<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>www.healthcouncil.nl Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Healthy working conditions How can employees be protected against working conditions that could harm their health? Environmental health Which environmental influences could have a positive or negative effect on health? Healthy nutrition Which foods promote good health and which carry certain health risks? Prevention Which forms of prevention can help realise significant health benefits? Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Areas of activity Advisory Reports The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands Thiotepa 2015/17 2015/17 Health-based calculated occupational cancer risk values Thiotepa Health Council of the Netherlands</pre>

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<pre>Thiotepa
    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 Thiotepa
Uw kenmerk             : DGV/BMO/U-932542
Ons kenmerk            : U-783200/BvdV/cn/459
Bijlagen               :1
Datum                  : 16 juli 2015
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
thiotepa.
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 thiotepa een carcinogene stof is. De commissie
is echter van mening dat wegens gebrek aan adequate humane en dierexperimentele gege-
vens het niet mogelijk is om de extra kans op kanker na blootstelling aan thiotepa te bereke-
nen.
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
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X D e n H a a g                                         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>Thiotepa
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. 2015/17, The Hague, July 16, 2015
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare 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. Thiotepa - Health-based calculated
occupational cancer risk values . The Hague: Health Council of the
Netherlands, 2015; publication no. 2015/17.
all rights reserved
ISBN: 978-94-6281-028-0
</pre>

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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 14
.3 Data 14
   Identity, toxicity profile and classification 15
.1 Identity and physical and chemical properties 15
.2 Classification as a carcinogenic substance 16
.3 Genotoxicity 16
.4 Non-carcinogenic effects 17
.5 Occupational exposure and existing occupational exposure limits 18
   Carcinogenicity studies 19
.1 Observations in humans 19
.2 Carcinogenicity studies in animals 21
.3 Risk assessment 23
.4 Additional consideration 23
   Contents                                                           7
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<pre>  References 25
  Annexes 27
A Request for advice 29
B The Committee 31
C The submission letter (in English) 33
D Comments on the public review draft 35
E Epidemiological studies 37
F Animal studies 39
G Evaluation of the Subcommittee on the Classification of Carcinogenic Substances 43
H Carcinogenic classification of substances by the Committee 51
  Health-based occupational risk calculations 53
  Thiotepa
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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 overeenko-
men met een vooraf vastgesteld extra risico op sterfte aan 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 Gezond-
heidsraad of de Europese Unie geclassificeerd zijn in categorie 1A of 1B en die
kankerverwekkend zijn via een stochastisch genotoxisch mechanisme. Voor de
schatting maakt de commissie gebruik van de Leidraad Berekening risicogetal-
len voor carcinogene stoffen van de Gezondheidsraad.1 In dit advies onderzoekt
de commissie de mogelijkheid om zo’n schatting voor thiotepa te maken. Thio-
tepa wordt als chemotherapeuticum aan patiënten toegediend. Beroepsmatige
blootstelling komt voor bij werknemers die betrokken zijn bij de productie,
bereiding en toediening van deze stof.
De commissie concludeert dat thiotepa een carcinogene stof is met een stochas-
tisch genotoxisch werkingsmechanisme.
    De commissie is van mening dat wegens gebrek aan adequate humane en
dierexperimentele gegevens het niet mogelijk is om de extra kans op kanker na
blootstelling aan thiotepa te berekenen.
Samenvatting                                                                      9
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<pre>0 Thiotepa</pre>

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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 mortality
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
the calculation of occupational cancer risk values of the Health Council.1 In this
report the Committee evaluates the possibility to establish such estimates for
thiotepa. Thiotepa is administered to patients as a chemotherapeutic agent.
Occupational exposure occurs in employees involved in the production,
preparation and administration of this substance.
In this report, the Committee concludes that thiotepa is a carcinogenic substance
with a stochastic genotoxic mechanism.
    The Committee is of the opinion that due to a lack of adequate human and
animal data, it is not possible to establish the health-based calculated
occupational cancer risk values for thiotepa.
Executive summary                                                                  11
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<pre>2 Thiotepa</pre>

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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). This evaluation should lead for thresholded genotoxic
        substances to a health-based recommended occupational exposure limit for the
        concentration of the substance in air. Such an exposure limit cannot be derived if
        the toxic action has no threshold, 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 stochastic genotoxic carcinogens by the European Union or by
        the Committee.
            For the establishment of the HBC-OCRVs, the Committee generally uses a
        linear extrapolation method, as described in the Committee’s reports Calculating
        cancer risk and Guideline for the calculation of occupational cancer risk
        values.1,2 The linear model to calculate occupational cancer risk is used as a
        Scope                                                                              13
</pre>

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<pre>    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 theotepa (see
    Annex G and H). 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 February 2015, the president of the Health Council released a draft of the
    report for public review. The individuals and organizations 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 Toxline,
    Medline and Chemical Abstracts, using carcinogenic properties, carcino*,
    cancer, neoplastic, thiotepa and CAS registry number as key words. In addition,
    in preparing this report the following reviews were consulted: IARC reviews and
    the NTP Report on Carcinogens.3-6 The last search covered the period 1997-May
    2015 (a previous search was conducted in 1997 and covered the period 1965 to
    January 1997).
 4  Thiotepa
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<pre> hapter      2
             Identity, toxicity profile and
             classification
2.1          Identity and physical and chemical properties
             Thiotepa is used as chemotherapeutic agent. Physical and chemical data shown
             below are from http://toxnet.nlm.nih.gov (HSDB and ChemIDplus data bases,
             accessed May 1, 2015 ).
 hemical name                                        :   tris(1-aziridinyl)phosphine sulfide
 AS number                                           :   52-24-4
 INECS number                                        :   200-135-7
 EC number                                           :   --
UPAC name                                            :   thiotepa
 ynonyms                                             :   triethylenethiophosphoramide;
                                                         N,N”-triethylenethiophosphamide;
                                                         N,N’,N”-tri-1,2-ethanediylphosphoro-thioictriamide; NSC-
                                                         6396; aziridine,
                                                         1,1’1”-phosphinothioylidynetris;
                                                         TSPA; WR-45312
 hysical description and colour                      :   Crystalline solid, white
Molecular formula                                    :   C6H12N3PS
 tructure                                            :
             Identity, toxicity profile and classification                                                        15
</pre>

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<pre>Molecular weight                                    :   189.2
Melting point                                       :   51.5 °C
 oiling point (101.3 kPa)                           :   no data
Density                                             :   no data
 olubility in water                                 :   190 g/L in water at 25 °C
 olubility in organic solvents                      :   soluble in alcohol, benzene, ether, chloroform, diethyl ether
Octanol/water partition coefficient, Log Poct/w     :   0.53
 apour pressure (25 °C)                             :   8.45E-3 mm Hg
 elative vapour density (air = 1)                   :   no data
 lash point                                         :   no data
Odour threshold                                     :   no data
 onversion factors (25 °C, 101.3 kPa)               :   no data
 U classification                                   :   no classification
2.2           Classification as a carcinogenic substance
              The European Union did not classify thiotepa. IARC concluded that there is
              sufficient evidence for the carcinogenicity of thiotepa in humans and in
              experimental animals and has classified the compound as a group 1 carcinogen
              (carcinogenic to humans).5 In 2011 the 12the NTP Report on Carcinogens
              considers thiotepa as known to be a human carcinogen based on sufficient
              evidence of carcinogenicity from studies in humans.6
                   In the present evaluation the Committee (DECOS) follows the
              recommendation of the DECOS Subcommittee on the Classification of
              Carcinogenic Substances and classifies thiotepa in category 1A (known to be
              carcinogenic to humans) (see Annex G and H).
2.3           Genotoxicity
              Thiotepa is a direct alkylating agent with potent genotoxic activity in a wide
              variety of prokaryotic, lower eukaryotic, and mammalian in vitro and in vivo test
              systems. Thiotepa causes DNA damage, mutations, micronucleus formation,
              and/or chromosomal aberrations in somatic and germ cells from exposed rodents,
              rabbits, and nonhuman primates and chromosomal aberrations in peripheral-
              blood lymphocytes from treated humans (NTP RoC 2011; IARC 1990; Chen et
              al., 1999; Casciano et al., 1999).5-8
                   The Committee (DECOS) follows the recommendation of the DECOS
              Subcommittee on the Classification of Carcinogenic Substances (see Annex G)
              and concludes that thiotepa is a stochastic genotoxic carcinogen.
