<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>4,4’-Methylene dianiline
Health based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp           : Aanbieding advies
Uw kenmerk          : DGV/BMO-U-932542
Ons kenmerk         : U 1888/AB/jt/459-H31
Bijlagen            :1
Datum               : 6 september 2000
Bij brief van 3 december 1993, nr DGV/BMO-U-932542, verzocht de Staatssecretaris
van Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en
Werkgelegenheid om gezondheidskundige advieswaarden af te leiden ten behoeve van de
bescherming van beroepsmatig aan stoffen blootgestelde personen.
Per 1 januari 1994 heeft mijn voorganger daartoe een commissie ingesteld die de werk-
zaamheden voortzet van de Werkgroep van Deskundigen (WGD). De WGD was een
door genoemde minister ingestelde adviescommissie.
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - een publicatie
van de commissie aan over 4,4'-methyleen dianiline.
Deze publicatie heb ik heden ter kennisname aan de Minister van Volksgezondheid Wel-
zijn en Sport en aan de Minister van Volkshuisvesting Ruimtelijke Ordening en Milieu-
beheer gestuurd.
w.g
prof. dr JJ Sixma
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<pre></pre>

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<pre>4,4’-Methylene dianiline
Health based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to
the Minister and State Secretary of Social Affairs and Employment
No. 2000/11OSH, The Hague, 6 September 2000
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<pre>Preferred citation:
Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards
(DECOS). 4,4’-Methylene dianiline; Health-based calculated occupational cancer risk
values. The Hague: Health Council of the Netherlands, 2000; publication no.
2000/11OSH.
all rights reserved
ISBN: 90-5549-338-4
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 14
2   4,4’-Methylene dianiline (MDA) 15
2.1 Introduction 15
2.2 Carcinogenicity studies and selection of study
    suitable for risk estimation in the occupational situation 15
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure 16
2.4 Health risk to humans 17
2.5 Calculation of the HBC-OCRV 18
2.6 Existing occupational exposure limits 18
    References 21
7   Contents
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<pre>  Annexes 23
A Request for advice 25
B The Committee 27
C Comments on the public draft 29
D Animal studies 31
8 4,4’-Methylene dianiline
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<pre>  Samenvatting
  Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid schat de Commissie
  WGD van de Gezondheidsraad het extra kankerrisico bij beroepsmatige blootstelling aan
  stoffen die door de Europese Unie of door de Commissie WGD als genotoxisch kanker-
  verwekkend zijn aangemerkt. In dit rapport maakt zij zo’n schatting voor methyleen dia-
  niline. Zij heeft daarbij gebruik gemaakt van de methode die is beschreven in het rapport
  ‘Berekening van het risico op kanker’ (1995/06WGD) (Dec95).
  Naar schatting van de commissie is de extra kans op kanker voor methyleen dianiline:
       4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0.009 mg/m3
       4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 0.9 mg/m3
9 Samenvatting
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<pre>10 4,4’-Methylene dianiline</pre>

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<pre>   Executive summary
   On request of the Minister of Social Affairs and Employment the Dutch Expert Commit-
   tee on Occupational Standards (DECOS), a committee of the Health Council of the
   Netherlands, estimates the additional lifetime cancer risk associated with occupational
   exposure to substances that have been classified by the European Union or the DECOS
   as genotoxic carcinogen. In this report the committee presents such estimates for methy-
   lene dianiline. It has used the method described in the report ‘Calculating cancer risks
   due to occupational exposure to genotoxic carcinogens’ (1995/06WGD) (Dec95).
   The committee estimated that the additional lifetime cancer risk for methylene dianiline
   amounts to:
       4 x 10-5 for 40 years of occupational exposure to 0.009 mg/m3
       4 x 10-3 for 40 years of occupational exposure to 0.9 mg/m3
11 Executive summary
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<pre>12 4,4’-Methylene dianiline</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for 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 Standards (DE-
        COS), a committee of the Health Council of the Netherlands, on request of the Minister
        of Social Affairs and Employment (annex A). This evaluation should lead to a health-ba-
        sed recommended exposure limit for the concentration of the substance in air. Such an
        exposure limit cannot be derived if the toxic action cannot be evaluated using a threshold
        model, as is the case for substances with genotoxic carcinogenic properties.
             In this case an exposure-response relationship is recommended for use in regulatory
        standard setting, ie. the calculation of so-called health-based calculated occupational
        cancer risk values (HBC-OCRVs). The committee calculates HBC-OCRVs for com-
        pounds which are classified as genotoxic carcinogens by the European Union or by the
        present committee.
