetic material of germ cells”. Currently, no in vivo
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<pre> chapter 07 | Germ cell mutagenicity                                      Emission during coal gasification | page 26 of 57
 7.3 Conclusion on classification and labelling for germ cell
       mutagenicity
 Based on limited evidence, the Committee recommends classifying the
 emission, which can be formed during coal gasification, as a germ cell
 mutagen in category 2 (“concern for humans owing to the possibility that
 they may induce heritable mutations in the germ cells of humans”).
 In addition, the committee concludes that the genotoxic components
 which can be found in the emission, which can be formed during coal
 gasification, may cause cancer by a stochastic genotoxic mechanism.
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<pre> chapter 08 | Carcinogenicity                          Emission during coal gasification | page 27 of 57
 08
 carcinogenicity
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<pre> chapter 08 | Carcinogenicity                                                                             Emission during coal gasification | page 28 of 57
 8.1 Summary and relevance of the provided information on                    hydrocarbon exposure was mainly based on job title; only in the study by
       carcinogenicity                                                       Gustavsson and Reuterwall, some polycyclic aromatic hydrocarbon expo-
                                                                             sure measurements were made.12 Furthermore, no sensitivity analyses
 8.1.1 Observations in humans                                                were performed to account for type of study design, and for smoking
                                                                             habits. In most cohort studies data on smoking habits were not collected
 Meta-analysis                                                               or reported. Overall, these uncertainties and limitations weaken the
 Bosetti et al. (2006) performed a meta-analysis to investigate the possible conclusion made in the meta-analysis.
 association between jobs with expected high polycyclic aromatic hydro-
 carbon exposure, including coal gasification workers, and the risk for      Prospective cohort studies
 certain cancer types.9 The analysis included data from 5 cohort studies in  Annex B describes three cohort studies with a prospective design. One is
 the coal gasification industry (Doll et al. 1972, Manz 1980, Hansen et al.  not considered by the committee due to limited reporting. Kawai et al.
 1986, Gustavsson and Reuterwall 1990, Berger and Manz 1992).10-14           (1967) and Doll et al. (1972) found a statistically significant positive asso-
 Details of the meta-analysis and the five cohort studies are given in       ciation between coal gasification work and lung cancer mortality.11,15 The
 Annex B. The meta-analysis revealed a statistically significant increase in small study by Kawai et al. (1967) showed also that in the age group of 45
 cancer mortality risk estimates for lung, respiratory tract, bladder and    to 56 years, workers with more than 20 years of employment had a statis-
 urinary tract cancer, in those working in coal gasification.                tically significant higher lung cancer death rate than workers from the
 Uncertainties and limitations. In the meta-analyses, a certain degree of    same age group with 10 to 19 years of employment.
 heterogeneity between studies was found. This is not surprising to the      Uncertainties and limitations. In none of the studies adjustments were
 committee, because the exposure circumstances in different coal gasifica-   made for smoking habits.
 tion facilities may vary. In addition, the committee noted that no descrip-
 tion was given on how the authors assessed the quality of the studies, and  Retrospective cohort studies
 to what degree each study contributed to the pooled relative risk estimate. Part of the retrospective cohort studies were limited in design or reporting
 The committee considers the study by Manz (1980) of low quality due to      (Annex B), including the study by Manz (1980), which was included in the
 limited reporting.14 Moreover, the committee noted that polycyclic aromatic
27       Health Council of the Netherlands | No. 2019/07                                                               2                                   29
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<pre> chapter 08 | Carcinogenicity                                                                                Emission during coal gasification | page 29 of 57
 meta-analysis by Bosetti et al. (2006).14 These low quality studies were       Uncertainties and limitations. Most studies did not account for tobacco
 not considered by the committee.                                               smoking, whereas this may seriously influence the outcome of lung cancer
 In three studies a statistically significant positive association was found    and bladder cancer risk estimates. However, Gustavsson and Reuterwall
 between exposure during coal gasification and, in particular, lung cancer      (1990) reported that the percentage of smokers among coal gasification
 mortality. Martin et al. (2000) reported a positive association only in the    workers and people living in large cities did not differ, and, therefore,
 group of workers with the highest exposure levels.16 Hansen et al. (1986)      suggested that smoking habits did not influence the outcomes for total
 found positive associations for lung cancer and general cancer mortality,      mortality.12 Martin et al. (2000) suggested that tobacco smoking had no or
 but did not find an association when years of employment or latency were       only a weak effect on cancer risk estimates, because smoking status is
 taken into account.13 Among German gas furnace workers, Berger and             often related to socio-economic status, and the reference group was a
 Manz (1992) found positive associations for all cancer mortality, including    reflection of the workers group.16 Berger and Manz (1992) performed a
 lung cancer mortality, stomach cancer mortality, and colon and rectum          subanalysis for stomach, colon and rectum cancer, comparing data from
 cancer mortality.10                                                            smokers with non-smokers (gas furnace workers).10 For stomach cancer,
 To the contrary, Gustavsson and Reuterwall (1990) did not find any asso-       a positive association was found for smokers, but not for non-smokers,
 ciation between exposure during coal gasification and cancer mortality.12      whereas for colon and rectum cancer this was the other way around. The
 In this study, exposure levels to benzo(a)pyrene in the Swedish gas            authors noted the imprecision of the risk estimates for colon and rectum
 production company at the top oven were reported to range between              cancer, because of the low frequencies of the observed and expected
 0.007 and 33 µg/m3 (1964), and between 0.021 and 1.29 µg/m3 (1965).12          cases. Overall, the committee concludes that smoking status may have
 The authors remark that these exposure levels are of the same magnitude        influenced the outcomes to a minor degree.
 as in American plants. Begraca et al. (1991) reported also on exposure
 levels.17 Coal tar pitch volatiles during coal gasification ranged from 1.2 to Conclusion observations in humans
 22,480 mg/m3; mean average personal exposure to polycyclic aromatic            Several cohort studies showed some evidence of a positive association
 hydrocarbon was 0.03 mg/m3.17 However, the documentation is too limited        between occupational exposure during coal gasification and lung cancer
 to conclude whether these exposure levels could have induced an excess         mortality, despite the variation in working and exposure conditions among
 of lung cancer in gas workers.                                                 the various coal gasification facilities. Also cancer at other sites of the
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<pre> chapter 08 | Carcinogenicity                                                                                 Emission during coal gasification | page 30 of 57
 body, such as in the bladder and stomach, have been reported. These              In the second study, Culp et al. (1998) fed female mice diets containing
 data indicate that exposure to emissions of coal gasification is likely to       coal tar, which was obtained from coal gasification plant sites.19 In the
 result in cancer at first site of contact (the lungs), and that it may result in highest exposure groups, histopathologic analyses revealed that these
 development of cancer at distant sites. The observed associations are            mice developed tumours in the lungs (adenomas and/or carcinomas), the
 most likely influenced to a minor degree by confounding factors, such as         liver (adenomas and/or carcinomas), the forestomach (papillomas and/or
 smoking. In conclusion, the committee is of the opinion that there is suffi-     carcinomas), and in the small intestines (adenocarcinomas). The authors
 cient evidence of an association between occupational exposure during            also noted that in these groups the survival rate was very low and that the
 coal gasification and increased cancer mortality, in particular lung cancer      animals had on average lower body weights and food intake compared to
 mortality.                                                                       the control group. Mice, which were given coal tar mixed from seven plant
                                                                                  sites showed statistically significant dose-related increase in number of
 8.1.2 Animal carcinogenicity studies                                             tumour bearing animals.
 In animal experiments various routes of exposure were used (see Annex C).        Although other animal studies are of low quality, they give some support
 None of these studies met the current OECD guidelines for assessing carci-       that coal tar or MGP, obtained from coal gasification sites, may induce
 nogenicity. At least two animal studies are of sufficient quality to be evalu-   tumours in the lungs, forestomach, and in the liver of mice (Weynand et al.
 ated, of which a description is given below.                                     1995, Rodriguez et al. 1997).7,20
                                                                                  Based on the inhalation study by Rittinghaussen et al. (1997) and the oral
 The first is the German inhalation study by Rittinghausen et al. (1997).18       study by Culp et al. (1998), the committee concludes that there is suffi-
 As shown in Annex C, female mice developed lung tumours (squamous                cient evidence that exposure to coal gasification samples causes cancer
 cell carcinomas) due to inhalation of coal gasification aerosol samples, or      in mice.
 after consuming diets to which tar/pitch condensation products (from coal
 gasification sites) were included. No description or analytical data on the      8.2 Classification for carcinogenicity
 aerosols were reported, but the aerosols are considered to be related to         Several cohort studies among workers in coal gasification processes show
 exposure during coal gasification. No data were presented on general             a positive association between exposure to the emission, which is formed
 toxicity, and on the development of tumours at other sites in the body.          during coal gasification, and cancer-related mortality, in particular lung
29       Health Council of the Netherlands | No. 2019/07                                                                    2                                 31
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<pre> chapter 08 | Carcinogenicity                                                 Emission during coal gasification | page 31 of 57
 cancer mortality. Other types of cancer observed include liver, stomach
 and skin cancer. Support for the carcinogenic properties of the emission of
 coal gasification samples comes from animal studies. Mice, which were
 chronically exposed to coal tar products of coal gasification by the diet or
 by inhalation, developed cancer at several sites of the body, such as in the
 lungs, the liver and the forestomach. Based on these findings, and
 according to the criteria set by the Health Council (see Annex E), the
 emission, which is formed during coal gasification, should be classified as
 “known to be carcinogenic to humans”, which corresponds to classification
 in category 1A.
