<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>Arsine
Evaluation of the carcinogenicity and genotoxicity
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<pre>Gezondheidsraad                                          Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : Aanbieding advies Arsine
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-5131/JR/pg/246-D12
Bijlagen                :1
Datum                   : 1 april 2008
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van arsine. Het maakt
deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen worden geclassifi-
ceerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan mensen tij-
dens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Het advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is voorgelegd aan de Commissie GBBS en vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en
Milieubeheer.
Hoogachtend,
prof. dr. J.A. Knottnerus
Bezoekadres                                                                 Postadres
Parnassusplein 5                                                            Postbus 16052
2 5 11 V X D e n          Haag                                              2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1                                      Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : j o l a n d a . r i j n k e l s @ g r. n l                    w w w. g r. n l
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<pre>Arsine
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the classification of carcinogenic substances of the
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2008/05OSH, The Hague, April 1, 2008
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues...” (Section
22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Housing, Spatial Planning & the Environment, Social
Affairs & Employment, and Agriculture, Nature & Food Quality. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to gov-
ernment policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Arsine; Evaluation of the carcinogenicity and
genotoxicity. The Hague: Health Council of the Netherlands, 2008; publication
no. 2008/05OSH.
all rights reserved
ISBN: 978-90-5549-690-7
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedures 13
1.3 Data 14
2   General information 15
2.1 Identity and physico-chemical properties 15
2.2 IARC classification 16
3   Carcinogenicity 17
3.1 Observations in humans 17
3.2 Carcinogenicity studies in animals 17
3.3 Additional information 17
4   Mutagenicity and genotoxicity 19
4.1 In vitro assays 19
4.2 In vivo assays 19
4.3 Additional information and possible mechanism of toxicity 19
    Contents                                                     7
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<pre>5   Classification 23
5.1 Evaluation of data on carcinogenicity and genotoxicity 23
5.2 Recommendation for classification 24
    References 25
    Annexes 27
A   Request for advice 29
B   The committee 31
C   Comments on the public review draft 33
D   Carcinogenic classification of substances by the committee 35
E   Guideline 93/21/EEG of the European Union 37
8   Arsine
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie arsine onder
de loep. De stof wordt voor diverse industriële doeleinden gebruikt.
Op basis van de beschikbare gegevens leidt de commissie af dat arsine onvol-
doende is onderzocht. Hoewel de gegevens het niet toelaten de stof te classifice-
ren als kankerverwekkend voor de mens of als moet beschouwd worden als
kankerverwekkend voor de mens, is waakzaamheid geboden. De commissie
adviseert daarom arsine te classificeren als verdacht kankerverwekkend voor de
mens. Dit is vergelijkbaar met een classificatie in categorie 3 volgens de richtlij-
nen van de Europese Unie. Binnen deze categorie komt de situatie het meest
overeen met subcategorie b.
Samenvatting                                                                         9
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<pre>10 Arsine</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of sub-
stances to which workers are occupationally exposed. The evaluation is per-
formed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council, here-
after called the committee. In this report, the committee evaluated arsine. The
agent is used for various industrial purposes.
Based on the available information, the committee is of the opinion that arsine
has been insufficiently investigated. While the available data do not warrant a
classification as carcinogenic to humans or as should be regarded as carcinogenic
to humans, they indicate that there is cause for concern. Therefore, the committee
recommends classifying arsine as a suspected human carcinogen. This recom-
mendation is comparable to the EU classification in category 3. The situation is,
furthermore, comparable with subcategory b of this category.
Executive summary                                                                  11
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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a classifica-
        tion (see Annex A). The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see Annex D). The criteria used for
        classification are partly based on an EU-directive (see Annex E). In addition to
        classifying substances, the Health Council also assesses the genotoxic properties
        of the substance in question.
        This report contains the evaluation of the carcinogenicity of arsine.
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the committee. The members of the committee
        are listed in Annex B. The first draft was prepared by H.E. Buist of TNO Quality
        of Life, location Zeist, by contract with the Ministry of Social Affairs and
        Employment.
