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

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<pre>Aan de staatssecretaris van Sociale zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Talc
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7252/BvdV/fs/246-K16
Bijlagen               :1
Datum                  : 24 juli 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
talk.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen wor-
den geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan
mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving van
de Gezondheidsraad.
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. H. Obertop,
waarnemend voorzitter
Bezoekadres                                                      Postadres
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X D e n          Haag                                   2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7                           Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
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<pre></pre>

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<pre>Talc
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of
the Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/11, The Hague, July 24, 2012
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, 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. Talc. Evaluation of the carcinogenicity and
genotoxicity. The Hague: Health Council of the Netherlands, 2012; publication
no. 2012/11.
all rights reserved
ISBN: 978-90-5549-903-8
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedures 13
.3 Data 14
   General information 15
.1 Identity and physicochemical properties 15
.2 IARC conclusion 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 28
.3 Cell transformation tests 31
   Mode of action 33
.1 Genotoxic mode of action 33
   Contents                                   7
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<pre>    Classification 35
 .1 Evaluation of data on carcinogenicity and genotoxicity 35
 .2 Recommendation for classification 37
    References 39
    Annexes 43
A   Request for advice 45
B   The Committee 47
C   The submission letter (in English) 49
D   Comments on the public review draft 51
E   IARC Monograph 53
F   Carcinogenic classification of substances by the Committee 65
    Talc
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<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid beoordeelt
de Gezondheidsraad de kankerverwekkende eigenschappen van stoffen waaraan
mensen tijdens de beroepsuitoefening kunnen worden blootgesteld. De evaluatie
en beoordeling worden verricht door de subcommissie Classificatie van Carcino-
gene Stoffen van de Commissie Gezondheid en Beroepsmatige Blootstelling aan
Stoffen van de raad, hierna kortweg aangeduid als de commissie. In het voorlig-
gende advies neemt de commissie talk onder de loep. De commissie heeft haar
oordeel gegoten in door de Europese Unie aangegeven termen. De beoordeling is
gericht op talk dat geen asbest of asbestvormige vezels bevat en op talkpoeder.
Mineraal talk wordt gebruikt in landbouwproducten, keramiek, verf en andere
deklagen, papier, plastic, dakbedekking, rubber, cosmetica, geneesmiddelen en
voor afvalbewerking. Cosmetische talk, wat meer dan 90% mineraal talk bevat,
is aanwezig in vele cosmetische producten en wordt gebruikt voor vele doelein-
den, inclusief baby poeder en hygiënische producten voor vrouwen.
    Op basis van de beschikbare gegevens, hoewel deze veelal wijzen op afwe-
zigheid van kankerverwekkende eigenschappen, is de commissie van mening dat
de gegevens over talk onvoldoende zijn om de kankerverwekkende eigenschap-
pen te beoordelen (categorie 3).*
Volgens het nieuwe classificatiesysteem van de Gezondheidsraad (zie bijlage F).
Samenvatting                                                                    9
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<pre>0 Talc</pre>

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<pre>Executive summary
At the 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 Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Safety of the Health Council,
hereafter called the Committee. In this report the Committee evaluated talc. The
evaluation is based on talc not containing asbestos or asbestiform fibres and talc
used as body powder. Mineral talc is used in agricultural products, ceramics,
paint and other coatings, paper, plastics, roofing, rubber, cosmetics and
pharmaceuticals and for waste treatment. Cosmetic talc, which contains more
than 90% mineral talc, is present in many cosmetic products and is used for
many purposes, including baby powders and feminine hygiene products.
    Based on the available information, although mainly indicating the absence
of carcinogenicity, the Committee is of the opinion that the data are insufficient
to evaluate the carcinogenic properties of talc (category 3).*
According to the new classification system of the Health Council (see Annex F).
Executive summary                                                                  11
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<pre>2 Talc</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. The Minister of Social Affairs and
        Employment has asked the Health Council of the Netherlands to study 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 and genotoxicity of
        talc.
1.2     Committee and procedures
        This document contains an evaluation by the Subcommittee of the Classification
        of Carcinogenic Substances of the Dutch Expert Committee on Occupational
        Safety of the Health Council, hereafter called the Committee. The members of
        the Committee are listed in Annex B. The submission letter (in English) to the
        State Secretary can be found in Annex C.
            In 2012, 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
        Scope                                                                               13
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<pre>    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 standardly based on
    scientific data, which are publicly available. The starting points of the
    Committees’ reports are, if possible, the monographs of the International Agency
    for Research on Cancer (IARC). This means that the original sources of the
    studies, which are mentioned in the IARC-monograph, are reviewed only by the
    Committee when these are considered most relevant in assessing the
    carcinogenicity and genotoxicity of the substance in question. In the case of
    metallic chromium, such an IARC-monograph is available, of which the
    summary and conclusion of IARC is inserted in Annex E. More recently
    published data were retrieved from the databases Medline, Toxline, Toxcenter
    (STN), Scisearch / Current Content (STN), Chemical Abstracts (STN) and
    Chembank using talc, talcum and CAS no. 14807-96-6 as key words in
    combination with key words representative for carcinogenesis and mutagenesis.
    The last updated online search was in June 2012. The new relevant data were
    included in this report.
 4  Talc
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<pre> hapter 2
        General information
2.1     Identity and physicochemical properties
        Chemical name            : Talc
        CAS registry number      : 14807-96-6
        EINECS number            : 238-877-9
        RTECS-number             : WW2710000
        Synonyms                 : soapstone, steatite, talcum, French chalk
        Appearance               : white, very fine crystalline powder
        Occurrence               : talc is a very common metamorphic mineral in metamorphic belts.
        Use                      : Mineral talc: used in agricultural products, for clarifying liquids by
                                   filtration; as pigment in paints, varnishes and rubber; as filler for
                                   paper, rubber and soap; in fireproof and cold-water paints for wood,
                                   metal and stone; in lubricating molds and machinery, as electric and
                                   heat insulator, in cosmetics and pharmaceuticals (filler for pills), as
                                   glove and shoe powder, and for waste treatment.
                                   Cosmetic talc (contains > 90% mineral talc): used in many cosmetic
                                   products and for many purposes, including baby powders and
                                   feminine hygiene products. Also used therapeutically (talc
                                   insufflation or talc pleurodesis) to treat non-malignant and
                                   malignant pulmonary disease.
        Chemical formula         : Mg3(OH)2Si4O10
        Molecular weight         : 379.3
        Boiling point            :
        Melting point            : 900-1,000 °C
        Vapour pressure          :
        Vapour density (air = 1) :
        Solubility               : insoluble in water, cold acids or in alkalines
        General information                                                                                15
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<pre>    Conversion factor            :
    flash point
    Stability and reactivity     :
    EU Classification            :   Talc is not classified in the Annex I of Directive 67/548/EEC as
                                     such, but it may be included in one of the group entries.
    Data from IARC1-3, Merck4, HSDB5, EC-JRC6, NIOSH7 and Baan8
    The term ‘talc’ refers to both mineral talc and industrial products that contain
    mineral talc in proportions that range from about 35% to almost 100% and are
    marketed under the name talc. Mineral talc is usually platy but may also occur
    occasionally and in exceptional cases as long, thin, asbestiform fibres in parallel
    bundles, which are easily separated from each other by hand pressure. It should
    be noted that the term “asbestiform” refers to a pattern of mineral growth (i.e., a
    habit) and not to the presence of other minerals. Therefore, asbestiform talc must
    not be confused with talc that contains asbestos. Talc products vary in their
    particle size, associated minerals and talc content depending on their source and
    application. Minerals commonly found in talc products include chlorite and
    carbonate. Less commonly, talc products contain tremolite, anthophyllite* and
    serpentine. The current evaluation is based on talc not containing asbestos or
    asbestiform fibres and on talc used as body powder.
2.2 IARC conclusion
    Talc was evaluated by IARC in a Working Group in 20061, the actual monograph
    was published in 20102. It was concluded that there was limited evidence in
    experimental animals for the carcinogenicity of talc not containing asbestos or
    asbestiform fibres. It was also concluded that there is inadequate evidence in
    humans for the carcinogenicity of inhaled talc not containing asbestos or
    asbestiform fibres, and limited evidence in humans for the carcinogenicity of
    perineal use of talc-based body powder.
    Perineal use of talc-based body powder was classified as possibly carcinogenic
    to humans (Group 2B). Inhaled talc not containing asbestos or asbestiform fibres
    is not classifyable as to its carcinogenicity (Group 3).
    Tremolite and anthophyllite are members of the amphibole group of silicate minerals.
 6  Talc
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
3.1.1   Epidemiological studies on inhalation exposure to talc
        Rubino et al. (1976) studied 1,514 miners and 478 millers employed for at least
        one year between 1921 and 1950 in talc mines and mills in the Germanasca and
        Chisone valleys (Piedmont) in Italy.9 The talc in those mines is described as quite
        pure, with only some tremolite micro-inclusions; no other fibrous mineral was
        reportedly found. Significant increases in specific cause of death among miners
        were found for silicosis (62 observed/30.9 expected) and for silico-tuberculosis
        (18/9.1). Significant deficits in cause-specific mortality were reported for
        malignant neoplasms at other sites (23/39.9). Two cases of pleural mesothelioma
        and a high occurrence of silicosis and silico-tuberculosis were found in the
        comparison group. [The IARC Working Group noted that the method used to
        derive the number of expected deaths is not adequately described. It was
        considered that the lack of comparability between the worker and comparison
        groups could be the main explanation for the mortality increases and deficits
        observed in this study.]