 6            Thiotepa
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<pre>2.4 Non-carcinogenic effects
    Thiotepa is poorly absorbed from the gastrointestinal tract. No data for the
    dermal or inhalation route of exposure were found.
    In rats, rabbits, dogs and humans tepa (N,N’,N”- triethylenephosphoramide) was
    found to be the main metabolite of thiotepa. In the mouse, thiotepa is
    metabolized to inorganic phosphate as the only detectable product. The
    conversion of thiotepa to tepa is catalyzed by specific cytochrome isoenzymes.
    Excretion of thiotepa and tepa can be monitored in urine, but the urinary
    excretion of thiotepa and tepa differs per species and accounts only for a limited
    fraction of the administered dose. (Maanen et al. (2000)9; EMA website: http://
    www.ema.europa.eu/ema/, accessed May 1, 2015).
    In humans, toxicity to the haemopoietic system (severe myelosuppression) was
    observed in 13 ovarian cancer patients treated with two intravenous bolus
    injections of thiotepa (60 and 80 mg, 4-week interval between doses).10 Other
    side effects in this study were limited to transient nausea and vomiting in two
    patients on the day of treatment with 80 mg.
        Myelosuppression was also observed in a study with 27 children with
    malignancies refractory to conventional therapy.11 Nineteen children received an
    intravenous bolus of thiotepa at a starting dose of 25 mg/m2 with escalations to
    50, 65 or 75 mg/m2 (only one escalation dose was allowed in an individual
    patient). Eight children received an 8-hour infusion at 50 or 65 mg/m2. The
    maximum tolerated bolus dose was 65 mg/m2, and the dose-limiting toxicity was
    myelosuppression, characterized by granulocytopenia and thrombocytopenia.
    Myelosuppression was the only clinically significant toxicity. Nausea and
    vomiting was uncommon (2 patients) up to the highest dose examined.
        In a study by Lazarus et al., twenty-five patients with malignancies resistant
    to conventional chemoradiation therapy or for which no effective therapy is
    known were treated with intravenous escalating doses of thiotepa (135-1,215
    mg/m2 over 3 days).12 Treatment was followed by reinfusion of previously
    cryopreserved autologous bone marrow (3 days after the last dose of thiotepa).
    The organs that were affected most by thiotepa were bone marrow,
    gastrointestinal tract and CNS. All patients experienced severe neutropenia and
    thrombocytopenia. The six patients treated with 135 or 270 mg/m2 developed
    minimal extramedullary toxicity. Five of the 14 patients treated with ≥810 mg/m2
    experienced moderate to severe diarrhoea, stomatitis, esophagitis or other
    Identity, toxicity profile and classification                                      17
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<pre>    mucosal injury. Five patients treated at ≥810 mg/m2 experienced severe infection
    while neutropenic, four of which died. One patient of the 810 mg/m2 group died
    due to intracranial haemorrhage. Damage to the CNS occurred in three patients,
    all treated at 1,005 mg/m2.
         Regarding experimental animals, the oral LD50 is 38 mg/kg bw in mice.13
    The LD50 in rats was approximately 9.5 mg/kg bw after intravenous injection
    and about 8.8 mg/kg bw after intra-arterial injection.5
         Thiotepa is teratogenic in mice treated at 1 mg/kg bw (intraperitoneal; lowest
    single teratogenic dose), and induces developmental effects in rats at 4 mg/kg bw
    by intraperitoneal injection on gestation day 12.5
2.5 Occupational exposure and existing occupational exposure limits
    Health-care professionals may be potentially exposed during the preparation and
    administration of the compound in cancer therapy.14,15 Also workers involved in
    its formulation and packaging may be potentially exposed. The (American)
    National Occupational Exposure Survey (1981-1983) indicated that 11,452
    workers, including 8,724 women, potentially were exposed to thiotepa (NIOSH
    1990).6,16 The Committee did not find reliable data with regard to the present
    size of the exposed population (Kauppinen et al. 2000).17
    Worldwide, no occupational exposure limits for thiotepa are set at the present
    time (http://www.ser.nl, accessed May 1, 2015).
 8  Thiotepa
</pre>

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<pre> hapter 3
        Carcinogenicity studies
3.1     Observations in humans
        Table 1 (Annex E) summarizes four main epidemiological studies with thiotepa.
            Kaldor et al. (1990) assessed the risk of acute or non-lymphocytic leukaemia
        associated with exposure to thiotepa, in a multicentre nested case-control study
        that was imbedded in a cohort of 99,113 survivors of ovarian cancer, previously
        treated with chemotherapeutics.18 In this study, 114 case patients who were
        diagnosed with leukaemia at least one year after the diagnosis with ovarian
        cancer were matched with control patients who survived free of a second cancer
        for at least as long as the interval between the diagnosis of ovarian cancer and
        leukaemia in the case patient (3 controls per case of leukaemia). The time
        between the diagnosis of ovarian cancer and leukaemia was between two and
        nine years in 74% of the cases, and acute or non-lymphocytic leukaemia’s
        represented 89% of the total. To investigate the association of thiotepa exposure
        with the risk of leukaemia, the analysis was conducted on patients with ovarian
        cancer for which the only chemotherapy had been thiotepa (9 cases with
        leukemia and 11 controls). These patients were assigned to a low dose group
        (4 cases, 5 controls) and a high dose group (5 cases, 6 controls). To create these
        groups, the median dose in controls (30 and 600 mg thiotepa for the low and high
        dose, respectively) was used as cutoff point. No other data on the treatment were
        given in the report. The relative risk for acute or non-lymphocytic leukaemia
        compared to patients receiving only radiotherapy or surgery was 8.3 (p<0.05) for
        Carcinogenicity studies                                                            19
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<pre>  the low dose and 9.7 (not statistically significantly different from 1.0) for the
  high dose. [The Committee considers this study well performed although it is
  aware of the small number of patients treated with thiotepa.]
      In the three other studies no increased risk of secondary malignancies was
  found among patients with colorectal or breast cancer and treated with thiotepa.
  In a study by Boice et al. (1980) (randomized clinical trial), 470 male patients
  with colorectal cancer received surgical resection and low-dose chemotherapy
  with thiotepa and were compared with 867 male colorectal patients treated with
  surgery alone.19 Thiotepa was administered at 0.8 mg/kg bw (4 doses of 0.2
  mg/kg bw at and two days after surgery) and the patients were followed up for up
  to 19 years with an average survival of 6.8 years. Due to the small number of
  non-white patients, analysis was limited to white patients. No difference in the
  observed/expected ratio of second malignancies was observed among patients
  treated with thiotepa (0.9; 28 cases observed /30.7 expected) compared to
  patients who received surgery alone (1.0; 57 cases observed /55.4 expected).
  [The Committee considers this a well-performed study, but recognizes that the
  number of patients included is not large].
      In a retrospective study of Chan et al. (1980) 633 breast cancer patients
  received simple or radical surgery (mastectomy) with or without postoperative
  radiotherapy and were then treated with 0.6 mg/kg bw thiotepa perisurgically
  followed by prophylactic therapy with 1 mg thiotepa/kg bw every three months
  for up to two years.20 A group of 632 breast cancer patients treated with surgery
  only or with surgery followed by radiotherapy were used as historical controls.
  All patients were followed between 5 to 10 years. The total incidence of
  secondary breast carcinoma was the same in the thiotepa group and the control
  group (5.7%). The total incidence of second non-breast malignancies was 6.3%
  in the thiotepa group and 5.4% in the control group. In total 12.0% of the
  thiotepa treated patients developed a secondary tumour compared with 11.1% in
  the control group. The authors concluded that prolonged adjuvant thiotepa
  chemotherapy does not seem to increase the risk of second primary cancer. [The
  Committee recognizes that the number of patients included is not large. Further it
  is noted that the thiotepa group and the control group were not comparable with
  respect to the fraction of patients given radiotherapy after surgery (7% and 36%
  in the thiothepa and control group, respectively).]
      In a prospective randomized clinical trial by Kardinal & Donegan (1980), 90
  women treated with radical mastectomy for early cancer of the breast were
  subsequently treated with 0.8 mg/kg bw thiotepa perisurgically and then with 0.2
  mg/kg bw thiotepa once weekly for one year.21 Seventy-seven breast cancer
  patients treated with radical mastectomy only served as control group. The
0 Thiotepa
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<pre>    average follow-up period was 64.6 months in the thiotepa group and 61.6 months
    in the control group. Excluding skin cancer (basal cell tumours), 11 patients
    developed second cancers: five (5.6%) in the thiotepa group and six (7.8%) in the
    control group. Using these numbers and total follow up values of 5,819 and
    4,746 person years for the thiotepa group and the control group, respectively, the
    Committee calculated a relative risk of 0.68 for developing a second malignancy
    after thiotepa treatment. The authors stated that the intergroup differences in total
    or site-specific second cancers were not significant. [However from the report it
    is not clear whether any statistical analysis was performed. Further, the
    Committee recognizes that the number of participants is too low.]
