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

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : aanbieding advies Naphthalene
Uw kenmerk              : DGV/MBO/U-932342
Ons kenmerk             : U-7476/BvdV/fs/T17
Bijlagen                :1
Datum                   : 7 december 2012
Geachte minister,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
naftaleen.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de 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
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                      Postadres
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X D e n          Haag                                   2500 BB Den     Haag
E - m a i l : s r. v i n k @ g r. n l                            w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 5 5 0 8
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<pre>Naphthalene
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances
of the Dutch Expert Committee on Occupational Safety (DECOS),
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2012/30, The Hague, December 7, 2012
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Naphthalene. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/30.
all rights reserved
ISBN: 978-90-5549-927-4
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<pre>   Contents
   Samenvatting 7
   Executive summary 8
   Scope 9
.1 Background 9
.2 Committee and procedures 9
.3 Data 10
   General information 11
.1 Identity and physico-chemical properties 11
.2 IARC classification 12
   Carcinogenicity 13
.1 Observations in humans 13
.2 Carcinogenicity studies in animals 14
.3 Cell transformation assays 18
.4 Conclusion 18
   Genotoxicity 19
.1 Gene mutation assays 19
.2 Cytogenetic assays 20
   Contents                                    5
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<pre> .3 Miscellaneous 20
 .4 Conclusion 21
    Classification 22
 .1 Evaluation of data on carcinogenicity and genotoxicity 22
 .2 Recommendation for classification 24
    References 25
    Annexes 29
A   Request for advice 30
B   The Committee 32
C   The submission letter 34
D   Comments on the public review draft 36
E   IARC Monograph 37
F   Genotoxicity data 40
G   Carcinogenic classification of substances by the Committee 42
    Contents                                                      6
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de Subcommissie
Classificatie van carcinogene stoffen van de Commissie Gezondheid en beroeps-
matige blootstelling aan stoffen van de raad, hierna kortweg aangeduid als de
commissie. In het voorliggende advies neemt de Commissie naftaleen onder de
loep. Naftaleen is een stof die onder andere wordt gebruikt als uitgangsmateriaal
bij de productie van ftalaatanhydride, azokleurstoffen, naftaleensulfonzuren en in
de synthese van diverse geneesmiddelen.
De commissie is van mening dat de gegevens over naftaleen niet voldoende zijn
om de kankerverwekkende eigenschappen te evalueren (categorie 3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage G).
Samenvatting                                                                       7
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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The evaluation is
performed by the Subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council,
hereafter called the Committee. In this report, the Committee evaluates
naphthalene. Naphthalene is among others used as a feedstock in the
manufacture of phthalic anhydride, in the production of azo dyes and
naphthalene sulphonic acids, and in the synthesis of a number of miscellaneous
chemicals and pharmaceuticals.
The Committee concludes that the available data are insufficient to evaluate the
carcinogenic properties of naphthalene (category 3).*
According to the classification system of the Health Council (see Annex G).
Executive summary                                                                8
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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and proposal for a classification are expressed in the form of standard
        sentences (see Annex G).
        This report contains the evaluation of the carcinogenicity of naphthalene.
1.2     Committee and procedures
        The evaluation is performed by the Subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter the Committee. The members of the Committee are
        listed in Annex B. The submission letter 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                                                                                9
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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
    naphthalene, 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 CD ROMs of Chemical
    Abstracts, Medline, and the internet database Toxline, covering the period from
    2002 to March 2012. The relevant data were included in this report.
    Scope                                                                            10
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<pre> hapter 2
        General information
2.1     Identity and physico-chemical properties
        The data have been retrieved from the European Union Risk Assessment report
        on naphthalene1, the IARC evaluation of naphthalene2 and the European
        Substance Information System (ESIS, which can be accessed via the ECB-site:
        http://ecb.jrc.it).
             Naphthalene is used as a feedstock in the manufacture of phthalic anhydride,
        in the production of azo dyes and naphthalene sulphonic acids, as a feed stock in
        the synthesis of a number of miscellaneous chemicals and pharmaceuticals, in
        the manufacture of mothballs, in special effects for the film industry and as an
        artificial pore former in the manufacture of grinding wheels to give a high
        porosity product.
        Chemical name         :  Naphthalene
        CAS registry number   :  91-20-3
        EINECS number         :  202-049-5
        Synonyms              :  antimite, naphthalin, naphthene, tar camphor
        Appearance            :  A colourless to brown solid, depending on manufacture and purity with
                                 a characteristic, readily detectable odour
        Chemical formula      : C10H8
        Chemical structure    :
        General information                                                                            11
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<pre>    Molecular weight         : 128.18
    Boiling point            : 217.9-218˚C at 1013 hPa
    Melting point            : 80.2-80.3˚C
    Vapour pressure          : Ca. 0.01 kPa
    Vapour density (air = 1) : 4.42
    Solubility               : Naphthalene is very slightly soluble in water (0.03 g/L), but is
                               appreciably soluble in many organic solvents (alcohol, benzene, ether)
    Conversion factor        : 1 ppm = 5.24 mg/m3; 1 mg/m3 = 0.19 ppm
    GHS Classification       : Carcinogenicity Category 2
                             : Acute toxicity Category 4
                             : Acute aquatic toxicity Category 1
                               Chronic aquatic toxicity Category 1
    Hazard statement(s)      : H302; Harmful if swallowed.
                               H351; Suspected of causing cancer.
                               H410; Very toxic to aquatic life with long lasting effects.
2.2 IARC classification
    Based on the evaluated data, IARC classified naphthalene in 2002 as possibly
    carcinogenic to humans (Group 2B: there is inadequate evidence in humans for
    the carcinogenicity of naphthalene; there is sufficient evidence in experimental
    animals for the carcinogenicity of naphthalene).2
    General information                                                                               12
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
        Data on workers exposed solely to naphthalene are lacking.3 The available
        human data are limited to a few cases reports.
        One case report involved a cluster of cancer cases among the employees of a
        naphthalene purification plant in former East Germany (original publications in
        German; cited in IARC).2 A total of fifteen employees operated in the unit of this
        plant during the preceding 20-30 years between 1917 and 1968. Seven
        employees were diagnosed with cancer, including four cases of laryngeal cancer
        (IARC reported a background incidence for laryngeal cancer in the former East
        Germany in 1970 of 6.3 per 100,000). These four workers (all of them being
        smokers) were exposed for 7 to 31 years, whereas the limit value for exposure to
        naphthalene at that time was 20 mg/m3, with peak values of 50 mg/m3. The
        concomitant exposure to other possible carcinogens, e.g. various tar products,
        was noted by IARC.