            The cohort of Piedmont talc workers (Rubino et al., 1976, 1979) was recently
        updated with a mortality analysis conducted among 1,244 miners and 551 millers
        who had worked ≥ 1 yr during 1946-1995.9,10 Compared with regional or
        national rates, total mortality among the workers was increased (SMR (standard
        Carcinogenicity                                                                     17
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<pre>  mortality ratio), 1.2; 95% CI, 1.1-1.3), which was mainly due to nonmalignant
  respiratory disease among the miners. There was no excess mortality for total
  cancer or for lung cancer, and no case of pleural or peritoneal mesothelioma was
  reported (Coggiola et al., 2003).11
      Selevan et al. (1979) carried out a study of talc exposures in five companies
  (two of which ceased operations in 1952 and 1960) in three regions in Vermont,
  USA.12 Analysis of airborne dust samples and talc bulk samples revealed no
  asbestos, either by X-ray diffraction or analytical electron microscopy. Levels of
  respirable free silica were below 0.25% in nearly all ore and product samples,
  and free silica was only occasionably detectable in air samples. Insufficient
  information was available to estimate cumulative exposures, but the authors
  stated that past exposure levels for miners and millers ‘far exceeded the present
  standard for nonfibrous talc of 20 mppcf ‘(million particles per cubic foot) (the
  statutory standard referred to was not further specified by the authors). They
  considered it probable that dust exposure for millers were higher than those for
  miners. In one mine, which had closed by the time of the study, ‘cobblestones’ of
  highly tremolitic serpentine rock were present but were avoided or discarded as
  far as possible prior to milling. The cohort consisted of all white male talc
  workers who had been radiographed as part of annual voluntary surveys of the
  Vermont Health Department, who were employed in the Vermont talc industry
  between 1 January 1940 and 31 December 1969, and who had worked in the
  industry for at least one year. [Because of the voluntary nature of the survey, the
  cohort may not have been representative.] There were 90 deaths among the 392
  members of this cohort; vital status was not established for four. For non-
  malignant respiratory disease and respiratory cancer, Vermont rates were used
  for comparison, because they are higher than national rates; for other causes of
  death, US rates were used. [The IARC Working Group noted this unconventional
  analytical approach.] While some increase was noted for malignant neoplasms,
  and specifically for respiratory neoplasms (6 observed /3.69 expected), these
  were not found to be significant. [The IARC Working Group noted that the
  results were not analysed by latency.] The excess of respiratory cancer occurred
  only among miners (5/1.15; p<0.05), and the significant excess for the non-
  malignant respiratory disease occurred only among millers (7/1.72; p<0.01).
  Most of those dying with non-malignant respiratory disease had radiographic
  evidence of pneumoconiosis (rounded opacities). Miners were also exposed to
8 Talc
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<pre>radon daughters at mean levels ranging up to 0.12 working levels, with single
peaks of 1.0 working level.*
     Léophonte et al. (1983) reported on the mortality of talc workers in Luzenac,
France. The talc in this region is said to contain no asbestos and levels of quartz
varying from 0.5-3%.13 The cohort comprised those who left employment
between 1 January1945 and 31 December 1981 having worked for at least one
year. Of 470 workers available for study, 256 were living, 209 had died and
5 were lost to follow-up; 192/204 with known occupational exposure had worked
only at Luzenac. When compared with the regional population, the median age
of death was not found to be influenced by dust exposure. There was no
significant excess in cancer mortality in general, and, specifically, mortality from
respiratory and digestive cancers was not increased. A significant increase in
mortality was found for non-malignant respiratory disease, especially for
pneumoconiosis and obstructive lung disease. [The IARC Working Group noted
the unconventional definition of the cohort, that no data on smoking habits were
available, and that causes of death were obtained for cases from local doctors,
hospitals or families but for controls from regional or national records.]
     A cohort study in Norway included 94 talc miners and 295 talc millers who
had been employed for ≥ 1 yr during 1944-1972 (miners) or ≥ 2 yr during 1935-
1972 (millers). The talc in this study is composed mainly of pure talc and
magnesite, and contains < 1% quartz, tremolite and anthophyllite. The
standardized incidence ratio (SIR) for all cancers was 1.4 (95% CI, 0.8-2.3; 15
observed cases) among the miners and 0.8 (95% CI, 0.5-1.1; 31 observed cases)
among the millers. In the groups of 80 workers in the highest exposure category,
a total of six cases of cancer were observed (SIR, 0.4 [95% CI, 0.2-1.1]), none of
which were cancer of the lung. There was no case of mesothelioma (Wergeland
et al., 1990).14
     Mortality rates among workers employed in the talc quarry in Luzenac,
France, were reported by Léophonte and Didier (1990).15 The talc in this region
contains chlorite and dolomite, 0.5-3% quartz, but no asbestos. The results
described in this report confirm those of the previous publication by these
authors (Léophonte et al., 1983).13
     A cohort-mortality study at the Luzenac talc quarry and milling plant in
France comprised 1070 men and 90 women employed ≥ 1 yr during 1946-1994.
The concentration of radon daughters is measured in units of working level (WL) which is a measure
of the potential alpha particles energy per litre of air. One WL of radon daughters corresponds to
approximately 200 pCi/L of radon in a typical indoor environment.
Carcinogenicity                                                                                    19
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<pre>  No statistically significant excess mortality was found for any cancer (Wild,
  2000).16
      A combined analysis comprised the 1070 workers at Luzenac and 542
  workers of three talc mines and mills in Austria, who had been employed ≥ 1 yr
  during 1972-1995. There was no excess of total cancer or lung cancer in the
  Austrian cohort. A nested-case control study was conducted with 30 lung cancer
  cases (23 from the French and 7 from the Austrian cohort) and 88 matched
  controls. Job tasks were categorized according to talc dust levels (no exposure;
  < 5 mg/m3; 5-30 mg/m3 and > 30 mg/m3) and cumulative talc exposure (in
  mg/m3-yr) was calculated for cases and controls. There was no evidence of
  increased lung cancer with increasing exposure. Adjusting for tobacco smoking,
  exposure to quartz or underground work did not change the results (Wild et al.,
  2002).17
      A meta-analysis of lung cancer mortality studies among miners and millers
  processing non-asbestiform talc in the United States (Selevan et al., 1979)12,
  France (Wild, 2000)16, Austria (Wild et al., 2002)17, Norway (Wergeland et al.,
  2003)14 and Italy (Coggiola et al., 2003)11 was performed by Wild (2006)18.
  Studies with populations in which no other occupational carcinogen was
  mentioned (only talc millers satisfied this criterion) reported no excess lung
  cancer mortality (overall SMR of 0.92; 95% CI, 0.67-1.25, 42 cases) (Wild,
  200618).
      In a community-based case-control study in Canada (Siemiatycki, 1991),
  information on job histories and on potential confounders was obtained through
  interviews.19 Over 4000 subjects were interviewed including patients with 20
  different types of cancer and a population control series. Potential occupational
  exposures included industrial talc, notably among painters, car mechanics and
  farmers. There were no statistically significant increases in cancer risk associated
  with exposure to talc.
  IARC (2006, 2010) summarises in their view on the abovementioned studies that
  he carcinogenic effect of exposure to talc not contaminated by asbestiform fibres
  has been investigated in five independent but relatively small cohort studies of
  talc miners and millers in the USA, Norway, Italy, France and Austria.1,2 The
  miners and to a lesser extent the millers in these cohorts were also exposed to
  quartz. In the miners in the US study, an excess risk for lung cancer was found,
  which may have been due to exposure to radon daughters and quartz in the
  workplace. In all the other groups of workers studied, there was no increased risk
  for lung cancer. In the two studies from Norway and Italy, which included an
  estimate of cumulative exposure to talc dust, the risk for lung cancer in the
0 Talc
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<pre>highest category was found to be close to or below unity. In a case-control study
nested in the combined cohorts of talc workers from France and Austria, there
was no tendency of higher risks for lung cancer by increasing cumulative
exposure of workers to talc dust. In four of five studies, it was explicitly stated
that no case of mesothelioma was observed [summary IARC 2006].
    Churg and Wiggs (1985) analyzed the total fibrous and non-fibrous mineral
content of the lung in 14 male lung cancer patients without history of
occupational dust exposure and 14 controls, matched by sex, age, smoking
history and general occupational class.20 Lung cancer patients had an average of
114 ± 161 talc mineral particles and 1.1 ± 1.4 talc mineral fibres/g dry lung,
while the controls had averages of 28 ± 20 talc mineral particles and 0.5 ± 0.5
talc mineral fibres/g dry lung [not clear whether the differences are statistically
significant]. However, lung cancer patients also had increased amounts of
kaolinite, mica, feldspars and crystalline silica mineral particles and mineral
fibres in the lung.20 Therefore, no conclusions can be drawn regarding the
association of (talc) mineral particles and fibres and lung cancer.
    Thomas and Stewart (1987, 1990) examined lung cancer mortality in a cohort
study among 2055 white men employed in three ceramic plumbing fixture
factories.21,22 In a cohort mortality study, 2055 white men, employed for at least
one year between 1939 and 1966 at three plants of a single USA company, were
followed through January 1981. Lung cancer mortality was significantly higher
than expected among workers whose jobs involved simultaneous exposure to
high silica and non-fibrous talc (standardized mortality ratio 2.54), but not
among workers exposed to only talc or only silica. In the group of workers
simultaneously exposed to silica and non-fibrous (nonasbestiform) talc, lung
cancer mortality risk increased with increasing number of years of exposure to
non-fibrous talc, but showed no pattern by number of years of exposure to silica.
Lung cancer risk increased with years since first non-fibrous talc exposure and
decreased with age at first exposure.21,22
    Chiazze et al. (1993) described a case-control study of malignant and non
malignant respiratory disease among employees of a fiberglass manufacturing
facility in Ohio.23 Employment histories from the fiberglass facility provided
information on employment characteristics (duration of employment, year of
hire, age at first hire) and an interview survey obtained information on
demographic characteristics (birthdate, race, education, marital state, parent’s
ethnic background, and place of birth), lifetime residence, occupational and
smoking histories, hobbies, and personal and family medical history. Matched,
unadjusted odds ratios (ORs) were used to assess the association between lung
cancer or non-malignant respiratory disease and the cumulative exposure history,
Carcinogenicity                                                                     21
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<pre>  demographic characteristics, and employment variables. Adjusted ORs for lung
  cancer and non malignant respiratory disease after talc use versus never exposed
  were 1.355 (95% CI 0.407-4.515) and 0.760 (95% CI 0.175-3.298),
  respectively.23 It must be noted that data may be difficult to interpret, since
  employees were also exposed to respirable fibers, fine fibers, asbestos,
  formaldehyde, silica, and asphalt fumes.
      Honda et al. (2002) evaluated mortality among workers at an industrial
  (tremolite) talc mining and milling facility in New York.24 Subjects were white
  men actively employed between 1948 and 1989 and known to have been alive in
  or after 1950. Analyses assessed cancer mortality during the period 1950-89 (809
  subjects) and non-cancer mortality during 1960-89 (782 subjects). Comparisons
  with regional general population death rates for 1960-89 indicated that the
  workers had more than expected deaths from all causes combined [209 observed/
  160 expected, standardized mortality ratio (SMR) = 1.31, 95% confidence
  interval (CI) = 1.14-1.50], due mainly to increased mortality from lung cancer
  (31/13, SMR = 2.32, CI = 1.57-3.29) and non-malignant respiratory disease
  (NMRD) (28/13, SMR = 2.21, CI = 1.47-3.20). The median estimated exposure
  to respirable dust was 511 mg/m3-days for all exposed employees, 739 mg/m3-
  days for mine workers and 683 mg/m3-days for mill workers. Employees with
  high, compared with low, estimated exposure to talc dust had a rate ratio of 0.5
  (CI = 0.2-1.3) for lung cancer and of 11.8 (CI = 3.1-44.9) for pulmonary
  fibrosis.24 It must be noted that the facility contains a high amount of non-
  asbestiform amphibole.