             For the establishment of the HBC-OCRV’s the committee generally uses a linear ex-
        trapolation method, as described in the committee’s report ‘Calculating cancer risk due
        to occupational exposure to genotoxic carcinogens’ (1995/06WGD). The linear model to
        calculate occupational cancer risk is used as a default method, unless scientific data
        would indicate that using this model is not appropriate.
             In the next phase of the three-step procedure, the Social and Economic Council advi-
        ses the Minister of Social Affairs and Employment on the feasibility of using the HBC-
13      Scope
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<pre>    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 derivation of HBC-OCRVs for methylene dianiline
    (MDA) by the committee. The members of the committee are listed in Annex B. The
    first draft of this report was prepared by MI Willems, from the TNO Nutrition and Food
    Research Institute in Zeist, by contract with the Ministry of Social Affairs and Employ-
    ment.
         In 1998, 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 an-
    nex C. The committee has taken these comments into account in deciding on the final
    version of the report.
14  4,4’-Methylene dianiline
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<pre>Chapter 2
        4,4’-Methylene dianiline (MDA)
2.1     Introduction
        The carcinogenicity of MDA (CAS no. 101-77-9) has been evaluated by DFG (Gre95),
        IARC (IARC86), and Fairhurst (Fai91). In addition, 4,4’-methylene dianiline has been
        classified as a category 2 carcinogen by the European Union.
            The present evaluation of the carcinogenicity was based on a review by IARC
        (IARC86). In addition, literature was retrieved from online databases Medline, Toxline
        and Cancerlit covering the period 1975 to 1996.
2.2     Carcinogenicity studies and selection of study suitable for risk estimation
        in the occupational situation
        No information was found to evaluate the possible carcinogenicity in humans. Liver da-
        mage is the main reported adverse effect in humans irrespective of the way of exposure
        (oral, dermal or inhalatory). Consumption of MDA-contaminated bread led to an out-
        break of 84 cases of jaundice in Epping, UK. From analysis of the MDA content of the-
        se bread samples, it has been estimated that individuals consumed about 3 mg MDA/kg
        bw. All patients made a good clinical recovery (IARC86). A follow-up study after 2 ye-
        ars did not point to progressive hepatic disease (Fai91). A second follow-up study after
        24 years did not allow firm conclusions regarding long-term health effects of MDA be-
        cause of limitations in the investigation (Fai91, Hal90).
15      4,4’-Methylene dianiline (MDA)
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<pre>           Table 1 (Annex D) summarizes the main carcinogenicity studies with experimental
    animals with test conditions and results. As appears from Table 1, the only studies suita-
    ble for quantitative risk assessment are the long-term studies performed in the frame-
    work of the National Toxicology Program (NTP) in mice and rats. The other studies re-
    viewed by DFG and IARC (two subcutaneous and three gavage studies in rats, and one
    oral study in dogs) are suitable neither to assess the carcinogenic potentential nor for
    quantitative risk assessment, due to poor study design, reporting etc. (see Table 1).
           In the NTP studies MDA was administered in drinking water for 103 weeks follo-
    wed by one week without treatment to groups of fifty male and fifty female mice and rats
    at concentration levels of 0, 0.015 or 0.03%. In rats given MDA there was good survival
    at both 78- and 105-weeks with no significant differences between the males and fema-
    les. In mice on MDA, survival of high-dose males was significantly reduced when com-
    pared with the survival of the low-dose and control groups (Wei84). Treatment-related
    increases in the incidences of thyroid follicular-cell adenomas and hepatocellular neo-
    plasms were observed in both male and female mice. In rats, treatment-related increases
    in the incidences of thyroid follicular-cell carcinomas and hepatic nodules were observed
    in males, and thyroid follicular-cell adenomas occurred in females (see Table 2, Annex
    D). The incidences of rats and mice with different tumour are listed in table 2 (Annex
    D).
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure
    To calculate the carcinogenic activity of MDA, the incidences of male rats and mice, gi-
    ven 0.03% MDA, with liver and thyroid tumours were used as starting point. For this
    calculation, the total number of treatment-related tumour-bearing animals should be
    used. However, since the available reports did not discriminate between animals with tu-
    mours in both thyroid and liver and those with tumours in one of these target organs
    only, the numbers of animals presented with liver or thyroid tumours are added up. In
    addition, the committee is of the opinion that the available data do not indicate that the
    use of the linear model is not appropriate.