    [The Committee recognizes that these three latter studies were clinical trials and
    not designed specifically to analyze the long term side-effects of thiotepa.
    Moreover due to the low number of patients none of the studies had sufficient
    power to find any side effects.]
3.2 Carcinogenicity studies in animals
    Table 2 (Annex F) summarizes the available carcinogenicity studies in
    experimental animals. Thiotepa was tested for carcinogenicity by intraperitoneal
    administration in male and female mice and rats and by intravenous
    administration in male rats. A short description of these studies is given below.
    In a screening assay by Stoner et al. (1973), based on accelerated induction of
    lung tumours in a mouse strain (A/He) highly susceptible to development of this
    neoplasm, ten mice per sex per dose received 19, 47 or 94 mg/kg bw thiotepa
    (total doses) by intraperitoneal injection over a period of 4 weeks.22 The
    experiment was terminated 24 weeks after the first injection. All thiotepa treated
    animals except one of the 47 mg/kg bw group survived. Survival in the control
    groups was 94% (untreated control) or 96% (vehicle control). The incidence of
    lung tumours was 11 (55%), 20 (100%) and 16 (80%) in the low, mid and high
    dose groups, respectively, compared to 19 (19%) and 38 (24%) in untreated and
    vehicle controls, respectively. The number of lung tumours per mouse at the mid
    and high dose was statistically significantly increased compared to controls. [The
    Committee noted that this study is limited (only one type of tumour investigated,
    small number of treated animals, short treatment and observation periods) and
    that a positive result in this pulmonary tumour screening assay should be
    confirmed by other test systems.]
    Carcinogenicity studies                                                               21
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<pre>      The carcinogenicity of thiotepa was also determined in a study performed by
  the National Cancer Institute (NCI) of the US Department of Health, Education,
  and Welfare.23 Male and female Sprague-Dawley rats (31-39/sex/dose) were
  treated intraperitoneally with thiotepa in phosphate-buffered saline at dose levels
  of 0.7, 1.4 or 2.8 mg/kg bw three times a week for a maximum period of 52
  weeks followed by observation periods (length depending on the dose level)
  resulting in experimental periods of 82-87 weeks. Mean body weights of all
  dosed male rats, particularly those of the mid- and high-dose groups, were
  depressed throughout the study, when compared with either matched or vehicle
  controls; those of the dosed females were less markedly depressed. Thiotepa
  decreased survival in a dose-related manner. At the high dose, all males and
  females were dead by week 19 and 21, respectively. At the mid dose, all males
  were dead by week 78 and only 8.6% of the females survived till the end of
  study. At the low dose, survival was 15.4% in males and 42% in females.
  Survival in controls was 80-100%. The high dose of 2.8 mg/kg bw was too toxic
  for an evaluation of carcinogenic activity. Treatment with thiotepa was
  associated with increased incidences of squamous-cell carcinoma in the skin or
  ear canal, neuroepitheliomas and nasal carcinomas in each sex, haematopoietic
  tumours (lymphoma, lymphocytic leukaemia, or granulocytic leukaemia) in male
  rats, adenocarcinoma of the uterus, and adenocarcinoma of the mammary gland.
  These tumours are considered to be relevant for humans. [Although this study
  has limitations, such as pooled control groups to obtain significance (see Table 2
  in Annex F), it allows the conclusion that thiotepa is carcinogenic in Sprague-
  Dawley rats.]
      In the same study by NCI, male and female B6C3F1 mice (35/sex/dose) were
  treated ip with thiotepa in phosphate-buffered saline at dose levels of 1.15 or 2.3
  mg/kg bw three times a week for a maximum period of 52 weeks followed by an
  observation period resulting in an experimental period of 86 weeks (or only 43 or
  56 weeks in high-dose females and males, respectively, due to mortality).23 Body
  weight depression was observed in high dose animals, particularly in females.
  All males and females of the high dose group were dead by week 56 and 43,
  respectively. At the end of the experimental period, 15 (43%) male and 17 (49%)
  female mice of the low dose group survived compared to 7 (46%) males and 12
  (80%) females in the vehicle control group. Treatment with thiotepa was
  associated with increased incidences of squamous cell carcinoma (at skin, ear
  and preputial gland) in male mice and of haematopoietic tumours (lymphoma
  and lymphocytic leukaemia) in male and female mice. These tumours are
  considered to be relevant for humans. [Although this study has limitations (see
2 Thiotepa
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<pre>    Table 2 in Annex F), it allows the conclusion that thiotepa is carcinogenic in
    B6C3F1 mice.]
         In the study of Schmähl and Osswald (1970), 48 male R46 rats were treated
    with 1 mg/kg bw thiotepa by intravenous injection once a week for 52 weeks.24
    Malignant tumours were observed in 9 of the 30 rats that were still alive when
    the first tumour appeared. These tumours occurred at a variety of sites (see Table
    1 in Annex E). The incidence of malignant tumours in controls was 4/65. The
    authors stated that the difference in total tumour incidence between treated rats
    and controls was statistically significant (no p value was reported). [The
    Committee noted that this study has several flaws (short exposure period, only
    one dose tested, only one sex used, no statistical analysis performed on
    individual tumour types, high early mortality in treated group).]
3.3 Risk assessment
    Limited evidence is available that thiotepa is carcinogenic to humans. Sufficient
    evidence is available that thiotepa is carcinogenic to animals. The Committee
    classifies thiotepa in category 1A (known to be carcinogenic to humans) and
    concludes that a stochastic genotoxic mechanisms underlies carcinogenicity.
         The logical approach to risk assessment would be the derivation of health-
    based calculated occupational cancer risk values (HBC-OCRVs). However, in
    view of the Committee none of the animal or human studies is sufficiently
    adequate for quantitative risk assessment. Therefore the Committee concludes
    that due to a lack of adequate human and animal data, it is not possible to
    establish the health-based calculated occupational cancer risk values for thiotepa.
3.4 Additional consideration
    In spite of this conclusion above (paragraph 3.3) the Committee decided to
    process the data from the epidemiological studies from Kaldor et al.18, Boice et
    al.19, Chan et al.20, Kardinal & Donegan21 in a quantitative risk calculation in
    order to speculate on the exposure levels related to an additional life-time cancer
    risk. The results of this calculation are presented in Annex I. However, given the
    uncertainties as discussed above (paragraph 3.1) and in Annex I the Committee
    decided not to use this calculation.
         The Committee emphasizes that thiotepa is a potent carcinogen. With the
    exception of cancer patients no individual should be exposed to this compound.
    Therefore, workers involved in handling the compound in patient-treatment, or
    in packaging etc., should avoid exposure.
    Carcinogenicity studies                                                             23
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<pre>4 Thiotepa</pre>

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<pre>  References
  Health Council of The Netherlands. Guideline for the calculation of occupational cancer risk values.
  The Hague: The Netherlands; 2012: publication no. 2012/16E.
  Health Council of The Netherlands. Calculating cancer risk. The Hague, The Netherlands: 1995:
  publication no. 1995/06WGD.
  IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: some aziridines,
  N-, S- & O-mustards and selenium. IARC Monogr Eval Carcinog Risk Chem Man 1975; 9: 85-94.
  Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC
  Monogr Eval Carcinog Risks Hum Suppl 1987; 7: 368-369.
  IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: Pharmaceutical
  drugs. IARC Monogr Eval Carcinog Risk Chem Man 1990; 50: 123-141.
  NTP 12th Report on Carcinogens. Rep Carcinog 2011; 12: iii-499.
  Chen T, Aidoo A, Mittelstaedt RA, Casciano DA, Heflich RH. Hprt mutant frequency and molecular
  analysis of Hprt mutations in Fischer 344 rats treated with thiotepa. Carcinogenesis 1999; 20(2): 269-
  277.
  Casciano DA, Aidoo A, Chen T, Mittelstaedt RA, Manjanatha MG, Heflich RH. Hprt mutant
  frequency and molecular analysis of Hprt mutations in rats treated with mutagenic carcinogens.