 8.3 Conclusion on classification and labelling for
       carcinogenicity
 The committee recommends classifying the emission, which is formed
 during coal gasification, in category 1A (“known to be carcinogenic to
 humans”).
30      Health Council of the Netherlands | No. 2019/07                                    2                                  32
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<pre> Literature                                             Emission during coal gasification | page 32 of 57
 literature
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<pre> Literature                                                                                             Emission during coal gasification | page 33 of 57
 1
    International Agency for Research on Cancer. Polynuclear aromatic          soils contaminated with coal tar. Environ Sci Technol 2001; 35(13):
    compounds, Part 3, industrial exposures in aluminium production, coal      2704-9.
    gasification, coke production, and iron and steel founding. IARC        9
                                                                               Bosetti C, Boffetta PF and La VC. Occupational exposures to polycyclic
    (WHO), Lyon, France, 1984; Monograph 34, pages 65-100.                     aromatic hydrocarbons, and respiratory and urinary tract cancers: a
 2
    International Agency for Research on Cancer. Overall evaluations of        quantitative review to 2005. Annals on Oncology 2005; 18(3): 431-46.
    carcinogenicity: an updating of IARC Monographs volumes 1 to 42.        10
                                                                               Berger J and Manz A. Cancer of the stomach and the colon-rectum
    IARC (WHO), Lyon, France, 1987; Supplement 7, pages 173-174.               among workers in a coke gas plant. Am J Ind Med 1992; 22(6): 825-34.
 3
    International Agency for Research on Cancer. Coal Gasification. IARC    11
                                                                               Doll R, Vessey MP, Beasley RW, Buckley AR, Fear EC, Fisher RE,
    (WHO), Lyon, France, 2012; Monograph 100F, pages 145-152.                  et al. Mortality of gasworkers - final report of a prospective study. Br J
 4
    Cizmas L, Zhou GD, Safe SH, McDonald TJ, Zhu L and Donnelly KC.            Ind Med 1972; 29(4): 394-406.
    Comparative in vitro and in vivo genotoxicities of 7H-benzo[c]fluorene, 12
                                                                               Gustavsson P and Reuterwall C. Mortality and incidence of cancer
    manufactured gas plant residue (MGP), and MGP fractions. Environ           among Swedish gas workers. British Journal of Industrial Medicine
    Mol Mutagen 2004; 43(3): 159-68.                                           1990; 47: 169-74.
 5
    Culp SJ and Beland FA. Comparison of DNA adduct formation in mice       13
                                                                               Hansen KS, Viskum S and Pedersen MS. [Mortality among gas
    fed coal tar or benzo[a]pyrene. Carcinogenesis 1994; 15(2): 247-52.        workers]. Ugeskr Laeger 1986; 148(10): 610-2.
 6
    Weyand EH, Wu Y, Patel S and Goldstein L. Biochemical effects of        14
                                                                               Manz A. Atem- und Harnwege als Lokalisationstellen berifsbedingter
    manufactured gas plant residue following ingestion by B6C3F1 mice. J       (Teer-)Karzinome bei Kokerei- und Rohmetzarbeitern. VDI-Berichte
    Toxicol Environ Health 1994; 42(1): 89-107.                                1980; 358: 227-35.
 7
    Weyand EH, Chen YC, Wu Y, Koganti A, Dunsford HA and Rodriguez          15
                                                                               Kawai M, Amamoto H and Harada K. Epidemiologic study of
    LV. Differences in the tumorigenic activity of a pure hydrocarbon and a    occupational lung cancer. Arch Environ Health 1967; 14(6): 859-64.
    complex mixture following ingestion: benzo[a]pyrene vs manufactured     16
                                                                               Martin JC, Imbernon E, Goldberg M, Chevalier A and Bonenfant S.
    gas plant residue. Chem Res Toxicol 1995; 8(7): 949-54.                    Occupational risk factors for lung cancer in the French electricity and
 8
    Koganti A, Singh R, Ma BL and Weyand EH. Comparative analysis of           gas industry: a case-control survey nested in a cohort of active
    PAH:DNA adducts formed in lung of mice exposed to neat coal tar and        employees. Am J Epidemiol 2000; 151(9): 902-12.
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<pre> Literature                                                                                                   Emission during coal gasification | page 34 of 57
 17
    Begraca M, Ukmata H, Morris SC, Canhasi B and Haxhiu MA. Study of              of substances and mixtures, amending and repealing Directives
    early appearance of skin lesions in coal gasification workers. Arh Hig         67/548/EEC and 1999/45/EC, and amending Regulation (EC) No
    Rada Toksikol 1991; 42(3): 287-94.                                             1907/2006, Annex I (Classification and labelling requirements for
 18
    Rittinghausen S, Mohr U and Dungworth DL. Pulmonary cystic                     hazardous substances and mixtures), Section 3.5 (Germ cell
    keratinizing squamous cell lesions of rats after inhalation/instillation of    mutagenicity). European Union, https://echa.europa.eu/regulations/clp/
    different particles. Exp Toxicol Pathol 1997; 49(6): 433-46.                   legislation, last visited: April 23, 2019.
 19
    Culp SJ, Gaylor DW, Sheldon WG, Goldstein LS and Beland FA. A               26
                                                                                   The Health Council of the Netherlands. Guideline to the classification of
    comparison of the tumors induced by coal tar and benzo[a]pyrene in a           carcinogenic compounds. Guide for classifying compounds in terms of
    2-year bioassay. Carcinogenesis 1998; 19(1): 117-24.                           their carcinogenic properties and for assesing their genotoxicity. The
 20
    Rodriguez LV, Dunsford HA, Steinberg M, Chaloupka KK, Zhu L, Safe              Health Council of the Netherlands, The Hague, report no. A10/07E,
    S, et al. Carcinogenicity of benzo[a]pyrene and manufactured gas plant         2010.
    residues in infant mice. Carcinogenesis 1997; 18(1): 127-35.                27
                                                                                   Klimisch HJ, Andreae M and Tillmann U. A systematic approach for
 21
    Christian HA. Cancer of the lung in employees of a public utility_A            evaluating the quality of experimental toxicological and ecotoxicological
    fifteen-year study (1946-1960). Journal of Occupational Medicine 1962;         data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
    4(3): 133-9.                                                                28
                                                                                   Money CD, Tomenson JA, Penman MG, Boogaard PJ and Jeffrey
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    Kenneway NM and Kenneway EL. A study of the incidence of cancer of             Lewis R. A systematic approach for evaluating and scoring human
    the lung and larynx. J Hyg 1936; 36(2): 236-67.                                data. Regul Toxicol Pharmacol 2013; 66(2): 241-7.
 23
    Wu W. Occupational cancer epidemiology in the People’s Republic of          29
                                                                                   Elm E von, Altman DG, Egger M, Pocock SJ, Gotzsche PC,
    China. Journal of Occupational Medicine 1988; 30(12): 968-74.                  Vandenbroucke JP, et al. The Strengthening the Reporting of
 24
    Brandon JL, Conti CJ, Goldstein LS, DiGiovanni J and Gimenez-Conti             Observational Studies in Epidemiology (STROBE) statement:
    IB. Carcinogenic effects of MGP-7 and B[a]P on the hamster cheek               guidelines for reporting observational studies. J Clin Epidemiol 2008;
    pouch. Toxicol Pathol 2009; 37(6): 733-40.                                     61(4): 344-9.
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    European Union. Regulation (EC No 1272/2008) of the European
    Parliamant and of the Council on classification, labelling and packaging
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<pre> Annexes                                              Emission during coal gasification | page 35 of 57
 annexes
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<pre> annex A | IARC evaluation and conclusion                                                                Emission during coal gasification | page 36 of 57
 A        IARC evaluation and                                                tion workers (Martin et al., 2000). In all studies an excess of lung cancer in
          conclusion                                                         association with coal gasification was found, which was not likely to be
                                                                             explained by other factors. There was evidence supporting a lung-cancer
                                                                             excess in a historical record-linkage study from the United Kingdom
 Occupational exposures during coal gasification are carcinogenic to         (Kennaway & Kennaway, 1947), in two smaller cohorts (Kawai et al.,
 humans (Group 1).                                                           1967; Hansen et al., 1986), and a large but inadequately reported Chinese
                                                                             study (Wu, 1988). In addition to lung cancer, the study from the United
 VOL.: 100F (2012) (p. 145 - 152).3                                          Kingdom (Doll et al., 1972) showed an excess of bladder cancer, and the
                                                                             German study (Berger & Manz, 1992) showed an excess of cancers of the
 Summary of Data Reported and Evaluation.                                    stomach and colon-rectum.