      Ramanakumar et al. (2008) analyzed lung cancer risk in relation to talc
  exposure, adjusted for several potential confounders, including smoking, in two
  large population based case-control studies of lung cancer carried out in
  Montreal. Detailed lifetime job histories were elicited, and a team of hygienists
  and chemists evaluated the evidence of exposure to a host of occupational
  substances. Several analyses were carried out separately in four study
  populations: Study I – using population controls, Study I – using cancer controls,
  Study II – males and Study II – females and a pooled analysis. Subjects with
  occupational exposure to industrial talc and cosmetic talc did not experience any
  detectable excess risk of lung cancer (ORs and 95%CIs in study I: 0.6; 0.2-2.7
  and 0.7; 0.3-1.7 for industrial talc using population controls and cancer controls,
  respectively; 0.3; 0.1-2.0 and 0.4; 0.3-3.6 for cosmetic talc using population
  controls and cancer controls, respectively; ORs and 95%CIs in study II: 1.4;
  0.4-3.1 for industrial talc in males; 0.4; 0.1-2.1 for cosmetic talc in females;
  pooled ORs and 95%CIs: 0.9; 0.5-1.3 for industrial talc and 0.7; 0.3-1.8 for
  cosmetic talc).25
2 Talc
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<pre>          Langseth and Andersen (1999) investigated the cancer risk among female
      Norwegian pulp and paper workers.26 The cohort included a total of 4,247
      workers employed for at least one year between 1920 and 1993 and the follow-
      up period for cancer was from 1953-1993. During the follow-up period, 380 new
      cases of cancer were observed vs. 322 expected (standard incidence ratio (SIR)
      1.2, 95% CI 1.07-1.30). An excess risk of ovarian cancer was found (SIR 1.5,
      95% CI 1.07-2.09). The SIR was highest among those younger than 55 years,
      and mostly among those working in paper departments. Short-term workers
      showed increased risk of lung and bladder cancer (SIR 3.0, 95% CI 1.29-5.89
      and SIR 3.7, 95% CI 1.00-9.38, respectively)26. It should be noted that, besides
      to talc, the women might also have been exposed to asbestos and different types
      of paper dust as well as to other chemicals used in the pulp and paper industry.
          Among others based on the previous cohort study, Langseth and Kjaerheim
      (2004) investigated the association between ovarian cancer and occupational talc
      exposure among Norwegian pulp and paper workers in a case-control set-up.
      Forty-six cases of ovarian cancer, with four controls each, were included in the
      study. No association between ever talc exposure in the Norwegian pulp and
      paper industry and ovarian cancer was found (odds ratio 1.10, 95% CI 0.56-
      2.18).27 It is not clear from the study description if there was an overlap in the
      study populations from the two Langseth studies.
          Hartge and Stewart (1994) investigated the occupational exposure to talc in
      relation to ovarian cancer risk. Job histories of 296 women aged 20-79 who were
      diagnosed with epithelial ovarian cancer in the Washington DC area in 1978-
      1981 were compared to 343 hospital controls, matched for age and race.
      Occupational exposure to talc for more than 10 years resulted in a relative risk of
      0.5 (95% CI 0.2-1.5) when compared to no occupational exposure to talc,
      indicating that occupational exposure to talc is not associated with an altered risk
      of ovarian cancer.28
3.1.2 Epidemiological studies on perineal use of talc-based body powders
      Talc-based body powder has been used by women on the perineum (or genital
      area) and on sanitary napkins. In total, data from one prospective cohort study
      and over 20 case-control studies are available to date (June 2012) to evaluate the
      association of use of talc-based body powder and risk for ovarian cancer. Also a
      number of meta-analyses are available as yet.
          Gertig et al. (2000) carried out the only prospective cohort analysis that
      reported an association between perineal use of talcum, baby or deodorant
      powder and the risk for ovarian cancer.29 This analysis was conducted among
      Carcinogenicity                                                                      23
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<pre>  participants in the Nurses’ HealthStudy. The study population included 78,630
  women who responded to the questions on powder use in 1982 and entailed 984
  212 person-years of follow-up. Between 1982 and June 1996, 307 incident cases
  of epithelial ovarian cancer were identified by self-reporting in a biennial
  questionnaire, by deaths that were reported by relatives or postal authorities or
  through the National Death Index. In 1982, 40.4% of the cohort reported a
  history of perineal talc use (n = 31 789) and 14.5% reported a history of daily use
  (n = 11 411). Overall, no association between ‘ever use’ of talcum powder and
  total risk for epithelial ovarian cancer (relative risk, 1.1; 95% CI, 0.9-1.4) and no
  trend of increased risk for ovarian cancer with increasing frequency of talc use
  were observed. However, a modest increase in risk for serous invasive cancers
  was associated with any history of talc use (relative risk, 1.4; 95% CI, 1.0-1.9)
  and a borderline significant trend was found with increasing frequency of use
  (p for trend = 0.05).
      IARC (20102, based on the activities of the working group in 20061)
  summarizes their view on the 19 of the case-control studies. They included
  between 77 and 824 cases and between 46 and 1,105 controls. Five were
  hospital-based designs and the others were population-based studies. The IARC
  Working Group selected a subset of 8 of these studies as being more informative
  based on the following characteristics: whether the study was population-based,
  was of a reasonable size, had acceptable participation rates and included
  information to allow control for potentially important confounders (Cramer et al.
  198230, Harlow BL et al. 199231, Chan & Risch 199732, Cook et al. 199733,
  Green et al. 199734, Cramer 199935, Ness et al. 200036, Mills et al. 200437).
      Cramer et al. (1982) reported a case-control study of ovarian cancer and talc
  exposure in the Boston, Massachusetts, USA, area between November 1978 and
  September 1981.30 Two-hundred-and-fifteen women with pathologically-
  confirmed epithelial ovarian cancers were identified and matched randomly by
  residence, race and age. Ninety-two (42.8%) cases regularly used talc either as a
  dusting powder on the perineum or on sanitary napkins compared with 61
  (28.4%) controls. Adjusted for parity and menopausal status, this difference
  yields a relative risk of 1.9 (p<0.003). Women who had regularly engaged in both
  practices had an adjusted relative risk of 3.3 (p<0.001) compared to women with
  neither exposure.
      Harlow et al. (1992) analysed perineal exposure to talc and the risk for
  ovarian cancer among 235 cases and 239 controls in the Boston, MA
  metropolitan area (USA).31 Cases were diagnosed with ovarian cancer between
  June 1984 and September 1987 at one of 10 Boston hospitals and controls were
  identified from town registers listing the name, age and address of all residents in
4 Talc
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<pre>Massachusetts. All cases were Caucasian women aged 18-76 years at diagnosis
and were similar to the controls with respect to race, age and area of residence. A
total of 526 women were contacted as potential controls. A history of ‘any’
perineal exposure to talc-containing powders was reported by 48.5% of cases and
39.3% of controls to yield an odds ratio of 1.5 (95% CI, 1.0-2.1).
    Green et al. (1997) evaluated the association between tubal ligation or
hysterectomy and the risk for ovarian cancer using the Australian study
population described by Purdie et al. (1995).34 [The analysis by Green et al.
(1997) used the same number of cases but five fewer controls than Purdie et al.
(1995).] A modest increase in risk for ovarian cancer was observed with
peritoneal use of talc (odds ratio, 1.3; 95% CI, 1.1-1.6). Neither duration of talc
use nor age at first use were associated with risk for ovarian cancer.
    Chang and Risch (1997) analysed the association between perineal use of
powder and the risk for ovarian cancer among 450 cases and 564 population
controls from metropolitan Toronto and southern Ontario, Canada.32 Forty-four
per cent of cases and 36% of controls reported ‘any’ talc use in the perineal area
to yield an odds ratio of 1.4 (95% CI, 1.1-1.9).
    Cook et al. (1997) evaluated the association between use of genital powders
or deodorants and the risk for ovarian cancer in a case-control study conducted in
three counties of western Washington State, USA.33 Cases were aged 20-79 years
at diagnosis, were diagnosed with borderline or invasive epithelial ovarian
cancer between 1986 and 1988 and were identified using the population-based
Cancer Surveillance System of western Washington. Controls were identified
using random-digit dialling, were residents of the three counties of interest and
were similar in age to the cases. Three hundred twenty nine cases were
interviewed (64.3%) and 313 were included in the analysis [61.1%]. Fivehundred
twenty one controls were interviewed and 422 were included in the analysis
[58.5%]. A history of ‘any’ lifetime genital powder use (perineal dusting,
diaphragm storage, use on sanitary napkins or use of deodorant spray) was
reported by 50.8% of cases and 39.3% of controls to yield an odds ratio of
1.5 (95% CI, 1.1-2.0) after adjustment for age. The authors also evaluated the
association between any genital use of powder and the risk for the major
histological subtypes of ovarian cancer. Risk was significantly elevated for
serous tumours (odds ratio, 1.7; 95% CI, 1.1-2.5) and all other tumour types
(odds ratio, 1.8; 95% CI, 1.1-2.8) but not for mucinous or endometrioid tumours.
    Cramer et al. (1999) analysed the association between genital exposure to
talc and the risk for primary epithelial ovarian cancer among 563 cases and 523
controls residing in eastern Massachusetts and New Hampshire, USA.35 Talc use
in non-genital areas was not associated with risk when compared with women
Carcinogenicity                                                                     25
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<pre>  who did not use personal powder (odds ratio, 1.1; 95% CI, 0.8-1.5). However,
  genital use of talc was associated with a significant 60% increase in risk (odds
  ratio, 1.6; 95% CI, 1.2-2.2). Women who reported more than one method of talc
  use in the genital area had an even greater risk for ovarian cancer (odds ratio, 2.2;
  95% CI, 1.3-3.6).
      Ness et al. (2000) examined whether factors related to an inflammatory
  response of the ovarian epithelium (such as exposure to talc, endometriosis, cysts
  and hyperthyroidism) played a role in the risk for ovarian cancer.36 The study
  was conducted among 767 recently diagnosed cases of epithelial ovarian cancer
  and 1,367 population-based controls. A history of talc use in the genital/rectal
  area was reported by 161 cases [21.0%] and 219 controls [16.0%] to yield an
  adjusted odds ratio of 1.5 (95% CI, 1.1-2.0). There was no clear trend between
  risk for ovarian cancer and increasing duration of use of talc on the genital and/or
  rectal area or feet.