  Mutat Res 1999; 431(2): 389-395.
  Maanen MJ, Smeets CJ, Beijnen JH. Chemistry, pharmacology and pharmacokinetics of N,N’,N” -
  triethylenethiophosphoramide (ThioTEPA). Cancer Treat Rev 2000; 26(4): 257-268.
0 Hagen B. Pharmacokinetics of thio-TEPA and TEPA in the conventional dose-range and its
  correlation to myelosuppressive effects. Cancer Chemother Pharmacol 1991; 27(5): 373-378.
  References                                                                                             25
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<pre>1 Heideman RL, Cole DE, Balis F, Sato J, Reaman GH, Packer RJ et al. Phase I and pharmacokinetic
  evaluation of thiotepa in the cerebrospinal fluid and plasma of pediatric patients: evidence for dose-
  dependent plasma clearance of thiotepa. Cancer Res 1989; 49(3): 736-741.
2 Lazarus HM, Reed MD, Spitzer TR, Rabaa MS, Blumer JL. High-dose i.v. thiotepa and
  cryopreserved autologous bone marrow transplantation for therapy of refractory cancer. Cancer Treat
  Rep 1987; 71(7-8): 689-695.
3 T317 tris(1-aziridinyl)phosphine sulfide. In: Richardson S, Gangollis S, editors. The dictionary
  ofsubstances and their effects. vol 10. 1994: 725-726.
4 Boiano JM, Steege AL, Sweeney MH. Adherence to Precautionary Guidelines for Compounding
  Antineoplastic Drugs: A Survey of Nurses and Pharmacy Practitioners. J Occup Environ Hyg 2015; 0
  [Epub ahead of print].
5 Zimmerman PF, Larsen RK, Barkley EW, Gallelli JF. Recommendations for the safe handling of
  injectable antineoplastic drug products. Am J Hosp Pharm 1981; 38(11): 1693-1695.
6 NIOSH. National Occupational Exposure Survey (1981-83). Unpublished provisional data as of 7/1/
  90. Cincinncati, OH: U.S. Department of Health and Human Services. (http://www.cdc.gov/noes/
  noes3/empl0001.html, accessed January 27, 2015); 1990.
7 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.
8 Kaldor JM, Day NE, Pettersson F, Clarke EA, Pedersen D, Mehnert W et al. Leukemia following
  chemotherapy for ovarian cancer. N Engl J Med 1990; 322(1): 1-6.
9 Boice JD, Greene MH, Keehn RJ, Higgins GA, Fraumeni JF, Jr. Late effects of low-dose adjuvant
  chemotherapy in colorectal cancer. J Natl Cancer Inst 1980; 64(3): 501-511.
0 Chan P, Sadoff L, Winkley J. Second malignancies following first breast cancer in prolonged thiotepa
  adjuvant chemotherapy. In: SE Salmon, SE Jones, editors. Adjuvant therapy of cancer. Amsterdam:
  Elsevier; 1977: 597-607.
1 Kardinal CG, Donegan WL. Second cancers after prolonged adjuvant thiotepa for operable carcinoma
  of the breast. Cancer 1980; 45(8): 2042-2046.
2 Stoner GD, Shimkin MB, Kniazeff AJ, Weisburger JH, Weisburger EK, Gori GB. Test for
  carcinogenicity of food additives and chemotherapeutic agents by the pulmonary tumor response in
  strain A mice. Cancer Res 1973; 33(12): 3069-3085.
3 Bioassay of thio-TEPA for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser 1978;
  58: 1-168.
4 Schmähl D, Osswald H. [Experimental studies on the carcinogenic effects of anticancer
  chemotherapeutics and immunosuppressive agents]. Arzneimittelforschung 1970; 20(10): 1461-
  1467.
5 Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of
  experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
6 Health Council of The Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: publication no. A10/07E.
6 Thiotepa
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<pre>A Request for advice
B The Committee
C Submission letter (English)
D Comments on the public review draft
E Epidemiological studies
F Animal studies
G Evaluation of the Subcommittee on the Classification of Carcinogenic
  Substances
H Carcinogenic classification of substances by the Committee
  Health-based occupational risk calculations
  Annexes
                                                                       27
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<pre>8 Thiotepa</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
          criteria-document that will be made available to the Health Council as part of a specific request
     Request for advice                                                                                        29
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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.
0 Thiotepa
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life; 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; National
        Institute for Public Health and the Environment, Bilthoven
     •  A.H. Piersma
        Professor of Reproductive Toxicology, National Institute for Public Health
        and the Environment, Bilthoven
     •  H.P.J. te Riele
        Professor of Molecular Biology, VU University Amsterdam; Netherlands
        Cancer Institute, Amsterdam
     The Committee                                                                   31
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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; Radboud UMC Outpatient Clinic for Occupational Clinical
      Toxicology, Nijmegen
  •   F.G.M. Russel
      Professor of Molecular Pharmacology and Toxicology, Radboud University,
      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.
2 Thiotepa
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<pre>nnex C
     The submission letter (in English)
     Subject         : Submission of the advisory report Thiotepa
     Uw kenmerk      : DGV/BMO/U-932542
     Ons kenmerk     : U-783200/BvdV/cn/459
     Enclosed        :1
     Date            : July 16, 2015
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     thiotepa.
     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)                                             33
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<pre>  In this report, the Committee concludes that thiotepa is a carcinogenic substance.
  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 thiotepa.
  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
4 Thiotepa
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in February 2015 for public review.
     The following organizations and persons have commented on the draft
     document:
     • Coggon D. University of Southampton, Southampton, UK
     • Lentz TJ, Ding M, Settle T. National Institute for Occupational Safety and
        Health (NIOSH), Cincinnati OH, USA.
     Comments on the public review draft                                            35
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<pre>6 Thiotepa</pre>

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<pre> nnex           E
                Epidemiological studies
 able 1 Thiotepa, epidemiological studies.
 tudy design and population                   Data on exposure and         Results                      Remarks
                                              health assessment
Kaldor et al.18                               Selected patients were       Relative risk of leukaemia   Study used to calculate
Nested case-control study.8                   divided into a low (30       (acute or nonlymphocytic)    cancer risk value.
  ountry: Canada, 7 European countries.       mg) and high (600 mg)        after thiotepa treatment     Well performed with
 articipants: 114 case patients with          dose group; median dose      compared to surgery and      limitations.
eukaemia and 342 matched controls             in controls was used as      radiotherapy is 8.3 in the   No details on treatment
 elected from a cohort of 99,113 ovarian      cutoff point to create       low-dose group (p<0.05)      reported; small number of
 ancer patients.                              dose groups. The risk of     and 9.7 (not statistically   cases and controls.
 hiotepa treated case patients with           leukaemia was                significantly different
eukaemia: 9 (4 low dose, 5 high dose);        determined relative to       from 1.0) in the high-dose
hiotepa treated matched control patients      patients receiving           group.
ree of a second cancer: 11 (5 low dose, 6 surgery or radiotherapy.
 igh dose).                                   Appropriate statistical
                                              analysis performed.
  oice et al.19                               Dose: 0.8 mg thiotepa/       Observed/Expected ratio      Well performed with
  andomized clinical trial.9                  kg bw in total (4 doses      of second malignancies       limitations.
  ountry: USA                                 of 0.2 mg/kg bw: 1 i.v.      among thiotepa-treated       Follow-up period (mean
 articipants (enrolled in the study between   and 1 i.p. at surgery, 2 i.v patients (0.9) not different survival 6.8 years) may be
 958 and 1964): 470 male patients with        on 1st and 2nd day after     from ratio in surgery-       too short; sample size of 470
 olorectal cancer treated with thiotepa after surgery).                    treated patients (1.0)       patients is not large.
 urgery, followed for 3102 person-years;      Appropriate statistical
 67 non-exposed controls (colorectal cancer   analysis performed.
reated with surgery only).
 ollow-up period: up to 19 years (1977),
mean survival 6.8 years.
