<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>(Di)benzoyl peroxide
     Evaluation of the carcinogenicity and genotoxicity
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<pre>Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp               : aanbieding advies (Di)benzoyl peroxide
Uw kenmerk              : DGV/MBO/U-932342
Ons kenmerk             : U-7439/JR/fs/246-I17
Bijlagen                :1
Datum                   : 23 november 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
(di)benzoylperoxide.
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
carcinogene 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></pre>

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<pre>(Di)benzoyl peroxide
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. 2012/24, The Hague, November 30, 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. (Di)benzoyl peroxide. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/24.
all rights reserved
ISBN: 978-90-5549-937-3
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 13
.3 Data 14
   General information 15
.1 Identity and physico-chemical properties 15
.2 IARC conclusion 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 18
.3 Cell transformation assays 20
   Mode of action 21
.1 Genotoxic mode of action 21
.2 Non-genotoxic mode of action 23
.3 Conclusion 23
   Contents                                    7
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<pre>    Classification 25
 .1 Evaluation of data on carcinogenicity and genotoxicity 25
 .2 Recommendation for classification 26
    References 27
    Annexes 31
A   Request for advice 33
B   The Committee 35
C   The submission letter 37
D    Comments on the public review draft 39
E   IARC Monograph 41
F   Genotoxicity data 45
G   Carcinogenic classification of substances by the Committee 47
    (Di)benzoyl peroxide
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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
Beroepsmatige blootstelling aan stoffen van de raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie (di)benzoyl-
peroxide onder de loep. (Di)benzoylperoxide wordt voornamelijk gebruikt als
radicaalinitiator voor polymerisaties. Daarnaast wordt het ook gebruikt als
bleekmiddel voor meel, vet, olie, was en melk; in verharding van rubber; in de
eindbewerking van sommige acetaatgarens, en in geneesmiddelen voor acnebe-
handeling.
De commissie concludeert dat de gegevens over (di)benzoperoxide niet vol-
doende zijn om de kankerverwekkende eigenschappen te evalueren (categorie
3).*
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage G).
Samenvatting                                                                   9
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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 the Committee. In this report the Committee evaluates (di)benzoyl
peroxide. (Di)benzoyl peroxide is mainly used as a radical initiator for
polymerisation. In addition, it is used as: a bleaching agent for flour, fats, oils,
waxes and milk; in rubber curing; as a finishing agent for some acetate yarns,
and in pharmaceuticals for topical treatment of acne.
The Committee concludes that the data on (di)benzoyl peroxide are insufficient
to evaluate the carcinogenic properties (category 3). *
According to the classification system of the Health Council (see Annex G).
Executive summary                                                                    11
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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 (di)benzoyl
        peroxide, further referred to as benzoyl peroxide.
1.2     Committee and procedure
        The evaluation is performed by the Subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the Committee. The members of the Committee
        are listed in Annex B. The submission letter to the State Secretary can be found
        in Annex C.
        Scope                                                                              13
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<pre>         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
    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
    benzoyl peroxide, 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 and
    XToxline, and Chemical Abstracts. The last updated online search was in March
    2012. The relevant new data were included in this report.
 4  (Di)benzoyl peroxide
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<pre> hapter 2
        General information
2.1     Identity and physico-chemical properties
        Benzoyl peroxide is predominantly used as a radical initiator for polymerization
        of acrylates (including dental cements and restoratives) and other polymers. In
        addition, it is used as: a bleaching agent for flour, fats, oils, waxes and milk; in
        the preparation of certain cheeses; in rubber curing; as a finishing agent for some
        acetate yarns; and, in pharmaceuticals for the topical treatment of acne.
