<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>             Health Council of the Netherlands
          Adriamycin
             Health-based calculated occupational cancer risk values
2015/06
</pre>

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<pre></pre>

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<pre>Adriamycin
    Health-based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Adriamycin
Uw kenmerk             : DGV/BMO/U-932542
Ons kenmerk            : U-8338/BvdV/cn/459-R71
Bijlagen               :1
Datum                  : 18 maart 2015
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling
aan adriamycine.
Dit advies maakt deel uit van een uitgebreide reeks, waarin concentratieniveaus in lucht
worden afgeleid die samenhangen met een extra kans op (overlijden aan) kanker van 4 per
1.000 en 4 per 100.000 door beroepsmatige blootstelling. De conclusies van het genoemde
advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige blootstelling aan
stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid
en omgeving.
In dit advies concludeert de commissie dat adriamycine een carcinogene stof is en beveelt
aan om deze stof te classificeren in categorie 1B (de stof moet beschouwd worden als kan-
kerverwekkend voor de mens). De commissie is echter van mening dat wegens gebrek aan
adequate humane en dierexperimentele gegevens het niet mogelijk is om de extra kans op
kanker na blootstelling aan adriamycine te berekenen.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                      Postadres
Rijnstraat 50                                                    Postbus 16052
2515 XP           Den Haag                                       2500 BB         Den Haag
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Adriamycin
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2015/06, The Hague, 18 maart 2015
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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 and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. 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.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Adriamycin - Health-based calculated
occupational cancer risk values. The Hague: Health Council of the Netherlands,
2015; publication no. 2015/06.
all rights reserved
ISBN: 978-94-6281-023-5
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<pre>   Contents
   Samenvatting 11
   Executive summary 13
   Scope 15
.1 Background 15
.2 Committee and procedure 16
.3 Data 16
   Identity, toxicity profile and classification 17
.1 Identity and physical and chemical properties 17
.2 Classification as a carcinogenic substance 18
.3 Genotoxicity 19
.4 Non-carcinogenic effects 19
.5 Occupational exposure and existing occupational exposure limits 21
   Carcinogenicity studies 23
.1 Human studies 23
.2 Animal experiments 24
.3 Selection of the suitable study for risk estimation in the occupational situation 24
.4 Calculation of the health-based occupational cancer risk values 24
   Contents                                                                             9
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<pre>   References 25
   Annexes 29
A  Request for advice 31
B  The Committee 33
C  The submission letter (in English) 35
D  Comments on the public review draft 37
E  Animal studies 39
F  Evaluation of the Subcommittee on the Classification of carcinogenic substances 41
G  Carcinogenic classification of substances by the Committee 53
 0 Adriamycin
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<pre>Samenvatting
Op verzoek van de minister van Sociale zaken en Werkgelegenheid, leidt de
Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van
de Gezondheidsraad, de concentraties van een stof in de lucht af die samenhan-
gen met een vooraf vastgesteld extra risico op kanker (4 per 1.000 en 4 per
100.000 individuen) door beroepsmatige blootstelling gedurende het arbeidzame
leven. Het gaat om kankerverwekkende stoffen die door de Gezondheidsraad of
de Europese Unie geclassificeerd zijn in categorie 1A of 1B en die kankerver-
wekkend zijn via een stochastisch genotoxisch mechanisme. Voor de schatting
maakt de commissie gebruik van de Leidraad Berekening Risicogetallen voor
kankerverwekkende stoffen van de Gezondheidsraad.1 In dit advies onderzoekt
de commissie de mogelijkheid om zo’n schatting te maken voor adriamycine.
Adriamycine is een cytotoxisch anthracycline dat wordt gebruikt in antimitoti-
sche chemotherapie.
De commissie concludeert dat adriamycine een carcinogene stof is met een sto-
chastisch genotoxisch werkingsmechanisme. De commissie beveelt aan om deze
stof onder te brengen in categorie 1B (stof moet beschouwd worden als kanker-
verwekkend voor de mens).
    De commissie is echter van mening dat wegens gebrek aan voldoende gege-
vens het niet mogelijk is om de extra kans op kanker na blootstelling aan adria-
mycine te berekenen.
Samenvatting                                                                     11
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<pre>Executive summary
At the request of the Minister of Social Affairs and Employment, the Dutch
Expert Committee on Occupational Safety (DECOS), a committee of the Health
Council of the Netherlands, derives so-called health-based calculated –
occupational cancer risk values (HBC-OCRVs) associated with excess cancer
levels of 4 per 1,000 and 4 per 100,000 as a result of working life exposure to
substances. It concerns substances which are classified by the Health Council or
the European Union in category 1A or 1B, and which are considered stochastic
genotoxic carcinogens. For the estimation, the Committee uses the Guideline for
calculating carcinogenic risks of the Health Council.1 In this report the
Committee evaluates the possibility to establish such estimates for adriamycin.
Adriamycin is a cytotoxic anthracycline antibiotic used in antimitotic
chemotherapy.
In this report, the Committee concludes that adriamycin is a carcinogenic
substance with a stochastic genotoxic mechanism. The Committee recommends
adriamycin to be classified in category 1B (substance presumed to be
carcinogenic to humans).
    The Committee is of the opinion that due to a lack of sufficient data, it is not
possible to estimate the additional lifetime cancer risk for adriamycin.
Executive summary                                                                    13
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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for genotoxic chemical
        substances are set using a three-step procedure. In the first step, a scientific
        evaluation of the data on the toxicity of the substance is made by the Dutch
        Expert Committee on Occupational Safety (DECOS), a committee of the Health
        Council of the Netherlands, at request of the Minister of Social Affairs and
        Employment (Annex A). For non-stochastic (thresholded) genotoxic substances
        this evaluation should lead to a health-based recommended exposure limit for the
        concentration of the substance in air. Such an exposure limit cannot be derived if
        the toxic action is not thresholded, as is the case for substances with stochastic
        genotoxic carcinogenic properties. In that case, an exposure-response
        relationship is recommended for use in regulatory standard setting, i.e. the
        calculation of so-called health-based calculated occupational cancer risk values
        (HBC-OCRVs). The Committee calculates HBC-OCRVs for compounds, which
        are classified as genotoxic carcinogens by the European Union or by the
        Committee.
            For the establishment of the HBC-OCRV’s, the Committee generally uses a
        linear extrapolation method, as described in the Committee’s report Calculating
        cancer risk due to occupational exposure to genotoxic carcinogens and
        Guideline for calculating carcinogenic risk.1,2 The linear model to calculate
        Scope                                                                              15
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<pre>    occupational cancer risk is used as a default method, unless scientific data would
    indicate that using this model is not appropriate.
        In the next phase of the three-step procedure, the Social and Economic
    Council advises the Minister of Social Affairs and Employment on the feasibility
    of using the HBC-OCRVs as regulatory occupational exposure limits. In the final
    step of the procedure the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present document contains the evaluation of the DECOS, hereafter called the
    Committee. The members of the Committee are mentioned in Annex B. The
    Committee requested the DECOS Subcommittee on the Classification of
    Carcinogenic Substances to evaluate the genotoxic mechanism of adriamycin
    (see Annex F and G). The recommendations of the Subcommittee were used by
    DECOS to decide on the appropriate approach to risk assessment. The
    submission letter (in English) to the Minister can be found in Annex C. In July
    2014, 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 advisory report. The received comments, and the
    replies by the Committee, can be found on the website of the Health Council.
1.3 Data
    The Committee’s recommendation has been based on scientific data, which are
    publicly available. Data were obtained from the online databases Chemical
    Abstracts, XToxline, and Medline, using carcinogen, cancer, tumour or
    neoplasm, and CAS registry number as keywords. In addition, in preparing this
    report the following reviews were consulted: IARC monographs from 1976 and
    1987.3,4 The last search was performed in December 2014.
