<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>Silicon carbide
     Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Silicon carbide
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7475/BvdV/fs/246-S17
Bijlagen               :1
Datum                  : 7 december 2012
Geachte minister,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige bloot-
stelling aan siliciumcarbide.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende
stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het
gaat om stoffen waaraan mensen tijdens de beroepsmatige uitoefening kunnen
worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie
Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS), de Sub-
commissie Classificatie van carcinogene stoffen. Het advies is getoetst door de
Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
      De commissie heeft in haar advies een aparte classificatie aanbevolen voor
vezelvormig siliciumcarbide (1A) en granulair siliciumcarbide (categorie 3). De
commissie maakt zich zorgen over de vraag of het commerciële granulaire s
iliciumcarbide voldoende vrij is van vezelvormig siliciumcarbide. Daarom
adviseert de commissie, in aanvulling op de voorgestelde classificaties, om het
kankerrisico te kwantificeren en om veilige blootstellingwaarden vast te stellen.
Bezoekadres                                                        Postadres
Parnassusplein 5                                                   Postbus 16052
2 5 11 V X D e n          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>Onderwerp              : aanbieding advies Silicon carbide
Ons kenmerk            : U-7475/BvdV/fs/246-S17
Page                   :2
Datum                  : 7 december 2012
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris
van Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en
Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                    Postadres
Parnassusplein 5                                               Postbus 16052
2 5 11 V X D e n          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>Silicon carbide
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances
of the Dutch Expert Committee on Occupational Safety (DECOS),
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2012/29, The Hague, December 7, 2012
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, 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. Silicon carbide. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/29.
all rights reserved
ISBN: 978-90-5549-922-9
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<pre>   Contents
   Samenvatting 7
   Executive summary 8
   Scope 9
.1 Background 9
.2 Committee and procedures 9
.3 Data 10
   General information 11
.1 Identity and physicochemical properties 11
.2 IARC classification 13
   Carcinogenicity studies 14
.1 Observations in humans 14
.2 Carcinogenicity studies in animals 23
   Mode of action 36
.1 Genotoxic mode of action 36
.2 Carcinogenic mechanism and comparison with asbestos 38
.3 Summary of the mechanistic data 41
   Contents                                               5
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<pre>    Classification 42
 .1 Evaluation of data on carcinogenicity and genotoxicity 42
 .2 Recommendation for classification 44
    References 45
    Annexes 48
A   Request for advice 49
B   The Committee 51
C   The submission letter 53
D   Comments on the public review draft 55
E   Carcinogenic classification of substances by the Committee 56
    Contents                                                      6
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens 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 deze commissie siliciumcar-
bide onder de loep. Siliciumcarbide is een stof die onder andere wordt gebruikt
als synthetisch slijpmiddel en in brandsteen-, metaalgieterij-, keramiek- en vul-
middelindustrieën.
    Op basis van de beschikbare gegevens concludeert de commissie dat silici-
umcarbide in vezelvorm (vezels, ‘whiskers’) kanker kan veroorzaken volgens
een niet-stochastisch genotoxisch werkingsmechanisme en geclassificeerd moet
worden als ‘kankerverwekkend voor de mens’ (in categorie 1A). De gegevens
over de granulaire vorm van siliciumcarbide zijn onvoldoende om de carcino-
gene eigenschappen hiervan te kunnen klassificeren (categorie 3).*
    De commissie maakt zich zorgen over de vraag of het commerciële granu-
laire siliciumcarbide voldoende vrij is van vezelvormig siliciumcarbide.
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage E).
Samenvatting                                                                      7
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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 Safety of the Health
Council, hereafter called the Committee. In this report, the Committee evaluated
silicon carbide. Silicon carbide is, among others, used as an artificial abrasive,
and also in the refractory, foundry, ceramic and filler industries.
     Based on the available information, the Committee concludes that fibrous
silicon carbide (fibers, whiskers) may cause cancer according to a non-stochastic
mechanism and should be classified as ‘carcinogenic to humans’ (in category
1A). The data on the non-fibrous form of silicon carbide are considered
insufficient to classify the carcinogenic properties of this substance (category 3).*
     The Committee is concerned about the question whether the commercial
non-fibrous silicon carbide is sufficiently free of fibrous silicon carbide.
According to the classification system of the Health Council (see Annex E).
Executive summary                                                                     8
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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 a classification are expressed in the form of
        standard sentences (see Annex E).
        This report contains the evaluation of the carcinogenicity of silicon carbide.
1.2     Committee and procedures
        The evaluation is performed by the Subcommittee on the Classification of
        Carcinogenic Substances of the Dutch Expert Committee on Occupational Safety
        (DECOS) 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.
        Scope                                                                             9
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<pre>    In July 2011, the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft 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 generally based on
    scientific data, which are publicly available. The starting points of the
    committees’ reports are, where 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 relevant in assessing the
    carcinogenicity and genotoxicity of the substance in question. In the case of
    silicium carbide, an IARC-monograph was not available.
         The relevant data were obtained from the online databases Toxline, Medline
    and Chemical Abstracts, using carcinogenic, cancer, carcinogenicity or
    mutagenic, mutagenicity, chromosome and CAS no. 409-21-2 as key words. The
    last updated online search was performed in August 2012.
    Scope                                                                                10
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<pre> hapter 2
        General information
2.1     Identity and physicochemical properties
        The data have been retrieved from the European Substance Information System
        (ESIS)*, an IUCLID chemical data sheet, which can be accessed via the same
        website, and the Hazardous Substances Data Bank (HSDB)**.
        Chemical name             : Silicon carbide
        CAS registry number       : 409-21-2
        EINECS number             : 206-991-8
        Synonyms                  : Silicon monocarbide, carborundum, carbofrax m, carbon silicide
        Appearance                : Exceedingly hard, green to bluish-black, iridescent, sharp crystals
        Use                       : Abrasive for cutting and grinding metals, grinding wheels, refractory in
                                    non-ferrous metallurgy, ceramic industry and boiler furnaces, composite
                                    tubes for steam reforming operations. Fibrous form is used in filament-
                                    wound structures and heat-resistant, high-strength composites.
        Chemical formula          : SiC
        Molecular weight          : 40.07
        Boiling point             : > 2300 ˚C at 1013 hPa
        Melting point             : -
        Vapour pressure           : -
        Vapour density (air = 1)  : -
        Solubility                : Silicon carbide is not soluble in water or other common solvents
        ESIS can be accessed via the ECB-site: http://esis.jrc.ec.europa.eu/ (accessed September 9, 2012).
 *      HSDB; http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (accessed September 9, 2012).
        General information                                                                                  11
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<pre>Conversion factor      : 1 mg/m3 = 0,5990 × ppm at 20o C
EU Classification      : Not classified
(100% solution)
In addition, silicon carbide (SiC) appears in several crystal modifications based
on how the different silicon and carbon layers are stacked.1,2 The following
definitions will be used in this report:
• “Non-fibrous” silicon carbide is an amorphous and/or particulate material.
    This term is often used alongside with other terms, such as silicon carbide
    dust (an average particle size 1-20 µm), silicon carbide particles, or granular
    silicon carbide (particle size not specified in the available literature).
    Exposure to silicon carbide dust can occur at enterprises manufacturing or
    using synthetic abrasive materials. Despite being called non-fibrous, long
    fibrous particles with length > 100 µm have been shown also to occur in this
    type of material.
• Silicon carbide fibres, sometimes also addressed as siliconcarbide continuous
    fibres, or silicon carbide ceramic fibres, which is often a polycrystalline
    material, and mostly generated during silicon carbide crystal production.
    Exposure to silicon carbide fibres may also occur when silicon carbide
    particles are produced. The size and diameter of these fibres varies in quite
    broad ranges, but can fulfill the definition of WHO fibres (see below).
• Silicon carbide whiskers, which are single crystal structures possessing a fine
    fibrous morphology similar to that of amphibole asbestos. They are
    approximately cylindrical in shape with an aspect ratio equal to or greater
    than 3 and a diameter less than 5 µm. Silicon carbide whiskers were
    developed as a durable asbestos substitute and are used for ceramic seals,
    sandblast nozzles, and structural materials for use at high temperatures.
    Workers may be exposed to silicon carbide whiskers during manufacture of
    the whiskers, during production of the composite material, or as a result of
    machining and finishing a component made of the composite material. The
    silicon carbide whiskers can also occur as a byproduct of silicon carbide
    production for the abrasive industry.
    Several types of silicon carbide whiskers exist; the following well-
    characterized types are described in this report: SiCW 1, SiCW 2 and
    SiCW 3. The typical parameters of these whiskers are presented below:
General information                                                                 12
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<pre>    Type                 Fibre              Percentage of fibres Percentage of fibres
                         total/µg           >5.0 µm length       <0.3 µm diameter,
                                                                 >8.0 µm length
    SiCW 1               7.6 x l06          31.0                 3.8
    SiCW 2               1.61 x 105         93.7                 6.9
    SiCW 3               1.05 x 107         30.8                 10.8
    Furthermore, the term “WHO fibres” is used in this report. WHO fibres refer to
    particles longer than 5 µm with a width of less than 3 µm and an aspect ratio of
    more than 3.1
2.2 IARC classification
    Silicon carbide has not been evaluated by IARC.
    General information                                                               13
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<pre> hapter 3
        Carcinogenicity studies
3.1     Observations in humans
3.1.1   Cohort studies
        Infante-Rivard et al.3 published a retrospective cohort study among 585 Québec
        silicon carbide production workers who had worked at any time between 1950
        and 1980 at the three Québec silicon production plants. The vital status of these
        workers was ascertained up to December 31, 1989. Data collected during a
        hygiene survey in two of the three plants were also used to assess the relation
        between exposure and mortality. The workers were classified according to 29 job
        titles grouped under the main production process areas. Exposure data were
        collected on respirable quartz, cristobalite (both substances being a form of SiO2
        which is considered to be one of the major contaminants in silicon carbide
        production industry, forming islets at the surface of silicon carbide crystals), and
        polycyclic aromatic hydrocarbons, but as this information was not available for
        all jobs, it was decided to use only total dust concentrations. Estimates were
        based on 121 dust samples. Total dust cumulative exposure was defined as a sum
        of the products of exposure concentration and duration for each job held, and was
        expressed as mg/m3-years. A baseline category of less than 105 mg/m3-years
        corresponding to the 50th percentile of the distribution was defined, and the
        division between the two more highly exposed groups corresponded to 75th
        percentile.
        Carcinogenicity studies                                                              14
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<pre>    Standardized mortality ratios (SMR) and 95% CI were estimated using the
age- and calendar-specific death rates for Québec males between 1931 and 1985.
The upper age limit for calculation of person-years and observed deaths was 85
years. Mean age at hire in the cohort was 29.9 (standard deviation (SD) = 14.2).