            Occupational exposure may occur during production, use in plastics, rubber
        and pharmaceutical industries, and in food processing.1,2
        The identity of benzoyl peroxide and some of its physico-chemical properties are
        given below.1,2
        General information                                                                  15
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<pre>    Chemical name       :  benzoyl peroxide
    CAS registry number :  94-36-0
    EC/EINECS number    :  202-327-6
    Synonyms            :  dibenzoyl peroxide; benzoic acid, peroxide; benzoperoxide; benzoyl
                           superoxide; diphenylglyoxal peroxide
    Colour and physical :  white granular crystalline solid with a faint odour of benzaldehyde
    Molecular weight    :  242.22
    Molecular formula   :  C14H10O4
    Structure           :
                                       O
                                               O
                                           O
                                                  O
    Melting point       :  104-106 °C
    Vapour pressure     :  <13 Pa at 20 °C
    Relative density    :  1.33 g/cm3
    Solubility          :  slightly soluble in water (9.1 mg/L at 25 °C); soluble in acetone, diethyl
                           ether, ethanol and most other organic solvents
    Reactivity          :  highly flammable, explosive and oxidising
    Conversion factors  :  1 ppm = 0.101 x mg/m3
    (25 °C, 760 mm Hg)     1 mg/m3 = 9.91 x ppm
2.2 IARC conclusion
    In 1999, IARC considered benzoyl peroxide not classifiable as to its
    carcinogenicity to humans (Group 3). According to IARC, there was inadequate
    evidence in humans for the carcinogenicity of benzoyl peroxide, and there was
    limited evidence in experimental animals for the carcinogenicity of benzoyl
    peroxide.
 6  (Di)benzoyl peroxide
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
        Limited human data are available, and only involve exposure to benzoyl
        peroxide via the dermal route.
        In England, a pilot case-control study of malignant melanoma has been
        performed under patients who had used benzoyl peroxide for acne treatment
        (Cartwright et al.3, cited in IARC).1 This case control study involved 159 cases
        seen by their general practitioner between 1984 and 1986, who were compared to
        213 controls matched for general practitioner, sex and age. No increased risk was
        found. The risk ratio between use of benzoyl peroxide and malignant melanoma
        was 0.5 (95% CI, 0.2-1.5).
            In a Canadian population-based case-control study, the relationship between
        skin cancer of the head and neck, and use of benzoyl peroxide for acne treatment,
        was investigated. Cases (n= 964) selected from the Saskatchewan cancer registry
        were linked to four age- and sex-matched controls for each case (Hogan et al.4,
        cited in IARC).1 Interviews were conducted in 1989 among female residents
        aged 10-56 and male residents aged 10-51 years, benzoyl peroxide was marketed
        in Canada from 1966 onwards. The response rate was 91% for cases, and 80%
        for controls. Of the cases that responded 92.3% had basal-cell carcinoma, 4.8%
        squamous-cell carcinoma, and 2.9% malignant melanoma. Nine percent of the
        cases, and 10.1% of the controls, recalled use of preparations containing benzoyl
        Carcinogenicity                                                                   17
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<pre>      peroxide, for average periods of two and a half and two years, respectively. The
      odds ratio for use of benzoyl peroxide for all cases combined was 0.8 (95% CI,
      0.5-1.3). There was no association found for the use of any specific preparation
      containing benzoyl peroxide.
      The Committee concludes that the available human data, and the apparent lack of
      positive findings despite long term use, indicate that clinical dermal use of
      benzoyl peroxide does not represent a dermal carcinogenic hazard.
3.2   Carcinogenicity studies in animals
3.2.1 Carcinogenicity studies
      Inhalation exposure
      No inhalation studies are available.
      Oral administration
      Sharratt et al. conducted a study on the treatment of wholemeal flour with
      benzoyl peroxide.5 Albino rats and albino mice (groups of 25 animals/sex/
      species; strain and age were unspecified) were fed a diet with increasing amount
      of Novadelox, a commercial powder containing 18% benzoyl peroxide (purity
      unspecified). Control groups received a diet lacking Novadelox. According to
      the authors, treatment groups received 10, 100 or 1,000 times the daily intake, for
      120 weeks (rats) or 80 weeks (mice). The estimated doses of benzoyl peroxide as
      calculated by IARC amounted to 28, 280 and 2,800 mg/kg diet.
          In parallel, groups of rats and mice (100 animals sex/species/group) were fed
      untreated bread crumbs (control), bread crumbs containing normal levels of
      Novadelox, or bread crumbs containing 10 times the normal amount of
      Novadelox.