            Ajao et al. reported on 23 consecutive cases of colorectal carcinoma admitted
        during June 1982 and May 1984, to a university college hospital in Nigeria (Ajao
        et al., 1988; cited in IARC).4 Of these patients, eleven were 30 years old or
        younger at the moment of diagnosis. Based on family history, gastrointestinal
        investigations, and autopsy, no indication of familial polyposis among these
        cases was ascertained. Half of the patients mentioned a history of taking Kafura,
        Carcinogenicity                                                                    13
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<pre>      a local indigenous treatment for anorectal problems, which contains naphthalene.
      However, the other half did not know whether they had been given the same drug
      during early childhood or not.
3.2   Carcinogenicity studies in animals
3.2.1 Inhalation
      In an inhalation study by the National Toxicology Program (NTP) using Fischer
      344/N rats, groups of 49 males or 49 females were exposed in inhalation
      chambers to 0, 10, 30 or 60 ppm (0, 52, 157 or 314 mg/m3) naphthalene (>99%
      pure) for 6 hours per day, 5 days per week, for a total of 105 weeks.5,6 Mean body
      weights of all exposed groups of male rats were less than that of the chamber
      control group throughout the study. Survival rates in all exposed groups were
      similar to that of the chamber controls.
          An increase in neuroblastoma of the olfactory epithelium was observed, both
      in male and in female rats. These olfactory neuroblastomas had not been
      observed in the historical controls. Also adenomas of the nasal respiratory
      epithelium were observed, most notably in males. In addition to the nasal
      neoplasms, a variety of non-neoplastic lesions of the nasal tract in both male and
      female rats were observed in naphthalene-exposed animals compared with
      controls.
          The incidences of (both carcinogenic and non-carcinogenic) respiratory
      lesions reported by the NTP are summarised in Table 1.
      In another study of the NTP, groups of male or female B6C3F1 mice were
      exposed to 0, 10 ppm (52 mg/m3) or 30 ppm (157 mg/m3) naphthalene (>99%
      pure) for 6 hours per day, 5 days per week, for 104 weeks (75 animal per group
      for the control group and middle dose; 150 animals per group for the high dose).7
      Mean body weights of exposed mice were slightly lower than that of the controls
      throughout the study. Survival rates at the end of the study were significantly
      lower in control male mice compared to exposed males, according to the authors
      due to wound trauma and secondary infection related to fighting.
          Exposed male mice showed increased incidences of bronchiolo-alveolar
      adenomas and carcinomas but these were not statistically significant. There was
      a statistically significant increase in the incidence of bronchiolo-alveolar
      Carcinogenicity                                                                    14
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<pre> able 1 Data reported by the NTP on respiratory and olfactory non-neoplastic and neoplastic lesions observed in rats.5
                                                         0 ppm            10 ppm            30 ppm           60 ppm
                                                         (0 mg/m3)        (52 mg/m3)        (157 mg/m3)      (314 mg/m3)
Males
 eoplastic lesions (nose)
 espiratory epithelium, adenoma                          0/49 (0%)        6/49 (12%)#       8/48 (17%)#      15/48 (31%)#
Olfactory epithelium neuroblastoma                       0/49 (0%)        0/49 (0%)         4/48 (8%)        3/48 (6%)
 on-neoplastic lesions (nose)
Olfactory epithelium, hyperplasia, atypical              0/49 (0%)        48/49 (98%)#      45/48 (94%)#     46/48 (96%)#
Olfactory epithelium, atrophy                            3/49 (6%)        49/49 (100%)#     48/48 (100%)#    47/48 (98%)#
Olfactory epithelium, chronic Inflammation               0/49 (0%)        49/49 (100%)#     48/48 (100%)#    48/48 (100%)#
Olfactory epithelium, degeneration, hyaline              3/49 (6%)        46/49 (94%)#      40/48 (83%)#     43/48 (90%)#
 espiratory epithelium, hyperplasia                      3/49 (6%)        21/49 (43%)#      29/48 (60%)#     29/48 (60%)#
 espiratory epithelium, squamous metaplasia              0/49 (0%)        15/49 (31%)#      23/48 (48%)#     18/48 (38%)#
 espiratory epithelium, degeneration, hyaline            0/49 (0%)        20/49 (41%)#      19/48 (40%)#     19/48 (40%)#
 espiratory epithelium, hyperplasia, goblet cell         0/49 (0%)        25/49 (51%)#      29/48 (60%)#     26/48 (54%)#
Glands, hyperplasia                                      1/49 (2%)        49/49 (100%)#     48/48 (100%)#    48/48 (100%)#
Glands, metaplasia, squamous                             0/49 (0%)        3/49 (6%)         14/48 (29%)#     26/48 (54%)#
 emales
 eoplastic lesions (nose)
 espiratory epithelium, adenoma                          0/49 (0%)        0/49 (0%)         4/49 (8%)        2/49 (4%)
Olfactory epithelium neuroblastoma                       0/49 (0%)        2/49 (4%)         3/49 (6%)        12/49 (24%)#
 on-neoplastic lesions (nose)
Olfactory epithelium, hyperplasia, atypical              0/49 (0%)        48/49 (98%)#      48/49 (98%)#     43/49 (88%)#
Olfactory epithelium, atrophy                            0/49 (0%)        49/49 (100%)#     49/49 (100%)#    47/49 (96%)#
Olfactory epithelium, chronic Inflammation               0/49 (0%)        47/49 (96%)#      47/49 (96%)#     45/49 (92%)#
Olfactory epithelium, degeneration, hyaline              13/49 (27%)      46/49 (94%)#      49/49 (100%)#    45/49 (92%)#
 espiratory epithelium, hyperplasia                      0/49 (0%)        18/49 (37%)#      22/49 (45%)#     23/49 (47%)#
 espiratory epithelium, squamous metaplasia              0/49 (0%)        21/49 (43%)#      17/49 (35%)#     15/49 (31%)#
 espiratory epithelium, degeneration, hyaline            8/49 (16%)       33/49 (67%)#      34/49 (69%)#     28/49 (57%)#
 espiratory epithelium, hyperplasia, goblet cell         0/49 (0%)        16/49 (33%)#      29/49 (59%)#     20/49 (41%)#
Glands, hyperplasia                                      0/49 (0%)        48/49 (98%)#      48/49 (98%)#     42/49 (86%)#
Glands, metaplasia, squamous                             0/49 (0%)        2/49 (4%)         20/49 (41%)#     20/49 (41%)#
 P < 0.05 (corresponding dose group compared to controls using Poly-3 test)
 ource: NTP (2000).5
             adenomas in high-dose females. Also, one bronchiolo-alveolar carcinoma was
             noted in a high-dose female. Non-neoplastic changes were seen only in the lungs
             and nose. A dose-related increase in bronchiolo-alveolar inflammation was seen
             both in males and females. Virtually all exposed animals but none of the controls
             had chronic nasal inflammation, respiratory epithelial hyperplasia and metaplasia
             of the olfactory epithelium.
