<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>www.healthcouncil.nl Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Healthy working conditions How can employees be protected against working conditions that could harm their health? Environmental health Which environmental influences could have a positive or negative effect on health? Healthy nutrition Which foods promote good health and which carry certain health risks? Prevention Which forms of prevention can help realise significant health benefits? Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Areas of activity Advisory Reports The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory opinions that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands 4,4-Methylenedianiline 2015/28 2015/28 Health-based calculated occupational cancer risk values 4,4-Methylenedianiline Health Council of the Netherlands</pre>

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

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies 4,4’-Methylenedianiline
Uw kenmerk             : DGV/BMO/U-932542
Ons kenmerk            : U-847210/BvdV/cn/459-B72
Bijlagen               :1
Datum                  : 17 november 2015
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
4,4’-methyleendianiline.
Dit advies maakt deel uit van een uitgebreide reeks, waarin concentratieniveaus in lucht
worden afgeleid die samenhangen met een extra kans op kanker van 4 per 1.000 en 4 per
100.000 door beroepsmatige blootstelling. De conclusies van het genoemde advies zijn
opgesteld door de Commissie Gezondheid en beroepsmatige blootstelling aan stoffen
(GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep Volksgezondheid.
In dit advies concludeert de commissie dat 4,4’-methyleendianiline een carcinogene stof is
met een stochastisch genotoxisch werkingsmechanisme. Gebaseerd op dierexperimentele
gegevens schat de commissie de extra kans op kanker voor 4,4’-methyleendianiline op:
• 4 per 100.000 bij 40 jaar beroepsmatige blootstelling aan 16 µg/m3
• en 4 per 1.000 bij 40 jaar beroepsmatige blootstelling aan 1,6 mg/m3.
Ik onderschrijf de aanbevelingen en het advies van de commissie.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                        Postadres
Parnassusplein 5                                                   Postbus 16052
2 5 11 V X       Den Haag                                          2500 BB         Den Haag
E - m a i l : b . v. d . v o e t @ g r. n l                        w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>4,4’-Methylenedianiline
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety (DECOS),
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2015/28, The Hague, November 17, 2015
</pre>

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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare and Sport, Infrastructure and the Environment, Social Affairs
and Employment, and Economic Affairs. The Council can publish advisory
reports on its own initiative. It usually does this in order to ask attention for
developments or trends that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. 4,4’-Methylenedianiline - Health-based
calculated occupational cancer risk values. The Hague: Health Council of the
Netherlands, 2015; publication no. 2015/28.
all rights reserved
ISBN: 978-94-6281-064-8
</pre>

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<pre>    Contents
    Samenvatting 9
    Executive summary 11
    Scope 13
 .1 Background 13
 .2 Committee and method of work 14
 .3 Data 14
    Hazard assessment 15
 .1 Hazard identification 15
 .2 Risk assessment 18
 .3 Groups at extra risk 21
 .4 Health-based recommended occupational cancer risk values (HBC-OCRV) 21
 .5 Biological monitoring 21
    References 23
    Annexes 27
A   Request for advice 29
B   The Committee 31
C   The submission letter (in English) 33
    Contents                                                               7
</pre>

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<pre>D Comments on the public review draft 35
E Evaluation of the Subcommittee on Classification of carcinogenic substances 37
F Carcinogenic classification of substances by the Committee 47
G Human and animal carcinogenicity data on 4,4’-methylenedianiline 49
  4,4’-Methylenedianiline
</pre>

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<pre>Samenvatting
Op verzoek van de Minister van Sociale zaken en Werkgelegenheid, leidt de
Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van
de Gezondheidsraad, de concentraties van een stof in de lucht af die samenhan-
gen met een vooraf vastgesteld extra risico op kanker (4 per 1.000 en 4 per
100.000 individuen) door beroepsmatige blootstelling gedurende het arbeidzame
leven. Het gaat om kankerverwekkende stoffen die door de Gezondheidsraad of
de Europese Unie geclassificeerd zijn in categorie 1A of 1B en die kankerver-
wekkend zijn via een stochastisch genotoxisch mechanisme. Voor de schatting
maakt de commissie gebruik van de Leidraad Berekening Risicogetallen voor
kankerverwekkende stoffen van de Gezondheidsraad.1 In dit advies onderzoekt
de commissie de mogelijkheid om zo’n schatting te maken voor 4,4’-methyleen-
dianiline. 4,4’-Methyleendianiline is een intermediair produkt dat gebruikt wordt
bij de productie van polyurethanen en epoxyharsen.
De commissie concludeert dat 4,4’-methyleendianiline een carcinogene stof is
met een stochastisch genotoxisch werkingsmechanisme. Gebaseerd op dierexpe-
rimentele gegevens schat de commissie de extra kans op kanker voor 4,4’-methy-
leendianiline op:
• 4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 16 µg/m3
• en 4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 1,6 mg/m3.
Samenvatting                                                                      9
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<pre>0 4,4’-Methylenedianiline</pre>

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<pre>Executive summary
At the request of the Minister of Social Affairs and Employment, the Dutch
Expert Committee on Occupational Safety (DECOS), a committee of the Health
Council of the Netherlands, derives so-called health-based calculated
occupational cancer risk values (HBC-OCRVs) associated with excess cancer
levels of 4 per 1,000 and 4 per 100,000 as a result of working life exposure to
substances. It concerns substances which are classified by the Health Council or
the European Union in category 1A or 1B, and which are considered stochastic
genotoxic carcinogens. For the estimation, the Committee uses the Guideline for
calculating carcinogenic risks of the Health Council.1 In this report the
Committee evaluates the possibility to establish such estimates for 4,4’-
methylenedianiline. 4,4’-Methylenedianiline is a chemical intermediate used in
the production of polyurethanes and epoxyresins.
In this report, the Committee concludes that 4,4’-methylenedianiline is a
carcinogenic substance with a stochastic genotoxic mechanism. Based on animal
data the Committee estimates that the additional lifetime cancer risk for 4,4’-
methylenedianiline amounts to:
• 4 x 10-5 for 40 years of occupational exposure to 16 µg/m3
• and 4 x 10-3 for 40 years of occupational exposure to 1.6 mg/m3.
Executive summary                                                                11
</pre>

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<pre>2 4,4’-Methylenedianiline</pre>

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<pre> hapter 1
        Scope
1.1     Background
        At the request of the Minister of Social Affairs and Employment (Annex A), the
        Dutch Expert Committee on Occupational Safety (DECOS), a Committee of the
        Health Council of the Netherlands, performs scientific evaluations of the toxicity
        of substances to which man can be exposed at the workplace. The purpose of
        these evaluations is to recommend a health-based recommended occupational
        exposure limit (HBROEL) or health-based calculated occupational cancer risk
        value (HBC-OCRV) for the concentration of the substance in air, provided the
        database allows the derivation of such value. These recommendations serve as a
        basis in setting legally binding limit values by the minister. As a preference, the
        minister has requested the Health Council to align, if possible, with the
        evaluations of other European organizations.
        In 2000, DECOS published an advice on the toxicity of 4,4’-methylenedianiline
        (MDA).2 Several years later, the German Committee on Hazardous Substances
        (AGS) and the European Scientific Committee on Occupational Exposure Limits
        (SCOEL) published an evaluation on the toxicity of MDA as well.3,4 The risk
        evaluation of the SCOEL was qualitative. The AGS applied a quantitative
        method of linear extrapolation which leads to cancer risk values.
        Scope                                                                               13
</pre>

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<pre>    In the present advice, the Committee reconsiders the former health based
    calculated occupational cancer risk values for MDA based on the previous report
    of the Committee (2000)2, the advice of the AGS published in 20103, the advice
    of the SCOEL published in 20124, and additional published studies till June
    2015. The Committee decides to perform a quantitative risk assessment of MDA
    according to its own guidelines and methodology.
1.2 Committee and method of work
    The present document contains the re-assessment of the toxicity and
    carcinogenicity of MDA by DECOS. The members of the DECOS are listed in
    Annex B. The submission letter (in English) to the Minister can be found in
    Annex C. In July 2015, the DECOS released a draft version of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex D. DECOS has taken these comments into account in finalising
    its report.
1.3 Data
    In Chapter 2 of the present document, the Committee evaluates the toxicity and
    carcinogenicity of MDA and recommends, if possible, a health-based
    occupational cancer risk value for MDA. This evaluation is based on the data
    described in Annex G of the present report.
    Annex G of the present document constitutes an update of a Health Council
    report, issued in 2000. For the present report, relevant data were extracted from
    the more recent reports on MDA from the AGS and the SCOEL published in
    2010 and 2012 respectively. Additional data were searched from the literature
    published using the online databases Toxline, Medline and Chemical Abstracts
    (CAPlus), using “4,4-methylenedianiline” and CAS no 101-77-9 as keywords.
    The last search was performed in June 2015.
 4  4,4’-Methylenedianiline
</pre>

