<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Advisory Reports Areas of activity The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands www.healthcouncil.nl Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Environmental health Which environmental influences could have a positive or negative effect on health? Prevention Which forms of prevention can help realise significant health benefits? Healthy working conditions How can employees be protected against working conditions that could harm their health? Healthy nutrition Which foods promote good health and which carry certain health risks? Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Health Council of the Netherlands Ethylene Evaluation of the carcinogenicity and genotoxicity 2013/24 620166_V23_GR-Paars_Om_EN.indd Alle pagina's 30-09-13 10:32</pre>

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<pre>Ethylene
    Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Ethylene
Uw kenmerk             : DGV/BMO-U-932542
Ons kenmerk            : U-7909/BV/fs/246-X18
Bijlagen               :1
Datum                  : 18 oktober 2013
Geachte minister,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
ethyleen.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen wor-
den geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan
mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit 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 getoetst door de Beraadsgroep Gezondheid en omgeving van
de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                      Postadres
Rijnstraat 50                                                    Postbus 16052
2515 XP Den               Haag                                   2500 BB Den     Haag
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Ethylene
Evaluation of the carcinogenicity and genotoxicity
to:
the Minister of Social Affairs and Employment
No. 2013/24, The Hague, October 18, 2013
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Ethylene - Evaluation of the carcinogenicity
and genotoxicity. The Hague: Health Council of the Netherlands, 2013;
publication no. 2013/24.
all rights reserved
ISBN: 978-90-5549-970-0
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Data 14
   General information 15
.1 Identity and physico-chemical properties 15
.2 IARC conclusion 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 18
.3 Summary of the carcinogenicity studies 19
   Genotoxicity 21
.1 Gene mutation assays 21
.2 Cytogenetic assays 22
   Contents                                    7
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<pre> .3 Summary of the genotoxicity studies 22
 .4 Role of ethylene oxide 22
    Classification 27
 .1 Evaluation of data on carcinogenicity and genotoxicity 27
 .2 Recommendation for classification 28
    References 29
    Annexes 33
A   Request for advice 35
B   The Committee 37
C   The submission letter 39
D   Comments on the public review draft 41
E   IARC Monograph 43
F   Genotoxicity data 47
G   Carcinogenic classification of substances by the Committee 49
    Ethylene
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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 beroeps-
matige blootstelling aan stoffen van de raad, hierna kortweg aangeduid als de
commissie. In het voorliggende advies neemt de commissie ethyleen onder de
loep.
Ethyleen wordt geproduceerd door het stoomkraken van koolwaterstoffen en
wordt vooral gebruikt als chemisch intermediair in de productie van polymeren
en andere industriële chemicaliën zoals ethyleenoxide, ethyleendichloride en
ethylbenzeen; kleine hoeveelheden worden gebruikt om het rijpen van fruit en
groente te bevorderen, en voor het lassen en snijden van metaal.
    Op basis van de beschikbare gegevens over ethyleen meent de commissie dat
deze niet voldoende zijn om de kankerverwekkende eigenschappen van deze stof
te evalueren (categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage G).
Samenvatting                                                                  9
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<pre>0 Ethylene</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
substances to which workers are occupationally exposed. The evaluation is
performed by the Subcommittee on the Classification of Carcinogenic
Substances of the Dutch Expert Committee on Occupational Standards of the
Health Council, hereafter called the Committee. In this report the Committee
evaluated ethylene.
Ethylene is produced by steam-cracking of hydrocarbons and mainly used as a
chemical intermediate in the production of polymers and other industrial
chemicals such as polyethylene, ethylene oxide, ethylene dichloride and
ethylbenzene; minor amounts are used to promote the ripening of fruits and
vegetables, and for welding and cutting metals.
    The Committee is of the opinion that the available data are insufficient to
evaluate the carcinogenic properties of ethylene (category 3).*
According to the classification system of the Health Council (see Annex G).
Executive summary                                                               11
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<pre>2 Ethylene</pre>

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<pre> hapter 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
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for classification are expressed in the form of
        standard sentences (see Annex G).
        This report contains the evaluation of the carcinogenicity of ethylene.
1.2     Committee and procedure
        The evaluation is performed by the Subcommittee on the Classification of
        Carcinogenic Substances of the Dutch Expert Committee on Occupational Safety
        of the Health Council, hereafter called the Committee. The members of the
        Committee are listed in Annex B. The submission letter (in English) to the
        Minister can be found in Annex C.
            In June 2013 the President of the Health Council released a draft of the report
        for public review. The individuals and organisations that commented on the draft
        Scope                                                                               13
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<pre>    are listed in Annex D. The Committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the Committee is based on scientific
    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
    genotoxicity of the substance in question. In the case of ethylene, such an IARC-
    monograph is available, of which the summary and conclusion are inserted in
    Annex E.
    More recently published data were retrieved from the DIMDI database Medline
    and XToxline, and Chemical Abstracts. The last updated online search was in
    August 2013. The new relevant data were included in this report.