 6  Adriamycin
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<pre> hapter 2
        Identity, toxicity profile and
        classification
2.1     Identity and physical and chemical properties
        Adriamycin (doxorubicin) is a cytotoxic anthracycline antibiotic used in
        antimitotic chemotherapy. It is infused intravenously to treat a variety of
        cancers.5 Since 1996, a concentrate of adriamycin hydrochloride in a pegylated
        liposomal formulation has been authorized in Europe.6 Occupational exposure
        might occur during drug preparation and administration or cleanup of medical
        waste or indirectly during nursing of patients via the dermal route. Inhalation
        exposure is considered to be negligible taking into consideration the very low
        vapour pressure of adriamycin and the supply in vials and administration by
        infusion.5
            The identity and some physicochemical properties of adriamycin are given
        below.4,5,7-10
        Chemical name (CAS)                : (8S-cis)-10-[(3-amino-2,3,6-trideoxy-L-
                                             hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-
                                             8-(hydroxyacetyl)-1-methoxy-5,12-naphtacenedione
        CAS registry number                : 23214-92-8
        EC number                          : 245-495-6
        RTECS number                       : AV9800000
        IUPAC name                         : (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-
                                             methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-
                                             hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-
                                             5,12-dione
        Identity, toxicity profile and classification                                                  17
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<pre>    Synonyms                             : 14-hydroxydaunomycin; Adriablastina; doxorubicin
                                           hydrochloride; NCS 123127
    Molecular formula                    : C27H29NO11
    Physical description and colour      : red, crystalline solid
    Structure                            :
    Molar mass                           : 543.5 g/mol
    Melting point                        : 229-231°C
    Boiling point                        : not available
    (Relative) density                   : not available
    Solubility in water                  : 20 g/L (temperature not indicated)
    Solubility in organic solvents       : soluble in aqueous alcohols; moderately soluble in
                                           anhydrous methanol; insoluble in non-polar organic
                                           solvents
    Log P (n-octanol/water)              : 1.27 at pH 7.4
    Vapour pressure                      : 1.20x10-22 Pa (calculated)
    Relative vapour density              : not available
    Flash point (open/closed cup)        : not available
    Odour threshold                      : not available
    Conversion factor (20 °C, 101.3 kPa) : 1 mg/m3 = 4.50 ppm; 1 ppm = 0.22 mg/m3
2.2 Classification as a carcinogenic substance
    Adriamycin is not classified by the European Union. In her latest classification
    (1987) IARC has classified the compound as a 2A carcinogen (probably
    carcinogenic to humans).3,9 [In 2014 the 13th NTP Report on Carcinogens
    considers adriamycin as reasonably anticipated to be a human carcinogen based
    on sufficient evidence of carcinogenicity from studies in experimental animals.5]
         In 1995, DECOS concluded that there was inadequate evidence that
    adriamycin was carcinogenic to humans, that adriamycin was carcinogenic in
    rats by iv, sc and intravesicular administration and that adriamycin was
    mutagenic to bacteria and mammalian cells in vitro.11 DECOS, in 1995,
    classified the compound as a genotoxic carcinogen.11
         In the present evaluation the Committee (DECOS) follows the
    recommendation of the DECOS Subcommittee on the Classification of
    Carcinogenic Substances and classified adriamycin in category 1B (substance
    presumed to be carcinogenic to humans)(see Annex F and G).
 8  Adriamycin
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<pre>2.3 Genotoxicity
    IARC concluded previously that adriamycin is a potent genotoxicant.3,4,12
    Adriamycin is mutagenic in bacteria, in mammalian cells in vitro, and in vivo in
    Drosophila.13-18 It causes chromosomal anomalies in hamster cells and human
    lymphocytes in vitro and in mouse bone marrow cells in vivo.19-24 Adriamycin
    produces cell transformation in mouse fibroblast cells and in Fisher rat embryo
    cells in vitro.15,25 Patients treated with adriamycin showed significant increases
    in the incidence of chromosomal aberrations and sister chromatid exchanges.26,27
    Detailed description of the studies is given in Annex F.
        Adriamycin is a chemotherapeutic agent whose mode of action includes
    intercalation into the DNA double helix thus preventing their unwinding for
    replication and resulting in DNA damage, binding of DNA-associated enzymes
    such as topoisomerase II.28,29 It is very likely that for genotoxicity of adriamycin
    similar mechanisms as for anti-tumour effects apply. According to the
    Committee non-covalent inhibition of topoisomerase II (enzyme active in
    replication) may play an important role but also simple DNA intercalation or
    generation of oxidative stress may contribute to the development of both
    mutagenicity and genotoxicity.6,28,30,31
        The Committee concludes in accordance with the recommendation of the
    DECOS Subcommittee on the Classification of Carcinogenic Substances (see
    Annex F) that adriamycin acts by a stochastic genotoxic mechanism.11,32,33
    Therefore, it is recommended that health-based calculated occupational cancer
    risk values (HBC-OCRVs) should be calculated for regulatory standard setting.
2.4 Non-carcinogenic effects
    Limited information is available on uptake, distribution, and excretion of
    adriamycin after inhalation, or dermal exposure.34 It is not stable in gastric acid,
    and animal studies indicate that the drug undergoes little, if any, absorption from
    the GI tract. The drug is extremely irritating to tissues and, therefore, must be
    administered intravenously.9 Adriamycin hydrochloride displays extensive tissue
    distribution and a rapid elimination clearance (24-73 L/h/m2).6
        Sixty seven percent mortality was observed in rats after a single dose of 9
    mg/kg bw (route not specified). In dogs, 0.5 mg/kg bw per day iv was lethal after
    5-10 doses, while 0.125-0.25 mg/kg bw per day was toxic (inhibition of
    haemopoiesis) to both dogs and rats, but not lethal.7 For humans, LDLos of 15
    Identity, toxicity profile and classification                                        19
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<pre>  mg/kg bw (iv, single dose) and 380 mg /kg bw (31-week, repeated-dose) have
  been reported.
      Clinical observations, supported by studies in vitro and in in experimental
  animals, report a number of toxic effects. Administration of adriamycin leads to
  dose-related myelosuppression and mucositis. Adriamycin is a potent myotoxin,
  causing cardiomyopathy and fibrosis.34 Cardiotoxicity is considered the most
  important limitation for high dose adriamycin treatment.29 The neurotoxic
  properties of adriamycin are reported to be mediated by transport of the
  substance to the brain followed by neuronal damage (‘suicide retrograde axonal
  transport’).35,36 Adriamycin is also known to cause hepatotoxicity, related to
  overproduction of ROS. Moreover, adriamycin may cause nephropathy and
  proteinuria by injuring glomerular podocytes.29
      Otterson et al. (2007) evaluated the toxicity profile of inhalational
  doxorubicin in patients with malignant disease in the lung.37 The
  OncoMystModel CDD-2a inhalation device aerosolizes compounds to particles
  of 2 to 3 µm and prevents exhaled aerosol from escaping into the environment.
  Treatment was repeated every 3 weeks. No more than moderate pulmonary
  dysfunction was permitted (forced expiratory volume in 1s, forced vital capacity,
  and diffusing capacity for carbonmonoxide, all > 50% predicted; resting SaO2 >
  90%). Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4
  mg/m2.The most common histologic diagnoses were sarcoma (n = 19) and non-
  small cell lung cancer (n = 16). Dose-limiting pulmonary toxicity (DLT) was
  observed at the 9.4 mg/m2 dose level in two of four patients. Of 11 patients
  treated at the 7.5 mg/m2 dose level, only one showed DLT consisting of a decline
  in forced vital capacity of >20% from baseline. No significant systemic drug-
  related toxicity was observed. Several patients experienced declines in
  pulmonary function test variables, which were attributed to progressive disease.
  Observed activity included a partial remission in a patient with metastatic soft
  tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. The
  authors conclude that inhaled doxorubicin is safe up to a dose of 7.5 mg/m2 every
  3 weeks in patients with cancer who had normal to moderately impaired
  pulmonary function.
      Reduction in ovary size and weight, and ovulation rate correlating with a
  reduction in the population of secondary and primordial follicles was observed
  up to one month after treatment in female mice injected intraperitoneally with 7.5
  mg/kg bw. Oocytes showed no morphological or chromosomal changes.38 Male
  rats treated at 15 and 22 days of age with 5 mg/kg bw intraperitoneally showed
  germ cell depletion, tubular vacuolization, multinucleated formations of
0 Adriamycin
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<pre>    spermatids and germ cells, reduction of seminiferous tubule volume and
    diameter, and reduced spermatogenesis resulting in infertility.39
2.5 Occupational exposure and existing occupational exposure limits
    Occupational exposure to adriamycin occurs via inhalation, dermal exposure or
    ingestion. Probable occupational exposure scenarios are limited to handling of
    adriamycin in pharmacies, patient handling by hospital staff, sanitary and similar
    services, research and education (Pieri et al., 2010).40 The Committee did not
    find reliable data with regard to the present size of the exposed population
    (Kauppinen et al., 2000).41 Although teratogenic and adverse reproductive
    outcomes and increased cancers have been reported in health care workers
    exposed to antineoplastic drugs, data on exposure to adriamycin alone are
    lacking (Connor et al., 2006; Dranitsaris et al., 2005).42,43
    No occupational exposure limits have been established for adriamycin.
    Identity, toxicity profile and classification                                      21
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<pre>2 Adriamycin</pre>

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<pre> hapter 3
        Carcinogenicity studies
3.1     Human studies
        Human carcinogenicity studies have been summarized and evaluated by IARC
        (IARC 1976, 1982, 1987).3,4,12 They concluded from the epidemiological data
        that the evidence for carcinogenicity to humans was inadequate.3,4,12 No
        epidemiological studies were identified by IARC that evaluated the relationship
        between human cancer and exposure specifically to adriamycin. However, some
        cancer patients who received adriamycin in combination with alkylating agents
        and radiotherapy developed acute non lymphocytic leukemia and bone cancer
        (osteosarcoma)(IARC 1982).44
            DECOS did not find any new, published epidemiological data on the effects
        of exposure to adriamycin alone. Several follow-up studies were performed in
        which patients with Hodgkin’s disease were treated with adriamycin in
        combination with bleomycin, vinblastine and dacarbazine or patients with Ewing
        sarcoma or primitive neuroectodermal tumour of bone were treated with
        adriamycin in combination with vincristine, ifosfamide, cyclophosphamide and
        etoposide.3,12,45-49 However, the results of these studies are not suitable for the
        risk assessment of the carcinogenic risk of adriamycin since adriamycin was
        always given in combination with other chemotherapeutic agents or radiation.