          Body weight gain was depressed in male and female rats consuming the diets
      containing the two highest levels of benzoyl peroxide. The authors stated that
      Novadex at the top dosage levels marginally reduced the concentration of one or
      several nutrients in the diet. There were some statistically significantly different
      mortality rates observed in rats between experimental groups and controls, and in
      mice in the middle dose group that suffered from a large number of accidental
      deaths. No evidence for benzoyl peroxide-related carcinogenicity was observed.
          The Committee notes the limitations in the design and reporting of the study.
 8    (Di)benzoyl peroxide
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<pre>Dermal application
Sharrat et al. injected groups of 25 male and 25 female rats, and 25 male and 25
female mice subcutaneously with 120 mg (rats) or 50 mg (mice) benzoyl
peroxide, as a 20% suspension in a starch solution.5 Another group, consisting of
25 male and 25 female mice, were painted on the back of the neck on 6 days per
week with approximately 50 mg of a 50% suspension of benzoyl peroxide paste.
No significant difference between control groups and groups treated with
benzyol peroxide, either subcutaneously or topically, in mortality or
development of tumours was reported.
Additional data on the potential carcinogenic properties of benzoyl peroxide
after dermal exposure can be derived from initiator-promotion studies that have
included benzoyl peroxide as a control group. Below, only those studies are
summarised in which animals were exposed to benzoyl peroxide alone.
In an extensive study by the National Toxicology Program (NTP), benzoyl
peroxide was tested for promoting properties but was also applied as single agent
to B6C3F1, Swiss (CD-1) and Sencar mice.6 Two control groups (one as
promotion control for DMBA, and one for MNNG) (30/sex/strain) were exposed
to 20 mg benzoyl peroxide alone once a week for 52 weeks. Control animals
received 0.1 mL acetone alone. Necropsies were conducted after 52 weeks. In the
strains used, no skin tumours were observed.
    Kurokawa et al. applied 0.2 mL of a 100 mg/mL solution of benzoyl peroxide
in acetone, twice weekly for 51 weeks to a group to the shaved skin of 20 female
SEN mice, four weeks of age (Kurokawa et al.7, cited in IARC).1 A group of 15
mice that served as controls received 0.2 mL acetone alone, There were no skin
tumours among the control mice at the termination of the experiment, whereas
eight tumours were noted in the benzoyl peroxide-treated mice (p < 0.05; five
squamous-cell carcinomas). Kraus et al. has questioned the outcome reported by
Kurokawa et al., due to potential methodological limitations, and the fact that an
unusually high responsiveness of the model was observed.8
    In a study by Spalding et al., groups of five male heterozygous TG:AC mice
(carrying a v-Ha-ras gene) derived from the wild-type FVB/N strain were treated
with 0, 1, 5 or 10 mg benzoyl peroxide in 0.2 mL acetone on the shaved dorsal
skin, twice a week for 20 weeks (Spalding et al.9, cited in IARC).1 Groups of five
male FVB/N mice were similarly treated. An increase in papillomas was noted in
TG:AC mice at the two top dose groups (incidences of 0/5, 0/5, 3/5 and 3/4 in
order of increasing doses). In addition, one papilloma-bearing mouse in the 10-
Carcinogenicity                                                                    19
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<pre>      mg group died before the end of the experiment. No papillomas developed in the
      FVB/N mice.
           In a promotion study in Syrian hamsters (age unknown), 20 animals received
      160 mg benzoyl peroxide in 1 mL acetone to the shaved dorsal skin three times
      per week for 16 months (Schweizer et al.10, cited in IARC).1 The formation of a
      general and pronounced melanosis, coinciding with a usually moderate skin
      scaling, and a mild hyperplasia was reported. Melanotic tumours were not
      observed.
           In addition to the studies noted in IARC, several other subcutaneous and/or
      dermal carcinogenicity studies with benzyol peroxide are reported in an
      extensive review by Kraus et al. (1995).8 These involve mainly control groups in
      dermal promotion studies in mice, all with negative results.