 4  Ethylene
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<pre> hapter 2
        General information
2.1     Identity and physico-chemical properties
        Ethylene, the petrochemical manufactured in largest volume worldwide, is
        produced primarily by steam-cracking of hydrocarbons. It is used mainly as a
        chemical intermediate in the production of polymers and other industrial
        chemicals such as polyethylene, ethylene oxide, ethylene dichloride and
        ethylbenzene; minor amounts are used to promote the ripening of fruits and
        vegetables, and for welding and cutting metals. Ethylene is introduced into the
        environment from both natural and man-made sources with estimated total
        emissions of 74 and 26%, respectively, and includes emissions from vegetation,
        as a product of burning of organic material (such as cigarettes) and of incomplete
        combustion of fossil fuels, and in its production and use. In addition, ethylene is
        endogenously produced in mammals and humans (and also in plants). Possible
        endogenous sources of ethylene are lipid peroxidation, oxidation of free
        methionine, oxidation of haemin in haemoglobin and metabolism of intestinal
        bacteria.1,2
            Background levels of ethylene in ambient air at rural and remote sites range
        from <1-15 µg/m3, and in urban and indoor air contaminated with combustion
        products from a few to over 1,000 µg/m3.1-3 Ethylene in cigarette smoke amounts
        to 1-2 mg ethylene per cigarette, i.e. levels of 56-110 µg/m3 were measured in
        smoky tavern air. Human endogenous production may yield atmospheric
        concentrations up to around 100 µg/m3 from exhalation in a closed system.4 Few
        General information                                                                 15
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<pre>    data are available on levels of occupational exposure. Monitoring of ethylene
    levels during use for ripening of bananas showed air concentrations to be in the
    range of 0.02-3.35 ppm (0.02-3.85 mg/m3). In a petrochemical plant the mean
    exposure level was 4.5 mg/m3. In a study on exposure of firefighters, samples
    taken during the “knockdown” phase of a fire showed a concentration of 46 ppm
    (53 mg/m3) ethylene.1,2
         The identity of ethylene and some of its physicochemical properties are given
    below.1
    Chemical name              : ethylene
    CAS registry number        : 74-85-1
    EC/EINECS number           : 200-815-3
    Synonyms                   : ethene, acetene, bicarburetted hydrogen, elayl, olefiant gas
    Colour and physical state  : colourless gas
    Molecular weight           : 28.05
    Molecular formula          : C2H4
    Structure                  : H2C=CH2
    Melting/boiling point      : -169/-103.7 °C
    Relative vapour density    : 0.9686
    (air = 1)
    Vapour pressure            : 4,270 kPa at 0 °C
    Stability: Lower explosive : 2.75 vol% or 34.6 g/m3 at 100 kPa and 20°C
    limit (in air)
    Solubility                 : very slightly soluble in water (0.26% vol/vol; 131 mg/L at 20 °C);
                                 slightly soluble in acetone, benzene and ethanol; soluble in diethyl
                                 ether
    Conversion factors         : 1 ppm = 1.15 x mg/m3
    (25 °C, 760 mm Hg)           1 mg/m3 = 0.87 x ppm
    EU Classification          : Flam. Gas 1: H220 (Extremely flammable gas)
                                 Press. Gas: H336 (May cause drowsiness or dizziness)
                                 STOT SE 3
2.2 IARC conclusion
    In 1994, IARC1 concluded that there is inadequate evidence for the
    carcinogenicity of ethylene in experimental animals and humans. Therefore,
    according to the IARC guidelines, ethylene was considered to be not classifiable
    as to its carcinogenicity to humans (Group 3).
 6  Ethylene
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
        Two nested case-control studies are available. The first study (Leffingwel et al.,
        1983)5 investigated the elevated standardised mortality ratios (>200) found at a
        Texas petrochemical plant for neoplasms of the brain (17 cases; 102 controls).
        Possible associations between gliomas of the brain and job title, departmental
        employment history, chemical exposure history, geographic location within the
        plant, dates of employment, and residence were examined. For ethylene odds
        ratios (OR) of 1.17-4.03 were found for the time intervals of 0-14, >15 years or
        ever possibly exposed to ethylene with or without maintenance men included in
        the pool of cases and controls; no dependence on duration of exposure was seen
        and confidence intervals were wide and included 1 (confounding factor of
        smoking was not investigated). Moreover, workers had been exposed to multiple
        chemicals and exposure levels are not known. Therefore, the uncertainty of this
        study is large as indicated by the wide confidence intervals including 1 and no
        conclusion can be drawn from this study.
            In a nested case-control study (Bond et al., 1986)6 among male workers
        (cases 308; controls 588) at Dow Chemical’s Texas Operations, a potential
        association between frequency of occupational exposure to a number of agents
        and lung cancer deaths between 1940 and 1981 was investigated. Potential
        confounding factors such as smoking were taken into account. Ethylene and
        ethylene oxide showed no relation with lung cancer without or with a latency
        Carcinogenicity                                                                    17
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<pre>      period (no latency period: ethylene: OR 0.99 (95% CI 0.62-1.58); cases 31;
      ethylene oxide: OR 0.90 (95%CI 0.47-1.72); cases 14). Since all workers were
      exposed to multiple agents, including known carcinogenic agents, no conclusion
      concerning pulmonary carcinogenic potential of ethylene can be drawn from this
      study.
3.2   Carcinogenicity studies in animals
3.2.1 Carcinogenicity studies
      Fischer-344 rats (n=120/dose/sex) were exposed to 0, 300, 1,000 or 3,000 ppm
      (0, 345, 1,150 or 3,450 mg/m3) of ethylene (>99.9% pure) for 6 h/day, 5 days/
      week for 2 years.1,2,7 The highest concentration was chosen as to avoid explosion
      hazard. Necropsies were conducted after 6 and 12 months (5/dose/sex), and after
      18 (19-20/dose/sex) and 24 months (all survivors) of exposure. Body weight was
      determined. Haematological, urinalysis and clinical chemistry parameters were
      measured in interim sacrificed animals and at 24 months. Tissues from animals at
      0 and 3,000 ppm were examined histologically. There was no significant
      difference in survival between control and treated groups. No treatment-related
      toxicity or increased incidence in neoplasms was reported. Rostron (1985)8
      remarked that in the above study no discussion on the incidence of mononuclear
      cell leukaemia was present. The number of animals affected (out of 90) rose from
      12 and 8 in the male and female control group to 21 and 11, in males and females
      at 3,000 ppm respectively. As ethylene oxide is known to induce this type of
      cancer in F344 rats9 and ethylene oxide is one of the major metabolites of
      ethylene, it may be responsible for this type of cancer observed here.