        Data on exposure to adriamycin alone are lacking.
        Carcinogenicity studies                                                             23
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<pre>3.2 Animal experiments
    The compound is carcinogenic to rats after intravenous and subcutaneous
    injection. Adriamycin produced malignant tumours in the bladder after
    intravesical instillation.
        The animal carcinogenicity data are summarized in Annex E and described in
    detail in Annex F. These studies include subcutaneous and intravenous studies
    and one study in which adriamycin was instilled intravesically into the urinary
    bladder. There were no oral, inhalatory or dermal carcinogenicity studies.
        After repeated subcutaneous injections, 0.75 mg/kg/day (2 x 4 days with 3
    days in between) adriamycin induced local sarcomas and mammary tumors in
    CD and Wistar-Lewis rats.50
        A single intravenous injection of adriamycin in female rats resulted in an
    increased number of rats with mammary tumours. Most of these tumours were
    histologically defined as fibroadenomas.15,51-53
        Intravesicular instillation of adriamycin into the urinary bladder in rats
    resulted in a low incidence of bladder papillomas (exposure period: 12 weeks,
    experimental period: 36 weeks). In the same experiment adriamycin appeared to
    enhance the number of bladder tumors in rats pretreated with N-butyl-N-(4-
    hydroxybutyl)-nitrosamine (BBN).54
3.3 Selection of the suitable study for risk estimation in the
    occupational situation
    From the results of the studies summarized above, DECOS concluded that
    adriamycin is an animal carcinogen. The animal experiments were restricted to
    single or short-term exposure regimens and no exposure routes relevant for the
    occupational situation were included. The Committee considered none of the
    described experiments sufficiently suitable (considering length of exposure and
    experimental period, relevance of exposure routes, relevance of the tumours,
    purity of the test substance used, mortality before the end of the experimental
    period, dose-dependency of tumour development, see Annex E) for calculating
    the cancer risk of adriamycin under occupational conditions of exposure.
3.4 Calculation of the health-based occupational cancer risk values
    Calculation of the health-based occupational cancer risk values is not possible as
    indicated in paragraph 3.3.
 4  Adriamycin
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<pre>  References
  Health Council of The Netherlands. Guideline for calculating carcinogenic risks. The Hague: Health
  Council of The Netherlands: 2012: publication no. 2012/16E.
  Health Council of the Netherlands. Calculating cancer risk. The Hague: Health Council of The
  Netherlands: 1995: publication no. 1995/06WGD.
  Adriamycin (Group 2A). IARC monographs on the evaluation of carcinogenic risks to humans
  1987;(Suppl. 7): 82-83.
  Adriamycin. IARC monographs on the evaluation of carcinogenic risk of chemicals to man 1976; 10:
  43-49.
  Adriamycin. 13th Report on Carcinogens (RoC), National Toxicology Program (2014). National
  Toxicology Program. http://ntp.niehs.nih.gov/pubhealth/roc/roc13/index.html consulted: 10-12-2014.
  Caelyx: EPAR - Product Information. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
  medicines/human/medicines/000089/human_med_000683.jsp&mid=WC0b01ac058001d124
  &jsenabled=true consulted: 10-12-2014.
  A57. Adriamycin. In: The dictionary of substances and their effects. Cambridge, UK: Royal Society
  of Chemistry; 1992: 104-107.
  Doxorubicin. Merck Index, 12th edition, 1996
  Doxorubicin. Hazardous Substances Data Bank. http://toxnet.nlm.nih.gov/cgi-bin/sis/search2/f?./
  temp/~n59OTF:3 consulted: 10-12-2014.
0 Adriamycin. In: Pohanish R, editor. Sittig's Handbook of Toxic and Hazardous Chemicals. Oxford,
  UK: Elsevier; 2012: 79-80. Internet: http://books.google.nl/
  books?id=RYt0Wzb60b4C&pg=PA79&lpg=PA79&dq=adriamycin+RTECS+number&source=bl&o
  ts=-E067keUzz&sig=jEef8O6Kgz-MNGfjXeGF7VXr6Is&hl=nl&sa=X&ei=rZwqT_n0N8rS8g
  References                                                                                         25
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<pre>  OzoLTiDg&ved=0CEQQ6AEwBA#v=onepage&q=adriamycin%20RTECS%20number&f=false
  consulted: 10-12-2014.
1 Dutch Expert Commitee on Occupational Standards. Scientific documentation on the Dutch list of
  occupational carcinogens (I). Ministerie van Sociale Zaken en Werkgelegenheid (SZW); 1995: RA1/
  95.
2 Adriamycin (Group 2B). IARC monographs on the evaluation of carcinogenic risk of chemicals to
  man 1982;(Suppl 4): 29-31.
3 Bhuyan BK, Zimmer DM, Mazurek JH, Trzos RJ, Harbach PR, Shu VS et al. Comparative
  genotoxicity of adriamycin and menogarol, two anthracycline antitumor agents. Cancer Res 1983;
  43(11): 5293-5297.
4 Clements J, Phillips M, Todd N. Mutagenicity of adriamycin in Drosophila melanogaster. Mutat Res
  1984; 135(3): 175-179.
5 Marquardt H, Philips F, Sternberg S. Tumorigenicity in vivo and induction of malignant
  transformation and mutagenesis in cell cultures by adriamycin and daunomycin. Cancer Res 1976;
  36(6): 2065-2069.
6 Matheson D, Brusick D, Carrano R. Comparison of the relative mutagenic activity for eight
  antineoplastic drugs in the Ames Salmonella/microsome and TK+/- mouse lymphoma assays. Drug
  Chem Toxicol 1978; 1(3): 277-304.
7 Suter W, Brennand J, McMillan S, Fox M. Relative mutagenicity of antineoplastic drugs and other
  alkylating agents in V79 Chinese hamster cells, independence of cytotoxic and mutagenic responses.
  Mutat Res 1980; 73(1): 171-181.
8 Matney TS, Nguyen TV, Connor TH, Dana WJ, Theiss JC. Genotoxic classification of anticancer
  drugs. Teratog Carcinog Mutagen 1985; 5(5): 319-328.
9 Au WW, Hsu TC. The genotoxic effects of adriamycin in somatic and germinal cells of the mouse.
  Mutat Res 1980; 79(4): 351-361.
0 Au WW, Johnston DA, Collie-Bruyere C, Hsu TC. Short-term cytogenetic assays of nine cancer
  chemotherapeutic drugs with metabolic activation. Environ Mutagen 1980; 2(4): 455-464.
1 Au WW, Butler MA, Matney TS, Loo TL. Comparative structure-genotoxicity study of three
  aminoanthraquinone drugs and doxorubicin. Cancer Res 1981; 41(2): 376-379.
2 Kram D, Bynum GD, Senula GC, Schneider EL. In utero sister chromatid exchange analysis for
  detection of transplacental mutagens. Nature 1979; 279(5713): 531.
3 Vig BK. Chromosome aberrations induced in human leukocytes by the antileukemic antibiotic
  adriamycin. Cancer Res 1971; 31(1): 32-37.
4 West C, Stratford IJ, Barrass N, Smith E. A comparison of adriamycin and mAMSA in vitro: cell
  lethality and SCE studies. Br J Cancer 1981; 44(6): 798-809.
5 Price PJ, Suk WA, Skeen PC, Chirigos MA, Huebner RJ. Transforming potential of the anticancer
  drug adriamycin. Science 1975; 187(4182): 1200-1201.
6 Musilova J, Michalova K, Urban J. Sister-chromatid exchanges and chromosal breakage in patients
  treated with cytostatics. Mutat Res 1979; 67(3): 289-294.
6 Adriamycin
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<pre>7 Nevstad NP. Sister chromatid exchanges and chromosomal aberrations induced in human
  lymphocytes by the cytostatic drug adriamycin in vivo and in vitro. Mutat Res 1978; 57(2): 253-258.
8 McClendon AK, Osheroff N. DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 2007;
  623(1-2): 83-97.
9 Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity
  and novel drug delivery systems. J Pharm Pharmacol 2013; 65(2): 157-170.
0 Farmaki E, Mkrtchian S, Papazian I, Papavassiliou A, Kiaris H. ERp29 regulates response to
  doxorubicin by a PERK-mediated mechanism. Biochim Biophys Acta 2011; 1813(6): 1165-1171.
1 Pereira G, Silva A, Diogo C, Carvalho F, Monteiro P, Oliveira P. Drug-induced cardiac mitochondrial
  toxicity and protection: from doxorubicin to carvedilol. Curr Pharm Des 2011; 17(20): 2113-2129.
