<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>Iodoform
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 Iodoform
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-1480/JR/pg/246-U11
Bijlagen                :1
Datum                   : 12 december 2007
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van iodoform. Het
maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen worden geclas-
sificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen 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>Iodoform
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. 2007/08OSH, The Hague, December 12, 2007
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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. Iodoform; Evaluation of the carcinogenicity
and genotoxicity. The Hague: Health Council of the Netherlands, 2007; publica-
tion no. 2007/08OSH.
all rights reserved
ISBN: 978-90-5549-672-3
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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 studies 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 19
    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   Carcinogenic classification of substances by the committee 33
E   Guideline 93/21/EEG of the European Union 35
8   Iodoform
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie iodoform
onder de loep. Iodoform is een antiseptisch en desinfecterend middel.
De commissie meent dat iodoform onvoldoende is onderzocht. Hoewel de gege-
vens het niet toelaten de stof te classificeren als kankerverwekkend voor de mens
of als moet beschouwd worden als kankerverwekkend voor de mens, is de com-
missie van mening dat waakzaamheid geboden is. De commissie adviseert
daarom iodoform te classificeren als verdacht kankerverwekkend voor de mens.
Volgens de richtlijnen van de Europese Unie komt dit overeen met een classifica-
tie in categorie 3. Binnen deze categorie komt de situatie het meest overeen met
subcategorie b.
Samenvatting                                                                      9
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<pre>10 Iodoform</pre>

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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 iodoform.
Iodoform is an antisepticum and desinfectance.
The committee concludes that iodoform has been insufficiently investigated.
While the available data do not warrant a classification as carcinogenic to
humans or as should be regarded as carcinogenic to humans, they indicate that
there is cause for concern for man. This recommendation corresponds to EU
classification in category 3. This situation is, furthermore, comparable with sub-
category b of this category.
Executive summary                                                                  11
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<pre>12 Iodoform</pre>