           The incidence per mg MDA/kg bw/day (lifespan conditions, assuming a linear dose
    response relationship), Idose, is calculated as follows:
                                                          Ie - Ic
           I*dose = C x (Xpo /L) x (Xpe /L) x exposure hours per day/24 x exposure days per week/7
*   Idose = the carcinogenic activity attributable to the exposure to the substance per unit daily dose under lifespan condi-
    tions assuming a linear dose response relationship
    Ie and Ic = incidence of tumour bearing animals or tumours in exposed and control amnimals, respectively,
    Xpo = exposure period, Xpe = experimental period
16  4,4’-Methylene dianiline
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<pre>    For male rats this results in an
                           ( 10 + 25 )−( 49
                                          1
                                            + 50
                                               1
                                                 )
           I dose =          48 50
                                                            = 8.5x10 −2 [mg/kg/d]−1
                    15[mg⋅kg −1 ⋅d −1 ]x 1000d
                                            721d 728d
                                                  x 1000d
    For male mice this results in an
                         ( 29  + 16 ) - ( 10  +0 )
           I dose =        50 49          49 47
                                                             = 1.5 x 10 −2 [mg/kg/d] −1
                    50 [mg x kg −1 x d −1 ] x 721     x 728
                                                 750 750
    Since the highest risk was calculated for rats, the incidence of 8.5 x 10-2 is used as a
    starting point for quantitative risk estimation in humans as a way of precaution.
    For calculating the dose in mg/kg bw/day the following standard values were used:
     Table 3
                                    standard                     weight           water      water
                                    lifespan                     kg               ml/day     ml/kg bw/day
     rat male                       1000 days                    0.5              25         50
     rat female                     1000 days                    0.35             20         57
     mouse male                     750 days                     0.03             5          167
     mouse female                   750 days                     0.025            5          200
2.4 Health risk to humans
    To estimate the additional lifetime risk of cancer in humans under lifespan conditions on
    the basis of results in animal experiments, it is assumed that no difference exists between
    experimental animals and man with respect to toxicokinetics, mechanism of tumour in-
    duction, target, susceptibility etc, unless specific information is available which justifies
    a different approach. Furthermore, it is assumed that the average man lives 75 years,
    weights 70 kg and is exposed 24 hours per day 7 days/week, 52 weeks per year for life-
    time.
    and L = standard lifespan for the animals in question (L rat is assumed to be 1000 days)
17  4,4’-Methylene dianiline (MDA)
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<pre>2.5 Calculation of the HBC-OCRV
    To estimate the additional lifetime risk of cancer in humans under workplace conditions,
    it is assumed that the average man lives 75 years, is exposed 8 hours per day, five days a
    week, 48 weeks a year, for 40 years, and inhales 10 m3 air per 8 hour-working day.
    Using as starting point the estimated incidence of 8.5 x 10-2 per mg/kg bw/day, the addi-
    tional lifetime cancer risk per mg/m3 under occupational exposure conditions, the HBC-
    OCRV, amounts to:
          HBC-OCRV = 8.5x10 −2 x 75y x 52w           x 7d x 70kg = 4.3 x 10 −3 [mg/m 3 ] −1
                                            40y  48w 5d 10m     3
    Based on the HBC-OCRV of 4.3 x 10-3 per mg/m3 the reference additional lifetime can-
    cer risk amounts to:
          4 x 10-5 for 40 years of exposure to 0.009 mg/m3
          4 x 10-3 for 40 years of exposure to 0.9 mg/m3
2.6 Existing occupational exposure limits
    Table 4 summarizes the occupational exposure limits established by the regulatory
    authorities of Germany, United Kingdom, USA-ACGIH and USA-OSHA.
          The lowest occupational exposure limit settled by these countries amounts to 0.08
    mg/m3 (UK, HSE95). In the United Kingdom, it was concluded that considering the car-
    cinogenicity data, a threshold could not be identified and that consequently a maximum
    exposure limit (MEL)* (0.08 mg/m3) was appropriate. This concentration is about a fac-
    tor 10 lower than the concentration leading to an additional cancer risk of 4 x 10-3 (i.e.,
    0.9 mg/m3) and about a factor 9 higher than the concentration leading to an additional
    cancer risk of 4 x 10-5 (i.e., 0.009 mg/m3 ).
