<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>Trichlormethine hydrochloride
Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Gezondheidsraad                                          Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : Aanbieding advies Trichlormethine hydrochloride
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-5137/JR/pg/246-J12
Bijlagen                :1
Datum                   : 1 april 2008
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van trichlormethine
hydrochloride. Het maakt deel uit van een uitgebreide reeks waarin kankerverwekkende
stoffen worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stof-
fen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Het advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is voorgelegd aan de Commissie GBBS en vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en
Milieubeheer.
Hoogachtend,
prof. dr. J.A. Knottnerus
Bezoekadres                                                                 Postadres
Parnassusplein 5                                                            Postbus 16052
2 5 11 V X D e n          Haag                                              2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1                                      Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : j o l a n d a . r i j n k e l s @ g r. n l                    w w w. g r. n l
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<pre></pre>

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<pre>Trichlormethine hydrochloride
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the classification of carcinogenic substances of the
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2008/10OSH, The Hague, April 1, 2008
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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...” (Section
22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Housing, Spatial Planning & the Environment, Social
Affairs & Employment, and Agriculture, Nature & Food Quality. 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 gov-
ernment policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
  I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Trichlormethine hydrochloride; Evaluation of
the carcinogenicity and genotoxicity. The Hague: Health Council of the Nether-
lands, 2008; publication no. 2008/10OSH.
all rights reserved
ISBN: 978-90-5549-697-6
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedures 13
1.3 Data 14
2   General information 15
2.1 Identity and physico-chemical properties 15
2.2 IARC classification 16
3   Carcinogenicity 17
3.1 Observations in humans 17
3.2 Carcinogenicity studies in animals 17
4   Mutagenicity and genotoxicity 19
4.1 In vitro assays 19
4.2 In vivo assays 20
    Contents                                    7
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<pre>5   Classification 21
5.1 Evaluation of data on carcinogenicity and genotoxicity 21
5.2 Recommendation for classification 21
    References 23
    Annexes 25
A   Request for advice 27
B   The committee 29
C   Comments on the public review draft 31
D   IARC Monograph 33
E   Carcinogenic classification of substances by the committee 35
F   Guideline 93/21/EEG of the European Union 37
8   Trichlormethine hydrochloride
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie trichlorme-
thine hydrochloride onder de loep. De stof wordt onder andere gebruikt als cyto-
staticum bij de behandeling van kanker en artritis, maar ook bij de productie van
kleurstoffen voor textiel.
Op basis van de beschikbare gegevens leidt de commissie af dat trichlormethine
hydrochloride beschouwd moet worden als kankerverwekkend voor de mens. Dit
is vergelijkbaar met een classificatie in categorie 2 volgens de richtlijnen van de
Europese Unie. De commissie is verder van mening dat de stof een stochastisch
genotoxisch werkingsmechanisme heeft.
Samenvatting                                                                        9
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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of sub-
stances to which workers are occupationally exposed. The evaluation is per-
formed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council, here-
after called the committee. In this report, the committee evaluated trichlorme-
thine hydrochloride. The agent is used as a cytostatic agent in the treatment of
cancer and arthritis, and is furthermore used in the production of textile dyes.
Based on the available information, the committee is of the opinion that trichlo-
rmethine hydrochloride should be considered as carcinogenic to humans. This
recommendation is comparable to the EU classification in category 2. The com-
mittee is furthermore of the opinion that trichlormethine hydrochloride acts by a
stochastic genotoxic mechanism.
Executive summary                                                                 11
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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a classifica-
        tion (see Annex A). The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see Annex E). The criteria used for
        classification are partly based on an EU-directive (see Annex F). In addition to
        classifying substances, the Health Council also assesses the genotoxic properties
        of the substance in question.
        This report contains the evaluation of the carcinogenicity of trichlormethine
        hydrochloride.
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the committee. The members of the committee
        are listed in Annex B. The first draft was prepared by I.A. van de Gevel and M.I.