             Carcinogenicity                                                                                              15
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<pre>     The incidences of (both carcinogenic and non-carcinogenic) lung and nasal
lesions reported by the NTP are summarised in Table 2.
Table 2 Data reported by the NTP on lung and nasal non-neoplastic and neoplastic lesions observed
in mice.7
                                            0 ppm               10 ppm              30 ppm
                                            (0 mg/m3)           (52 mg/m3)          (157 mg/m3)
Males
Neoplastic lesions (lung)
Alveolar/bronchiolar adenoma                7/70 (10%)          15/69 (22%)         27/135 (20%)
  Adjusted ratea                            25.7%               28.8%               22.7%
Alveolar/bronchiolar carcinoma              0/70 (0%)           3/69 (4%)           7/135 (5%)
  Adjusted ratea                            0.0%                5.5%                5.9%
Combined                                    7/70 (10%)          17/69 (25%)         31/135 (23%)
  Adjusted ratea                            25.7%               31.9%               26.0%
Non-neoplastic lesions (lung)
Lymphocyte infiltration                     3/70 (4%)           0/69 (0%)           8/135 (6%)
Histiocyte infiltration                     1/70 (1%)           12/69 (17%)#        16/135 (12%)#
Inflammation                                0/70 (0%)           21/69 (30%)#        56/135 (41%)#
Inflammation, granulomatous                 0/70 (0%)           19/69 (28%)#        15/135 (11%)#
Hyperplasia alveolar epithelium             2/70 (3%)           7/69 (10%)          12/135 (9%)
Inflammation glands                         7/70 (10%)          14/69 (20%)         22/135 (16%)
Non-neoplastic lesions (nose)
Inflammation                                0/70 (0%)           67/69 (97%)#        133/135 (99%)#
Metaplasia olfactory epithelium             0/70 (0%)           66/69 (96%)#        134/135 (99%)#
Hyperplasia respiratory epithelium          0/70 (0%)           66/69 (96%)  #      134/135 (99%)#
Females
Neoplastic lesions (lung)
Alveolar/bronchiolar adenoma                5/69 (7%)           2/65 (3%)           28/135 (21%)#
Alveolar/bronchiolar carcinoma              0/69 (0%)           0/65 (0%)           1/135 (1%)
Non-neoplastic lesions (lung)
Lymphocyte infiltration                     11/69 (16%)         21/65 (33%)#        46/135 (34%)#
Histiocyte infiltration                     1/69 (1%)           5/65 (8%)           4/135 (3%)
Inflammation                                3/69 (4%)           13/65 (20%)#        52/135 (39%)#
Inflammation, granulomatous                 0/69 (0%)           38/65 (58%)#        42/135 (31%)#
Hyperplasia alveolar epithelium             3/69 (4%)           6/65 (9%)           12/135 (9%)
Inflammation glands                         1/69 (1%)           3/65 (5%)           15/135 (11%)#
Non-neoplastic lesions (nose)
Inflammation                                1/69 (1%)           65/65 (100%)#       135/135 (100%)#
Metaplasia olfactory epithelium             0/69 (0%)           65/65 (100%)#       135/135 (100%)#
Hyperplasia respiratory epithelium          0/69 (0%)           65/65 (100%)#       135/135 (100%)#
a    In view of the high intercurrent mortality in male controls, adjusted rates of neoplasms are also
     specified; # p < 0.05 (pairwise comparison between the controls and corresponding dose group).
     Source: NTP (1992).7
Carcinogenicity                                                                                        16
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<pre>      Furthermore, a screening assay for lung tumours in highly susceptible A/J mice
      has been conducted with naphthalene.8 Groups of 30 female mice were exposed
      in inhalation chambers to 0, 10 or 30 ppm (0, 52 or 157 mg/m3) naphthalene
      (purity 98-99%) for 6 hours per day, 5 days per week, for 6 months. Survival was
      unaffected by treatment. Exposure to 10 or 30 ppm resulted in a non-significant
      increase in the incidence of lung adenomas (expressed as the number of tumours
      per animal) compared with controls. The number of tumours per lung of tumour-
      bearing animals, however, was reported as significantly different when compared
      to controls.
3.2.2 Oral exposure
      In an oral administration study, a group of 28 rats (both strain BD I and BD III;
      further allocation and use of control animals not specified) were fed a diet
      containing spectrographically pure naphthalene in oil at a dose of 10-20 mg (not
      further specified in IARC) per day, on 6 days per week for 100 weeks (Schmähl,
      1955; cited in IARC).2 Animals were kept under observation until death. The
      average longevity was 800 days. All animals were subjected to necropsy with
      histopathological examination of abnormal tissues only. No tumours were found
      in any of the examined rats. The small number of animals and incomplete
      reporting of the study were noted by IARC.
3.2.3 Other routes
      In a study by La Voie et al. (1988), a group of 31 male and a group of 16 female
      CD-1 mice received intraperitoneal injections of 0.05 M solution of naphthalene
      (unspecified purity) in dimethyl sulfoxide on days 1, 8 and 15 after birth.9 The
      total dose received was reported as 1.75 µmol (0.22 mg) per mouse. Mice were
      weaned at 21 days, separated by gender, and maintained until termination at 52
      weeks, at which time they were necropsied, and gross lesions as well as liver
      sections were examined histo-pathologically. There was no increase in the
      incidence of tumours in the naphthalene-treated mice compared to the vehicle
      controls.
      IARC has also evaluated a series of studies in rats using intraperitoneal or
      subcutaneous administration (Schmähl, 1955; cited in IARC).2 BD I and BD III
      rats (sex and age not specified) received weekly intraperitoneal or subcutaneous
      injections of 20 mg naphthalene (spectrographically pure) as 2% solution in
      “specially purified oil” for 40 weeks.2 Average life span was reported as being
      Carcinogenicity                                                                   17
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<pre>    similar to survival of controls (without further details). All animals were
    necropsied with histopathological examination of abnormal tissues only. No
    tumours were found in any of the rats examined. Due to limitations in study
    design (e.g., small number of animals) and reporting, no conclusions can be
    drawn from this study.