2 Lijst van kankerverwekkende, mutagene, en voor de voortplanting giftige stoffen SZW.
  Staatscourant. https://zoek.officielebekendmakingen.nl/stcrt-2013-18885.html/ consulted: 10-12-
  2014.
3 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague: Health Council of The Netherlands: 2010: publication no. A10/07E.
4 Riggs CE, Sharp SA. Adriamycin: Review of clinical pharmacology and toxicity of an effective
  anticancer drug (Drug therapy review). Iowa Med 1987; 77: 242-251.
5 McLoon L, Kirsch J, Cameron S, Wirtschafter JD. Injection of doxorubicin into rabbit eyelid does
  not result in loss of facial motor neurons. Brain Res 1994; 641(1): 105-110.
6 Kooy D van der, Zito K, Roberts D. Evidence of the retrograde neurotoxicity of doxorubicin.
  Neurosci Lett 1985; 53(2): 215-219.
7 Otterson GA, Villalona-Calero MA, Sharma S, Kris MG, Imondi A, Gerber M et al. Phase I study of
  inhaled Doxorubicin for patients with metastatic tumors to the lungs. Clin Cancer Res 2007; 13(4):
  1246-1252.
8 Ben-Aharon I, Bar-Joseph H, Tzarfaty G, Kuchinsky L, Rizel S, Stemmer S et al. Doxorubicin-
  induced ovarian toxicity. Reprod Biol Endocrinol 2010; 8: 20.
9 Brilhante O, Stumpp T, Miraglia S. Long-term testicular toxicity caused by doxorubicin treatment
  during pre-pubertal phase. Int J Medicine Med Sci 2011; 3(2): 52-60.
0 Pieri M, Castiglia L, Basilicata P, Sannolo N, Acampora A, Miraglia N. Biological monitoring of
  nurses exposed to doxorubicin and epirubicin by a validated liquid chromatography/fluorescence
  detection method. Ann Occup Hyg 2010; 54(4): 368-376.
1 Kauppinen T, Toikkanen J, Pedersen D, Young R, Ahrens W, Boffetta P et al. Occupational exposure
  to carcinogens in the European Union. Occup Environ Med 2000; 57(1): 10-18.
2 Connor TH, McDiarmid MA. Preventing occupational exposures to antineoplastic drugs in health
  care settings. CA Cancer J Clin 2006; 56(6): 354-365.
3 Dranitsaris G, Johnston M, Poirier S, Schueller T, Milliken D, Green E et al. Are health care providers
  who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-
  analysis of the literature. J Oncol Pharm Pract 2005; 11(2): 69-78.
  References                                                                                              27
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<pre>4 Certain combined chemotherapy for lymphomas (including MOPP)(Group 1). IARC monographs on
  the evaluation of carcinogenic risk of chemicals to man 1982; (Suppl 4): 75-77.
5 André M, Mounier N, Leleu X, Sonet A, Brice P, Henry-Amar M et al. Second cancers and late
  toxicities after treatment of aggressive non- Hodgkin lymphoma with the ACVBP regimen: a GELA
  cohort study on 2837 patients. Blood 2004; 103(4): 1222-1228.
6 André M, Brice P, Cazals D, Hennequin C, Ferme C, Kerneis Y et al. Results of three courses of
  adriamycin, bleomycin, vindesine and dacarbazine with subtotal nodal irradiation in 189 patients
  with nodal Hodgkin disease (stage I, II, III). Hematol Cell Ther 1997; 39(2): 59-65.
7 Brusamolino E, Baio A, Orlandi E, Arcaini L, Passamonti F, Griva V et al. Long-term events in adult
  patients with clinical stage IA-IIA nonbulky hodgkin’s lymphoma treated with four cycles of
  doxorubicin, bleomycin, vinblastine, and dacarbazine and adjuvant radiotherapy: a single-instituion
  15-year follow-up. Clin Cancer Res 2006; 12(21): 6487-6493.
8 Delwail V, Jais J, Colonna P, Andrieu J. Fifteen-year secondary leukaemia risk observed in 761
  patients with Hodgkin disease propspectively treated by MOPP or ABVD chemotherapy plus high
  radiation. Br J Haematol 2002; 118(1): 189-194.
9 Bhatia S, Krailo M, Chen Z, Burden L, Askin F, Dickman P et al. Therapy-related myelodysplasia
  and acute myeloid leukemia after Ewing sarcoma and primitive neuroectodermal tumor of bone: a
  report from the Children’s Oncology Group. Blood 2007; 109(1): 46-51.
0 Casazza A, Bellini O, Formelli F, et al. Tumors and dental and ocular abnormalities after treatment of
  infant rats with adriamycin. Tumori 1977; 63(4): 331-338.
1 Bertazzoli C, Chieli T, Solcia E. Different incidence of breast carcinomas or fibroadenomas in
  daunomycin or adriamycin treated rats. Experientia 1971; 27(10): 1209-1210.
2 Jang J, Takahashi M, Hasegawa R, et al. Mammary and renal tumor induction by low doses of
  adriamycin in Sprague-Dawley rats. Carcinogenesis 1987; 8(8): 1149-1153.
3 Bucciarelli E. Mammary tumor induction in male and female Sprague-Dawley rats by adriamycin
  and daunomycin. Journal of The National cancer Institute (JNCI) 1981; 66(1): 81-84.
4 Ohtani M, Fukushima S, Okamura T, et al. Effects of intravesical instillation of antitumor
  chemotherapeutic agents on bladder carcinogenesis in rats treated with N-butyl-N-(4-
  hydroxybutyl)nitrosamine. Cancer 1984; 54(8): 1525-1529.
8 Adriamycin
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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 Animal studies
F Evaluation of the Subcommittee on the Classification of Carcinogenic
  Substances
G Carcinogenic classification of substances by the Committee
  Annexes
                                                                       29
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<pre>0 Adriamycin</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     Request for advice                                                                                     31
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<pre>  •   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
      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.
2 Adriamycin
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<pre>nnex B
     The Committee
     •  RA Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  P.J. Boogaard
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders (NECORD), Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht, and
        National Institute for Public Health and the Environment, Bilthoven
     •  A.H. Piersma
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, and National Institute for Public Health and the Environment,
        Bilthoven
     •  H.P.J. te Riele
        Professor of Molecular Biology, VU University Amsterdam, and Netherlands
        Cancer Institute, Amsterdam
     The Committee                                                                33
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<pre>  •   I.M.C.M. Rietjens
      Professor of Toxicology, Wageningen University and Research Centre,
      Wageningen
  •   G.B.G.J. van Rooy
      Occupational Physician, Arbo Unie Expert Centre for Chemical Risk
      Management, and Radboud UMC Outpatient Clinic for Occupational
      Clinical Toxicology, Nijmegen
  •   F. Russel
      Professor of Pharmacology and Toxicology, Radboud University Medical
      Centre, Nijmegen
  •   G.M.H. Swaen
      Epidemiologist, Maastricht University, Maastricht
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
  •   P.B. Wulp
      Occupational Physician, Labour Inspectorate, Groningen
  •   B.P.F.D. Hendrikx, advisor
      Social and Economic Council, The Hague
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of the Netherlands, The Hague
  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.
4 Adriamycin
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<pre>nnex C
     The submission letter (in English)
     Subject          : Submission of the advisory report Adriamycin
     Your Reference   : DGV/MBO/U-932342
     Our reference    : U-8338/BvdV/cn/459-R71
     Enclosed         :1
     Date             : March 18, 2015
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     adriamycin.
     This advisory report is part of an extensive series in which carcinogenic
     substances are evaluated for the possibility to establish health-based
     occupational cancer risk values in accordance with European Union guidelines.
     This involves substances to which people can be exposed under working
     conditions.
     The advisory report was prepared by the Dutch Expert Committee on
     Occupational Safety (DECOS) of the Health Council. The advisory report has
     been assessed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                             35
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<pre>      In this report, the Committee concludes that adriamycin is a carcinogenic
  substance (category 1B, substance presumed to be carcinogenic to humans).
      The Committee is of the opinion that due to a lack of adequate data, it is not
  possible to estimate the additional lifetime cancer risk for adriamycin.
  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 J.L. Severens,
  Vice President
6 Adriamycin
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in July 2014 for public review. The
     following organization and persons have commented on the draft document:
     • T.J. Lentz, T. Connor and L. Rojanasakul. National Institute for Occupational
         Safety and Health (NIOSH), Cincinnati OH, USA.
     Comments on the public review draft                                             37
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<pre>8 Adriamycin</pre>

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<pre> nnex          E
               Animal studies
 tudy design and          Data on exposure and   Results                                      Remarks
nimal species             effect endpoints
arcinogenicity study;     intravenous; 1x 8      Incidence of mammary tumours in animals      In the adriamycin group 18 of
at, SD; 25F per dose      mg/kg bw;              sacrificed at the end of the experiment:     25 rats died in the course of
 roup                     Xpo = single injection Test group: 6/7 mammary tumours, mostly      the experiment due to severe
  ertazolli, 197151       Xpe = 1 year           fibroadenomas                                renal damage or bone marrow
                                                 Controls: 0/25                               aplasia. Only one of these 18
                                                                                              rats had a mammary tumour.