      Unfortunately, no animals at intermediate dose levels were examined
      histologically. However, the OECD SIDS report2 and the National Institute for
      Public Health and the Environment (RIVM)10 state that mononuclear cell
      leukemia may occur in F344 rats at high background levels. Moreover, these
      incidences were within the historical incidence for control rats of this strain
      reported in NTP studies (Haseman et al., 1990)11.Therefore, chemically induced
      mononuclear cell leukemia in F344 rats are considered to be not relevant for
      carcinogenicity in humans.
3.2.2 Tumour-initiation-promotion study
      Ethylene was shown to have no initiating capacity in the following test. Sprague-
      Dawley male and female rats ( 3-5 days old) were exposed to 0 or 11,500 mg/m3
 8    Ethylene
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<pre>    of ethylene (saturated metabolism; purity not given) by inhalation for 8 h/day,
    5 days/week for 3 weeks.12 One week later, the rats were given 10 mg/kg bw
    Clophen A 50 (a mixture of polychlorinated biphenyls) by gavage twice a week
    for 8 weeks and livers were screened for foci with a deficiency in ATPase, a
    biomarker for initiating carcinogenic capacity. The number of ATPase-deficient
    foci in ethylene-exposed rats did not exceed the control values. In the same
    experiment, ethylene oxide, administered at 99 mg/m3 and 180 mg/m3 as a
    positive control, produced a significant increase in the incidence of ATPase-
    deficient foci in females.
3.3 Summary of the carcinogenicity studies
    Only two nested case-control studies were available. Leffingwell et al. (1983)5
    found a relation between gliomas of the brain and ethylene exposure, but in this
    study the number of cases was very limited, and workers had been additionally
    exposed to unknown levels of multiple chemicals leading to a large uncertaintly
    as indicated by the wide confidence intervals. Bond et al. (1986)6 found no
    relation with lung cancer exposure. Also in this study all workers were exposed
    to multiple agents and exposure levels were not known. Both human studies did
    not allow conclusions on the carcinogenicity of ethylene. In a 2-year study in
    F344 rats7 no increased incidence of neoplasms related to ethylene was observed.
    [The Committee observed mononuclear cell leukemia in this study but this was
    considered animal specific and not related to the chemical exposure.] An
    initiation-promotion study in rats did not indicate ethylene as an initiator of
    carcinogenicity.12
    Carcinogenicity                                                                  19
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<pre>0 Ethylene</pre>

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<pre> hapter 4
        Genotoxicity
        In vitro and in vivo genotoxicity data of ethylene are summarized below and are
        presented in a table in Annex F.
4.1     Gene mutation assays
4.1.1   In vitro
        Ethylene (99.5% pure) did not induce gene mutations in Salmonella typhimurium
        TA100 exposed for 7 hours to 0.5-20% ethylene in air with or without metabolic
        activation.13 The NTP showed that Salmonella typhimurium TA97, TA98, TA100
        and TA1535 did not induce gene mutations when exposed to ethylene vapour
        (concentration not specified) with or without metabolic activation (10-30%
        S9-mix).14 Exposure to 20,000 or 100,000 ppm ethylene vapour using
        Salmonella typhimurium TA 98, TA100, TA1535 and TA1537 did also not
        induce mutations, with and without metabolic activation, compared to the
        controls (only summary available).7
4.1.2   In vivo
        Walker et al. (2000)15 showed that repeated inhalation exposure to ethylene (up
        to 3,450 mg/m3) did not increase hprt mutant frequencies in splenic T cells of
        exposed rats and mice compared with control animals.
        Genotoxicity                                                                    21
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<pre>4.2   Cytogenetic assays
4.2.1 In vitro
      In a cytogenetic assay using CHO cells no increase in chromosomal aberrations
      was noted on exposure to ethylene up to 25 vol% in nitrogen (3 hours) with or
      without metabolic activation.2
4.2.2 In vivo
      Exposure of F344 rats and B6C3F1 mice to ethylene up to 3,450 mg/m3 for
      6 h/day, 5 days/week for 4 weeks gave no increased frequency of micronuclei in
      the bone marrow cells.16 Exposure of F344 rats to ethylene up to 11,473 mg/m3
      ethylene for 6 h/day, 5 days/week did not induce any increase in the frequencies
      of micronucleated peripheral blood reticulocytes, or any increase in the
      frequencies of micronucleated bone marrow polychromatic erythrocytes.17
4.3   Summary of the genotoxicity studies
      Ethylene did not induce gene mutations in Salmonella typhimurium strains or
      chromosomal aberrations in CHO cells with and without metabolic activation.
      No increased frequency in micronuclei was found in bone marrow from rat and
      mouse in vivo studies.
4.4   Role of ethylene oxide
      Only 5.6% of ethylene inhaled by humans is absorbed and becomes systemically
      available. Ethylene is also endogenously produced in mammals and humans.
      Both the ethylene absorbed and endogenously formed are partly metabolised to
      ethylene oxide1. Ethylene oxide binds to macromolecules, forming hydroxyethyl
      adducts with haemoglobin and DNA. Moreover ethylene oxide was found to be
      mutagenic in vitro and in vivo and carcinogenic in experimental animals
      (IARC,1994)1,18.
