<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 recommendation on occupational exposure limits
To: the State Secretary of Social Affairs and Employment
No. 2018/25, The Hague, December 7, 2018
                                                            2 2
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<pre> Contents                                                                                  4,4’-Methylene bis (2-chloroaniline) | page 2 of 40
 contents
      Samenvatting3                                                03 Carcinogenicity studies                                              16
                                                                       3.1  Human studies                                                    17
      Executive summary                                          5    3.2  Animal experiments                                               17
                                                                       3.3  Selection of the suitable study for risk estimation in
 01 Scope7                                                                 the occupational situation                                       19
      1.1  Background                                            8    3.4  Calculation of the health-based occupational cancer risk values  20
      1.2  Committee and procedure                               8    3.5  Skin notation                                                    22
      1.3  Data                                                  9    3.6  Health-based biological limit value                              24
                                                                       3.7  Groups with increased risk                                       26
 02 Identity, toxicity profile and classification              10     3.8  Conclusions and recommendation                                   26
      2.1  Uses, identity and physical and chemical properties  11
      2.2  Classification as a carcinogenic substance           11    Literature27
      2.3  Toxicity profile                                    12
      2.4  Existing occupational exposure limits               15     Annexes32
                                                                       A    Epidemiological studies                                          33
                                                                       B    Animal studies                                                   34
                                                                       C    BMD-analysis                                                     37
1       Health Council of the Netherlands | No. 2018/25                                                    2                                   3
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<pre> Samenvatting                                                                                          4,4’-Methylene bis (2-chloroaniline) | page 3 of 40
 samenvatting                                                                                          overeenkomen met die risiconiveaus, uitgaande
                                                                                                       van 40 jaar beroepsmatige blootstelling.
 Op verzoek van de minister van Sociale Zaken         zijn in de kunststof- en rubberindustrie kunnen  Streefrisiconiveau en verbodsrisiconiveau
 en Werkgelegenheid (SZW) heeft de                    ermee in aanraking komen.                        Het streefrisiconiveau is 4 op 100.000.
 Gezondheidsraad gezondheidskundige                                                                    Dat betekent dat tot en met 4 extra gevallen op
 advieswaarden afgeleid voor de beroepsmatige         Gezondheidskundige advieswaarden op              100.000 beroepsmatig blootgestelde mensen
 blootstelling aan de kankerverwekkende stof          basis van extra risico op kanker                 geen extra beschermende maatregelen
 4,4’-methyleenbis(2-chlooraniline). Dit advies is    Voor kankerverwekkende stoffen die               genomen hoeven te worden. Het
 tot stand gekomen in de Commissie Gezondheid         geclassificeerd zijn in categorie 1A of 1B en    verbodsrisiconiveau is 4 op 1.000. Dat betekent
 en beroepsmatige blootstelling aan stoffen           directe schade aan het DNA veroorzaken           dat het niveau van 4 extra gevallen op 1.000
 (GBBS). Op www.gezondheidsraad.nl staat              (stochastisch genotoxisch                        beroepsmatig blootgestelde mensen niet
 meer informatie over de taken van deze vaste         werkingsmechanisme) kan geen                     overschreden mag worden.
 commissie van de Gezondheidsraad.                    blootstellingsniveau worden afgeleid waar onder
 De samenstelling van de commissie is te              geen kankerverwekkende effecten kunnen           Geraadpleegde onderzoeken
 vinden achterin dit advies.                          optreden. Om voor deze stoffen toch een          Er zijn geen onderzoeken beschikbaar met
                                                      grenswaarde te kunnen bepalen, heeft de          blootstelling aan 4,4’-methyleenbis(2-
 Gebruik van 4,4’-methyleenbis(2-                     minister van SZW risiconiveaus vastgelegd.       chlooraniline) en het optreden van kanker bij de
 chlooraniline)                                       Deze risiconiveaus betreffen het extra risico op mens die geschikt zijn voor het afleiden van
 4,4’-Methyleenbis(2-chlooraniline) wordt             kanker door beroepsmatige blootstelling          gezondheidskundige advieswaarden. Er zijn
 hoofdzakelijk gebruikt als verhardingsmiddel         gedurende het arbeidzame leven. Als              verschillende dieronderzoeken gedaan naar het
 voor polyurethaan prepolymeren bij het               advieswaarden schat de commissie de              optreden van kanker door blootstelling aan
 vervaardigen van producten van gietbare              concentraties van een stof in de lucht die       4,4’-methyleenbis(2-chlooraniline).
 urethaanrubber. Vooral mensen die werkzaam                                                            De commissie heeft deze onderzoeken
2        Health Council of the Netherlands | No. 2018/25                                                              2                                  4
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<pre> Samenvatting                                                                                         4,4’-Methylene bis (2-chloroaniline) | page 4 of 40
 beoordeeld en de meest geschikte geselecteerd.      0,026 milligram (mg)/per kubieke meter lucht
 In dat onderzoek werden ratten levenslang           (m3). Een extra risico op kanker van 4 per 1.000
 blootgesteld aan 4,4’-methyleenbis                  (het verbodsrisiconiveau) komt overeen met een
 (2-chlooraniline) via het voer en kregen ze         concentratie van 2,6 mg/m3. Beide schattingen
 verschillende soorten tumoren. Het aantal           gaan uit van een 40 jaar beroepsmatige
 longtumoren is door de commissie gebruikt           blootstelling.
 voor het afleiden van de gezondheidskundige
 advieswaarden.                                      Verder adviseert de commissie om een
                                                     huidnotatie (H-aanduiding) toe te passen voor
 Advies aan de staatssecretaris                      4,4’-methyleenbis(2-chlooraniline) omdat
 De commissie schat de concentratie van              huidopname van deze stof substantieel kan
 4,4’-methyleenbis(2-chlooraniline) in de lucht die  bijdragen aan het risico op kanker.