 Exposure data                                                               Animal carcinogenicity data
 Coal gasification is a process by which coal is reacted with oxygen, steam  Crude coal-tars from gas works were shown to induce skin papillomas and
 and carbon dioxide by incomplete combustion to release fuel, tars, oils,    carcinomas in mice and rabbits after skin application. Manufactured gas
 phenols, heavy hydrocarbons and gas products. In addition to polycyclic     plant residues (MGP) were shown to be carcinogenic in mice after
 aromatic hydrocarbons, workers in coal gasification may be exposed to       exposure by the feed and after intraperitoneal injection. In these studies,
 many compounds, including asbestos, silica, amines, arsenic, cadmium,       several carcinomas were found, including hepatocellular adenomas,
 lead, nickel, vanadium, hydrocarbons, sulfur dioxide, sulfuric acid and     alveolar/bronchiolar adenomas, forestomach papillomas, small intestine
 aldehydes.                                                                  adenocarcinomas, as well as haemangiosarcomas and histiocytic
                                                                             sarcomas.
 Human carcinogenicity data
 Two cohort studies of coal-gasification workers in the United Kingdom       Other relevant data
 (Doll et al., 1972) and Germany (Berger & Manz, 1992), and a case–          There is strong evidence from experiments for a genotoxic mode of action
 control study nested within a cohort of French gas- and electricity-produc- for coal gasification samples. Although there are no human studies, it is
35       Health Council of the Netherlands | No. 2019/07                                                                 2                                37
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<pre> annex A | IARC evaluation and conclusion                                                                Emission during coal gasification | page 37 of 57
 highly likely that genotoxicity is the mechanism relevant to the               Overall evaluation
 carcinogenic hazards from exposures to emissions of coal gasification.         Occupational exposures during coal gasification are carcinogenic to
                                                                                humans (Group 1).
 Evaluation
 There is sufficient evidence in humans for the carcinogenicity of coal         Previous evaluations:
 gasification. Coal gasification causes cancer of the lung. There is sufficient Coal gasification was considered by previous IARC Working Groups in
 evidence in experimental animals for the carcinogenicity of coal-tars from     1983, 1987, and 2005 (IARC, 1984, 1987, 2010).
 gas-works and manufactured gas plant residues. There is strong evidence
 of a genotoxic mechanism for coal gasification samples based on
 experimental studies. Although there are no human studies, it is highly
 likely that genotoxicity is the mechanism for the carcinogenic effects of
 coal-gasification emissions, predominantly due to the presence of
 mutagenic polycyclic aromatic hydrocarbons.
36       Health Council of the Netherlands | No. 2019/07                                                               2                                 38
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<pre> annex B | Details epidemiological studies                                                                                                             Emission during coal gasification | page 38 of 57
 B              details epidemiological studies
 Association between occupational exposure to emissions of coal gasification and cancer development.
 Meta-analysis by Bosetti et al. 20069
   Study design and               Data on exposure and health assessment                                            Results                                                   Remarks and reliability (Annex G)
   population
   5 cohort studies of coal       Search period: Up to December 2005                                                Outcome: positive association between coal gasification   Appropriate design
   gasification workers (with                                                                                       work and cancer in the lungs, the respiratory tract, the
   potential PAH exposure)        Inclusion criteria: workers in industries with high PAH exposure; cohort design; bladder and the urinary tract                              No sensitivity analysis performed; data
                                  mortality or incidence data on cancer risk (the lungs, the respiratory tract, the                                                           on smoking habits missing; no quality
   Details of the individual      bladder, the urinary tract)                                                       Order: standardized mortality ratio (SMR), observed/      assessment performed on the
   cohort studies are shown                                                                                         expected no. of cases, pooled RR (95% confidence          individual studies
   in the list below (indicated   Quality assessment individual studies: not performed or reported                  intervals), p=value for heterogeneity
   as a)                                                                                                                                                                      Reliability 2
                                  Meta-analysis: pooled relative risk (RR; calculated as a weighted average of      Lung cancer (4 cohorts)
                                  the SMRs, using the inverse of the variance as weight), fixed-effects model,      SMR, 2.14, 188/87.7, 2.29 (1.98-2.64), p<0.0001
                                  chi-square test for heterogeneity                                                 Respiratory tract cancers (5 cohorts)
                                                                                                                    SMR, 2.40, 251/104.7, 2.58 (2.28-2.92), p<0.0001
                                                                                                                    Bladder cancer (2 cohorts)
                                                                                                                    SMR, 2.38, 12/5, 2.39 (1.36-4.21), p=0.77
                                                                                                                    Urinary tract cancers (3 cohorts)
                                                                                                                    SMR, 2.99, 18/6.02, 3.27 (2.06-5.19), p=0.17
 a
    Data of the study used in meta-analysis by Bosetti et al. (2006).9
37            Health Council of the Netherlands | No. 2019/07                                                                                                               2                                       39
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<pre> annex B | Details epidemiological studies                                                                                                     Emission during coal gasification | page 39 of 57
 Prospective cohort studies
  Reference      Study design and population                Data on exposure and health                 Results                                                                    Remarks and reliability
                                                            assessment                                                                                                             (Annex G)
  Kawai et al.   Prospective cohort study;                  Exposure based on years of work:            Outcome: positive association found for lung cancer mortality; positive    Appropriate study design,
  196715         Gas generator plant at a steel plant,      1) <10 years (short)                        association found for years of employment; no associations found for other adequate selection of study
                 Japan; follow-up 1953-1965 (up to 12       2) 10-19 years (mid)                        cancer at other sites of the body                                          subjects
                 years); N = 504 gas generator workers, N   3) ≥20 years (high)
                 = 25,760 controls (workers in the same                                                 Standardized mortality ratio (obs/exp) of lung cancer:                     Small study; possibility of
                 industry but not exposed to tar fumes);    Information on lung cancer mortality        • all: 0.44 (6/0.135), p<0.001                                             serious bias (e.g., smoking
                 participants followed until age of 55 year based on death records; age-specific        • short: 0.18 (1/0.056), p=0.05                                            habits) not taken into
                                                            mortality was computed; statistical         • mid: 0.35 (2/0.057), p=0.001                                             account
                 Note: gas generator plant was closed in    analyses by Poisson distribution            • long: 1.36 (3/0.022), p<0.001
                 1953                                                                                   All lung cancer cases were observed in the age group of 45-54 years        Reliability 2
                                                                                                        Years of employment (age group 45-56 years old), death rate/100,000
                                                                                                        population:
                                                                                                        10-19 yrs: 496, 3 death cases, 604.5 persons at risk
                                                                                                        > 20 yrs or more: 2,688, 5 death cases, 186 persons at riskp
                                                                                                        p=0.022
                                                                                                        No other cancer significantly affected
  Doll et al.    Prospective cohort study; coal carbonizing No data on exposure levels; length of       Outcome: positive association for lung and bladder cancer mortality        Appropriate study design;
  197211 a       plants for making gas (4 locations), the   exposure rated as regular, intermittent, or                                                                            adequate selection of study
                 UK;                                        minimal/no exposure                         Standardized cancer mortality ratio (obs/exp (standardized annual death    subjects
                 follow-up 1953-1965 (up to 12 years); N                                                rates per 1,000 men)):
                 (A) = 2,444 coal carbonizing process       Information on cancer mortality based on                                                                               Limited documentation;
                 workers, N (C1) = 579 process and          death certificate; statistical analyses by  Coal workers (A)                                                           possibility of serious bias,
                 maintenance workers in chemical and        Poisson analysis                            • lung: 1.79 (3.82/2.13), p=0.001, 99 deaths                               such as smoking habits, not
                 by-product plant; controls, death rates in                                             • bladder: 2.35 (0.4/0.17), p=0.03, 10 deaths                              taken into account
                 male population England & Wales                                                        • skin and scrotum: 6.00 (0.12/0.02), p=0.0, 3 deaths
                                                                                                        • other cancer: 1.06 (2.70/2.55), 70 death                                 Reliability 2
                                                                                                        Maintenance workers (C1)
                                                                                                        • lung: 0.75 (1.59/2.13), 11 deaths
                                                                                                        • bladder: 0.76 (0.13/0.17), 1 death
                                                                                                        • skin and scrotum: 0,00 (0.00/0.02), 0 deaths
                                                                                                        • other cancer: 0.94 (2.39/2.55), 17 deaths
                                                                                                        No subgroup analysis on duration of exposure
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<pre> annex B | Details epidemiological studies                                                                                                               Emission during coal gasification | page 40 of 57
   Reference          Study design and population                      Data on exposure and health                  Results                                                                    Remarks and reliability
                                                                       assessment                                                                                                              (Annex G)
   Christian          Prospective cohort study; public utility, the    No data on exposure levels                   Outcome: data do not allow a conclusion                                    No clear criteria in the
   196221             USA; follow-up 1946-1961 (15 years);                                                                                                                                     selection study subjects;
                      N=1,031 gas plant workers                        Workers were observed for lung cancer        During follow-up, 125 lung cancer cases were observed, of which 123        possibility of serious bias,
                      (full cohort = 23,571 workers)                   development                                  cases were heavy smokers. This corresponds with 35.4 cases per year per such as smoking habits not
                                                                                                                    100,000 population (full cohort)                                           taken into account; no
                                                                                                                                                                                               statistical analyses
                                                                                                                    Gas plant workers:                                                         performed
                                                                                                                    • 23 cases/1,031 workers
                                                                                                                    • 149 cases per 100,000 man-year observation                               Reliability 3
                                                                                                                    (no other data presented)
 A
    Data of the study used in meta-analysis by Bosetti et al. (2006).9
 Retrospective cohort studies
   Reference        Study design and                  Data on exposure and           Results                                                                         Remarks and reliability (Annex G)
                    population                        health assessment
   Martin et al.    Case control survey nested        No data on exposure levels;    Outcome: only positive association found for lung cancer mortality in the       Well-documented study; data were adjusted for
   200016           in a retrospective cohort         MATEX job exposure matrix      highest exposed group                                                           serious bias, such as socioeconomic situation, and
                    study; national electricity and   was used, which is based on                                                                                    exposure to asbestos, PCBs, and polychlorinated
                    gas company, France; data         occupational groups. The       A total 310 lung cancer cases were registered (mean age at time of diagnosis biphenyls.