                Epidemiological studies                                                                                            37
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<pre>  han et al.20                              Dose: 0.6 mg/kg bw        No difference in incidence  Well performed with
  etrospective study.10                     perisurgical, followed by of second primary cancers   limitations.
  ountry: USA                               prophylactic therapy (1   (12% in thiotepa treated    Follow-up period (5-10
 articipants (treated with mastectomy from  mg/kg bw) 3 months        patients, 11% in controls). years) may be too short;
 953-1967):                                 after surgery and then                                sample size of 633 patients
  ases: 633 breast cancer patients treated  every three months for                                is not large; treated and
with long-term adjuvant thiotepa therapy    maximally 2 years (total                              control group differed with
 fter mastectomy with or without            dose in each 3-month                                  respect to fraction of patients
adiotherapy.                                period did not exceed 60                              treated with radiotherapy
Historical controls: 632 breast cancer      mg).                                                  (7% in control group, 36%
 atients treated with mastectomy with or                                                          in treated group); no
without radiotherapy.                                                                             statistical analysis
 ollow-up period: 5-10 years.                                                                     performed.
Kardinal et al.21                           Dose: 0.8 mg/kg bw i.v.   No difference in survival   Well performed with
 rospective randomized clinical trial.11    perisurgical, and then    between the groups.         limitations.
  ountry: USA                               0.2 mg/kg bw once         Relative risk of second     Follow-up period (about 5
 articipants (accrued from 1963-1972):      weekly for 1 year.        malignancies (skin basal    years) may be too short;
 reast cancer patients treated with radical                           cell tumours excluded)      small number of
mastectomy and then randomly assigned to                              after thiotepa treatment is participants; no information
ong-term adjuvant thiotepa therapy (90                                0.68 (5/5819 person-year)/  on statistical analysis.
 atients) or no further treatment (77                                 (6/4746 person year). The
 atients, control group).                                             authors stated that this
 ollow-up period: 64.4 and 61.6 months                                difference was not
average) in thiotepa and control group,                               significant.
espectively.
.p. = intraperitoneal; i.v. = intravenous
  8            Thiotepa
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<pre> nnex          F
               Animal studies
 able 2 Thiotepa, animal studies.
 tudy design and    Data on exposure and      Results                                             Remarks
nimal species       effect endpoints
 toner et al.22     Intraperitoneal           Survival: 20/20, 19/20, 20/20 in low, mid, and      Klimisch score: 3
Mouse (A/He)        injection, total doses of high dose, resp., 94/100 and 154/160 in untreated   Supportive study.
 reated: 10/sex/    19, 47, 94 mg/kg bw       and vehicle controls, resp.                         Positive result in A mouse lung
 ose                (12 injections in 0.1     Lung tumour incidence:                              tumour screening assay should
 ontrol: 50/sex     mL tricaprylin, 3 times/  11/20, 20/20, 16/20 in low, mid, high dose, resp.,  be confirmed by other test
 ntreated and 80/ week)                       19/100 and 38/160 untreated and vehicle controls,   systems.
ex vehicle control Xpo = 4 weeks              resp.                                               Histopathology restricted to
                    Xpe = 24 weeks            Number of lung tumours per mouse was                lungs and suspicious tissues
                                              statistically significantly higher at the high dose seen at necropsy; gross
                                              (1.50; p<0.001) and mid dose (0.74; p<0.05)         examination limited to liver,
                                              compared to vehicle controls (male 0.24, female     kidneys, spleen, thymus,
                                              0.20).                                              intestines, and salivary and
                                                                                                  endocrine glands. Short
                                                                                                  administration and observation
                                                                                                  period. Insufficient number of
                                                                                                  animals. Not clear whether
                                                                                                  decedents were included in
                                                                                                  statistical analysis.
               Animal studies                                                                                                  39
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<pre>NCI23                 Intraperitoneal           Survival: High dose: no survivors by week 19         Klimisch score: 2
  prague Dawley rat   injection, 0.7, 1.4, 2.8  (males) or 21 (females). Mid dose: no male           Well performed with
 5 rats/sex at mid    mg/kg bw, 3 times/        survivors by week 78, 8.6% of females survived       limitations.
 nd high dose, 39     week                      till end of study.                                   Pooled control groups used to
males and 31          Xpo = 21 weeks (high      Low dose: 15.4 and 42% survival by the end of        obtain statistical significance
emales at low         dose), 34 weeks (mid      the study.                                           (too few concurrent controls);
 ose.                 dose), 52 weeks (low      Control: 80% (males) or 70% (females) survival       maximum tolerated dose
  oncurrent control:  dose and controls)        in mid and high dose vehicle controls, 100%          exceeded in mid and high dose
 0 untreated and 10   Xpe = high dose 21        (males) or 90% (females) in low dose vehicle         group; no microscopy
 ehicle treated rats/ weeks, mid dose 78        controls.                                            conducted on high-dose rats
 ex;                  (males) or 81 (females)   Adverse effects: Decreased mean body weight in       (because of high mortality);
  ooled control:      weeks, low dose and       males (especially at the mid and high dose).         short exposure period.
 ehicle controls      controls 82-87 weeks.     Effect in females less pronounced.                   To control respiratory disease
rom different         Appropriate statistical   Tumour incidences (relative to pooled controls):     (clinically evident in treated
 tudies added to      analysis performed (for   Haematopoietic (lymphoma, lymphocytic                rats and controls),
 ive a total of 30    tumours: based solely     leukaemia or granulocytic leukaemia) in males: 6/    oxytetracycline was given in
ats/sex in each of 2  on rats surviving 52 wk   34* at low dose, 6/16* at mid dose, 0/29 low-dose    weeks 24-35 (in drinking
 ooled vehicle        or, when tumour of        control, 0/30 mid-dose control.                      water).
 ontrol groups (one   interest was seen         Squamous-cell carcinoma of skin or ear canal:
or the low dose,      earlier, at least as long Males: 7/33* at low dose, 3/13* at mid dose, 0/29
 ne for the mid       as the time at which the  low-dose control, 0/30 mid-dose control;
 ose).                first tumour of interest  Females: 8/21* at mid dose, 0/28 in mid-dose
                      was seen;                 control. Adenocarcinoma uterus: 2/29 at low
                      high-dose animals         dose, 7/21* at mid dose, none in control.
                      excluded because of       Adenocarcinomas mammary gland: 8/24* at mid
                      high early mortality).    dose, 1/28 in mid-dose control.
                                                Neuroepitheliomas or nasal carcinomas: 3 in low
                                                dose males, 2 in low dose females, 2 in mid dose
                                                females, 0 in controls.
                                                * Statistically significantly different from pooled
                                                control.
NCI23                 Intraperitoneal           Survival: All high dose males and females were       Klimisch score: 2
  6C3F1 mouse         injection, 1.15 and 2.3   dead by week 56 and 43, resp. Survivors at end       Well performed with
  reated: 35 mice/    mg/kg bw, 3 times/        experimental period: low dose 15/35 males and        limitations.
 ex/dose.             week                      17/35 females; vehicle control 7/15 males and 12/    Maximum tolerated dose
  oncurrent control:  Xpo = 43 weeks            15 females.                                          exceeded in the high dose
 5 untreated and 15   (females high dose), 52   Adverse effects: Body weight depression high         group; short exposure period.
 ehicle treated       weeks (other groups)      dose animals, in particular females.
mice/sex              Xpe = 43 weeks            Tumour incidences:
  ooled control:      (females high dose), 56   Lymphoma and lymphocytic leukaemia combined:
 ehicle controls      weeks (males high         Males: 2/24 at low dose, 26/28* at high dose, 1/8
rom different         dose), 86 weeks (low      vehicle control, 1/18 pooled control; Females: 5/
 tudies added to      dose and controls).       26 at low dose, 32/32* at high dose, 0/14 vehicle
 ive a total of 30    Appropriate statistical   control, 0/29 pooled control.
mice/sex in each of   analysis performed (for   Squamous-cell carcinoma of skin, preputial gland
  pooled vehicle      tumours: based solely     and ear canal combined: Males: 14/24* at low
 ontrol groups (one   on mice surviving 52      dose, 1/2 at high dose, 0/8 vehicle control, 0/18
or the low dose,      wk or, when tumour of     pooled control.
 ne for the high      interest was seen         * Statistically significantly different from vehicle
 ose).                earlier, at least as long control and pooled control.
                      as the time at which the
                      first tumour of interest
                      was seen).
  0           Thiotepa
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<pre> chmähl &            Intravenous,1 mg/kg     Survival: 30/48 treated, 65/89 control. Mean       Klimisch score: 3
Osswald24            bw, once a week         survival time in treated group was about 7 months  Supportive study.
Male BR46 rat        Xpo = 52 weeks          shorter compared to controls which survived on     Short exposure period; only
 8 treated,          Xpe = not indicated     average about 2 years. Infection of respiratory or one dose tested; only one sex
 9 untreated control                         gastrointestinal tract predominant cause of death  used; no statistical analysis on
                                             in treated animals.                                individual tumour types; high
                                             Malignant tumours: (number of tumour bearing       early mortality in treated group
                                             animals relative to number of animals still alive  due to infection.