                                                                                              No relationship was found
                                                                                              between death and presence
                                                                                              or absence of tumours.
 arcinogenicity study;    intravenous in femoral tumour incidence: Test group 15/17:          another group of 20 rats given
at, SD; 25F per dose      vein;                  19 mammary tumours (16 fibroadenomas,        1 x 10 mg/kg bw iv died
 roup                     1 x 5 mg/kg bw         1 adenocarcinoma), 1 adrenal carcinoma,      within 15 weeks
Marquardt, 197615         Xpo = single injection 1 Schwannoma; Controls: 5/20, 3 mammary
                          Xpe = 1 year           tumours (1 fibroadenoma, 2 carcinoma),
                                                 1 cervical polyp, 1 lipoma
 arcinogenicity study;    subcutaneous; 0.75     tumour incidence: Males 6/6:2 fibrosarcomas, purity: ?;a
at, CD;                   mg/kg/day              1 osteosarcoma,
 - to 6-days old at start Xpo= 2 x 4 days        1 epidermoid carcinoma, 2 unclassified
 f treatment              (3 days in between)    sarcomas. Females 13/13: 5 mammary
reated: 6M + 13F/dose     Xpe= 2 years           adenomas, 4 mammary fibroadenomas,
 roup; controls: 11M                             1 mammary adenocarcinoma,
 7F                                              1 fibrosarcoma (with lung metastases),
  asazza, 197750                                 1 cervical polyp, 1 unclassified sarcoma.
                                                 Controls: 0/11 males, 3/7 females
                                                 (3 mammary adenomas)
               Animal studies                                                                                               39
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<pre> arcinogenicity study;    subcutaneous; 0.5, 0.75   Males: high dose: 11/20: 6 fibrosarcomas,       purity: ?;a
at, Wistar-Lewis, 2- to   mg/kg/day                 1 osteosarcoma, 1 mammary adenocarcinoma,
 -days old at start of    Xpo= 2 x 4 days           1 fibroma, 1 schwannoma, 1
reatment                  (3 days in between)       neurofibrosarcoma, 1 leiomyoma
  reated: 20M +18F/       Xpe= 2 years              low dose:10/20: 3 neurofibromas,
 ose group; controls:                               2 fibrosarcomas, 1 leiomyosarcoma,
 3M +19F                                            1 leiomyoma, 1 fibrous hystiocytoma,
  asazza, 197750                                    1 unclassified sarcoma, 1 unclassified tumour
                                                    controls: 1/23: 1 fibrosarcoma
                                                    Females: high dose: 12/18: 4 fibrosarcomas,
                                                    2 mammary fibroadenomas, 2 mammary
                                                    adenocarcinomas, 1 leiomyosarcoma,
                                                    3 unclassified sarcoma, 1 unclassified tumour
                                                    low dose: 11/18: 1 mammary adenoma,
                                                    1 mammary fibroadenomas, 1 mammary
                                                    adenocarcinoma, 1 fibroma, 1 schwannoma,
                                                    1 leiomyosarcoma, 3 unclassified sarcoma,
                                                    1 unclassified tumour
                                                    controls: 1/19: 1 mammary fibroadenoma
epeated dose study;       intravesical; 4 wks:      Treatment with BBNb followed by saline and/     purity: ?; a
at; n=31-61               pretreatment with         or no treatment induced papillary or nodular    only bladder effects
  /dose group             0.05% BBNb) in            hyperplasia, papillomas, and cancer             investigated;
Ohtani, 198454            drinking water,           Treatment with adriamycin (without              adriamycin shows tumour
                          1 wk: without             pretreatment) induced only hyperplasia and      promoting activities
                          treatment,                papilloma
                          12 wks: intravesical      After pretreatment with BBNb adriamycin
                          application of            induced papillary or nodular hyperplasia,
                          adriamycin (0.15 mg/ papillomas, and cancer.
                          0.3 ml, 0.3 mg/ 0.3 ml) Two-stage bladder carcinogenesis is promoted
                          for 1 hour, once per wk by adriamycin.
                          controls: 12 wks saline
                          or no treatment or
                          adriamycin (0.3 mg/
                          0.3 ml) without
                          pretreatment; Xpo=
                          12 wks
                          Xpe= 36 wks
 -y carcinogenicity       Intravenous in tail vein; deaths: All high dose animals (group 1),        purity : ?;a
 tudy; rat, SD; 40M + 1. single dose,               4M + 4F (group 2), 37M +16F (group 3),          other tumours no significant
 0F/dose group/           10 mg/kg bw               1F (controls)                                   differences; high mortality
 ang, 198752              2. single dose,           mammary tumors (all rats, except those with     due to pulmonary infection
                          2 mg/kg bw                advanced autolysis were examined); 1. F         and irreversible toxic
                          3. 5 x 2 mg/kg bw         0/34, M 0/33, 2. F 11/37, M 2/40, 3. F 15/37,   damage; dysplastic foci are
                          within 2 days             M 0/37, 4. F 3/40, M 0/40; 22 of these tumors   considered to be the earliest
                          4. 5 x 0.9 % NaCl         were fibroadenomas, 9 were adenocarcinomas      manifestation of renal cell
                          within 2 days             renal effects (only rats surviving until        tumors.
                          Xpo = 1, 2 days           termination)
                          Xpe = 1 year              -dysplastic foci: 2. F 1/36, M 6/36; 3. F 8/24,
                                                    M 0/3; 4. F 0/39, M 0/40
                                                    -renal cell tumour: 2. F 2/36, M 3/36; 3. F
                                                    1/36, M 0/3; 4.F 0/39, M 0/40
     Purity is not given in publication.
     BBN = N-butyl-N-(4-hydroxybutyl)nitrosamine).
  0           Adriamycin
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<pre>nnex F
     Evaluation of the Subcommittee on
     the Classification of carcinogenic
     substances
     Adriamycin is not classified by the European Union. In her latest classification
     (1987) IARC has classified the compound as a 2A carcinogen (probably
     carcinogenic to humans).1 [In 2014 the 13th NTP Report on Carcinogens
     considers adriamycin as reasonably anticipated to be a human carcinogen based
     on sufficient evidence of carcinogenicity from studies in experimental animals.2]
         In 1995, DECOS concluded that there was inadequate evidence that
     adriamycin was carcinogenic to humans, that adriamycin was carcinogenic to
     rats by iv, sc and intravesicular administration and that adriamycin is mutagenic
     to bacteria and mammalian cells in vitro.3 DECOS, in 1995, classified the
     compound as a genotoxic carcinogen.3 [This is probably the reason that
     adriamycin appeared on the list of carcinogenic substances of the Department of
     Social Affairs and Employment (Staatscourant, 2013).4]
         In the present update (April 2014) the DECOS Subcommittee on the
     Classification of Carcinogenic Substances evaluated the existing and new
     information regarding human, animal and in vitro studies on carcinogenicity and
     genotoxicity of adriamycin.
     Human studies
     IARC concluded from the epidemiological data that the evidence for
     carcinogenicity to humans was inadequate (IARC 1976, 1982, 1987).1,5,6 No
     epidemiological studies were identified by IARC that evaluated the relationship
     Evaluation of the Subcommittee on the Classification of carcinogenic substances   41
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<pre>  between human cancer and exposure specifically to adriamycin. However, some
  cancer patients who received adriamycin in combination with alkylating agents
  and radiotherapy developed acute non-lymphocytic leukemia and bone tumour
  (osteosarcoma) (IARC 1982).6
      In the present update the Subcommittee notes that several follow-up studies
  were performed in which patients with Hodgkin’s disease were treated with
  adriamycin in combination with bleomycin, vinblastine and dacarbazine (IARC
  1982, 1987; André et al., 2004; André et al., 1997; Brusamolino et al., 2006;
  Delwail et al., 2002) or patients with Ewing sarcoma or primitive
  neuroectodermal tumour of bone were treated with adriamycin in combination
  with vincristine, ifosfamide, cyclophosphamide and etoposide (Bhatia et al.,
  2007).1,7-12 The main objectives of these clinical studies were to test the
  effectiveness of the chemotherapeutic regimen, to define the risk of developing
  secondary cancer and late toxicity using this regimen.
      The Subcommittee observes that in these studies adriamycin is always given
  in combination with other chemotherapeutic agents or radiation and that data on
  exposure to adriamycin alone are lacking. Therefore, the Subcommittee is of the
  opinion that a conclusion on the carcinogenic risk of adriamycin itself is not
  possible.