      Mills et al. (2004) evaluated the association between perineal exposure to talc
  and the risk for ovarian cancer in an ethnically diverse population from 22
  counties of central California, USA.37 The study included 256 incident cases
  diagnosed between 1 January 2000 and 31 December 2001 and identified
  through two regional cancer registries using rapid case ascertainment procedures
  and 1,122 controls identified by random-digit dialling. Controls were frequency-
  matched to the cases by age and ethnicity. A history of perineal talc use was
  reported by 42.6% of the cases and 37.1% of the controls to yield an adjusted
  odds ratio of 1.4 (95% CI, 1.0-1.9). A significant trend (P = 0.015) with
  increasing frequency of talc use was observed. The greatest risk for ovarian
  cancer was observed among women with the highest frequency of use (odds
  ratio, 1.7 for use 4-7 times per week; 95% CI, 1.1-2.6).
      These 8 studies selected by IARC included at least 188 cases and had
  participation rates generally ranging from 60 to 75%. Among these eight studies,
  the prevalence of perineal use of talc-based body powder among controls ranged
  from 16 to 52%; however, information on exposure was not collected in a
  comparable manner across studies. In addition, frequency and duration of use or
  total lifetime applications were reported in several studies as well as
  consideration of prior tubal ligation or hysterectomy. Only sparse data were
  available on whether women had used body powder prior to or after the mid-
  1970s.
      The relative risks for ovarian cancer among body powder users (versus non-
  users) were homogenous across this relatively diverse set of eight studies, each
  of which indicated a 30-60% increase in risk [significance not mentioned].
  Among the other 11 case-control studies, most also reported relative risks of this
6 Talc
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<pre>magnitude or higher. The subset of studies that assessed use of talc on a
diaphragm was relatively uninformative due to low precision.
    Results on exposure-response relationships were presented in the cohort
study (Gertig et al. 2000)29 and in seven of the more informative case-control
studies. In the cohort study, no exposure-response trend was apparent. Positive
exposure-response trends were apparent in the two Boston-based studies, which
presented the most comprehensive analysis. In the remaining five studies,
consistent trends were not observed.
    Several meta-analyses were performed with regard to the association of
perineal talc use and ovarian cancer which were not included in the IARC
monography. Meta-analyses of nine case-control studies that have been
published that address the purported association between talc use and an
increased risk of ovarian cancer were performed by Gross & Berg (1995). Meta-
analyses were performed for crude and adjusted risk, and for malignant and
borderline tumors together and epithelial tumors only. Crude risk, both tumor
types: RR 1.27 (1.09-1.48); adjusted risk, both tumor types: 1.31 (1.08-1.58);
crude risk, epithelial tumors: 1.20 (1.01-1.44); adjusted risk, epithelial tumors:
1.29 (1.02-1.63).38
    According to Cramer et al. (1999), the combined OR from 14 case control
studies on the risk for ovarian cancer with genital use of talc was 1.36 (95% CI
1.24-1.49), which is statistically significant.35
    Huncharek et al. (2003) performed a meta-analysis to evaluate the
association between perineal cosmetic talc use and increased risk of epithelial
ovarian cancer (never vs. ever or none vs. any). Data from 16 observational
studies were pooled using a general variance based meta-analytic method. This
resulted in a RR of 1.33 (95% CI 1.16-1.45), a statistically significant result.
Nevertheless, the data showed a lack of a clear dose-response relationship. Since
hospital-based studies did not show a significant relationship between talc use
and ovarian cancer risk (RR 1.19, 95% CI 0.99-1.41), in contrast to population-
based studies (RR 1.38, 95% CI1.25-1.52), the authors suggest that selection bias
and/or uncontrolled confounding may account for the positive association
observed in many studies.39
    In addition, Huncharek et al. (2008) performed another meta-analysis, in
which 9 observational studies were included which have studied the association
of ovarian cancer risk and direct exposure of the female genital tract to talc via
dusting of contraceptive diaphragms. [Some of the studies included were also
used for the meta-analysis of 2003.] Adjusted ORs ranged from 0.5-1.56 and
none of the studies reached a significant effect on ovarian cancer risk. Data were
Carcinogenicity                                                                    27
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<pre>      pooled using a general variance based meta-analytic method. The results yielded
      a non-statistically significant summary relative risk of 1.03 (95% CI 0.8-1.37).40
           In addition, Muscat and Huncharek (2008) reported in a review that in 7
      studies that gathered information on (talc-dusted) condom use, none of these
      studies found an increased risk with ovarian cancer. Crude RRs ranged from
      0.49-1.0.41
           More recently, a review was published by Langseth et al. (2008).42 This
      review included the association between talc use in the perineal region and
      ovarian cancer investigated in one cohort study, and 20 case-control studies. In
      the cohort study, there was no association between cosmetic talc use and risk of
      all subtypes of ovarian cancer combined. The various case-control studies
      provided indications of either a significant excess risk (10 studies) or non-
      significant excess risk or null (10 studies), with odds ratios (ORs) ranging from
      1.0 to 3.9 (see Table 1). None of the studies reported relative risks below 1.0.
      Pooled odds ratios, calculated by fixed effects model, were 1.40 (95% CI 1.29-
      1.52), 1.12 (95% CI 0.92-1.36) and 1.35 (95% CI 1.26-1.46) for population-
      based, hospital-based and all case control studies combined, respectively. No
      clear trend of exposure-response associations, in terms of frequency of use or
      length of use in years was found in the studies. Before 1976, talc was to some
      extent contaminated with asbestos, so that the early studies relating talc to
      ovarian cancer may have been confounded by the asbestos. However, the
      association between talc exposure and ovarian cancer is as strong in recent
      studies, as in earlier ones, diminishing the likelihood that all these results are
      influenced by contamination of talc by asbestos.42
3.2   Carcinogenicity studies in animals
3.2.1 Inhalation studies
      The IARC Working Group noted that in most of the studies of talc described
      below, no or limited characterization of the mineralogy of the sample employed
      was given, and, in particular, there was a lack of information on fibre content or
      particle size. In most studies, information was insufficient to determine whether
      the talc contained asbestiform fibres.
           Wistar-derived rats (24/sex/group), six to eight weeks of age, were exposed
      by inhalation to a mean respirable dust concentration of 10.8 mg/m3 Italian talc
      (grade 00000; ready milled; mean particle size, 25 µm; containing 92% talc, 3%
      chlorite, 1% carbonate minerals and 0.5-1% quartz) for 7.5 h per day on five days
      a week for six (24 rats) or twelve (24 rats) months (cumulative exposures, 8,200
 8    Talc
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<pre>and 16,400 mg/m3 × h, respectively). Ten days after the end of each exposure
period, six rats in each group were killed; a further four rats were killed in each
group one year later. Within 28 months of the start of the study, a further 12
animals in each group had died. No lung tumours were observed in rats exposed
to talc for six months, while one lung adenoma occurred among those exposed
for twelve months. No lung tumour was found in the controls (Wagner et al.,
1977).43 [The IARC Working Group noted the limited number of animals
allowed to survive longer than 12 months after the end of each exposure period.]
     Syrian golden hamsters (50/sex/group), four weeks old, were exposed to an
aerosol of talc body powder, prepared from Vermont talc by flotation (95% w/w
platy talc with trace quantities of magnesite, dolomite, chlorite and rutile), for 3,
30 or 150 min per day on five days a week for 30 days. The mean total aerosol
concentration was 37.1 mg/m3, with a mean respirable fraction of 9.8 mg/m3 and
a mass median aerodynamic diameter of 4.9 µm. Two further groups of hamsters,
seven weeks old, were exposed to talc aerosol for 30 or 150 min per day for 300
days or until death. The mean total aerosol concentration was 27.4 mg/m3, with a
mean respirable fraction of 8.1 mg/m3 and a mass median aerodynamic diameter
of 6 µm. Two control groups (25/sex/group) were sham exposed. No primary
neoplasm was found in the respiratory system of any hamster. The incidence of
alveolar-cell hyperplasia was 25% in the groups exposed to aerosol for 30 or 150
min per day for 300 days, compared with 10% in the control group (Wehner et
al., 1977, 1979).44,45[The IARC Working Group noted the inadequate duration of
the study.]
     Syrian golden hamsters (24/sex/group), nine weeks old, received 18 weekly
intratracheal injections of 3 mg talc (United States Pharmacopeia grade; 93.3%
below 25 µm) in 0.2 ml saline, with or without 3 mg benzo[α]pyrene, or 0.2 ml
saline only, or were untreated. The animals were allowed to live out their lifespan
(average 50% survival, 46-55 weeks). No respiratory-tract tumour was observed
in animals exposed to talc alone or in saline-treated or untreated controls. In
hamsters exposed to talc with benzo[α]pyrene, 33/45 animals had benign and
malignant tumours of the respiratory tract (larynx to lung) (Stenbäck and
Rowland, 1978).46 [The IARC Working Group noted that no group received
benzo[α]pyrene alone and that the survival in all groups was relatively short.]
     Male and female Fischer 344N rats were exposed by inhalation to aerosols of
0, 6, or 18 mg/m3 talc (MP 10-52; maximum particle size, 10 µm) for 6 h/day on
5 days/wk for up to 113 wk (males) and 122 wk (females). MP 10-52 grade talc
is a high-purity microtalc from a Montana strip mine that is reported to contain
no tremolite or any asbestiform minerals; it was found to be free of asbestos by
polarized light microscopy and transmission electron microscopy. The survival
Carcinogenicity                                                                       29
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<pre>      of the exposed rats was similar to that of the controls. No clinical findings were
      attributed to exposure to talc. Exposure to talc produced a spectrum of
      inflammatory, reparative and proliferative processes in the lungs. The incidences
      of alveolar/bronchiolar carcinoma or adenoma and carcinoma (combined) in
      female rats were control, 1/50; low-dose, 0/48; and high-dose, 13/50 (carcinoma,
      5/50), and were significantly higher in the high-dose group than in controls
      (p < 0.001). The incidences of pulmonary neoplasms in exposed male rats were
      similar to those in controls. Adrenal medulla phaeochromocytomas (benign and
      malignant combined) occurred with a significant positive trend in males (control,
      26/49; low-dose, 32/48; high-dose, 37/47; p = 0.006) and females (control,
      13/48; low-dose, 14/47; high-dose, 23/49; p = 0.02). Incidences of malignant
      phaeochromocytomas in females were: control, 0/48; low-dose, 1/47; high-dose,
      10/49 (p = 0.001) (revisited).47 [The IARC Working Group discussed the high
      background incidence of the phaeochromocytomas in this strain of rats and noted
      that this type of tumor was not reported in particle inhalation studies other than
      those of the National Toxicology Program. The IARC Working Group did not
      consider it probable that the increased incidence of phaeochromocytomas was
      causally related to talc, but based on the experimental data available, neither can
      talc-related effects be excluded.]