Mean duration of follow-up was 22.9 years (SD = 9.3). A total of 13,394 person-
years were accumulated. SMRs for all malignant diseases were not increased,
whereas they were increased for stomach cancer (7 observed versus 3.19
expected; SMR = 2.18; 95% CI 0.88-4.51; not significant), and lung cancer
(24 observed versus 14.14 expected; SMR = 1.69; 95% CI 1.09-2.52; significant
p < 0.05). Among the 24 workers with lung cancer, 21 were smokers at the time
of the interview, and 3 were ex-smokers. For all workers, smoking status was
unknown for 3 subjects; 374 were reported smokers, 118 were ex-smokers and
80 were non-smokers. Controlling for smoking, the risk of lung cancers
increased with the level of exposure (rate ratio (RR) = 1.48 for category 2
[cumulative exposure level 105-275 mg/m3]) in comparison with baseline, and
1.67 for category 3 (cumulative exposure level above 275 mg/m3). After a
15-year latency period, although somewhat lower, rate ratios also increased with
exposure.
    Although the results of this study seem to support the hypothesis of an
increased risk for lung cancer among production workers in the silicon carbide
industry, the fact that only total dust exposure was assessed limits the
interpretation of the results. Furthermore, confounding by smoking is of concern;
however, the authors found only very small difference: 86% of ever-smokers in
the cohort versus 82% in a similar age cohort of men in the comparison
population. Assuming that smokers were 20 times more likely to die from lung
cancer than non-smokers, the lung cancer SMR due to smoking was calculated to
be 1.05, giving a smoking-adjusted SMR of 1.61 (95% CI 1.04-2.41).
    In the Québec plants the concentrations of quartz and cristobalite measured
were much below the ones considered to entail health risks; quartz
concentrations ranged from 0 to 113 µg/m3 and cristobalite concentrations from
0 to 36 µg/m3. The authors also could not measure asbestos fibres neither in this
industry nor in the lungs of deceased workers. Polycyclic aromatic hydrocarbons
could only be detected at the head of one of the furnaces, but their concentration
away from the head of the furnace and in the ambient air rapidly decreased.
    Romundstad et al. (2001)4 studied cancer incidence among 2,620 men
employed for more than 6 months in three Norwegian silicon carbide smelters.
The company records included 2,720 men; 40 had died before the start of the
follow-up and 60 (3%) were not traceable. Follow-up of cancer incidence was
performed from January 1, 1953, and continued until December 31, 1996, or
Carcinogenicity studies                                                            15
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<pre>until the date of death or emigration, giving 59,251 person-years of follow-up.
Smoking habits were determined for 80% of the cohort, 26% of whom were
never smokers, 63% of whom were current smokers, and 11% of whom were
former smokers. For this time period, The Cancer Registry of Norway offers
complete coverage of the population for all site and types of cancer except basal
cell carcinoma of the skin.
     Estimation of exposure was based mainly on industrial hygiene
measurements and on descriptions of changes in the process technology and
work practices over time. To categorize the dust, silicon carbide fibre and
crystalline silica (quartz and cristobalite) measurements were performed between
1982 and 1988.
     The cohort’s incidence of lung cancer was increased (74 observed cases
versus 39.9 expected; Standardized incidence ratio (SIR) = 1.9; 95% CI 1.5-2.3),
and the numbers of stomach cancer (39 observed cases versus 26.5 expected; SIR
= 1.5; 95% CI 1.1-2.0) and cancers of the upper respiratory tract (16 observed
cases versus 9.6 expected; 95% CI 1.0-2.7) were also higher than expected. The
overall incidence of lung cancer was elevated at all three plants, with SIR of 1.7
(8 cases), 1.9 (60 cases) and 2.0 (6 cases). The SIR of lung cancer was associated
with cumulative exposure to different types of dust, showing an increasing
incidence with increasing cumulative exposure. Total dust, silicon carbide fibre,
silicon carbide particle, and crystalline silica exposure measures all showed the
same pattern. The standardized incidence ratio (SIR) for the upper silicon carbide
fibre exposure category (indicated by ≥ 5 fibres/mL×year) was 2.9 (95% CI 1.8-
4.5), and, when exposure was lagged by 20 years 3.5 (95% CI 2.1-5.6). In the
upper exposure category there was a further increment in risk with increasing
cumulative exposure, with SIR = 7.1 (95% CI 1.6-16.7) for cumulative
exposures of more than 25 fibres/mL×year. The associations between cumulative
exposure to SiC fibres and the SIRs of lung cancer were almost similar between
workers who were first employed before or in 1960 and those employed later.
     The SIR for stomach cancer increased only slightly with increasing
cumulating exposure to total dust, but it was more pronounced with increasing
exposure to silicon carbide particles (SIR = 2.3; 95% CI 1.2-4.0 for silicon
carbide particles ≥ 40 fibres/mL×year). For lag times of 20 years or more the
association diminished gradually (SIR = 1.3; 95% CI 0.4-3.3 for silicon carbide
particles ≥ 40 fibres/mL×year). The incidence of stomach cancer was highest
among workers employed in a refinery department, where the silicon carbide
products were crushed, cleaned, and packed. For workers employed in a refinery
department for more than 1 year, the SIR was 2.6 (95% CI 1.5-4.1). However, no
further increment in risk was observed with increasing duration of employment
Carcinogenicity studies                                                            16
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<pre>in these departments. In addition, no association was observed between exposure
to various particulates and the incidence of upper respiratory tract cancer.
    This study revealed a dose-response relation between lung cancer incidence
and cumulative exposure to various types of particulates. Smoking could
probably be excluded as an important confounder in the present study. Asbestos
was also not a likely explanation for the observed effect of lung cancer, as it has
been used on only a small scale, with the highest level of exposure among
maintenance workers, and the SIR of lung cancer for more than 5 years of
maintenance work was 1.7 (95% CI 0.8-3.3) compared with 3.1 (99.5% CI 1.9-
4.9) for more than 5 years of work in the sorting or oven department.
Polyaromatic hydrocarbons (PAH) were present in the oven departments of these
plants, but in low concentrations and mainly as volatiles and therefore of less or
no carcinogenic potency. Measurements of samples at the Norwegian plants
suggested exposure levels of less than 10 µg/m3 for particulate PAH (n = 10) and
less than 0.1 µg/m3 for benzo[α]pyrene (n = 3). Crystalline silica exposure would
be a more likely causal agent, but the general exposure level also seemed to be
low when compared to the substantial lung cancer risk observed in the present
study.
    The elevated risk of stomach cancer was restricted mainly to employment in
the refinery department, where the main exposure has been to silicon carbide
particles. However, the association between stomach cancer risk and silicon
carbide particles was modest and disappeared with lag times of longer than
10 years.
    Bugge et al. (2010)5 analyzed the same cohort as Romundstad et al.4 after
nine more years of follow-up. This follow-up focused on cancer risk among
short- and long-term workers, based on the assumption that these two groups had
different exposure and lifestyle characteristics. Short-term workers were defined
as having < 3 years (and long-term workers as as having ≥ 3 years) of total
employment in the industry. Altogether 531 cancer cases among the 2,612
workers in the total cohort were observed, compared to the expected number of
424.9, which gives a SIR of 1.3 (95% CI 1.1-1.4). The most important single
cancer site contributing to the observed excess was an increased lung cancer
incidence with 103 cases versus the 51.7 expected (SIR 2.0; 95% CI 1.6-2.4).
    Among the short-term workers, they observed an overall excess incidence of
cancer (SIR 1.4; 95% CI 1.2-1.6, with an excess of lung cancer (SIR 2.6, 95% CI
1.9-3.5) as the most important contributing factor. The long term workers also
had an excess incidence of total cancer (SIR 1.2; 95% CI 1.1-1.3) and lung
cancer (SIR 1.7; 95% CI 1.2-2.2).
Carcinogenicity studies                                                             17
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<pre>           The short term workers also had increased incidence of non-melanoma skin
      cancer, thyroid cancer, Hodgkin’s lymphoma and cancer at ‘unspecified sites’.
      Elevated SIR levels, although not significant, were seen for several other cancers
      sites, such as lip, esophagus, stomach, liver, pleura, and bladder. In the long-term
      worker group, there was an increased incidence of lip cancer and leukemia, in
      addition to a borderline increased incidence of prostate cancer. Non-significant
      excesses of cancers of the stomach, nose and skin were also observed.
           They conclude that dust exposure in the silicon carbide industry may have
      contributed to the increased risk among long-term workers, whereas the
      increased risk among short-term workers may be due to a combination of
      occupational and lifestyle factors.
           In another follow-up study Bugge et al. (2012)6 examined the relative
      importance of the exposure factors quartz, cristobalite, SiC particles and SiC
      fibers, with respect to lung cancer risk, by using a comprehensive historic job
      exposure matrix based on about 8000 measurements (Føreland et al., 20127). The
      study cohort was based on the above-mentioned cohort in the Norwegian silicon
      carbide industry (Bugge et al., 20108, Romundstad 2001 et al.4) and consisted of
      1,687 men, employed between 1913 and 2003, and alive after 1 January 1953.
      Standardized incidence ratios for lung cancer, with follow up during 1953-2008,
      were calculated stratified by cumulative exposure categories.
           The lung cancer incidence was about twofold increased at the highest level of
      cumulative exposure to each of the exposure factors (standardized incidence
      ratios 1.9-2.3 for all agents). Internal analyses showed associations between
      exposure level and lung cancer incidence for all investigated factors, but a
      significant trend only for total dust and cristobalite. In multivariate analysis,
      cristobalite showed most consistent associations, followed by silicon carbide
      fibers.
           The results indicated that crystalline silica in the form of cristobalite was the
      most important occupational exposure factor responsible for lung cancer excess
      in the Norwegian silicon carbide industry, but silicon carbide fibers seemed to
      have an additional effect.
           Exposure to quartz and silicon carbide particles did not seem to influence the
      lung cancer incidence.
3.1.2 Additional human studies
      The additional cohort studies are summarized in Table 1 relating exposure to
      silicon carbide (next tot other substances) to the risk of cancer. Moreover two
      studies on non-malignant mortality are included in the table which are based on
      Carcinogenicity studies                                                                18
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<pre>              data from the same abovementioned population of silicon carbide workers in
              Norway. In these latter two studies increased mortality from non-malignant
              respiratory disease was observed (Romundstad et al. 20029; Bugge et al. 201110).
 able 1 Overview of additional human studies.