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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 with reference to an EU-directive (see annex A and E). In addition to classi-
        fying substances, the Health Council also assesses the genotoxic properties of the
        substance in question. The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see annex D). This report contains
        the evaluation of the carcinogenicity of iodoform.
1.2     Committee and procedures
        The evaluation is performed by the committee on Classifying Carcinogenic Sub-
        stances 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 J.Th.J. Stouten and M.I.
        Willems, from the Department of Occupational Toxicology of the TNO Nutrition
        and Food Research, by contract with the Ministry of Social Affairs and Employ-
        ment.
        Scope                                                                               13
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<pre>         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). In the case of iodoform, no such an IARC-monograph is
    available.
         Data were retrieved from the online databases Medline, Toxline, Chemical
    Abstracts, and RTECS. The last updated online search was in March 2007. Data,
    which were considered relevant according to the committee, were included in
    this report.
14  Iodoform
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<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        Iodoform is used as a germicide in human medicine.1 Furthermore, in veterinary
        medicine, it is used as an antiseptic, and a disinfectant on superficial lesions and
        for lesions in the female reproductive tract. Occupational exposure may occur
        during manufacturing or packaging, or during the final preparation and adminis-
        tration to patients or animals.
             Below is given the identity and some of its physico-chemical properties.1
        Name                      : iodoform
        CAS no                    : 75-47-8
        EINECS no                 : 200-874-5
        EEC no                    : -
        CAS name; IUPAC name :      methane, triiodo; triiodomethane
        Description               : yellow or greenish-yellow powder or crystalline solid
        Chemical formula          : CHI3
        Molecular weight          : 393.78
        Boiling point (101.3 kPa) : decomposes at high temperature with evolution of iodine (210 °C)
        Melting point (101.3 kPa) : 119-123 °C
        Vapour pressure           : not available
        Relative density          : 4.01 g/mL (20°/4°C)
        Solubility in water       : slightly soluble in water (0.1 g/L at 25°C)
        General information                                                                          15
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<pre>    Solubility in organic sol- : soluble in ether (134 g/L at 25°C), ethyl alcohol (78 g/L at 78°C), chlo-
    vents                        roform, benzene, acetone, ethanol, diethyl ether, olive oil, carbon disul-
                                 phide, and glycerine
    Conversion factors         : 1 ppm = 16.4 mg/m3
    (101.3 kPa; 20°C)            1 mg/m3 = 0.06 ppm
2.2 IARC classification
    IARC did not evaluate the carcinogenic and genotoxic properties of iodoform.
16  Iodoform
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<pre>Chapter 3
        Carcinogenicity studies
3.1     Observations in humans
        No data were available to evaluate the carcinogenicity of iodoform in humans.
3.2     Carcinogenicity studies in animals
        The American National Cancer Institute (1978) reported on an animal carcinoge-
        nicity study, in which Osborne-Mendel rats and B6C3F1 mice (n=50/group/sex/
        strain) received iodoform by oral administration.2 During the study, dose levels
        were adjusted (decreased in male rats after 28 weeks, increased in female rats
        after 18 weeks, increased in male and female mice after 8 and 10 weeks) result-
        ing in the administration of time-weighted average doses of 142 and 71 mg/kg
        bw per day for male rats, 55 and 27 mg/kg bw per day for female rats, and 93 and
        47 mg/kg bw per day for male and female mice. They received the test com-
        pound for 5 days per week during 78 weeks, and were thereafter left untreated
        during 34 weeks for rats and 13 or 14 weeks for mice. For both species, there
        were vehicle- and untreated-control groups (n=20/sex/control group).
            In male rats, a significant dose-related high mortality was observed (mortal-
        ity high dose: 50% by week 46; mortality low dose: 52% by week 76), indicating
        that the maximum tolerated dose was exceeded. Unfortunately, the increased
        mortality was not explained further in the report, possibly due to a lack of param-
        eters tested, i.e., haematology and clinical chemistry. In these animals, there was
        Carcinogenicity studies                                                             17
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<pre>   an increase in the incidence of follicular cell tumours (carcinomas + adenomas)
   of the thyroid, despite the high mortality (incidence in vehicle control, low-, and
   high-dose males: 0/16, 8/35*, 4/18, respectively; * p<0.05 Fischer exact test).
   The incidences of thyroid tumours in both test groups were much higher than his-
   torical control incidences from the test facility (historical control incidence: 11
   thyroid tumours/200 male rats). Incidences of non-neoplastic changes in the thy-
   roid (viz., follicular cysts, follicular-cell hyperplasia) were not or only weakly
   indicative of a relationship between exposure and thyroid pathology. During the
   dosing period, body weights of the exposed male animals were slightly lower
   than those of controls (graphic presentation only). Data on organ weights were
   not presented. Finally, there were no other differences between exposed and con-
   trol male rats with respect to inflammatory, degenerative, or proliferative lesions.
       In exposed female rats and exposed male and female mice, no toxicity, as
   presented by body weight changes or clinical signs, was observed, indicating that
   these animals may not have been treated with the maximum tolerated dose. No
   effect on thyroid was observed in female rats and in male and female mice. The
   absence of a thyroid effect in female rats may have been caused by the lower
   doses used. No other treatment-related toxic or neoplastic effects were identified.
       No other animal carcinogenicity studies were available to the committee.
18 Iodoform
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<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        Iodoform was tested in the Salmonella typhimurium mutagenicity assay. A sum-
        mary of the outcomes is presented in table 4.1. Overall, iodoform showed to be
        mutagenic in various strains.
            In Syrian hamster embryo cells, iodoform induced a treatment-related
        increase in unscheduled DNA synthesis (dose range tested: 1-30 µg/mL), and
        morphological transformations (dose range: 3-30 µg/mL; exposure duration: 48
        hours).3 It furthermore increased, in a dose-related manner, the frequency of sis-