           In a parallel study, male and female B6C3F1 mice were exposed by
      inhalation (6 h/day on 5 days/wk for up to 104 wk) to 0, 6, or 18 mg/m3 MP 10-
      52 talc. Survival and final mean body weights of the exposed mice were similar
      to those of the controls, and no clinical findings were attributed to exposure to
      talc. No significant increase in the incidence of neoplasms was observed and the
      incidence of pulmonary neoplasms was similar in exposed and control groups.47
           [According to Oberdörster and the ILSI Risk Science Institute, the lung
      tumours found in the rat study are a secondary effect of chronic pulmonary
      overload and not a direct carcinogenic effect of talc. In mice and hamsters,
      tumorigenesis has not been observed after lung overload. It is still not known
      with certainty whether high lung burdens of poorly soluble particles as talc can
      lead to lung cancer in humans via mechanisms similar to those of the rat.48,49]
3.2.2 Oral studies
      Wistar rats (25/sex/group), ten weeks of age, received about 50 mg/kg bw per
      day commercial talc [characteristics unspecified] in the diet or standard diet for
      life (average survival, 649 days). No significant difference in tumour incidence
      was found in comparison with controls (Gibel et al., 1976).50
 0    Talc
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<pre>          Wistar-derived rats (16/sex/group), 21-26 weeks of age, were exposed to 100
      mg Italian talc (grade 00000; ready milled; mean particle size, 25 µm; containing
      92% talc, 3% chlorite, 1% carbonate minerals and 0.5-1% quartz) per day per rat
      in the diet for five months and then maintained on basal diet for life (average
      survival, 614 days). A control group of 16 rats was fed basal diet. No difference
      in tumour incidence was found between the two groups (Wagner et al., 1977).43
      [The IARC Working Group noted the limited exposure period and the advanced
      age of the animals at the start of exposure.]
3.2.3 Other studies
      In one study in rats (Pott et al. 1974)51 and two studies in mice (Bischoff &
      Bryson, 1976)52 of intraperitoneal administration of talc, no increase in the
      incidence of mesotheliomas was observed. Two other studies of intraperitoneal
      administration, one in rats and one in mice, were found to be inadequate for
      evaluation. One study in rats and one study in mice by intrathoracic
      administration were found to be inadequate for evaluation. In one study by
      intrapleural injection of talc in rats (Wagner et al.,1977)43 and in another study by
      intrapleural implantation of various talcs in rats, tumour incidence was not
      increased (Stanton et al.,1981)53. A single subcutaneous injection of talc in mice
      did not produce local tumours (Neukomm & de Trey, 1961)54. No tumour was
      produced in rats in one study of administration of talc in the diet or in another
      study by implantation of talc into the ovary Hamilton et al.,1984).55 Tumour
      incidence was not increased following administration of talc to hamsters by
      inhalation or intratracheal administration (Stenbäck & Rowlands, 1978).46
3.3   Cell transformation tests
      Normal human epithelial (OSE2a) and granulosa ovarian (GC1a) cell lines and
      polymorphonuclear neutrophils (PMN) were incubated with talc (0-500 µg/mL)
      from 24 to 120 h. Talc significantly increased proliferation, induced neoplastic
      transformation (in the OSE2a cells at 5 and 20 µg/mL talc and in the GC1a cells
      at 5, 20 and 100 µg/mL talc). In addition, talc increased reactive oxygen species
      (ROS) generation time-dependently in the ovarian cells (at 20 µg/mL (72 and
      120 h) and 50 µg/mL in OSE2a cells and with 0.5, 20 and 50 µg/mL (72 and 120
      h), as well as 5 and 100 µg/mL (120 h) in GC1a cells, compared with the
      respective 24 h values), and dose-dependently in the PMN (significant at 0.5, 5,
      20, 50 µg/mL (24 h) and 100 and 500 µg/mL (24 and 72 h)).56
      Carcinogenicity                                                                       31
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<pre>2 Talc</pre>

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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
4.1.1   Gene mutation assay
        In vitro
        Talc was not mutagenic to Salmonella typhimurium TA1530 or his G46 or to
        Saccharomyces cerevisiae D3 in vitro [full details not given].3
        In vivo
        Talc was not mutagenic in host-mediated assays in mice (30-5,000 mg/kg bw)3.
        Neither chromosomal aberrations nor dominant lethal mutations were induced in
        rats following oral administration of 30-5,000 mg/kg bw talc.3
4.1.2   Cytogenetic assays
        In vitro
        Chromosomal aberrations were not induced in human WI38 cells treated with
        talc at 2-200 µg/mL.3 Endo-Capron and colleagues (1993) tested the genotoxicity
        of 3 talc samples (French, Italian and Spanish talc) in cultures of rat pleural
        Mode of action                                                                  33
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<pre>  mesothelial cells (RPMC) using genotoxicity assays for unscheduled DNA
  synthesis (UDS) and sister chromatid exchanges (SCEs). Each talc sample
  contained 90-95% talc, other compounds being chlorite and dolomite. For UDS,
  cells were treated with talc concentrations of 0, 10, 20 and 50 µg/cm2 (or 0, 50,
  100 and 250 µg/L) for 24 hours. For the SCE assay, cells were treated with 0, 2,
  5, 10 or 15 µg/cm2 (or 0, 15, 37.5, 75 or 112.5 µg/L) for 48 hours in the dark.
  None of the talc samples induced enhancement of UDS or SCEs in treated
  cultures, in contrast to the positive controls (Rhodesian chrysotile and crocidolite
  asbestos).57
  In vivo
  Single intraperitoneal injections of 20 mg talc plus 2 mg particulate prednisolone
  acetate in saline into mice induced significant numbers of multinucleated giant
  cells within 48 h. Neither compound alone induced this response. The
  multinucleate cells arose by cell fusion and the resultant polykarions exhibited
  severe structural chromosomal abnormalities (bridges, acentrics and dispersed
  chromosomes). Prednisone in combination with talc also elicited the formation
  of multinucleated giant cells. Polykarions were not observed when talc was
  injected in combination with cortexone acetate, cortisone or testosterone
  isobutyrate (Dreher et al., 1978).58
4 Talc
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data with regard to the carcinogenic effects of ingestion of talc were available
        in humans.
            Carcinogenicity following the inhalation of talc (not containing asbest or
        asbestiform fibers, although sometimes contaminated with other dusts) has been
        extensively studied in workers of talc mines, mills or factories chronically
        exposed to talc dusts. A meta-analysis of lung cancer mortality studies among
        miners and millers processing non-asbestiform talc in the United States (Selevan
        et al., 1979)12, France (Wild, 2000)16, Austria (Wild et al., 2002)17, Norway
        (Wergeland et al., 2003)14 and Italy (Coggiola et al., 2003)11 was performed by
        Wild (2006)18. This analysis indicates that studies with populations of talc
        millers exposed to high levels of relatively pure talc in which no other
        occupational carcinogen was mentioned, no excess lung cancer mortality was
        reported (overall SMR of 0.92; 95% CI, 0.67-1.25, 42 cases). These studies are
        in support of the view that talc is not carcinogenic to man. On the other hand, in
        some population studies of talc miners and talc workers in other industrial
        settings the cancer mortality risks were in excess. However, in these studies
        coexposures to carcinogens such as quartz may obscure either the presence or
        absence of a carcinogenic effect of talc. Therefore, the results of these studies are
        not sufficient to exclude talc as a carcinogen.
        Classification                                                                        35
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<pre>      Twenty case-control studies were identified on the association between
  perineal use of talc-based body powders and risk of ovarian cancer and used for a
  meta-analysis. Six were hospital-based designs and the others were population-
  based studies. While none of the hospital-based studies showed a significant
  increase in the risk of ovarian cancer following perineal talc use, 10 of the
  population-based studies did. Moreover, a meta-analysis of all population-based
  studies as well as a meta-analysis of all hospital- and population-based studies
  combined showed a significant increase in risk of ovarian cancer (1.40; 95%
  CI 1.29-1.52 and 1.35; 95% CI 1.26-1.46) (Langseth et al., 2008).42 In contrast,
  in a cohort study no indications for an association between perineal talc use and
  ovarian cancer were found. A clear exposure-response relationship (either
  frequency based or length in years based) was lacking in most of the studies or
  not even investigated. Several factors have to be kept in mind, such as the
  possibility of recall bias, selection bias and uncontrolled confounding. In
  addition, adequate mechanistic data are still absent, and the fact that several
  studies, including a cohort study are negative do raise questions regarding the
  exact association of perineal talc use and risk of ovarian cancer. The Committee
  considers the association between perineal exposure and ovarial cancer not very
  convincing but taken together the data are not sufficient to exclude talc as a
  carcinogen.
      The Committee is of the opinion that, if only the results of the occupational
  studies in talc millers were to be evaluated, talc could be classified as not
  carcinogenic to humans. However, the Committee is also aware of the
  occupational studies on talc miners and other industrial populations which do not
  justify to exclude talc as a lung carcinogen. In addition, the Committee is aware
  of the human studies on perineal exposure which do not exclude talc in talc-
  based body powder as an ovarian carcinogen. Taken together, the Committee is
  of the opinion that the epidemiological studies not sufficiently prove that talc is
  not a carcinogen.
  Oral studies in rats do not indicate that talc is carcinogenic. In addition,
  subcutaneous, intraperitoneal, intrathoracic and intrapleural injections in mice
  and/or rats did not increase the incidence of tumors. Also, no tumours were
  induced in rats in one study where talc was implantated into the ovary.
      Inhalation of aerosols of talc (18 mg/m3, 6h/d, 5d/w, 122w) resulted in a
  significantly higher incidence of adrenal medulla phaeochromocytomas (benign
  and malignant combined) in male (37/47 vs 26/49 in controls) and female
  Fischer rats (23/49 vs 13/48 in controls). However, it is not probable that this is
  causally related to talc, since Fischer rats show a high background incidence of
6 Talc
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<pre>    phaeochromocytomas, and phaeochromocytomas were not observed in other
    (NTP) studies. In female rats (but not in male rats) a significantly higher
    incidence of alveolar/bronchiolar carcinoma or adenoma and carcinoma
    (combined) was observed. Tumour incidence (either local or not local) was not
    increased following repeated inhalation exposure in other studies in rats, mice
    and hamsters (doses up to 10.8 mg/m3, 7.5h/d, 5d/w, 12 m; 18 mg/m3, 6h/d,
    5d/w, 104w; 9.8 mg/m3, 2.5h/d, 5d/w, 30d). The lung tumours found in the first
    rat study are suggested to be a secondary effect of chronic pulmonary overload
    and not a direct carcinogenic effect of talc. However, currently it cannot be
    excluded that a similar mechanism could also occur in humans. Thus, in spite of
    the adrenal medulla phaeochromocytomas observed in one inhalation study in
    rats, which are probably not talc-related, further animal data do not indicate a
    direct carcinogenic potency of talc not containing asbest or asbestiform fibers.