        Finally, IARC reports on a study in which groups of 38 white inbred rats
    (age, strain and sex unspecified) received seven subcutaneous injections of 0 or
    50 mg/kg bw naphthalene (purified by chromatography) as a 15% solution in
    sesame oil, at intervals of around 14 days, extending over 3.5 months (Knake,
    1956; cited in IARC).2 In the test group, a total of five sarcomas (one uterine and
    four lymphosarcomas) and a single mammary fibroadenoma developed and, in
    the control group, a single sarcoma and a single mammary fibroadenoma.
    However, due to a high mortality rate during study, in both treated animals and
    controls, no conclusions can be drawn from this study.
3.3 Cell transformation assays
    Naphthalene tested negative in cell transformation assays with BALB/c 3T3 cells
    and Rauscher leukemia virus (RLV)-infected Fischer rat embryo cells, in absence
    of an exogenous metabolic system.2
3.4 Conclusion
    The Committee considers the available human data not sufficient to draw a
    conclusion on the carcinogenicity of naphthalene in humans.
        Based on the available animal data, the Committee considers naphthalene
    carcinogenic in animals.
    Carcinogenicity                                                                     18
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<pre> hapter 4
        Genotoxicity
        The genotoxicity data are summarised in Annex F.
4.1     Gene mutation assays
        In vitro assays
        Naphthalene was inactive in several types of bacterial mutagenicity assays, under
        standard conditions*, either with or without metabolic activation.10-24
             No increase in mutation frequency was observed at the tk or htrp locus in
        human MCL-5B-lymphoblastoid cells.25
        In vivo assays
        No results from mammalian in vivo gene mutation assays with naphthalene are
        available to the Committee.
        In the presence of nitrogen-containing reagents under photo-oxidising or photolytic conditions,
        mutagenic properties of naphthalene have been observed.2
        Genotoxicity                                                                                    19
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<pre>4.2 Cytogenetic assays
    In vitro
    Naphthalene induced sister chromatid exchange (either in the presence or
    absence of S9) in Chinese hamster ovary cells, but not in human lymphocytes.7,26
    Naphthalene treatment resulted in chromosomal aberrations (only in the presence
    of S9) in Chinese hamster ovary cells.7
        An increase in the frequency of CREST-negative micronuclei was reported in
    human MCL-5B lymphoblastoid cells, and a weak positive response has been
    reported in a micronucleus assay conducted with newt larvae erythrocytes.25,27
        In isolated rat hepatocytes, no increase in single strand DNA breaks as
    measured by alkaline elution was observed after exposure to naphthalene for 3 h
    up to 3 mM (380 µg/mL).28
    In vivo
    Two in vivo micronucleus assays are available. In the first, groups of five male
    ICR Swiss mice were given a single oral dose (50, 250, or 500 mg/kg bw).29 At
    25 hours after administration, femoral bone marrow cells were harvested and
    scored for the presence of micronuclei. The second micronucleus test, conducted
    under OECD-guideline, involved CD-1 mice receiving a single intraperitoneal
    dose of 250 mg/kg bw (reported to be a sub-lethal dose).23 Femoral bone marrow
    was harvested at 30, 48 and 72 hours after dosing. In both studies, no increase in
    micronucleated bone marrow cells was observed.
        Rats received single oral doses of 359 mg naphthalene/kg bw, 21 hours and 4
    hours before sacrifice.30 No increase of DNA damage in isolated hepatocytes, as
    measured by alkaline elution, was observed.
        In the Drosophila melanogaster wing-spot test following larval feeding,
    naphthalene induced predominantly homologous recombination, whereas gene
    mutations may also contribute to the induction of wing spots.31
4.3 Miscellaneous
    In vitro
    No increase in unscheduled DNA synthesis was detected in cultures of isolated
    rat hepatocytes exposed to naphthalene concentrations of 0.16-16 µg/mL.23
    Genotoxicity                                                                       20
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<pre>    In vivo
    In two independent experiments (performed according to OECD guidelines),
    animals were sacrificed at two or fourteen hours after exposure, livers were
    perfused and hepatocytes harvested.23 Naphthalene did not cause unscheduled
    DNA synthesis in hepatocytes from rats exposed to a single oral dose as high as
    1,600 mg/kg bw.
        However, DNA fragmentation has been observed in brain and liver tissue
    from rats exposed to 110 mg/kg bw/day (0.05 LD50 according to the authors) for
    up to 120 days.32 This was accompanied by increased lipid peroxidation,
    suggesting the involvement of oxidative stress. Similar results have been
    obtained in mice (particularly p53 knock-out) given single doses of 22, 220 or
    1,100 mg/kg bw (0.01, 0.1 or 0.5 LD50, respectively, according to the
    authors).33,34
4.4 Conclusion
    Based on the negative results in in vitro gene mutation assays and in vivo
    cytogenicity assays, the Committee concludes that naphthalene acts by a non-
    genotoxic mode of action.
    Genotoxicity                                                                    21
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        The number of available human studies on naphthalene is very limited, and does
        not provide any specific information on naphthalene. Therefore, the Committee
        considers the human data to be inadequate for drawing conclusion on the
        carcinogenic properties of naphthalene.
            Two NTP inhalation studies, one in rats and one in mice, have reported local
        tumours in the respiratory tract upon exposure to naphthalene. In both male en
        female rats, increased incidences of respiratory epithelial adenoma and olfactory
        epithelial neuroblastoma of the nose have been observed. The Committee notes
        that both types of tumours are relatively rare in rats, and considers them related
        to the exposure to naphthalene.
            The study in male mice has been compromised by a high intercurrent
        mortality. In female mice an increase in lung tumours – a tumour with a
        relatively high background incidence in mice – is reported only at the highest
        exposure group. Therefore, the Committee considers the outcome equivocal.
            Overall, data on animal studies indicate that naphthalene is carcinogenic in
        animals.
            The genotoxicity data indicate that naphthalene acts by a non-genotoxic
        mechanism.
        Classification                                                                     22
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<pre>The carcinogenic effects that have been observed in rats and mice after exposure
to naphthalene occur at specific sites and in specific tissues (i.e. neuroblastoma
of the olfactory epithelium in rats and alveolar/bronchiolar adenomas and
carcinomas in mice). Concurrently, pronounced inflammatory responses were
present at these sites. The Committee considers it likely that the carcinogenic
effects are a consequence of chronic tissue damage and repair.
    The metabolism and bioactivation of naphthalene have been identified as key
determinants in naphthalene toxicity, and have been studied extensively.35-37
Multiple competing pathways exist in which cytochrome p450s play a critical
role in the formation of several reactive metabolites (e.g., 1,2-naphthalene
oxide,1,2-naphthoquinone, and 1,4-naphthoquinone), leading to an array of
conjugated and non-conjugated metabolites that are excreted predominantly in
the urine.35 The metabolic processes vary considerably between different species
and between different tissues. This explains, at least partly, the reported
differences in sensitivity towards naphthalene and the selective induction of
tumours.