        Willems, from the Department of Occupational Toxicology of the TNO Nutrition
        Scope                                                                               13
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<pre>    and Food Research, by contract with the Ministry of Social Affairs and Employ-
    ment.
         In 2007 the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex C. The committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the committee is standardly based on sci-
    entific data, which are publicly available. The starting points of the committees’
    reports are, if possible, the monographs of the International Agency for Research
    on Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the committee when
    these are considered most relevant in assessing the carcinogenicity and genotox-
    icity of the substance in question. In the case of trichlormethine hydrochloride,
    such an IARC-monograph is available, of which the summary and conclusion of
    IARC is inserted in Annex D.
         More recently published data were retrieved from the online databases Med-
    line, Toxline, Chemical Abstracts, and RTECS. The last updated online search
    was in June 2007. The new relevant data were included in this report.
14  Trichlormethine hydrochloride
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<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        Trichlormethine hydrochloride belongs to the class of nitrogen mustards, which
        are related to mustard gas.
            The agent is used as a cytostatic agent in the treatment of certain cancers,
        such as Hodgkin’s disease and leukemia. It is furthermore tested for use in the
        treatment of arthritis. Moreover, it is used as a fixing agent in textile dyes.1 Occu-
        pational exposure may occur during manufacturing or packaging, or during the
        final preparation and administration to patients.
            Below is given the identity and some of its physical and chemical properties.1
        Chemical name              :  Trichlormethine hydrochloride
        CAS registry number        :  817-09-4
        EEC number                 :  212-442-3
        IUPAC name                 :  Ethanamine-2-chloro-N,N-bis(2-chloroethyl) hydrochloride
        Synonyms                   :  HN3; HN3 hydrochloride; NSC-30211; R-47; SK-100; tri(β-
                                      chloroethyl)amine hydrochloride; trichlorotriethylamine hydro-
                                      chloride; 2,2', 2''-trichlorotriethylamine hydrochloride; trimus-
                                      tine; trimustine hydrochloride; tris(2-chloroethyl)-amine
                                      hydrochloride; tri (β-chloroethyl)amine hydrochloride; tri(2-
                                      chloroethyl)amine monohydrochloride; tris(β-chloroet-
                                      hyl)amine monohydrochloride; tris-N-lost; TS-160; Lekamin;
                                      Sinalost; Trichlormethine; Trillekamin; Trimitan
        General information                                                                             15
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<pre>    Description               :   Crystals prepared by treating triethanolamine with thionyl chlo-
                                  ride. Trichlormethine is not known to occur naturally
    Molecular formula         :   C6H12Cl3N.HCl
    Structure                 :
    Molecular weight          :   241.0
    Melting point             :   130-131 °C
    Solubility                :   Very soluble in water; soluble in ethanol
    Stability                 :   Aqueous solutions deteriorate rapidly
2.2 IARC classification
    In 1990, IARC concluded that there is sufficient evidence for the carcinogenicity
    of trichlormethine hydrochloride in animals, but that no data were available from
    studies in humans.1 Therefore, it classified the agent in group 2B, indicating that
    it possibly carcinogenic to humans.
16  Trichlormethine hydrochloride
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<pre>Chapter 3
        Carcinogenicity
3.1     Observations in humans
        No data were available to evaluate the carcinogenicity of trichlormethine hydro-
        chloride in humans.
3.2     Carcinogenicity studies in animals
        Animal carcinogenicity data is mainly limited to dermal exposure.
             The Working Group of IARC evaluated the study of Boyland and Horning
        (1949).1,2 In that study, twenty mice (strain not specified) received subcutaneous
        injections of the agent at a dose of 1 mg/kg bw, once per week for ten weeks. At
        the end of the exposure period only four mice were still alive. At about 18
        months of survival, three of these mice had tumours in the lungs (one animal,
        adenoma; two animals, carcinomas), and one of them had a spindle-cell sarcoma
        at the site of the injection. A control group of forty mice was killed between 14
        and 18 months. In this group six animals had lung adenomas, two had hepato-
        mas, and three had enlarged lymph nodes. The working group noted the very
        small number of treated animals that survived.