3.2.2 Tumour promoting properties
      Mancuso et al. showed that Car-S mice treated with DMBA and subsequent
      promotion twice weekly with benzoyl peroxide developed 11.0 (± 1.3)
      papillomas/mouse (a tumour incidence of 86%), whereas animals treated with
      DMBA alone had not yet developed papillomas.11
           IARC and Kraus et al. (1995) further report several additional studies where
      benzoyl peroxide has been tested for initiating, and in particular, promoting
      properties.1,8 Benzoyl peroxide did not display initiating properties in two studies
      in mice. Results of promotion studies have been both positive and negative,
      depending on the initiator, the vehicle and animal model used. Clear evidence of
      promoting activity of benzoyl peroxide has been reported for well-known
      initiating agents DMBA, MNNG and BaP – but not ultraviolet light - in several
      strains of mice, especially the responsive SENCAR strain.
           The Committee concludes that the overall weight of the available initiating-
      promotion studies shows that benzoyl peroxide displays tumour promoting
      properties in various mouse models when applied dermally. This promoting
      activity of benzoyl peroxide has been associated with the generating ability of
      oxygen radicals.1,12 The Committee considers these findings of low relevance for
      subsequent classification for carcinogenicity.
3.3   Cell transformation assays
      Rivedal et al. did not observe an increased number of transformed colonies in the
      SHE cell transformation assay with benzoyl peroxide.29
 0    (Di)benzoyl peroxide
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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
        The in vitro and in vivo genotoxicity data are summarised below and presented
        in Annex F.
4.1.1   Gene mutation assays
        In vitro
        Several bacterial mutagenicity assays have been conducted using benzoyl
        peroxide, consistently with negative results (references13-20, cited by IARC and
        Kraus et al.).1,8
            The only data on mammalian gene mutation assays are reported in an
        abstract, that describes positive results under unspecified conditions in T51B
        epithelial cells (Swierenga et al.21, cited by Kraus et al.8).
        In vivo
        No data on mammalian in vivo gene mutation assays with benzoyl peroxide are
        available.
        Mode of action                                                                   21
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<pre>4.1.2 Cytogenetic assays
      In vitro
      Benzoyl peroxide did not cause chromosomal aberrations or aneuploidy in
      Chinese hamster lung cells without activation (Ishidate et al.17, cited in IARC
      and Kraus et al.).1,8
          However, benzoyl peroxide has been shown to induce DNA single-strand
      breaks in human bronchial epithelial cells (Saladino et al.22 cited in IARC)1 and
      sister chromatid exchange in CHO cells (Järventaus et al.23 ,cited in Kraus et al.)8
      and V79 cells (Swierenga et al.21, abstract cited in Kraus et al.).8
      In vivo
      No in vivo cytogenetic data from tests in somatic cells on benzoyl peroxide are
      available.
          No significant increase in dominant lethal mutation rate was observed in
      mice following intraperitoneal injection of 54 or 62 mg/kg bw benzoyl peroxide
      (Epstein et al.24, cited in IARC and Kraus et al.).1,8
4.1.3 Miscellaneous
      In vitro
      In human bronchial epithelial cells, DNA single-strand breaks and DNA-protein
      cross-links were observed in the absence of a metabolic activation system
      (Saladino et al.22 cited in IARC).1
          DNA strand breaks and subsequent DNA repair in primary hepatocytes were
      noted in an abstract of Swierenga et al. (Swierenga et al.21, cited by Kraus et al.).8
          Incubation of calf thymus DNA with benzoyl peroxide alone, or benzoyl
      peroxide and chelated iron, did not result in DNA single-strand breaks, as
      measured by S1-nuclease hydrolysis. Deoxyribose degradation, as measured by
      thiobarbituric acid product formation, was moderately (125% of control) affected
      by benzoyl peroxide, and significantly (175% of control) when combined with
      chelated iron.25
          Hazlewood and Davies showed that benzoyl peroxide in the presence of
      Cu(I) resulted in benzoyloxyl and phenyl radicals.12 Also DNA adduct formation
      occurred when the compound was added to DNA in solution.
 2    (Di)benzoyl peroxide
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<pre>        Incubation of benzoyl peroxide with DNA fragments obtained from the
    human p53 tumour suppressor gene and c-Ha-ras-1 protooncogene, did not
    induce DNA damage in the presence of Cu(I).26 When Cu(I) was added, an
    increase in DNA cleavage was noted in single and double stranded DNA.
        Benzoyl peroxide induced the formation of 8-hydroxy-2’-deoxyguanosine in
    the DNA of murine keratinocytes.27 Addition of a copper chelator blocked this
    formation. Depletion of intracellular glutathione resulted in increased levels of 8-
    OHdG formation, while addition of intracellular glutathione protected cells
    against DNA damaging.