    The human relevance of respiratory tumours observed in rodents has been
questioned due to qualitative and quantitative metabolic differences that exist
between species, and the relatively high exposure levels applied in animal
studies.36,38-41 The Committee also questions whether the exposure conditions at
which the carcinogenic effects occurred in rats are relevant for humans, but notes
that exposure conditions are not taken into account in the Committee’s
evaluation. With respect to the mode of action, the Committee notes particularly
an analysis of Rhomberg et al.41 which consists of a detailed weight-of-evidence
approach to assess the carcinogenicity data on naphthalene. Rhomberg et al.41
discussed each identified key event in the development of cancer in rats and mice
after naphthalene exposure, i.e. metabolism, cytotoxicity, inflammation,
genotoxicity and ultimately, tumour formation, in the context of the available
data.
    Rhomberg et al.41 reasoned that the mouse lung tumours and rat nasal
tumours developed after naphthalene exposure by a common mode of action,
involving local cytotoxicity and subsequent genotoxicity and carcinogeniticy.
These cytotoxic responses result from the generation of reactive metabolites
(most likely by CYP2F), under conditions at which glutathione levels are
depleted. In a thorough analysis, Rhomberg et al. evaluated the available data
and addressed the (in)consistencies, and the subsequent uncertainties concerning
the carcinogenic hazard for humans. Based on the data available, the authors
considered it most plausible that humans have insufficient metabolic capacity to
generate levels of reactive metabolites that deplete glutathione and produce
Classification                                                                     23
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<pre>    cytotoxicity when exposed to naphthalene. They concluded therefore that it is not
    likely that the mode of action that leads to carcinogenicity in rats and mice, will
    operate in humans (for details see Rhomberg et al.41).
        The Committee agrees with a weight of evidence approach, and values the
    approach that has been proposed for naphthalene. The Committee concurs with
    the line of argument set forth by Rhomberg et al. and considers the available
    information sufficient to conclude that it is unlikely that upon naphthalene
    exposure, reactive metabolites are formed in humans to a degree that leads to
    cytotoxicity and subsequent carcinogenicity.
        Therefore, the Committee considers the mode of carcinogenic action of
    naphthalene in rodents not relevant for humans.
5.2 Recommendation for classification
    The Committee concludes that the available data are insufficient to evaluate the
    carcinogenic properties of naphthalene, and proposes to classify the compound in
    category 3.*
    According to the classification system of the Health Council (see Annex G).
    Classification                                                                      24
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<pre>  References
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  Toxicology and carcinogenesis studies of naphthalene (CAS No. 91-20-3) in F344/N rats (inhalation
  studies). 2000: NTP TR 500, NIH Publication No. 01-4434.
  Long PH, Herbert RA, Peckham JC, Grumbein SL, Shackelford CC, Abdo K. Morphology of nasal
  lesions in F344/N rats following chronic inhalation exposure to naphthalene vapors. Toxicol Pathol
  2003; 31(6): 655-664.
  Toxicology and carcinogenesis studies of naphthalene (CAS No. 91-20-3) in B6C3F1 Mice
  (inhalation studies). Research Triangel Park, NC.; 1992: NTP Technical Report No. 410; NIH Publ.
  No. 92-3141.
  Adkins B, Jr., Van Stee EW, Simmons JE, Eustis SL. Oncogenic response of strain A/J mice to
  inhaled chemicals. J Toxicol Environ Health 1986; 17(2-3): 311-322.
  LaVoie EJ, Dolan S, Little P, Wang CX, Sugie S, Rivenson A. Carcinogenicity of quinoline, 4- and 8-
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0 Connor TH, Theiss JC, Hanna HA, Monteith DK, Matney TS. Genotoxicity of organic chemicals
  frequently found in the air of mobile homes. Toxicol Lett 1985; 25(1): 33-40.
  References                                                                                          25
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<pre>1 Florin I, Rutberg L, Curvall M, Enzell CR. Screening of tobacco smoke constituents for mutagenicity
  using the Ames' test. Toxicology 1980; 15(3): 219-232.
2 Gatehouse D. Mutagenicity of 1,2 ring-fused acenaphthenes against S. typhimurium TA1537 and
  TA1538: structure-activity relationship. Mutat Res 1980; 78(2): 121-135.
3 Ho CH, Clark BR, Guerin MR, Barkenbus BD, Rao TK, Epler JL. Analytical and biological analysis
  of test materials from the synthetic fuel technologies. Mutat Res 1981; 85(5): 335-345.
4 Ho YL, Ho SK. The induction of a mutant prophage lambda in Escherichia coli: a rapid screening test
  for carcinogens. Virology 1979; 99(2): 257-264.
5 Kaden DA, Hites RA, Thilly WG. Mutagenicity of soot and associated polycyclic aromatic
  hydrocarbons to Salmonella typhimurium. Cancer Res 1979; 39(10): 4152-4159.
6 Mamber SW, Bryson V, Katz SE. Evaluation of the Escherichia coli K12 inductest for detection of
  potential chemical carcinogens. Mutat Res 1984; 130(3): 141-151.
7 McCann J, Choi E, Yamasaki E, Ames BN. Detection of carcinogens as mutagens in the Salmonella/
  microsome test: assay of 300 chemicals. Proc Natl Acad Sci U S A 1975; 72(12): 5135-5139.
8 Mortelmans K, Haworth S, Lawlor T, Speck W, Tainer B, Zeiger E. Salmonella mutagenicity tests: II.
  Results from the testing of 270 chemicals. Environ Mutagen 1986; 8 Suppl 7: 1-119.
9 Nakamura SI, Oda Y, Shimada T, Oki I, Sugimoto K. SOS-inducing activity of chemical carcinogens
  and mutagens in Salmonella typhimurium TA1535/pSK1002: examination with 151 chemicals.
  Mutat Res 1987; 192(4): 239-246.
0 Narbonne JF, Cassand P, Alzieu P, Grolier P, Mrlina G, Calmon JP. Structure-activity relationships of
  the N-methylcarbamate series in Salmonella typhimurium. Mutat Res 1987; 191(1): 21-27.
1 Nohmi T, Miyata R, Yoshikawa K, Ishidate M, Jr. [Mutagenicity tests on organic chemical
  contaminants in city water and related compounds. I. Bacterial mutagenicity tests]. Eisei Shikenjo
  Hokoku 1985;(103): 6O-4.