Design, number of      Control          Exposure                      Effects               Effect               Reference
workers, gender,                        assessment
 ountry; follow up
years)
  ohort of 86 males, General male       Exposure to polishing         18 death, 7 died of  RR (95% CI)2.5        Järvholm et
 weden exposed for population of        pastes (tallow, beeswax,      cancer               (0.9-4.8)             al., 198211
 t least 5 years,      Sweden           carnauba wax, alundum,                             No definite
ollow up 10 years                       silicon carbide, ferric oxide                      conclusions, slightly
                                        and chalk)                                         increased risk of
                                                                                           stomach cancer
  ohort of 521 males, General            Exposure to abrasives        79 death, 17 died of RR (95% CI): 2.7      Edling et
 weden for at least 5 population of     (aluminium oxide and          cancer, 24 cancer    (0.7-6.8)             al,.198712
 ears,                 Sweden           silicon carbide), possible    cases in total       No significant
ollow up 25 years                       exposure to silica and                             increase in total and
                                        formaldehyde                                       cancer mortality
                                                                                           Increased risk of
                                                                                           lymphoma/myeloma
  ohort of 727 males, Reference         Exposure to metal dust        112 cancer cases     RR (95% CI): 0.9      Jacobsson et
 weden exposed for cohorts of 3,965 (stainless steel; 18% nickel,                          (0.7-1.2)             al., 199713
 t least 1 year,       other industrial 8% chromium) and dust
ollow up 41 years      workers and      from the abrasives                                 Only increased risk
                       8,092 fishermen (including silicon carbide,                         of colon cancer
                                        aluminium oxide,
                                        amorphous carbon dioxide,
                                        clay, and phenol-
                                        formaldehyde resins
Mortality among        General male     Exposure to SiC fibers,       Cancer (n=204)       SMR (95% CI): 1.2     Romundstad
 ,562 men, working population of        quartz, crystobalite, SiC                          (1.0-1.4)             et al., 20029
n one of three silicon Norway           particles
 arbide smelters in                                                   Asthma, bronchitis, SMR (95% CI):
he Norwegian SiC                                                      emphysema (n=45) 2.2(1.6-3.0)
ndustry between
 962 and 1996.                                                        Pneumoconiosis       SMR (95% CI): 7.9
                                                                      (n=6)                (2.9-17.1)
Mortality among        General male     Exposure to SiC fibers,       Cancer (n=201)       SMR (95% CI): 1.2     Bugge et al.,
 ,687 long-term        population of    quartz, crystobalite, SiC                          (1.0-1.4)             201110
workers employed in Norway              particles using a newjy-
 913-2003 in the                        revised job exposure matrix Asthma, bronchitis, SMR (95% CI): 2.0
Norwegian SiC                                                         emphysema (n=45) (1.5-2.7)
ndustry
                                                                      Pneumoconiosis       SMR (95% CI): 15
                                                                      (n=7)                (7.0-31)
              Carcinogenicity studies                                                                                       19
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<pre>3.1.3 Case studies
      Massé et al.14 reported the results of examination of three workers with the
      history of long-term exposure to silicon carbide after they had been admitted to a
      hospital. Patient 1 was a 72-year old man with the history of working at a silicon
      carbide plant for 35 years prior to retirement at age 65. He had no history of
      exposure to other industrial dust and had been a moderate smoker. He died soon
      after admission of ventricular arrhythmia. At autopsy both lungs showed
      multiple 1- to 3-mm firm “silicotic” nodules with a predilection for the upper
      lobes and a right ventricular hypertrophy. Patient 2 was a 60-year old man who
      worked for 30 years at a silicon carbide plant and diagnosed with silicosis at 56.
      At that time he complained of moderate dyspnoea and pulmonary function tests
      revealed a very slight decrease in vital capacity. One year later, he developed a
      well-differentiated squamous cell carcinoma of the lung for which he had a
      pneumonectomy and remained disease-free at follow-up. He died of central
      nervous system complications following carotid surgery. Patient 3 was a 69-year
      old man who had worked for 40 years at a silicon carbide plant before retiring at
      age 66. He died of a metastatic undifferentiated large cell carcinoma of the lung
      with a minor component of neoplastic multinucleated giant cells.
          Based on light microscopic examination of lung tissues and intrathoracic
      lymph nodes in all three patients (i.e. nodules containing variable amounts of
      small needle-shaped birefringent crystalline particles consistent with silica), and
      scanning electron microscopy and X-ray dispersive spectrometry on a lung
      sample of patient 3, the authors believe that these tumours and nodular lesions
      were the result of lung reaction to silicon-containing particles and could,
      therefore, be considered as silicotic, i.e. inducing pneumoconiosis. The extensive
      association of anthracotic deposits was thought to be caused by inhalation of
      unfused finely ground carbon used in the manufacturing process or in the
      milling, crushing and screening procedures. The ferruginous bodies were
      believed to be formed in reaction to silicon carbide fibres and were the cause of
      interstitial fibrosis. They shared features with the uncoated fibrous silicon
      carbide particles found in the alveoli where a severe macrophagic reaction was
      observed.
          Funahashi and co-workers15 came to the same conclusion with regard to
      pneumoconiosis induction by prolonged exposure to silicon carbide. They
      examined two men, both smokers, who were exposed to silicon carbide for many
      years in a factory manufacturing refractory bricks and subsequently developed
      progressive dyspnoea and bilateral reticulonodular densities, using different
      Carcinogenicity studies                                                             20
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<pre>instruments and techniques, e.g. pulmonary function tests, chest roentgenograms,
energy dispersive X-ray analysis, and High resolution X-ray powder diffraction
analysis.
     Dufresne et al.16 evaluated the fibrous inorganic content of post-mortem lung
material obtained from 15 men who worked in the primary silicon carbide
industry. Lung tissue samples were obtained from pathology departments of six
hospitals in Québec. The lungs were examined by transmission electron
microscopy, X-ray diffraction, and phase contrast microscopy. Five of the lungs
showed evidence of neither lung fibrosis nor lung cancer, six showed evidence of
lung fibrosis but not lung cancer, and four showed evidence of both lung fibrosis
and lung cancer. Mean duration of exposure was 23.4 (SD = 6.9) years in the first
group (lungs that showed evidence of neither lung fibrosis or lung cancer), 28.8
(SD = 5.5) in the second group (evidence of lung fibrosis, but not lung cancer)
and 32.3 (SD = 9.0) in the third group (evidence of both lung fibrosis and lung
cancer). Smoking consumption was 50.6 pack-years (SD = 30) in the first group,
59.8 (SD = 32.2) in the second group and 39.2 (SD = 25.8) in the third group.
Mean years since last exposure were 7.9 (SD = 7.1) in the first group, 7.0 (SD =
1.6) in the second group and 5.0 (SD = 3.5) in the third group.
     A substantial number of silicon carbide fibres was observed in the lungs of
the subjects in the second and the third groups. The morphology, chemistry and
mineralogy of the fibres were similar to those observed in the occupational
environment. The geometric mean concentrations of fibres < 5 µm were found to
be two and three times higher in the second and third groups in comparison to the
first group, though these differences did not approach statistical difference. In the
case of silicon carbide ceramic fibres ≥ 5 µm, an excess pulmonary retention was
observed in the second and third groups, that approached statistical significance
(p = 0.06) when compared to controls; for other types of fibres (such as mica,
clays, etc.) no statistically significant differences between the first group and the
other two groups were observed for both lengths. A substantial number of
ferruginous bodies was measured in lung tissues, as was also observed by both
Massé et al.14, and by Funahashi and co-workers15, and there was a statistically
significant difference for lung retention of ferruginous bodies between the first
group and the other two groups (p = 0.02). Also for silicon angular particles
(quartz, cristobalite or silicon carbide) pulmonary retention showed an excess in
the second and third group cases that approached statistical significance (p =
0.06). These results were taken to indicate that SiC fibres ≥ 5 µm and angular
particles containing silicon, and especially ferruginous bodies in lung at higher
concentrations relate to lung fibrosis and lung cancer induction. This observation
Carcinogenicity studies                                                               21
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<pre>      arises among workers with 23 to 32 years of exposure who had ceased to be
      exposed for 5 to 9 years.
3.1.4 Summary of the human data
      Silicon carbide production workers have shown increased risk of lung cancer. In
      all epidemiological studies concomitant exposure to several other (potentially)
      carcinogenic substances occurred; therefore lung cancer risk or mortality
      observed may not be assigned with complete certainty to a single exposure
      factor. However, the case studies of Masse et al.14 suggest that the exposure to
      silicon carbide dust may cause a distinctive pneumoconiosis, and, more
      importantly, the study of Romundstad et al.4 showed an increased incidence of
      lung cancer among workers in three SiC smelter plants. These latter investigators
      also found an increased incidence of stomach cancer. The exposure to other
      carcinogenic agents, i.e. asbestos, crystalline silica and polyaromatic
      hydrocarbons, was not a likely explanation for these observed effects. The
      incidence of stomach cancer was highest among workers employed in a refinery
      department, where the SiC products were crushed, cleaned, and packed.
      Elevated incidences of lung and stomach cancer were also reported by Infante-
      Rivard et al.3 among 585 Québec silicon carbide production workers; however,
      concomitant exposure to crystalline silica could not be excluded in this case.
           The most recent study of Bugge et al. (2012)6 however, examined the relative
      importance of the exposures including quartz, cristobalite, silicon carbide
      particles and silicon carbide fibers, with respect to lung cancer risk. The results
      indicated that crystalline silica in the form of cristobalite was the most important
      occupational exposure factor responsible for lung cancer excess in the
      Norwegian silicon carbide industry, but silicon carbide fibers seemed to have an
      additional effect. Exposure to quartz and silicon carbide particles did not seem to
      influence the lung cancer incidence. This is the only human study discriminating
      between the contribution of fibrous and non-fibrous silicon carbide to the effect.
      Carcinogenicity studies                                                              22
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<pre>3.2   Carcinogenicity studies in animals
3.2.1 Exposure by inhalation
      Fibrous forms
      Davis et al.17 studied the biological effects of man-made mineral fibres,
      including silicon carbide whiskers, in long-term inhalation toxicity studies with
      rats. Two groups of 40 specific-pathogen-free (SPF) rats of AF/HAN strains
      were whole-body exposed for 7 hours/day, 5 days/week, for almost 41 weeks to
      each dust. The target airborne fibre concentration was 1,000 fibres/mL (fibre
      length > 5 µm). The used fibres were glass microfibers, silicon carbide whisker
      fibres, used commercially for the reinforcement of specialized plastic and metal
      products and with a mean diameter of 0.45 µm, and an amosite asbestos sample.
      In addition to the long-term inhalation studies, studies of pulmonary
      inflammation were performed, as well as intratracheal and intraperitoneal
      injection studies (the results of the latter studies are reported in the respective
      sections below). Fibre number concentrations and fibre size distribution for the
      experimental dust clouds were assessed from membrane filter “snatch” samples
      collected on 26 sampling days in the case of silicon carbide. In the case of silicon
      carbide, the following values were obtained: of 984 fibres/mL with the length
      5 µm 615 were of length 5-10 µm, 167 of length 10-15 µm, 100 of length 15-20
      µm and 102 > 20 µm. Groups of 4 rats from each experimental study were killed
      after the 12-month inhalation period to examine levels of tissue damage at this
      stage. The remaining animals were left for their full life span until they showed
      some kind of debilitation or until the number of survivors in each group had
      dropped to six. For estimations of advanced alveolar interstitial fibrosis
      occurring in the oldest animals, all those dying within 2 months of the final
      killing date were included. In practice this produced 9 animals in the case of
      silicon carbide.
           For each type of dust a very heavy lung burden was achieved at the end of the
      12-month exposure period, with approximately 500×106 fibres > 10 µm per rat
      lung. However, for glass microfiber treatment group the lung burden of fibres
      below 5 µm in length was more than 5 times higher than with the other dusts.
      Also, although the number of long fibres (> 15 µm in length) in the dust clouds
      had been very closely matched, animals treated with microfiber had fewer of
      these long fibres in their lungs at the end of the 12-month exposure period than
      animals treated with the other two dusts. This difference was particularly marked
      Carcinogenicity studies                                                              23
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<pre>for fibres > 20 µm. Following the end of dusting, clearance for silicon carbide
was minimal 12 months after the end of the exposure period, independently of
the fibre length, whereas in the case of amosite and glass microfibers the shortest
material was largely eliminated, although the removal of fibres > 5 µm in length
was slower.