        Scope                                                                               13
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<pre>         In 2007 the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex C. The committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the committee is standardly based on sci-
    entific data, which are publicly available. The starting points of the committees’
    reports are, if possible, the monographs of the International Agency for Research
    on Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the committee when
    these are considered most relevant in assessing the carcinogenicity and genotox-
    icity of the substance in question. In the case of arsine no such an IARC-mono-
    graph is available. However, IARC evaluated arsenic and arsenic compounds as
    a group.
         More recently published data were retrieved from the online databases Med-
    line, Toxline, Chemical Abstracts, and RTECS. The last updated online search
    was in June 2007. The new relevant data were included in this report.
14  Arsine
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<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        Arsine is produced when metalic arsenides are decomposed by water or reducing
        acids. It is used as a pure gas or in mixtures with an inert background gas: in the
        semiconductor industry for epitaxial growth of gallium arsenide; as a doping
        agent for silicon-based solid-state electronic devices; and, in the manufacture of
        light-emitting diodes.1,2 Furthermore, it is regularly formed by accident, in partic-
        ular in the chemical and non-ferrous metallurgical industries. Finally, it has also
        been reported to be used as a chemical warfare gas.
            Below is given the identity and some of its physical and chemical proper-
        ties.1,2
        Chemical name             :  arsine
        CAS registry number       :  7784-42-1
        EINECS number             :  232-066-3
        Synonyms                  :  arsenic hydride, arsenic trihydride, arsenous hydride, hydrogen
                                     arsenide, arseniuretted hydrogen
        Description               :  colourless, extremely flammable gas with a garlic-like odour
        Occurrence                :  arsine is a vapour heavier than air and accumulates close to the
                                     surface; decomposes on exposure to light, or when it comes into
                                     contact with moisture in the air, depositing shiny black arsenic; in
                                     water, it rapidly hydrolyses to other arsenic compounds
        Molecular formula         :  AsH3
        Molecular weight          :  77.95
        General information                                                                               15
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<pre>    Melting point            :  -116.9 °C
    Boiling point            :  -62 °C
    Relative vapour density  :  2.7 (air = 1)
    Vapour pressure          :  1043 kPa at 20 °C
    Solubility               :  soluble in benzene and chloroform; slightly soluble in alcohol, and
                                alkalis; and, slightly soluble in water (saturation, 8.93 mM)
    Conversion factors       :  1 mg/m3 = 0.309 ppm
    (20 °C)                     1 ppm = 3.24 mg/m3
    EU risk phrases          :  R12: extremely flammable
                                R26: very toxic by inhalation
                                R48/20: harmful: danger of serious damage to health by prolonged
                                exposure through inhalation
                                R50/53: very toxic to aquatic organisms, may cause long-term
                                adverse effects in the aquatic environment
2.2 IARC classification
    In 1980, the Working Group of IARC evaluated arsenic and arsenic compounds.2
    Apart from chemical, physical, production, and acute toxicity data no informa-
    tion was presented on the carcinogenicity of arsine, due to a lack of information.
         However, regarding the group of arsenic compounds, IARC concluded that
    “there is inadequate evidence for the carcinogenicity in animals, but there is suf-
    ficient evidence that inorganic arsenic compounds are skin and lung carcinogens
    in humans. The data suggesting an increased risk for cancer at other sites are
    inadequate for evaluation.” As a result, in 1987 IARC classified the group of
    arsenic and arsenic compounds in group 1, indicating that these are carcinogenic
    to humans.3 In addition, the same conclusion was made by the Working Group
    when considering arsenic in drinking water.4 IARC emphasized that the classifi-
    cation applies to the group of chemicals as a whole, and not necessarily to all
    individual chemicals within the group.
16  Arsine
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<pre>Chapter 3
        Carcinogenicity
3.1     Observations in humans
        No data were available on the carcinogenicity of arsine in humans.