                                             when first tumour appeared): 9/30 treated (2
                                             sarcomas of abdominal cavity; 1 lymphosarcoma;
                                             1 myelosis; 1 seminoma, 1 fibrosarcoma and 1
                                             haemangioendothelioma of salivary gland, 1
                                             mammary sarcoma, 1 phaeochromocytoma); 4/65
                                             control (3 mammary sarcomas, 1 phaeochromo-
                                             cytoma).
                                             Mean time of onset of tumours in treated animals
                                             was about 8 months shorter compared to controls
                                             in which the mean time of onset was about 23
                                             months.
Xpo= duration of exposure; Xpe= duration of the experiment.
Klimisch scores were based on Klimisch et al..25
             Animal studies                                                                                                   41
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<pre>2 Thiotepa</pre>

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<pre>nnex G
     Evaluation of the Subcommittee on
     the Classification of Carcinogenic
     Substances
     The European Union did not classify thiotepa (tris-(1-aziridinyl)phosphine
     sulphide). IARC (1990) concluded that there is sufficient evidence for the
     carcinogenicity of thiotepa in humans and in experimental animals and has
     classified the compound as a group 1 carcinogen (carcinogenic to humans).1 [In
     2011 the 12th NTP Report on Carcinogens considers thiotepa as known to be a
     human carcinogen based on sufficient evidence of carcinogenicity from studies
     in humans].
         In the present evaluation (November 2013) 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 thiotepa.
     Human studies (see Table 1 in Annex E)
     Exposure to thiotepa is specifically associated with leukemia in humans (IARC
     1975,1987,1990; NTP RoC 2011).1-4 Adamson & Seiber (1981) summarized
     nine case reports from 1970 to 1978 of secondary development of
     nonlymphocytic leukemia in patients with primary cancer at other sites who had
     received only thiotepa as a therapeutic agent.5 Additional evidence was provided
     by a case-control study by Kaldor et al. (1990).6 Kaldor et al. (1990) assessed the
     risk of acute or non-lymphocytic leukaemia associated with exposure to thiotepa
     in a multicentre nested case-control study that was imbedded in a cohort of
     Evaluation of the Subcommittee on the Classification of Carcinogenic Substances     43
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<pre>  99,113 survivors of ovarian cancer.6 In this study, 114 case patients who were
  diagnosed with leukaemia at least one year after the diagnosis with ovarian
  cancer were matched with control patients who survived free of a second cancer
  for at least as long as the interval between the diagnosis of ovarian cancer and
  leukaemia in the case patient (3 controls per case of leukaemia). The time
  between the diagnosis of ovarian cancer and leukaemia was between two and
  nine years in 74% of the cases, and acute or no lymphocytic leukaemia’s
  represented 89% of the total. To investigate the association of thiotepa exposure
  with the risk of leukaemia, the analysis was conducted on patients for which the
  only chemotherapy was thiotepa (9 cases and 11 controls). These patients were
  assigned to a low dose group (4 cases, 5 controls) and a high dose group (5 cases,
  6 controls). To create these groups, the median dose in controls (30 and 600 mg
  thiotepa for the low and high dose, respectively) was used as cutoff point. No
  other data on the treatment were given in the report. The relative risk for acute or
  non-lymphocytic leukaemia compared to patients receiving radiotherapy or
  surgery was 8.3 (p<0.05) for the low dose and 9.7 (not statistically significantly
  different from 1.0) for the high dose. [The Subcommittee considers this study
  well performed although it is aware of the small number of patients treated with
  thiotepa.]
      In three other studies no increased risk of secondary malignancies was found
  among patients with colorectal or breast cancer. In a study by Boice et al. (1980)
  (randomized clinical trial), 470 male patients with colorectal cancer received
  surgical resection and low-dose chemotherapy with thiotepa and were compared
  with 867 male colorectal patients treated with surgery alone.7 Patients were
  followed up for up to 19 years. No difference in the observed/expected ratio of
  second malignancies was observed among patients treated with thiotepa (0.9)
  compared to patients who received surgery alone (1.0).
      In a retrospective study of Chan et al. (1977) 633 breast cancer patients
  received simple or radical surgery (mastectomy) with or without postoperative
  radiotherapy and were then treated with thiotepa for up to two years.8 A group of
  632 breast cancer patients treated with surgery only or with surgery followed by
  radiotherapy were used as historical controls. All patients were followed between
  5 to 10 years. In total 12.0% of the thiotepa treated patients developed a
  secondary tumour compared with 11.1% in the control group. The authors
  concluded that prolonged adjuvant thiotepa chemotherapy does not seem to
  increase the risk of second primary cancer.
      In a prospective randomized clinical trial by Kardinal et al. (1980), 90
  women treated with radical mastectomy for early cancer of the breast were
  subsequently treated with 0.8 mg/kg bw thiotepa perisurgically and then with 0.2
4 Thiotepa
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<pre>mg/kg bw thiotepa once weekly for one year.9 Seventy-seven breast cancer
patients treated with radical mastectomy only served as control group. The
average follow-up period was approximately 60 months in both the thiotepa
group and the control group. A relative risk of 0.68 was calculated for
developing a second malignancy after thiotepa treatment.
     [The Subcommittee recognizes that these three studies were clinical trials
and not designed specifically to analyze the long term side-effects of thiotepa.
Moreover the number of patients in all three studies was too low to find such an
effect. The thiotepa group and the control group in the Chan et al. study were not
comparable regarding radiotherapy.8 From the Kardinal et al. study it is not clear
whether any statistical analysis was performed.9]
     The Subcommittee recognizes that only one reliable study exists (Kaldor et
al.) showing the association of thiotepa with leukemia and agrees that limited
evidence exists for the carcinogenicity of thiothepa to humans.6
Animal studies (see Table 2 in Annex F)
In the NTP-RoC report (2011) it was summarized that thiotepa administered by
intraperitoneal injection caused lymphoma and/or leukemia (lymphocytic or
granulocytic) in mice of both sexes and in male rats.2 It also caused benign lung
tumors in mice of both sexes, cancer of the mammary gland and uterus in female
rats, cancer of the skin or ear canal (squamous-cell carcinoma) in rats of both
sexes and in male mice, and cancer of the preputial gland (squamous cell
carcinoma) in male mice (IARC 1975,1990; NCI 1978).1,3,10 In male rats
administered thiotepa by intravenous injection, cancer occurred at numerous
tissue sites, including the abdominal cavity, mammary gland, blood vessels, bone
marrow, lymphatic system, salivary glands, adrenal gland, and testis (IARC
1975,1987,1990).1,3,4
     Table 2 (Annex F) summarizes the details of the carcinogenicity studies in
experimental animals described below. In a screening assay by Stoner et al.
(1973), based on accelerated induction of lung tumours in a mouse strain (A/He)
highly susceptible to development of this neoplasm, ten mice per sex per dose
received 19, 47 or 94 mg/kg bw thiotepa (total doses) by intraperitoneal injection
over a period of 4 weeks.11
     The experiment was terminated 24 weeks after the first injection. All thiotepa
treated animals except one of the 47 mg/kg bw group survived. Survival in the
control groups was 94% (untreated control) or 96% (vehicle control). The
incidence of lung tumours was 11 (55%), 20 (100%) and 16 (80%) in the low,
mid and high dose groups, respectively, compared to 19 (19%) and 38 (24%) in
Evaluation of the Subcommittee on the Classification of Carcinogenic Substances     45
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<pre>  untreated and vehicle controls, respectively. The number of lung tumours per
  mouse at the mid and high dose was statistically significantly increased
  compared to controls. The Subcommittee noted that this study is limited (only
  one type of tumour investigated, small number of treated animals, short
  treatment and observation periods) and that a positive result in this pulmonary
  tumour screening assay should be confirmed by other test systems.