                    retrieved from 1978-1989;         matrix includes quantitative   was 49.9 years, which was identical to that of the controls)
                    1,400,00 person-years based       levels of exposure and                                                                                         Data on smoking habits were not available. Authors
                    on male workers employed          exposure times.                Odds ratio (cases/controls, 95% confidence interval), coal gas production:      remark that smoking habits often are related to
                    between 1978-1989 for at                                                                                                                         socioeconomic status, and therefore expect that this
                    least one year; for each case     Lung cancer mortality          Overall (adjusted: no or yes):                                                  confounding factor is weak or absent
                    four age-matches controls         identified by social security  • no: 1.89 (26/12, 0.93-3.86)
                    were randomly selected            fund of company; for each      • yes: 1.64 (-/-, 0.80-3.40)                                                    Reliability 1
                                                      case of lung cancer
                                                      4 age-matched controls from    Cumulative exposure (percentiles, adjusted):
                                                      cohort were randomly           • not exposed: 1.00 (1,176/291, -)
                                                      selected;                      • <25th: 1.02 (7/2, 0.21-4.94)
                                                      statistical analyses by        • 25th-50th: 1.59 (7/3, 0.39-6.49)
                                                      conditional logistic           • 50th-75th: 0.55 (7/1, 0.07-4.57)
                                                      regression models, trend       • ≥ 75th: 3.87 (5/6, 1.15-12.9)
                                                      odds ratio’s                   Trend odd ratio: 1.10 (1.01-1.21)
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<pre> annex B | Details epidemiological studies                                                                                                    Emission during coal gasification | page 41 of 57
  Reference    Study design and              Data on exposure and         Results                                                                       Remarks and reliability (Annex G)
               population                    health assessment
  Gustavsson   Retrospective cohort study;   Exposure to B[a]P (top oven, Outcome: no associations found                                                Well-documented study; study subjects adequately
  and          coal gas production           area sampling) measured:                                                                                   selected
  Reuterwall   company, Sweden; data         1964: 0.007-33 µg/m3         Standardized Mortality Ratio (exp/obs, 95% confidence interval), expected
  199012 a     retrieved from 1966-1988      1965: 0.021-1.29 µg/m    3
                                                                          based on ‘employed in Stockholm’                                              Limited number of participants; limited number of
               (mortality) and 1966-1983                                                                                                                cases; possibility of serious bias not taken into
               (cancer incidence); N=295     Workers were divided into    Overall:                                                                      account
               workers employed for at       departments (coke ovens,     • all malignant tumours: 1,14 (22 /19.3, 0.71-1.72)
               least one year between 1965   steam and generator central, • lung cancer: 0.82 (4/4.85, 0.22-2.11)                                       Authors report that the percentage daily smokers
               and June 1972, when the       coke department, byproduct                                                                                 among coal gas workers (52%) were comparable with
               coal gasification stopped;    workers, workshop and        Employment period (years):                                                    daily smokers in large cities. Therefore, they stated
               reference rates for mortality maintenance workers,         All malignant tumours                                                         that excess of causes did not seem to be caused by
               were based on mortality all   outside workers, sample      1-29 y: 1.03 (17/16.6, 0.6-1.64)                                              smoking habits.
               man in ‘greater Stockholm’ or preparation), or by          ≥ 30 y: 1.43 (8/5.6, 0.62-2.82)
               ‘employed in Stockholm’       employment period            Lung cancer                                                                   Reliability 2
                                                                          1-29 y: 0.00 (0/1.3, 0-2.79)
                                             Expected numbers of deaths ≥ 30 y: 1.41 (2/1.4, 0.17-5.09)
                                             based on
                                             local death rates among      Department:
                                             occupationally active men,   Coke oven department:
                                             expected numbers of cancer • All malignant tumours: 1.43 (5 /3.5)
                                             based on national statistics • Lung cancer: 0 (0/0.9)
                                                                          Steam and generator department:
                                                                          • all malignant tumours: 2.22 (2/0.95)
                                                                          • lung cancer: 0 (0/0.2)
                                                                          Coke department:
                                                                          • malignant tumours: 2.11 (6/2.8)
                                                                          • lung cancer: 2.84 (2/0.7)
  Berger       Retrospective cohort study;   No data on exposure levels   Outcome: positive association for cancer mortality (all cancers, lung cancer, Well-documented study; study subjects adequately
  and Manz     Hamburg coke gas plant,                                    stomach cancer) in gas furnace workers; non-smokers had no excess risk in     selected; serious possibility for bias was taken into
  199210 a     Germany; data retrieved for   Subcohorts based on job      stomach cancer mortality                                                      account (smoking habits and health worker effect)
               the period 1953-1989; N =     titles:
               4,908 male workers            (I) gas furnace workers      Standardized mortality ratio (obs/exp, 95% confidence interval)               Reliability 2
               employed for ≥ 10 years (in   (exposed to high
               the period 1900 to 1989)      concentrations of coal tar   Subcohort I
                                             gas, in particular PAH and   • all cancers: 1.86 (190/102.2, 1.61-2.14)
                                             different heterocyclics; 789 • lung cancer: 2.88 (78/27.1, 2.28-3.59)
                                             workers)                     • stomach cancer: 1.77 (31/1.5, 1.20-2.51)
                                                                          • colon and rectum cancer: 1.84 (13/7.1, 0.98-3.15)
40         Health Council of the Netherlands | No. 2019/07                                                                                                     2                                              42
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<pre> annex B | Details epidemiological studies                                                                                                        Emission during coal gasification | page 42 of 57
  Reference      Study design and                Data on exposure and           Results                                                                      Remarks and reliability (Annex G)
                 population                      health assessment
                                                 (II) workers in other parts of Subcohort II
                                                 the plant occasionally         • all cancers: 0.96 (384/399.6, 0.87-1.06)
                                                 exposed to several             • lung cancer: 0.96 (102/106.3, 0.78-1.17)
                                                 chemicals, 3,401 workers)      • stomach cancer: 1.13 (72/63.7, 0.88-1.42)
                                                 (III) white-collar workers (no • colon and rectum cancer: 1.70 (48/ 28.3, 1.25-2.25)
                                                 exposure, 718 workers)
                                                                                Subcohort III
                                                 Mortality and cause of death   • all cancers: 0.56(59/104.9, 0.43-0.73)
                                                 from company and personal      • lung cancer: 0.45 (12/26.2, 0.23-0.79)
                                                 medical records; Internal      • stomach cancer: 0.57 (10/17.5, 0.27-1.05)
                                                 control = white-collar         • colon and rectum cancer: 0.92 (7/7.6, 0.37-1.90)
                                                 workers, external controls =
                                                 calendar period-, age-, and    Smoking in subcohort I
                                                 cause-specific death rates of  • stomach cancer:
                                                 males for Germany (from        no: 1.40 (3/2.15, 0.29-4.09), N=103
                                                 1952-1989); statistical        yes: 2.56 (22/8.61, 1.60-3.87, N=546
                                                 analyses by likelihood-ratio-  • colon and rectum cancer:
                                                 test, chi-square test for      no: 4.35 (4/0.92, 1.18-1,11), N=103
                                                 homogeneity, confidence        yes: 1.68 (8/4.76, 0.73-3.31), N=546
                                                 intervals by Poisson
                                                 distribution; smoking habits
                                                 taken into account
  Hansen et      Cohort; Denmark; 47 male        No data on exposure levels     Outcome: positive association for lung cancer and general cancer mortality;  Small study, appropriate design
  al. (1986)13 a workers employed >1 year                                       no association with year of employment or latency
                 any time between 1911-          Mortality all causes, all                                                                                   No data on smoking habits or other confounding
                 1970; 141 non-exposed           cancers, and lung cancer       Standardized mortality ratio (SMR) (95% confidence interval), cases/controls factors
                 age-matched controls,
                 selected from population                                       Lung cancer                                                                  Reliability 2
                 registers; period of follow-up,                                SMR 8.9 (-), 7/6
                 no data                                                        Odds ratio 3.94, p=0.01
                                                                                Other cancers
                                                                                SMR - (-), 7/8
                                                                                Odds ratio, 2.91, p=0.02
41         Health Council of the Netherlands | No. 2019/07                                                                                                          2                                       43
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<pre> annex B | Details epidemiological studies                                                                                              Emission during coal gasification | page 43 of 57
  Reference    Study design and             Data on exposure and         Results                                                                Remarks and reliability (Annex G)
               population                   health assessment
  Begraca et   Retrospective cohort study;  Exposure data collected      Outcome: data do not allow a conclusion                                Limited documented study; small study; limited data