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<pre> hapter 2
        Hazard assessment
        This chapter contains a short summary of the relevant data on the effects of
        exposure to MDA, based mainly on the data summarized in Annex G of the
        present report. In addition, the Committee evaluates the carcinogenicity of MDA
        and recommends health-based calculated occupational cancer risk values for
        MDA.
2.1     Hazard identification
        The Committee evaluated both the human and animal studies on MDA and
        observed that in the period following the publication of the previous DECOS
        report (2000) hardly any new human or animal data have been published.
2.1.1   Observations in humans
        Gastrointestinal complaints and in particular liver damage were reported among
        humans after occupational exposure and short-term intoxication by contaminated
        food (icterus, cellular infiltration, bile duct inflammations, cholestasis,
        hyperbilirubinaemia and increased serum transaminase levels).3-9 No reliable
        information is available about concentrations or doses. Various studies definitely
        demonstrated sensitisation to MDA in humans.3,4,10,11
        Hazard assessment                                                                  15
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<pre>      No information was found to evaluate the possible carcinogenicity in humans.
      The validity of the available human data on occupational exposure to MDA is
      generally limited because of methodological shortcomings (such as small
      cohorts, no determination of exposure, confounding factors not taken into
      account and mixed exposure). These studies suggest an association between
      MDA exposure at the workplace and an increased incidence of bladder
      cancer.3,4,12,13
2.1.2 Animal data
      The thyroid and liver were the most relevant target organs after repeated
      administration, rats being more sensitive than mice.3,4,14-16 Follicular hyperplasia
      and/or hypertrophy were observed in the thyroid of rats in several studies.3,4,14-16
      Hepatotoxic effects included increased serum levels of liver-specific
      transaminases, hepatocellular degeneration as well as necrotic alterations and
      bile duct hyperplasia.3,4,17-20 Haematotoxicity was another relevant end point in
      animal studies (anaemia and extramedullary haematopoiesis).3,21 MDA was
      slightly irritating to the skin and eyes of animals.3,21 No reliable animal studies or
      any human data are available for reproductive toxicity.3,21
      The only studies suitable for quantitative risk assessment of the carcinogenic
      potential are the long-term studies performed in the framework of the National
      Toxicology Program (NTP) in mice and rats.14-16 The other studies reviewed
      (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.22-25
      In the NTP studies MDA was administered in drinking water for 103 weeks
      followed by one week without treatment to groups of fifty male and fifty female
      mice (B6C3Fa) and rats (F344) at concentration levels of 0, 0.015 or 0.03%
      (0, 150 or 300 mg/L).14-16
      In rats given MDA there was good survival at both 78- and 105-weeks with no
      significant differences between the males and females. In MDA-exposed mice
      high-dose males showed significantly reduced survival when compared to the
      low-dose and control groups.
      Treatment-related increases in the incidences of thyroid follicular-cell adenomas
      and hepatocellular neoplasms were observed in both male and female mice.
 6    4,4’-Methylenedianiline
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<pre>              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.
              The tumour incidences in rats and mice are listed in Table 1.
 able 1 Tumour incidences in rats and mice treated with MDA (NTP 1984; WGD 2000; Weisburger 1984; Lamb 1986).2,14-16
ats                           % MDA in drinking water
                              males                                      females
                               0                0.015        0.03         0             0.015         0.03
MDA, mg/kg bw/day
 alculated                     0                7.5         15            0             8.6          17.1
measured*                      0                9           16            0           10             19
hyroid gland                  n=49            47            48           47           47             48
ollic. cell adenoma            1                4            3            0             2            17
ollic. cell carcinoma          0                0            7            0             2             2
  -cell adenoma                1                2            1            0             3             6
  -cell carcinoma              2                             1            1             2             1
iver                          n=50            50            50           50           50             50
 epatocellular adenoma         1              12            25            4             8             8
 arcinoma                      0                1            1            0             0             0
mice                          % MDA in drinking water
                              males                                                   females
                               0                0.015        0.03         0             0.015         0.03
MDA, mg/kg bw/day
 alculated                     0              25            50            0           30             60
measured*                      0              25            57            0           19             43
hyroid gland                  n=47            49            49           50           47             50
ollic. cell adenoma            0                3           16            0             1            13
ollic. cell carcinoma          0                0            0            0             0             2
iver                          n=49            50            50           50           50             50
 epatocellular adenoma         7              10             8            3             9            12
 arcinoma                     10              33            29            1             6            11
  MDA intake was calculated from measured water intake.
              Hazard assessment                                                                                   17
</pre>

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<pre>2.1.3 Carcinogenic classification and genotoxic mechanism
      DECOS consulted its Subcommittee on the Classification of carcinogenic
      substances to evaluate the carcinogenic classification and the underlying
      genotoxic mechanism of MDA. From the available in vitro and in vivo data on
      genotoxicity, the Subcommittee concludes that MDA is a presumed human
      carcinogen, and recommends classifying the compound in category 1B
      (presumed to be carcinogenic to man).26 This is in agreement with the EU
      classification.27 In addition, the Subcommittee is of the opinion that MDA can
      damage the DNA directly and that a stochastic genotoxic mode of action plays
      the predominant role in the development of the carcinogenicity (see Annex E
      and F for further details on the Subcommittee’s opinion).
      For stochastic genotoxic substances a risk to develop cancer exists at all
      concentration levels while no safe level (threshold) exists below which no cancer
      is to be expected. Therefore DECOS calculates cancer risk values for these
      substances associated with an excess cancer risk of 4 per 1,000 and 4 per 100,000
      caused by occupational exposure.1 These risk values serve as a basis in setting
      legally binding limit values by the minister.
2.2   Risk assessment
      The Committee is of the opinion that the epidemiological studies on MDA do not
      provide a reliable starting point for quantitative risk assessment. There is
      insufficient epidemiological evidence that MDA is carcinogenic for humans; the
      majority of the studies does not show increased risks, while in those studies with
      increased risks there is no statistical significance. Based on the currently
      available human data no reliable calculation can be made.* Therefore the
      Committee based the risk assessment on animal data.
      The Committee is aware of the uncertainties associated with a risk assessment
      based on animal data. However, the Committee emphasises that the tumours
      found in experimental animals only are specifically attributed to exposure to
      MDA. Therefore the Committee prefers to derive health-based calculated
      The Committee confirms the conclusions regarding the epidemiological studies in its own earlier
      report (2000) and in those of the SCOEL (2010) and the AGS (2012) in that these studies are not
      suitable for quantitative risk assessment.2-4
 8    4,4’-Methylenedianiline
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<pre>occupational cancer risk values from animal data and considers the oral NTP
(1984) study as the most suitable study for an estimation of the cancer risk values
after exposure by inhalation during a lifetime.
In its previous report (2000), the Committee used the same NTP study to
calculate cancer risk values based on a combination of liver- and thyroid tumours
in male rats in the highest dose group (0.03%=300 mg/L). The Committee
realizes that combining different tumours is no longer conforming to its current
guideline and scientific insights. Therefore the Committee now performs a
quantitative risk assessment based solely on liver tumours.
First the Committee explores the possibility to derive a bench mark dose (BMD)
and applies the EPA software (2.6) to establish the best fitting dose-response.
After testing various descriptive models the Committee concludes that the animal
data from the NTP study do not provide a reliable derivation of a dose-response
relationship and a BMD(L)10 as starting point for quantitative risk assessment.
Next, according to its guideline, the Committee resorts to making a
representative point estimate of the tumour incidence based on the animal data
from the lowest dose group providing significant differences in tumour incidence
(this concerns the dose of 0.015%=150 mg/L and the increase of liver tumours
from 1/50 in the controls to 13/50 in the exposed male rats).
From these data14-16, the incidence per unit dose (mg/kg bw/day) was calculated
(Idose).
                                           Ie-Ic
Idose =                                                                                  =
       D x (Xpo/L) x (Xpe/L) x (exposure hours per day/24) x (exposure days per week/7)
                      (13/50) – (1/50)
      =                                                 = 5.08 x10-2 [mg/kg bw per day]-1
       (9 mg/kg bw per day) x (721/1000) x (728/1000)
Where:
• D is the administered daily dose, generally expressed in mg per kg of body
     weight
• Idose is the carcinogenic activity attributable to the exposure to the substance
     per unit daily dose under lifespan conditions, assuming a linear dose response
     relationship, usually expressed per mg/m3 or per mg/kg bw per day
Hazard assessment                                                                          19
</pre>