    Nevertheless, alveolar/bronchiolar carcinomas were observed in rats due to lung
    overload with talc particles, indicating that carcinogenesis might occur as a
    secondary effect to inhalation exposure to talc. This secondary carcinogenic
    effect of talc may also be relevant for humans.
         With respect to the animal studies the Committee is of the opinion that, in
    spite of one reliable (NTP) study, their number is limited and their quality is not
    sufficient to conclude on the carcinogenic potential of talc.
    No data on the genotoxicity of talc in humans were available. The results of the
    few in vitro studies and the single in vivo study available on the genetic
    toxicology of talc were negative. Therefore, the available data indicate that talc is
    not genotoxic.
5.2 Recommendation for classification
    Based on the available information, although mainly indicating the absence of
    carcinogenicity, the Committee is of the opinion that the data are insufficient to
    evaluate the carcinogenic properties of talc (category 3).*
    According to the new classification system of the Health Council (see Annex F).
    Classification                                                                        37
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<pre>8 Talc</pre>

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<pre>  References
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  IARC. Talc. IARC Monographs on the Evaluation of Carcinogenic Risks of Chemicals to Humans
  2010; 93: 277-413.
  IARC. Talc. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans
  1987; 42: 185-224.
  The Merck Index, 14th edition. An Encyclopedia of Chemicals, Drugs, and Biologicals. 2006.
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  NIOSH. http://www.cdc.gov/niosh/npg/npgd0584.html (accessed July 2, 2012).
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  asbestos or asbestiform fibers: recent evaluations by an IARC Monographs Working Group. Inhal
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  Rubino GF, Scansetti G, Piolatto G, Romano CA. Mortality study of talc miners and millers. J Occup
  Med 1976; 18(3): 187-193.
0 Rubino GF, Scansetti G, Piolatto G. Mortality and morbidity among talc miners and millers in Italy.
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  Exposures to Fibrous and Particulate Dust and Their Extension into the Environment. Park Forst
  South: Pathotox Publisher Inc; 2012: 357-363.
1 Coggiola M, Bosio D, Pira E, Piolatto PG, La Vecchia C, Negri E et al. An update of a mortality study
  of talc miners and millers in Italy. Am J Ind Med 2003; 44(1): 63-69.
  References                                                                                            39
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<pre>2 Selevan SG, Dement JM, Wagoner JK, Froines JR. Mortality patterns among miners and millers of
  non-asbestiform talc: preliminary report. J Environ Pathol Toxicol 1979; 2(5): 273-284.
3 Leophonte P, Basset MF, Pincemin J et al. Mortality of talc workers in France: a retrospective
  epidemiological study. Rev Fr Mal Respir 1983; 11: 489-490.
4 Wergeland E, Andersen A, Baerheim A. Morbidity and mortality in talc-exposed workers. Am J Ind
  Med 1990; 17(4): 505-513.
5 Leophonte P, Didier A. French talc pneumoconiosis. In: Bignon J, editor. Health Effects of
  Phyllosilicates. Berlin, Heidelberg: Springer Verlag; 1990: 203-209.
6 Wild P. An epidemiological mortality study in the Talc-producing industry. Study Report (INSR/EE
  Report TMT), Paris, Institut National de la Recherche Scientifique (in French) 2000.
7 Wild P, Leodolter K, Refregier M, Schmidt H, Zidek T, Haidinger G. A cohort mortality and nested
  case-control study of French and Austrian talc workers. Occup Environ Med 2002; 59(2): 98-105.
8 Wild P. Lung cancer risk and talc not containing asbestiform fibres: a review of the epidemiological
  evidence. Occup Environ Med 2006; 63(1): 4-9.
9 Risk Factors for Cancer in the Workplace. Siemiatycki J. Risk Factors for Cancer in the Workplace.
  Boca Raton, FL: CRC Press; 1991.
0 Churg A, Wiggs B. Mineral particles, mineral fibers, and lung cancer. Environ Res 1985; 37(2):
  364-372.
1 Thomas TL, Stewart PA. Mortality from lung cancer and respiratory disease among pottery workers
  exposed to silica and talc. Am J Epidemiol 1987; 125(1): 35-43.
2 Thomas TL. Lung cancer mortality among pottery workers in the United States. IARC Sci Publ
  1990;(97): 75-81.
3 Chiazze L, Jr., Watkins DK, Fryar C, Kozono J. A case-control study of malignant and non-malignant
  respiratory disease among employees of a fiberglass manufacturing facility. II. Exposure assessment.
  Br J Ind Med 1993; 50(8): 717-725.
4 Honda Y, Beall C, Delzell E, Oestenstad K, Brill I, Matthews R. Mortality among workers at a talc
  mining and milling facility. Ann Occup Hyg 2002; 46(7): 575-585.
5 Ramanakumar AV, Parent ME, Latreille B, Siemiatycki J. Risk of lung cancer following exposure to
  carbon black, titanium dioxide and talc: results from two case-control studies in Montreal. Int J
  Cancer 2008; 122(1): 183-189.
6 Langseth H, Andersen A. Cancer incidence among women in the Norwegian pulp and paper industry.
  Am J Ind Med 1999; 36(1): 108-113.
7 Langseth H, Kjaerheim K. Ovarian cancer and occupational exposure among pulp and paper
  employees in Norway. Scand J Work Environ Health 2004; 30(5): 356-361.
8 Hartge P, Stewart P. Occupation and ovarian cancer: a case-control study in the Washington, DC,
  metropolitan area, 1978-1981. J Occup Med 1994; 36(8): 924-927.
9 Gertig DM, Hunter DJ, Cramer DW, Colditz GA, Speizer FE, Willett WC et al. Prospective study of
  talc use and ovarian cancer. J Natl Cancer Inst 2000; 92(3): 249-252.
0 Talc
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<pre>0 Cramer DW, Welch WR, Scully RE, Wojciechowski CA. Ovarian cancer and talc: a case-control
  study. Cancer 1982; 50(2): 372-376.
1 Harlow BL, Cramer DW, Bell DA, Welch WR. Perineal exposure to talc and ovarian cancer risk.
  Obstet Gynecol 1992; 80(1): 19-26.
2 Chang S, Risch HA. Perineal talc exposure and risk of ovarian carcinoma. Cancer 1997; 79(12):
  2396-2401.
3 Cook LS, Kamb ML, Weiss NS. Perineal powder exposure and the risk of ovarian cancer. Am J
  Epidemiol 1997; 145(5): 459-465.
4 Green A, Purdie D, Bain C, Siskind V, Russell P, Quinn M et al. Tubal sterilisation, hysterectomy and
  decreased risk of ovarian cancer. Survey of Women's Health Study Group. Int J Cancer 1997; 71(6):
  948-951.
5 Cramer DW, Liberman RF, Titus-Ernstoff L, Welch WR, Greenberg ER, Baron JA et al. Genital talc
  exposure and risk of ovarian cancer. Int J Cancer 1999; 81(3): 351-356.
6 Ness RB, Grisso JA, Cottreau C, Klapper J, Vergona R, Wheeler JE et al. Factors related to
  inflammation of the ovarian epithelium and risk of ovarian cancer. Epidemiology 2000; 11(2):
  111-117.
7 Mills PK, Riordan DG, Cress RD, Young HA. Perineal talc exposure and epithelial ovarian cancer
  risk in the Central Valley of California. Int J Cancer 2004; 112(3): 458-464.
8 Gross AJ, Berg PH. A meta-analytical approach examining the potential relationship between talc
  exposure and ovarian cancer. J Expo Anal Environ Epidemiol 1995; 5(2): 181-195.
9 Huncharek M, Geschwind JF, Kupelnick B. Perineal application of cosmetic talc and risk of invasive
  epithelial ovarian cancer: a meta-analysis of 11,933 subjects from sixteen observational studies.
  Anticancer Res 2003; 23(2C): 1955-1960.
0 Huncharek M, Muscat J, Onitilo A, Kupelnick B. Use of cosmetic talc on contraceptive diaphragms
  and risk of ovarian cancer: a meta-analysis of nine observational studies. Eur J Cancer Prev 2007;
  16(5): 422-429.
1 Muscat JE, Huncharek MS. Perineal talc use and ovarian cancer: a critical review. Eur J Cancer Prev
  2008; 17(2): 139-146.
2 Langseth H, Hankinson SE, Siemiatycki J, Weiderpass E. Perineal use of talc and risk of ovarian
  cancer. J Epidemiol Community Health 2008; 62(4): 358-360.
3 Wagner JC, Berry G, Cooke TJ et al. Animal experiments with talc. In: Walton Wh, McGovern B,
  editors. Inhaled Particles. Oxford: Pergamon Press; 1977: 647-654.
4 Wehner AP, Zwicker GM, Cannon WC. Inhalation of talc baby powder by hamsters. Food Cosmet
  Toxicol 1977; 15(2): 121-129.
5 Wehner AP, Stuart BO, Sanders CL. Inhalation studies with Syrian golden hamsters. Prog Exp Tumor
  Res 1979; 24: 177-198.
6 Stenback F, Rowlands J. Role of talc and benzo(a)pyrene in respiratory tumor formation. An
  experimental study. Scand J Respir Dis 1978; 59(3): 130-140.
  References                                                                                            41
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<pre>7 NTP Toxicology and Carcinogenesis Studies of Talc (CAS No. 14807-96-6)(Non-Asbestiform) in
  F344/N Rats and B6C3F1 Mice (Inhalation Studies). Natl Toxicol Program Tech Rep Ser 1993; 421:
  1-287.
8 Oberdorster G. The NTP talc inhalation study: a critical appraisal focused on lung particle overload.
  Regul Toxicol Pharmacol 1995; 21(2): 233-241.
9 The relevance of the rat lung response to particle overload for human risk assessment: a workshop
  consensus report. ILSI Risk Science Institute Workshop Participants. Inhal Toxicol 2000; 12(1-2):
  1-17.
0 Gibel W, Lohs K, Horn KH, Wildner GP, Hoffmann F. [Experimental study on cancerogenic activity
  of asbestos filters (author's transl)]. Arch Geschwulstforsch 1976; 46(6): 437-442.
1 Pott F, Dolgner R, Friedrichs KH, Huth F. [The oncogenic effect of fibrous dust. Animal experiments
  and their relationship with human carcinogenesis]. Ann Anat Pathol (Paris) 1976; 21(2): 237-246.
2 Bischoff F, Bryson G. Talc at the rodent intrathoracic, intraperitoneal, and subcutaneous sites
  (Abstract No 1). Proc Am Assoc Cancer Res 1976; 17(1).
3 Stanton MF, Layard M, Tegeris A et al. Relation of particle dimension to carcinogenicity in
  amphibole asbestoses and other fibrous materials. J Natl Cancer Inst 1981; 67: 965-975.