      Ethylene oxide is currently classified by the IARC as a known human carcinogen
      (Group 1). The general conclusion from IARC (1994)1,18 is that the actual tissue
      burden of ethylene oxide resulting from ethylene exposure was too low to lead to
      an increased tumour incidence. Data on ethylene oxide directly relevant to the
 2    Ethylene
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<pre>      formation of ethylene oxide from ethylene will be discussed below. [Further
      information on ethylene oxide and its mechanism of carcinogenicity is outside
      the scope of this report and can be found in the IARC monographs9,19.]
4.4.1 Quantification of ethylene oxide
      The ethylene oxide blood levels in ethylene-exposed mice and humans are not
      reported yet. Only in rats, exposed to ethylene concentrations of between 300
      and 1000 ppm, ethylene oxide-blood concentrations were quantified directly by
      gas chromatography with flame ionization detection.20
      The formation of ethylene oxide can be quantified indirectly by measurement of
      its hydroxyethyl adduct to the N-terminal valine of haemoglobin (N-(2-hydroxy-
      ethyl)valine (HOEtVal) (mostly investigated in humans) and its adduct at the
      N7-position of guanine in DNA, 7-hydroxyethylguanine (7-HEG; animals only).1
      At low exposure levels, both HOEtVal and 7-HEG increase linearly with
      exposure21, but the exact relationship between 7-HEG and HOEtVal formation
      may vary with length of exposure, interval since exposure, species and tissue or
      even with cell type, due to differences in formation, persistence, repair, and
      chemical depurination of 7-HEG and toxicokinetic effects on erythrocytes.15,22-27
4.4.2 Estimation of the ethylene oxide level upon ethylene inhalation
      In several studies ethylene oxide levels have been estimated measuring HOEtVal
      in humans exposed to ethylene. Non-smoking ethylene-exposed fruit store
      workers showed a statistically significant increase in HOEtVal levels in
      haemoglobin compared to non-smoking non ethylene-exposed referents. It was
      calculated that 1 ppm of ethylene in air would give rise to the same haemoglobin
      adduct level as 0.0345 mg/m3 (0.03 ppm) of ethylene oxide which would
      correspond to a conversion rate of approximately 3% (1-10%).28 A comparable
      value was found for alveolar retention of 2 ± 0.8% for ethylene by Filser et al.4
      They also determined that the metabolism of ethylene followed first-order
      kinetics up to 57.5 mg/m3 exposure and they expect at higher concentrations a
      saturation of ethylene metabolism similar to observations in rats1,4.
      Granath et al.29 performed two studies in Swedish workers in the plastics
      industry. in the first study, exposure to ethylene was estimated in 8 workers to be
      4 mg/m3 (95% CI 0.5-7.5) for high exposure using relevant (1988-1990)
      measurements available from the plant’s hygienic surveillance programme. The
      Genotoxicity                                                                        23
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<pre>      mean HOEtVal adduct level measured was 101 pmol/g (range 56-200). The mean
      HOEtVal level in the control group (n=9) was 15 pmol/g (range 9-32); the mean
      background levels in human nonsmokers range from 13 to 60 pmol/g Hb (Table
      8 in Csanady18). The fraction of ethylene metabolised to ethylene oxide for 7
      non-smokers was estimated to amount to 0.5% (95% CI 0.31-0.83).29 For
      comparison, smoking contributes between 7 and 11 pmol/g Hb of HOEt Val per
      cigarette smoked per day.30
          In the second study, airborne exposure to ethylene was monitored in 4 non-
      smoking men during 5 consecutive workdays and blood samples were collected
      at 3 times (5 days apart) for determination of HOEtVal. The average exposure
      level was 4.36 mg/m3 and from the measured HOEtVal levels it was estimated
      that on average 0.47 ± 0.09% of the ethylene was converted to ethylene oxide.