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<pre>  •    Ie and Ic are the tumour incidences representing the exposed and control
       animals respectively
  •    Xpo and Xpe are the exposure and experimental periods, respectively
  •    L is the standard lifespan for the animals in question (L rat is assumed to be
       1000 days).
  Subsequently the extra cancer risk per unit concentration (HBC-OCRV) was
  calculated for humans occupationally exposed during a working life.
                           40 years     48 weeks       5 days      10 m3
  HBC-OCRV = Idose x                  x             x            x          = 2.55 x10-3 [mg/m3]-1
                           75 years     52 weeks       7 days      70 kg
  Where it is assumed:
  • that biological availability of 4,4’-methylenedianiline is 100% both after oral
       and inhalatory dosing and that targets for tumour induction are similar for
       both routes;
  • that no difference exists between experimental animals and man with respect
       to toxicokinetics, mechanism of tumour induction, target, susceptibility etc.,
       unless specific information is available which justifies a different approach;
  • that the average man lives 75 years, weighs 70 kg and is exposed 24 hours
       per day, 7 days per week, 52 weeks per year for lifetime;
  • that the average man is occupationally exposed for 40 years, 48 weeks per
       year, 5 days per week, 8 hours per day, and inhales 10 m3 air per 8-hour-
       working day.
  The Committee estimated that the concentration of 4,4’-methylenedianiline in
  the air, which corresponds to an excess cancer risk of
  • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to
       1,569 µg/m3
  • and 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
       16 µg/m3.*
  The SCOEL did not perform a quantitative risk assessment.4 The AGS however, performed a
  quantitative risk assessment based on animal data from the NTP study.3 Just like DECOS the AGS
  based its calculation on the liver tumours in male rats in the lowest dose group, applied a method of
  linear extrapolation, but chose another starting point (T25) This resulted in exposure of 7 and
  731 µg/m3 at an excess cancer risk of 4 per 100,000 and 4 per 1,000).
0 4,4’-Methylenedianiline
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<pre>2.3 Groups at extra risk
    No groups at extra risk could be identified.
2.4 Health-based recommended occupational cancer risk values
    (HBC-OCRV)
    The Committee concludes that since the publication of its previous report in
    2000 no new useful data have been published for quantitative risk assessment.
    The Committee uses animal data based on the same study as chosen in her
    previous report but applies a procedure that reflects its current guideline and
    scientific insights.
    The Committee estimates that the concentration of 4,4’-dimethylaniline in the
    air, which corresponds to an excess cancer risk of
    • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to 1.6 mg/m3
    • and 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
         16 µg/m3.
    The Committee recommends to use this outcome as a basis in setting legally
    binding limit values by the minister.
2.5 Biological monitoring
    The Committee is aware that in industrial practice exposure assessment of
    workers to MDA is routinely carried out by biological monitoring rather than by
    ambient monitoring. MDA has a very low vapour pressure and the main route of
    systemic exposure is dermal penetration. As a consequence, it is generally
    recognized that occupational exposure is best controlled by biological
    monitoring of MDA in urine.28,29 A health-based biological limit value (BLV)
    corresponding with the above proposed value (as OEL) of 1.6 mg/m3 for an
    additional life time risk of cancer of 4 x 10-3 for 40 years of occupational
    exposure to MDA was calculated applying the general formula for urinary
    excretion of a substance in urine:
    U = f x F x {(r x t) – [(r/k) x (1 – e-k x t)]}
    Hazard assessment                                                                  21
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<pre>  Where:
  • U is the cumulated amount of substance excreted into the urine at time t
  • f is the fraction of absorbed amount that is excreted into the urine; the value
       applied was that for the rat (5%) since the human value has not been
       determined
  • F is the biological availability (by inhalation); the value applied was that for
       aniline (90%) since the human value has not been determined
  • r is the maximum absorption, which equals the ventilation rate multiplied by
       the exposure concentration
  • k is the elimination constant
  • t is the time.
  Assuming an hourly ventilation rate of 1.25 m3 for an operator and an 8-h
  working day, the totally inhaled volume per day is 10 m3 and the average amount
  of creatinine excreted during the day in the urine is denoted by cr, a BLV (in
  mg/g creatinine) can be calculated from the following formula:
  BLV = [(f x F)/cr] x {(10 x OEL) – [[(10 x OEL)/(8 x k)] x (1 – e(-8 x k))]} or, considering k equals
  (ln 2)/t½ ,
  BLV = [(f x F)/cr] x (10 x OEL) x (1 – {[(ln2)/(8 x t½)] x (1 – e[(-8 x (ln2))/t½])}, with ln 2 = 0.693
  and cr = 1.5 g,
  BLV = 6.7 x f x F x OEL x {1 – 0.18 x t½ x (1 - e(-5.54/t½))}
  Using an urinary half-life of MDA of approximately 13 h, and a value for OEL
  of 1.6 mg/m3 this leads to the following value for the BLV:
  BLV = 6.7 x 0.05 x 0.9 x 1.6 x {1 – 0.18 x 13 x (1 - e(-5.54/13))} = 0.092 mg/g creatinine.
  The value of 92 µg/g creatinine is equivalent to 53 µmol/mol creatinine. The UK
  HSE as well as the Finnish Institute of Occupational Health have set biological
  limit values of 50 µmol/mol creatinine.30
2 4,4’-Methylenedianiline
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<pre>  References
  Health Council of the Netherlands. Guideline for calculating carcinogenic risks. The Hague, Health
  Council of the Netherlands; 2012: publication no. 2012/16E.
  Health Council of The Netherlands, Dutch Expert Committee on Occupational Standards. Methylene
  dianiline - Health-based calculated occupational cancer risk values. The Hague: Health Council of
  The Netherlands; 2000: Publication no. 2000/11 OSH.
  Ausschuss für Gefahrstoffe. 4,4’-Methylenedianiline: Bundesanstalt fur Arbeitsschutz und
  Arbeitsmedizin. 2010.
  Scientific Committee on Occupational Exposure Limits. 4,4’-Diaminophenylmethane (MDA),
  European Commission. 2012: SCOEL/SUM/107.
  Bastian PG. Occupational hepatitis caused by methylenedianiline. Med J Aust 1984; 141(8): 533-535.
  Hall AJ, Harrington JM, Waterhouse JA. The Epping jaundice outbreak: a 24 year follow up.
  J Epidemiol Community Health 1992; 46(4): 327-328.
  Kopelman H, Robertson MH, Sanders PG, Ash I. The Epping jaundice. Br Med J 1966; 1(5486):
  514-516.
  Kopelman H. The Epping jaundice after two years. Postgrad Med J 1968; 44(507): 78-81.
  Williams SV, Bryan JA, Burk JR, Wolf FS. Letter: Toxic hepatitis and methylenedianiline. N Engl
  J Med 1974; 291(23): 1256.
0 Fortina AB, Piaserico S, Larese F, Recchia GP, Corradin MT, Gennaro F et al.
  Diaminodiphenylmethane (DDM): frequency of sensitization, clinical relevance and concomitant
  positive reactions. Contact Dermatitis 2001; 44(5): 283-288.
1 Isaksson M, Gruvberger B. Patch test sensitization to methylchloroisothiazolinone +
  methylisothiazolinone and 4,4’-diaminodiphenylmethane. Contact Dermatitis 2003; 48(1): 53-54.
  References                                                                                         23
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<pre>2 Liss GM, Guirguis SS. Follow-up of a group of workers intoxicated with 4,4’-methylenedianiline.
  Am J Ind Med 1994; 26(1): 117-124.
3 Selden A, Berg P, Jakobsson R, de LJ. Methylene dianiline: assessment of exposure and cancer
  morbidity in power generator workers. Int Arch Occup Environ Health 1992; 63(6): 403-408.
4 Lamb JC, Huff JE, Haseman JK, Murthy AS, Lilja H. Carcinogenesis studies of
  4,4’-methylenedianiline dihydrochloride given in drinking water to F344/N rats and B6C3F1 mice.
  J Toxicol Environ Health 1986; 18(3): 325-337.
5 National Toxicology Program. Carcinogenesis Report of 4,4’-Methylene dianiline dihydrochloride
  (CAS no. 13552-44-8) in F344/N rats and B6CrF1 mice (drinking water studies). US Department of
  Health and Human Services (Public Health Srvice, National Institutes of Health); 1984: Technical
  Report Series, no.248.
6 Weisburger EK, Murthy AS, Lilja HS, Lamb JC. 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(6): 1457-1463.
7 Bailie MB, Mullaney TP, Roth RA. Characterization of acute 4,4’-methylene dianiline hepatotoxicity
  in the rat. Environ Health Perspect 1993; 101(2): 130-133.
8 Dugas TR, Kanz MF, Hebert VY, Hennard KL, Liu H, Santa C, V et al. Vascular medial hyperplasia
  following chronic, intermittent exposure to 4,4’-methylenedianiline. Cardiovasc Toxicol 2004; 4(1):
  85-96.
9 Kanz MF, Kaphalia L, Kaphalia BS, Romagnoli E, Ansari GA. Methylene dianiline: acute toxicity
  and effects on biliary function. Toxicol Appl Pharmacol 1992; 117(1): 88-97.
0 Kwon SB, Park JS, Yi JY, Hwang JW, Kim M, Lee MO et al. Time- and dose-based gene expression
  profiles produced by a bile-duct-damaging chemical, 4,4’-methylene dianiline, in mouse liver in an
  acute phase. Toxicol Pathol 2008; 36(5): 660-673.
1 European Union Risk Assessment Report. 4,4’-methylenedianiline. European Chemicals Bureau,
  Joint Research Centre, European Commission; 2001: EUR 19727 EN.
2 Deichmann WB, MacDonald WE, Coplan M, Woods F, Blum E. Di(4-aminophenyl)-methane
  (MDA): 4-7 year dog feeding study. Toxicology 1978; 11(2): 185-188.
3 Griswold DP, Jr., Casey AE, Weisburger EK, Weisburger JH. The carcinogenicity of multiple
  intragastric doses of aromatic and heterocyclic nitro or amino derivatives in young female sprague-
  dawley rats. Cancer Res 1968; 28(5): 924-933.
4 Schoental R. Carcinogenic and chronic effects of 4,4’-diaminodiphenylmethane, an epoxyresin
  hardener. Nature 1968; 219(5159): 1162-1163.
5 Steinhoff D, Grundmann E. [Carcinogenic effect of 4,4’-diaminodiphenylmethane and
  2,4’-diaminodiphenylmethane]. Naturwissenschaften 1970; 57(5): 247-248.
6 Health Council of The Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: Publication no. A10/07E.
7 European Parliament and Council. Regulation (EC) No 1272/2008 of the European Parliament and of
  the Council of 16 December 2008 on classification, labelling and packaging of substances and
4 4,4’-Methylenedianiline
</pre>