 samenhangt met een extra kans op kanker van
 4 per 100.000 (het streefrisiconiveau) gelijk aan
3       Health Council of the Netherlands | No. 2018/25                                                             2                                   5
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<pre> Executive summary                                                                                       4,4’-Methylene bis (2-chloroaniline) | page 5 of 40
 executive summary                                                                                       exposed people, no additional protective
                                                                                                         measures need to be taken. The prohibitive risk
                                                                                                         level is 4 per 1,000. This means that the
 At the request of the Ministry of Social Affairs     Advisory values based on extra risk of             concentration leading to 4 extra cancer cases
 and Employment, the Health Council of the            cancer                                             per 1,000 occupationally exposed people, must
 Netherlands has derived health-based advisory        For carcinogenic substances that have been         not be exceeded.
 values for 4,4’-methylene bis (2-chloroaniline).     classified in category 1A or 1B and directly
 This advisory report has been composed by the        interact with DNA (stochastic genotoxic            Consulted research
 Dutch Expert Committee on Occupational Safety        mechanism), no exposure level can be derived       There are no studies in humans available on
 (DECOS). More information on the tasks of this       below which no carcinogenic effects can occur.     exposure to 4,4’-methylene bis (2-chloroaniline)
 permanent committee of the Health Council of         To be able to set occupational exposure limits     and the occurrence of cancer that are suitable
 the Netherlands can be found at www.                 for these substances, the Minister of Social       for deriving health-based advisory values. There
 gezondheidsraad.nl. The members of the               Affairs and Employment has determined risk         are different animal carcinogenicity studies
 Committee are listed on the last page of this        levels. These risk levels relate to the extra risk available. The Committee has evaluated these
 report.                                              of cancer due to lifetime occupational exposure.   studies and selected the most suitable one. In
                                                      As advisory values, the Committee estimates        this study, rats exposed to 4,4’-methylene bis
 Use of 4,4’-methylene bis (2-chloroaniline)          the concentrations in the air that correspond to   (2-chloroaniline) via feed during lifetime
 4,4’-Methylene bis (2-chloroaniline) is primarily    these risk levels, taking into account 40 years of developed different types of tumours. The
 used as a curing agent for polyurethane pre-         occupational exposure.                             number of lung tumours has been used by the
 polymers in the manufacture of castable                                                                 Committee to derive the health-based advisory
 urethane rubber products. Particularly workers       Target risk level and prohibitive risk level       values.
 in the plastic and rubber industry can be            The target risk level is 4 per 100,000. This
 exposed to this substance.                           means that for concentrations leading up to 4
                                                      extra cancer cases per 100,000 occupationally
4        Health Council of the Netherlands | No. 2018/25                                                                 2                                 6
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<pre> Executive summary                                       4,4’-Methylene bis (2-chloroaniline) | page 6 of 40
 Recommendation to the State Secretary
 The Committee estimates the concentration of
 4,4’-methylene bis (2-chloroaniline) in the air
 that corresponds to an extra cancer risk of 4 per
 100,000 (the target risk level) equal to 0.026
 milligram (mg)/per cubic metre air (m3). An extra
 risk of cancer of 4 per 1,000 (the prohibitive risk
 level) corresponds to a concentration of 2.6
 mg/m3. Both estimates are based on 40 years of
 occupational exposure.
 In addition, the Committee recommends to
 apply a skin notation for 4,4’-methylene bis
 (2-chloroaniline) because skin absorption can
 contribute substantially to the risk of cancer.
5        Health Council of the Netherlands | No. 2018/25               2                                   7
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<pre> chapter 01 | Scope                                    4,4’-Methylene bis (2-chloroaniline) | page 7 of 40
 01
 scope
6      Health Council of the Netherlands | No. 2018/25               2                                   8
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<pre> chapter 01 | Scope                                                                                         4,4’-Methylene bis (2-chloroaniline) | page 8 of 40
 1.1 Background                                                                by the European Commission or by the Committee as carcinogens in
 At the request of the minister of Social Affairs and Employment, the Dutch    category 1A or 1B.
 expert Committee on Occupational Safety (DECOS), a committee of the           For the establishment of the risk-based advisory values, the Committee
 Health Council of the Netherlands, performs scientific evaluations on the     generally uses a linear extrapolation method, as described in the
 toxicity of substances that are used in the workplace. The purpose of         Committee’s reports Calculating cancer risk and Guideline for the
 these evaluations is to recommend health-based occupational exposure          calculation of occupational cancer risk values.1,2 The linear model to
 limits, which specify levels of exposure to airborne substances, at or        calculate occupational cancer risk is used as a default method, unless
 below which it may be reasonably expected that there is no risk of            scientific data would indicate that using this model is not appropriate.
 adverse health effects.                                                       In the next phase of the three-step procedure, the Social and Economic
 For carcinogenic substances that directly interact with DNA (stochastic       Council advises the Minister of Social Affairs and Employment on the
 genotoxic mechanism), no exposure level can be derived below which no         feasibility of implementing a statutory occupational exposure limit at the
 carcinogenic effects can occur. To be able to set a limit value for these     target level. In the final step of the procedure, the Minister sets the
 substances, the Minister of Social Affairs and Employment has determined      statutory occupational exposure limit.
 risk levels. These risk levels relate to the extra risk of cancer due to life
 time occupational exposure. The target risk level is 4 per 100,000. This      1.2 Committee and procedure
 means that for concentrations leading up to 4 extra cancer cases per          The present document contains the evaluation of the DECOS, hereafter
 100,000 occupationally exposed people, no additional measures need to         called the Committee. The members of the Committee are listed at the
 be taken. The prohibitive risk level is 4 per 1,000. This means that the      end of this report.
 concentration leading to 4 extra cancer cases per 1,000 occupationally        In 2018, the president of the Health Council released a draft of the report
 exposed people, must not be exceeded.                                         for public review. The Committee has taken the comments received into
 DECOS estimates the concentrations in the air that correspond to these        account in deciding on the final version of the report. These comments,
 risk levels, taking into a 40-year occupational exposure. The Committee       and the reply by the Committee, can be found on the website of the Health
 calculates risk-based advisory values for compounds which are classified      Council.