3.2     Carcinogenicity studies in animals
        Holland and Acevedo (1964) reported in an abstract of a carcinogenicity study in
        rabbits.5 The animals (species and number of animals not specified) inhaled ars-
        ine gas for 20 to 26 months. One exposed rabbit developed a malignant mesothe-
        lioma of the pleura in the lungs. No further details were given. The committee
        considers this study inadequate for evaluation, due to insufficient reporting.
            No other data were available on the carcinogenicity of arsine in animal
        experiments.
3.3     Additional information
        Arsine belongs to a group of inorganic arsenic compounds, which have been
        evaluated on carcinogenicity by various organizations.2-4,6 In summary, in
        humans, long term exposure to arsenic in drinking water is causally related to
        increased risk of cancer in the urinary bladder, lung and skin.4,6 Furthermore,
        occupational exposure to arsenic by inhalation is causally related to lung cancer.
        Overall, animal carcinogenicity studies are difficult to interpret, due to shortcom-
        Carcinogenicity                                                                      17
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<pre>   ings in study design and reporting, with some exceptions.2-4,6 For instance, in a
   long-term study, (pentavalent) arsenic given in the drinking water caused
   increased incidences of tumours in various organs, such as in the lung, liver, gas-
   trointestinal tract and skin of mice.6 Furthermore, arsenic trioxide, a compound
   that may be formed by oxidation of arsine in lung tissue, induced lung adenomas
   in mice, which were given the agent by perinatal treatment; and lung adenomas,
   carcinomas and papillomas in the respiratory tract of hamsters after intratracheal
   installation.3
18 Arsine
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<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        No specific in vitro studies are available on the genotoxic potential of arsine per
        se.
4.2     In vivo assays
        No in vivo studies are available on the genotoxic potential of arsine per se.
4.3     Additional information and possible mechanism of toxicity
4.3.1   Arsine
        The toxicity of arsine is thought to be dependent on its metabolism.7 However,
        the metabolism and mechanism of toxic action have not been clarified yet. Below
        is given a brief summary of the state of the art.
            Regarding metabolism, some information indicate that inhaled arsine is rap-
        idly removed from the lung and transported to the systemic circulation.1,7,8
        Research focusing on blood revealed that the agent is rapidly distributed to the
        red blood cells causing hemolysis and potential global cellular hypoxia.7 Other
        organs can be affected although it is not known whether the effects are a result of
        a direct interaction between the tissue and arsine or indirect effects from red
        Mutagenicity and genotoxicity                                                       19
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<pre>      blood cell contents.7 A small amount of inorganic arsenic oxides and unknown
      metabolites can be formed during the arsine metabolism.7
           It is hypothesized that the major route of metabolism to the ultimate metabo-
      lite(s) is via interaction of hemoproteins in the red blood cells, and the formation
      of inorganic arsenic oxides.7-9 Metabolites of arsine are mainly excreted via the
      urine, as shown by case reports. For instance, in the urine of workers who acci-
      dentally inhaled arsine gas, various metabolites of the agent were found, includ-
      ing trivalent arsenic (III), arsenobetaine, dimethylarsinate, monomethylarsonate,
      and to al lesser extent pentavalent arsenic (V).1,10,11 However, it was suggested
      that arsenobetaine was from dietary origin. When rats inhaled arsine gas at a con-
      centration of up to 80 mg/m3 for one hour, in the urine the same metabolites were
      found, except arsenobetaine.1,12
           Using an in vitro test system, Ayala-Fierro et al. (1999) determined whether
      arsine itself or its metabolite trivalent arsenic was required for toxicity.9 For this
      study, they used red blood cells, primary hepatocytes, and primary renal cortical
      epithelial cells from rats. Based on their findings, the investigators concluded
      that unchanged arsine was able to produce toxicity (lactate dehydrogenase leak-
      age, and decreases in intracellular K+) in these cells, and that the toxic potency
      was tissue-dependent.