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<br><br>====================================================================== Pagina 26 ======================================================================

<pre>  mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending
  Regulation (EC) No 1907/2006. 2008.
8 Brouwer DH, Hoogendoorn L, Bos PM, Boogaard PJ, van Hemmen JJ. Proposal for the assessment
  to quantitative dermal exposure limits in occupational environments: Part 2. Feasibility study for
  application in an exposure scenario for MDA by two different dermal exposure sampling methods.
  Occup Environ Med 1998; 55(12): 805-811.
9 Cocker J, Gristwood W, Wilson HK. Assessment of occupational exposure to 4,4’-
  diaminodiphenylmethane (methylene dianiline) by gas chromatography-mass spectrometry analysis
  of urine. Br J Ind Med 1986; 43(9): 620-625.
0 Boogaard PJ. Biomonitoring of the Workplace and Environment. In: Ballantyne B, Marrs T, Syversen
  T, editors. General and Applied Toxicology. Wiley Online Library; 2009: Internet: http://
  onlinelibrary.wiley.com/doi/10.1002/9780470744307.gat126/ abstract. Accessed October 27, 2015.
1 Agency for Toxic Substances and Disease Registry. Toxicological profile for Methylenedianiline. US
  Department of Health and Human Services; Public Health Service; 1998.
2 Montelius J. Consensus Report for 4,4’-Methylenedianiline (MDA). In: Montelius J, editor.
  Scientific Basis for Swedish Occupational Standards XXIII. Solna, Sweden: Arbete och Hälsa,
  Arbetemiljöinstitutet; 2002: 1-14.
3 Beratergremium für Umweltrelevante Altstoffe.:4,4’-Methylenedianilin. Stuttgart: Hirzel Verlag;
  1994: BUA-Stoffbericht 132S.
  References                                                                                         25
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<pre>6 4,4’-Methylenedianiline</pre>

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<pre>A Request for advice
B The Committee
C The submission letter (in English)
D Comments on the public review draft
E Evaluation of the Subcommittee on Classification of carcinogenic
  substances
F Carcinogenic classification of substances by the Committee
G Human and animal carcinogenicity data on 4,4’-methylenedianiline
  Annexes
                                                                   27
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<pre>8 4,4’-Methylenedianiline</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     Request for advice                                                                                     29
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<pre>  •   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 the
      case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated
      concentration in air corresponding with reference tumour incidences of 10-4 and 10-6 per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
0 4,4’-Methylenedianiline
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<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life, and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  P.J. Boogaard
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders (NECORD), Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht, and
        National Institute for Public Health and the Environment, Bilthoven
     •  A.H. Piersma
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, and National Institute for Public Health and the Environment,
        Bilthoven
     •  H.P.J. te Riele
        Professor of Molecular Biology, VU University Amsterdam, and Netherlands
        Cancer Institute, Amsterdam
     The Committee                                                                31
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<pre>  •   I.M.C.M. Rietjens
      Professor of Toxicology, Wageningen University and Research Centre,
      Wageningen
  •   G.B.G.J. van Rooy
      Occupational Physician, Arbo Unie Expert Centre for Chemical Risk
      Management, and Radboud UMC Outpatient Clinic for Occupational
      Clinical Toxicology, Nijmegen
  •   F. Russel
      Professor of Pharmacology and Toxicology, Radboud University Medical
      Centre, Nijmegen
  •   G.M.H. Swaen
      Epidemiologist, Maastricht University, Maastricht
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
  •   P.B. Wulp
      Occupational Physician, Labour Inspectorate, Groningen
  •   B.P.F.D. Hendrikx, advisor
      Social and Economic Council, The Hague
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of the Netherlands, The Hague
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
2 4,4’-Methylenedianiline
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<pre>nnex C
     The submission letter (in English)
     Subject         : Submission of the advisory report 4,4’-Methylenedianiline
     Your Reference: DGV/BMO/U-932542
     Our reference : U-847210/BvdV/cn/459-B72
     Enclosed        :1
     Date            : November 17, 2015
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     4,4’-methylenedianiline.
     This advisory report is part of an extensive series in which carcinogenic
     substances are evaluated for the possibility to establish health-based
     occupational cancer risk values in accordance with European Union guidelines.
     This involves substances to which people can be exposed under working
     conditions.
     The advisory report was prepared by the Dutch Expert Committee on
     Occupational Safety (DECOS) of the Health Council. The advisory report has
     been assessed by the Health Council’s Standing Committee on Public Health.
     The submission letter (in English)                                             33
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<pre>  In this report, the Committee concludes that 4,4’-methylenedianiline is a
  carcinogenic substance with a stochastic genotoxic mechanism. The Committee
  estimated that the additional lifetime cancer risk for 4,4’-methylenedianiline
  amounts to:
  • 4 x 10-5 for 40 years of occupational exposure to 16 µg/m3
  • and 4 x 10-3 for 40 years of occupational exposure to 1.6 mg/m3.
  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor J.L. Severens
  Vice President
4 4,4’-Methylenedianiline
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in July 2015 for public review. The
     following organization and persons have commented on the draft document:
     • Lentz TJ, B’Hymer C, Reynolds S, National Institute for Occupational Safety
         and Health (NIOSH), Cincinnati OH, USA.
     Comments on the public review draft                                            35
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<pre>6 4,4’-Methylenedianiline</pre>