7        Health Council of the Netherlands | No. 2018/25                                                                   2                                  9
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<pre> chapter 01 | Scope                                                    4,4’-Methylene bis (2-chloroaniline) | page 9 of 40
 1.3 Data
 The Committee’s recommendation has been based on scientific data
 which are publicly available. Data were obtained from the online
 databases Toxline and Medline, using carcino*, cancer, neoplastic,
 4,4’-methylene bis (2-chloroaniline) and CAS registry number as key
 words.
 In addition, reviews from the following organisations were consulted:
 • Health Council of The Netherlands3
 •  European Scientific Committee on Occupational Exposure Limits
    (SCOEL)4
 •  International Agency for Research on Cancer (IARC)5-7
 •  Agency for Toxic Substances and Disease Registry (ATSDR)8
 •  National Toxicology Program (NTP)9.
The last literature search was performed in April 2018.
8       Health Council of the Netherlands | No. 2018/25                              2                                   10
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<pre> chapter 02 | Identity, toxicity profile and classification 4,4’-Methylene bis (2-chloroaniline) | page 10 of 40
 02
 identity, toxicity profile
 and classification
9      Health Council of the Netherlands | No. 2018/25                     2                                   11
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<pre> chapter 02 | Identity, toxicity profile and classification                                                                         4,4’-Methylene bis (2-chloroaniline) | page 11 of 40
                                                                                                 Chemical name                                   : 4’4-Methylene bis (2-chloroaniline)
 2.1 Uses, identity and physical and chemical properties                                         Solubility                                        Slightly soluble in water (13.9 mg/l);
                                                                                                                                                   very soluble in benzene, diethyl ether and ethanol;
 4,4’-Methylene bis (2-chloroaniline) is used for the production of                                                                                soluble in (g/100 ml): trichloroethylene (4.2),
                                                                                                                                                 : toluene (7.5), ethoxyethyl acetate (34.4), methyl
 polyurethane pre-polymers in the manufacture of castable rubber                                                                                   ethyl ketone (43.0), tetrahydrofuran (55.5),
 products. More information on the industrial uses, process and product                                                                            dimethylformamide (61.7), and dimethyl sulfoxide
                                                                                                                                                   (75.0)
 categories, sectors of end use and environmental release categories of                          Octanol/water partition coefficient, Log Poct/w : 3.91
 4,4’-methylene bis (2-chloroaniline) is available in the disseminated                           Vapour pressure (60°C)                          : 1.3 x 10-5 mmHg (1.7 mPa)
                                                                                                 Relative vapour density (air = 1)               : No data
 registration dossier of this substance on the ECHA website.10 Physico-                          Flash point                                     : No data
 chemical data shown below are derived from the Hazardous Substances                             Odour threshold                                 : No data
                                                                                                 Conversion factor (25 °C, 101.3 kPa, mg/m3 =      1 mg/m3 = 0.090 ppm
 Data Bank (HSDB) and IARC.5,6,11                                                                molecular weight / 24.45 * ppm)
                                                                                                                                                 :
                                                                                                                                                   1 ppm = 10.9 mg/m3
                                                                                                 EU Harmonised Classification & Labelling          Acute Tox 4: H302; Carc. 1B: H350
  Chemical name                        :  4’4-Methylene bis (2-chloroaniline)                                                                    :
                                                                                                 (EC No 1272/2008 of 16 December 2008)
  CAS number                           :  101-14-4
  EC number                            :  202-918-9
  IUPAC name                           :  4-[(4-Amino-3-chlorophenyl)methyl]-2-chloroaniline
  Synonyms                                MOCA, MBOCA, 4,4’-Methylenebis(o-
                                                                                                2.2 Classification as a carcinogenic substance
                                       :
                                          chloroaniline; 2,2’-dichloro-4,4’-methylenedianiline, The European Commission has classified 4,4’-methylene bis
                                          3,3’-dichloro-4,4’-diamino-diphenylmethane;
                                          methylene-bis-ortho-chloroaniline                     (2-chloroaniline) as a Category 1B carcinogen (presumed to have
  Physical description and colour      :  solid, colourless crystals
                                                                                                carcinogenic potential for humans). In the Netherlands, 4,4’-methylene bis
  Molecular formula                    :  C13H12Cl2N2
  Structure                                                                                     (2-chloroaniline) is included on the SZW-list of carcinogenic substances
                                                                                                and processes, which involves substances classified as category 1A or 1B
                                       :
                                                                                                carcinogen and substances considered as carcinogenic by the Health
  Molecular weight                     :  267.15                                                Council of the Netherlands. IARC has classified 4,4’-methylene bis
  Melting point                        :  110 °C                                                (2-chloroaniline) as a Group 1 carcinogen (Carcinogenic to humans).7
  Boiling point (101.3 kPa)            :  378.9 °C
  Density                              :  1,440 kg/m3
10         Health Council of the Netherlands | No. 2018/25                                                                                             2                                             12
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<pre> chapter 02 | Identity, toxicity profile and classification                                            4,4’-Methylene bis (2-chloroaniline) | page 12 of 40
 2.3 Toxicity profile                                                        and IARC provided limited information on non-neoplastic toxic effects
                                                                             observed in carcinogenicity studies.