*   In setting a Maximum Exposure Limit (MEL), not only the protection of the health of the employee is considered, also
    socio-economic factors are taken into account. A cost benefit assessment is prepared to assist the considerations of the-
    se. In practice, MELs have been most often allocated to carcinogens, respiratory sensitizers and to other substances for
    which no threshold level of exposure for the effects can be identified and for which there is no doubt about the seri-
    ousness of the hazard(s) posed by the substance.
18  4,4’-Methylene dianiline
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<pre>     Table 4 Occupational exposure limits for MDA.
   country                   level                          time relation      notations        ref.
                                                 3
                             ppm           mg/m
                     a
   The Netherlands           -             -                -                  -                -
              be
   Germany                   -             (0.1)            -                  skin,            DFG96
                                                                               sensibilisation
   UK                        0.01          0.08 (MEL)       8-h TWA            skin, new        HSE95
            c
   Sweden                    -             -                -                  -                NBO93
                  d
   USA-ACGIH                 0.1           0.81             8-h TWA            skin             ACG96
   a
         The substance is listed as a carcinogen
   b
         The DFG classifies MDA as a category A2 carcinogen; DFG category A carcinogens are not assig-
         ned a health-based occupational limit, but a so called TRK-value (TRK = Technische Richtkon-
         zentrationen), a concentration feasible with currently available technical means. TRK-values are
         given in brackets.
   c
         In Sweden, MDA is placed under section 9 (carcinogen) and may only be handled by permission
         of the Labour Inspectorate.
   d
         Classified as A3 carcinogen: animal carcinogen .
   For the committee,
   The Hague, 6 September 2000
   dr ASAM van der Burght,                           Prof. dr GJ Mulder,
   scientific secretary                              chairman
19 4,4’-Methylene dianiline (MDA)
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<pre>20 4,4’-Methylene dianiline</pre>

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<pre>       References
ACG96  American Conference of Governmental Industrial Hygienists (ACGIH). 1996. TLVs(R) and BEIs(R). Thres-
       hold Limit Values for chemical substances and physical agents. Biological Exposure Indices. Cincinnati
       OH, USA: ACGIH, 1996: 27.
DEC95  Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS). Cal-
       culating cancer risk. The Hague: Health Council of the Netherlands, 1995 publication no 1995/06WGD.
DFG96  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher Ar-
       beitsstoffe. MAK- und BAT-Werte-Liste 1996. Maximale Arbeitssplatz-Konzentrationen und biologische
       Arbeitsstofftoleranzwerte. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1996: 42, 107, 127 (Mittei-
       lung 32).
Fai91  Fairhurst S. Toxicity review for WATCH, 4,4’-Methylene dianiline (MDA), 1991; ACTS/26/91 Annex 5.
Hal90  Hall A, Waterhouse J, Harrington JM. The ‘Epping Jaundice’ outbreak - A 24 year follow-up. Birming-
       ham, UK: University of Birmingham, Institute of Occupational Health, 1990. Undated draft. Received by
       III Scientific Office 22 March 1990.
Gre95  Greim H, ed. 4,4’-Diaminodiphenylmethan H,S und -Dihydrochlorid. In: Gesundheitsschädliche Arbeits-
       stoffe. Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werte (Maximale Arbeit-
       splatz-Konzentrationen). 1st-21st ed. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1995.
HSE95  Health and Safety Executive (HSE). Occupational exposure limits 1995. Sudbury (Suffolk), UK: HSE
       Books, 1995: 21, 28 (Guidance note 40/95).
IARC86 International Agency for Research on Cancer (IARC). 4,4’-Methylenedianiline and its dihydrochloride.
       Some chemicals used in plastics and elastomers. Lyon, France: IARC, 1986: 347-65. In: IARC mono-
       graphs on the evaluation of the carcinogenic risk of chemicals to humans; Vol 39.
21     References
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<pre>ISZW95 Inspectiedienst van het Ministerie van Sociale Zaken en Werkgelegenheid (I-SZW). De Nationale MAC-
       lijst 1995. The Hague, The Netherlands: Sdu Servicecentrum Uitgeverijen, 1995: 42, 63 (pub no P145).
NBO93  National Board of Occupational Safety and Health (NBOSH). Occupational exposure limits. Solna, Swe-
       den: NBOSH, 1993: 74 (Ordinance AFS 1993/9).