     As age increased, animals dying from the silicon carbide treatment group
showed progressively more involvement of alveolar walls in bronchoalveolar
hyperplasia. Multiple areas of lung tissue up to 1 cm in diameter showed marked
thickening of alveolar walls with increase in connective tissue staining and
complete conversion of the lining epithelium to rounded cells of Type II
pneumocyte pattern. Within these thick-walled alveoli there were usually
aggregates of fibre-containing macrophages and desquamated epithelial cells. In
the oldest animals pathological changes had sometimes become so marked that
there was some restructuring of the lung tissue, with epithelial lined spaces no
longer corresponding to the original alveoli. These changes could progress in two
directions. Sometimes fibrous thickening of the airspace walls predominated,
although spaces were lined with rounded epithelial cells; in others, hyperplasia of
the epithelium was more apparent with much smaller epithelial-lined spaces that
presented a pattern of adenomatosis. In animals treated with microfiber, these
advanced lesions were almost entirely absent. Areas of advanced fibrosis/
bronchoalveolar hyperplasia were estimated in all animals from the treatment
groups that survived until 2 months or less before the end of the study. In the 9
silicon carbide-treated animals that lived until 2 months or less before the final
killing date the mean areas of advanced fibrosis were 8.7% of the lung
parenchyma.
     In 42 silicon carbide-treated rats that were allowed to survive beyond the end
of the dusting period, 20 tumours of the lung and pleura were recorded (5 car-
cinomas, 5 adenomas and 10 malignant mesotheliomas). A few animals had
more than one type of tumour so that the number of tumour-bearing animals was
16. In comparison, in the group of rats treated with microfibers only 4 out of 38
rats developed single benign pulmonary neoplasms. Furthermore, several of the
benign tumours found in silicon carbide-treated animals were quite large lesions
several millimetres in diameter and visible at autopsy, while all four found in the
microfiber treatment group were < 1 mm in diameter and were only found by
microscopic examination following step sectioning of the lung.
     In comparison to amosite, silicon carbide produced slightly fewer tumours in
the lung parenchyma, but produced a total of 10 mesotheliomas compared with 2
with amosite. Some of these mesotheliomas were obvious at autopsy where they
Carcinogenicity studies                                                             24
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<pre>had caused haemorrhage into the pleural cavity or pericardium, in some cases
leading to pericardial rupture.
    The group of control rats designated for this group of inhalation studies was
run synchronously with the later experiments and still had some survivors at the
moment of article publication. In the previous batch of controls of the same rat
strain maintained in the same laboratory, the figures for pulmonary tumours were
1 adenoma and 1 carcinoma in 47 rats.
    For estimations of advanced alveolar interstitial fibrosis occurring in the
oldest 9 animals in the case of silicon carbide, there was a marked macrophage
reaction with most of the cells containing numerous fibres, next to other
pathological changes. This was mainly located at the bifurcations of the terminal
and respiratory bronchioles, where much fibre had become interstitialised. Fibres
were present in macrophages, but there was a significant increase in the number
of other interstitial cells including fibroblasts, with an increase in staining for
both reticulin and collagen. In contrast, animals treated with glass microfibers
showed much less reaction to inhaled dust, the amount of this change was
probably < 1% of that occurring with the amosite treatment.
    Miller et al.18 used the data of Davis et al.17 to examine the influence of fibre
dimensions, persistence in the lung, and dissolution and cell toxicity in vitro, on
the risks of developing lung tumours in rats. The silicon carbide whisker fibres in
the Davis study were found to include a significant proportion of fibres with
unusual shapes, resembling complexes of joined fibres, shaped, variously, like a
“7”, or a “T”, or a “W”. To avoid including the very large number of variables
represented by a complete bivariate set of length and diameter variables, airborne
fibre concentrations were summarized not only in cumulative length categories
but also in two diameter classes according to whether the fibre diameters were
greater or smaller than 0.95 µm. The incidence of tumours was treated as a
binomial response variable. Its relationship with characteristics of individual
fibre types was investigated by standard methods of multiple logistic regression
using the statistical software package Genstat. Despite the small number of data
points, the results suggested a primary influence of the airborne concentrations of
the numbers of fibres thinner than 1 µm and longer than 20 µm, and of the
measured dissolution rate of the fibres. The obtained results were thus consistent
with the hypothesis that, for inhalation studies, lung carcinogenicity of man-
made fibres in rats is a function of fibre length and that the man-made fibres
longer than 20 µm, longer than would be easily engulfed by macrophages, had
the greatest potency to be carcinogenic. The length influence in man-made fibres
appeared to be similar to that of the asbestos minerals. The authors also
Carcinogenicity studies                                                               25
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<pre>      concluded that the dissolution measure of the fibres was a somewhat better
      predictor of carcinogenicity than the direct biopersistence measure.
      Non-fibrous forms
      No long-term animal studies designed to detect carcinogenicity could be
      retrieved on inhalatory exposure to non-fibrous silicon carbide particles (see also
      Table 3).
3.2.2 Intrapleural administration
      Fibrous forms
      Stanton et al.19 implanted durable minerals, including silicon carbide whiskers,
      in the form of particles of respirable size in the pleurae of outbred female
      Osborne-Mendel rats for periods of more than 1 year. A total of 72 experiments
      were performed, by applying a standard 40 mg dose of particles (corresponding
      to ca. 145 mg/kg bw*) uniformly dispersed in hardened gelatine by open
      thoractomy directly to the left pleural surface of 12- to 20-week-old rats. In each
      experiment, 30-50 rats were treated and followed for 2 years, at which time the
      survivors were killed. All rats were necropsied and all organs and tissues were
      examined microscopically. A positive response was the occurrence of pleural
      sarcomas that resembled the mesenchymal mesotheliomas of man, developing
      after 1 year. Three types of controls were considered: untreated rats, rats that
      received thoratectomies but no pleural implant, and rats with pleural implants of
      non-fibrous material. There were two types of spontaneous tumours observed in
      the studies: the fibrosarcomas of left mammary gland and the subcutaneous
      fibrosarcomas induced by suture material. Vigilance and early surgical removal
      accounted for most mammary tumours; the use of synthetic, biodegradable,
      polyglycolic acid sutures largely eliminated suture sarcomas.
          Silicon carbide used in the study was a single sample (whiskers), which was
      of exceptionally fine uniform dimension.
          The incidence of clearly apparent pleural neoplasms in untreated, aged
      outbred Osborne-Mendel female rats was essentially non-existent. However, a
      few pleomorphic sarcomas that might be confused with pleural tumours occurred
      in the left thorax of both treated and, to a lesser degree, untreated controls.
      The value has been calculated using the default value for average body weight of female rats of 275
      gram in chronic studies.20
      Carcinogenicity studies                                                                             26
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<pre>Although these tumours involved the thickness of the chest wall, in most cases
the tumours appeared to be derived either from mammary gland fibroadenoma or
from suture granuloma in the subcutaneous tissues. But there remained a few
tumours for which no definite origin could be determined and which were
histologically comparable with pleural sarcomas. In both the experimental
groups and the control groups these questionable tumours were counted as
pleural sarcomas. The incidence of pleural sarcomas in all 3 control groups
combined was 7.7 ± 4.2% (calculated by the life table method). The incidence of
pleural sarcoma in a particular experimental group was significantly greater than
the incidence in the combined control group only if it exceeded 30%. For silicon
carbide, actual tumour incidence was 17/26, with the common log particles of
dimensions ≤ 0.25 µm × > 8 µm/mg of 5.15.
    In general, the results indicated that particles in the relatively thin- and long-
dimensional categories were associated with higher tumour probabilities. The
best correlation was obtained with the fibres that measure ≤ 0.25 µm × > 8 µm.
    Johnson and Hahn21 investigated whether silicon carbide whiskers are
carcinogenic in the intrapleural inoculation assay, by injecting 3 groups of 30
female F344/N rats, 6 to 8 weeks old, intrapleurally with 20 mg (corresponding
to ca. 73 mg/kg bw*) of 3 different silicon carbide whiskers samples (SiCW 1,
SiCW 2 and SiCW 3), suspended in 0.4 ml saline. The mean fibre length in three
samples was determined by scanning electron microscopy and amounted to 4.5
(±0.23), 20.1 (±1.01) and 6.6 (±0.40) µm and the diameter < 1 µm. The number
of fibres in three samples was 7.6×106, 1.6×105 and 1.1×107 fibres per 1 mg
samples, respectively, resulting in the doses of 5.6×108 fibres/kg bw, 1.2×107
fibres/kg bw and 8×108 fibres/kg bw. The rats were killed by intraperitoneal
injection of sodium pentobarbitone when moribund or when 20% of the longest
surviving group of rats remained alive. All rats were necropsied and examined
for gross lesions. The first rat died from respiratory distress at 166 days after
inoculation with SiCW 2, and the first tumour was found 273 days after
inoculation with SiCW 2. Rats inoculated with SiCW 1 or 2 had the shortest life
spans, which were significantly shorter than those of the control animals treated
with saline. The life spans of the rats treated with SiCW 3 were not significantly
different from those of control rats.
    Out of 30 animals treated with SiCW 1 and SiCW 2, 27 (90% CI) and 26
(87% CI) developed pleural mesotheliomas, with the median survival time (days
after injection) of 453 (±21) and 519 (±20) days, respectively. In contrast, 7 rats
This value has been calculated using the default value for average body weight of female rats of 275
gram in chronic studies.20
Carcinogenicity studies                                                                              27
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<pre>      (27% CI) of the rats treated with SiCW 3 developed pleural mesotheliomas, in
      comparison to 57% of those treated with the positive control (crocidolite). No
      tumours were identified in the animals treated with saline. The tumours
      identified, with one exception, were sarcomatous in appearance and, in all but
      one case, involved the visceral pleura. Fibres were found in sections from all
      treatment groups.
           Vasil’eva et al.22 (article published in Russian) studied the carcinogenicity of
      silicon carbide by injecting three times groups of 93 male and female rats into the
      pleural cavity with 20 mg of silicon carbide in 1 mL of physiological solution.
      The interval between injections was one month. Ninety-six rats of the second
      group were injected three times with the same doses of chrysotile B (positive
      control) and 52 rats with physiological salt solution (negative control). The
      animals were observed until their natural death and tumours, as well as organs,
      were subjected to morphological evaluation. Pleural mesothelioma’s were
      induced in 47.7% of the silicon carbide treated group and in 34.1% of chrysotule
      B treated group, while in the control group no mesothelioma’s were seen. [The
      Committee was unable to evaluate the details of this study.]
      Non-fibrous forms
      No relevant animal studies were retrieved on pleural administration of non-
      fibrous silicon carbide particles (see also Table 3).