2 Sakai M, Yoshida D, Mizusaki S. Mutagenicity of polycyclic aromatic hydrocarbons and quinones on
  Salmonella typhimurium TA97. Mutat Res 1985; 156(1-2): 61-67.
3 Schreiner CA. Genetic toxicity of naphthalene: a review. J Toxicol Environ Health B Crit Rev 2003;
  6(2): 161-183.
4 Yan J, Wang L, Fu PP, Yu H. Photomutagenicity of 16 polycyclic aromatic hydrocarbons from the US
  EPA priority pollutant list. Mutat Res 2004; 557(1): 99-108.
5 Sasaki JC, Arey J, Eastmond DA, Parks KK, Grosovsky AJ. Genotoxicity induced in human
  lymphoblasts by atmospheric reaction products of naphthalene and phenanthrene. Mutat Res 1997;
  393(1-2): 23-35.
6 Tingle MD, Pirmohamed M, Templeton E, Wilson AS, Madden S, Kitteringham NR et al. An
  investigation of the formation of cytotoxic, genotoxic, protein-reactive and stable metabolites from
  naphthalene by human liver microsomes. Biochem Pharmacol 1993; 46(9): 1529-1538.
7 Djomo JE, Ferrier V, Gauthier L, Zoll-Moreux C, Marty J. Amphibian micronucleus test in vivo:
  evaluation of the genotoxicity of some major polycyclic aromatic hydrocarbons found in a crude oil.
  Mutagenesis 1995; 10(3): 223-226.
  References                                                                                            26
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<pre>8 Sina JF, Bean CL, Dysart GR, Taylor VI, Bradley MO. Evaluation of the alkaline elution/rat
  hepatocyte assay as a predictor of carcinogenic/mutagenic potential. Mutat Res 1983; 113(5): 357-
  391.
9 Harper BL, Ramanujam VM, Gad-El-Karim MM, Legator MS. The influence of simple aromatics on
  benzene clastogenicity. Mutat Res 1984; 128(2): 105-114.
0 Kitchin KT, Brown JL, Kulkarni AP. Predictive assay for rodent carcinogenicity using in vivo
  biochemical parameters: operational characteristics and complementarity. Mutat Res 1992; 266(2):
  253-272.
1 Delgado-Rodriguez A, Ortiz-Marttelo R, Graf U, Villalobos-Pietrini R, Gomez-Arroyo S. Genotoxic
  activity of environmentally important polycyclic aromatic hydrocarbons and their nitro derivatives in
  the wing spot test of Drosophila melanogaster. Mutat Res 1995; 341(4): 235-247.
2 Bagchi D, Bagchi M, Balmoori J, Vuchetich PJ, Stohs SJ. Induction of oxidative stress and DNA
  damage by chronic administration of naphthalene to rats. Res Commun Mol Pathol Pharmacol 1998;
  101(3): 249-257.
3 Bagchi D, Balmoori J, Bagchi M, Ye X, Williams CB, Stohs SJ. Role of p53 tumor suppressor gene
  in the toxicity of TCDD, endrin, naphthalene, and chromium (VI) in liver and brain tissues of mice.
  Free Radic Biol Med 2000; 28(6): 895-903.
4 Bagchi D, Balmoori J, Bagchi M, Ye X, Williams CB, Stohs SJ. Comparative effects of TCDD,
  endrin, naphthalene and chromium (VI) on oxidative stress and tissue damage in the liver and brain
  tissues of mice. Toxicology 2002; 175(1-3): 73-82.
5 Agency for Toxic Substances and Disease Registry. Toxicological profile for naphthalene, 1-
  methylnaphtalene, and 2-methylnaphthalene. 2005.
6 Bogen KT, Benson JM, Yost GS, Morris JB, Dahl AR, Clewell HJ, III et al. Naphthalene metabolism
  in relation to target tissue anatomy, physiology, cytotoxicity and tumorigenic mechanism of action.
  Regul Toxicol Pharmacol 2008; 51(2 Suppl): S27-S36.
7 Buckpitt A, Boland B, Isbell M, Morin D, Shultz M, Baldwin R et al. Naphthalene-induced
  respiratory tract toxicity: metabolic mechanisms of toxicity. Drug Metab Rev 2002; 34(4): 791-820.
8 Griego FY, Bogen KT, Price PS, Weed DL. Exposure, epidemiology and human cancer incidence of
  naphthalene. Regul Toxicol Pharmacol 2008; 51(2 Suppl): S22-S26.
9 Magee B, Samuelian J, Haines K, Chappel M, Penn I, Chin D et al. Screening-level population risk
  assessment of nasal tumors in the US due to naphthalene exposure. Regul Toxicol Pharmacol 2010;
  57(2-3): 168-180.
0 Piccirillo VJ, Bird MG, Lewis RJ, Bover WJ. Preliminary evaluation of the human relevance of
  respiratory tumors observed in rodents exposed to naphthalene. Regul Toxicol Pharmacol 2012;
  62(3): 433-440.
1 Rhomberg LR, Bailey LA, Goodman JE. Hypothesis-based weight of evidence: a tool for evaluating
  and communicating uncertainties and inconsistencies in the large body of evidence in proposing a
  carcinogenic mode of action--naphthalene as an example. Crit Rev Toxicol 2010; 40(8): 671-696.
  References                                                                                            27
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<pre>2 Mersch-Sundermann V, Mochayedi S, Kevekordes S, Kern S, Wintermann F. The genotoxicity of
  unsubstituted and nitrated polycyclic aromatic hydrocarbons. Anticancer Res 1993; 13(6A): 2037-
  2043.
3 Seixas GM, Andon BM, Hollingshead PG, Thilly WG. The aza-arenes as mutagens for Salmonella
  typhimurium. Mutat Res 1982; 102(3): 201-212.
4 Bagchi M, Bagchi D, Balmoori J, Ye X, Stohs SJ. Naphthalene-induced oxidative stress and DNA
  damage in cultured macrophage J774A.1 cells. Free Radic Biol Med 1998; 25(2): 137-143.
5 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague: Health Council of the Netherlands, 2010: publication no. A10/07E.
  References                                                                                        28
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E IARC Monograph
F Genotoxicity data
G Classification of substances with respect to carcinogenicity
  Annexes
                                                               29
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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
     tal advisory structure, to improve the integration of the development of recommendations for health
     based occupation standards and the development of comparable standards for the general population.
     A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
     Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
     by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
     exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
     (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        30
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<pre>    for advice. If possible this evaluation should lead to a health based recommended exposure limit,
    or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
    calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
    per year.
