<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 bis (2-chloroaniline)
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 bis (2-chlooraniline).
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 bis (2-chloroaniline)
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. 2000/09OSH, 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 bis (2-chloroaniline); Health-based calculated occupational
cancer risk values. The Hague: Health Council of the Netherlands, 2000; publication no.
2000/09OSH.
all rights reserved
ISBN: 90-5549-336-8
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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 bis (2-chloroaniline) 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 18
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 bis (2-chloroaniline)
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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 4,4’-methyleen
  bis (2-chlooraniline). 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 4,4’-methyleen bis
  (2-chlooraniline):
       4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0.02 mg/m3
       4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 2 mg/m3
9 Samenvatting
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<pre>10 4,4’-Methylene bis (2-chloroaniline)</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
   4,4’-methylene bis (2-chloroaniline). It has used the method described in the report ‘Cal-
   culating cancer risks due to occupational exposure to genotoxic carcinogens’
   (1995/06WGD) (Dec95).
   The committee estimated that the additional lifetime cancer risk for 4,4’-methylene bis
   (2-chloroaniline) amounts to:
       4 x 10-5 for 40 years of occupational exposure to 0.02 mg/m3
       4 x 10-3 for 40 years of occupational exposure to 2 mg/m3
11 Executive summary
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<pre>12 4,4’-Methylene bis (2-chloroaniline)</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 4,4’-methylene bis
    (2-chloroaniline) 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
    Employment.
        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 bis (2-chloroaniline)
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<pre>Chapter 2
        4,4’-Methylene bis (2-chloroaniline)
2.1     Introduction
        The carcinogenicity of 4,4’-methylene bis (2-chloroaniline) (CAS no. 101-14-4) has
        been evaluated by IARC (IARC74, IARC87), ACGIH (ACG91) and DFG (Gre95). Ac-
        cording to IARC there is sufficient evidence for carcinogenicity to animals, but in-
        adequate evidence for carcinogenicity to humans (IARC87). The European Union has
        classified 4,4’-methylene bis (2-chloroaniline) as a category 2 carcinogen.
            This evaluation of the carcinogenicity was based on a review by IARC (IARC74,
        IARC87). 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
        The available epidemiological data do not allow quantitative risk assessment for
        4,4’-methylene bis (2-chloroaniline).
            Table 1 (Annex D) summarizes the carcinogenicity studies with experimental ani-
        mals. 4,4’-methylene bis (2-chloroaniline) induces neoplasms in livers and lungs of rats
        (Gru70; Stu71, Stu75), rats and mice (Rus75), pulmonary adenomas and adenocarci-
        nomas, mammary adenocarcinomas, Zymbal gland carcinomas and hepatocellular carci-
        nomas in male rats (Kom78) and bladder cancer in dogs (Stu77). Subcutaneous admini-
15      4,4’-Methylene bis (2-chloroaniline)
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<pre>    stration of 4,4’-methylene bis(2-chloroaniline) in mice resulted in malignant primary
    lung tumours and liver cell carcinomas (see Table 1, Ste71).
         Since no inhalation studies are available, oral studies are used to calculate the carci-
    nogenic activity in experimental animals.
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure
    Four of the studies listed in Table 1 (Annex D) met the criteria for estimation of the
    carcinogenic potency viz. the rat studies of Grundmann and Steinhoff (Gru70), Stula et
    al. (Stu71, Stu75), Kommineni et al. (Kom78) and the mice study of Russfield et al.
    (Rus75). The committee is of the opinion that the available data do not indicate that the
    use of the linear model is not appropriate.
         Below the calculations are given for each of these studies (DEC95a).
    Grundmann and Steinhoff (Gru70)
    The number of male and female rats with malignant tumours is used as starting point to
    calculate the incidence per mg/kg body weight per day. Taking 27 g as total intake of the
    test substance per kg body weight and 890 and 835 days (average 863 days) as exposure
    period for males and females, respectively, the intake of the test substance amounts to
    31.3 mg per kg bw per day taken males and females together.
         The incidence of tumour-bearing animals per mg test substance/kg bw/day (lifespan
    conditions, assuming a linear dose response relationship) is calculated as follows:
                                                      Ie - Ic
         I*dose = Cx (Xpo /L) x (Xpe/L) x exposure hours per day/24 x exposure days per week/7
                         43/50 - 0/50
         = 31.3 x 863/1000 x 863/1000 x 24/24 x 7/7      = 3.7 x 10-2 [mg/kg/d]-1
    Stula et al. (Stu71, Stu75)
    To calculate the incidence per mg 4,4’-methylene bis (2-chloroaniline)/kg bw/day the ob-
    served number of animals (male and female rats) showing lung adenocarcinomas are
    used. Assuming an average daily intake of 45 g of food per kg body weight for male and
*   I =the carcinogenic activity attributable to the exposure to the substance per unit daily dose under lifespan conditions
    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
    and L = standard lifespan for the animals in question (L rat is assumed to be 1000 days)
16  4,4’-Methylene bis (2-chloroaniline)
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<pre>   female rats, the dose rate of 1000 ppm corresponds to 1000 x 0.045 = 45 mg/kg bw/day
   (DEC95).