  al. 199117   Coal gasification plant,     several days between                                                                                on statistical methodology
               Kosovo; data retrieved from  1981-1985:                   Incidence of skin cancer (rate, age adjusted):
               1971-1986; study performed   • area exposure was highly   • gas workers: 1.9/1,000 (13 cases)                                    Data on smoking habits reported (28% in workers,
               in 1986; N=622 male workers    variable (range coal tar   • reference population: 1.5/1,000 (7 cases)                            31% in reference group), but unclear whether these
               (ever been employed            pitch volatile, 1.2-22,480 •                                                                      are taken into account in the analysis
               through 1980);                 mg/m3)
               N=442 reference population   • mean personal exposure                                                                            Reliability 3
               (open-pit lignite miners)      (mg/m3, range): benzene,
                                              0.16 (<0.02-20.0); total
                                              hydrocarbons, 0.42
                                              (<0.02-43.0); PAH, 0.03
                                              (<0.002-0.62); total
                                              particles, 0.22
                                              (<0.01-10.0)
                                            • there was extensive
                                              surface contamination (no
                                              details given)
                                            Data based on employment
                                            and medical records of
                                            periodical occupational
                                            medical checks; only skin
                                            cancer was addressed;
                                            Average age: 34.2 years;
                                            average duration of
                                            experience: 10 years
  Kennaway     Retrospective mortality      No data on exposure levels;  Outcome: data do not allow a conclusion                                Appropriate study design, but limited reporting and
  and          study;                       job history was based on                                                                            analyses
  Kennaway     gas industry, the UK;        death certificates           Gas stokers and coke-oven chargers (estimated population 12,818)
  193622       N=18,275 death certificates                                                                                                      No statistical analyses performed; no data on
               from England and Wales       Death certificates revealed  Standardized cancer mortality ratio (obs/exp):                         smoking habits or other possible confounders
               analysed for the years       8,808 cases of lung cancer   • lung: 3,42 (37/10.8)
               1921-1932; annual total data mortality and 9,472 cases of • larynx: 1,86 (20/10.7)                                               Reliability 3
               for cases in women used for  larynx cancer mortality      •
               comparison
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<pre> annex B | Details epidemiological studies                                                                                                    Emission during coal gasification | page 44 of 57
   Reference        Study design and                  Data on exposure and       Results                                                              Remarks and reliability (Annex G)
                    population                        health assessment
   Wu et al.        Retrospective cohort study;       No data on exposure levels Outcome: data do not allow a conclusion                              Data from secondary source, and listed as short
   198823           six coal gas plants, China;                                                                                                       summary: IARC 20123
                    data retrieved from 1971-         Death cases identified     Standardized Risk Ratios (confidence interval):
                    1981; N=3,107 workers;            among workers who were     • all causes: 1.29 (1.16-1.44), 234 deaths                           No other data available
                    reference population were         employed in 1971, and who  • all cancer: 1.73 (1.46-2.02), 109 deaths
                    workers in a steel rolling mill   died during the next 10    • lung cancer: 3.66 (2.36-5.43)                                      Reliability 4
                                                      years
   Manz             Cohort; Germany; 5.405            No data on exposure levels Outcome: data do not allow a conclusion                              Data obtained from secondary source: Bosetti et al.
   (1980)14 a       workers in one company;                                                                                                           (2006)9
                    period of employment:             Mortality                  Standardized mortality ratio (SMR) (95% confidence interval)
                    1953-1977; period of                                                                                                              No other data available
                    follow-up: no data                                           Respiratory tract cancer
                                                                                 SMR 3.7, 63 death cases                                              Reliability 4
                                                                                 Urinary tract cancer
                                                                                 SMR 6.1, 6 death cases
 a
    Data of the study used in meta-analysis by Bosetti et al. (2006).9
43           Health Council of the Netherlands | No. 2019/07                                                                                                 2                                            45
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<pre> annex C | Details animal carcinogenicity studies                                                                                              Emission during coal gasification | page 45 of 57
 C details animal carcinogenicity studies
 Cancer development in animals, which are exposed to waste products of the coal gasification process.
 Inhalation studies
  Reference            Animal species  Data on exposure and effect endpoints                         Results                                                          Remarks and reliability
                                       Xpo = exposure period; Xpe = exposure +                                                                                        (Annex F)
                                       observation period
  Rittinghausen et al. Female Crl:[WI] Tar/pitch condensation aerosol (source unknown) of            Number of tumour bearing animals                                 Sufficient number of animals;
  199718               BR Wistar rats; several B[a]P concentrations: 0 (clean air), 20 µg B[a]P /m , (in order of increasing exposure)
                                                                                                  3
                                                                                                                                                                      sufficient duration of exposure
  Germany              N=72/group      50 µg B[a]P /m3, or 125 µg B[a]P/m3
                                                                                                     Exposure scenario 1:                                             Histopathological examination
                                       Exposure scenario 1:                                          • Pulmonary cystic keratinizing squamous cell carcinoma: 0/72,   limited to the lungs; no data on:
                                       17 h/day, 5 days/week for 30 months; Xpo=10 months;              0/72, 23/72*, 38/72*                                          non-carcinogenic effects, number
                                       Xpe=30 months                                                 • Pulmonary keratinizing squamous cell carcinoma: 0/72, 1/72,    of tumours per anima; early
                                                                                                        4/72, 3/72                                                    mortality, trends in food
                                       Exposure scenario 2:                                          • Total number of pulmonary squamous cell carcinomas: 0, 1/72,   consumption and body weight
                                       Exposure: 18 h/day, 5 days/week for 30 months; Xpo=20            27/72*, 41/72*
                                       months; Xpe=30 months                                                                                                          Reliability 2
                                                                                                     Exposure scenario 2:
                                       Histopathological examination on lung lesions                 • Pulmonary cystic keratinizing squamous cell carcinoma: 0/72,
                                                                                                        19/72*, 63/72*, 62/72*
                                                                                                     • Pulmonary keratinizing squamous cell carcinoma: 0/72, 4/72,
                                                                                                        5/72, 4/72
                                                                                                     • Total number of pulmonary squamous cell carcinomas: 0, 23/72*,
                                                                                                        68/72*, 66/72*
                                                                                                     * statistically different from control, p<0.001
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<pre> annex C | Details animal carcinogenicity studies                                                                                           Emission during coal gasification | page 46 of 57
 Oral administration
  Reference          Animal species      Data on exposure and effect endpoints            Results                                                                       Remarks and reliability
                                         Xpo = exposure period; Xpe = exposure +                                                                                        (Annex F)
                                         observation period
  Culp et al. 199819 Female B6C3F1 mice; Coal tar (from coal gasification plant waste     Percentage survival whole treatment period (in order of increasing exposure): Well-documented study; data
  The USA            N=48/group          sites) added to the diet:                        Mixture 1: 65, 71, 69, 63, 21, 0, 0                                           included food consumption, body
                                         • Mixture 1: composite of coal tar from seven    Mixture 2: 65, 65, 65, 15                                                     weight, organ weights and
                                           sites (0.1% in diet corresponds with 2.2       In highest dose groups significant decrease in food consumption. Also lower   percentage of survival; sufficient
                                           ppm B[a]P); 0 (solvent, control), 0.01, 0.03,  body and organ weight reported.                                               number of animals per group
                                           0.1, 0.3, 0.6 and 1.0% in diet*
                                         • Mixture 2: composite of coal tar from two of   Number of tumour bearing animals                                              No data on general toxicity; no
                                           the seven sites + one site with known high     (in order of increasing exposure; * p< 0.05)                                  data on coal tar consumption
                                           level of B[a]P content in coal tar (0.1% in                                                                                  expressed as mg/kg bw/day; only
                                           diet corresponds with 3.7 ppm B[a]P): 0        Mixture 1 (all exposure levels):                                              female mice tested
                                           (solvent, control), 0.03, 0.1 and 0.3% in diet • Liver hepatocellular adenomas and/or carcinomas: 0/47, 4/48, 2/46, 3/48,