           Regarding its toxic mechanism, arsine is predominantly known as a
      hemolytic agent. Based on studies on mainly blood cells, it was postulated that
      arsine or its metabolites exert their toxic effects by oxidative stress depleting glu-
      tathione. However, conflicting findings have been reported, so the subject is still
      a matter of debate.9,13 Others have suggested that the toxic mechanism depends on
      the reaction with sulfhydryl groups of Na+K+-ATPase.14 The latter causes impair-
      ment in the sodium-potassium pump mechanism, with subsequent induction of
      abnormalities in the structure of cell membranes, for instance resulting in hemo-
      lysis of red blood cells. It is known that trivalent arsenic has a high affinity for
      sulfhydryl groups.
4.3.2 Arsenic and arsenic compounds
      The metabolites of arsine, which are found in the urine, are also the major metab-
      olites found after exposure to arsenic and other arsenic compounds.1 For this rea-
      son it is of interest to evaluate data on mutagenicity and genotoxicity of some of
      these inorganic arsenic compounds. In addition, it is proposed that the trivalent
      species are implicated in the mechanism of arsenic-induced carcinogenicity.4
           Andrewes et al. (2003) investigated the in vitro genotoxicity of various inor-
      ganic and organic arsenic compounds using supercoiled DNA.15 Negative out-
20    Arsine
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<pre>comes were observed for the inorganic compounds arsine, arsenate and arsenite.
The DNA damaging potency for methylated arsenic compounds varied from
strong positive (dimethylarsenite, trimethylarsine oxide) to negative (monometh-
ylarsenate).
    Regarding arsenic, the Working Group of IARC evaluated several studies,
and concluded that in humans arsenic has limited ability to induce point muta-
tions, but that it has the capacity to induce large deletions and rearrangements in
chromosomes.2-4 In addition, it showed clastogenic effects (i.e., micronuclei,
chromosomal aberrations, aneuploidy) in humans. In in vitro bioassays arsenic
did not act as a mutagen, but it did have clastogenic effects in mammalian cells,
and it showed to be a synergistic co-mutagen.
    Concerning arsenite and arsenate, these compounds did not induce mutations
in various in vitro bioassays, except at the tk locus of mouse lymphoma L5178Y
cells.2-4,16 However, in various test systems they showed to be clastogenic (i.e.,
micronuclei, sister chromatid exchanges, chromosomal aberrations) in vitro.
    Monomethylarsonic acid and dimethylarsinic acid not only induced gene
mutations at the tk locus of mouse lymphoma L5178Y cells, but also chromo-
somal aberrations and micronuclei formation in the same cells.4,16
    Other arsenic compounds, such as trimethylarsine oxide, arsenobetaine,
methylarsonous acid and dimethylarsinous acid, were also clastogenic.4
    IARC noted that methylated trivalent arsenic had a higher genotoxic potency
than trivalent inorganic arsenic, whereas methylated pentavalent arsenic had a
lower potency than pentavalent inorganic arsenic.4
    In summary, the overall weight of evidence indicate that arsenic compounds
can cause clastogenic effects in exposed individuals and animals, but that results
on mutagenicity are largely negative.4,6
    Finally, several mechanisms for genotoxicity of arsenic and arsenic com-
pounds have been proposed, including reactive oxygen radical DNA-damage,
and impairment of DNA repair, but the exact genotoxic mechanism is still under
debate.4,6
Mutagenicity and genotoxicity                                                       21
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<pre>22 Arsine</pre>

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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data on the carcinogenicity and genotoxicity of arsine in humans and animals
        were available, nor were there any data presented on the mutagenic and geno-
        toxic potency in vitro. Due to a lack of data, there is insufficient direct evidence
        that arsine is carcinogenic and genotoxic.
            Yet, arsine belongs to a group of arsenic and arsenic compounds, which share
        the same kind of metabolism and metabolites. Based on data on arsenic com-
        pounds, the committee is not able to conclude on the height of the carcinogenic
        potency of arsine, but the information obtained on these compounds gives insight
        into the possible carcinogenic and genotoxic potential of the compound. Overall,
        arsenic and arsenic compounds as a group are considered carcinogenic to
        humans. In addition, the European Union classified arsenic trioxide, arsenic
        oxide, and arsenic acid and its salts in carcinogenic category 1 (known to be car-
        cinogenic to humans). Furthermore, arsenic and arsenic compounds have limited
        or no ability to induce mutations. However, they are clearly clastogenic, and for
        this reason arsenic compounds are considered genotoxic agents that mainly act
        by a non-stochastic mechanism. At least, the assumed metabolites of arsine have
        shown to possess some carcinogenic potential, although the set of data is limited.