  Animal studies
  IARC (1987) concluded that the compound is carcinogenic to rats after
  intravenous and subcutaneous injection. Adriamycin produced tumours in the
  bladder after intravesical instillation (IARC 1976, 1982, 1987).1,5,6
      Casazza et al. (1977) treated newborn CD and Wistar-Lewis rats with
  repeated sc injections (dose groups 0.5 and 0.75 mg/kg/day).13 Two cycles of 4
  treatments each (days 1 to 4 and 8 to 11) were given, with a 3-day rest period
  between the 2 cycles. CD rats treated with the dose of 0.75 mg/kg/day were
  observed for 2 years for tumour appearance. In male controls, no tumours were
  detected; in female controls 3 of 7 rats showed the appearance of mammary
  tumours that were classified histologically as adenomas. All the rats treated with
  adriamycin did develop tumours. The most common tumours were sarcomas
  (fibro-, osteo- and unclassified, all close to the injection site) and mammary
  tumours in females, most of which were adenomas and fibroadenomas; only 1 of
  10 mammary tumours was classified as an adenocarcinoma. Tumours generally
  appeared after 1 year from the beginning of treatment, except for the
  adenocarcinoma and 1 sarcoma that occurred earlier in female rats. Also Wistar-
  Lewis rats treated with 0.5 and 0.75 mg/kg/day were observed for 2 years for
2 Adriamycin
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<pre>tumour appearance. In the controls, 1 fibrosarcoma was detected in 23 males, and
1 fibroadenoma out of 19 females. In the adriamycin-treated groups, the
incidence of rats that developed tumours was about 50% in males and 66% in
females. In male rats treated with 0.5 mg/kg/day, 6 of 10 tumours were classified
as benign neoplasms, while in male rats treated with the higher dose only 2 of 12
tumours were benign (1 leiomyoma and 1 fibroma). In females, no significant
difference was observed as regards malignancy of tumours in the groups treated
with the 2 dose levels. In this strain of rats also, tumours generally appeared at
least 1 year after the treatment; the majority of tumours (25 of 47 total tumours)
appears between 400 and 500 days after treatment. In the animals treated with the
higher dose (0.75 mg/kg/day), both males and females, 12 tumours appeared
before day 400; while in those treated with the lower dose, only 1 tumour
appeared before day 400. Lung metastases were detected in some animals
bearing fibrosarcomas, sarcomas and leiomyosarcomas.
    Bertazolli et al. (1971) assessed the carcinogenicity of adriamycin in
Sprague-Dawley rats. In female rats treated iv with a single high dose of
adriamycin (8 mg/kg), high incidence of mammary tumours was observed in a
relatively short time.14 The first adriamycin-induced tumour appeared after 156
days and the mean induction time was 223 days. Besides this, in the adriamycin
group 1 meningioma and 2 uterine polypi were noticed. No tumours were found
in the control animals. Eighteen of the 25 rats treated with adriamycin died, due
to severe renal damage or bone marrow aplasia. In the 7 survivors 6 animals had
developed tumours (fibroadenomas). No relationship was found between death
and presence or absence of tumours; in fact many rats died before tumour
occurrence. After 1 year of observation, all survivors and control rats were
sacrificed and examined carefully. In each tumour-bearing rat only 1 breast
tumour and no metastases were found on extensive autoptic and histological
examination.
    Marquard et al. (1976) confirmed the findings of Bertazolli et al. that
adriamycin can induce mammary tumours.15 In this study twenty female Sprague
Dawley rats received a single iv injection of 5 mg/kg adriamycin and were
observed for the duration of the experiment. By the end of 1 year there were 16
fibroadenomas and 3 adenocarcinomas in 17 adriamycin-treated rats. Another
group of 20 rats received adriamycin in the dose of 10 mg/kg. All died without
tumours within 15 weeks.
    Bucciarelli (1981) administered iv injections of 10 or 5 mg/kg adriamycin in
groups of male and female Sprague-Dawley rats (age 30-36 days).16 Multiple
mammary tumors, mostly adenocarcinomas, were observed in 67 and 29% of the
females given 5 and 10 mg adriamycin/kg, respectively. The mean induction
Evaluation of the Subcommittee on the Classification of carcinogenic substances    43
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<pre>  time for females receiving 10 mg/kg adriamycin was 135 days, for those
  receiving 5 mg/kg it was 114 days. Single mammary tumours, also mostly
  adenocarcinomas, were observed an average of 279 days from injection in 31%
  of the males given 5 mg/kg adriamycin. No tumours were observed in the males
  given 10 mg/kg adriamycin but these survived for only 79 days after treatment. It
  is noted in this study that tumours were induced at a dosage which was lethal in
  other studies. Remarkable also is the higher prevalence of adenocarcinomas
  versus fibroadenomas when compared to other studies.
      Jang et al. (1987) studied the oncogenic potential of adriamycin in both male
  and female of Sprague-Dawley rats.17 Single iv injection of 10 or 2 mg and
  repeated iv injections of 2 mg adriamycin/kg bw within 2 weeks were performed
  on rats. Multiple mammary tumours, mostly fibroadenomas, were observed in 30
  and 41% of the females given single low (2 mg/kg) or repeated doses (5x2 mg/
  kg) respectively. These incidences were significantly higher than those for the
  corresponding control group (8%). Two male rats in the low dose group also
  developed mammary tumours (fibro- and carcinoadenomas). Both sexes
  receiving the single high dose (10 mg/kg) injection demonstrated early mortality
  due to marked toxicity. The mortality of five repeated-treatment group was lower
  than a single high-dose group. Renal cell tumours were evident in five rats of the
  single, low dose groups and dysplastic foci of renal tubular epithelium occurred
  in the groups given a single low or repeated dose of adriamycin.
      Othani et al. (1984) studied the effect of weekly intravesicular instillation of
  adriamycin into the urinary bladder of female F344 rats.18 Following
  intravesicular instillation of adriamycin (1 mg/mL) (exposure period: 12 weeks,
  experimental period: 36 weeks) the incidence of papillary or nodular hyperplasia
  and papilloma was significantly higher in rats given ADR, than in control rats
  given saline only. In the same experiment, in rats pretreated with N-butyl-N-(4-
  hydroxybutyl)-nitrosamine (BBN), instillation of adriamycin not only enhanced
  the incidence of papillary or nodular hyperplasia and papilloma but also
  appeared to enhance the number of bladder tumours.
      The Subcommittee notes that there are no oral, inhalatory or dermal
  carcinogenicity studies. When adriamycin was administered parenterally (iv) to
  rhesus and cynomolgus monkeys a single malignant tumour was observed at the
  injection site in one monkey (NTP RoC 2014; Thorgeirsson et al., 1994;
  Schoeffner & Thorgeirsson 2000).2,19,20
      The Subcommittee is of the opinion that adriamycin is carcinogenic to
  animals. However, the increased tumour development is found after exposure to
  adriamycin along routes which are not relevant for occupational exposure of
  humans.
4 Adriamycin
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<pre>Cell transformation assays
Marquard et al. (1976) showed that adriamycin is a powerful transforming agent.
Exposure to concentrations of 0.001 to 0.01 µg/mL adriamycin caused
transformation of M2 cells (clone of mouse fibroblasts).15
    Price et al. (1975) observed transformation in Fischer rat embryo cells grown
for 4 weeks in a culture medium containing 0.l5 ng/mL adriamycin.21 Local
fibrosarcomas were produced in 3/10 and 4/10 newborn Fischer rats given sc
injections of the transformed cells.
Genotoxicity
Mutagenicity assays
In vitro
McCann et al. (1975) observed that adriamycin induced reverse mutations in
Salmonella typhimurium strain 908 without metabolic activation.22 Also
Matheson et al. (1978) tested adriamycin (0.1-1.0 µg/plate) in Salmonella
typhimurium strains (TA 1535, 1537, 1538 and TA 98).23 In this study
adriamycin was mutagenic in strain T98 and did not require metabolic activation.
Au et al. (1981) tested 6.5, 32.5, 65, and 130 mM of adriamycin in Salmonella
typhimurium bacterial strains TA98, TA100 and TA1537 with and without S-9.24
Adriamycin was mutagenic in all strains especially in TA98 and did not require
metabolic activation to become mutagenic. Bhuyan et al. (1983) tested bacterial
mutagenicity of adriamycin for Salmonella typhimurium strains TA98 and
TA100 and concluded that adriamycin was a strong mutagen for TA98, both with
and without metabolic activation, but was much less mutagenic to TA100.25
    Marquard et al. (1976) used V79 Chinese hamster cells to determine
adriamycin (compared to another tetracycline) induced mutation.15 The absolute
number of mutants in dishes treated with adriamycin was significantly greater
than in controls. Adriamycin induced major changes in mutation rate in a dose
dependent manner in the concentration range between 0.01 and 0.1 µg/mL. Suter
et al. (1980) and Bhuyan et al. (1983) used the same system of V79 Chinese-
hamster cells and also found a dose-dependent increase of the mutation
frequency (respective concentration ranges 0-0.1 and 0.1-1.0 µg/mL).25,26
Evaluation of the Subcommittee on the Classification of carcinogenic substances   45
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<pre>  Matheson et al. (1978) tested a number of antineoplastic agents including
  adriamycin (0.1-0.5 µg/mL) in a mouse lymphoma cell line.23 Adriamycin was
  mutagenic in this assay and did not require metabolic activation.