             Sykora et al. (1981) treated groups of ten male and ten female random-bred
        SPF Wistar rats with trichlormethine hydrochloride, by giving them daily subcu-
        taneous injections at doses of 0.1 or 0.25 mg/kg bw, or by given them weekly
        subcutaneous injections at a dose of 1 mg/kg bw, for six months.3 After the end of
        Carcinogenicity                                                                    17
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<pre>   exposure the animals were observed for one year before the experiment was ter-
   minated. In males receiving daily injections survival was decreased. The main
   types of tumours observed were spindle-cell sarcomas at the injection site: 70%
   in 0.1 mg/kg bw group, 79% in 0.25 mg/kg bw group, and 45% in 1.0 mg/kg bw
   group. Furthermore, 21% of the animals receiving daily injections of 0.25 mg/kg
   bw had mucus-secreting intestinal adenocarcinomas. No tumours were observed
   in a nontreated group.
       The same group also administered trichlormethine hydrochloride to newborn
   rats by intraperitoneal (0.27 mg/kg bw) or subcutaneous (0.005 mg/kg bw) injec-
   tions, from the first day after birth up to 20 days.4 After the last injection the ani-
   mals were observed for one year. No increased tumour incidences were
   observed. The committee does not consider this study for evaluation on carcino-
   genicity, because of the short exposure time and the insufficient reporting on
   study design and results.
18 Trichlormethine hydrochloride
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<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        The Working Group of IARC reported on induction of forward point mutations
        in Schizosaccharomyces pombe strains.5 Furthermore, trichlormethine clearly
        induced forward mutations in Escherichia coli K12/343/113 strain, when a 24-
        hour period of liquid holding was interpolated between treatment and growth
        phase.6 Trichlormethine hydrochloride did not induce mutations in the conven-
        tional Ames test using Salmonella typhimurium strains TA97, TA98, TA100 and
        TA1535, in the presence nor in the absence of an exogenous metabolic system.7
            Using a liquid micromethod modification of the DNA-repair test, Marhan
        (1995) found positive outcomes when E. coli strains WP100, CM571 and
        CM611 were used, in the presence and absence of an exogenous metabolic sys-
        tem.8 Negative scores were found in E. coli strains WPuvrA, WP67, and CM561.
        Trichlormethine hydrochloride inhibited DNA synthesis, and induced mutations
        in the hprt locus of Chinese hamster V79 cells.1,9 The Working Group also
        reported on increased frequencies of chromosomal aberrations in transplanted
        Walker rat carcinoma cells, and in transplanted Ehrlich and Krebs tumour cells
        following intraperitoneal injection into animals carrying these cells.1 However,
        detailed evaluation was not possible due to insufficient data presentation.
        Mutagenicity and genotoxicity                                                    19
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<pre>4.2 In vivo assays
    Trichlormethine hydrochloride showed to be highly mutagenic in the sex-linked
    lethal test using wild type Drosophila melanogaster flies.10,11 It also decreased
    fertility, which was probably related to chromosome rearrangements. However,
    regarding the latter, the authors remarked that the agent was tested on a too small
    scale to make the results convincing.
    A single intraperitoneal injection of 5 mg trichlormethine hydrochloride/kg bw
    led to dominant lethal mutations in male mice.1,12 Also, intraperitoneal injections
    at a dose of 0.5 mg/kg bw, for seven consecutive days, resulted in an increased
    frequency of dominant lethals.13 The dose tested was equivalent to the human
    therapeutic dosage, and is below the LD50 for this compound. Furthermore, the
    results in the latter study suggest that the agent not only showed genotoxic, but
    also cytotoxic effects. The dominant lethal test is used to demonstrate genetic
    risk through chromosome segregation or integrity, and is mainly associated to
    chromosomal breaks.
20  Trichlormethine hydrochloride
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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data on the genotoxicity and carcinogenicity of trichlormethine hydrochlo-
        ride in humans were available, nor were there any data available on inhalation
        exposure in animals.