 2.3.1 Humans
 Information on acute toxicity in humans was available from two cases of     Acute toxicity
 accidental occupational exposure. A worker which was accidentally           Following a single oral dose of 2,000 mg/kg bw, one out of three female
 sprayed with hot liquid 4,4’-methylene bis (2-chloroaniline) over the face  Sprague-Dawley rats died two days after dosing. Clinical symptoms
 (with some of the substance entering his mouth) complained about            included red discolouration of ear auricles and limbs, and changes in
 burning of the eyes and face and feeling ill in the stomach, and he was     movement and respiration. These symptoms disappeared within two days.
 diagnosed with conjunctivitis in both eyes. Urinalysis suggested            Necropsy of the dead animal revealed white foci in the liver, dark red
 decreased renal tubular protein reabsorption, and possible transient        adrenals, dark red foci in the stomach, and dark red contents in the small
 damage to the renal tubules.12 Another worker was sprayed accidentally      intestines. At 300 and 2,000 mg/kg bw, reduced growth or weight loss
 with molten 4,4’-methylene bis (2-chloroaniline) on his chest, abdomen      occurred during the first few days after dosing. Wistar rats (5/sex) were
 and extremities. He showed slight erythema and complained of a burning      exposed dermally to 4,4’-methylene bis (2-chloroaniline) at 2,000 mg/kg
 sensation of the affected skin.13 The level of exposure in these two cases  bw for 24 hours (occlusive application of a 20% w/w formulation in
 was not known.                                                              propylene glycol at the back; area approximately 25 and 18 cm2 in males
                                                                             and females, respectively). All rats survived and showed normal growth
 2.3.2 Animals                                                               during the 14-day observation period. These two studies indicate low
 Information on acute toxicity, skin and eye irritation/corrosion, skin      acute toxicity of 4,4’-methylene bis (2-chloroaniline) (LD50 approximately
 sensitisation, sub-chronic repeated-dose toxicity and reproduction toxicity 2,000 mg/kg bw for oral exposure and higher than 2,000 mg/kg bw for
 was obtained from the disseminated registration dossier of 4,4’-methylene   dermal exposure).
 bis (2-chloroaniline) on the ECHA website.10 These recent studies
 (reported in 2005 or 2010) were conducted according to OECD and/or EU       Skin and eye irritation and corrosion
 guidelines and Good Laboratory Practice (GLP). The reviews of ATSDR         In vitro, in a human epidermis model (EU guideline B. 46) 4,4’-methylene
                                                                             bis (2-chloroaniline) (10 mg, ground and moistened with 5 µL water) was
11       Health Council of the Netherlands | No. 2018/25                                                               2                                  13
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<pre> chapter 02 | Identity, toxicity profile and classification                                              4,4’-Methylene bis (2-chloroaniline) | page 13 of 40
 non-irritant to skin. The results of a bovine corneal opacity and              50 mg/kg bw, the female rats had decreased weight gain during gestation
 permeability test (OECD guideline 437) showed that 4,4’-methylene bis          with decreased body weights on gestation days 14 and 20. Haematology
 (2-chloroaniline) (applied as a 20% w/w formulation in physiological saline,   showed decreased haemoglobin concentration and haematocrit value and
 357-381 mg per cornea) was not severely irritant or corrosive to the eye.      increased reticulocyte and platelet count in male rats, increased Heinz
                                                                                bodies-containing erythrocytes in female rats, and decreased erythrocyte
 Skin sensitisation                                                             count and methaemoglobin in both sexes at 50 mg/kg bw. Clinical
 4,4’-Methylene bis (2-chloroaniline) was negative in a mouse local lymph       chemistry changes at 50 mg/kg bw included: decreased total protein and
 node assay (OECD guideline 429) in which the substance was tested at           albumin in both sexes; increased total cholesterol, triglycerides and
 concentrations of 10, 25 and 50% in dimethylformamide.                         inorganic phosphorus in male rats; and increased lactate dehydrogenase
                                                                                and gamma-glutamyltransferase activity in both sexes, most pronounced
 Repeated-dose toxicity                                                         in females. Organ weight changes at 50 mg/kg bw consisted of increased
 The toxicity of 4,4’-methylene bis (2-chloroaniline) after sub-chronic         liver and spleen weights in both sexes, and increased kidney and thyroid
 repeated exposure was examined in a combined repeated dose toxicity            weights in females. Treatment-related histopathological changes at 50 mg/
 study with reproduction/ developmental toxicity screening test (OECD           kg bw occurred in the liver, kidneys and spleen. Hepatic changes
 guideline 422). Sprague-Dawley rats (12/sex/dose) were treated with 0,         consisted of swelling and fatty degeneration of hepatocytes in rats of both
 0.4, 2, 10 or 50 mg/kg bw of 4,4’-methylene bis (2-chloroaniline) dissolved    sexes, and single cell necrosis of hepatocytes in male rats. In the kidneys
 in olive oil, once daily during 42 days (males) or up to 4 days after delivery basophilic change of renal tubules occurred at increased incidence and
 (females) by oral gavage. No adverse health effects were observed up to        severity in male rats. Changes in the spleen (red pulp) consisted of
 a dose of 2 mg/kg bw. Adverse effects at 10 mg/kg bw included:                 increases in the severity (from mild to moderate) of hemosiderin deposits
 decreased plasma concentrations of total protein and albumin in female         in both sexes, and extramedullary haematopoiesis in female rats.
 rats; increased relative kidney weight in female rats; and slight
 histopathological alterations in the kidneys (increased incidence and          Information on non-cancer effects upon chronic exposure to
 severity of basophilic change of renal tubules) and spleen (increased          4,4’-methylene bis (2-chloroaniline) is available from the carcinogenicity
 severity, from mild to moderate, of hemosiderin deposits) in male rats. At     studies evaluated by the Committee (see Chapter 3 and Table in Annex
12       Health Council of the Netherlands | No. 2018/25                                                                 2                                  14
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<pre> chapter 02 | Identity, toxicity profile and classification                                                 4,4’-Methylene bis (2-chloroaniline) | page 14 of 40
 C). In several of these studies 4,4’-methylene bis (2-chloroaniline)            Reproduction toxicity
 adversely affected survival, growth and liver. In a feeding study by            4,4’-Methylene bis (2-chloroaniline) is not classified for reproduction
 Kommineni et al. (1979)14, rats were exposed to approximately 40 mg/kg          toxicity. The results of the above noted combined repeated dose toxicity
 bw/day for 18 months. Compared to controls, they gained markedly less           study with reproduction/developmental toxicity screening test in rats did
 weight and had slightly lower levels of haemoglobin and haematocrit. In a       not show changes indicative of reproduction or developmental toxicity.