        In a unconventional in vitro test for the prediction of carcinogenicity, benzoyl
    peroxide increased the number of foci in bovine papillomavirus DNA-carrying
    C3H/10T1/2 cells compared to controls. This result was interpreted as positive
    by the authors.28
4.2 Non-genotoxic mode of action
    No data are available.
4.3 Conclusion
    The Committee is of the opinion that the available genotoxicity data do not allow
    any conclusions on the mode of action of benzoyl peroxide.
    Mode of action                                                                       23
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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        Limited epidemiological data are available for benzoyl peroxide and only
        address the dermal route. Two case-control studies showed no evidence for
        carcinogenicity of benzoyl peroxide. The majority of animal carcinogenicity data
        consist of results obtained in mouse dermal initiator-promotion studies. The
        overall evidence from these studies suggest that benzoyl peroxide can act as a
        promoter.
            For conclusions on the carcinogenic properties, insufficient data are
        available.
            Benzoyl peroxide did not induce gene mutations in bacterial assays. Standard
        in vitro gene mutation assays in mammalian cells are lacking. One in vitro
        chromosomal aberration test conducted without metabolic activation was
        negative; whereas one sister chromatid exchange assay was positive in the
        presence of a metabolic activation system. Positive results have been reported in
        several in vitro DNA damage assays. In vivo genotoxicity data are lacking, with
        the exemption of a dominant lethal mutation assay in mice with negative results.
            Overall, due to absence of several standard in vitro and particularly in vivo
        genotoxicity assays, the Committee cannot draw conclusions concerning the
        genotoxic properties of benzoyl peroxide.
        Classification                                                                    25
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<pre>5.2 Recommendation for classification
    The Committee concludes that the data on benzoyl peroxide are insufficient to
    evaluate the carcinogenic properties (category 3).*
    According to the classification system of the Health Council (see Annex G).
 6  (Di)benzoyl peroxide
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<pre>  References
  Benzoyl peroxide. IARC monographs on the evaluation of carcinogenic risks to humans. 1999: 71 Pt
  2: 345-58.
  Benzoyl Peroxide. SIDnitial Assessment Report For SIAM 15. 2002.
  Cartwright RA, Hughes BR, Cunliffe WJ. Malignant melanoma, benzoyl peroxide and acne: a pilot
  epidemiological case-control investigation. Br J Dermatol 1988; 118(2): 239-242.
  Hogan DJ, To T, Wilson ER, Miller AB, Robson D, Holfeld K e.a. A study of acne treatments as risk
  factors for skin cancer of the head and neck. Br J Dermatol 1991; 125(4): 343-348.
  Sharratt M, Frazer AC, Forbes OC. Study of the biological effects of benzoyl peroxide. Food Cosmet
  Toxicol 1964; 527-538.
  Comparative initiation/promotion skin paint studies of B6C3F1 mice, Swiss (CD-1) mice, and Sencar
  mice. 1996: Technical Report Series No. 441.
  Kurokawa Y, Takamura N, Matsushima Y, Imazawa T, Hayashi Y. Studies on the promoting and
  complete carcinogenic activities of some oxidizing chemicals in skin carcinogenesis. Cancer Lett
  1984; 24(3): 299-304.
  Kraus AL, Munro IC, Orr JC, Binder RL, LeBoeuf RA, Williams GM. Benzoyl peroxide: an
  integrated human safety assessment for carcinogenicity. Regul Toxicol Pharmacol 1995; 21(1): 87-
  107.
  Spalding JW, Momma J, Elwell MR, Tennant RW. Chemically induced skin carcinogenesis in a
  transgenic mouse line (TG.AC) carrying a v-Ha-ras gene. Carcinogenesis 1993; 14(7): 1335-1341.
0 Schweizer J, Loehrke H, Edler L, Goerttler K. Benzoyl peroxide promotes the formation of melanotic
  tumors in the skin of 7,12-dimethylbenz[a]anthracene-initiated Syrian golden hamsters.
  Carcinogenesis 1987; 8(3): 479-482.