        ter chromatid exchanges (dose range: 1-30 µg/mL; exposure duration: 18-20 h,
        p<0.05).3 However, this increase never reached a double level of the vehicle-con-
        trol.
            Hikiba et al. (2005) did not find increased levels of chromosomal aberrations
        in Syrian hamster embryo cells after iodoform exposure (0-240 μM).4 The com-
        mittee noted the low relative colony forming efficiency at the higher exposure
        doses.
            No other data on the genotoxicity in vitro was available.
4.2     In vivo assays
        No genotoxicity studies using in vivo test assays were available.
        Mutagenicity and genotoxicity                                                      19
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<pre>   Table 4.1 Iodoform mutagenicity in Salmonella typhimurium test.
   Salmonella           rat liver S9 mix   dose applied (μg/plate) score reference
   typhimurium strain
   TA98                 -                  10 – 333                +     Haworth et al. 19835
                        +                  10 – 888                +
                        + (hamster S9)     10 – 444                +
   TA100                -                  10 – 333                +     Haworth et al. 19835
                        +                  10 – 888                +
                        + (hamster S9)     10 – 444                +
   TA1535               -                  10 – 333                -     Haworth et al. 19835
                        +                  10 – 888                +
                        + (hamster S9)     10 – 444                -
   TA1537               -                  10 – 333                -     Haworth et al. 19835
                        +                  10 – 888                +
                        + (hamster S9)     10 – 444                -
   BA13 (L-arabinose    -                  < 1.8 μmol/plate        +     Roldán-Arjona et al.
   resistance test)     +                  < 1.8 μmol/plate        +     1991 and 19936,7
20 Iodoform
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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        In the literature, no case-reports or observational studies were available on the
        possible carcinogenicity of iodoform in humans. So far known, there is only one
        carcinogenicity study performed on animals. In that study, iodoform induced
        tumours of the thyroid in male rats, but not in female rats or in mice. Overall,
        there is insufficient evidence for carcinogenicity of iodoform, but the findings in
        the animal study worries the committee.
            Iodoform clearly induced mutations in vitro, which indicates that iodoform
        has mutagenic and genotoxic potential. The findings concerning clastogenicity
        are controversial and limited. No data are available on the possible mutagenic
        and genotoxic properties of iodoform by in vivo assays.
            The committee did not find information that the observations in the animal
        study, and the genotoxic action in the in vitro assays, would not occur in humans.
5.2     Recommendation for classification
        The committee concludes that iodoform has been insufficiently investigated.
        While the available data do not warrant a classification as carcinogenic to
        humans or as should be regarded as carcinogenic to humans, they indicate that
        there is cause for concern for man. This recommendation corresponds to EU
        Classification                                                                      21
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<pre>   classification in category 3. This situation is, furthermore, comparable with sub-
   category b of this category.
22 Iodoform
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<pre>  References
1 Richardson M, Gangolli S. I46 Iodoform. In: Dictionary of substances and their effects. Volume 2.
  Cambridge, the UK: Royal Society of Chemistry; 1993.
2 National Cancer Institute. Bioassay of iodoform for possible carcinogenicity (CAS No. 75-47-8).
  Natl Cancer Inst Carcinog Tech Rep Ser 1978; 110: 1-107.
3 Suzuki H. [Assessment of the carcinogenic hazard of 6 substances used in dental practices. (II)
  Morphological transformation, DNA damage and sister chromatid exchanges in cultured Syrian
  hamster embryo cells induced by formocresol, iodoform, zinc oxide, chloroform, chloramphenicol,
  tetracycliine hydrochloride] In Japanese. Shigaku 1987; 74: 1385-1403.
4 Hikiba H, Watanabe E, Barrett JC, Tsutsui T. Ability of fourteen chemical agents used in dental
  practice to induce chromosome aberrations in Syrian hamster embryo cells. J Pharmacol Sci 2005;
  97(1): 146-152.
5 Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E. Salmonella mutagenicity test results for
  250 chemicals. Environ Mutagen 1983; 5 Suppl 1: 1-142.
6 Roldan-Arjona T, Garcia-Pedrajas MD, Luque-Romero FL, Hera C, Pueyo C. An association
  between mutagenicity of the Ara test of Salmonella typhimurium and carcinogenicity in rodents for
  16 halogenated aliphatic hydrocarbons. Mutagenesis 1991; 6(3): 199-205.
7 Roldan-Arjona T, Pueyo C. Mutagenic and lethal effects of halogenated methanes in the Ara test of
  Salmonella typhimurium: quantitative relationship with chemical reactivity. Mutagenesis 1993; 8(2):
  127-131.
  References                                                                                          23
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<pre>24 Iodoform</pre>

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<pre>A Request for advice
B The committee
C Comments on the public review draft
D Carcinogenic classification of substances by the committee
E Guideline 93/31/EEG of the European Union
  Annexes
                                                             25
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<pre>26 Iodoform</pre>

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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 Iodoform
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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
          Center, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Nutrition and Food Research, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis,
          University 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 Iodoform
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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:
      • G. Jonkers, Vereniging van Verf en Drukinktfabrikanten, the Netherlands;
      • 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 Iodoform</pre>

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<pre>Annex         D
              Carcinogenic classification of
              substances 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                                             33
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<pre>Annex E
      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                                                             35
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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.
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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                                                                 37
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