 lifespan study by Russfield et al. (1975)15, rats given 4,4’-methylene bis
 (2-chloroaniline) via their diet had approximately 6% (20 mg/kg bw/day) or      2.3.3 Genotoxicity studies
 13% (40 mg/kg bw/day) lower mean body weights than controls at the end          Studies investigating the genotoxicity of 4,4’-methylene bis
 of the 18-month treatment period. These differences persisted to the time       (2-chloroaniline) have been summarised by the International Agency for
 of necropsy. Liver changes were observed by Stula et al. (1975)16 in rats       Research on Cancer (IARC)5,6, the Agency for Toxic Substances and
 fed 4,4’-methylene bis (2-chloroaniline) at 40 mg/kg bw/day for 2 years,        Disease Registry (ATSDR)8 and by McQueen et al. (1990)17. A short
 and included hepatocytomegaly, fatty change, necrosis, fibrosis and bile        compilation of their reviews is given below.
 duct proliferation (incidences of these findings were not reported). Liver      The reviews show that 4,4’-methylene bis (2-chloroaniline) is mutagenic in
 changes were also seen in dogs treated orally (capsules) with                   the Salmonella typhimurium strains TA98 and TA100, and at the Tk locus
 approximately 10 mg/kg bw/day for up to 9 years. Histopathologic                in mouse lymphoma L5178Y cells, after metabolic activation. Furthermore,
 examination revealed nodular hepatic hyperplasia (distorted liver               unscheduled DNA synthesis was induced in HeLa cells18 and in primary
 architecture; sharp demarcation of nodule from surrounding liver) in three      hepatocytes from rats, mice, hamsters, and rabbits19. In vivo, the
 of the six treated dogs, but not in controls. Clinical chemistry revealed       substance-induced sister chromatid exchange in rat lymphocytes20,
 statistically significantly higher activity of glutamic pyruvic transaminase in mutations in Drosophila melanogaster21, and micronuclei in the bone
 blood of treated dogs compared with controls. In addition, treated dogs         marrow of mice22. Increased frequencies of sister chromatid exchanges in
 had increased numbers of erythrocytes, leukocytes and epithelial cells in       peripheral lymphocytes20, and of micronuclei in peripheral lymphocytes
 the urine sediment (some epithelial cells showed changes suggestive of          and exfoliated urothelial cells23,24, were observed in small groups of
 neoplasia in the genitourinary tract).                                          workers exposed to 4,4’-methylene bis (2-chloroaniline).
13       Health Council of the Netherlands | No. 2018/25                                                                    2                                  15
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<pre> chapter 02 | Identity, toxicity profile and classification                                                            4,4’-Methylene bis (2-chloroaniline) | page 15 of 40
 4,4’-Methylene bis (2-chloroaniline) induced DNA adducts in the liver, lung Table 1. Occupational exposure limits of 4,4’-methylene bis (2-chloroaniline)a
                                                                               Country                                   OEL       OEL        Time-         Type of           Skin
 and kidney of rats following a single oral dose25, in the liver and bladder   (Organisation)                            (ppm)     (mg/m3)    weighted      exposure          notation
                                                                                                                                              average       limita
 epithelium of dogs after a single or multiple doses26, and in cultured
                                                                               The Netherlands                           -         0.02       8h            OEL               yes
 canine and human urinary bladder cells27. DNA adducts were also               European Commission                       -         -          -             -                 yes
 detected in exfoliated urothelial cells present in urine samples obtained     Germany (DFG)                             -         -          -             -                 yes
                                                                               Germany (AGS)                             -         -          -             -                 -
 from a worker between 4 and 98 hours after his accidental exposure to
                                                                               UK (HSE)                                  -         0.005      8h            WEL               yes
 4,4’-methylene bis (2-chloroaniline).   13,28
                                                                               Denmark                                   0.01      0.11       8h            OEL               yes
                                                                               Sweden                                    -         -          -             -                 -
 The Committee noticed that the above genotoxicity data are from studies
                                                                               USA (NIOSH)                               -         0.003      -             REL               yes
 published in the open literature and predate modern test guidelines and        Abbreviations: OEL, occupational exposure limit; WEL, workplace exposure limit; REL, recommended exposure
                                                                                limit.
 GLP. There are no publicly available genotoxicity studies conducted         a
                                                                                Sources: SER OEL database (https://www.ser.nl/en/oel_database.aspx); GESTIS International Limit Values
                                                                                (http://limitvalue.ifa.dguv.de/) [accessed October, 2018]
 according to OECD guidelines. Based on the available data and in
 consultation with the Health Council’s Subcommittee on the Classification   The SCOEL evaluated the carcinogenicity of 4,4’-methylene bis
 of carcinogenic substances, the Committee considers 4,4’-methylene bis      (2-chloroaniline) and concluded that this substance is a genotoxic
 (2-chloroaniline) to be a carcinogen acting by a stochastic genotoxic       carcinogen to which a threshold cannot be assigned. Therefore, the
 mechanism.                                                                  SCOEL did not assign a health-based occupational exposure limit to
 The SCOEL considers 4,4’-methylene bis (2-chloroaniline) as a Group A       4,4’-methylene bis (2-chloroaniline).4
 carcinogen (non-threshold genotoxic carcinogen).4
 2.4 Existing occupational exposure limits
 Table 1 summarizes the occupational exposure limits established by
 national and international regulatory authorities.