      The carcinogenicity of thiotepa was also determined in a study performed by
  the National Cancer Institute (NCI) of the US Department of Health, Education,
  and Welfare.10 Male and female Sprague-Dawley rats (31-39/sex/dose) were
  treated with thiotepa in phosphate-buffered saline at dose levels of 0.7, 1.4 or 2.8
  mg/kg bw three times a week for a maximum period of 52 weeks followed by
  observation periods (length depending on the dose level) resulting in
  experimental periods of 82-87 weeks. Mean body weights of all dosed male rats,
  particularly those of the mid- and high-dose groups, were depressed throughout
  the study, when compared with either matched or vehicle controls; those of the
  dosed females were less markedly depressed. Thiotepa decreased survival in a
  dose-related manner. At the high dose, all males and females were dead by week
  19 and 21, respectively. At the mid dose, all males were dead by week 78 and
  only 8.6% of the females survived till the end of study. At the low dose, survival
  was 15.4% in males and 42% in females. Survival in controls was 80-100%. The
  high dose of 2.8 mg/kg bw was too toxic for an evaluation of carcinogenic
  activity. Treatment with thiotepa was associated with increased incidences of
  squamous-cell carcinoma in the skin or ear canal, neuroepitheliomas and nasal
  carcinomas in each sex, haematopoietic tumours (lymphoma, lymphocytic
  leukaemia, or granulocytic leukaemia) in male rats, adenocarcinoma of the
  uterus, and possibly adenocarcinoma of the mammary gland. These tumours are
  considered to be relevant for humans. Although this study has limitations (see
  Table 2 in Annex F), it allows the conclusion that thiotepa is carcinogenic in
  Sprague-Dawley rats.
      In the same study by NCI, male and female B6C3F1 mice (35/sex/dose) were
  treated with thiotepa in phosphate-buffered saline at dose levels of 1.15 or 2.3
  mg/kg bw three times a week for a maximum period of 52 weeks followed by an
  observation period resulting in an experimental period of 86 weeks (or only 43 or
  56 weeks in high-dose females and males, respectively, due to mortality).10 Body
  weight depression was observed in high dose animals, particularly in females.
  All males and females of the high dose group were dead by week 56 and 43,
  respectively. At the end of the experimental period, 15 (43%) male and 17 (49%)
  female mice of the low dose group survived compared to 7 (46%) males and 12
  (80%) females in the vehicle control group. Treatment with thiotepa was
6 Thiotepa
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<pre>associated with increased incidences of squamous cell carcinoma (at skin, ear
and preputial gland) in male mice and of haematopoietic tumours (lymphoma
and lymphocytic leukaemia) in male and female mice.
     These tumours are considered to be relevant for humans. Although this study
has limitations (see Table 2 in Annex F), it allows the conclusion that thiotepa is
carcinogenic in B6C3F1 mice.
     In the study of Schmähl & Osswald (1970), 48 male R46 rats were treated
with 1 mg/kg bw thiotepa by intravenous injection once a week for 52 weeks.
Malignant tumours were observed in 9 of the 30 rats that were still alive when
the first tumour appeared.12 These tumours occurred at a variety of sites (see
Table 2 in Annex F). The incidence of malignant tumours in controls was 4/65.
The authors stated that the difference in total tumour incidence between treated
rats and controls was statistically significant (no p value was reported). The
Committee noted that this study has several flaws (short exposure period, only
one dose tested, only one sex used, no statistical analysis performed on
individual tumour types, high early mortality in treated group).
     The Subcommittee did not retrieve animal studies of a more recent date and
agrees with IARC and the NTP that thiotepa is carcinogenic to animals.1,2
Mechanism of genotoxicity
Thiotepa is a direct alkylating agent with potent genotoxic activity in a wide
variety of prokaryotic, lower eukaryotic, and mammalian in vitro and in vivo test
systems. Thiotepa causes DNA damage, mutations, micronucleus formation,
and/or chromosomal aberrations in somatic and germ cells from exposed rodents,
rabbits, and nonhuman primates and chromosomal aberrations in peripheral-
blood lymphocytes from treated humans (NTP RoC 2011; IARC 1990; Chen et
al., 199913; Casciano et al., 1999; Dertinger el el., 2014; Labash et al., 2015).
1,2,13,14-16
     The Subcommittee agrees with IARC that thiotepa is a genotoxic carcinogen
and concludes that a stochastic genotoxic mechanism underlies its
carcinogenicity.
Recommendation
Limited evidence is available that thiotepa is carcinogenic to humans. Moreover,
sufficient evidence is available that thiotepa is carcinogenic to animals. The
Subcommttee recommends to classify thiotepa in category 1A (‘substance
known to be carcinogenic to humans’) (see Annex H). Moreover, the
Evaluation of the Subcommittee on the Classification of Carcinogenic Substances     47
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<pre>  Subcommittee is of the opinion that a stochastic genotoxic mechanism underlies
  carcinogenicity. The Subcommittee recommends health-based calculated
  occupational cancer risk values (HBC-OCRVs) to be calculated for regulatory
  standard setting.
  References (in Annex G)
  IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: Pharmaceutical
  drugs. IARC Monogr Eval Carcinog Risk Chem Man 1990; 50: 123-141.
  NTP 12th Report on Carcinogens. Rep Carcinog 2011; 12: iii-499.
  IARC monographs on the evaluation of the carcinogenic risk of chemicals to man: some aziridines,
  N-, S- & O-mustards and selenium. IARC Monogr Eval Carcinog Risk Chem Man 1975; 9: 85-94.
  Overall evaluations of carcinogenicity: an updating of IARC Monographs volumes 1 to 42. IARC
  Monogr Eval Carcinog Risks Hum Suppl 1987; 7: 368-369.
  Adamson RH, Seiber SM. Chemically induced leukemia in humans. Environ Health Perspect 1981;
  39: 93-103.
  Kaldor JM, Day NE, Pettersson F, Clarke EA, Pedersen D, Mehnert W et al. Leukemia following
  chemotherapy for ovarian cancer. N Engl J Med 1990; 322(1): 1-6.
  Boice JD, Greene MH, Keehn RJ, Higgins GA, Fraumeni JF, Jr. Late effects of low- dose adjuvant
  chemotherapy in colorectal cancer. J Natl Cancer Inst 1980; 64(3): 501- 511.
  Chan P, Sadoff L, Winkley J. Second malignancies following first breast cancer in prolonged thiotepa
  adjuvant chemotherapy. In: SE Salmon, SE Jones, editors. Adjuvant therapy of cancer. Amsterdam:
  Elsevier; 1977: 597-607.
  Kardinal CG, Donegan WL. Second cancers after prolonged adjuvant thiotepa for operable carcinoma
  of the breast. Cancer 1980; 45(8): 2042-2046.
0 Bioassay of thio-TEPA for possible carcinogenicity. Natl Cancer Inst Carcinog Tech Rep Ser 1978;
  58: 1-168.
1 Stoner GD, Shimkin MB, Kniazeff AJ, Weisburger JH, Weisburger EK, Gori GB. Test for
  carcinogenicity of food additives and chemotherapeutic agents by the pulmonary tumor response in
  strain A mice. Cancer Res 1973; 33(12): 3069-3085.
2 Schmähl D, Osswald H. [Experimental studies on the carcinogenic effects of anticancer
  chemotherapeutics and immunosuppressive agents]. Arzneimittelforschung 1970; 20(10): 1461-
  1467.
3 Chen T, Aidoo A, Mittelstaedt RA, Casciano DA, Heflich RH. Hprt mutant frequency and molecular
  analysis of Hprt mutations in Fischer 344 rats treated with thiotepa. Carcinogenesis 1999; 20(2): 269-
  277.
4 Casciano DA, Aidoo A, Chen T, Mittelstaedt RA, Manjanatha MG, Heflich RH. Hprt mutant
  frequency and molecular analysis of Hprt mutations in rats treated with mutagenic carcinogens.
  Mutat Res 1999; 431(2): 389-395.
8 Thiotepa
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<pre>5 Dertinger SD, Phonehepswath S, Avlasevich SL, Torous DK, Mereness J, Cottom J, Bemis JC,
  Macgregor JT. Pig-a gene mutation and micronucleated retuculocyte induction in rats exposed to
  tumorigenic doses of the leukemogenic agents chlorambucil, thiotepa, melphalan, and 1,3-propane
  sultone. Environ Mol Med 2014; 55(4): 299-308.
6 Labash C, Carlson K, Avlasevich SL, Berg A, Bemis JC, MacGregor JT, Dertinger SD. Induction of
  pig-a gene mutant erythrocytes in male and female rats exposed to 1,3-propane sultone, ethyl
  carbamate, or thiotepa. Mutat Res Genet Toxicol Environ Mutagen 2015; 782: 24-29.