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<pre>nnex E
     Evaluation of the Subcommittee on
     Classification of carcinogenic
     substances
     On request of the Minister of Social Affairs and Employment the Dutch Expert
     Committee on Occupational Safety (DECOS), a committee of the Health Council
     of the Netherlands, estimates the additional lifetime cancer risk associated with
     occupational exposure to substances that have been classified by the European
     Union or by Health Council in category 1A or 1B, and which are considered
     ‘stochastic genotoxic’ carcinogens.
         [Previously IARC classified 4,4’methylenedianiline in category 2B
     (‘possibly carcinogenic to humans’).1]
         To date, 4,4’-methylene dianiline has been classified by the European Union
     in carcinogenicity category 1B (‘presumed to be carcinogenic to humans’)
     according to regulation no 1272/2008), and is incorporated in the latest list of
     carcinogenic substances of the Netherlands’ Department of Social Affairs and
     Employment.2,3
     More than a decade ago (2000) DECOS quantified the additional lifetime cancer
     risk for 4.4’-methylenedianiline by calculating health-based occupational cancer
     risk values (HBC-OCRVs).4 In its present report DECOS evaluates whether it
     can concur with, and benefit from, the recently (2010) published risk calculations
     for carcinogenicity by the German Committee on Hazardous Substances (AGS).5
         As part of this evaluation DECOS requested its Subcommittee on the
     Classification of carcinogenic substances to evaluate the specific information
     regarding the mechanisms of genotoxicity.
     Evaluation of the Subcommittee on Classification of carcinogenic substances        37
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<pre>  Genotoxic mechanism
  Detailed reviews on the genotoxic mechanisms of 4,4’-diaminodiphenylmethane
  are available (IARC, 1986; McQueen & Williams, 1990; EU-RAR, 2001; AGS,
  2010; SCOEL, 2012).1,5-8 Original studies were consulted when this was
  considered necessary by the Subcommittee. The main results are summarized
  below.
  Gene mutation assays
  In vitro
  Studies in bacteria (Salmonella typhimurium) showed mainly dose-related
  mutagenic effects after metabolic activation. The results were all negative
  without activation. More specifically; after metabolic activation, 4,4’-
  diaminodiphenylmethane is mutagenic in the Ames test in Salmonella
  typhimurium TA100 (Andersen et al., 1980; Cocker et al., 1986; Darby et al.,
  1978; Klopman et al., 1985; Lavoie et al., 1979; McCarthy et al., 1982; Messerly
  et al., 1987; Parodi et al., 1981; Rao et al., 1982; Shimizu et al., 1982; Takemura
  & Shimizu 1978; Tanaka et al., 1985).9-20 In strains TA98 and TA1538, 4,4’-
  diaminodiphenylmethane is not or only weakly mutagenic (Darby et al., 1978;
  Klopman et al., 1985; Lavoie et al., 1979; Messerly et al., 1987; Parodi et al.,
  1981; Rannug et al., 1984; Rao et al., 1982; Takemura & Shimizu, 1978).11-13,15-
  17,19,21
       4,4’-Diaminodiphenylmethane was activated more effectively by rat liver
  microsomes induced with phenobarbital than by those induced with Aroclor
  (Rao et al., 1982).17 After activation with PCB-induced rat liver microsomes,
  4,4’-diaminodiphenylmethane was mutagenic in S. typhimurium TA100 at
  concentrations of 10-1,000 µg/plate; in TA98 the substance was less mutagenic
  (Rao et al., 1982).17
       The metabolites, N-acetyl-4,4’-diaminodiphenylmethane and N,N’-diacetyl-
  4,4’-diaminodiphenylmethane, were not mutagenic in the Ames test system
  (Cocker et al.,1986; Tanaka et al., 1985) with and without metabolic activation,
  whereas the metabolites N’-11 nitroso- and N’-hydroxy-N-acetyl MDA were
  mutagenic both with or without metabolic activation (ATSDR, 1998; BUA,
  1994; EU-RAR, 2001; Montelius, 2002; Morgott et al.,1982).6,10,20,22-25
8 4,4’-Methylenedianiline
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<pre>In vivo
No information on in vivo mutagenicity could be retrieved.
Cytogenetic assays
In vitro
In mammalian cells in vitro, induction of chromosome aberrations was detected
(CHO cells; positive with metabolic activation; questionable result without
activation), and marginally positive results were obtained for the induction of
sister chromatid exchanges (SCE) using the same test system (Gulati et al., 1989,
McQueen & Williams, 1990).8,26
    A weakly positive result was obtained in the mouse lymphoma test (tested
only 27 without metabolic activation)(McGregor et al., 1988).27
    Zhong et al. (2001) demonstrated a dose-related induction of micronuclei in
V79 cells; the micronuclei were negative for anti-kinetochore antibodies and
thus provided evidence of the clastogenic effects of MDA.28
    Matsuoka et al. (2008) confirmed the chromosome-damaging effect in CHL
cells (SCE and, to a lesser extent, chromosome gaps and chromosome breaks),
which had already been observed in earlier studies in CHO cells.29
    Robbiano et al. (1999) observed no DNA breaks or micronuclei formation in
primary kidney cells from rats or humans.30
    Martelli et al. (2002) also reported a negative result in primary cultures of the
kidneys, bladder and ovaries of rats and primary human kidney and bladder
cells.31 However, these authors detected DNA breaks in primary rat and human
hepatocytes and thyreocytes, which are typical target organs for the
carcinogenicity of MDA. In more detail Martelli et al. reported that after
exposure for 4 and 20-h to 4,4’-diaminodiphenylmethane concentrations ranging
from 10 to 180 µM, a statistically significant increase in the frequency of DNA
lesions was revealed by the Comet assay in primary hepatocytes and thyreocytes
from donors of both species, the response being dose dependent up to 56-100 µM
4,4’-diaminodiphenylmethane. DNA fragmentation was more marked after 4
than after 20-h exposure in all four cell types. DNA was damaged to a lesser
extent in human hepatocytes and thyreocytes than in corresponding rat cells and
in both species in hepatocytes than in thyreocytes. In both rat and human
hepatocytes a 20-h exposure to the same 4,4’-diaminodiphenylmethane
concentrations elicited a modest amount of DNA repair synthesis, as evaluated
by autoradiography. Evidence of a partial reduction of DNA damage, and
Evaluation of the Subcommittee on Classification of carcinogenic substances           39
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<pre>  therefore of only partial DNA repair, was observed in rat hepatocytes and in rat
  and human thyreocytes incubated for 16 h in 4,4’-diaminodiphenylmethane free
  medium after a 4-h 4,4’-diaminodiphenylmethane treatment. A 4-h exposure to
  56, 100, and 180 µM 4,4’-diaminodiphenylmethane did not induce DNA lesions
  in primary cultures of cells from three rat organs, kidney, urinary bladder
  mucosa, and brain, which are resistant to 4,4’-diaminodiphenylmethane
  carcinogenic activity. Under the same experimental conditions evidence of DNA
  damage was absent in primary kidney and urinary bladder cells from human
  donors. The authors interpreted their results to indicate that 4,4’-
  diaminodiphenylmethane is activated to DNA-damaging reactive species by
  hepatocytes and thyreocytes in both rats and humans.
      In human leukocytes, the findings for chromosome aberrations and SCE were
  negative both with or without metabolic activation.
  In vivo
  In vivo tests in mice for the induction of micronuclei in the bone marrow and
  peripheral blood cells yielded weakly positive results after i.p. injection (up to
  140 mg/kg), (Shelby et al., 1993; Morita et al., 1997).32,33
      Intraperitoneal injection of 4,4’-diaminodiphenylmethane doses of 9 or 18
  mg/kg body weight into male Swiss mice caused a dose-dependent increase in