      Comparing the abovementioned HOEtVal adduct level for ethylene (minus
      background) of 85 pmol/g Hb after exposure for 40 h per week at 4 mg/m3 (3.6
      ppm) and the adduct level of 2,400 pmol/g Hb after exposure to ethylene oxide
      for 40 h per week at 1.8 mg/m3 (1 ppm), suggests that the adduct levels induced
      by exposure to ethylene is about 100 times lower than those induced by ethylene
      oxide at the same molar exposure level, suggesting that approximately 0.5 % of
      the ethylene becomes bioavailable as ethylene oxide.29
      Csanady et al.18 developed a physiological toxicokinetic model to describe the
      uptake and elimination of ethylene, and the endogenous production of ethylene/
      ethylene oxide in rats, mice and humans. The predictions for humans reflected
      actually measured haemoglobin adducts. The ethylene oxide concentration in
      blood from endogenous ethylene was predicted to be 0.04 nmol/L, assuming the
      formed ethylene oxide is 100% bioavailable. Exposure to about 0.063 mg/m3
      (0.055 ppm) ethylene (8 h/day, 5 days/week) leads according to the model to an
      average ethylene concentration in blood of about twice that of the endogenous
      value. Li et al. (2011)14,31 determined kinetic parameters of ethylene and
      ethylene oxide in vitro in subcellular liver fractions of mice, rats and humans, for
      comparison with in vivo kinetic data. The results showed agreement between in
      vitro and in vivo data to a certain degree and may be used to improve the
      toxicokinetic model by Csanady et al.18
4.4.3 Adduct formation
      The presence of 7-HEG itself in DNA does not induce mutagenicity, but labile
      alkylated DNA adducts, such as 7-HEG and 3-hydroxyethyladenine, may be
      depurinated by base excision repair and form mutagenic apurinic/apyrimidynic
 4    Ethylene
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<pre>      sites.22,32 However, Rusyn et al.32 found no increase in the number of aldehydic
      DNA lesions, an indicator of apurinic/apyrimidynic sites, in brain, liver or spleen
      of rats exposed to ethylene (up to 3,450 mg/m3) or ethylene oxide (115 mg/m3)
      for 1,3 or 20 days by inhalation. The existence of labile DNA adducts was
      confirmed for ethylene oxide exposure by an increase in heat-induced AP sites
      compared to controls. Several genes for base excision DNA repair were not
      statistically significantly upregulated (or even downregulated) in the liver and
      target organs brain and spleen – only polymerase β and AP endonuclease in the
      brain were significantly upregulated – on exposure to ethylene (3,450 mg/m3),
      while for ethylene oxide (115 mg/m3) polymerase β was significantly
      upregulated in the spleen as well as a number of genes in the liver. This suggests
      that DNA damage induced by ethylene or ethylene oxide exposure is repaired
      without accumulation of AP sites and is associated with biologically
      insignificant changes in base excision DNA repair gene expression in target
      organs. The authors concluded that accumulation of AP sites is not likely to be a
      primary mechanism for mutagenicity and carcinogenicity of ethylene oxide.32
          In rats, ethylene metabolism follows first-order kinetics up to about 92
      mg/m3 and a saturation of ethylene metabolism occurs at about 1,150
      mg/m3.1,4,18,33,34 Rusyn et al.32, Bolt et al.35 and Walker et al.15 explained the lack
      of mutagenicity/carcinogenicity of ethylene in rodents by the fact that not
      sufficient ethylene oxide can be formed due to saturation of metabolic activation
      at concentrations >1,150 mg/m3. Moreover, Walker et al.15 showed that repeated
      inhalation exposure to ethylene (up to 3,450 mg/m3) did not increase hprt mutant
      frequencies in splenic T cells of exposed rats and mice compared with control
      animals, while exposure to 360 mg/m3 ethylene oxide for 4 weeks did induce a
      5- to 6-fold increase compared to control.
4.4.4 Conclusion regarding the role of ethylene oxide
      Ethylene can be converted to ethylene oxide which gives rise to adduct
      formation. However, it seems likely that not enough ethylene oxide is formed to
      induce carcinogenicity in view of the following:
      • no carcinogenic effects were found in rats after exposure up to 3,450 mg/m3
      • the absence of tumour initiating capacity in rats after exposure to ethylene at
          a 100 times higher concentration than an effective concentration of ethylene
          oxide
      • exposure of animals to ethylene concentrations of a factor 15-30 higher than
          ethylene oxide concentrations showed a smaller amount of adduct formation
      Genotoxicity                                                                            25
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<pre>  •  the amount of ethylene oxide formed as estimated from HOEtVal
     concentration in humans is only 0.5-3% of ethylene exposure and the
     measured adduct levels induced by ethylene are about 100 times lower than
     the measured adduct level of ethylene oxide at equimolar exposure.
6 Ethylene
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No reliable data on the carcinogenicity in humans were available. In a 2-year
        study in rats no increased incidence of neoplasms related to ethylene was
        observed.
            Ethylene did not induce C-G gene mutations in Salmonella typhimurium
        strains or chromosomal aberrations in CHO cells with and without metabolic
        activation. No increased frequency in micronuclei was found in bone marrow
        from rat and mouse in vivo studies.
            No evidence is available to suggest that ethylene is genotoxic and/or
        carcinogenic by inhalation. Less than 10% of ethylene is taken up by the lungs
        and converted to ethylene oxide, a known genotoxic carcinogen. Although
        ethylene oxide is genotoxic and carcinogenic, the amount of ethylene oxide
        formed seems to be not sufficient to induce genotoxic or carcinogenic effects The
        potential damage to DNA induced by the ethylene oxide formed, seems to be
        adequately repaired by the mechanism present for the endogenously produced
        ethylene/ethylene oxide in rats up to 3450 mg/m3. In humans, the level of
        ethylene oxide formed was estimated from HOEtVal adducts to be 3 or 0.5% of
        ethylene exposure after exposure for 8 h/day, 5 days/week to 0.063 mg/m3 or
        4 mg/m3 of ethylene, respectively.
        Classification                                                                    27
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<pre>5.2 Recommendation for classification
    The Committee is of the opinion that the available data are insufficient to
    evaluate the carcinogenic properties of ethylene (category 3).*
    According to the classification system of the Health Council (see Annex G).
 8  Ethylene
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<pre>  References
  Ethylene. IARC Monogr Eval Carcinog Risks Hum 1994; 60: 45-71.
  Ethylene. OECD SIDS publication. http://webnet.oecd.org/HPV/UI/handler.axd?id=e5d777a4-516f-
  4fdb-a76d-4ffec89e3aa3 (accessed August 21, 2013).
  Alberta Environment. Assessment report on ethylene for developing ambient air quality objectives.
  2003: Pub. No: T/691. Science and Standards branche, Alberta Environment, Edmonton, Alberta.
  Filser J, Denk B, Tornqvist M, et al. Pharmacokinetics of ethylene in man; body burden with ethylene
  oxide and hydroxylethylation of hemoglobin due to endogenous and environmental ethylene. Arch
  Toxicol 1992; 66(3): 157-163.