            A few animal studies concerned subcutaneous injections of the agent. In
        these studies increased incidences of tumours at the site of injection were
        observed, as well as tumour development at other sites of the body. Although the
        study designs and reporting were limited, the overall picture gives sufficient evi-
        dence for the carcinogenicity of trichlormethine hydrochloride.
            The agent showed to be mutagenic in in vitro and in vivo bioassays, but not in
        the conventional Ames test. It also showed clastogenic activity in vitro. Overall,
        based on the presented results, the committee considers trichlormethine hydro-
        chloride as a genotoxic compound that acts by a stochastic mechanism.
            The committee did not find indications that the observations in animals, and
        the proposed carcinogenic mechanism would not occur in humans.
5.2     Recommendation for classification
        Based on the available information, the committee is of the opinion that trichlo-
        rmethine hydrochloride should be considered as carcinogenic to humans. This
        recommendation is comparable to the EU classification in category 2. The com-
        Classification                                                                      21
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<pre>   mittee is furthermore of the opinion that trichlormethine hydrochloride acts by a
   stochastic genotoxic mechanism.
22 Trichlormethine hydrochloride
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<pre>  References
1 International Agency for Research on Cancer. Trichlormethine (trimustine hydrochloride). IARC
  Monographs, Evaluationa on carcinogenic risk in humans, Lyon, France, Volume 50; pp 143-149;
  1990.
2 Boyland E, Horning ES. The induction of tumours with nitrogen mustards. Br J Cancer 1949; 3: 118-
  123.
3 Sykora I, Vortel V, Marhan O, Dynterova A. Carcinogenicity of trichloromethine hydrochloride (TS-
  160 Spofa) and morphological damage after its intraamniotic injection. Neoplasma 1981; 28(5): 565-
  574.
4 Sykora I, Vortel V. Comparability of results of postnatal and long-term tests for carcinogenicity.
  Neoplasma 1993; 40(5): 321-327.
5 International Agency for Research on Cancer. Some azaridines, N-, S-, and O-mustards and
  selenium. IARC Monographs on teh evaluation of the carcinogenic risk of chemicals to man, Lyon,
  France, Volume 9, pp 229-234; 1975.
6 Zijlstra JA. Liquid holding increases mutation induction by formaldehyde and some other cross-
  linking agents in Escherichia coli K12. Mutat Res 1989; 210(2): 255-261.
7 Marhan J. Mutagenicity of cytostatic drugs in a bacterial system. I. Ames test. Folia Microbiol
  (Praha) 1995; 40(5): 457-461.
8 Marhan J. Mutagenicity of cytostatic drugs in a bacterial system. II. DNA-repair test. Folia Microbiol
  (Praha) 1995; 40(5): 462-466.
9 Slamenova D, Dusinska M, Budayova E, Gabelova A. The genetic effects of the cytostatic drug
  TS160 on Chinese hamster fibroblasts in vitro. Mutat Res 1983; 116(3-4): 431-440.
  References                                                                                             23
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<pre>10 Auerbach C, Robson JM, Carr JG. The chemical production of mutations. Science 1947; 105(2723):
   243-247.
11 Auerbach C, Robson JM. Tests of chemical substances for mutagenic action. Proc R Soc Edinburgh
   1947; 62B: 284-291.
12 Sykora I, Gandalovicova D. Dominant-lethal assay of selected cytostatics. Neoplasma 1978; 25(5):
   523-533.
13 Sykora I, Gandalovicova D. Trichlormethine hydrochloride and correlation of its mutagenic and toxic
   effects on male germ cells in mice. Mutat Res 1992; 266(2): 291-297.
24 Trichlormethine hydrochloride
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<pre>A Request for advice
B The committee
C Comments on the public review draft
D IARC Monograph
E Carcinogenic classification of substances by the committee
F Guideline 93/21/EEG of the European Union
  Annexes
                                                             25
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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
      Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
      and Employment wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
      tal advisory structure, to improve the integration of the development of recommendations for health
      based occupation standards and the development of comparable standards for the general population.