3.2.3 Intraperitoneal injection
      Fibrous forms
      Adachi et al.23 evaluated the carcinogenic risk of man-made fibres, including
      silicon carbide whiskers, based on mesothelioma incidence in female F344 rats
      after intraperitoneal administration. Female F344/Jslc rats were administered
      intraperitoneally a suspended solution (1 mg/ml) of fibres in saline. Five
      millilitres was the highest volume administered to a rat in a week. At first, all
      types of fibres were examined at a dose of 10 mg/rat (corresponding to ca. 36
      mg/kg bw*). Based on the tumour incidence at 10 mg/rat, doses for the second
      experiment were either increased to 20 mg/rat (corresponding to ca. 73 mg/kg
      bw*), or reduced to 5 mg/rat (corresponding to ca. 18 mg/kg bw*). Rats were
      This value has been calculated using the default value for average body weight of male and female
      rats of 375 gram in chronic studies.20
      Carcinogenicity studies                                                                           28
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<pre>observed for two years after the administration. The number of fibres were
counted by scanning electron microscopy, resulting in 414·103 fibres/µg. This
corresponded to the doses of 4.14 ×109 fibres/kg bw for the dose of 10 mg/rat;
8.3×109 fibres/kg bw for the dose of 20 mg/rat and 2.1×109 fibres/kg bw for the
dose of 5 mg/rat.
     All rats administered 10 mg of silicon carbide whisker developed peritoneal
mesothelioma within a year. In the group of rats administered 5 mg of silicon
carbide whisker, incidence of mesothelioma was 70% at one year after the
administration. The authors estimated the carcinogenic potency of silicon carbide
whiskers as 2.4 times that of IUCC chrysolite B. The fastest development of
peritoneal mesothelioma was identified in the rat administered 5 mg of silicon
carbide whisker at 133 days of the experiment. At autopsy, hemorrhagic ascites
fully filled the abdominal cavity and numerous nodules, ranging from 1 to 3 mm,
were spread at the abdominal wall and epithelium of the organs. These lesions
were found in most (95%) rats which eveloped peritoneal mesothelioma at the
terminal stage.
     Tumour cells spread the whole gamut of abdominal cavity, however, no
metastases to other organ were found. Adhesive growth of the tumour between
liver and diaphragm was common in the rats with mesothelioma and coagulation
of deposited fibres at the same site was also common in the autopsied rats at the
end of the experiment. Microscopically, tumour cells showed a variety of
characteristics including epithelial or sarcomatous structures and some of the
extensive cases had osseous formation in the tumour.
     Miller et al.24 tested a range of man-made mineral fibres, including silicon
carbide whiskers, for evidence of carcinogenicity by injection into the peritoneal
cavity of 24 male SPF Wistar rats and monitored them for the rest of their lives
for the development of mesothelioma. The target dose was designed as the
estimated mass required to contain 109 fibres > 5 µm in length and amounted to
14.2 mg silicon carbide (corresponding to ca. 30 mg/kg bw* and 2.1×1010 fibres/
kg bw). The fibres were < 0.95 µm in diameter.
     Out of 24 rats administered silicon carbide whiskers, 22 (92% CI) developed
mesothelioma, with median mesothelioma survival of 257 days (SD = 52).
Similarly to the study of Adachi et al.23, the samples of silicon carbide whiskers
was found to produce mesotheliomas earlier and at a faster rate than any other
fibre type which was tested, at least in the first 300 days after injection. However,
mesothelioma production appeared to slow down relative to the other fibres, after
This value has been calculated based on the default value for average body weight of male rats of 475
gram in chronic studies.20
Carcinogenicity studies                                                                               29
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<pre>a particularly rapid start. A plausible explanation suggested by authors include
the hypothesis that silicon carbide with its unusually complex fibrous shape may
undergo some modification in vivo that reduces its carcinogenic potential over
time, or possible variations between animals in the actual dose injected or
reaching the target organs.
    To assess the ability of amosite, silicon carbide, and microfiber to produce
mesotheliomas, Davis et al. 199617 injected intraperitoneally a dose of 1 x l09
fibers (length > 5 pm) into groups of 24 rats. The appropriate mass of fiber was
suspended in saline so that the required dose was administered as a single
intraperitoneal injection of 2 ml. Following the intraperitoneal injection, the
numbers of mesotheliomas developing in groups of 24 rats were 21 for amosite,
22 for silicon carbide, and 8 for microfiber. The silicon carbide produced
mesotheliomas particularly rapidly, and even with amosite almost half of the
mesothelioma deaths had occurred before any of the microfiber group died from
mesothelioma. The median survival time (at which 50% survival was achieved)
was 257 days for silicon carbide and 509 days for amosite. For the microfiber, it
was 679 days, although the smaller number of mesothelioma deaths causes a
much less precise estimate for this fiber.
    A steep dose-response relationship for tumours was reported by Pott et al.25
after application of 0.05 to 25 mg (corresponding to ca. 0.13 mg/kg bw and 91
mg/kg bw*) of SiC whiskers in a chronic intraperitoneal injection study in rats.
The percentage of tumours steadily increased from 12.5% up to 97% as a
function of the quantity of these whiskers. The whiskers contained 107,000,000
fibres > 5 µm in length and < 2 µm in width and an aspect ratio > 5/1 per 1 mg of
the sample. This corresponded to doses of 1.4×106 and 7.1×108 fibres/kg bw for
0.05 mg and 25 mg doses, respectively. Unfortunately, the experiment was
disturbed by an infection occurring in the months 12 and 13. About 34% of the
rats died, mainly in the groups with low exposure. Therefore the percentage of
mesotheliomas and sarcomas observed in the abdominal cavity was not a
function of all the rats that were present at the start, but only of those that either
survived 56 weeks or died earlier and were diagnosed as tumour-bearing.
Non-fibrous forms
Roller et al.26 examined groups of male or female rats for 30 months for tumours
in the abdominal cavity after repeated intraperitoneal injections with dust
This value has been calculated based on the default value for average body weight of female rats of
275 gram in chronic studies.20
Carcinogenicity studies                                                                             30
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<pre>                             suspensions of mineral and vitreous fibres. Two groups of 48 female and 72 male
                             rats were injected either 5 or 20 times with 50 mg of granular silicon carbide
                             (corresponding to total doses of approximately 667 mg/kg bw and 2,666 mg/kg
                             bw*). Two mesotheliomas were found in a total of 395 evaluated rats treated with
                             saline or granular silicon carbide. Other tumours are listed in Table 2.
 able 2 Tumours except mesothelioma in the abdominal cavity of rats.
    Treatment (total dose)                                                                                                                      Suprarenal gland                                                                                       Abdominal cavity
                                           Rats evaluated                                                                                                              Mesentery       Lymph nodes
                                                                Uterus       Ovary       Testicle       Liver       Pancreas       Kidney                                                                Scrotum       Intestine       Bile-duct
                                Sex
NaCl 40 mL                    female      93                12           -           -              1           -              -            -                      1               1                 -             -               -               1
                              male        69                -            -           2              -           -              -            1                      -               1                 1             -               -               -
 iC                           Female      47                6            2           -              -           -              -            -                      1               -                 -             -               -               -
 granular)                    male        71                -            -           -              1           -              -            2                      1               -                 -             -               -               -
 50 mg
 iC                           female      45                7            1           -              -           -              -            -                      1               -                 -             -               -               -
 granular)                    male        70                -            -           1              -           -              -            -                      -               -                 -             -               -               -
 ,000 mg
                                  In contrast to their above-mentioned study on whiskers Pott and co-workers
                             observed no increase in tumours in a carcinogenicity study with nonfibrous
                             silicon carbide27, which was injected in Wistar rats (WU/Kiβlegg-Iva: WIWU,
                             8-10 weeks) intraperitoneally under CO2 anaesthesia as dust suspensions in 2 ml
                             buffered 0.9% sodium chloride solution. Silicon carbide was injected repeatedly
                             at intervals of two weeks into 48 female and 72 male rats at two dose levels
                             (5 times 50 mg and 20 times 50 mg, corresponding to total doses of ca. 667
                             mg/kg bw and 2,666 mg/kg bw*).
                                  One year after the first intraperitoneal injection of silicon carbide, the
                             average body weight of the rats injected with 20×50 mg was about 5% lower in
                             both sexes than in the control group injected 20 times with 2 ml saline. Six
                             months later this difference was between 7 and 8% in both sexes. The mortality
                             was less than 20% after 90 weeks in all silicon carbide groups. No serosal
                             tumours were found in the abdominal cavity of 35 histopathologically examined
                             rats. Observations 90 weeks after the start of the experiment did not indicate any
                             This value has been calculated using the default value for average body weight of male and female
                             rats of 375 gram in chronic studies.20
                             Carcinogenicity studies                                                                                                                                                                                                            31
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<pre>      obviously acute or chronic toxic effect in male and female rats due to 1000 g
      nonfibrous silicon carbide dust administered intraperitoneally.
           Rödelsperger and Brückel1 analyzed the results reported by Pott et al.27 to
      determine whether the granular silicon carbide may still contain fibrous cleavage
      fragments which fulfil the definition of WHO fibres. Samples of the original
      granular and fibrous silicon carbide were suspended in water and filtered. One
      half of each filter was analyzed by scanning electron microscopy (SEM,
      magnification ×2,500) and transmission electron microscopy (TEM,
      magnification ×10,000). The concentration of WHO fibres was determined to be
      58,000 fibres/mg for the granular sample compared to 48,000,000 (SEM) and
      42,000,000 (TEM) fibres/mg for the whiskers. The aspect ratio exceeded 10/1 for
      only 3.3% of the fragments in the granular sample, but in each analysis for 96%
      of the whiskers. In addition, 0% of the fragments in the granular sample
      compared to 44% and 30% of the whiskers were more than 10 µm long. In total,
      15 and 58×106 WHO fibres were injected with 250 mg and 1000 mg of the
      granular silicon carbide, respectively, even though only 0.8% and 0% tumours
      were recorded. However, 20.1% and 43.3% tumours would have been expected
      if the carcinogenic potency were the same for the fragments and for the whiskers.
           The authors concluded that the carcinogenic potency appeared to be a
      function of the shapes of the WHO fibres and was much lower for silicon carbide
      cleavage fragments than for whiskers. They concluded that carcinogenicity was
      mainly restricted to a subgroup of WHO fibres longer than about 10 µm and
      thinner than about 1 µm.
3.2.4 Additional animal studies
      Besides the studies reported above, a number of additional studies were
      available, which did not demonstrate occurrence of neoplastic lesions upon
      exposure to silicon carbide (see Table 3). Exposure periods in these studies were
      generally too short for such lesions to develop.
           Akiyama et al.28 exposed 42 male Wistar rats to silicon carbide whiskers for
      6 h/day, 5 days/wk for 1 yr by inhalation. The control rats were exposed to clean
      air in identical, adjacent chambers under similar conditions of flow, temperature,
      and humidity.The mass median aerodynamic diameter, the geometric mean fibre
      diameter and the geometric mean fibre length were 2.4 µm (± 2.2), 0.5 µm
      (± 1.5) and 2.8 µm (± 2.3), respectively. The daily average exposure
      concentrations were 2.6 ± 0.4 mg/m3 (98 ± 19 fibres/mL) The rats were
      sacrificed at 6 days and 3,6, and 12 months after the exposure.