4 Neukomm S, de Trey M. Study of possible carcinogenic and/or co-carcinogenic brightening agents.
  Med Exp 1961; 4: 298-306.
5 Hamilton TC, Fox H, Buckley CH, Henderson WJ, Griffiths K. Effects of talc on the rat ovary. Br J
  Exp Pathol 1984; 65(1): 101-106.
6 Buz’Zard AR, Lau BH. Pycnogenol reduces talc-induced neoplastic transformation in human ovarian
  cell cultures. Phytother Res 2007; 21(6): 579-586.
7 Endo-Capron S, Renier A, Janson X, Kheuang L, Jaurand MC. In vitro response of rat pleural
  mesothelial cells to talc samples in genotoxicity assays (sister chromatid exchange and DNA repair).
  Toxic in vitro 1993; 7(1): 7-14.
8 Dreher R, Keller HU, Hess MW, Roos B, Cottier H. Early appearance and mitotic activity of
  multinucleated giant cells in mice after combined injection of talc and prednisolone acetate. A model
  for studying rapid histiocytic polykarion formation in vivo. Lab Invest 1978; 38(2): 149-156.
9 Health Council of The Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague: 2010.
2 Talc
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<pre>A Request for advice
B The Committee
C The submission letter (in English)
D Comments on the public review draft
E IARC Monograph
F Carcinogenic classification of substances by the Committee
  Annexes
                                                             43
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<pre>4 Talc</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        45
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
6 Talc
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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, Leids 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
        Toxicologist, Health Council of the Netherlands, The Hague
     The Committee                                                             47
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<pre>  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
8 Talc
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<pre>nnex C
     The submission letter (in English)
     Subject         : Submission of the advisory report Talc
     Our reference : DGV/MBO/U-932342
     Your Reference : U-7257/BvdV/fs/246-M16/E
     Enclosed        :1
     Date            : 24 July 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     Talc.
     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 Classifying
     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 (in English)                                             49
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<pre>  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)
  Prof. H. Obertop,
  Acting President
0 Talc
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in February 2012 for public review.
     The following organisations and persons have commented on the draft
     document:
     • Scientific Association of the European Talc Industry (EUROTALC aisbl),
        Brussels, Belgium
     • Talc/Wollastonite Section of the Industrial Minerals Association North
        America (IMA-NA), Washington DC, USA
     • IMERYS Talc America Inc, San Jose, CA, USA
     Comments on the public review draft                                            51
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<pre>2 Talc</pre>

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<pre>nnex E
     IARC Monograph
     Talc (perineal use of talc-based body powder and inhaled talc not containing
     asbestos or asbestiform fibres) has been evaluated by IARC in 2006.
     The summary and evaluation of IARC on the perineal use of talc-based body
     powder and inhaled talc not containing asbestos or asbestiform fibres in IARC
     monograph 93 (2010) is provided.
     D.1        VOL: 93
     CAS No.: 14807-96-6
     Summary of Data Reported and Evaluation
     Exposure data
     The term ‘talc’ refers to both mineral talc and industrial products that contain
     mineral talc in proportions that range from about 35% to almost 100% and are
     marketed under the name talc. Mineral talc occurs naturally in many regions of
     the world where metamorphosed mafic and ultramafic rocks or magnesium
     carbonates occur. Mineral talc is usually platy but may also occur as asbestiform
     fibres. (Asbestiform refers to a habit, i.e. a pattern of mineral growth and not to
     the presence of other minerals. Asbestiform talc must not be confused with talc
     IARC Monograph                                                                      53
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<pre>  that contains asbestos.) Together with platy talc, asbestiform talc is found in the
  Gouverneur District of New York State, USA, and occasionally elsewhere; it
  may be associated with other minerals as observed by transmission electron
  microscopy.
  Talc products vary in their particle size, associated minerals and talc content
  depending on their source and application. Minerals commonly found in talc
  products include chlorite and carbonate. Less commonly, talc products contain
  tremolite, anthophyllite and serpentine.
  Mineral talc is valued for its softness, platyness, inertness and ability to absorb
  organic matter. It is used in agricultural products, ceramics, paint and other
  coatings, paper, plastics, roofing, rubber, cosmetics and pharmaceuticals and for
  waste treatment. Cosmetic talc, which contains more than 90% mineral talc, is
  present in many cosmetic products and is used for many purposes, including
  baby powders and feminine hygiene products. The type of talc that is currently
  used for cosmetic purposes in the USA does not contain detectable levels of
  amphibole, including asbestos. Based on information from Pakistan, it is not
  known whether this is true in other countries.
  Workers are exposed to talc during its mining and milling. Reported exposure
  levels to respirable dust are typically in the range of 1-5 mg/m3 (geometric
  mean). Workers may also be exposed in user industries, primarily in the rubber,
  pulp and paper and ceramic industries. Exposure in the user industries is difficult
  to assess because of the lack of data from such industries and concomitant
  exposure to many other particles. Consumer exposure by inhalation could occur
  during the use of loose powders that contain talc.
  Accurate estimates of prevalence are not available, but the use for feminine
  hygiene of body powders, baby powders, talcum powders and deodorizing
  powders, most of which contain cosmetic talc in varying amounts, has been
  reported to be as high as 50% in some countries, based on the controls from the
  ovarian-cancer epidemiological studies. Perineal use for such purposes seems to
  be common practise in the USA, Canada, Australia and the United Kingdom.
  Based on information from Pakistan, the prevalence of use may be considerable
  in other countries as well.
4 Talc
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<pre>Human carcinogenicity data
The carcinogenic effect of exposure to talc not contaminated by asbestiform
fibres has been investigated in five independent but relatively small cohort
studies of talc miners and millers in the USA, Norway, Italy, France and Austria.
The miners and to a lesser extent the millers in these cohorts were also exposed
to quartz. In the miners in the US study, an excess risk for lung cancer was found,
which may have been due to exposure to radon daughters and quartz in the
workplace. In all the other groups of workers studied, there was no increased risk
for lung cancer. In the two studies from Norway and Italy, which included an
estimate of cumulative exposure to talc dust, the risk for lung cancer in the
highest category was found to be close to or below unity. In a case-control study
nested in the combined cohorts of talc workers from France and Austria, there
was no tendency of higher risks for lung cancer by increasing cumulative
exposure of workers to talc dust. In four of five studies, it was explicitly stated
that no case of mesothelioma was observed.
    In female workers in the Norwegian pulp and paper industry there was an
increased risk for ovarian cancer, which, however, was attributed to exposure to
asbestos. A community-based case-control study did not find an increased risk
for ovarian cancer associated with occupational exposure to talc, but prevalence
of exposure was low.
Body powder has been used by women on the perineum (or genital area) and on
sanitary napkins. In total, data from one prospective cohort study and 19 case-
control studies were reviewed to evaluate the association of use of talc-based
body powder and risk for ovarian cancer. The information collected on perineal
use varied substantially by study (e.g. ever use versus regular use, whether
information on mode of application, frequency or duration of use was available).
    The cohort study was conducted among nurses in the USA and included 307
cases of ovarian cancer that occurred over 900 000 person-years of observation
and a maximum of 14 years of follow-up. Information was collected on
frequency but not duration of regular use. Perineal use of talc-based body powder
was not associated with risk for ovarian cancer.
The 19 case-control studies were conducted in the USA, Canada, the United
Kingdom, Australia, Greece, Israel and China and included between 77 and 824
cases and between 46 and 1105 controls. Five were hospital-based designs and
the others were population-based studies. The Working Group selected a subset
of these studies as being more informative based on the following characteristics:
IARC Monograph                                                                      55
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<pre>  whether the study was population-based, was of a reasonable size, had
  acceptable participation rates and included information to allow control for
  potentially important confounders.
  Eight population-based case-control studies from Australia, Canada (Ontario)
  and the USA (two non-overlapping studies in Boston, and one each in eastern
  Massachusetts and New Hampshire, California, Delaware Valley and
  Washington State) were thereby identified as being more informative. The
  selected studies included at least 188 cases and had participation rates generally
  ranging from 60 to 75%. Among these eight studies, the prevalence of perineal
  use of talc-based body powder among controls ranged from 16 to 52%; however
  information on exposure was not collected in a comparable manner across
  studies. In addition, frequency and duration of use or total lifetime applications
  were reported in several studies as well as consideration of prior tubal ligation or
  hysterectomy. Only sparse data were available on whether women had used body
  powder prior to or after the mid-1970s.
  The relative risks for ovarian cancer among body powder users (versus non-
  users) were homogenous across this relatively diverse set of eight studies, each
  of which indicated a 30-60% increase in risk. Among the other 11 case-control
  studies, most also reported relative risks of this magnitude or higher. The subset
  of studies that assessed use of talc on a diaphragm was relatively uninformative
  due to low precision.
  Results on exposure-response relationships were presented in the cohort study
  and in seven of the more informative case-control studies. In the cohort study, no
  exposure- esponse trend was apparent. Positive exposure-response trends were
  apparent in the two Boston-based studies, which presented the most
  comprehensive analysis. In the remaining five studies, consistent trends were not
  observed.
  The cohort study and four of the eight more informative case-control studies
  presented results on histological type of ovarian cancer. When the analysis of the
  cohort study was restricted to the 160 serous invasive cases, a statistically
  significant increase in risk of about 40% was observed. The risk increased with
  increasing frequency of body powder use. Relative risks for serous ovarian
  cancer were somewhat greater than those for other histological types in two of
  the four case-control studies that presented results on histological type. Results
  for other histological types were inconclusive.
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<pre>The Working Group carefully weighed the various limitations and biases that
could have influenced these findings. Non-differential misclassification of talc
use, given the relatively crude definitions available, would have attenuated any
true association. Although the available information on potential confounders
varied by study, most investigators accounted for age, oral contraceptive use and
parity. In most studies, only the adjusted relative risks were presented; however,
in the three studies in which both age-adjusted and fully adjusted estimates were
provided, relative risks did not differ materially, suggesting minimal residual
confounding by these factors.
It is possible that confounding by unrecognised risk factors may have distorted
the results. One or more such factors, if they are causes of ovarian cancer and
also associated in the population with perineal use of talc, could induce the
appearance of an association between the use of talc and ovarian cancer where
there is none. In order for such an unrecognised risk factor to induce the
consistent pattern of excess risks in all the case-control studies, it would be
necessary for the factor to be associated with perineal talc use across different
countries and different decades. While the range of countries and decades
covered by the more informative case-control studies is not very broad, it
provides some diversity of social and cultural context and thereby reduces the
likelihood of a hidden confounder.