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<pre> chapter 03 | Carcinogenicity studies                  4,4’-Methylene bis (2-chloroaniline) | page 16 of 40
 03
 carcinogenicity studies
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<pre> chapter 03 | Carcinogenicity studies                                                                   4,4’-Methylene bis (2-chloroaniline) | page 17 of 40
 3.1 Human studies                                                            non-invasive papillary tumours of the bladder were identified, two in
 The Committee has identified four epidemiological studies with               non-smoking men aged 28-29 years and one in a 44-year old ex-smoker.
 4,4’-methylene bis (2-chloroaniline). In Annex A these studies have been     In a retrospective cohort study by Linch et al. (1971)33, 31 workers who
 summarised.                                                                  had been exposed to 4,4’-methylene bis (2-chloroaniline) for between 6
 In a retrospective cohort study, Dost et al. (2009)29 compared the mortality months and 16 years and 31 controls were recruited for urine cytology. No
 and cancer incidence in 308 male production workers from seven               deaths and no malignancies were observed in exposed and non-exposed
 factories, manufacturing polyurethane elastomers using 4,4’-methylene        individuals.
 bis (2-chloroaniline), with expected values based on national rates. All     The studies described above have significant limitations in design and or
 workers were exposed to 4,4’-methylene bis (2-chloroaniline) for at least    reporting (see Annex A), including: lack of information on exposure levels
 12 months. Overall cancer mortality and incidence were below average         and/or duration; lack of control group; small number of participants;
 but there was a single death from bladder cancer, and a non-significant      possible exposure to other carcinogens. Therefore, the Committee
 excess of malignant bladder cancer based on two cases only.                  concludes that these studies are inadequate to evaluate the relationship
 In a retrospective cohort study by Chen et al. (2005)30, 76 workers          between human cancer and exposure to 4,4’-methylene bis
 potentially exposed to 4,4’-methylene bis (2-chloroaniline) and another 92   (2-chloroaniline).
 non-exposed workers of four Taiwanese factories were recruited for
 bladder cancer screening. Among the 70 exposed workers who                   3.2 Animal experiments
 participated in the screening program, one proven bladder carcinoma was      Annex B summarises the available carcinogenicity studies in animals.
 observed. In addition, one worker with suspected malignant cells on urine    These studies comprise eight oral studies: six performed with rats, one
 cytology (suspected bladder cancer), and one worker with atypical            with mice, and one with dogs. Furthermore, one study in rats with
 cytology combined with gross haematuria were identified. Both workers        subcutaneous injection is available. No long-term inhalation or dermal
 refused additional cystoscopic examination.                                  studies were available. In three of the oral rat studies, a protein-deficient
 Ward et al. (1988, 1990)31,32 conducted a bladder cancer incidence study     diet was used. Grundmann and Steinhoff (1970)34 used a protein-deficient
 (retrospective cohort, no control group) among approximately 540 workers     diet on account of findings in older studies, which showed delay or
 exposed to 4,4’-methylene bis (2-chloroaniline). Three cases with            prevention of the appearance of liver tumours in rats fed azo-compounds
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<pre> chapter 03 | Carcinogenicity studies                                                                      4,4’-Methylene bis (2-chloroaniline) | page 18 of 40
 in protein-adequate diet compared with rats fed diet deficient in protein      bw/day and showed a dose-related response. The tumours in the other
 and other nutrients. Thereafter, Kommineni et al. (1979)14 and Stula et al.    organs occurred at lower incidences than those in the lung.
 (1975)16 examined the carcinogenicity of 4,4’-methylene bis                    In a well-performed study by Stula et al. (1971, 1975)16,35, male and female
 (2-chloroaniline) in rats kept on either protein-deficient diet or normal diet Charles River CD (SD) rats (50/sex/group) received normal diet (23%
 adequate in protein. The studies in rats administered 4,4’-methylene bis       protein) containing 0 or 1,000 mg of 4,4’-methylene bis (2-chloroaniline)
 (2-chloroaniline) via protein-deficient diet or subcutaneously are not         per kg diet for up to two years. These dietary concentrations were
 relevant for derivation of occupational cancer risk values due to the          equivalent to 40 and 50 mg/kg bw/day in male and female rats,
 unphysiological testing conditions or use of an irrelevant exposure route.     respectively (based on default food intake values of 40 and 50 g/kg body
 The five remaining oral studies are described below.                           weight/day in male and female rats, respectively). Lifespan was shortened
                                                                                in the rats exposed to 4,4’-methylene bis (2-chloroaniline). The substance-
 In a well-performed study by Kommineni et al. (1979)14, male Sprague-          induced lung adenomatosis (preneoplastic lesion progressing to
 Dawley rats received protein-adequate diet containing 4,4’-methylene bis       adenocarcinomas) and lung adenocarcinomas in many male and female
 (2-chloroaniline) at 0, 250, 500 or 1,000 mg/kg diet (100, 100, 75 and 50      rats. The incidences of these lung tumours in treated male and female rats
 rats per group, respectively). These dietary concentrations were               were statistically significantly higher compared with controls. Squamous-
 equivalent to 10, 20 and 40 mg/kg bw/day, respectively (based on a             cell carcinoma of the lung, pleural biphasic tumours, hepatocellular
 default food intake value of 40 g/kg bw/day). The rats were fed the            adenomas and hepatocellular carcinomas were observed in one or a few
 substance for 18 months, after which they were maintained on their             treated male and female rats but not in controls.