      Carcinogenicity studies                                                            32
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<pre> able 3 Additional animal studies with silicon carbide.
 pecies/Strain/ Route of exposure, exposure             Fibrous/non- Observed effects                                Reference
No. per Sex per duration                                fibrous form
Group
                  Concentration tested
  ats (gender not Inhalation                            Fibrous form Increased lung weight; Inflammatory             Lapin et
 pecified)/       6 hours/day, 5 days/week for 13       (=whiskers) lesions; bronchiolar, alveolar, and pleural      al., 199129
 prague-Dawley/ weeks                                                wall thickening; local pleural fibrosis in
  = 50                                                               lung; reactive lymphoid hyperplasia in
                  0.09, 3.93, 10.7 and 60.5 mg/m3 (0,                bronchial and mediastinal lymph nodes
                  630, 1,746 and 7,276 SiC whiskers/
                  mL)
Male rats /       Inhalation                            Fibrous form Increased lung weight; fibrotic changes in      Akiyama
Wistar/ n=42      6 hours/day, 5 days/week for one      (=whiskers) lungs                                            et al.,
                  year                                                                                               200728
                  2.6 ± 0.4 mg/m3 (98 ± 19 fibres/mL)
 emale rats/      Inhalation exposure for five hours a Non-fibrous Increased lymph node weights; No                  Bruch et
Wistar n=50/      day on five consecutive days,         form (grain significant changes in lung weights. High        al., 199330
 roup and n=42/ followed by a rest period of two        size < 3 µm) total cell numbers as well as alveolar
 roup             days and a re-exposure period of                   macrophages three days after the end of
                  five consecutive days. Total                       inhalation. SiC produced no specific
                  exposure time was 50 hours.                        stimulation of granulocytes.
                  Observation period up to 90 days                   No divergent results from those of controls.
                                                                     SiC is deposited practically inert in the lung.
                  20 mg/m3
 emale rats/      Single intratracheal administration, Fibrous form Extensive pulmonary granuloma; fibrosis,         Vaughan et
 344/50           followed by 18 months observation (=whiskers) interstitial pneumonia, atelectasis, bronchial       al., 199331
                  period                                             mucosal hyperplasia, squamous metaplasia
                  1 mg SiC/100 mL minute respiratory
                  volume) and 5 mg SiC/100 mL
                  minute respiratory volume
 emale rats/      Single intratracheal administration, Non-fibrous No significant histopathological changes          Vaughan et
 344/50           followed by 18 months observation form                                                             al., 199331
                  period                                (=platelets)
                  1 mg SiC/100 mL minute respiratory
                  volume and 5 mg SiC/100 mL
                  minute respiratory volume
 emale rats/      Single intratracheal injection,       Non-fibrous Slight increase in average lymph node            Bruch et
Wistar            followed by observation period of 3, form          weights with no further alterations from        al., 199332
                  8 and 12 months                       (diameter    three to 12 months. Completely inert
                                                        < 3 µm)      deposition of SiC dust in the lung and the
                  50 mg SiC/0.50 mL                                  lymph nodes. The dust was compactly
                                                                     located without accompanying cellular
                                                                     responses (no granulocytes). No collagen
                                                                     development was not identified. SiC dust
                                                                     can be considered inert from the
                                                                     experimental results.
              Carcinogenicity studies                                                                                        33
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<pre>heep n=8/group Intratracheal, catheterisation of the Fibrous form Peribronchiolar fibrosing alveolitis. Nodular Begin et
                  tracheal lobe, followed by 8 month              lesions in the parenchyma composed of         al., 198933
                  observation period                              multinucleated macrophages, monocytes and
                                                                  a few neutrophils and containing several SiC
                  100 mg in 100 mL                                fibers and “bodies”.
                                                                  Cellularity (macrophages,lymphocytes,
                                                                  neutrophils) was increased with an
                                                                  attenuation over time. This pattern was also
                                                                  seen in the response of LDH over time.
                                                                  Fibronectin production at month 8 was
                                                                  significantly increased. Fibroblast growth
                                                                  activity was increased Essentially the
                                                                  whiskers produced a sustained nodular
                                                                  fibrosing alveolitis.
heep n=8/group Intratracheal catheterisation of the  Non-fibrous Slight and transient early increase in         Begin et
                  tracheal lobe, followed by 8 month form         cellularity (macrophage population,           al., 198933
                  observation period                              lymphocytes and neutrophils). Essentially
                                                                  granular SiC appeared inert.
                  100 mg in 100 mL
 ats (gender not Single intraperitoneal              Fibrous form Diffuse, intense desmoplastic reaction of     Vaughan et
pecified)/F344/ administration, followed by 18       (=whiskers) serosal surfaces, peritoneal fibrosis          al., 199331
0                 months observation period
                  20 mg/mL
                 The amount of silicon carbide whiskers deposited in rat lungs 6 days after the
             end of the inhalation period of 12 months was 5.3 ± 1.4 mg. This amount
             declined exponentially. A biological half life of 16 months was calculated using a
             one-compartment kinetic model.
                 Histopathological observations were made at 6 days and 12 mo after 1 yr of
             inhalation. Small fiber-aggregated foci were diffused in the alveolar space in the
             entire lung field shortly at 6 days after 1 yr of inhalation. Some of the silicon
             carbide whiskers were deposited in the interstitial tissue and some of them were
             accompanied by collagenous material. The infiltration of inflammatory cells
             around the aggregated fibers was not remarkable. There was a slight thickening
             of a part of the pleura due to fiber deposition.
                 One year after the end of the 1-yr inhalation exposure, fibrotic changes were
             remarkable around some fiber-aggregated regions. In these regions, fibrous
             thickening of the alveolar wall around fiber aggregations and infiltration of
             inflammatory cells, mainly macrophages and monocytes, were found. They were
             observed in the lung field as a magnified image of alveolitis at low
             magnification. Bronchoalveolar hyperplasia formation was observed in two
             animals in the exposed group. Fibrous aggregations were scattered in the
             bronchoalveolar hyperplasia. No neoplastic lesions were observed. No follow up
             more than 1 year was performed after the end of the inhalation period.
             Carcinogenicity studies                                                                                    34
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<pre>3.2.5 Summary of the animal data
      From the available animal data it can be concluded that the fibrous form of
      silicon carbide is able to induce tumours upon inhalation, as well as upon
      intraperitoneal and intrapleural administration.
      Upon inhalation Davis et al.17 reported the development of carcinomas,
      adenomas and methotheliomas in lungs of rats exposed to silicon carbide fibres.
      In addition, bronchoalveolar hyperplasia and advanced fibrosis of the lung
      parenchyma were found in two available studies.28,29 Dose-response studies were
      unfortunately not available. Findings of Miller and co-workers18 suggest that
      silicon carbide is carcinogenic when present in the fibrous form, and its
      carcinogenicity is a function of the fibre length, with fibres longer than 20 µm
      having the greatest effect on carcinogenicity. In a short-term inhalation study (90
      days) in rats non-fibrous silicon carbide was considered inert (Bruch et al.30), but
      data from long term studies are lacking.
           Intraperitoneal administration of silicon carbide fibres to rats could lead to
      early development of peritoneal mesotheliomas. A steep dose-response
      relationship for tumours was reported by Pott and co-workers25 in a chronic
      intraperitoneal injection study in rats after application of silicon carbide
      whiskers. However, no increased tumour incidence was found in rats which had
      received an injection of non-fibrous silicon carbide.
           Stanton et al.19 reported the increased incidence of pleural carcinomas,
      resembling mesenchymal mesotheliomas in man, 1 year after intrapleural
      administration of silicon carbide in rats. The development of pleural
      mesotheliomas was also reported in other studies upon intrapleural
      administration. Also development of adenocarcinomas in combination with
      mesotheliomas, and development of peritoneal mesotheliomas upon intrapleural
      administration of silicon carbide to rats was reported. The overall frequency of
      mesotheliomas was found to be comparable to that of rats injected with asbestos,
      used as a positive control in some studies. No animal data on pleural
      administration of non-fibrous silicon carbide were retrieved.
           Intratracheal administration of fibrous silicon carbide did not result in tumour
      development. In rats hyperplasia and metaplasia were observed, in sheep a
      sustained nodular fibrosing alveolitis developed. Non-fibrous silicon carbide did
      not lead to significant histopathological changes in rats and sheep.
      Carcinogenicity studies                                                               35
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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
4.1.1   Gene mutation assays
        In vitro
        No data on mutagenicity of silicon carbide in prokaryotes and yeast have been
        recovered from public literature.
        In vivo
        No in vivo data (from humans and experimental animals) on mutagenicity of
        silicon carbide have been recovered from public literature.
4.1.2   Cytogenetic assays
        In vitro
        Peraud and Riebe-Imre34 studied the toxic and chromosome-damaging properties
        of several man-made fibres, including silicon carbide, in an in vitro cell system
        of epithelial lung cells M3E3/C3 of the Syrian golden hamster. The test
        substances suspended in growth medium were added at concentrations of 0.1, 1.0
        Mode of action                                                                    36
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<pre>      and 2.0 µg/ml to the cell cultures. As a measure of toxicity mitotic indexes were
      determined by evaluating the relationship between binucleated and
      mononucleated cells of 1,000 scored cells. The authors also evaluated the
      amount of micronuclei with a kinetochore, which allows the discrimination
      between whole chromosome or a centric fragment as the origin of the
      micronucleus.
           A rise in the number of cells with micronuclei with increasing concentration
      was observed for all fibres. Chrysolite was most effective in micronucleus
      induction, followed by silicon carbide. A depression of the mitotic index was
      observed upon silicon carbide treatment. An evaluation of the amount of
      micronuclei with a kinetochore indicated that the relative portion of kinetochore-
      positive micronuclei was in the range of the untreated control for silicon carbide.
      It may be concluded that the substance is clastogenic and not aneugenic.
      In vivo
      No in vivo data (from humans and experimental animals) on genotoxicity of
      silicon carbide have been recovered from public literature.
4.1.3 Miscellaneous
      In vitro
      Brown et al.35 studied the intrinsic hydroxyl radical activity of several types of
      man-made fibres, including silicon carbide, by supercoiled plasmid DNA
      scission and high-performance liquid chromatography using a hydroxyl radical
      trap salicylate. The authors used rat lung lining fluid to coat the fibres to
      determine whether the oxidant-generating ability could be modulated by
      modifying the fibre surface reactivity. The role of iron in mediating hydroxyl
      radical production was assessed by the use of the chelator desferrioxamine-B,
      and the hydroxyl radical scavenger mannitol was utilized in some assays. The
      concentration used in the experiments was adjusted to equal 8.24×107 fibres/mL,
      as this concentration was found to be non-toxic to cells in the culture. The length
      distribution in silicon carbide fibres was as follows: 60.86% had a length above
      10 µm and 27.6% had a length above 20 µm.
           All tested fibres displayed some free radical activity; however, except of
      long-fibre amosite asbestos, which caused 55% depletion of supercoiled DNA, it
      ranged from 5 to 20% and was not significantly different from control. The
      effects of the hydroxyl radical scavenger and rat lung surfactant were examined
      Mode of action                                                                      37
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<pre>    therefore only for amosite asbestos. The introduction of these agents in the assay
    resulted in supercoiled DNA depletion being limited to a level that was not
    significantly different from the control. Silicon carbide also did not exhibit
    hydroxyl radical generation in salicylic acid assay. The authors concluded that
    free radicals are either not involved in silicon carbide carcinogenicity, or that the
    assay conditions were not sensitive enough to detect free radical generation in
    this case.