            All data considered, there is insufficient information on the carcinogenic and
        genotoxic potential of arsine, but the limited information on its metabolites is
        cause for concern to the committee.
        Classification                                                                       23
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<pre>5.2 Recommendation for classification
    Based on the available information, the committee is of the opinion that arsine
    has been insufficiently investigated. While the available data do not warrant a
    classification as carcinogenic to humans or as should be regarded as carcinogenic
    to humans, they indicate that there is cause for concern. Therefore, the committee
    recommends classifying arsine as a suspected human carcinogen. This recom-
    mendation is comparable to the EU classification in category 3. The situation is,
    furthermore, comparable with subcategory b of this category.
24  Arsine
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<pre>   References
1  Czerczak S, Fishbein L. Arsine: human health aspects. Geneva: World Health Organization; 2002:
   Concise international chemical assessment document 47.
2  International Agency for Research on Cancer. Some metals and metallic compounds. IARC
   Monographs on the evaluation of carcinogenic risk on humans, Lyon, France, Volume 23; 1980.
3  International Agency for Research on Cancer. Overall evaluations of carcinogenicity: an updating of
   IARC Monographs volumes 1 to 42. IARC monographs on the evaluation of carcinogenic risk to
   humans, Lyon, France, Supplement 7; 1987.
4  International Agency for Research on Cancer. Some drinking-water disinfectants and contaminants,
   including arsenic. IARC Monographs on the evaluation of carcinogenic risk on humans, Lyon,
   France, Volume 84; 2004.
5  Holland RH, Acevedo AR. The carcinogenicity of inhaled arsine and triphemyl in rabbits (abstract
   no. 107). Proc Am Assoc Cancer Res 1964; 5: 28.
6  World Health Organization. Arsenic and arsenic compounds. Environmental Health Criteria 224.
   WHO, Geneva, Switzerland; 2001.
7  Carter DE, Aposhian HV, Gandolfi AJ. The metabolism of inorganic arsenic oxides, gallium
   arsenide, and arsine: a toxicochemical review. Toxicol Appl Pharmacol 2003; 193(3): 309-334.
8  Landrigan PJ, Costello RJ, Stringer WT. Occupational exposure to arsine. An epidemiologic
   reappraisal of current standards. Scand J Work Environ Health 1982; 8(3): 169-177.
9  Ayala-Fierro F, Barber DS, Rael LT, Carter DE. In vitro tissue specificity for arsine and arsenite
   toxicity in the rat. Toxicol Sci 1999; 52(1): 122-129.
10 Apostoli P, Alessio L, Romeo L, Buchet JP, Leone R. Metabolism of arsenic after acute occupational
   arsine intoxication. J Toxicol Environ Health 1997; 52(4): 331-342.
   References                                                                                          25
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<pre>11 Romeo L, Apostoli P, Kovacic M, Martini S, Brugnone F. Acute arsine intoxication as a consequence
   of metal burnishing operations. Am J Ind Med 1997; 32(3): 211-216.
12 Buchet JP, Apostoli P, Lison D. Arsenobetaine is not a major metabolite of arsine gas in the rat. Arch
   Toxicol 1998; 72(11): 706-710.
13 Hatlelid KM, Carter DE. Reactive oxygen species do not cause arsine-induced hemoglobin damage. J
   Toxicol Environ Health 1997; 50(5): 463-474.
14 Pakulska D, Czerczak S. Hazardous effects of arsine: a short review. Int J Occup Med Environ Health
   2006; 19(1): 36-44.
15 Andrewes P, Kitchin KT, Wallace K. Dimethylarsine and trimethylarsine are potent genotoxins in
   vitro. Chem Res Toxicol 2003; 16(8): 994-1003.