                                         • - Positive control: B[a]P only                    14/45*, 1/42, 5/43                                                         Reliability 2
                                                                                          • Lung (alveolar/bronchiolar) adenomas and/or carcinomas: 2/47, 3/48, 4/48,
                                         * Food intake is estimated at 0.35 g/day;           4/48, 27/47, 25/47*, 21/45*
                                         average body weigt estimated to be 25 gram.      • Forestomach papillomas and/or carcinomas: 0/47, 2/47, 6/45, 3/47, 14/46*,
                                         Doses in diet correspond to approximately           15/45*, 6/41
                                         1.4, 4.2, 14, 42, 84 and 420 mg B[a]P/kg bw/     • Small intestine adenocarcinomas: 0/47, 0/46, 0/45, 0/47, 0/42, 22/36*,
                                         day                                                 36/41*
                                                                                          • Haemangiosarcomas: 1/48, 0/48, 1/48, 1/48, 11/48*, 17/48*, 1/45
                                         Exposure on daily basis for 2 years; Xpe=2       • Histiocytic sarcomas: 1/48, 0/48, 0/48, 1/48, 7/48, 5/48, 0/45
                                         years, Xpo=2 years                               • Sarcomas: 1/48, 4/48, 3/48, 2/48, 7/48, 1/48, 2/45
                                                                                          For all tumour types a dose significant trend was observed
                                         Gross pathology and histopathology               (p = 0.003-0.00001)
                                         performed on the liver, lungs, small intestines,
                                         stomach, tongue and esophagus                    Mixture 2 (0.03%, 0.3% and 0.6%):
                                         Full histopathology performed (except in         • Liver hepatocellular adenomas and/or carcinomas: 7/47, 4/47, 10/45*
                                         mixture 1 group, 0.03%)                          • Lung (alveolar/bronchiolar) adenomas and/or carcinomas: 4/48, 10/48*,
                                                                                             23/47*
                                                                                          • Forestomach papillomas and/or carcinomas: 3/47, 2/47, 13/44*
                                                                                          • Small intestine adenocarcinomas: 0/47, 0/47, 1/37
                                                                                          • Haemangiosarcomas: 1/48, 4/48, 17/48*
                                                                                          • Histiocytic sarcomas: 3/48, 2/48, 11/48*
                                                                                          • Sarcomas: 0/48, 4/48, 5/48
                                                                                          Not tested for dose related trends
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<pre> annex C | Details animal carcinogenicity studies                                                                                       Emission during coal gasification | page 47 of 57
  Reference           Animal species   Data on exposure and effect endpoints           Results                                                                        Remarks and reliability
                                       Xpo = exposure period; Xpe = exposure +                                                                                        (Annex F)
                                       observation period
  Weyand et al. 19946 Male and female  0.0% (control) or 0.5% MGP* residue in basal No signs of acute toxicity or early mortality. Mean body weight in highest        Number of animals too low for
  The USA             B6C3F1 mice;     gel diet; 0.005% B[a]P in diet served as        dosed group was lower compared to non-exposed animals.                         statistical robustness of the
                      N=12/sex/group   positive control                                                                                                               outcome; exposure duration too
                                                                                       Number of tumour bearing animals (in order of negative control, positive       short for tumour development;
                                       * Intake of 0.5% MGP: B[ɑ]P content in          control and 0.5% MGP):                                                         only one dose of MGP tested
                                       diet=1,560 mg/kg bw; food intake=5.7            • Forestomach, squamous-cell carcinoma: Male, 0/10, 0/10, 1/10; Female, no
                                       g/d/mouse (females). Based on average body        data;                                                                        Reliability 3
                                       weight of 25g during the study, MGP intake is No correlation with exposure to MG
                                       estimated at 1,140 mg B[a]P/kg bw/day (for
                                       males: 1,480 mg/kg bw/day)                      Preneoplastic lesions: low and sporadic incidence, no correlation with
                                                                                       exposure to MGP
                                       Exposure on daily base for 185 days; Xpo
                                       and Xpe=185 days;
                                       All organs histopathologicaly examined for
                                       gross lesions
  Weyand et al. 19957 Female A/J mice; 0.0% (control), 0.10% or 0.25% MGP*             Mice fed gel diet without MGP (control group) consumed less food and had       Duration of study too short for
  The USA             N=30/group       residue in basal gel diet;                      lower body weights (authors did not have an explanation for this observation). maximum tumour development;
                                       11 and 67 mg B[a]P per mouse served as          Mortality rates ranged from 3 to 30% in control, MGP fed, and B[a]P exposed    limited histopathologival
                                       positive control (administered by a single      animal groups.                                                                 examination; tumour types not
                                       intraperitoneal injection)                                                                                                     specified; in negative control
                                                                                       Number of tumour bearing animals (in order of increasing exposure):            group early mortality was noted
                                       * Based on an average body weight of 25 g       lung tumours: 4/21, 19/27*, 29/29* (B[a]P: 14/27*), * p<0.05                   Study not reliable
                                       during the study, the exposures correlate to 0, forestomach tumours: 0/21, 0/27, 0/29 (B[a]P: 27/27*), * p<0.05
                                       100 and 236 mg B[a]P/kg bw/day                                                                                                 Reliability 3
                                                                                       Number of tumours per mouse (multiplicity; in order of increasing exposure):
                                       Exposure on daily base for 260 days; Xpo        lung tumours: 0.19±0.09, 1.19±0.21*, 12.17±0.14* (B[a]P: 0.59±0.12), *
                                       and Xpe = 260 days                              p<0.05
                                                                                       forestomach tumours: 0, 0, 0 (B[a]P: 4.22±0.41*), * p<0.05
                                       Histopatholic examination of the lungs and
                                       stomach on tumour development
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<pre> annex C | Details animal carcinogenicity studies                                                                                               Emission during coal gasification | page 48 of 57
 Dermal application
  Reference               Animal species                         Data on exposure and effect endpoints                                      Results                      Remarks and reliability (Annex F)
                                                                 Xpo = exposure period; Xpe = exposure + observation period
  Brandon et al. 200924   Male Syrian hamsters; N=4/group        MGP residue applied at doses of 50% and 100% solution in mineral           No tumours in cheek pouch    Limited experimental set-up: only
  The USA                                                        oil; mineral oil served as negative control;                               (only diffuse epithelial     cheek pouch examined; small
                                                                 2% B[a]P and 0.5% DMBA served as positive controls (applied in             hyperplasia at 32 weeks)     number of animals; no data on
                                                                 mineral oil)                                                                                            general toxicity
                                                                 200 µL applied topically into the right cheek pouch                                                     Reliability 3
                                                                 Exposure 3 times per week: Xpo and Xpe 12, 16, 20, 28 and 32
                                                                 weeks;
                                                                 Histopathologic examination of the right cheek pouch
 Intraperitoneal injection
  Reference               Animal species           Data on exposure and effect endpoints                        Results                                                   Remarks and reliability (Annex F)
                                                   Xpo = exposure period; Xpe = exposure +
                                                   observation period
  Rodriguez et al. 199720 Male and female B6C3F1   Single injection of:                                         No forestomach tumour found in any group. Few             Irrelevant route of exposure for
  The USA                 mice (infant, 15 days    • MGP-4*, 1,140 mg/kg bw                                     pulmonary tumours were observed, but no correlation       humans; no statistical analyses
                          old); N=30/group         • MGP-M7*, 285, 570 and 1,140 mg/kg bw                       with exposure to MGP.                                     performed; no whole body
                                                   • B[a]P served as positive control                                                                                     histopathological examination; no
                                                                                                                Liver tumours (data presented are from week 52; in order  data on general toxicity
                                                   * MGP-4 represents coal tar from a single site, MGP-M7 of corn oil only (control), MGP-4, MGP-M7 low, medium
                                                   is a residue composite of 7 sites                            and high, B[a]P):                                         Reliability 3
                                                                                                                Number of tumour bearing animals:
                                                   Xpo: 26, 39 and 52 weeks                                     Males: 3/63, 12/28, 4/34, 8/32, 17/29, 19/24
                                                                                                                Females: no treatment related tumours
                                                   Histopathologic examination on the lung, liver and           Number of tumours per mouse:
                                                   forestomach tissues                                          Males: 1.0, 1.7, 1.2, 1.4, 1.8, 2.5
                                                                                                                Females: no treatment related tumours
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<pre> annex D | EU Classification criteria on germ cell mutagenicity                                                                      Emission during coal gasification | page 49 of 57
                                                                                           somatic and germ cells in vivo are also considered in classifying substances and
 D EU Classification criteria on                                                           mixtures within this hazard class.