 respective diet without the substance for 6 months. Survival was               In a supportive study by Russfield et al. (1975)15, male Charles River CD-1
 statistically significantly lower at 20 and 40 mg/kg bw/day compared with      rats (25/group) received normal diet containing the hydrochloride salt of
 controls. Body weight gain was markedly lower at 40 mg/kg bw/day               4,4’-methylene bis (2-chloroaniline) at 500 or 1,000 mg/kg diet for 18
 compared with controls. 4,4’-methylene bis (2-chloroaniline) induced lung      months, and then kept untreated for 6 months. These dietary
 adenocarcinomas, mammary adenocarcinomas, Zymbal gland                         concentrations were equivalent to 20 and 40 mg/kg bw/day, respectively
 carcinomas and hepatocellular carcinomas. The incidences of the lung           (based on a default food intake value of 40 g/kg bw/day). Survival of
 tumours were statistically significantly increased at 10, 20 and 40 mg/kg      treated rats did not differ greatly from that of controls. Mean body weights
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<pre> chapter 03 | Carcinogenicity studies                                                                    4,4’-Methylene bis (2-chloroaniline) | page 19 of 40
 were slightly lower compared with controls (on average up to 13% at 40       higher (not statistically significantly) in treated male and female mice than
 mg/kg bw/day at 18 months and thereafter). Hepatomas (without                in concurrent controls. As the incidence of vascular tumours in treated
 malignancy features) and lung adenomatosis were seen in several treated      mice was in the historical control range, the occurrence of these tumours
 rats, most frequently at the highest dose level, but in none of the controls cannot be attributed unequivocally to the treatment with 4,4’-methylene bis
 (differences were not statistically significant).                            (2-chloroaniline).
 Stula et al. (1978)36 treated female beagle dogs (six/dose) with 0 or 100
 mg of 4,4’-methylene bis (2-chloroaniline) by capsule (orally), 3 or 5 days/ In conclusion, of the eight available oral carcinogenicity studies in animals,
 week, for up to nine years (average dose 8-15 mg/kg bw/day). The             three were considered not relevant for derivation of occupational cancer
 substance-induced urinary bladder papillary transitional cell carcinoma in   risk values due to unphysiological testing conditions (protein-deficient
 four of the six treated dogs. Another treated dog developed a composite      diet). The well-performed rat feeding study by Kommineni et al. (1979)14
 tumour (transitional cell carcinoma/adenocarcinoma) in the urethra. The      was considered most suitable for assessment of cancer risk (see next
 sixth treated dog had no tumours (this dog died after 3.4 years due to       section). The other oral studies were less adequate for this purpose due to
 causes not related to treatment with 4,4’-methylene bis (2-chloroaniline)).  limitations in design (only one dose level tested and/or low number of
 In a study by Russfield et al. (1975)15, HaM/ICR mice (25/sex/group) were    animals), but provided supportive evidence that 4,4’-methylene bis
 exposed to the hydrochloride salt of 4,4’-methylene bis (2-chloroaniline)    (2-chloroaniline) is carcinogenic in experimental animals.
 at 1,000 or 2,000 mg/kg diet for 18 months, and then kept untreated for 6
 months. These dietary concentrations were equivalent to 120 and 240          3.3 Selection of the suitable study for risk estimation in the
 mg/kg bw/day in males and 130 and 260 mg/kg bw/day in females (based                occupational situation
 on default food intake values of 120 and 130 g/kg bw/day in male and         The Committee considers the study by Kommineni et al. (1979)14 in male
 female mice, respectively). Compared with controls, the incidence of         Sprague-Dawley rats, kept on a normal protein-adequate diet, to be the
 hepatomas was statistically significantly increased in female mice at 130    most suitable study available for estimation of the potential cancer risk in
 and 260 mg/kg bw/day. Malignancy features were seen in hepatomas of          humans under occupational exposure conditions. The study is well
 some treated mice. Additionally, the incidence of vascular tumours           performed, the exposure period covered the largest part of the standard
 (generally subcutaneous haemangiomas and haemangiosarcomas) was              lifespan of the experimental animals, group sizes are adequate, and
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<pre> chapter 03 | Carcinogenicity studies                                                                      4,4’-Methylene bis (2-chloroaniline) | page 20 of 40
 sufficient dose levels have been tested. The study is adequate to use the      starting point for quantitative hazard assessment. The study of
 benchmark dose method for estimation of a starting point for quantitative      Grundmann and Steinhoff (1970)37 included only one (high) dose level and
 risk estimation. Limitations of this study are that individual animal data are is, therefore, not adequate for the benchmark dose method. Moreover, a
 not reported and only one sex has been tested. The incidence of lung           protein-deficient diet was used in the study of Grundmann and Steinhoff
 adenocarcinomas was selected as basis for cancer risk derivation since         (1970)37. Such unphysiological testing conditions render the study less
 this type of tumour is relevant for humans, and its incidence was dose-        suitable for derivation of occupational cancer risk values.
 dependently and statistically significantly increased from the lowest dose     As concluded at the end of section 2.3, the Committee considers
 level tested (250 mg/kg diet, equivalent to 10 mg/kg bw/day). The              4,4’-methylene bis (2-chloroaniline) to be a carcinogen acting by a
 incidences of the other malignant tumours induced by 4,4’-methylene bis        stochastic genotoxic mechanism.
 (2-chloroaniline) in this study were increased to a lesser extent and did not
 reach statistical significance at all dose levels tested.                      3.4 Calculation of the health-based occupational cancer risk
 In its previous evaluation of 4,4’-methylene bis (2-chloroaniline) (published         values
 in 2000)3, the Committee calculated cancer risk values (0.02 and 2 mg/m3
 for an extra cancer risk of 4 per 100,000 and 4 per 1,000, respectively) on    3.4.1 Carcinogenic activity in experimental animals, lifetime
 the basis of the incidence of the number of rats (males and females                    exposure
 combined) with malignant tumours in the oral carcinogenicity study of          To calculate the carcinogenic activity expressed as the incidence per unit
 Grundmann and Steinhoff (1970)34. This study was selected because it           daily dose (mg per kg bw per day) of 4,4’-methylene bis (2-chloroaniline),
 yielded the highest tumour incidence per unit daily dose (calculations were    the number of male rats with lung adenocarcinomas was used as starting
 also made for three other studies that were considered suitable, namely:       point. Since the actual values for daily food or 4,4’-methylene bis
 the rat studies of Stula et al. (1975)16 and Kommineni et al.(1979)14, and     (2-chloroaniline) intake per kg body weight are not given in the available
 the mouse study of Russfield et al. (1975)15).                                 publication, the standard value for daily food intake per kg body weight (40
 In the present re-evaluation, the Committee selected the study of              g/kg bw/day for male rats) mentioned in the report of the Health Council of
 Kommineni et al. (1979)14 for derivation of cancer risk values because this    the Netherlands on calculating cancer risk1 was used to calculate the daily
 study is adequate to use the benchmark dose method for estimation of a         dose of 4,4’-methylene bis (2-chloroaniline). Hence, the dietary levels of
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<pre> chapter 03 | Carcinogenicity studies                                                                4,4’-Methylene bis (2-chloroaniline) | page 21 of 40
 250, 500 and 1,000 mg/kg diet were calculated to provide 10, 20 and 40    Where:
 mg/kg bw/day, respectively. The Committee prefers the benchmark dose      • Idose= the carcinogenic activity attributable to the exposure to the
 (BMD) method for estimation of the starting point for calculation of the      substance per unit daily dose expressed per mg/kg bw/day.