  References                                                                                         27
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<pre>1 Mancuso M, Pazzaglia S, Tanori M, Rebessi S, Di M, V, Covelli V e.a. Only a subset of 12-O-
  tetradecanoylphorbol-13-acetate-promoted mouse skin papillomas are promotable by benzoyl
  peroxide. Mutat Res 2004; 548(1-2): 35-45.
2 Hazlewood C, Davies MJ. Benzoyl peroxide-induced damage to DNA and its components: direct
  evidence for the generation of base adducts, sugar radicals, and strand breaks. Arch Biochem
  Biophys 1996; 332(1): 79-91.
3 Mutagenic evaluation of benzoyl peroxide. 1975: NTIS Pub. No. PB-245-494/AS.
4 De Flora S., Zanacchi P, Camoirano A, Bennicelli C, Badolati GS. Genotoxic activity and potency of
  135 compounds in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res 1984;
  133(3): 161-198.
5 De Flora S., Camoirano A, Zanacchi P, Bennicelli C. Mutagenicity testing with TA97 and TA102 of
  30 DNA-damaging compounds, negative with other Salmonella strains. Mutat Res 1984; 134(2-3):
  159-165.
6 Dillon D, Combes R, Zeiger E. The effectiveness of Salmonella strains TA100, TA102 and TA104 for
  detecting mutagenicity of some aldehydes and peroxides. Mutagenesis 1998; 13(1): 19-26.
7 Ishidate M, Jr., Sofuni T, Yoshikawa K, Hayashi M, Nohmi T, Sawada M e.a. Primary mutagenicity
  screening of food additives currently used in Japan. Food Chem Toxicol 1984; 22(8): 623-636.
8 Matula TL, Downie RH, Barret N. Mutagenicity studies of benzoyl peroxide in bacteria. Environ
  Mutat 1987; 9 (Suppl. 8): 69.
9 Yamaguchi T, Yamashita Y. Mutagenicity of hydroperoxides of fatty acids and some hydrocarbons.
  Agric Biol Chem 1980; 44: 1675-1678.
0 Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K. Salmonella mutagenicity tests: IV.
  Results from the testing of 300 chemicals. Environ Mol Mutagen 1988; 11 Suppl 12: 1-157.
1 Swierenga SH, Hasnain SH, Lee FJ. An evaluation of cytotoxicity and genotoxicity of benzoyl
  peroxide (abstract). Environ Mutat 1987; 9 (Suppl. 8): 105.
2 Saladino AJ, Willey JC, Lechner JF, Grafstrom RC, LaVeck M, Harris CC. Effects of formaldehyde,
  acetaldehyde, benzoyl peroxide, and hydrogen peroxide on cultured normal human bronchial
  epithelial cells. Cancer Res 1985; 45(6): 2522-2526.
3 Järventaus H, Norppa J, Linnainmaa K, Sorsa M. SCE induction in CHO cells by peroxides used in
  the plastics industry. Mutat Res 1984; 130: 249.
4 Epstein SS, Arnold E, Andrea J, Bass W, Bishop Y. Detection of chemical mutagens by the dominant
  lethal assay in the mouse. Toxicol Appl Pharmacol 1972; 23(2): 288-325.
5 Iqbal M, Sharma SD, Mizote A, Fujisawa M, Okada S. Differential role of hydrogen peroxide and
  organic hydroperoxides in augmenting ferric nitrilotriacetate (Fe-NTA)-mediated DNA damage:
  implications for carcinogenesis. Teratog Carcinog Mutagen 2003; Suppl 1: 13-21.
6 Kawanishi S, Oikawa S, Murata M, Tsukitome H, Saito I. Site-specific oxidation at GG and GGG
  sequences in double-stranded DNA by benzoyl peroxide as a tumor promoter. Biochemistry 1999;
  38(51): 16733-16739.
8 (Di)benzoyl peroxide
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<pre>7 King JK, Egner PA, Kensler TW. Generation of DNA base modification following treatment of
  cultured murine keratinocytes with benzoyl peroxide. Carcinogenesis 1996; 17(2): 317-320.
8 Kowalski LA, Assi KP, Wee RK, Madden Z. In vitro prediction of carcinogenicity using a bovine
  papillomavirus DNA--carrying C3H/10T 1/2 cell line (T1). II: Results from the testing of 100
  chemicals. Environ Mol Mutagen 2001; 37(3): 231-240.