        According to the equation noted above, the estimated incidence of tumour-bearing
   animals per mg/kg bw/day (lifespan conditions) amounts to
                      48/88 - 0/88
        45 x 726/1000 x 726/1000 x 24/24 x 7/7
                                                = 2.3 x 10-2 [mg/kg/d]-1
   Russfield et al. (Rus75)
   The number of male and female mice with vascular tumours in the 0.2 % group is used
   as starting point to calculate the incidence per mg/kg body weight per day. Assuming
   that the daily food consumption amounts to 120 and 130 g/kg body weight per day in
   males and females, respectively, the intake of the test substance amounts to 250 mg/kg
   bw/day taken males and females together.
        The incidence of tumour-bearing animals per mg per kg body weight /day (lifespan
   conditions). according to the equation above amounts to
                     14/34 - 1/38
        250 x 546/750 x 730/750 x 24/24 x 7/7  = 2.2 x 10-3 [mg/kg/d]-1
   Kommineni et al. (Kom78)
   To calculate the incidence per mg 4,4’-methylene bis (2-chloroaniline)/kg bw/day the ob-
   served number of animals (male rats) showing lung adenocarcinomas are used. At the
   dose level of 250 ppm a significant increase in the number of males with lung
   adenocarcinomas was observed. Assuming an average daily intake of 40 g of food per kg
   body weight for male rats, the dose rate of 250 ppm corresponds to 250 x 0.040 = 10
   mg/kg bw/day (DEC95).
        The incidence of tumour-bearing animals per mg/kg bw/day (lifespan conditions)
   amounts to:
                    14/100 - 0/100
        10 x 546/1000 x 728/1000 x 24/24 x 7/7  = 3.5 x 10-2 [mg/kg/d]-1
17 4,4’-Methylene bis (2-chloroaniline)
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<pre>    Conclusion
    The highest calculated cancer incidence in the above studies, i.e. 3.7 x 10-2 per mg/kg
    bw/day from the study of Grundmann and Steinhoff (Gru70), is used as starting point for
    quantitative risk estimation in humans.
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.
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 3.7 x 10-2 per mg/kg bw/day, the addi-
    tional lifetime cancer risk per mg/m3 under occupational conditions, the HBC-OCRV,
    amounts to:
          HBC-OCRV = 3.7x10 −2 x 75y x 52w      x 7d x 70kg = 1.9 x 10 −3 [mg/m 3 ] −1
                                        40y  48w 5d 10m   3
    Based on the HBC-OCRV of 2 x 10-3 per mg/m3 the reference additional lifetime cancer
    risk amounts to:
          4 x 10-5 for 40 years of exposure to 0.02 mg/m3
          4 x 10-3 for 40 years of exposure to 2 mg/m3.
2.6 Existing occupational exposure limits
    Table 2 summarizes the occupational exposure limits established by the regulatory
    authorities of Germany, United Kingdom and Sweden, and by USA-ACGIH. No occu-
    pational exposure limits have been established in The Netherlands, Germany and Swe-
    den.
18  4,4’-Methylene bis (2-chloroaniline)
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<pre>      Table 2 Occupational exposure limits for 4,4’-methylene bis (2-chloroaniline).
    country                      level                        time relation    notations        ref.
                                                   3
                                 ppm        mg/m
                      a
    The Netherlands              -          -                 -                -                ISZW95
               b
    Germany                      -          (0.02)            -                skin             DFG96
    UK                           -          0.005             8-h TWA          skin             HSE95
                                            (MEL)
    Swedenc                      -          -                 -                -                NBO93
                   d
    USA-ACGIH                     0.01      0.11              8-h TWA          skin             ACG96
    a
          In the Netherlands, this compound is listed as a carcinogen.
    b
          In Germany, this compound is classified as a category A2 carcinogen. DFG category A carcinogens
          are not assigned a health-based occupational exposure limit, but a so called TRK-value (TRK =
          Technische Richtkonzentrationen), a concentration feasible with currently available technical me-
          ans. TRK-values are given in brackets.
    c
          In Sweden, this compound is placed under section 9 (carcinogen) and may only be handled by per-
          mission of the Labour Inspectorate.
    d
          Classified as A2 carcinogen: suspected human carcinogen.