      A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
      by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
      exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
      (MAC-values) for substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as fol-
      lows:
      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                                                                                        27
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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 calcu-
       lated 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 classifica-
       tion 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.
28 Trichlormethine hydrochloride
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<pre>Annex B
      The committee
      •   G..J. Mulder, chairman
          emeritus professor of toxicology, Leiden University, Leiden
      •   P.J. Boogaard
          toxicologist, SHELL International BV, The Hague
      •   Ms. M.J.M. Nivard
          molecular biologist and genetic toxicologist, Leiden University Medical Cen-
          ter, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Quality of Life, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis, Uni-
          versity Medical Center, Leiden
      •   E.J.J. van Zoelen
          professor of cell biology, Radboud University Nijmegen, Nijmegen
      •   J.M. Rijnkels, scientific secretary
          Health Council of the Netherlands, The Hague
      The committee consulted an additional expert, Prof. dr. G. Mohn, working at
      Department of Radiation Genetics and Chemical Mutagenesis of the University
      of Leiden, with respect to the genotoxic data.
      The committee                                                                    29
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<pre>   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health Coun-
   cil Committee. Transparency regarding possible conflicts of interest is nonethe-
   less important, both for the President 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 mate-
   rial 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 establishment meeting the declarations issued are dis-
   cussed, so that all members of the Committee are aware of each other’s possible
   interests.
30 Trichlormethine hydrochloride
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2007 for public review. The follow-
      ing organisations and persons have commented on the draft document:
      • E. González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain;
      • R.D. Zumwalde, National Institute for Occupational Safety and Health, the
          USA.
      Comments on the public review draft                                               31
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<pre>32 Trichlormethine hydrochloride</pre>

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<pre>Annex D
      IARC Monograph
      Vol.: 50 (1990) (p. 143)1
      CAS No.: 817-09-4
      Chem. Abstr. Name: Ethanamine-2-chloro-N,N-bis(2-chloroethyl)
      hydrochloride
      Summary of Data Reported and Evaluation
      Exposure data
      Trichlormethine is a cytostatic agent that has been used since 1946 for the treat-
      ment of leukaemia and lymphoma.
      Experimental carcinogenicity data
      Trichlormethine was tested for carcinogenicity by subcutaneous injection in mice
      and rats. The study in mice was inadequate for evaluation. In rats, trichlorme-
      thine induced a high incidence of sarcomas (mostly spindle-cell type) in animals
      of each sex at the site of subcutaneous injection, as well as a few intestinal ade-
      nocarcinomas; neither tumour type was seen in controls.
      IARC Monograph                                                                      33
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<pre>   Human carcinogenicity data
   No data were available to the Working Group.
   Other relevant data
   In single studies, trichlormethine induced dominant lethal mutations in mice and
   gene mutations in Chinese hamster cells.
   Evaluation
   There is sufficient evidence for the carcinogenicity of trichlormethine in experi-
   mental animals.
       No data were available from studies in humans on the carcinogenicity of
   trichlormethine.
   Overall evaluation
   Trichlormethine is possibly carcinogenic to humans (Group 2B).
   Previous evaluations: Vol. 9 (1975) (p. 229); Suppl. 7 (1987) (p. 73)
34 Trichlormethine hydrochloride
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<pre>Annex         E
              Carcinogenic classification of sub-
              stances by the committee
The committee expresses its conclusions in the form of standard phrases:
Judgment of the committee                                                                       Comparable with EU class
This compound is known to be carcinogenic to humans                                             1
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound should be regarded as carcinogenic to humans                                      2
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound is a suspected human carcinogen.                                                  3
•   This compound has been extensively investigated. Although there is insufficient evidence    (A)
    for a carcinogenic effect to warrant a classification as ‘known to be carcinogenic to
    humans’ or as ‘should be regarded as carcinogenic to humans’, they indicate that there is
    cause for concern.
•   This compound has been insufficiently investigated. While the available data do not war-    (B)
    rant a classification as ‘known to be carcinogenic to humans’ or as ‘should be regarded as
    carcinogenic to humans’, they indicate that there is a cause for concern.