  sister chromatid exchange (SCE)(Parodi et al., 1983).34
      Likewise, in the bone marrow cells of BALB/c mice, a significant increase in
  sister chromatid exchange was seen after the highest 4,4’-
  diaminodiphenylmethane dose of 35 mg/kg (the dose range tested was 1-35
  mg/kg) (Gorecka-Turska et al., 1983).35
      Another study on DNA-damaging effects (induction of strand breaks) in
  various organs of mice after oral exposure (250 mg/kg) reported positive effects
  in the stomach, liver, kidney, bladder, lung and brain, but not in the colon or bone
  marrow (Sasaki et al. 1999a,b).36,37
      Robbiano et al. (1999) observed no DNA fragmentation or micronuclei
  formation in rat kidney cells (oral exposure; 415 mg/kg once or 277 mg/kg
  3 times).30
      Suzuki et al. (2005) exposed rats once to MDA at doses of up to 400 mg/kg
  orally or 34 by i.p. injection (route unclear).38 They investigated the induction of
  micronuclei in the peripheral blood (negative) and in hepatocytes (first
  laboratory: negative; second laboratory: positive at the highest dose at an
  increased mortality; only 2 animals examined).
0 4,4’-Methylenedianiline
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<pre>Miscellaneous assays
In vitro
Studies on the induction of unscheduled DNA synthesis (UDS) in rat hepatocytes
yielded inconsistent results under comparable test conditions (Mori et al.
1988).39
     Kenyon et al. (2004) detected DNA adducts after 24-hour exposure of
human skin to MDA in vitro. They differentiated three different adducts, but did
not characterize them in detail. The number of adducts (total) per 106 nucleotides
as well as for one of the adducts were increased in relation to the dose, whereas
no dose-response relationship was found for the other two adducts.40
     With the alkaline elution method it was demonstrated that 4,4’-diamino-
diphenylmethane at concentrations of 1 to 3 mM caused DNA strand breaks in
Chinese hamster V79 cells (Swenberg, 1981).41
     Clearly positive results were obtained with 4,4’-diaminodiphenylmethane in
one DNA 6 repair test with rat hepatocytes (UDS test) (Mori et al., 1988),
negative results in another 7 (Mirsalis et al., 1989).39,42
     Pretreatment with inducers of hepatic monooxygenases increases the
sensitivity of the DNA repair test in rat hepatocytes and produces clearly positive
results with 4,4’-diaminodiphenylmethane (Shaddock et al., 1989).43
In vivo
No induction of UDS was observed in rats and mice after oral doses of up to the
range of the LD50. DNA breaks were reported after i.p. injection of 74 mg/kg
(LD50) in the rat liver (Mirsalis et al., 1989).42
     An increase in the level of DNA strand breaks in the liver was found after
intraperitoneal injection of a 4,4’-diaminodiphenylmethane dose of 0.37 mmol/
kg (74 mg/kg) into male rats (Parodi et al., 1981).16
     A study in rats provided evidence of primary genotoxicity in vivo; Schütze et
al. (1996) studied DNA adducts after application (i.p. injection) of radiolabelled
4,4’-diaminodiphenylmethane (up to 23.1 mg/kg to rats) and reported DNA
adduct formation in the liver.44 The DNA-binding potency appeared in the range
of weakly genotoxic compounds. The major adducts found in the liver did not
correspond to previously synthesised standards. However, it was possible to
release 4,4’-diaminodiphenylmethane and 4,4’-diaminodiphenylmethane-d4
Evaluation of the Subcommittee on Classification of carcinogenic substances         41
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<pre>  from DNA of rats dosed with 4,4’-diaminodiphenylmethane and/or 4,4’-
  diaminodiphenylmethane-d4 using strong base hydrolysis.
       In a study by Vock et al. (1996), rats were orally exposed to MDA (3 times up
  to 50 mg/kg).45 Dose-related DNA adduct formation was detected in the liver.
  Mechanistic considerations
  4,4’-Methylenedianiline is a genotoxic substance which induces genetic damage
  in bacterial, and mammalian systems in vitro and in vivo.
       The Subcommittee is of the opinion that there is sufficient evidence that
  stochastic genotoxic mechanisms underly carcinogenicity of 4,4’-methylene-
  aniline.
  Recommendation
  The Subcommittee concludes that MDA is a presumed human carcinogen, and
  recommends classifying the compound in category 1B (presumed to be
  carcinogenic to man). In addition the Subcommittee concludes that stochastic
  genotoxic mechanisms underly carcinogenicity.
       For regulatory standard setting the Subcommittee recommends health-based
  occupational cancer risk values (HBC-OCRVs) to be calculated.
  References (for Annex E)
   4,4’-Methylenedianiline and its dihydrochloride. IARC Monogr Eval Carcinog Risk 1 Chem Hum
  1986; 39: 347-365.
  European Parliament and Council. REGULATION (EC) No 1272/2008 OF THE EUROPEAN
  PARLIAMENT AND OF THE COUNCIL of 16 December 2008 on classification, labelling and
  packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/
  EC, and amending Regulation (EC) No 1907/2006 . 2008.
  Ministerie van Sociale Zaken en Werkgelegenheid. SZW lijst van kankerverwekkende, mutagene, en
  voor de voortplanting giftige stoffen. 2014: Nr 1758.
  Health Council of The Netherlands, Dutch Expert Committee on Occupational Standards. Methylene
  dianiline: Health-based calculated occupational cancer risk values. The Hague: Health Council of
  The Netherlands; 2000: Publication no. 2000/11 OSH.
  Ausschuss für Gefahrstoffe. 4,4’-Dimethylenedianiline. Bundesanstalt für Arbeitsschutz und
  Arbeitsmedizin, 2010.
  European Union Risk Assessment Report. 4,4’-methylenedianiline. European Chemicals Bureau,
  Joint Research Centre, European Commission; 2001: EUR 19727 EN.
2 4,4’-Methylenedianiline
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<pre>  Scientific Committee on Occupational Exposure Limits. 4,4’-Diaminophenylmetane (MDA).
  European Commission, 2012: SCOEL/SUM/107.
  McQueen CA, Williams GM. Review of the genotoxicity and carcinogenicity of 4,4’-methylene-
  dianiline and 4,4’-methylene-bis-2-chloroaniline. Mutat Res 1990; 239(2): 133-142.
  Andersen M, Binderup ML, Kiel P, Larsen H, Maxild J. Mutagenic action of isocyanates used in the
  production of polyurethanes. Scand J Work Environ Health 1980; 6(3): 221-226.
0 Cocker J, Gristwood W, Wilson HK. Assessment of occupational exposure to 4,4’-
  diaminodiphenylmethane (methylene dianiline) by gas chromatography-mass spectrometry analysis
  of urine. Br J Ind Med 1986; 43(9): 620-625.
1 Darby TD, Johnson HJ, Northup SJ. An evaluation of a polyurethane for use as a medical grade
  plastic. Toxicol Appl Pharmacol 1978; 46(2): 449-453.
2 Klopman G, Frierson MR, Rosenkranz HS. Computer analysis of toxicological data bases:
  mutagenicity of aromatic amines in Salmonella tester strains. Environ Mutagen 1985; 7(5): 625-644.
3 LaVoie E, Tulley L, Fow E, Hoffmann D. Mutagenicity of aminophenyl and nitrophenyl ethers,
  sulfides, and disulfides. Mutat Res 1979; 67(2): 123-131.
4 McCarthy DJ, Struck RF, Shih TW, Suling WJ, Hill DL, Enke SE. Disposition and metabolism of the
  carcinogen reduced Michler's ketone in rats. Cancer Res 1982; 42(9): 3475-3479.
5 Messerly EA, Fekete JE, Wade DR, Sinsheimer JE. Structure-mutagenicity relationships of benzidine
  analogues. Environ Mol Mutagen 1987; 10(3): 263-274.
6 Parodi S, Taningher M, Russo P, Pala M, Tamaro M, Monti-Bragadin C. DNA-damaging activity in
  vivo and bacterial mutagenicity of sixteen aromatic amines and azo-derivatives, as related
  quantitatively to their carcinogenicity. Carcinogenesis 1981; 2(12): 1317-1326.
7 Rao TK, Dorsey GF, Allen BE, Epler JL. Mutagenicity of 4,4’-methylenedianiline derivatives in the
  Salmonella histidine reversion assay. Arch Toxicol 1982; 49(3-4): 185-190.
8 Shimizu H, Suzuki Y, Takemura N. Mutagenicity of epoxy resin hardeners. Proceedings of the 41st
  Annual meeting of the Japanese Cancer Association, Osaka, Japan, August 23-25, 1982.