  In vivo
  Adriamycin, at concentrations ranging from 250 µg/mL to 1 mg/mL, was shown
  to be capable of inducing sex-linked recessive lethal mutations in Drosophila
  (Clements et al. (1984).27
  Clastogenicity assays
  In vitro
  Adriamycin (0.01-1.0 µg/mL) was analyzed by Au et al. (1980, 1981) in an in
  vitro cell culture using a Chinese-hamster ovary (CHO) cell line with respect to
  its cytogenetic effect with or without metabolic activation using liver fraction
  S9.24,28 Adriamycin was most potent in induction of chromosomal breakage,
  sister chromatid exchange, but its clastogenic activity was reduced after
  metabolic conversion.
       West et al. (1981) studied the action of adriamycin in cultured Chinese-
  hamster V79 cells in vitro, using cell survival and sister-chromatid exchange as
  end-points. Adriamycin dose-dependently increased cytotoxicity and levels of
  sister-chromatid exchanges in V79 cells.29 Also Bhuyan et al. (1983) studied
  adriamycin in Chinese-hamster V79 cells in culture on chromosome breakage
  and sister chromatid exchange (SCE).25 Adriamycin caused mostly chromosome
  and chromatid breaks with few chromosome rearrangements. Adriamycin
  significantly increased the number of sister chromatid exchanges per cell.
       Vig (1971) showed that adriamycin caused chromosomal damage when used
  on human peripheral leukocytes in in vitro cultures at concentrations as low as
  0.02 µg/ml for 24 hr or 0.05, 0.10, or 0.15 µg/ml for 3 to 4 hr.30 Aberrations of all
  conceivable types (intra- as well as inter-chromatid, -chromosome , and
  chromatid-chromosome type) are observed.
  In vivo
  The genotoxic effects of adriamycin on somatic and germinal cells were studied
  by Au et al. (1980) in mice treated with single injections of 3, 12 or 24 mg/kg of
  the drug.31 From 1 to 5 days post-injection, chromosome aberrations were
6 Adriamycin
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<pre>observed in bone-marrow cell and in diakineses-metaphase 1 cells from the
testes. The frequency of chromosome breakages peaked at 5 h or 1 day for the
bone marrow and at 3 and 5 days for the testis.
    Kram et al. (1979) studied sister chromatid exchange (SCE) frequencies
simultaneously studied in fetal cells as well as in maternal bone marrow in
pregnant female mice.32 To examine in utero SCE induction adriamycin was
injected into pregnant females on day 13 of gestation. Baseline SCE in fetal cells
were lower than in maternal cells. SCE induction in fetal cells was one third of
that in maternal cells but significantly higher than baseline levels.
    Bhuyan et al. (1983) injected Sprague-Dawley rats with adriamycin (1.25
mg/kg) and removed the bone marrow after 30 hr.25 For each rat, 500 polychroma-
tophilic erythrocytes and, as a control for artifacts, normochromatophilic
erythrocytes were examined for micronuclei. Adriamycin significantly increased
the number of micronuclei per 500 polychromatophilic erythrocytes.
    In peripheral whole blood lymphocyte cultures from a patient studied in a
short-term treatment with adriamycin, Nevstad (1978) noted a striking rise in the
number of SCEs.33 Also Musilova et al. (1979) investigated the frequency of
structural chromosomal rearrangements and SCEs in peripheral lymphocytes
cultured from adriamycin treated patients.34 The SCE rate was increased and was
proportional to the number of chromosome breaks, the ratio of SCE to breaks
being about 100: 1. The increase in the SCE number was maintained for several
months after the termination of cytostatic therapy.
Mechanism of genotoxicity
IARC concluded previously that adriamycin is a potent genotoxicant.1,5,6,35
Adriamycin is mutagenic in bacteria (McCann et al. 1976; Matheson et al.,1978;
Au et al., 1981; Bhyan et al.,1983), in mammalian cells in vitro (Marquard et al.,
1976; Suter et al., 1980, Bhyuan et al., 1983; Matheson et al., 1978), and in vivo
in Drosophila (Clements et al., 1984).15, 22-27 lt causes chromosomal anomalies in
hamster cells (Au et al.,1980, 1981; West et al., 1981; Bhyan et al.,1983) and
human lymphocytes in vitro (Vig 1971) and in mouse bone marrow cells in vivo
(Au et al., 1980; Kram et al., 1979). 24, 25, 28-32 It produces cell transformation in
mouse fibroblast cells and in Fischer rat embryo cells (Price et al., 1975;
Marquard et al.,1976).15, 21 Patients treated with adriamycin showed significant
increases in the incidence of chromosomal aberrations and sister chromatid
exchanges (Musilova et al., 1979; Nevstad 1978). 33, 34
Evaluation of the Subcommittee on the Classification of carcinogenic substances        47
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<pre>  Adriamycin is a chemotherapeutic agent whose mode of action includes
  intercalation of adjacent base pairs of the DNA double helix thus preventing their
  unwinding for replication and resulting in DNA damage, binding of DNA-
  associated enzymes such as topoisomerase II (enzyme active in replication)
  (Tacar, 2010; McClendon & Osheroff, 2007).36, 37 It is very likely that for
  genotoxicity of adriamycin similar mechanisms as for anti-tumour effects apply.
  According to the Committee non covalent inhibition of topoisomerase II
  (McClendon & Osheroff, 2007) may play an important role but also simple DNA
  intercalation or generation of oxidative stress (Caelix Product Information;
  Farmaki et al. 2011; Pereira et al., 2011) may contribute to the development of
  both mutagenicity and genotoxicity.36, 38-40 The Committee is aware of the
  ongoing experimental research into the mechanisms of genotoxicity but is of the
  opinion that this research is not conclusive as yet (Islaih et al., 2005; Spencer
  et al., 2008; Navarro et al., 2006; Lyu et al., 2007; Lehmann et al., 2003; Valadares
  et al., 2008; de Rezende et al., 2009; de Rezende, 2011 and Sousa et al., 2009).41-49
       The Subcommittee concludes that non-thresholded stochastic genotoxic
  mechanisms are involved.
  Recommendation
  Epidemological studies are inconclusive regarding carcinogenicity of
  adriamycin. However, sufficient evidence is available that adriamycin is
  carcinogenic to animals. Therefore, the Subcommittee recommends to classify
  adriamycin in category 1B (‘substance presumed to be carcinogenic to man’).
       Furthermore, the Subcommittee is of the opinion that stochastic genotoxic
  mechanisms are involved.
   References
  Adriamycin (Group 2A). IARC monographs on the evaluation of carcinogenic risks to humans 1987;
  (Suppl. 7): 82-83.
  13th Report on carcinogens. National Toxicology Program (2014). http://ntp.niehs.nih.gov/pubhealth/
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  Dutch Expert Committee on Occupational Standards. Scientific documentation on the Dutch list of
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  Lijst van kankerverwekkende, mutagene, en voor de voortplanting giftige stoffen SZW.
  Staatscourant. https://zoek.officielebekendmakingen.nl/stcrt-2013-18885.html/ consulted: 10-12-
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8 Adriamycin
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<pre>  Adriamycin. IARC monographs on the evaluation of carcinogenic risk of chemicals to man 1976; 10:
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  Adriamycin (Group 2B). IARC monographs on the evaluation of carcinogenic risk of chemicals to
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  Certain combined chemotherapy for lymphomas (including MOPP)(Group 1). IARC monographs on
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  André M, Mounier N, Leleu X, Sonet A, Brice P, Henry-Amar M et al. Second cancers and late
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  André M, Brice P, Cazals D, Hennequin C, Ferme C, Kerneis Y et al. Results of three courses of
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0 Bhatia S, Krailo M, Chen Z, Burden L, Askin F, Dickman P et al. Therapy-related myelodysplasia
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1 Brusamolino E, Baio A, Orlandi E, Arcaini L, Passamonti F, Griva V et al. Long-term events in adult
  patients with clinical stage IA-IIA nonbulky hodgkin’s lymphoma treated with four cycles of
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2 Delwail V, Jais J, Colonna P, Andrieu J. Fifteen-year secondary leukaemia risk observed in 761
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3 Casazza A, Bellini O, Formelli F, et al. Tumors and dental and ocular abnormalities after treatment of
  infant rats with adriamycin. Tumori 1977; 63(4): 331-338.
4 Bertazzoli C, Chieli T, Solcia E. Different incidence of breast carcinomas or fibroadenomas in
  daunomycin or adriamycin treated rats. Experientia 1971; 27(10): 1209-1210.
5 Marquardt H, Philips F, Sternberg S. Tumorigenicity in vivo and induction of malignant
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  36(6): 2065-2069.
6 Bucciarelli E. Mammary tumour induction in male and female Sprague-dawley rats by adriamycin
  and daunomycin. Journal of the National Cancer Institute (JNCI) 1981; 66 (1): 81-84.
7 Jang J, Takahashi M, Hasegawa R, et al. Mammary and renal tumor induction by low doses of
  adriamycin in Sprague-Dawley rats. Carcinogenesis 1987; 8(8): 1149-1153.