  Leffingwell S, Waxweiler R, Alexander V, et al. Case-control study of gliomas of the brain among
  workers employed by a Texas city, Texas chemical plant. Neuroepidemiology 1983; 2(3-4): 179-195.
  Bond G, Flores G, Shellenberger R, et al. Nested case-control study of lung cancer among chemical
  workers. Am J Epidemiol 1986; 124(1): 53-66.
  Hamm TE jr, Guest D DJ. Chronic toxicity and oncogenicity bioassay of inhaled ethylene in Fisher-
  344 rats. Fund Appl Toxicol 1984; 4(3 Pt 1): 473-478.
  Rostron C. Ethylene metabolism and carcinogenicity. Food Chem Toxic 1985; 24: 70.
  Ethylene oxide. IARC Monogr Eval Carcinog Risks Hum 1994; 60: 73-159.
0 Wolterink G, Turkstra G, Muller A, et al. Factsheets for the (eco)toxicological risk assessment
  strategy of the National Institute for Public Health and the Environment, Part V. 2005: 601516013.
1 Haseman JK, Clark AM. Carcinogenicity results for 114 laboratory animal studies used to assess the
  predictivity of four in vitro genetic toxicity assays for rodent carcinogenicity. Environ Mol Mutagen
  1990; 16 Suppl 18: 15-31.
  References                                                                                            29
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<pre>2 Denk B, Filser J, Oesterle D, Deml E, Greim H. Inhaled ethylene oxide induces preneoplastic foci in
  rat liver. J Cancer Res Clin Oncol 1988; 114(1): 35-38.
3 Victorin K, Stahlberg M. A method for studying the mutagenicity of some gaseous compounds in
  Salmonella typhimurium. Environ mol Mutag 1988; 11(1): 65-79.
4 Salmonella test (ethylene). National Toxicology Program USEPA. http://tools.niehs.nih.gov/cebs3/
  ntpViews/?studyNumber=A93805 (accessed 20-08-2013).
5 Walker V, Wu KY, Upton PB, et al. Biomarkers of exposure and effect as indicators of potential
  carcinogenic risk arising from in vivo metabolism of ethylene to ethylene oxide. Carcinogenesis
  2000; 21(9): 1661-1669.
6 Vergnes J, Pritts I. Effects of ethylene on micronucleus formation in the bone marrow of rats and
  mice following four weeks of inhalation exposure. Mutat Res 1994; 324(3): 87-91.
7 ECHA. REACH Dossier on Ethylene. 2010: (list number 200-815-3)http://echa.europa.eu/
  information-on-chemicals/registered-substances (accessed 20-08-2013).
8 Csanady G, Denk B, Putz C, et al. A physiological toxicokinetic model for exogenous and
  endogenous ethylene and ethylene oxide in rat, mouse, and human: formation of 2-hydroxyethyl
  adducts with hemoglobin and DNA. Toxicol Appl Pharmacol 2000; 165(1): 1-26.
9 Ethylene oxide. IARC Monograph Eval Carcinog Risks Hum 2012; 100F: 379-400.
0 Fennell TR, Snyder RW, Parkinson C, Murphy J, James RA. The effect of ethylene exposure on
  ethylene oxide in blood and on hepatic cytochrome p450 in Fischer rats. Toxicol Sci 2004; 81(1):
  7-13.
1 Sittert NJ van, Boogaard PJ, Natarajan AT, Tates AD, Ehrenberg LG, Tornqvist MA. Formation of
  DNA adducts and induction of mutagenic effects in rats following 4 weeks inhalation exposure to
  ethylene oxide as a basis for cancer risk assessment. Mutat Res 2000; 447(1): 27-48.
2 Segerbäck D. Alkylation of DNA and haemoglobin in the mouse following exposure to ethene and
  ethene oxide. Chem Biol Interactions 1983; 45(2): 139-151.
3 Walker V, Fennell TR, Upton PB, et al. Molecular dosimetry of ethylene oxide: formation and
  persistence of 7-(2-hydroxyethyl)guanine in DNA following repeated exposures of rats and mice.
  Cancer Res 1992; 52(16): 4328-4334.
4 Walker V, MacNeela JP, Swenberg JA, et al. Molecular dosimetry of ethylene oxide: formation and
  persistence of N-(2-hydroxyethyl)valine in hemoglobin following repeated exposures of rats and
  mice. Cancer Res 1992; 52(16): 4320-4327.
5 Walker V, Fennell T, Upton P, et al. Molecular dosimetry of DNA and hemoglobin adducts in mice
  and rats exposed to ethylene oxide. Env Health Perspect 1993; 99: 11-17.
6 Pauwels W, Veulemans H. Comparison of ethylene, propylene and styrene 7,8-oxide in vitro adduct
  formation on N-terminal valine in human haemoglobin and on N-7-guanine in human DNA. Mutat
  Res 1998; 418(1): 21-33.
7 Eide I, Hagemann R, Zahlsen K, et al. Uptake, distribution and formation of haemoglobin and DNA
  adducts after inhalation of C2-C8 1-alkene (olefins) in the rat. Carcinogenesis 1995; 16(7):
  1603-1609.
0 Ethylene
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<pre>8 Törnqvist M, Almberg JBE, et al. Ethylene oxide doses in ethene-exposed fruit store workers. Scand
  J Work Environ Health 1989; 15(6): 436-438.
9 Granath F, Rohlen O, Goransson C, et al. Relationship between dose in vivo of ethylene oxide and
  exposure to ethene studied in exposed workers. Hum Exp Toxicol 1996; 15(10): 826-833.