9 Rivedal E, Mikalsen SO, Sanner T. Morphological transformation and effect on gap junction
  intercellular communication in Syrian hamster embryo cells as screening tests for carcinogens devoid
  of mutagenic activity. Toxicol In Vitro 2000; 14(2): 185-192.
0 Martinez A, Urios A, Blanco M. Mutagenicity of 80 chemicals in Escherichia coli tester strains
  IC203, deficient in OxyR, and its oxyR(+) parent WP2 uvrA/pKM101: detection of 31 oxidative
  mutagens. Mutat Res 2000; 467(1): 41-53.
1 Guideline to the classification of carcinogenic compounds. The Hague: Health Council of the
  Netherlands; 2010: publication no. A10/07E.
  References                                                                                           29
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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 Genotoxicity data
G Carcinogenic classification of substances by the Committee
  Annexes
                                                             31
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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                                                                                        33
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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.
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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                                                              35
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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.
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<pre>nnex C
     The submission letter
     Subject            : Submission of the advisory report (di)benzoyl peroxide
     Your Reference     : DGV/MBO/U-932342
     Our reference      : U-7439/JR/fs/246-I17
     Enclosed           :1
     Date               : November 23, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     (di)benzoyl peroxide.
     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 has been
     assessed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter                                                          37
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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
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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:
     • Mr. T.J.Lentz, National Institute for Occupational Safety and Health, USA.
     Comments on the public review draft                                            39
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<pre>nnex E
     IARC Monograph
     VOL: 36
     CAS No.: 94-36-0
     Summary of Data Reported and Evaluation
     Exposure data
     Benzoyl peroxide has been produced commercially since 1921. Major sources of
     exposure are its use in the plastics industry (principally for polyester resin
     production) and in acne medications. Another potential source is its use in
     bleaching foods.
     Experimental data
     Benzoyl peroxide was tested for carcinogenicity in mice and rats by oral
     administration in the diet and by subcutaneous administration, and in mice by
     skin application. In three studies by skin application in mice, benzoyl peroxide
     was tested for either initiating or promoting activity. All of the studies were
     inadequate for an evaluation of complete carcinogenicity; two studies indicated
     that benzoyl peroxide has promoting activity in mouse skin.
     IARC Monograph                                                                   41
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<pre>  The available data are inadequate to evaluate the teratogenic potential of benzoyl
  peroxide in mammals.
  Benzoyl peroxide was not mutagenic in bacteria. It did not induce chromosomal
  aberrations in mammalian cells in vitro and did not induce dominant lethal
  mutations in mice.
  Human data
  Among a small factory population, two cases of lung cancer were found in young
  men who were involved primarily in the production of benzoyl peroxide but
  were also exposed to benzoyl chloride and other chemicals.
  Evaluation
  There is inadequate evidence for the carcinogenicity of benzoyl peroxide to
  experimental animals. There is inadequate evidence for the carcinogenicity of
  benzoyl peroxide to humans. No evaluation could be made of the carcinogenicity
  to humans of benzoyl peroxide.
  VOL: 71 (1999) (p.345)
  Summary of Data Reported and Evaluation
  Exposure data
  Exposure to benzoyl peroxide may occur in its manufacture and use as an
  initiator in polymer production, food bleaching and rubber curing. Consumer
  exposure occurs from acne medications and dental products containing benzoyl
  peroxide.
  Human carcinogenicity data
  Two case-control studies have evaluated exposure to benzoyl peroxide among
  cases of malignant melanoma. One of these studies (the smallest) (among
  chemists) suggested a greater frequency of exposure among cases than controls.
  A third large population-based case-control study, designed specifically to
  evaluate the possible risk of benzoyl peroxide used as an acne medication among
2 (Di)benzoyl peroxide
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<pre>young persons, included largely cases of basal-cell carcinoma of the skin. There
was no association with use of benzoyl peroxide in this study.
Animal carcinogenicity data
Benzoyl peroxide was tested in two studies by skin application in strains of mice
susceptible to the development of skin papillomas and in several skin-painting
studies in mice and in one study in hamsters in combination with known
carcinogens. In one study by skin application in mice, it induced benign and
malignant skin tumours and, in the other study, benign tumours. Benzoyl
peroxide was active as a skin tumour promoter in several strains of mice.