8 Ohtani M, Fukushima S, Okamura T, et al. Effects of intravesical instillation of antitumor
  chemotherapeutic agents on bladder carcinogenesis in rats treated with N-butyl-N-(4-
  hydroxybutyl)nitrosamine. Cancer 1984; 54(8): 1525-1529.
9 Schoeffner DJ, Thorgeirsson UP. Susceptibility of nonhuman primates to carcinogens of human
  relevance. In Vivo 2000; 14(1): 149-156.
  Evaluation of the Subcommittee on the Classification of carcinogenic substances                        49
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<pre>0 Thorgeirsson UP, Dalgard DW, Reeves J, Adamson RH. Tumor incidence in a chemical
  carcinogenesis study of nonhuman primates. Regul Toxicol Pharmacol 1994; 19(2): 130-151.
1 Price PJ, Suk WA, Skeen PC, Chirigos MA, Huebner RJ. Transforming potential of the anticancer
  drug adriamycin. Science 1975; 187(4182): 1200-1201.
2 McCann J, Ames BN. Detection of carcinogens as mutagens in the Salmonella/microsome test: assay
  of 300 chemicals: discussion. Proc Natl Acad Sci USA 1976; 73(3): 950-954.
3 Matheson D, Brusick D, Carrano R. Comparison of the relative mutagenic activity for eight
  antineoplastic drugs in the Ames Salmonella/microsome and TK+/- mouse lymphoma assays. Drug
  Chem Toxicol 1978; 1(3): 277-304.
4 Au WW, Butler MA, Matney TS, Loo TL. Comparative structure-genotoxicity study of three
  aminoanthraquinone drugs and doxorubicin. Cancer Res 1981; 41(2): 376-379.
5 Bhuyan BK, Zimmer DM, Mazurek JH, Trzos RJ, Harbach PR, Shu VS et al. Comparative
  genotoxicity of adriamycin and menogarol, two anthracycline antitumor agents. Cancer Res 1983;
  43(11): 5293-5297.
6 Suter W, Brennand J, McMillan S, Fox M. Relative mutagenicity of antineoplastic drugs and other
  alkylating agents in V79 Chinese hamster cells, independence of cytotoxic and mutagenic responses.
  Mutat Res 1980; 73(1): 171-181.
7 Clements J, Phillips M, Todd N. Mutagenicity of adriamycin in Drosophila melanogaster. Mutat Res
  1984; 135(3): 175-179.
8 Au WW, Johnston DA, Collie-Bruyere C, Hsu TC. Short-term cytogenetic assays of nine cancer
  chemotherapeutic drugs with metabolic activation. Environ Mutagen 1980; 2(4): 455-464.
9 West C, Stratford IJ, Barrass N, Smith E. A comparison of adriamycin and mAMSA in vitro: cell
  lethality and SCE studies. Br J Cancer 1981; 44(6): 798-809.
0 Vig BK. Chromosome aberrations induced in human leukocytes by the antileukemic antibiotic
  adriamycin. Cancer Res 1971; 31(1): 32-37.
1 Au WW, Hsu TC. The genotoxic effects of adriamycin in somatic and germinal cells of the mouse.
  Mutat Res 1980; 79(4): 351-361.
2 Kram D, Bynum GD, Senula GC, Schneider EL. In utero sister chromatid exchange analysis for
  detection of transplacental mutagens. Nature 1979; 279(5713): 531.
3 Nevstad NP. Sister chromatid exchanges and chromosomal aberrations induced in human
  lymphocytes by the cytostatic drug adriamycin in vivo and in vitro. Mutat Res 1978; 57(2): 253-258.
4 Musilova J, Michalova K, Urban J. Sister-chromatid exchanges and chromosal breakage in patients
  treated with cytostatics. Mutat Res 1979; 67(3): 289-294.
5 Adriamycin. IARC monographs on the evaluation of carcinogenic risk of chemicals to man
  1987;(Suppl 6): 35-39.
6 McClendon AK, Osheroff N. DNA topoisomerase II, genotoxicity, and cancer. Mutat Res 2007;
  623(1-2): 83-97.
7 Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity
  and novel drug delivery systems. J Pharm Pharmacol 2013; 65(2): 157-170.
0 Adriamycin
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<pre>8 Caelyx: EPAR - Product Information. http://www.ema.europa.eu/ema/index.jsp?curl=pages/
  medicines/human/medicines/00002589/human_med_000683.jsp&mid=WC0b01ac058001d124
  &jsenabled=true consulted: 10-12-2014.
9 Farmaki E, Mkrtchian S, Papazian I, Papavassiliou A, Kiaris H. ERp29 regulates response to
  doxorubicin by a PERK-mediated mechanism. Biochim Biophys Acta 2011; 1813(6): 1165-1171.
0 Pereira G, Silva A, Diogo C, Carvalho F, Monteiro P, Oliveira P. Drug-induced cardiac mitochondrial
  toxicity and protection: from doxorubicin to carvedilol. Curr Pharm Des 2011; 17(20): 2113-2129.
1 Islaih M, Halstead BW, Kadura IA, Li B, Reid-Hubbard JL, Flick L, Altizer JL, Thom Deahl J,
  Monteith DK, Newton RK, Watson DE. Relationships between genomic, cell cycle, and mutagenic
  responses of TK6 cells exposed to DNA damaging chemicals. Mutat Res 2005; 578 (1-2): 100-116.
2 Spencer DM, Bilardi RA, Koch TH, Post GC, Nafie JW, Kimura K, Cutts SM, Phillips DR. DNA
  repair in response to anthracycline-DNA adducts: a role for both homologous recombination and
  nucleotide excision repair. Mutat Res 2008; 638 (1-2): 110-121.
3 Navarro R, Busnadiego I, Ruiz-Larrea MB, Ruiz-Sanz JI. Superoxide anions are involved in
  doxorubicin-induced ERK activation in hepatocytes cultures. Ann N Y Acad Sci 2006; 1090:
  419-428.
4 Lyu YL, Kerrigan JE, Lin CP, Azarova AM, Tsai YC, Ban Y, Liu LF. Topoisomerase IIbeta mediated
  DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by
  dexrazoxane. Cancer Res 2007; 67 (18): 8839-8846.
5 Lehmann M, Franco A, de Souza Prudente Vilar K, Lukza Reguly M, de Andrade HH. Doxorubicin
  and two of its analogues are preferential inducers of homologous recombination compared with
  mutational events in somatic cells of Drosophila melanogaster. Mutat Res 2003; 539 (1-2): 167-175.
6 Valadares BL, Graf U, Spano MA. Inhibitory effects of water extract of propolis on doxorubicin-
  induced somatic mutation and recombination in Drosophila melanogaster. Food Chem Toxicol 2008;
  46 (3): 1103-1110.
7 Rezende AA de, Graf U, Guterres Zda R, Kerr WE, Spano MA. Protective effects of
  proanthocyanidins (Vitis vinifera L.) seeds on DNA damage induced by Doxorubicin in somatic cells
  of Drosophila melanogaster. Food Chem Toxicol 2009; 47 97): 1466-1472
8 Rezende AA de, Silva ML, Tavares DC, Cunha WR, Rezende KC, Bastos JK, Lehman M, de
  Andrade HH, Guterres ZR, Silva LP, Spano MA. The effect of the dibenzylbutyrolactolic lignin
  (-)-cubebin on doxorubicin mutagenicity and recombinogenicity in wing somatic cells of Drosophila
  melanogaster. 2011; 49 (6): 1235-1241.
9 Sousa NC de, de Rezende AA, da Silva RM, Guterres ZR, Graf U, Kerr WE, Spano MA. Modulatory
  effects of Tabebuia impetiginosa (lamiales, Bignoniaceae) on doxorubicin-induced somatic mutation
  and recombination in Drosophila melanogaster. Genet Mol Biol 2009; 32 (2): 382-388.
  Evaluation of the Subcommittee on the Classification of carcinogenic substances                     51
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<pre>  The Subcommittee
  •   R.A. Woutersen, chairman
     Toxicologic Pathologist, TNO Innovation for Life, Zeist, and Professor of
     Translational Toxicology, Wageningen University and Research Centre,
     Wageningen
  •  J. van Benthem
     Genetic Toxicologist, National Institute for Public Health and the
     Environment, Bilthoven
  •  P.J. Boogaard
     Toxicologist, Shell International BV, The Hague
  •  G.J. Mulder
     Emeritus Professor of Toxicology, Leiden University, Leiden
  •  M.J.M. Nivard
     Molecular Biologist and Genetic Toxicologist, Leiden University Medical
     Center, Leiden
  •  G.M.H. Swaen
     Epidemiologist, Maastricht University, Maastricht
  •  E.J.J. van Zoelen
     Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
  •  G.B. van der Voet, scientific secretary
     Toxicologist, Health Council of The Netherlands
  Date meeting: April 09, 2014.
2 Adriamycin
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<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be as carcinogenic to humans.          2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guidelines to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.33
             Carcinogenic classification of substances by the Committee                                                 53
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<pre>4 Adriamycin</pre>

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