16 Moore MM, Harrington-Brock K, Doerr CL. Relative genotoxic potency of arsenic and its
   methylated metabolites. Mutat Res 1997; 386(3): 279-290.
26 Arsine
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<pre>A Request for advice
B The committee
C Comments on the public review draft
D Carcinogenic classification of substances by the committee
E Guideline 93/21/EEG of the European Union
  Annexes
                                                             27
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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
      Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
      and Employment wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
      tal advisory structure, to improve the integration of the development of recommendations for health
      based occupation standards and the development of comparable standards for the general population.
      A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
      by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
      exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
      (MAC-values) for substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as fol-
      lows:
      The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
      aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
      report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
      quality at the work place. This implies:
      •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
           criteria-document that will be made available to the Health Council as part of a specific request
      Request for advice                                                                                        29
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<pre>       for advice. If possible this evaluation should lead to a health based recommended exposure limit,
       or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calcu-
       lated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6 per
       year.
   •   The evaluation of documents review the basis of occupational exposure limits that have been
       recently established in other countries.
   •   Recommending classifications for substances as part of the occupational hygiene policy of the
       government. In any case this regards the list of carcinogenic substances, for which the classifica-
       tion criteria of the Directive of the European Communities of 27 June 1967 (67/548/EEG) are
       used.
   •   Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
   Social Affairs and Employment the President of the Health Council agreed to
   establish DECOS as a Committee of the Health Council.
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<pre>Annex B
      The committee
      •   G..J. Mulder, chairman
          emeritus professor of toxicology, Leiden University, Leiden
      •   P.J. Boogaard
          toxicologist, SHELL International BV, The Hague
      •   Ms. M.J.M. Nivard
          molecular biologist and genetic toxicologist, Leiden University Medical Cen-
          ter, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Quality of Life, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis, Uni-
          versity Medical Center, Leiden
      •   E.J.J. van Zoelen
          professor of cell biology, Radboud University Nijmegen, Nijmegen
      •   J.M. Rijnkels, scientific secretary
          Health Council of the Netherlands, The Hague
      The committee consulted an additional expert, Prof. dr. G. Mohn, working at
      Department of Radiation Genetics and Chemical Mutagenesis of the University
      of Leiden, with respect to the genotoxic data.
      The committee                                                                    31
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<pre>   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health Coun-
   cil Committee. Transparency regarding possible conflicts of interest is nonethe-
   less important, both for the President and members of a Committee and for the
   President of the Health Council. On being invited to join a Committee, members
   are asked to submit a form detailing the functions they hold and any other mate-
   rial and immaterial interests which could be relevant for the Committee’s work.
   It is the responsibility of the President of the Health Council to assess whether
   the interests indicated constitute grounds for non-appointment. An advisorship
   will then sometimes make it possible to exploit the expertise of the specialist
   involved. During the establishment meeting the declarations issued are dis-
   cussed, so that all members of the Committee are aware of each other’s possible
   interests.
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2007 for public review. The follow-
      ing organisations and persons have commented on the draft document:
      • E. González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain;
      • R.D. Zumwalde, National Institute for Occupational Safety and Health, the
          USA.
      Comments on the public review draft                                               33
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<pre>Annex         D
              Carcinogenic classification of sub-
              stances by the committee
The committee expresses its conclusions in the form of standard phrases:
Judgment of the committee                                                                       Comparable with EU class
This compound is known to be carcinogenic to humans                                             1
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound should be regarded as carcinogenic to humans                                      2
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound is a suspected human carcinogen.                                                  3
•   This compound has been extensively investigated. Although there is insufficient evidence    (A)
    for a carcinogenic effect to warrant a classification as ‘known to be carcinogenic to
    humans’ or as ‘should be regarded as carcinogenic to humans’, they indicate that there is
    cause for concern.
•   This compound has been insufficiently investigated. While the available data do not war-    (B)
    rant a classification as ‘known to be carcinogenic to humans’ or as ‘should be regarded as
    carcinogenic to humans’, they indicate that there is a cause for concern.