           germ cell mutagenicity
                                                                                           3.5.2.2. For the purpose of classification for germ cell mutagenicity, substances are
                                                                                           allocated to one of two categories as shown in Table 3.5.1
                                                                                           3.5.2.3 Specific considerations for classification of substances as germ cell mutagens
 Source: Regulation (EC No. 1272/2008) of the European Parliament and                      3.5.2.3.1. To arrive at a classification, test results are considered from experiments
 of the Council of 10 August 2009 on classification, labelling and packaging               determining mutagenic and/or genotoxic effects in germ and/or somatic cells of
                                                                                           exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall
 (CLP) of substances, Annex I “Classification and labelling requirements for
                                                                                           also be considered.
 hazardous substances and mixtures”, Section 3.5.25
                                                                                           3.5.2.3.2. The system is hazard based, classifying substances on the basis of their
 3.5 Germ cell mutagenicity                                                                intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant
                                                                                           for the (quantitative) risk assessment of substances.
 3.5.1. Definitions and general considerations
                                                                                           Table 3.5.1. Hazard categories for germ cell mutagens
 3.5.1.1. A mutation means a permanent change in the amount or structure of the
 genetic material in a cell. The term ‘mutation’ applies both to heritable genetic changes  Categories        Criteria
 that may be manifested at the phenotypic level and to the underlying DNA                   CATEGORY 1:       Substances known to induce heritable mutations or to be regarded as if they induce
                                                                                                              heritable mutations in the germ cells of humans.
 modifications when known (including specific base pair changes and chromosomal
                                                                                                              Substances known to induce heritable mutations in the germ cells of humans.
 translocations). The term ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise    Category 1A:      The classification in Category 1A is based on positive evidence from human epidemio-
 to an increased occurrence of mutations in populations of cells and/or organisms.                            logical studies. Substances to be regarded as if they induce heritable mutations in the
                                                                                                              germ cells of humans.
 3.5.1.2. The more general terms ‘genotoxic’ and ‘genotoxicity’ apply to agents or          Category 1B:      The classification in Category 1B is based on:
 processes which alter the structure, information content, or segregation of DNA,
                                                                                                              — positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or
 including those which cause DNA damage by interfering with normal replication
 processes, or which in a non-physiological manner (temporarily) alter its replication.                       — positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combi-
 Genotoxicity test results are usually taken as indicators for mutagenic effects.                             nation with some evidence that the substance has potential to cause mutations to germ
                                                                                                              cells. It is possible to derive this supporting evidence from mutagenicity/ genotoxicity
 3.5.2. Classification criteria for substances                                                                tests in germ cells in vivo, or by demonstrating the ability of the substance or its metab-
                                                                                                              olite(s) to interact with the genetic material of germ cells; or
 3.5.2.1. This hazard class is primarily concerned with substances that may cause
 mutations in the germ cells of humans that can be transmitted to the progeny.                                — positive results from tests showing mutagenic effects in the germ cells of humans,
                                                                                                              without demonstration of transmission to progeny; for example, an increase in the fre-
 However, the results from mutagenicity or genotoxicity tests in vitro and in mammalian
                                                                                                              quency of aneuploidy in sperm cells of exposed people.
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<pre> annex D | EU Classification criteria on germ cell mutagenicity                                                                            Emission during coal gasification | page 50 of 57
  Categories      Criteria                                                                                 3.5.2.3.6. Mutagenicity/genotoxicity tests in germ cells, such as:
  CATEGORY 2:     Substances which cause concern for humans owing to the possibility that they may
                  induce heritable mutations in the germ cells of humans. The classification in Category 2 (a) mutagenicity tests:
                  is based on:
                                                                                                           — mammalian spermatogonial chromosome aberration test;
                  — positive evidence obtained from experiments in mammals and/or in some cases
                  from in vitro experiments, obtained from:                                                — spermatid micronucleus assay;
                           — somatic cell mutagenicity tests in vivo, in mammals; or                       (b) Genotoxicity tests:
                           — other in vivo somatic cell genotoxicity tests which are supported by positive — sister chromatid exchange analysis in spermatogonia;
                           results from in vitro mutagenicity assays.
                                                                                                           — unscheduled DNA synthesis test (UDS) in testicular cells.
                  Note: Substances which are positive in in vitro mammalian mutagenicity assays, and
                  which also show chemical structure activity relationship to known germ cell mutagens,    3.5.2.3.7. Genotoxicity tests in somatic cells such as:
                  shall be considered for classification as Category 2 mutagens.
                                                                                                           — liver Unscheduled synthesis test (UDS) in vivo;
 3.5.2.3.3. Classification for heritable effects in human germ cells is made on the basis
 of well conducted, sufficiently validated tests, preferably as described in Regulation                    — mammalian bone marrow Sister Chromatid Exchanges (SCE);
 (EC) No 440/2008 adopted in accordance with Article 13(3) of Regulation (EC) No
                                                                                                           3.5.2.3.8. In vitro mutagenicity tests such as:
 1907/2006 (‘Test Method Regulation’) such as those listed in the following paragraphs.
 Evaluation of the test results shall be done using expert judgement and all the                           — in vitro mammalian chromosome aberration test;
 available evidence shall be weighed in arriving at a classification.
                                                                                                           — in vitro mammalian cell gene mutation test;
 3.5.2.3.4. In vivo heritable germ cell mutagenicity tests, such as:
                                                                                                           — bacterial reverse mutation tests.
 — rodent dominant lethal mutation test;
                                                                                                           3.5.2.3.9. The classification of individual substances shall be based on the total weight
 — mouse heritable translocation assay.                                                                    of evidence available, using expert judgement (See 1.1.1). In those instances where a
                                                                                                           single well-conducted test is used for classification, it shall provide clear and
 3.5.2.3.5. In vivo somatic cell mutagenicity tests, such as:
                                                                                                           unambiguously positive results. If new, well validated, tests arise these may also be
 — mammalian bone marrow chromosome aberration test;                                                       used in the total weight of evidence to be considered. The relevance of the route of
                                                                                                           exposure used in the study of the substance compared to the route of human
 — mammalian erythrocyte micronucleus test.                                                                exposure shall also be taken into account.
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<pre> annex D | EU Classification criteria on germ cell mutagenicity                                                                                Emission during coal gasification | page 51 of 57
 3.5.3 Classification criteria for mixtures                                                                3.5.3.3.1. Where the mixture itself has not been tested to determine its germ cell
                                                                                                           mutagenicity hazard, but there are sufficient data on the individual ingredients and
 3.5.3.1. Classification of mixtures when data are available for all ingredients or only for
                                                                                                           similar tested mixtures (subject to paragraph 3.5.3.2.1), to adequately characterise the
 some ingredients of the mixture
                                                                                                           hazards of the mixture, these data shall be used in accordance with the applicable
 3.5.3.1.1. The mixture shall be classified as a mutagen when at least one ingredient                      bridging rules set out in section 1.1.3.
 has been classified as a Category 1A, Category 1B or Category 2 mutagen and is
                                                                                                           3.5.4. Hazard communication
 present at or above the appropriate generic concentration limit as shown in Table 3.5.2
 for Category 1A, Category 1B and Category 2 respectively.                                                 3.5.4.1. Label elements shall be used in accordance with Table 3.5.3, for substances
                                                                                                           or mixtures meeting the criteria for classification in this hazard class.