   The lowest occupational exposure limit settled by these countries amounts to 0.005
   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)* (0.005 mg/m3) was appropriate. This concentration is a factor
   400 lower than the concentration leading to an additional cancer risk of 4 x 10-3 (2
   mg/m3) and a factor 4 lower than the concentration leading to an additional cancer risk
   of 4x10-5 (0.02 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.
19 4,4’-Methylene bis (2-chloroaniline)
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<pre>   For the committee,
   The Hague, 6 September 2000
   dr ASAM van der Burght,              Prof. dr GJ Mulder,
   scientific secretary                 chairman
20 4,4’-Methylene bis (2-chloroaniline)
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<pre>      References
ACG91 American Conference of Governmental Industrial Hygienists (ACGIH). 4,4’-Methylene
      bis(2-chloroaniline). In: Documentation of the Threshold Limit Values and Biological Exposure Indices.
      6th ed. Cincinnati, OH, USA: ACGIH, 1991: 988-95.
ACG96 American Conference of Governmental Industrial Hygienists (ACGIH). 1996. TLVs(R) and
      BEIs(R).Threshold Limit Values for chemical substances and physical agents. Biological Exposure Indi-
      ces. Cincinnati OH, USA: ACGIH, 1996: 27.
DEC95 Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS).
      Calculating cancer risk. The Hague, The Netherlands: Health Council of the Netherlands, 1995; pub no
      1995/06WGD.
DFG96 Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher Ar-
      beitsstoffe. MAK- und BAT-Werte-Liste 1996. Maximale Arbeitsplatzkonzentrationen und biologische
      Arbeitsstofftoleranzwerte. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1996: 72, 108, 129 (Mittei-
      lung 32).
Gre95 Greim H, ed. 4,4’-Methylen-bis(2-chloranilin). In: Gesundheitsschädliche Arbeitsstoffe. Toxikologisch-
      arbeitsmedizinische Begründungen von MAK-Werten (Maximale Arbeitsplatz-Konzentrationen). 1st -
      21st ed. Weinheim, FRG: VCH Verlagsgesell-schaft mbH, 1995.
Gru70 Grundmann E, Steinhoff D. Leber- und Lungentumoren nach 3,3’-Dichlor-4,4’-diaminodiphenylmethan
      bei ratten. Z Krebsforsch 1970; 74: 28-39.
HSE95 Health and Safety Executive (HSE). Occupational exposure limits 1995. Sudbury (Suffolk), UK: HSE
      Books, 1995: 27 (Guidance note 40/95).
21    References
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<pre>IARC74 International Agency for Research on Cancer (IARC). 4,4’Methylene bis (2-chloroaniline).Some aromatic
       amines, hydrazine and related substances, N-nitroso compounds and miscellaneous alkylating agents.
       Lyon, France: IARC, 1974: 65-71. In: IARC monographs on the evaluation of carcinogenic risk of chemi-
       cals to man, Vol 4.
IARC87 International Agency for Research on Cancer (IARC). 4,4’Methylene bis (2-chloroaniline) (MOCA).
       Overall evaluations of carcinogenicity: an updating of IARC monographs. Lyon, France: IARC, 1987:
       246-7 In: IARC monographs on the evaluation of carcinogenic risks to humans, Volumes 1 to 42; Suppl
       7.
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: 28, 42, 63 (pub no
       P145).
Kom78  Kommineni C, Groth DH, Frockt IJ, et al. Determination of the tumorigenic potential of methylene-bis-
       orthochloroaniline. J Environ Pathol Toxicol 1978; 2: 149-71.
NBO93  National Board of Occupational Safety and Health (NBOSH). Occupational exposure limits. Solna, Swe-
       den: NBOSH, 1993: 74 (Ordinance AFS 1993/9).
Rus75  Russfield AB, Homburger F, Boger E, et al. The carcinogenic effect of
       4,4’-methylene-bis-(2-chloroaniline) in mice and rats. Toxicol Appl Pharmacol 1975; 31: 47-54.
Stu71  Stula EF, Sherman H, Zapp JA, et al. Experimental neoplasia in ChR-CD rats with the oral administra-
       tion of 3,3’-dichlorobenzidine, 4,4’-methylene-bis(2-chloroaniline) and
       4,4’-methylene-bis-(2-methylaniline). Toxicol Appl Pharmacol 1971; 19: 380-1.
Stu75  Stula EF, Sherman H, Zapp JA, et al. Experimental neoplasia in rats from oral administration of
       3,3’-dichlorobenzidine, 4,4’-methylene-bis(2-chloroaniline) and 4,4’-methylene-bis-(2-methylaniline).