0 Boogaard PJ. Use of haemoglobin adducts in exposure monitoring and risk assessment. J Chromatogr
  B Analyt Technol Biomed Life Sci 2002; 778(1-2): 309-322.
1 Li Q, Csanady GA, Kessler W, Klein D, Pankratz H, Putz C et al. Kinetics of ethylene and ethylene
  oxide in subcellular fractions of lungs and livers of male B6C3F1 mice and male fischer 344 rats and
  of human livers. Toxicol Sci 2011; 123(2): 384-398.
2 Rusyn I, Asakura S, Li Y, et al. Effects of ethylene oxide and ethylene inhalation on DNA adducts,
  apurinic/apyrimidinic sites and expression of base excision DNA repair genes in rat brain, spleen, and
  liver. DNA Repair 2005; 4(10): 1099-1110.
3 Bolt HM, Filser JG, Stormer F. Inhalation pharmacokinetics based on gas uptake studies. V.
  Comparative pharmacokinetics of ethylene and 1,3-butadiene in rats. Arch Toxicol 1984; 55(4):
  213-218.
4 Shen J, Kessler W, Denk B, Filser JG. Metabolism and endogenous production of ethylene in rat and
  man. Arch Toxicol Suppl 1989; 13: 237-239.
5 Bolt H. The carcinogenic risk of ethene (ethylene). Toxicol Pathol 1998; 26(3): 454-456.
6 Landry M, Fuerst R. Gas ecology of bacteria. Dev Ind Microbiol 1968; 9: 370-381.
7 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: publication no. A10/07E.
  References                                                                                             31
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<pre>2 Ethylene</pre>

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<pre>A Request for advice
B The Committee
C The Submission letter
D Comments on the public review draft
E IARC Monograph
F Genotoxicity data
G Carcinogenic classification of substances by the Committee
  Annexes
                                                             33
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<pre>4 Ethylene</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        35
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
6 Ethylene
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Quality of Life, Zeist, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms. M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemical NV, Terneuzen (until April 1, 2013);
        Exponent, Menlo Park, United States (from August 15, 2013)
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  G.B. van der Voet, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              37
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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
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
8 Ethylene
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<pre>nnex C
     The submission letter
     Subject            : Submission of the advisory report Ethylene
     Your Reference     : DGV/MBO/U-932342
     Our reference      : U-7909/BV/fs/246-X18
     Enclosed           :1
     Date               : October 18, 2013
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     Ethylene.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
     The advisory report was prepared by the Subcommittee on the Classification of
     Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety (DECOS). The advisory report
     The submission letter                                                          39
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<pre>  has been assessed by the Health Council’s Standing Committee on Health and
  the Environment.
  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor W.A. van Gool,
  President
0 Ethylene
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in June 2013 for public review. The
     following organisations and persons have commented on the draft document:
     •   National Institute for Occupational Safety and Health (NIOSH), Cincinncati,
         USA
     •   Lower Olefins Sector Group (LOSG), European Chemical Industry Council
         (CEFIC), Brussels, Belgium
     •   Prof. D. Coggon, University of Southampton, Southampton, UK.
     Comments on the public review draft                                             41
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<pre>2 Ethylene</pre>

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<pre>nnex E
     IARC Monograph
     D.1 Volume 19, 1979 (Excerpt from Ethylene and polyethylene,
     pp. 157-161)
     Summary of Data Reported and Evaluation*.
     Experimental data
     No data on the carcinogenicity or mutagenicity of ethylene were available to the
     Working Group.
     Human data
     The massive production of ethylene (and polyethylene) and the general use of the
     polymer over the past several decades indicate that exposure of workers and the
     general population is common. No epidemiological studies relating to the
     carcinogenicity of ethylene were available to the Working Group
     only conclusions with regard to ethylene – not polyethylene – are copied here
     IARC Monograph                                                                   43
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<pre>  Evaluation
  No information was available to the Working Group for evaluating the possible
  carcinogenic effects of ethylene in humans. Experimental carcinogenicity studies
  on ethylene are recommended.
  D.2 Volume 60, 1994 (Excerpt from Ethylene, pp. 45-71)
  Summary of Data Reported and Evaluation
  Exposure data
  Ethylene, the petrochemical manufactured in largest volume worldwide, is
  produced primarily by the steam-cracking of hydrocarbons. It is used mainly as a
  chemical intermediate in the production of polymers and other industrial
  chemicals; small amounts are used to promote the ripening of fruits and
  vegetables. Ethylene is introduced into the environment from both natural and
  man-made sources, including emissions from vegetation, as a product of burning
  of organic material (such as cigarettes) and of incomplete combustion of fossil
  fuels, and in its production and use. Few data are available on levels of
  occupational exposure.
  Human carcinogenicity data
  The available data did not allow the Working Group to evaluate the
  carcinogenicity of ethylene to humans.
  Animal carcinogenicity data
  Ethylene was tested for carcinogenicity in one experiment in rats exposed by
  inhalation. No increase in tumour incidence was reported.
  Other relevant data
  Endogenous but unidentified sources of ethylene exist in man and experimental
  animals. Steady-state alveolar retention of ethylene is less than 10% in both man
  and rat. The biological half-time of ethylene in humans is about 0.65 h. In rats
  and man, the processes of uptake, exhalation and metabolism are described by
  first-order kinetics, at least up to 50 ppm; in rats, ethylene metabolism follows
4 Ethylene
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<pre>first-order kinetics up to about 80 ppm. The maximal rate of metabolism in rats is
reached at about 1000 ppm, the initial metabolite being ethylene oxide;
hydroxyethyl cysteine is a urinary metabolite in mice. Because ethylene
metabolism can be saturated, the maximal possible concentration of ethylene
oxide in rat tissues is about 0.34 nmol/ml (15 ng/g bw).