9 Takemura N, Shimizu H. Mutagenicity of some aromatic amino- and nitro-compounds. Mutat Res
  1978; 54: 256 (abstract 35).
0 Tanaka K, Ino T, Sawahata T, Marui S, Igaki H, Yashima H. Mutagenicity of N-acetyl and
  N,N’-diacetyl derivatives of 3 aromatic amines used as epoxy-resin hardeners. Mutat Res 1985;
  143(1-2): 11-15.
1 Rannug A, Rannug U, Ramel C. Genotoxic effects of additives in synthetic elastomers with special
  consideration to the mechanism of action of thiurams and dithiocarbamates. Prog Clin Biol Res 1984;
  141: 407-419.
2 Agency for Toxic Substances and Disease Registry. Toxicological profile for Methylenedianiline. US
  Department of Health and Human Services; Public Health 16 Service; 1998.
3 Beratergremium für Umwelrelevante Altstoffe. 4,4’-Methylenedianilin. Stuttgart: Hirzel Verlag;
  1994: BUA-Stoffbericht 132S.
  Evaluation of the Subcommittee on Classification of carcinogenic substances                         43
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<pre>4 Montelius J. Consensus Report for 4,4’-Methylenedianiline (MDA). In: Montelius J, editor.
  Scientific Basis for Swedish Occupational Standards XXIII. Solna, Sweden: Arbete och Hälsa,
  Arbetemiljöinstitutet; 2002: 1-14.
5 Morgott D, Cornish H, Weber W. Metabolism and Toxicokinetics of 4,4’-Methylenedianiline.
  submitted by International Isocyanate Institute; 1982: NTIS/OTS0514789.
6 Gulati DK, Witt K, Anderson B, Zeiger E, Shelby MD. Chromosome aberration and sister chromatid
  exchange tests in Chinese hamster ovary cells in vitro. III. Results with 27 chemicals. Environ Mol
  Mutagen 1989; 13(2): 133-193.
7 McGregor DB, Brown A, Cattanach P, Edwards I, McBride D, Riach C et al. Responses of the
  L5178Y tk+/tk- mouse lymphoma cell forward mutation assay: III. 72 coded chemicals. Environ Mol
  Mutagen 1988; 12(1): 85-154.
8 Zhong BZ, Depree GJ, Siegel PD. Differentiation of the mechanism of micronuclei induced by
  cysteine and glutathione conjugates of methylenedi-p-phenyl diisocyanate from that of
  4,4’-methylenedianiline. Mutat Res 2001; 497(1-2): 29-37.
9 Matsuoka A, Haishima Y, Hasegawa C, Matsuda Y, Tsuchiya T. Organic-solvent extraction of model
  biomaterials for use in the in vitro chromosome aberration test. J Biomed Mater Res A 2008; 86(1):
  13-22.
0 Robbiano L, Carrozzino R, Puglia CP, Corbu C, Brambilla G. Correlation between induction of DNA
  fragmentation and micronuclei formation in kidney cells from rats and humans and tissue-specific
  carcinogenic activity. Toxicol Appl Pharmacol 1999; 161(2): 153-159.
1 Martelli A, Carrozzino R, Mattioli F, Brambilla G. DNA damage induced by 4,4'-methylenedianiline
  in primary cultures of hepatocytes and thyreocytes from rats and humans. Toxicol Appl Pharmacol
  2002; 182(3): 219-225.
2 Morita T, Asano N, Awogi T, Sasaki YF, Sato S, Shimada H et al. Evaluation of the rodent
  micronucleus assay in the screening of IARC carcinogens (groups 1, 2A and 2B) the summary report
  of the 6th collaborative study by CSGMT/JEMS MMS. Collaborative Study of the Micronucleus
  Group Test. Mammalian Mutagenicity Study Group. Mutat Res 1997; 389(1): 3-122.
3 Shelby MD, Erexson GL, Hook GJ, Tice RR. Evaluation of a three-exposure mouse bone marrow
  micronucleus protocol: results with 49 chemicals. Environ Mol Mutagen 1993; 21(2): 160-179.
4 Parodi S, Zunino A, Ottaggio L, de FM, Santi L. Lack of correlation between the capability of
  inducing sister-chromatid exchanges in vivo and carcinogenic potency, for 16 aromatic amines and
  azo derivatives. Mutat Res 1983; 108(1-3): 225-238.
5 Gorecka-Turska D, Mekler U, Gorski T. Sister chromatid exchanges in BALB/c mouse bone marrow
  in response to carcinogenic and non-carcinogenic products and intermediates from dye manufacture.
  Bromat Chem Toksykol 1983; 16: 37-42.
6 Sasaki YF, Fujikawa K, Ishida K, Kawamura N, Nishikawa Y, Ohta S et al. Erratum to: The alkaline
  single cell gel electrophoresis assay with mouse multiple organs: results with 30 aromatic amines
  evaluated by the IARC and U.S. NTP. Mutat Res 1999a; 444(1): 249-255.
4 4,4’-Methylenedianiline
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<pre>7 Sasaki YF, Fujikawa K, Ishida K, Kawamura N, Nishikawa Y, Ohta S et al. The alkaline single cell
  gel electrophoresis assay with mouse multiple organs: results with 30 aromatic amines evaluated by
  the IARC and U.S. NTP. Mutat Res 1999b; 440(1): 1-18.
8 Suzuki H, Ikeda N, Kobayashi K, Terashima Y, Shimada Y, Suzuki T et al. Evaluation of liver and
  peripheral blood micronucleus assays with 9 chemicals using young rats. A study by the
  Collaborative Study Group for the Micronucleus Test (CSGMT)/Japanese Environmental Mutagen
  Society (JEMS)-Mammalian Mutagenicity Study Group 25 (MMS). Mutat Res 2005; 583(2):
  133-145.
9 Mori H, Yoshimi N, Sugie S, Iwata H, Kawai K, Mashizu N et al. Genotoxicity of epoxy resin
  hardeners in the hepatocyte primary culture/DNA repair test. Mutat Res 1988; 204(4): 683-688.
0 Kenyon SH, Bhattacharyya J, Benson CJ, Carmichael PL. Percutaneous penetration and genotoxicity
  of 4,4’-methylenedianiline through rat and human skin in vitro. Toxicology 2004; 196(1-2): 65-75.
1 Swenberg JA. In: Stich HF RSR, editor. Short-term tests for chemical carcinogens. New York:
  Springer-Verlag; 1981: p48.
2 Mirsalis JC, Tyson CK, Steinmetz KL, Loh EK, Hamilton CM, Bakke JP et al. Measurement of
  unscheduled DNA synthesis and S-phase synthesis in rodent hepatocytes following in vivo treatment:
  testing of 24 compounds. Environ Mol Mutagen 1989; 14(3): 155-164.
3 Shaddock JG, Heflich RH, McMillan DC, Hinson JA, Casciano DA. Pretreatment with mixed-
  function oxidase inducers increases the sensitivity of the hepatocyte/DNA repair assay. Environ Mol
  Mutagen 1989; 13(4): 281-288.
4 Schutze D, Sagelsdorff P, Sepai O, Sabbioni G. Synthesis and quantification of DNA adducts of
  4,4’-methylenedianiline. Chem Res Toxicol 1996; 9(7): 1103-1112.
5 Vock EH, Hoymann HG, Heinrich U, Lutz WK. 32P-postlabeling of a DNA adduct derived from
  4,4’-methylenedianiline, in the olfactory epithelium of rats exposed by inhalation to
  4,4’-methylenediphenyl diisocyanate. Carcinogenesis 1996; 17(5): 1069-1073.
  The Subcommittee
  •    R.A. Woutersen, chairman
       Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
       Translational Toxicology, Wageningen University and Research Centre,
       Wageningen
  •    J. van Benthem
       Genetic Toxicologist, National Institute for Public Health and the
       Environment, Bilthoven
  •    P.J. Boogaard
       Toxicologist, Shell International BV, The Hague
  •    G.J. Mulder
       Emeritus Professor of Toxicology, Leiden University, Leiden
  Evaluation of the Subcommittee on Classification of carcinogenic substances                         45
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<pre>  •   M.J.M. Nivard
      Molecular Biologist and Genetic Toxicologist, Leiden University Medical
      Center, Leiden
  •   G.M.H. Swaen
      Epidemiologist, Maastricht University, Maastricht
  •   E.J.J. van Zoelen
      Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of The Netherlands
  Date meeting: September 04, 2014
6 4,4’-Methylenedianiline
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<pre> nnex        F
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                (before               (as from
                                                                                16 Decemb er 2008) 16 Decemb er 2008)
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be carcinogenic to humans.             2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.26
             Carcinogenic classification of substances by the Committee                                                47
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<pre>8 4,4’-Methylenedianiline</pre>