Wei84  Weisburger EK, Krishna Murthy AS, Lilja HS et al. Neoplastic response of F344 rats and B6C3F1 mice
       to the polymer and dyestuff intermediates 4,4’-methylenebis- (N,N-dimethyl)-benzenamine,
       4,4’-oxydianiline, and 4,4’-methylenedianiline. J Natl Cancer Inst 1984; 72: 1457-63.
22     4,4’-Methylene dianiline
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<pre>A  Request for advice
B  The committee
C  Comments on the public draft
D  Animal studies
   Annexes
23
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<pre>24 4,4’-Methylene dianiline</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 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 conse-
      quence 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 de-
      cree 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 for
            advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in
25    Request for advice
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<pre>       the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated con-
       centration 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 recent-
       ly 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 an-
   nex B.
26 4,4’-Methylene dianiline
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<pre>Annex B
      The Committee
         GJ Mulder, chairman
         professor of toxicology; Leiden University, Leiden
         RB Beems
         toxicologic pathologist; National Institute of Public Health and the Environment,
         Bilthoven
         PJ Borm
         toxicologist; Heinrich Heine Universität Düsseldorf (Germany)
         JJAM Brokamp, advisor
         Social and Economic Council, The Hague
         VJ Feron,
         professor of toxicology; TNO Nutrition and Food Research Institute, Zeist
         DJJ Heederik
         epidemiologist; Wageningen University, Wageningen
         LCMP Hontelez, advisor
         Ministry of Social Affairs and Employment, The Hague
         G de Jong
         occupational physician; Shell International Petroleum Maatschappij, The Hague
         J Molier-Bloot
         occupational physician; BMD Akers bv, Amsterdam
         IM Rietjens
         professor in Biochemical toxicology; Wageningen University, Wageningen.
27    The Committee
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<pre>        H Roelfzema, advisor
        Ministry of Health, Welfare and Sport, Den Haag
        T Smid
        occupational hygienist; KLM Health Safety & Environment, Schiphol and professor
        of working conditions, Free University, Amsterdam
        GMH Swaen
        epidemiologist; Maastricht University, Maastricht
        HG Verschuuren
        toxicologist; DOW Europe, Horgen (Switzerland)
        F de Wit
        occupational physician; Labour Inspectorate, Arnhem
        CA Bouwman, scientific secretary
        Health Council of the Netherlands, Den Haag
        ASAM van der Burght, scientific secretary
        Health Council of the Netherlands, Den Haag
   The first draft of the present advisory report was prepared by M Willems, from the De-
   partment of Occupational Toxicology of the TNO Nutrition and Food Research Institu-
   te, by contract with the Ministry of Social Affairs and Employment.
   Secretarial assistance: J Toet.
   Lay-out: J van Kan.
28 4,4’-Methylene dianiline
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<pre>Annex C
      Comments on the public draft
      A draft of the present report was relased in 1998 for public review. The following orga-
      nisations and persons have commented on the draft document:
          WF ten Berge, DSM, Heerlen
29    Comments on the public draft
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<pre>30 4,4’-Methylene dianiline</pre>

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<pre>Annex D
      Animal studies
      See tables on the next pages.
31    Animal studies
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<pre>Table 1 Carcinogenicity studies with 4,4’-methylene dianiline (MDA).
authors               species                 exposure                           findings                                      remark
                                              characteristics
Steinhoff and Grund- rat, Wistar              subcutaneous                       MDA group: 29 benign tumours, 33 malig-       limited reporting.