•   The evaluation of documents review the basis of occupational exposure limits that have been
    recently established in other countries.
•   Recommending classifications for substances as part of the occupational hygiene policy of the
    government. In any case this regards the list of carcinogenic substances, for which the
    classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
    EEG) are used.
•   Reporting on other subjects that will be specified at a later date.
In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
Social Affairs and Employment the President of the Health Council agreed to
establish DECOS as a Committee of the Health Council. The membership of the
Committee is given in Annex B.
Request for advice                                                                                    31
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  J. van Benthem
        Genetic Toxicologist, National Institute for Public Health and the
        Environment, Bilthoven
     •  P.J. Boogaard
        Toxicologist, SHELL International BV, The Hague
     •  G.J. Mulder
        Emeritus Professor of Toxicology, Leiden University, Leiden
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemicals NV, Terneuzen
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  S.R. Vink, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              32
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<pre>The Health Council and interests
Members of Health Council Committees are appointed in a personal capacity
because of their special expertise in the matters to be addressed. Nonetheless, it
is precisely because of this expertise that they may also have interests. This in
itself does not necessarily present an obstacle for membership of a Health
Council Committee. Transparency regarding possible conflicts of interest is
nonetheless important, both for the chairperson and members of a Committee
and for the President of the Health Council. On being invited to join a
Committee, members are asked to submit a form detailing the functions they
hold and any other material and immaterial interests which could be relevant for
the Committee’s work. It is the responsibility of the President of the Health
Council to assess whether the interests indicated constitute grounds for non-
appointment. An advisorship will then sometimes make it possible to exploit the
expertise of the specialist involved. During the inaugural meeting the
declarations issued are discussed, so that all members of the Committee are
aware of each other’s possible interests.
The Committee                                                                      33
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<pre>nnex C
     The submission letter
     Subject            : Submission of the advisory report Naphthalene
     Your Reference     : DGV/MBO/U-932342
     Our reference      : U-7476/BvdV/fs/T17
     Enclosed           :1
     Date               : December 7, 2012
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     naphthalene.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
         The advisory report was prepared by the Subcommittee on the Classification
     of Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety. The advisory report as been
     assessed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter                                                          34
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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)
Professor W.A. van Gool
President
The submission letter                                                         35
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in June 2012 for public review. The
     following organisations and persons have commented on the draft document:
     • Mr. W. Cremers, Coal Chemicals Sector Group, Brussels, Belgium
     • Ms. A. LeHuray, The Naphthalene Council, Inc., Alexandria, USA.
     Comments on the public review draft                                            36
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<pre>nnex E
     IARC Monograph
     Volume 82, 2002 (excerpt from Naphthalene, pp 367), CAS no. 91-20-3
     Summary of Data Reported and Evaluation.
     1           Exposure data
     Naphthalene is a commercially important aromatic hydrocarbon which is
     produced from coal tar and petroleum. It is used mainly as an intermediate in the
     production of phthalic anhydride, naphthalene sulfonates and dyes and to a lesser
     extent as a moth-repellent. Human exposure to naphthalene can occur during its
     production, in creosote treatment of wood, in coal coking operations, during its
     use as an industrial intermediate, as a result of its use as a moth-repellent, and as
     a result of cigarette smoking.
     2           Human carcinogenicity data
     The only data available to the Working Group were two case series. No inference
     on the carcinogenicity of naphthalene could be drawn from these.
     IARC Monograph                                                                        37
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<pre>3           Animal carcinogenicity data
Naphthalene was tested for carcinogenicity by oral administration in one study in
rats, by inhalation in one study in mice and one in rats and in one screening assay
in mice, by intraperitoneal administration in newborn mice and in rats, and by
subcutaneous administration in two studies in rats. Exposure of rats by inhalation
was associated with induction of neuroblastomas of the olfactory epithelium and
adenomas of the nasal respiratory epithelium in males and females. Both of these
tumours were considered to be rare in untreated rats. In the screening assay study
by inhalation using only female mice, there was an increase in lung adenomas
per tumour-bearing mouse. In the inhalation study in mice, there was an increase
in the incidence of bronchioloalveolar adenomas in female mice. An apparent
increase in the incidence of these tumours in male mice was not statistically
significant.
    The studies by oral administration in rats, intraperitoneal administration in
mice and subcutaneous administration in rats were too limited for an evaluation
of the carcinogenicity of naphthalene.
4           Other relevant data
Animal studies suggest that naphthalene is readily absorbed following oral or
inhalation exposure. Although no data are available from human studies on
absorption of naphthalene, the determination of metabolites in the urine of
workers indicates that absorption does occur, and there is a good correlation
between exposure to naphthalene and the amount of 1-naphthol excreted in the
urine. A number of metabolites, including quinones, naphthols and conjugates
(glucuronides, sulfates, glutathione) are derived from the 1,2-epoxide either
directly or through multiple metabolic steps.
    Naphthalene causes cataracts in humans, rats, rabbits and mice. Humans
accidentally exposed to naphthalene by ingestion develop haemolytic anaemia,
but there is no evidence of haemolytic anaemia in rodents. Cases of haemolytic
anaemia have been reported in children and infants after oral or inhalation
exposure to naphthalene or after maternal exposure during pregnancy.
    Naphthalene causes lung toxicity in mice, but not rats, following either
intraperitoneal injection or inhalation exposure. In mice, the injury is dose-
dependent and Clara cell-specific. After repeated administration of naphthalene,
mouse Clara cells become tolerant to the naphthalene-induced injury that occurs
IARC Monograph                                                                      38
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<pre>following a single dose of naphthalene. Acute and chronic exposure to
naphthalene caused nasal toxicity in both mice and rats.
    In isolated mouse Clara cells, 1,4-naphthoquinone and naphthalene 1,2-oxide
were more toxic than naphthalene. Injury to Clara cells in perfused lungs
occurred at lower concentrations of naphthalene 1,2-oxide compared with
naphthalene or its other metabolites.
    There is some evidence of developmental toxicity in rats and mice at dose
levels that caused clear maternal toxicity. Clara cells of neonatal mice are more
sensitive than those of adult mice to the cytotoxic effects of naphthalene.
    There is little evidence for induction of gene mutations by naphthalene. In
contrast, positive results were obtained in assays for micronucleus formation,
chromosomal aberrations and chromosomal recombinations in vitro, which are
consistent with a clastogenic potential.
    Overall, the proposed mechanism of carcinogenic action is that the higher
rates of metabolism of naphthalene in mice lead to cytotoxic metabolites in the
lung, causing increased cell turnover and tumours. The absence of lung tumours
in rats is entirely consistent with this mechanism. The maximal rates of
metabolism measured in human lung microsomes are about 10-100 times lower
than those in mice.