This compound cannot be classified                                                              not classifiable
•   There is a lack of carcinogenicity and genotoxicity data.
•   Its carcinogenicity is extensively investigated. The data indicate sufficient evidence sug-
    gesting lack of carcinogenicity.
              Carcinogenic classification of substances by the committee                                             35
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<pre>Annex E
      Guideline 93/21/EEG of the European
      Union
      4.2            Criteria for classification, indication of danger, choice of risk phrases
      4.2.1          Carcinogenic substances
      For the purpose of classification and labelling, and having regard to the current state of knowledge,
      such substances are divided into three categories:
      Category 1:
      Substances known to be carcinogenic to man.
      There is sufficient evidence to establish a causal association between human exposure to a substance
      and the development of cancer.
      Category 2:
      Substances which should be regarded as if they are carcinogenic to man.
      There is sufficient evidence to provide a strong presumption that human exposure to a substance may
      result in the development of cancer, generally on the basis of:
      •    appropriate long-term animal studies
      •    other relevant information.
      Guideline 93/21/EEG of the European Union                                                             37
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<pre>   Category 3:
   Substances which cause concern for man owing to possible carcinogenic effects but in
   respect of which the available information is not adequate for making a satisfactory assess-
   ment.
   There is some evidence from appropriate animal studies, but this is insufficient to place the substance
   in Category 2.
   4.2.1.1       The following symbols and specific risk phrases apply:
   Category 1 and 2:
   T; R45 May cause cancer
   However for substances and preparations which present a carcinogenic risk only when inhaled, for
   example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with
   skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be
   used:
   T; R49 May cause cancer by inhalation
   Category 3:
   Xn; R40 Possible risk of irreversible effects
   4.2.1.2       Comments regarding the categorisation of carcinogenic substances
   The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into
   Categories 2 and 3 is based primarily on animal experiments.
   For classification as a Category 2 carcinogen either positive results in two animal species should be
   available or clear positive evidence in one species; together with supporting evidence such as geno-
   toxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship
   with other known carcinogens, or data from epidemiological studies suggesting an association.
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<pre>Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is
     insufficient for classification in Category 2. Additional experiments would not be expected to
     yield further relevant information with respect to classification.
b    substances which are insufficiently investigated. The available data are inadequate, but they
     raise concern for man. This classification is provisional; further experiments are necessary
     before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experimental tumour induction in view of possible human exposure. These argu-
ments, especially in combination, would lead in most cases to classification in Category 3, even
though tumours have been induced in animals:
•    carcinogenic effects only at very high levels exceeding the 'maximal tolerated dose'. The maxi-
     mal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go
     along with physical changes such as about 10% retardation in weight gain;
•    appearance of tumours, especially at high dose levels, only in particular organs of certain species
     is known to be susceptible to a high spontaneous tumour formation;
•    appearance of tumours, only at the site of application, in very sensitive test systems (e.g. i.p. or
     s.c. application of certain locally active compounds);
•    if the particular target is not relevant to man;
•    lack of genotoxicity in short-term tests in vivo and in vitro;
•    existence of a secondary mechanism of action with the implication of a practical threshold above
     a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological
     regulation, chronic stimulation of cell proliferation;
•    existence of a species - specific mechanism of tumour formation (e.g. by specific metabolic
     pathways) irrelevant for man.
For a distinction between Category 3 and no classification arguments are relevant which exclude a
concern for man:
•    a substance should not be classified in any of the categories if the mechanism of experimental
     tumour formation is clearly identified, with good evidence that this process cannot be extrapo-
     lated to man;
•    if the only available tumour data are liver tumours in certain sensitive strains of mice, without
     any other supplementary evidence, the substance may not be classified in any of the categories;
•    particular attention should be paid to cases where the only available tumour data are the occur-
     rence of neoplasms at sites and in strains where they are well known to occur spontaneously with
     a high incidence.
Guideline 93/21/EEG of the European Union                                                                 39
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<br><br>