        Vaughan et al.36 studied DNA synthesis after exposure to SiC whiskers in
    BALB/3T3 embryonic mouse cells (clone A31). Two types of whiskers were
    used, one (SiCW-1) with a diameter of 0.8 (SD = 0.3) µm, average length of 18.1
    (SD = 14.3) µm and aspect ratio of 23.3 (SD = 18.7), and another (SiCW-2) with
    the diameter of 1.5 (SD = 0.6) µm, average length of 19.0 (SD = 11.0) µm and
    aspect ratio of 15.3 (SD = 11.2). Crocidolite was used as a positive control, while
    saline vehicle was used as a negative control. The rate of DNA synthesis in cells
    exposed to fibres was determined by measuring the incorporation of
    [3H]thymidine (100 µCi/mM) into DNA. The cells were exposed to test materials
    suspended in complete medium at concentrations ranging from 0.0 to 2.0 µg/cm2
    followed by 2 hours exposure to [3H]thymidine (2.0 µCi/mL). The amount of
    [3H]thymidine incorporated into DNA was determined by liquid scintillation
    counting. Cells were also scored for multinuclearity after incubation with the test
    material at 5 µg/cm2 for 48 h.
        The authors found that DNA synthesis rates in fibre/whisker-exposed cells
    were generally elevated relative to the controls, often by a factor of as much as
    2.5, but the results were inconsistent. Significant increases in total cellular DNA
    content were consistently observed 10-20 generations after treatment, with cells
    treated with SiCW-1 having a 39% and cells treated with SiCW-2 a 42% increase
    in comparison to the negative control. Cells treated with the positive control
    crocidolite showed a 75% increase of total cellular DNA content.
    In vivo
    No relevant in vivo data (from humans and experimental animals) were retrieved
    from public literature.
4.2 Carcinogenic mechanism and comparison with asbestos
    Brown and co-workers37 studied a panel of mineral fibres, including silicon
    carbide, for their ability to cause translocation of the transcription factor NF-kB
    to the nucleus in A549 lung epithelial cells, as detected by immunofluorescent
    Mode of action                                                                        38
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<pre>staining. The authors hypothesize that translocation of NF-kB results in
transcriptional activation of genes for pro-inflammatory cytokines. Treatment of
A549 cells for eight hours with silicon carbide (1.3 to 16.48 x 106 fibres/ml)
resulted in a concentration-dependent increase in positively stained cells. Silicon
carbide proved more than twice as potent as other pathogenic fibres (amosite
asbestos and refractory fibre 1) in this assay, while non-pathogenic fibres did not
induce a significant effect. Based on these observations the authors conclude that
nuclear translocation of NF-kB in A549 cells can be used as a short term in vitro
assay to discriminate pathogenic and non-pathogenic fibres. In the same study
Brown and co-workers showed that the positive effect of silicon carbide could be
mimicked by hydrogen peroxide, while antioxidants such as curcumin and
nacystelin blocked the effect of silicon carbide on NF-kB translocation. Based on
these observations the authors conclude that silicon carbide exerts its activity by
induction of oxidative stress and possibly a subsequent inflammatory response.
    The same investigators (Brown et al.)38 also studied the ability of several
types of fibres, including silicon carbide, to deplete antioxidants glutathione and
ascorbate in lung lining fluid and lung epithelial cells in vitro. Rat lung lining
fluid was used. As positive control chemically produced oxidants, i.e. superoxide
and hydroxyl radicals, were used. Also the ability to deplete glutathione and
ascorbate in pure solutions was investigated for comparison.
    The results indicate that silicon carbide, as well as other fibres, was able to
deplete the glutathione contents in lung lining liquid; however, the most
significant effects were observed with two glass fibres which were shown to be
non-pathogenic in animal studies. The depletion of glutathione in lung lining
liquid was clearly number dependent. The same glass fibres also significantly
depleted the ascorbate levels in lung lining fluid. The authors concluded that
antioxidant depletion in lung lining liquid in vitro is not a reliable discriminator
of fibre pathogenicity.
    Vaughan et al.36 studied the cytotoxicity on and transformation of BALB/3T3
embryonic mouse cells (clone A31) upon exposure to SiC whiskers. Two types
of whiskers were used, one (SiCW-1) with the diameter of 0.8 (SD = 0.3) µm,
average length of 18.1 (SD = 14.3) µm and aspect ratio of 23.3 (SD = 18.7), and
another (SiCW-2) with the diameter of 1.5 (SD = 0.6) µm, average length of 19.0
(SD = 11.0) µm and aspect ratio of 15.3 (SD = 11.2). Crocidolite was used as a
positive control, while saline vehicle was used as a negative control. Cytotoxicity
was determined by dye exclusion and by 51Cr release. The effect of silicon
carbide on cell proliferative ability was also studied by seeding 300 cells per 60-
mm culture dish and incubating for 24 h before treatment with the test material at
varying concentrations, with the subsequent colony counting by inverted phase
Mode of action                                                                       39
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<pre>microscopy. Transformation frequency was determined after the exposure to the
test material at 5 µg/cm2 for 24 hours, by scoring foci exhibiting layered cell
growth and the swirling pattern characteristic of transformed colonies as
positive. In addition, total DNA content was estimated in fibre-exposed cells.
    Within 24 h of being added to cell cultures, numerous fibres which could be
detected by phase contrast were found associated with the cells, attached to cell
surfaces, or internalized. Silicon carbide whiskers too large to be engulfed were
found to be penetrating cell surfaces, often entering the cell on one side, and
exiting on the other as if the cell were “skewered”.
    Based on the dye exclusion studies, silicon carbide exhibited similar level of
concentration-dependent cytotoxicity as crocidolite asbestos in the first 24 h.
SiCW-1, SiCW-2 and crocidolite were found to induce, with eight generations of
exposure, changes in cellular growth habits and structure generally held to be
characteristic of cellular transformation. Transformation frequency of ca. 0.6·10-
2% was obtained as a result of exposure to 5.0 µg/cm2 SiCW, in comparison to
less than 0.1·10-2% in saline control. Positive control crocidolite asbestos
produced a transformation frequency of 0.0069% (SD = 0.0046%).
    Svensson et al. (1997)39 investigated the toxicity of different fibrous silicon
carbide (whiskers) and non-fibrous silicon carbide (powder) in comparison with
crocidolite in a number of in vitro assays. All materials showed concentration-
dependent inhibition of the cloning efficiency of V79 hamster fibroblast cells.
The inhibition by the most toxic whiskers (EC50 0.9 to 4.2 µg/cm2) was in the
same order of magnitude as that of crocidolite (1.4 µg/cm2). Silicon carbide
powder was less toxic (EC50 31.4 µg/cm2) than the whiskers. There was a high
DNA breaking potential (nick translation assay) for crocidolite and silicon
carbide whiskers and a rather low one for silicon carbide powder. Formation of
hydroxyl radicals was found for crocidolite and one of the silicon carbide
whiskers and not for the silicon carbide powder. Silicon carbide whiskers had the
highest ability to stimulate human neutrophils to generate reactive oxygen
species.
Silicon carbide fibers belong to a group of man-made mineral fibers. Asbestos
fibres are of natural origin. Both fibre types differ chemically in their gross
formula being SiC (silion carbide) and Mg3Si2O5(OH)4 (asbestos). In spite of
these chemical differences both fibre types are respirable and biopersistent,
although silicon carbide fibers are less biopersistent than asbestos fibers.40
    The mechanism of asbestos carcinogenesis is not entirely clear at present.
The direct or indirect action of asbestos on DNA and proteins can cause many
different types of DNA and chromosomal damage. The main cellular functions
Mode of action                                                                      40
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<pre>    that are affected by asbestos fibres include oxidative stress response,
    inflammation, DNA damage repair, mitochondrial activity and apoptosis. Many
    genes and pathways involved in these functions have been identified.40
         With the abovementioned studies in mind, the Committee is aware of some
    similarities between (carcinogenic) mechanisms of silicon carbide and asbestos,
    such as the development of lung tumours, the involvement of oxidative stress
    through free radicals, imbalance in oxidant-antioxidant levels, the involvement
    of NF-kB.(which is known to coordinate the inflammatory and proliferative
    response to asbestos).40
         The Committee observes an important difference with asbestos in that, seen
    until now, silicon carbide exposure leads to mesotheliomas only in animals but
    not in humans.
4.3 Summary of the mechanistic data
    Standard genotoxicity tests in vitro or in vivo were not available. Only Peraud
    and Riebe-Imre34 reported on an in vitro micronucleus test, showing a
    concentration-dependent increase in the number of Syrian golden hamster
    epithelial lung cells with micronuclei, after treatment with SiC. In addition, an in
    vitro study focussed on the interaction of silicon carbide with DNA; Vaughan et
    al.36 demonstrated whiskers to induce increased DNA synthesis and total cellular
    DNA content in embryonic mouse cells. Some similarities may exist between
    mechanisms of silicon carbide and asbestos.
    Mode of action                                                                       41
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        Silicon carbide was not evaluated by IARC.
        Summarizing the above, the following biological effects are observed:
        • Epidemiological evidence indicates that inhalation exposure to silicon
            carbide fibres is responsible for an increased incidence of lung and stomach
            tumours in man3-6 although the contribution of possible confounders can not
            be completely excluded.
        • In one recent epidemiological study it was specifically argued that non-
            fibrous silicon carbide did not seem to contribute to the cancer risk.6
        • Available animal studies demonstrate that silicon carbide fibres induce the
            development of various tumours, including mesotheliomas, after
            inhalation17,18. This was supported by similar findings after intraperitoneal
            and intrapleural administration. The inhalatory carcinogenicity appears to be
            dependent primarily on the fibre length, with fibres longer than 5 µm and
            diameter below 1 µm being carcinogenic. Non-fibrous forms of silicon
            carbide did not induce any adverse effects in a number of short term animal
            studies after inhalatory, intraperitoneal, intrapleural and intratracheal
            administration. However, due to the absence of long term exposure studies no
            conclusions can be drawn on the carcinogenicity of non-fibrous silicon
            carbide.
        Classification                                                                    42
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<pre>•   Standard genotoxicity tests in vitro or in vivo were not available. Only
    Peraud and Riebe-Imre34 reported on an in vitro study showing the potential
    of silicon carbide to induce micronuclei in Syrian golden hamster epithelial
    lung cells. Moreover, an experimental in vitro study demonstrated silicon
    carbide whisker’s capability of inducing DNA synthesis and total cellular
    DNA content in embryonic mouse cells.36
This profile of fibrous silicon carbide has some resemblance with that of
asbestos, which after inhalation can cause asbestosis (a type of pneumoconiosis),
lung cancer, and malignant mesothelioma. Moreover, the in vitro assays
described in this report with asbestos materials as positive controls, show some
comparable intrinsic properties of the two particulates. On the other hand, the
Committee observes an important difference with asbestos in that silicon carbide
exposure leads to mesotheliomas only in animals but not in humans.
The Committee is of the opinion that, in general, test systems for the
genotoxicity of fibres are ambiguous and that the data for silicon carbide are
limited. The oxidative potential seems to be less important than for asbestos.