       Toxicol Appl Pharmacol 1975; 31: 159-76.
Stu77  Stula EF, Barnes JR, Sherman H, et al. Urinary bladder tumors in dogs from
       4,4’-methylene-bis(2-chloroaniline). J Environ Pathol Toxicol 1977; 1: 31-50.
.
22     4,4’-Methylene bis (2-chloroaniline)
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<pre>A  Request for advice
B  The committee
C  Comments on the public draft
D  Animal studies
   Annexes
23
</pre>

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<pre>24 4,4’-Methylene bis (2-chloroaniline)</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 bis (2-chloroaniline)
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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 bis (2-chloroaniline)
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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 bis (2-chloroaniline)</pre>

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<pre>Annex D
      Animal studies
      See table on the next page.
31    Animal studies
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<pre>Table 1 Carcinogenicity studies with 4,4’-methylene bis (2-chloroaniline).
authors             species      exposure     dose         exposure and experimental     findings
                                 characte-                 period
                                 ristics
Gru70               rat (25/     low protein  0.1% (total  Xpo =Xpe =lifespan            controls: 0/50, no malignant tumours (2 female animals
                    sex/group)   diet         27 g/kg bw   lifespan: male: 890 days      had mammary adenomas).
                                              for male and (average survival 565 days);  Treatment group:
                                              female)      female: 835 days (average     male: 23/25 with malignant tumours (1 primary lung tu-
                                                           survival 535 days).           mour, 7 liver + primary lung, 15 liver).
                                                                                         female: 20/25 with malignant tumours (15 liver, 3 liver +
                                                                                         primary lung, 2 primary lung)
Russfield et al.    rata (25 ma- diet         0.05 and     Xpo = 18 months               hepatomas male: 0/22, 1/22, 4/19 in 0, 0.05 and 0.1%
(1973), in I-       les/ group)               0.1%         Xpe = 24 months               group, respectively
ARC74; Rus75                                                                             remark: the incidences were not statistically significant
                                                                                         different from controls
                       b
Kom78               rat (males) diet          0, 250, 500, Xpo = 18 months               in the 0, 250, 500 and 1000 ppm groups, respectively:
                                              1000 ppm     Xpe = 24 months               lung adenocarcinomas 0/100, 14/100c, 20/75c, 31/50c
                                                                                         all primary lung neoplasms 1/100, 23/100c, 28/75c, 35/50c
                                                                                         -mammary adenocarcinomas 1/100, 5/100, 8/75c, 14/50c
                                                                                         -zymbal gland carcinomas 1/100, 8/100c, 5/75, 11/50c
                                                                                         -hepatocellular carcinomas 0/100, 3/100, 3/75, 18/50c
Stu71, Stu75        rata (50/    diet         0, 1000 ppm  Xpo = Xpe =lifespan           control group:
                    sex/group)                             lifespan: average survival    lung adenomatosis: male1/44, female 1/44.
                                                           time male 560d days and       Treatment group:
                                                           548d days for female (sur-    lung adenomatosis: male14/44, female 11/44.
                                                           vival time controls male 564  lung adenocarcinoma: male21/44, female 27/44
                                                           days, for female 628 days)
Stu77               doge (6 fe-  oral (capsu- 0 and 100    Xpo = Xpe = 9 years           five treated dogs showed malignant nodules in the bladder
                    males/       les)         mg/day       treatment: first six weeks, 3 after 9 years
                    group)                    (8-15 mg/kg  days/week, then 5 days/week
                                              bw/d)
Rus75               mouse        diet         0, 0.1%,     Xpo = 18 months               vascular tumours male: 0/18, 3/13, 8/20; female: 1/20,
                    (25/sex/                  0.2%         Xpe = 25 months               0/21, 6/14.
                    group)                                                               Hepatomas male: 3/18, 3/13, 4/20; female: 0/20, 9/21,
                                                                                         7/14
                                                                                         in 0, 0.1 and 0.2% group, respectively
Grundmann & rat                  subcutane- total dose:    Xpo = 620 days                controls: 13 tumours in 50 control rats
Steinhoff           (17/sex/     ous          25 mg/kg                                   (no malignant lung or liver cell carcinomas).
(1971), in          group)       once a       bw                                         Test: 9 rats with liver cell carcinomas, 7 rats with
IARC74                           week                                                    primary lung tumours
a
     ChR-CD-1rat
b
     Sprague-Dawley rats
c
     Statistically significant different from controls
d
     Range of days on test: male 152-733 days; female 224-719 days
e
     Beagle dogs
32               4,4’-Methylene bis (2-chloroaniline)
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<pre>33 Animal studies</pre>

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<br><br>