Exposure to ethylene results in the formation of adducts with proteins. In
nonsmokers, the background concentrations of the hydroxyethyl valine adduct of
haemoglobin were 12-188 pmol/g haemoglobin. Environmental ethylene
contributes to these concentrations; the endogenous contribution was calculated
to be about 12 pmol/g haemoglobin in nonsmoking control subjects. The
increment of N-terminal hydroxyethyl valine formed during a 40-h work week
has been estimated as 100-120 pmol/g haemoglobin per part per million of
ethylene. Tobacco smoke contributes to formation of this adduct: smoking 10-30
cigarettes/day was reported to result in 600-690 pmol/g haemoglobin.
Background concentrations of 7-hydroxyethyl guanine were 8.5 nmol/g DNA in
one study of human peripheral lymphocytes and ranged from 2 to 6 nmol/g DNA
in various tissues of rats and mice. A single exposure of mice to 50 ppm ethylene
for 1 h resulted in 0.1-0.2 nmol/g DNA.
No data were available on the genetic and related effects of ethylene in exposed
humans. In a single study, no micronuclei were induced in bone-marrow cells of
mice and rats exposed in vivo. Gene mutation was not induced in Salmonella
typhimurium. Although the genetic effects of ethylene have not been well
studied, its metabolite, ethylene oxide, is genotoxic in a broad range of assays.
Evaluation
There is inadequate evidence in humans for the carcinogenicity of ethylene.
There is inadequate evidence in experimental animals for the carcinogenicity of
ethylene.
Overall evaluation
Ethylene is not classifiable as to its carcinogenicity to humans (Group 3).
IARC Monograph                                                                     45
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<pre>6 Ethylene</pre>

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<pre> nnex          F
               Genotoxicity data
               Genotoxic as well as possibly related DNA effects of ethylene are shown in this
               Table.
 est system                           Dosea (LED or HID)                                    Resultb      Ref.
                                      atmospheric          dose relative to body weigth     exogenous
                                      concentration        animal/human                     metabolic
                                                                                            activation
                                                                                            without with
 almonella typhimurium TA100, reverse 20 vol% (225,000                                      –          – 13
mutation                              mg/m3)
 almonella typhimurium TA97, TA98,    not specified                                         –          – 14
 A100, TA1535, reverse mutation
 almonella typhimurium TA98, TA100,   115,000 mg/m3                                         –          – 7
 A1535, TA1537, reverse mutation
 scherichia coli, forward mutation    not specified                                         –            36
 hinese Hamster Ovary cells,          25 vol% in nitrogenc                                  –          – 2
 hromosome aberrations, in vitro      (10 mM solution)
Micronucleus test, mouse bone marrow  3,450 mg/m3          1,490 mg/kg bw/d                 –            16
 ells, in vivo                                             (inhal. 6 h, 5d/wk, 4 wks, resp.
                                                           volume 1.8 l/h, bw 25 g)
Micronucleus test, rat bone marrow    3,450 mg/m3          776 mg/kg bw/d                   –            16
 ells, in vivo                                             (inhal. 6 h, 5d/wk, 4 wks, resp.
                                                           volume 6 l/h, bw 160 g)
               Genotoxicity data                                                                              47
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<pre>DNA adduct formation
  inding (covalent) to mouse DNA in        57.5 mg/m3                3.96 mg/kg bw/d                    +                22
 ivo                                                                 (inhal. 8 h, resp. volume 1.8 l/h,
                                                                     bw 25 g)
 -alkylguanine formation in rat in vivo 345 mg/m3                    blood: 0.3 µmol/kg (12 h/d, 3 d) +                  27
 -hydroxyethylguanine formation in rat 3,450 mg/m3                   310 mg/kg bw/d                     +                32
n vivo                                                               (inhal. 6 h, 20 d, resp volume 6
                                                                     l/h, bw 400 g
     LED = lowest effective dose; HID = highest ineffective dose; in vitro tests: µg/ml; in vivo tests: mg/kg bw/d; doses were
     calculated by the author of this report as it was not clear how values in the IARC were calculated
     + = positive; – = negative
     due to the explosive properties of ethylene in air, nitrogen was used to be able to test a high enough concentration; with
     nitrogen only 3 hour exposure was possible
 8            Ethylene
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<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory      Judgement of the committee (GRGHS)                                    Comparable with EU Category
                                                                                    67/548/EEC         EC No 1272/2008
                                                                                    (before            (as from
                                                                                    12/16/2008         12/16/2008
A             The compound is known to be carcinogenic to humans.                   1                  1A
              • It acts by a stochastic genotoxic mechanism.
              • It acts by a non-stochastic genotoxic mechanism.
              • It acts by a non-genotoxic mechanism.
              • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
B             The compound is presumed to be as carcinogenic to humans.             2                  1B
              • It acts by a stochastic genotoxic mechanism.
              • It acts by a non-stochastic genotoxic mechanism.
              • It acts by a non-genotoxic mechanism.
              • Its potential genotoxicity has been insufficiently investigated.
                 Therefore, it is unclear whether the compound is genotoxic.
              The compound is suspected to be carcinogenic to man.                  3                  2
3)            The available data are insufficient to evaluate the carcinogenic      Not applicable     Not applicable
              properties of the compound.
4)            The compound is probably not carcinogenic to man.                     Not applicable     Not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.37
             Carcinogenic classification of substances by the Committee                                                49
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<pre>0 Ethylene</pre>

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