  The Subcommittee
  •    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
  •    M.J.M. Nivard
       Molecular Biologist and Genetic Toxicologist, Leiden University Medical
       Center, Leiden
  •    G.M.H. Swaen
       Epidemiologist, Exponent International, Menlo Park, USA
  •    E.J.J. van Zoelen
       Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
  •    G.B. van der Voet, scientific secretary
       Toxicologist, Health Council of The Netherlands, The Hague
  Date meeting: November 11, 2013.
  Evaluation of the Subcommittee on the Classification of Carcinogenic Substances                 49
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<pre>0 Thiotepa</pre>

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<pre> nnex        H
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be as carcinogenic to humans.          2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.26
             Carcinogenic classification of substances by the Committee                                                51
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<pre>2 Thiotepa</pre>

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<pre>nnex I
     Health-based occupational risk
     calculations
     Portengen L. & Heederik D. Department of Environmental Epidemiology,
     Institute for Risk Assessment Sciences, Utrecht University, Utrecht
     Introduction
     Currently, there are no occupational exposure limits for Thiotepa anywhere in the
     world. To derive these occupational exposure limits, four epidemiological
     studies, which included cancer patients who were treated for a primary tumor
     with Thiotepa, have been reviewed to calculate risk values.1-4 No studies are
     available which describe health risks for occupationally exposed individuals.
     The article with the most clearly increased risk after Thiotepa use is the study of
     Kaldor et al. (1990).1 In this study patients received chemotherapy with
     alkylating agents for the treatment of ovarian cancer. A total of 9 patients only
     received Thiotepa as chemotherapeutic agent divided in a group of a median
     dose of 30 mg (4 patients and 5 controls) and a median dose of 600 mg
     (5 patients and 6 controls). Follow-up was more than 9 years. Kaldor et al.
     concluded that treatment with Thiotepa for ovarian cancer increased the risk of
     leukemia with a relative risk of 8.3 for the 30 mg dose group and 9.7 for the 600
     mg group. Patients were compared with patients receiving only surgery and/or
     radiotherapy.
     Three other studies found no significant increase in hematopoietic cancers after
     treatment with Thiotepa. In a study by Chan et al. (1977) 633 patients received
     Thiotepa and were compared with 632 patients who only received surgery and/or
     Health-based occupational risk calculations                                         53
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<pre>               radiotherapy.2 They found 3 cancers cases in the hematopoietic system after
               treatment with Thiotepa and 4 cases in the control group. Also in a study by
               Boice et al. (1980) only 3 cases of leukemia were found after treatment with
               Thiotepa in a group of 470 treated patients.3 The control group consisted of 595
               patients were 4 cases of leukemia were found. In an even smaller study by
               Kardinal and Donegan (1980) just 1 case of leukemia was found in group of 90
               patients who were treated with Thiotepa.4 77 patients were randomly assigned as
               a control group who were treated with surgery alone. None of those patients
               developed leukemia. Follow-up for all these studies was between 5 and 10 years.
 able 1 Number of patients with leukemia after Thiotepa-treatment.
                               Thiotepa-treated patients                Control patients
                                                                        (treated with other therapies than Thiotepa)
                               Total           Leukemia     No Leukemia Total           Leukemia         No Leukemia
Kaldor et al.1                    9              4            5         208               21             187
30 mg)
Kaldor et al.1                  11               5            6         208               21             187
600 mg)
 han et al.2                   632               2          630         630                2             628
388 mg)a
 oice et al.3                  470               3          467         595                4             591
0.8*70 = 56 mg)
Kardinal & Donegan4             90               1           89           77               0              77
11.2*70 = 784 mg)
    different doses are given in the appendix.
               Exposure-Response modelling
               We estimate the dose-response curve for Thiotepa and the cumulative incidence
               of leukemia using a binomial regression model with a log link as follows:
                   E(log(Ci /Ni )) = µ s[i] + β*dosei
               In this formula i indexes the different groups, and C = number of leukemia cases,
               N = total number of subjects, s = the study, and dose = administered dose of
               Thiotepa. µ s[i] is the study-specific (log-transformed) baseline risk (i.e. risk for
               the unexposed), and is included to account for different background risks in the
               different study populations.
               Under this model the Relative Risk (RR) or Cumulative Incidence Ratio (CIR) at
               a dose of 10 mg can be estimated as exp(µ s[i] + β*10)/ exp(µ s[i] + β*0) =
               exp(β*10). The estimated RR [95%CI] at a dose of 10 mg is 1.023 [1.008-1.034].
 4             Thiotepa
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<pre>If we subtract the estimated study-specific baseline risks from the observed
(empirical) risks, we can standardize results from the different studies and plot
the estimated regression line along with study-specific data to asses model fit. In
figure 1 the risks were standardized using the Kaldor study as the reference.
From this figure it is clear that the risks for most groups cannot be estimated very
precisely, but that the regression line is consistent with most of the individual
data points, except for the 30 mg dose group in the Kaldor study. If this group is
removed from the analysis, estimated RR [95%CI] at a dose of 10 mg slightly
changes to 1.024 [1.009-1.036]. This result is due to a decrease in the estimated
baseline risk for the Kaldor et al. study. Based on data from the Kaldor study
alone, the estimated RRs [95%CI] at a dose of 10 mg are 1.024 [1.008-1.035]
and 1.025 [1.010-1.037] including respectively excluding the 30 mg dose-group.
Excluding all data from the Kaldor study results in a lower estimated slope of
1.012 [0.976-1.061], which is no longer statistically significant. The pooled
results are very close to that obtained using only the Kaldor et al. data, which can
be explained by the much greater precision of risk estimates at higher doses for
that study.
Figure 1 Regression plot of the relation between administered dose of Thiotepa and risk of leukemia
(including (solid line) respectively excluding (dotted line) the 30 mg dose group in the Kaldor study).
Health-based occupational risk calculations                                                             55
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<pre>  Excess Risk calculations
  Excess Risk (ER) calculations used information on incidence of leukemia
  (excluding lymphoma’s) in men and women. For a scenario with uniform
  exposure from age 20-65, the ER at age 75 for an exposure of 0.061 mg is
  estimated to be 40*10-6. For a scenario with uniform exposure from age 20-65,
  the ER at age 75 for an exposure of 4.82 mg is estimated to be 40*10-4.
  References (in Annex I)
  Kaldor JM, Day NE, Petterson F, Clarke EA, Pedersen D, Mehnert W et al. Leukemia following
  chemotherapy for ovarian cancer. N Engl J Med 1990; 322 (1): 1-6.
  Chan P, Sadoff L, Winkley J. Second malignancies following first breast cancer in prolonged thiotepa
  adjuvant chemotherapy. In: SE Salmon, SE Jones, editors. Adjuvant therapy of cancer. Amsterdam:
  Elsevier; 1977: 597-607.
  Boice JD, Greene MH, Keehn RJ, Higgins GA, Fraumeni JF, Jr. Late effects of low-dose adjuvant
  chemotherapy in colorectal cancer. J Natl Cancer Inst 1980; 64(3): 501-511.
  Kardinal CG, Donegan WL. Second cancers prolonged adjuvant thiotepa for operable carcinoma of
  the breast. Cancer 1980; 45(8): 2042-2046.
  Appendix
  Kaldor et al. (1990)1:
   30 mg                      Leukemia              No Leukemia
   Thiotepa                         4                     5
   No Thiotepa                     21                    187
   600 mg                     Leukemia              No Leukemia
   Thiotepa                         5                     6
   No Thiotepa                     21                    187
  Chan et al. (1977)2:
                              Leukemia             No Leukemia
   Thiotepa                         2                    630
   No Thiotepa                      2                    628
6 Thiotepa
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<pre>0,6 mg/kg (in first 3 days). After that cumulative doses are assigned to a number
of patients:
      65 patients  38 mg
      71 patients  136 mg
      65 patients  258 mg
      66 patients  390 mg
    366 patients  522 mg
Boice et al. (1980)3:
                        Leukemia          No Leukemia
 Thiotepa                   3                 467
 No Thiotepa                4                 591
0,8 mg/kg (in first 3 days). Assuming an average body weight of 70 kg amounts
to 56 mg in total.
Kardinal & Donegan (1980)4:
                        Leukemia          No Leukemia
 Thiotepa                   1                  89
 No Thiotepa                0                  77
0,8 mg/kg (in first 3 days) + 0,2 mg/kg weekly for 1 year (total = 11,2 mg/kg).
Assuming an average body weight of 70 kg amounts to 784 mg in total.
Health-based occupational risk calculations                                       57
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<pre>8 Thiotepa</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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