Overall, the Committee considers it likely that fibrous silicon carbide acts via a
non-stochastic mechanism. This implies that for further risk assessment and
derivation of a health based reference value a threshold approach may be
considered.
The Committee is of the opinion that during applications of non-fibrous silicon
carbide the presence of fibrous structures in the workplace may not be excluded
(see Section 2.1).1 Therefore, employees may be exposed to a mixture of non-
fibrous and fibrous forms and not just to the non-fibrous silicon carbide. These
fibrous structures may, depending on their form and quantity, still increase the
carcinogenic risk to humans.
The Committee is concerned about the question whether, in spite of the existing
regulations, the commercial granular material is sufficiently free of fibrous forms
to not pose a risk when used in the workplace. Therefore, the Committee advises
to quantify the carcinogenic risk and to establish safe occupational exposure
levels.
Classification                                                                      43
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<pre>5.2 Recommendation for classification
    Based on the available information, the Committee concludes that the fibrous
    forms of silicon carbide (fibers, whiskers) may cause cancer according to a non-
    stochastic genotoxic mechanism and should be classified as carcinogenic to
    humans (category 1A). The data on the non-fibrous form of silicon carbide are
    insufficient to classify the carcinogenic properties of this substance (category 3).*
    According to the classification system of the Health Council (see Annex E).
    Classification                                                                        44
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<pre>  References
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  Infante-Rivard C, Dufresne A, Armstrong B, Bouchard P, Theriault G. Cohort study of silicon carbide
  production workers. Am J Epidemiol 1994; 140(11): 1009-1015.
  Romundstad P, Andersen A, Haldorsen T. Cancer incidence among workers in the Norwegian silicon
  carbide industry. Am J Epidemiol 2001; 153(10): 978-986.
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  workers in the Norwegian silicon carbide industry. Scand J Work Environ Health 2010; 36(1): 71-79.
  Bugge MD, Kjaerheim K, Føreland S, Eduard W, Kjuus H. Lung cancer incidence among Norwegian
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  Føreland S, Bugge MD, Bakke B, Bye E, Eduard W. A novel strategy for retrospective exposure
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  Bugge MD, Kjuus H, Martinsen JI, Kjaerheim K. Cancer incidence among short- and long-term
  workers in the Norwegian silicon carbide industry. Scand J Work Environ Health 2010; 36(1): 71-79.
  Romundstad P, Andersen A, Haldorsen T. Non-malignant mortality among Norwegian silicon
  carbide smelter workers. Occup Environ Med 2002; 59(5): 345-347.
0 Bugge MD, Føreland S, Kjaerheim K, Eduard W, Martinsen JI, Kjuus H. Mortality from non-
  malignant respiratory diseases among workers in the Norwegian silicon carbide industry:
  associations with dust exposure. Occup Environ Med 2011; 68(12): 863-869.
  References                                                                                          45
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<pre>1 Jarvholm B, Thiringer G, Axelson O. Cancer morbidity among polishers. Br J Ind Med 1982; 39(2):
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2 Edling C, Jarvholm B, Andersson L, Axelson O. Mortality and cancer incidence among workers in an
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3 Jakobsson K, Mikoczy Z, Skerfving S. Deaths and tumours among workers grinding stainless steel: a
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4 Masse S, Begin R, Cantin A. Pathology of silicon carbide pneumoconiosis. Mod Pathol 1988; 1(2):
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5 Funahashi A, Schlueter DP, Pintar K, Siegesmund KA, Mandel GS, Mandel NS. Pneumoconiosis in
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6 Dufresne A, Loosereewanich P, Harrigan M, Sebastien P, Perrault G, Begin R. Pulmonary dust
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7 Davis JMG, Brown DM, Cullen RT, Donaldson K, Jones AD, Miller BG et al. A comparison of
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8 Miller BG, Jones AD, Searl A, Buchanan D, Cullen RT, Soutar CA et al. Influence of characteristics
  of inhaled fibres on development of tumours in the rat lung. Ann Occup Hyg 1999; 43(3): 167-179.
9 Stanton MF, Layard M, Tegeris A, Miller E, May M, Morgan E et al. Relation of particle dimension
  to carcinogenicity in amphibole asbestoses and other fibrous minerals. J Natl Cancer Inst 1981;
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0 Paulussen JJC, Mahieu CM, Bos PM. Default values in occupational risk assessment. TNO report
  1998; V98.390.
1 Johnson NF, Hahn FF. Induction of mesothelioma after intrapleural inoculation of F344 rats with
  silicon carbide whiskers or continuous ceramic filaments. Occup Environ Med 1996; 53(12): 813-
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2 Vasil'eva LA, Pylev LN, Kiianenko VV, Nikolaishvili AA. [Carcinogenic properties of silicon
  carbide whiskers]. Eksp Onkol 1989; 11(2): 13-15.
3 Adachi S, Kawamura K, Takemoto K. A trial on the quantitative risk assessment of man-made
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4 Miller BG, Searl A, Davis JM, Donaldson K, Cullen RT, Bolton RE et al. Influence of fibre length,
  dissolution and biopersistence on the production of mesothelioma in the rat peritoneal cavity. Ann
  Occup Hyg 1999; 43(3): 155-166.
5 Pott F, Roller M, Rippe RM, Germann P-G, Bellmann. Tumors by the intraperitoneal and intrapleural
  routes and their significance for the classification of mineral fibres. In: Brown RC, Hoskins JA,
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  Vol 223): New York: Plenum Press; 1991: 547-565.
6 Roller M, Pott F, Kamino K, Althoff GH, Bellmann B. Results of current intraperitoneal
  carcinogenicity studies with mineral and vitreous fibres. Exp Toxicol Pathol 1996; 48(1): 3-12.
  References                                                                                             46
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<pre>7 Pott F, Roller M, Kamino K, Bellmann B. Significance of durability of mineral fibers for their
  toxicity and carcinogenic potency in the abdominal cavity of rats in comparison with the low
  sensitivity of inhalation studies. Environ Health Perspect 1994; 102 Suppl 5: 145-150.
8 Akiyama I, Ogami A, Oyabu T, Yamato H, Morimoto Y, Tanaka I. Pulmonary effects and
  biopersistence of deposited silicon carbide whisker after 1-year inhalation in rats. Inhal Toxicol 2007;
  19(2): 141-147.
9 Lapin CA, Craig DK, Valerio MG, McCandless JB, Bogoroch R. A subchronic inhalation toxicity
  study in rats exposed to silicon carbide whiskers. Fundam Appl Toxicol 1991; 16(1): 128-146.
0 Bruch J, Rehn B, Song H, Gono E, Malkusch W. Toxicological investigations on silicon carbide. 1.
  Inhalation studies. Br J Ind Med 1993; 50(9): 797-806.
1 Vaughan GL, Trently SA, Wilson RB. Pulmonary response, in vivo, to silicon carbide whiskers.
  Environ Res 1993; 63(2): 191-201.
2 Bruch J, Rehn B, Song W, Gono E, Malkusch W. Toxicological investigations on silicon carbide. 2.
  In vitro cell tests and long term injection tests. Br J Ind Med 1993; 50(9): 807-813.
3 Begin R, Dufresne A, Cantin A, Masse S, Sebastien P, Perrault G. Carborundum pneumoconiosis.
  Fibers in the mineral activate macrophages to produce fibroblast growth factors and sustain the
  chronic inflammatory disease. Chest 1989; 95(4): 842-849.
4 Peraud A, Riebe-Imre M. Toxic and chromosome-damaging effects of natural and man-made mineral
  fibres in epithelial lung cells in vitro. In: Dungworth DL, Mauderly JL, Oberdorster G, editors. Toxic
  and carcinogenic effects of solid particles in the respiratory tract. ILSI Monograph (Mohr U, editor-
  in-chief); Washington DC: ILSI Press; 1994: 569-574.
5 Brown DM, Fisher C, Donaldson K. Free radical activity of synthetic vitreous fibers: iron chelation
  inhibits hydroxyl radical generation by refractory ceramic fiber. J Toxicol Environ Health A 1998;
  53(7): 545-561.
6 Vaughan GL, Jordan J, Karr S. The toxicity, in vitro, of silicon carbide whiskers. Environ Res 1991;
  56(1): 57-67.
7 Brown DM, Beswick PH, Donaldson K. Induction of nuclear translocation of NF-kappaB in
  epithelial cells by respirable mineral fibres. J Pathol 1999; 189(2): 258-264.
8 Brown DM, Beswick PH, Bell KS, Donaldson K. Depletion of glutathione and ascorbate in lung
  lining fluid by respirable fibres. Ann Occup Hyg 2000; 44(2): 101-108.
9 Svensson I, Artursson E, Leanderson P, Berglind R, Lindgren F. Toxicity in vitro of some silicon
  carbides and silicon nitrides: whiskers and powders. Am J Ind Med 1997; 31(3): 335-343.
0 Nymark P, Wikman H, Hienonen-Kempas T, Anttila S. Molecular and genetic changes in asbestos-
  related lung cancer. Cancer Lett 2008; 265(1): 1-15.
1 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague: Health Council of the Netherlands, 2010; publication no. A10/07E.
  References                                                                                               47
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E Carcinogenic classification of substances by the Committee
  Annexes
                                                             48
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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 governmen-
     tal advisory structure, to improve the integration of the development of recommendations for health
     based occupation standards and the development of comparable standards for the general population.
     A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
     Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
     by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
     exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
     (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        49
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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.
Request for advice                                                                                    50
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemicals NV, Terneuzen
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  G.B. van der Voet, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              51
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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.
The Committee                                                                      52
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<pre>nnex C
     The submission letter
     Subject            : Submission of the advisory report Silicon carbide
     Your Reference     : DGV/MBO/U-932342
     Our reference      : U-7475/BvdV/fs/246-S17
     Enclosed           :1
     Date               : December 7, 2012
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     Silicon carbide.
     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
     has been assessed by the Health Council's Standing Committee on Health and the
     Environment.
     The submission letter                                                          53
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<pre>    In its advisory report the Committee has recommended separate
classifications for fibrous silicon carbide (category 1A) and non-fibrous silicon
carbide (category 3).
    The Committee is concerned about the question whether, in spite of the
existing regulations, the commercial granular material is sufficiently free of
fibrous forms to not pose a risk when used in the workplace. Therefore, the
Committee advises to quantify the carcinogenic risk and to establish safe
occupational exposure levels.
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
The submission letter                                                             54
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in June 2012 for public review. The
     following organisations and persons have commented on the draft document:
     • Mr. T.J. Lentz, National Institute for Occupational Safety and Health
         (NIOSH), Cincinnati, USA
     • Mr. J. Cherrie, Institute of Occupational Medicine (IOM), Edinburgh, UK
     • Mr. C.L. König, ESD-SIC BV, Delfzijl, and Silicon Carbide Manufacturers
         Association (SiCMa), Luxembourg
     • Mr. P.S. ter Haar, Vereniging voor Oppervlaktetechnieken van Materialen
         (VOM).
     Comments on the public review draft                                            55
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<pre> nnex        E
             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
                                                                                 (before              (as from
                                                                                 16 December 2008)    16 December 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 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.41
             Carcinogenic classification of substances by the Committee                                                56
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