5           Evaluation
There is inadequate evidence in humans for the carcinogenicity of naphthalene.
    There is sufficient evidence in experimental animals for the carcinogenicity
of naphthalene.
Overall evaluation
Naphthalene is possibly carcinogenic to humans (Category 2B).
    For definition of the italicized terms, see Preamble Evaluation.
Synonyms
•   Naphthalin
•   Naphthene
•   Tar camphor
•   White tar.
Last updated: 4 December 2002
IARC Monograph                                                                    39
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<pre> nnex         F
              Genotoxicity data
              Modified from IARC2
n vitro test system                                        Result     HID or LEDa    Reference
                                                           - S9   +S9
  acterial gene mutation assay
 . coli K12 envA- uvrB-, prophage induction                NT     -   500            Ho & Ho (1981)14
 . coli GY5027 envA- uvrB-, GY40415 ampR, prophage         NT     -   2,000 µg/plate Mamber et al.
nduction                                                                             (1984)16
 . coli PQ37, SOS induction (chromotest)                   -      NT  NR             Mersch-Sundermann
                                                                                     et al. (1993)42
 . typhimurium TA1535/pSK1002, umu gene expression         -      -   83 µg/mL       Nakamura et al.
SOS-inducing activity)                                                               (1987)19
 . coli WP2/WP100 uvrA- recA- assay, differential toxicity NT     -   2,000 µg/plate Mamber et al.
                                                                                     (1984)16
 .typhimurium TA100, TA1535, TA1537, TA98, reverse         NT     -   100 µg/plate   McCann et
mutation                                                                             al.(1975)17
 . typhimurium TA100, TA98, reverse mutation               -      -   384 µg/plate   Florin et al. (1980)11
 . typhimurium TA100, TA98, UHT8413, UHT8414, reverse      -      -   2,000 µg/plate Connor et al.
mutation                                                                             (1985)10
 . typhimurium TA100, TA98, TA2637, reverse mutation       -      -   500 µg/plate   Nohmi et al.
                                                                                     (1985)21
 . typhimurium TA100, TA98, TA97, reverse mutation         -      -   50 µg/plate    Sakai et al. (1985)22
 . typhimurium TA100, TA1535, TA1537, TA98, reverse        -      -   33 µg/plate    Mortelmans et al.
mutation                                                                             (1986)18
 . typhimurium TA1535, reverse mutation                    NT     -   1,000 µg/plate Narbonne et al.
                                                                                     (1987)20
 . typhimurium TA1537, reverse mutation                    NT     -   100 µg/plate   Gatehouse (1980)12
 . typhimurium TA1537, reverse mutation                    NT     -   200 µg/plate   Seixas et al. (1982)43
              Genotoxicity data                                                                         40
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<pre> . typhimurium TA1538, reverse mutation                        NT          -           500 µg/plate         Gatehouse (1980)12
 . typhimurium TA98, reverse mutation                          NT          -           500 µg/plate         Ho et al. (1981)13
 . typhimurium TA98, reverse mutation                          NT          -           100 µg/plate         Narbonne et al.
                                                                                                            (1987)20
 . typhimurium TM677, reverse mutation                         NT          -           256 µg/plate         Kaden et al. (1979)15
 .typhimurium TA100, TA1535, TA1537, TA1538, TA98,             -           -           300 µg/plate         Schreiner (2003)23
everse mutation
 . typhimurium TA102, reverse mutation                         -           -           NR                   Yan et al. (2004)24
Mammalian cell genotoxicity test
DNA single strand breaks, rat hepatocytes, (alkaline elution)  -           NT          38                   Sina et al. (1983)28
Micronucleus formation, newt larvae (Pleurodeles waltl)        (+)                     0.25 ppm             Djomo et al.
 rythrocytes                                                                                                (1995)27
 ister chromatid exchange, Chinese hamster ovary cells         +           +           27                   National Toxicology
                                                                                                            Program (1992)7
  hromosomal aberrations, Chinese hamster ovary cells          -           +           30                   National Toxicology
                                                                                                            Program (1992)7
DNA fragmentation, macrophage J774A.1 cells,                   +           NT          26                   Bagchi et al.
 entrifugation                                                                                              (1998)44
Gene mutation, human MCL-5B-lymphoblastoid cells,              -           NT          40                   Sasaki et al. (1997)25
 K and HPRT loci
 ister chromatid exchange, human lymphocytes                   -           -           13                   Tingle et al. (1993)26
Micronucleus formation (CREST-), human MCL-5B-                 +           NT          30                   Sasaki et al. (1997)25
ymphoblastoid cells
Unschedules DNA synthesis, isolated rat hepatocytes            -           NT          16                   Schreiner (2003)23
n vivo test system                                             Result      Dose                             Reference
 omatic mutation; recombination in                             +           1, 5, 10 mM (feeding larvae)     Delgado-Rodriguez
Drosophila melanogaster                                                                                     et al. (1995)31
Micronucleus assay in ICR Swiss mice                           -           500 mg/kg bw by gavage           Harper et al.
                                                                                                            (1984)29
Micronucleus assay in CD-1 mice                                -           250 mg/kg bw p.i.                Schreiner (2003)23
Unscheduled DNA synthesis in rats                              -           0, 600, 1000 and 1,600 mg/kg     Schreiner (2003)23
                                                                           bw by gavage
DNA damage (alkaline elution)                                  -           2x359 mg/kg bw by gavage         Kitchin et al.
                                                                                                            (1992)30
DNA fragmentation in rats, liver; brain                        +           110 mg/kg, daily for 120 days Delgado-Rodriguez
                                                                                                            et al. (1995)31
                                                                                                            Bagchi et al.
                                                                                                            (1998)32
DNA fragmentation in mice, liver; brain                        +           single dose of 22, 220 or 1,100 Bagchi et al.
wildtype and p53 knock-out)                                                mg/kg bw                         (2000)33
                                                                                                            Bagchi et al (2002)34
     LED, lowest effective dose; HID, highest ineffective dose; in-vitro tests (in µg/ml unless otherwise specified).
             Genotoxicity data                                                                                                 41
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<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                  Comparable with EU Category
                                                                                 (before              (as from
                                                                                 16 December 2008)    16 December 2008)
A            The compound is known to be carcinogenic to humans.                 1                    1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be carcinogenic to humans.              2                    1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.                3                    2
3)           The available data are insufficient to evaluate the carcinogenic    not applicable       not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                   not applicable       not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.45
             Carcinogenic classification of substances by the Committee                                                42
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