This compound cannot be classified                                                              not classifiable
•   There is a lack of carcinogenicity and genotoxicity data.
•   Its carcinogenicity is extensively investigated. The data indicate sufficient evidence sug-
    gesting lack of carcinogenicity.
              Carcinogenic classification of substances by the committee                                             35
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<pre>Annex F
      Guideline 93/21/EEG of the European
      Union
      4.2            Criteria for classification, indication of danger, choice of risk phrases
      4.2.1          Carcinogenic substances
      For the purpose of classification and labelling, and having regard to the current state of knowledge,
      such substances are divided into three categories:
      Category 1:
      Substances known to be carcinogenic to man.
      There is sufficient evidence to establish a causal association between human exposure to a substance
      and the development of cancer.
      Category 2:
      Substances which should be regarded as if they are carcinogenic to man.
      There is sufficient evidence to provide a strong presumption that human exposure to a substance may
      result in the development of cancer, generally on the basis of:
      •    appropriate long-term animal studies
      •    other relevant information.
      Guideline 93/21/EEG of the European Union                                                             37
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<pre>   Category 3:
   Substances which cause concern for man owing to possible carcinogenic effects but in
   respect of which the available information is not adequate for making a satisfactory assess-
   ment.
   There is some evidence from appropriate animal studies, but this is insufficient to place the substance
   in Category 2.
   4.2.1.1       The following symbols and specific risk phrases apply:
   Category 1 and 2:
   T; R45 May cause cancer
   However for substances and preparations which present a carcinogenic risk only when inhaled, for
   example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with
   skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be
   used:
   T; R49 May cause cancer by inhalation
   Category 3:
   Xn; R40 Possible risk of irreversible effects
   4.2.1.2       Comments regarding the categorisation of carcinogenic substances
   The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into
   Categories 2 and 3 is based primarily on animal experiments.
   For classification as a Category 2 carcinogen either positive results in two animal species should be
   available or clear positive evidence in one species; together with supporting evidence such as geno-
   toxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship
   with other known carcinogens, or data from epidemiological studies suggesting an association.
38 Trichlormethine hydrochloride
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<pre>Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is
     insufficient for classification in Category 2. Additional experiments would not be expected to
     yield further relevant information with respect to classification.
b    substances which are insufficiently investigated. The available data are inadequate, but they
     raise concern for man. This classification is provisional; further experiments are necessary
     before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experimental tumour induction in view of possible human exposure. These argu-
ments, especially in combination, would lead in most cases to classification in Category 3, even
though tumours have been induced in animals:
•    carcinogenic effects only at very high levels exceeding the 'maximal tolerated dose'. The maxi-
     mal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go
     along with physical changes such as about 10% retardation in weight gain;
•    appearance of tumours, especially at high dose levels, only in particular organs of certain species
     is known to be susceptible to a high spontaneous tumour formation;
•    appearance of tumours, only at the site of application, in very sensitive test systems (e.g. i.p. or
     s.c. application of certain locally active compounds);
•    if the particular target is not relevant to man;
•    lack of genotoxicity in short-term tests in vivo and in vitro;
•    existence of a secondary mechanism of action with the implication of a practical threshold above
     a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological
     regulation, chronic stimulation of cell proliferation;
•    existence of a species - specific mechanism of tumour formation (e.g. by specific metabolic
     pathways) irrelevant for man.
For a distinction between Category 3 and no classification arguments are relevant which exclude a
concern for man:
•    a substance should not be classified in any of the categories if the mechanism of experimental
     tumour formation is clearly identified, with good evidence that this process cannot be extrapo-
     lated to man;
•    if the only available tumour data are liver tumours in certain sensitive strains of mice, without
     any other supplementary evidence, the substance may not be classified in any of the categories;
•    particular attention should be paid to cases where the only available tumour data are the occur-
     rence of neoplasms at sites and in strains where they are well known to occur spontaneously with
     a high incidence.
Guideline 93/21/EEG of the European Union                                                                 39
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<br><br>