mann                  25/sex/group            Dose: 30-50 mg/kg bw at one to     nant tumours                                  Study not suitable for
(1975) reviewed in                            3-week intervals (total dose 1.4   controls: 15 benign tumours, 16 malignant     assessment of carcin-
Gre95; Fair91;                                g/kg bw)                           tumours                                       ogenic potential of
IARC86                                        Xpo: 705 days                                                                    MDA
                                              Xpe: 970 - 1060 days (MDA);
                                              1007 days (controls)
Steinhoff and Dycka   rat, Sprague- Dawley    subcutaneous                       no significant increases in tumour incidence data not sufficiently
(1981)                30/sex/group            close: 01 ?                        in MDA-treated animals compared to con- reported
reviewed in Gre95                             Xpo: ?                             trols
                                              Xpe: lifetime
NTP-Study 1983        rat, F344/N             p.o. drinking water                treatment related increases in the incidences
(Wei84)               50/sex/group            dose levels: 0, 0.015, 0.03%       of thyroid follicular-cell carcinomas and he-
                                              Xpo: 103 weeks                     patic nodules in males and thyroid folli-
                                              Xpe: 104 weeks                     cular-cell adenomas in females (see Table 2
                                                                                 for actual numbers)
NTP-Study 1983        mouse, B6C3F1           p.o. drinking water                treatment related increases in the indidences
(Wei84)               50/sex/group            dose levels: 0, 0.015, 0.03%       of thyroid follicular- cell adenomas and he-
                                              Xpo: 103 weeks                     patocellular neoplasms (see Table 9.2 for
                                              Xpe: 104 weeks                     actual numbers)
Schoental (1968) re- rat, strain?             p.o. gavage                        tne hepatoma and a hemangioma-like tu-        study not suitable for
viewed in             N =16 (8/sex)           dose levels: 4 or 5 x 20 mg/animal mour of the kidney in a male (18 months).     evaluation of carcin-
Gre95                                         Xpo: < 8 months                    Uterus adenocarcinoma in one female (24       ogenic potential of
IARC86                                        Xpe: lifetime                      months)                                       MDA
Fai91
Munn (1967) revie-    rat, strain?            1) p.o. gavage, total dose 3300    all of the 24 animals had liver cirrhosis and studies not suitable for
wed in                males                   mg/kg                              two developed benign hepatomas                evaluation of carcin-
Gre95,                N = 24                  Xpo: 121 days                                                                    ogenic potential of
IARC86,                                       Xpe: lifetime                                                                    MDA
Fai91                                         2) p.o. gavage, total dose 6000    two animals developed “liver tumours” (ty-
                      similar experiment      mg/kg                              pe unspecified)
                                              Xpo: 18 months
                                              Xpe: lifetime
Griswold et al.       rat, Sprague-Dawley     p.o. gavage                        mammary lesions were found in 5/132 con-      no MDA induced tu-
(1968) reviewed in    females                 dose: 30 mg every 3 days for 30    trols and in 1 of 14 MDA-treated animals      mours were found.
Gre95                 N = 20                  days (total dose: 300 mg/rat)                                                    Study design focussed
IARC86                controls: 140 females   Xpo: 30 days                                                                     on the appearance of
Fai91                                         Xpe: 9 months                                                                    mammary tumours in
                                              Limited histopathology                                                           female SD-rats
Deichmann et al.      dog, Beagle             p.o. gelatineous capsules          no tumours of liver and bladder were found.   study not suitable for
(1978) reviewed in    females                 dose: 70 mg/dog, 3 times a week    MDA-induced liver damage was seen in all      assessment of carcin-
Gre95                 N = 5 pure MDA          Xpo: 4 - 7 years                   animals                                       ogenic potential of
IAR86                 N = 4 “crude” MDA       No control group included          pure MDA: one survivor                        MDA
Fai91                                                                            crude MDA: two survivors
Xpo = exposure period, Xpe = experimental period.
32              4,4’-Methylene dianiline
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<pre>Table 2 Tumour incidences in rats and mice treated with MDA (from Wei84; Gre95; IARC86; Fai91)a.
rats                               % MDA in drinking water
                                   males                                       females
                                   0              0.02           0.03          0             0.02     0.03
MDA, mg/kg bw/day
calculatedb                        0              7.5            15            0             8.6      17.1
measuredc                          0              9              16            0             10       19
thyroid gland                 n = 49              47             48            47            47       48
follic. cell adenoma               1              4              3             0             2        17 [<.001]
follic. cell carcinoma             0              0              7 [.012]      0             2        2
C-cell adenoma                     1              2              1             0             3        6 [<0.05]
liver                         n = 50              50             50            50            50       50
neoplastic nodule                  1              12 [.002]      25 [<.001]    4             8        8
mice                               % MDA in drinking water
                                   males                                      females
                                   0              0.015          0.03         0              0.015    0.03
MDA, mg/kg bw/day
calculatedb                        0              25             50           0              30       60
measuredc                          0              25             57           0              19       43
thyroid gland                 n = 47              49             49           50             47       50
follic. cell adenoma               0              3              16 [<.001]   0              1        13 [<.001]
follic. cell carcinoma             0              0              0            0              0        2
liver                         n = 49              50             50           50             50       50
adenoma                            7              10             8            3              9 [.049] 12 [<.008]
carcinoma                          10             33 [<.001]     29 [<.001]   1              6        11 {<.002]
a
      Numbers in brackets are P-values.
b
      See Table 3, page 17.
c
      Fai91. MDA intake was calculated from measured water intake.
33             Animal studies
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