There was a distinct pattern of excess risk discernible in all of the more
informative case-control studies when users were compared with non-users;
however, methodological factors need to be considered. First, while chance
cannot be ruled out as an explanation, it seems very unlikely to be responsible for
the consistent pattern of excess risks. A second possible explanation would be
recall bias, to which case-control studies may be particularly susceptible. This
may have resulted if there had been widespread publicity about the possible
association between use of body powder and cancer. Namely, in such
circumstances, it is possible that women who had ovarian cancer would more
likely report use of talc than women who did not have ovarian cancer. There was
a flurry of publicity in the USA in the mid-1970s concerning the possible risks
for cancer posed by the use of talc-based body powders, in response to which the
industry decided to market talc powders without asbestos contamination (levels
below the detection limit). It is the opinion of the Working Group that there has
not been widespread public concern about this issue, at least until very recently.
The Working Group therefore considers it unlikely that such a bias could explain
the set of consistent findings that stretch over two decades. Another source of
IARC Monograph                                                                      57
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<pre>  recall bias could result from the fact that women with a cancer may be more
  likely to remember or over-report a habit, such as body powder use, if they
  thought that it may have played a role in their illness. The Working Group
  believes this source of bias is a possibility inherent in the case-control studies
  and cannot be ruled out. The Working Group also considered publication and
  selection biases and these were not judged to have substantially influenced the
  pattern of findings.
  The Working Group searched for documentation on the presence of known
  hazardous minerals in talc-based body powders. There are strong indications that
  these products contained quartz in the mid-1970s and still do. There are
  indications that occasional small concentrations of asbestos were present in these
  products before the mid-1970s, but the available information is sparse, sampling
  methods and detection limits were not described, and the range of locations
  where data are available is extremely limited. As a result, the Working Group
  found it difficult to identify a date before which talc-based body powders
  contained other hazardous minerals and after which they did not, or to have
  confidence that this would be applicable worldwide. In addition, the
  epidemiological studies generally do not provide information about the years
  when the female subjects were exposed. Consequently, the Working Group could
  not identify studies where an uncontaminated form of talc was the only one used
  by study subjects. Nonetheless, the Working Group noted that even in the most
  recent studies in the USA, where exposure histories are less likely to have been
  affected by hazardous contaminants of talc, the risk estimates were not different
  from those of the early studies where the possibility of such exposure was more
  likely.
  In order to evaluate the evidence on whether perineal use of talc causes an
  increased risk for ovarian cancer, the Working Group noted the following:
  • The eight more informative case-control studies, as well as most of the less
      informative ones, provided overall estimates of excess risk that were
      remarkably consistent; seven of these eight case-control studies examined
      exposure-response relationships: two provided evidence supporting such a
      relationship and five did not.
  • The cohort study neither supports nor strongly refutes the evidence from the
      case-control studies;
  • Case-control studies were susceptible to recall biases, which could tend to
      inflate risk estimates but to an unknown degree;
8 Talc
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<pre>•   All studies were susceptible to other potential biases, which could increase or
    decrease the association;
•   All studies involved some degree of non-differential misclassification of
    exposure that would tend to underestimate any true underlying association.
Animal carcinogenicity data
Talc of different grades was tested for carcinogenicity in mice by inhalation
exposure, subcutaneous, intraperitoneal and intrathoracic injection, in rats by
oral administration, inhalation exposure, intraperitoneal injection, intrathoracic
injection and intrapleural and ovarian implantation, and in hamsters by inhalation
exposure and intratracheal injection.
    Male and female rats and male and female mice were exposed by inhalation
to a well-defined talc. The incidences of alveolar/bronchiolar carcinoma, and of
adenoma and carcinoma combined, were significantly increased in female rats.
Incidences of pheochromocytomas of the adrenal medulla (benign, malignant
and complex combined) showed a significant positive trend and the incidences in
high-dose male and female rats were significantly greater than those in controls.
The incidence of malignant pheochromocytomas was also increased in high-dose
female rats. The Working Group did not consider it probable that the increased
incidence of pheochromocytomas was causally related to talc, but based on the
experimental data available, neither can talc-related effects be excluded. Tumour
incidence was not increased in mice of either sex in this study.
    In one study in rats and two studies in mice of intraperitoneal administration
of talc, no increase in the incidence of mesotheliomas was observed. Two other
studies of intraperitoneal administration, one in rats and one in mice, were found
to be inadequate for evaluation. One study in rats and one study in mice by
intrathoracic administration were found to be inadequate for evaluation. In one
study by intrapleural injection of talc in rats and in another study by intrapleural
implantation of various talcs in rats, tumour incidence was not increased. A
single subcutaneous injection of talc in mice did not produce local tumours. No
tumour was produced in rats in one study of administration of talc in the diet or
in another study by implantation of talc onto the ovary. Tumour incidence was
not increased following administration of talc to hamsters by inhalation or
intratracheal administration.
IARC Monograph                                                                       59
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<pre>  Mechanistic considerations and other relevant data
  Different mechanisms are probably operative for the effects of talc on the lung
  and pleura depending on the method of exposure. (General particle
  characteristics and host factors that are considered to affect deposition and
  retention patterns of inhaled, poorly soluble particles such as talc are summarized
  in the monograph on carbon black.)
  In humans, deposition, retention and clearance of talc have been insufficiently
  studied. Talc particles have been found at autopsy in the lungs of talc workers.
  In humans and experimental animals, the effects of talc are dependent on the
  route of exposure, the dose and the properties of the talc. Talc pneumoconiosis is
  somewhat more prevalent and severe among miners exposed to talc containing
  asbestiform minerals and/or asbestos than among those exposed to talc without
  such contaminants. The role of quartz and asbestos in the observed
  pneumoconiosis could not be ruled out. Inadvertent exposure to talc in
  intravenous drug users results in microembolization in a variety of organs and
  alterations in pulmonary function.
  In animal studies, inhaled talc has been shown to cause granulomas and mild
  inflammation. Observations of effects in lungs of rats exposed by inhalation to
  talc suggest that there may be similar mechanisms operative as identified for
  carbon black. No teratological effects were observed in hamsters, rats, mice or
  rabbits following oral administration of talc. Talc is known to cause the release of
  cytokines, chemokines and growth factors from pleural mesothelial cells.
  In humans, intrapleural administration of talc as a therapeutic modality results in
  pleural inflammation leading to pleural fibrosis and symphysis. Pleural fibrosis is
  the intended effect of intrapleural administration of talc in patients with
  malignant pleural effusions or pneumothorax. Talc has been shown to cause
  apoptosis of malignant human mesothelioma cells in vitro. Animal studies
  suggest that extrapulmonary transport of talc following pleurodesis increases
  with decreasing particle size and increasing administered dose.
  Perineal exposure to cosmetic talc in women is of concern because of its possible
  association with ovarian cancer. A number of studies have been conducted to
  assess potential retrograde movement of particles through the reproductive tract
  to the ovaries. These studies have been conducted in women about to undergo
0 Talc
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<pre>gynaecological surgery, most of whom had diseases or complications of the
reproductive tract and organs that required surgery. The findings reported in
these studies may be confounded by the various levels of dysfunction in the
female reproductive tract due to underlying pathologies. In addition, most of the
studies had little or no further information on the use of talc products for perineal
hygiene or changes in habits that may have preceded surgery. On balance, the
Working Group considered that the evidence for retrograde transport of talc to
the ovaries in healthy women is weak. In women with a gynaecological
condition, there is some evidence of retrograde transport. Studies in animals
(rodents, lagomorphs and non-human primates) showed no evidence of
retrograde transport of talc to the ovaries. Conflicting data exist on the systemic
distribution of talc in experimental animals.
There is evidence that the presence of anti-MUC1 antibodies is inversely
associated with ovarian cancer risk. In a study among >700 women, anti-MUC1
antibodies were found in a significantly higher percentage of women who
reported no perineal use of talc than in those who regularly used talc.
No data were available on the genotoxic effects to humans of exposure to talc.
The results of the few in vitro studies available on the genetic toxicology of talc
were negative.
Evaluation
There is limited evidence in humans for the carcinogenicity of perineal use of
talc-based body powder.
There is inadequate evidence in humans for the carcinogenicity of inhaled talc
not containing asbestos or asbestiform fibres.
There is limited evidence in experimental animals for the carcinogenicity of talc
not containing asbestos or asbestiform fibres.
Overall evaluation
Perineal use of talc-based body powder is possibly carcinogenic to humans
(Group 2B).
IARC Monograph                                                                        61
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<pre>  Inhaled talc not containing asbestos or asbestiform fibres is not classifiable as to
  its carcinogenicity to humans (Group 3).
  Rationale
  In making this evaluation the Working Group considered the human and animal
  evidence as well as evidence regarding the potential mechanisms through which
  talc
  might cause cancer in humans.The Working Group found little or inconsistent
  evidence of an increased risk for cancer in the studies of workers occupationally
  exposed to talc. The studies of talc miners and millers were considered to provide
  the best source of evidence, but no consistent pattern was seen. One study
  observed an excess risk for lung cancer among miners, but confounding from
  exposure to other carcinogens made it difficult to attribute this to talc and no
  excess risk was seen in millers. Other studies also found no increased cancer risk
  or no higher risk with increasing cumulative exposure. Overall, these results led
  the Working Group to conclude that there was inadequate evidence from
  epidemiological studies to assess whether inhaled talc not containing asbestos or
  asbestiform fibres causes cancer in humans. For perineal use of talc-based body
  powder, many case-control studies of ovarian cancer found a modest, but
  unusually consistent, excess in risk, although the impact of bias and potential
  confounding could not be ruled out. In addition, the evidence regarding
  exposure-response was inconsistent and the one cohort study did not provide
  support for an association between talc use and ovarian cancer. Concern was also
  expressed that exposure was defined in a variety of ways and that some
  substances called talc may have contained quartz and other potentially
  carcinogenic materials. A small number of Working Group members considered
  the evidence to be inadequate. Despite these reservations, the Working Group
  concluded that the epidemiological studies taken together provide limited
  evidence of an association between perineal use of talc-based body powder and
  an increased risk for ovarian cancer.
       In one study of rats that inhaled talc, an excess incidence of malignant lung
  tumours was seen in females. The same study observed an excess incidence of
  pheochromocytomas in the adrenal medulla in both sexes, but the Working
  Group was divided as to whether these rare tumours could be attributed to
  exposure to talc. Other
2 Talc
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<pre>    studies in rats and mice using different routes of administration did not find
an excess of cancer, and two studies in rats were considered to be inadequate for
evaluation. Based on the one positive study, the Working Group found that there
was limited evidence of carcinogenicity of inhaled talc in experimental animals.
There was no agreement within the Working Group as to whether the evidence
on pheochromocytomas should be taken into account in the evaluation of animal
data.
IARC Monograph                                                                     63
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<pre>4 Talc</pre>

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<pre> nnex        F
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be as carcinogenic to humans.          2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07.59
             Carcinogenic classification of substances by the Committee                                                65
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<pre>6 Talc</pre>

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<br><br>