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<pre>nnex G
     Human and animal carcinogenicity
     data on 4,4’-methylenedianiline
     For the present report, DECOS extracted (below) and evaluated relevant data
     from the more recent reports on MDA from the AGS and the SCOEL published
     in 2010 and 2012 respectively. Additional data were searched in the published
     literature up till June 2015.
     Observations in humans
     AGS (2010)
     The validity of the available human data on occupational exposure to MDA is
     generally limited because of methodological inadequacies (such as small cohorts,
     no determination of exposure, confounding not taken into account and mixed
     exposure). These studies suggest an association between MDA exposure at the
     workplace and an increased occurrence of bladder cancer, but this would have to
     be verified by further studies (ATSDR, 1998; EU RAR, 2001; Montelius,
     2002).21,31,32
     SCOEL (2012)
     In a cohort of 595 power generator workers potentially exposed to MDA as a
     curing agent of an epoxy system, the overall standardised cancer incidence ratio
     (SIR) among males (n = 550), however, was only 0.52 [95% confidence interval
     (CI) 0.16-1.21] based on five observed cases. One male urinary bladder cancer
     case was found in comparison to 0.6 expected (SIR 1.67; 95% CI 0.04-9.31).
     Human and animal carcinogenicity data on 4,4’-methylenedianiline                 49
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<pre>  This case was identified in an unexposed subcohort. High levels of MDA
  metabolites were ascertained in the urine of currently exposed workers, probably
  following percutaneous absorption. It was noted that limitations of the study in
  regard to the size of the cohort, age and cancer latency precluded a definite risk
  assessment (Seldén et al., 1992).13
  Between 1967 and 1976, 10 workers at a plant in Ontario that used MDA as an
  epoxy hardener developed acute jaundice. This group was followed from the date
  of intoxication through to the end of 1991 for cancer incidence by matching with
  the Ontario Cancer Registry. At the time of publication (1994), one
  pathologically confirmed bladder cancer has developed [expected number based
  on provincial incidence rates: 0.64 for all cancers, 0.05 for bladder cancer] (Liss
  and Guirguis, 1994).12
  Additional publications
  No new publications were identified by the Committee.
  Animal data
  AGS (2010)
  Inhalation
  There are no studies available for inhalation.
  Oral route
  In an NTP study (1983; Weisburger et al., 1984; Lamb et al., 1986), F344 rats
  and B6C3F1 mice (50 per sex and dose) were exposed to MDA hydrochloride in
  the drinking water at concentrations of 150 and 300 mg/L (converted to MDA)
  for 103 weeks.14-16 The ingested doses were 9 and 16 mg/kg b.w. • d in male rats,
  10 and 19 mg/kg b.w. • d in female rats, 25 and 58 mg/kg b.w. • d in male mice
  and 19 and 43 b.w. mg/kg • d in female mice. Animals given drinking water that
  had been adjusted with HCl to the same pH as the test substance solution for the
  exposed animals served as controls.
      Drinking water consumption was reduced among the exposed groups with
  the exception of male mice. At the high dose, the body weight gain of female rats
  and mice of both sexes was reduced, and survival was lower in male mice of the
  high dose. No clinical signs occurred during treatment.
      Carcinogenicity was observed in the thyroid and liver of both rats and mice.
      In male rats, the incidence of follicular carcinomas of the thyroid was
  significantly increased in the high dose group (control: 0/49; 150 mg/L: 0/47;
0 4,4’-Methylenedianiline
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<pre>300 mg/L: 7/48); corresponding adenomas were significantly elevated in the
females (control: 0/47; 150 mg/L: 2/47; 300 mg/L: 17/48). Non-carcinogenic
lesions of the thyroid (follicular cysts) were also observed in female rats of the
high dose group.
    Significant and dose-related increases in the neoplastic nodules of the liver
(control: 1/50; 150 mg/L: 12/50; 300 mg/L: 25/50) and one carcinoma per dose
group were observed for male rats; in female rats, the incidence of neoplastic
nodules of the liver was not clearly related to the dose (control: 4/50; 150 mg/L:
8/50; 300 mg/L: 8/50). No hepatocellular carcinomas were found in female rats.
    The incidences of thyroid follicular adenomas were significantly elevated in
male mice (control: 0/47; 150 mg/L: 3/49; 300 mg/L: 16/49) and female mice
(control: 0/50; 150 mg/L: 1/47; 300 mg/L: 13/50). Significant effects on the liver
consisted of increased rates of hepatocellular carcinomas (males: control: 10/49;
150 mg/L: 33/50; 300 mg/L: 29/50; females: control: 1/50; 150 mg/L: 6/50; 300
mg/L: 11/50) and adenomas (females only: control: 3/50; 150 mg/L: 9/50; 300
mg/L: 12/50).
    Other statistically significant carcinogenic effects included:
• Phaeochromocytomas in male mice (control: 2/48; 150 mg/L: 12/49;
    300 mg/L: 14/49)
• Alveolar/bronchiolar adenomas in female mice (control: 1/50; 150 mg/L:
    2/50; 300 mg/L: 6/49)
• Malignant lymphomas in female mice (control: 13/50; 150 mg/L: 28/50;
    300 mg/L: 29/50).
    Moreover, an uncommon bile duct adenoma was observed in one male rat of
the high dose group and three urinary bladder papillomas were found (2 at the
low dose and 1 at the high dose).
After initiation with N-bis(2-hydroxypropyl)nitrosamine or different
nitrosamines given consecutively, oral exposure of rats to MDA had a tumour-
promoting effect on the thyroid but not on the liver, kidney or bladder (in most
studies after initiation with different nitrosamines). In addition to these studies,
several older studies are available, but these are not considered to be relevant for
assessment because of methodological inadequacies or insufficient
documentation (ATSDR, 1998; BUA, 1994; ECB, 2001).21,31,33
Dermal route
A study on the dermal exposure of C3Hf/BD mice reported a dose-related
increase in the incidence of liver tumours after 24-month exposure (3 times per
Human and animal carcinogenicity data on 4,4’-methylenedianiline                     51
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<pre>  week) to 5.3- 21.3 mg/kg • d. Since this strain is particularly sensitive as regards
  the formation of liver tumours, the findings need to be verified (ATSDR, 1998).31
  SCOEL (2012)
  The SCOEL presents a detailed description of the NTP study (1983) as published
  by Weisburger (1984) and Lamb (1986) similar to the AGS (above, and will not
  be copied here).4
  A group of 20 female Sprague-Dawley rats, 40 days old, received 30 mg
  (maximum tolerated dose) 4,4’-diaminodiphenylmethane dihydrochloride
  [purity unspecified] in 1 mL sesame oil by gastric intubation every three days for
  30 days (total dose, 300 mg/rat) and were observed for a further nine months. A
  group of 140 female rats receiving sesame oil alone served as negative controls
  and a group of 40 females receiving single doses of 18 mg 7,12-dimethyl-
  benz[a]anthracene (DMBA) served as positive controls. Survival after nine
  months was 14/20 in the 4,4’-diaminodiphenylmethane dihydrochloride-treated
  group, 127/ 140 in the negativecontrol group and 19/40 in the DMBA-treated
  group. Mammary lesions were found in 5/132 negative controls (three
  carcinomas, one fibroadenoma, five hyperplasias), 29/29 DMBA-treated
  (75 carcinomas, ten fibroadenomas, 47 hyperplasias) and 1/14 4,4’-diamino-
  diphenylmethane dihydrochloride-treated (one hyperplasia) animals (Griswold
  et al., 1968).23
  Groups of eight male and eight female rats [strain and age unspecified] received
  four or five doses of 20 mg/rat 4,4’-diaminodiphenylmethane [purity not stated]
  by gastric intubation over a period of less than eight months and were observed
  until death. One hepatoma and a haemangioma-like tumour of the kidney were
  found in a male rat after 18 months. An adenocarcinoma of the uterus was found
  in one female after 24 months. Most animals had varying degrees of liver fibrosis
  and inflammation (Schoental, 1968).24
  A group of five female pure-bred beagle dogs, five to six months of age, received
  oral administrations of 70 mg 4,4’-diaminodiphenylmethane (‘highly purified’,
  dissolved in corn oil and placed in gelatinous capsules) thrice weekly. A further
  four female beagles received capsules containing ‘crude’ 4,4’-diamino-
  diphenylmethane (50% 4,4’-diaminodiphenylmethane (50% higher molecular
  weight analogues). Total doses were 5.0- 6.26 g/kg bw ‘pure’ 4,4’-diamino-
  diphenylmethane over periods of four-and-a-half to seven years, at which time
  there was one survivor, and 4.0-6.25 g/ kg bw ‘crude’ 4,4’-diaminodiphenyl-
2 4,4’-Methylenedianiline
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<pre>              methane over periods of four to seven years, at which time there were two
              survivors. No tumour of the urinary bladder or liver was found (Deichmann,
              1978).22
              Groups of 25 male and 25 female Wistar rats [age unspecified] received
              subcutaneous injections of 30-50 mg/ kg bw 4,4’-diaminodiphenylmethane in
              physiological saline at one- to three-week intervals over a period of 705 days
              (total dose, 1.4 g/ kg bw). Mean survival times were 970 days for treated males
              and 1060 days for treated females, compared to 1007 days in controls. A total of
              29 benign tumours [types unspecified] and 33 malignant tumours [types
              unspecified] were found in treated rats compared with 15 benign and 16
              malignant tumours in controls. Four hepatomas were reported (Steinhoff and
              Grundmann, 1970).25
              Additional publications
              No new publications were identified by the Committee.
 able 2 Carcinogenicity studies in experimental animals with 4,4’-methylenedianiline (MDA).
 uthors            species             exposure characteristics          findings                         remark
NTP-Study          rat, F344/N         p.o. drinking water dose levels: treatment related increases in
1983)15 ;          50/sex/group        0, 0.015, 0.03%                   the incidences of thyroid
Weisburger et al.                      Xpo: 103 weeks                    follicular-cell carcinomas and
1984)16; Lamb                          Xpe: 104 weeks                    hepatic nodules in males and
 t al. (1986)14                                                          thyroid follicular- cell
                                                                         adenomas in females (see text
                                                                         for actual numbers)
NTP-Study          mouse, B6C3F1       p.o. drinking water dose levels: treatment related increases in
1983)15;           50/sex/group        0, 0.015, 0.03%                   the incidences of thyroid
Weisburger et al.                      Xpo: 103 weeks                    follicular- cell adenomas and
1984)16 ; Lamb                         Xpe: 104 weeks                    hepatocellular neoplasms (see
 t al. (1986)14                                                          text for for exact numbers)
Griswold et al.    rat, Sprague-       p.o. gavage dose: 30 mg every 3 mammary lesions were found         no MDA induced
1968)23            Dawley females      days for 30 days (total dose: 300 in 5/132 controls and in 1 of 14 tumours were found.
                   N = 20 controls:    mg/rat)                           MDA-treated animals              Study design focussed
                   140 females         Xpo: 30 days                                                       on the appearance of
                                       Xpe: 9 months                                                      mammary tumours in
                                       Limited histopathology                                             female SD-rats
 choental          rat, strain not     p.o. gavage dose levels:          a hepatoma and a                 study not suitable for
1968)24            specified           4 or 5 x 20 mg/animal             hemangioma-like tumour of        evaluation of
                   N =16 (8/sex)       Xpo: < 8 months                   the kidney in a male (18         carcinogenic potential
                                       Xpe: lifetime                     months).                         of MDA
                                                                         Uterus adenocarcinoma in one
                                                                         female (24 months)
              Human and animal carcinogenicity data on 4,4’-methylenedianiline                                                53
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<pre>Deichmann et al. dog, Beagle       p.o. gelatineous capsules      no tumours of liver and      study not suitable for
1978)22           females          dose: 70 mg/dog, 3 times       bladder were found.          assessment of
                  N = 5 pure MDA   a week                         MDA-induced liver damage     carcinogenic potential
                  N = 4 “crude”    Xpo: 4 - 7 years               was seen in all animals      of MDA
                  MDA              no control group included      pure MDA: one survivor
                                                                  crude MDA: two survivors
 teinhoff and     rat, Wistar      subcutaneous                   MDA group: 29 benign         limited reporting.
Grundmann         25/sex/group     dose: 30-50 mg/kg bw at one to tumours, 33 malignant        Study not suitable for
1975)25                            3-week intervals (total dose   tumours                      assessment of
                                   1.4 g/kg bw)                   controls: 15 benign tumours, carcinogenic potential
                                   Xpo: 705 days                  16 malignant tumours         of MDA
                                   Xpe: 970 - 1,060 days (MDA);
                                   1,007 days (controls)
Xpo=exposure period, Xpe=experimental period
 4           4,4’-Methylenedianiline
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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory opinions that    cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks                  realise significant                 which carry certain
and opportunities?                    health benefits?                    health risks?
Environmental                         Healthy working                     Innovation and
health                                conditions                          the knowledge
Which environmental                   How can employees                   infrastructure
influences could have                 be protected against                Before we can harvest
a positive or negative                working conditions                  knowledge in the
effect on health?                     that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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