Other relevant data
Benzoyl peroxide forms radicals that are involved in its covalent binding to
macromolecules. Its biological effects are inhibited by antioxidants.
Its genotoxic properties have received little attention. DNA damage has been
observed in treated mammalian cells, but it is not mutagenic in bacteria and does
not cause chromosomal damage in cultured mammalian cells or dominant lethal
effects in mice.
Evaluation
There is inadequate evidence in humans for the carcinogenicity of benzoyl
peroxide. There is limited evidence in experimental animals for the
carcinogenicity of benzoyl peroxide.
Overall evaluation
Benzoyl peroxide is not classifiable as to its carcinogenicity to humans (Group
3).
IARC Monograph                                                                    43
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<pre>nnex F
     Genotoxicity data
     Results from genotoxicity assays conducted with benzoyl peroxide.
     Test system                            Result a,b          Reference
                                            exogenous metabolic
                                            activation
                                            without      with
     Gene mutations
     In vitro
     Salmonella typhimurium                 –            –      13 (from Kraus et al.)
     Salmonella typhimurium                 –            –      19 (from Kraus et al.)
     Salmonella typhimurium                 –            –      14 (from Kraus et al.)
     Salmonella typhimurium                 –            –      15 (from Kraus et al.)
     Salmonella typhimurium                 –            –      17 (from IARC; Kraus et al.)
     Salmonella typhimurium                 +            –      18 (from Kraus et al.)
     Salmonella typhimurium                 –            –      20
     Salmonella typhimurium                 –            –      16
     Yeast gene conversion                  –            –      13 (from Kraus et al.)
     T51B mutation                          +b                  21 (from Kraus et al.)
     in vivo
     Dominant lethal test, mice             NA           –      24 (from IARC and Kraus et al.)
     Chromosomal aberrations
     In vitro
     Sister Chromatide Exchange, CHO cellsb –            +      23 (from Kraus et al.)
     Chromosomal aberrations,               –            NT     17 (from IARC; Kraus et al.)
     Chinese hamster lung cells
     Genotoxicity data                                                                          45
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<pre>  Sister Chromatide Exchange, V79 cells       +b                  21 (from Kraus et al.)
  Aneuploidy, Chinese hamster lung cells      –              NT   17 (from IARC)
  DNA single-strand breaks                    +              NT   22 (from IARC)
  Miscellaneous
  in vitro
  Escherichia coli DNA repair                 +              –    14 (from Kraus et al.)
  Escherichia coli WP2 uvrA/pKM101 and        –              NT   30
  IC203
  DNA-protein cross-links, human bronchial    +              NT   22 (from IARC)
  epithelial cells
  Hepatocyte DNA repair                       +b                  21 (from Kraus et al.)
  DNA strand breaks, calf thymus DNA          –              NT   25
  Deoxyribose degradation,                    ±              NT   25
  calf thymus DNA                             (+ with Fe)
  DNA adduct, calf thymus DNA                 +              NT   12
  Foci formation, bovine papillomavirus       +              NT   28
  DNA-carrying C3H/10T1/2 cells
  DNA cleavage, ss- and ds-DNA fragments      –              NT   26
  from human p53 and c-Ha-ras-1 gene, calf    (+ with Cu)
  thymus DNA and human leukemia cells
  (HL-60)
  Oxidized guanine in DNA, murine             +              NT   27
  keratinocytes
  a     Based only on abstract; methodology not completely clear.
  b     Presumed to be performed in absence of S9.
  NA = not applicable; NT = not tested.
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<pre> nnex       G
            Carcinogenic classification of
            substances by the Committee
            The Committee expresses its conclusions in the form of standard phrases:
 ategory   Judgement of the Committee (GRGHS)                                             Comparable with EU Category
                                                                                          67/584/EEC       EC No 1272/2008
                                                                                          (before         (as from
                                                                                          12/16/2008)     2/16/2008)
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.
 he Hague: Health Council, 2010; publication no. A10/07E.31
            Carcinogenic classification of substances by the Committee                                                   47
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<br><br>