 Table 3.5.2. Generic concentration limits of ingredients of a mixture classified as germ
 cell mutagens that trigger classification of the mixture                                                  Table 3.5.3. Label elements of germ cell mutagenicity
                              Concentration limits triggering classification of a mixture as:               Classification                     Category 1A or Category 1B                Category 2
  Ingredient classified as:   Category 1A mutagen          Category 1B mutagen          Category 2 mutagen  GHS Pictograms
  Category 1A mutagen         ≥ 0,1 %                      -                            -
  Category 1B mutagen         -                            ≥ 0,1 %                      -                   Signal word                        Danger                                    Warning
  Category 2 mutagen          -                            -                            ≥ 1,0 %             Hazard Statement                   H340: May cause genetic defects           H341: Suspected of causing
                                                                                                                                               (state route of exposure if it is conclu- genetic defects (state route of ex-
 Note. The concentration limits in the table above apply to solids and liquids (w/w units)                                                     sively proven that no other routes of     posure if it is conclusively proven
 as well as gases (v/v units).                                                                                                                 exposure cause the hazard)                that no other routes of exposure
                                                                                                                                                                                         cause the hazard)
 3.5.3.2. Classification of mixtures when data are available for the complete mixture                       Precautionary Statement Prevention P201, P202, P281                          P201, P202, P281
                                                                                                            Precautionary Statement Response   P308 + P313                               P308 + P313
 3.5.3.2.1. Classification of mixtures will be based on the available test data for the                     Precautionary Statement Storage    P405                                      P405
 individual ingredients of the mixture using concentration limits for the ingredients                       Precautionary Statement Disposal   P501                                      P501
 classified as germ cell mutagens. On a case-by-case basis, test data on mixtures may
                                                                                                           3.5.5. Additional classification considerations
 be used for classification when demonstrating effects that have not been established
 from the evaluation based on the individual ingredients. In such cases, the test results                  It is increasingly accepted that the process of chemical-induced tumorigenesis in
 for the mixture as a whole must be shown to be conclusive taking into account dose                        humans and animals involves genetic changes for example in proto-oncogenes and/or
 and other factors such as duration, observations, sensitivity and statistical analysis of                 tumour suppresser genes of somatic cells. Therefore, the demonstration of mutagenic
 germ cell mutagenicity test systems. Adequate documentation supporting the                                properties of substances in somatic and/or germ cells of mammals in vivo may have
 classification shall be retained and made available for review upon request.                              implications for the potential classification of these substances as carcinogens (see
                                                                                                           also Carcinogenicity, section 3.6, paragraph 3.6.2.2.6).
 3.5.3.3 Classification of mixtures when data are not available for the complete mixture:
 bridging principles
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<pre> annex E | Classification system on carcinogenicity                                                            Emission during coal gasification | page 52 of 57
 E         classification system on                                           The Committee expresses its conclusions in standard phrases:
           carcinogenicity                                                    Category Judgement by the Committee                           Comparable with EU
                                                                                                                                            Category
                                                                              1A       The compound is known to be carcinogenic to humans.  1A
                                                                                       • It acts by a stochastic genotoxic mechanism.
 In 2010, the Committee published a guideline for classifying substances in
                                                                                       • It acts by a non-stochastic genotoxic mechanism.
 terms of their carcinogenic properties, and for assessing their genotox-              • It acts by a non-genotoxic mechanism.
                                                                                       • Its potential genotoxicity has been insufficiently
 icity.26 The classification on carcinogenic properties is based on the Glob-            investigated. Therefore, it is unclear whether the
                                                                                         compound is genotoxic.
 ally Harmonized System, which is also used by the European Union for
                                                                              1B       The compound is presumed to be as carcinogenic to    1B
 the classification, labelling and packaging of substances and mixtures                humans.
                                                                                       • It acts by a stochastic genotoxic mechanism.
 (Regulation EC 1272/2008, Section 3.6 Carcinogenicity).25                             • 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. 2
                                                                              (3)      The available data are insufficient to evaluate the  not applicable
                                                                                       carcinogenic properties of the compound.
                                                                              (4)      The compound is probably not carcinogenic to man.    not applicable
51        Health Council of the Netherlands | No. 2019/07                                                                          2                           53
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<pre> annex F | Reliability testing of animal and in vitro studies                                                Emission during coal gasification | page 53 of 57
 F          reliability testing of animal and                                     Reliability 2 (reliable with restrictions)
            in vitro studies                                                      For example, acceptable, well-documented publication/study report which
                                                                                  meets basic scientific principles; basic data given: comparable to guide-
                                                                                  lines/standards; comparable to guideline study with acceptable restric-
 To assess the reliability of animal and in vitro studies, the Committee uses     tions.
 the criteria set by Klimisch et al. 1997.27 A summary of the criteria of the
 reliability scores is given below. Only studies with a reliability score of 1 or Reliability 3 (not reliable)
 2 are considered in assessing genotoxicity and carcinogenicity.                  For example, method not validated; documentation insufficient for assess-
                                                                                  ment; does not meet important criteria of today standard methods; rele-
 Reliability 1 (reliable without restriction)                                     vant methodological deficiencies; unsuitable test system.
 For example, guideline study (OECD, etc.); comparable to guideline study;
 test procedure according to national standards (DIN, etc.).                      Reliability 4 (not assignable)
                                                                                  For example, only short abstract available; only secondary literature
                                                                                  (review, tables, books, etc.).
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<pre> annex G | Reliability testing of epidemiological studies                                                  Emission during coal gasification | page 54 of 57
 G reliability testing of                                                     (5) The sample/exposure range was sufficient to study the question under
           epidemiological studies                                            investigation, so that effects estimates are not constrained by high impre-
                                                                              cision.
                                                                              (6) The data were analysed using appropriate statistical techniques to
 To assess the reliability of epidemiological studies, the Committee uses     address the research questions and model assumptions.
 the criteria set by Money et al.(2013).28 A summary of the reliability cate- (7) The methodology and results were comprehensively and transparently
 gories set by Money et al. (2013) is given below. Only studies with a reli-  reported according to relevant guidelines (e.g., the STROBE guidelines for
 ability score of 1 or 2 are considered in assessing genotoxicity and carci-  observational data, Von Elm et al. 2007).29
 nogenicity.
                                                                              Acute or specific outcomes
 Reliability 1 (reliable without restriction)                                 The same principles should be applied as for chronic, non-specific
                                                                              outcomes. The focus lies more with how well exposure has been charac-
 Chronic, non-specific outcomes                                               terised, and the disease outcome is defined.
 Appropriate study design to research question.
 (1) Selected subjects or persons at risk represent appropriate exposure      Reliability 2 (reliable with restrictions)
 distributions. Adequate procedures of follow-up and reduction of loss to
 follow up were performed.                                                    Chronic, non-specific outcomes
 (2) Exposure assessment was made independent of outcome with vali-           Applies to studies which possess most of the qualities of studies with
 dated methods, preferentially with individual exposure data.                 reliability 1. The overall quality is comprised due to minor, but obvious,
 (3) Effect data were collected independently from exposure status, using     methodological limitations. Examples include well-designed and
 standardized data collection procedures/registries.                          conducted studies, but with limited measurement data, possibility of some
 (4) The possibility of serious bias has been reduced by design, controlled   residual confounding, some imprecision due to small sample size or low
 through statistical adjustment, and/or quantified through sensitivity        exposure range.
 analyses.
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<pre> annex G | Reliability testing of epidemiological studies                                             Emission during coal gasification | page 55 of 57
 Acute or specific outcomes                                               design to the research question. Shortcomings may include using census
 The same principles should be applied as for chronic, non-specific       job titles as a surrogate for exposure.
 outcomes. Examples of shortcomings may include a lack of individual
 exposure data, and effects derived from self-reported outcomes.          Reliability 4 (not assignable)
                                                                          This includes studies or data which do not give sufficient details about
 Note: some studies with serious methodological limitations may provide   methodology used, or which are short listed in abstracts or secondary
 reliable information for an acute or specific outcome.                   literature.
 Reliability 3 (not reliable)
 The studies fail to meet one or more of the most basic standards
 necessary to interpret epidemiologic research, such as appropriate study
54       Health Council of the Netherlands | No. 2019/07                                                           2                                  56
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<pre>                                                                                                     Emission during coal gasification | page 56 of 57
 Committee
 The membership of the Subcommittee on Classifying Carcinogenic Substances for the evaluation of the
 genotoxicity and carcinogenicity of occupational exposure during coal gasification:
 •  H.P.J. te Riele, Professor of molecular biology, VU University Amsterdam, and Netherlands Cancer
    Institute, Amsterdam, chairman
 •  P.J. Boogaard, Professor of environmental health and human biomonitoring, Wageningen University
    and Research Centre, and toxicologist, SHELL International BV, The Hague
 •  M.J.M. Nivard, Molecular biologist and genetic toxicologist, Leiden University Medical Center,
    Leiden
 •  E. de Rijk, Toxicologic pathologist, Charles River Laboratories, ‘s Hertogenbosch
 •  J.J. Vlaanderen, Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
 •  J. van Benthem, Genetic toxicologist, RIVM, Bilthoven, structurally consulted expert
 Observer
 •  M. Woutersen, Bureau REACH, RIVM, Bilthoven
 Scientific secretary
 •  J.M. Rijnkels, The Health Council of the Netherlands, The Hague
55         Health Council of the Netherlands | No. 2019/07                                                        2                                  57
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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 Water Management, Social
 Affairs and Employment, and Agriculture, Nature and Food Quality. The Council can publish advisory reports on its own initiative. It usually does this in
 order to ask attention for developments or trends that are thought to be relevant to 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.
 This publiation can be downloaded from www.healthcouncil.nl.
 Preferred citation:
 Health Council of the Netherlands. Emission during coal gasification. Evaluation of the
 carcinogenicity and genotoxicity.
 The Hague: Health Council of the Netherlands, 2019; publication no. 2019/07.
 All rights reserved
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<br><br>