 carcinogenic activity. Until recently, the Committee used the BMDS        • BMR = benchmark response, expressed as an increase in tumour
 software by U.S. EPA. Here, the Committee decided to switch to the            incidence of 10%.
 PROAST software, which is developed by the RIVM and made available        • BMD = benchmark dose (estimate of the daily dose expected to yield
 by EFSA. PROAST provides model averaged BMDL and BMDU values,                 the BMR).
 taking into account various models, from which a weighted BMD can be      • Xpo and Xpe are the exposure and experimental periods, respectively.
 derived. This analysis takes into account all possible values of the true • L = standard lifespan for the animals in question (L rat is assumed to be
 BMD based on the available data, and is therefore used for calculation of     1,000 days).
 the HB-OCRV. The results of these BMD-analyses and the criteria for
 model acceptance are given in Annex C.                                    3.4.2 Health risk to humans, exposure under occupational
                                                                                    conditions
 The cancer incidence per unit daily dose (mg/kg bw/day) (lifespan         To estimate the additional lifetime risk of cancer in humans on the basis of
 conditions, assuming a linear concentration-response relationship) is     results in animal experiments, it is assumed that no difference exists
 calculated as follows:                                                    between experimental animals and man with respect to toxicokinetics,
                                                                           mechanism of tumour induction, target, susceptibility etc. Furthermore, it
                                                                           is assumed 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. To estimate the additional lifetime risk of cancer in humans under
                                                                           workplace exposure conditions it is further assumed that the average
                                                                           worker is exposed 8 hours per day, 5 days per week, 48 weeks per year
                                                                           for 40 years and inhales 10 m3 air per 8-hour-working day.
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<pre> chapter 03 | Carcinogenicity studies                                                                   4,4’-Methylene bis (2-chloroaniline) | page 22 of 40
 Using as starting point the estimated incidence of 3.0 x 10-2 per mg/kg bw,  need to prevent skin contamination when systemic effects may result from
 the additional lifetime cancer risk per mg/m3 under occupational exposure    percutaneous absorption of a substance as a gas, a solid, or a liquid. To
 conditions (= HBC-OCRV) amounts to:                                          determine whether a skin notation needs to be applied, the Committee
                                                                              uses the ECETOC document “Strategy for assigning a skin notation”.38
                                                                              According to the guidance, a skin notation is warranted when human
                                                                              experience indicates the importance of skin penetration. A skin notation
                                                                              should be applied when exposure of 2,000 cm2 of skin (both hands and
 3.4.3 Occupational cancer risk values                                        forearms) to 4,4’-methylene bis (2-chloroaniline) during one hour could
 Based on the HBC-OCRV of 1.5 x 10-3 per mg/m3 the Committee                  result in an absorbed amount exceeding 10% of the amount that can be
 estimated that the concentration of 4,4’-methylene bis (2-chloroaniline) in  absorbed via the lungs on exposure for eight hours to the HBC-OCRV.
 the air, which corresponds to an excess cancer risk of:                      Absorption through the skin is considered the major route of uptake of
 • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to     4,4’-methylene bis (2-chloroaniline) at the workplace.4 There are no skin
    2.6 mg/m3                                                                 absorption studies with 4,4’-methylene bis (2-chloroaniline) that have been
 •  4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to  conducted according to modern test guidelines. Data on absorption of
    0.026 mg/m3.                                                              4,4’-methylene bis (2-chloroaniline) through human skin is available from
                                                                              two older in vitro studies. These studies used different testing conditions
 The toxicity data as summarised in this report allows the Committee to       which do not meet modern guideline criteria. Particularly, these studies
 conclude that no adverse health effects other than carcinogenicity at the    used aqueous receptor fluids without protein, which in vivo would drive
 concentration levels associated with the referential cancer risk levels are  absorption through protein binding. The Committee estimated potentially
 expected.                                                                    absorbed amounts of 4,4’-methylene bis (2-chloroaniline) using absorption
                                                                              rates from both studies.
 3.5 Skin notation                                                            Chin et al (1983) exposed ten fresh, full-thickness human neonatal
 The Committee assessed whether for 4,4’-methylene bis (2-chloroaniline)      foreskins to dry 4,4’-methylene bis (2-chloroaniline) (on a coverglass) for
 a skin notation is needed. The purpose of a skin notation is to indicate the four hours, in a static system.39 He measured penetration rates between
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<pre> chapter 03 | Carcinogenicity studies                                                                     4,4’-Methylene bis (2-chloroaniline) | page 23 of 40
 0.27 and 1.29 µg/cm2 in 4 hours (corresponding to 0.068 and 0.32 µg/cm2/      In both studies, a significant amount of 4,4’-methylene bis (2-chloroaniline)
 hour), based on the recovery of radioactivity on the supporting membrane      was retained in the skin, which was not accounted for in the skin
 filter below the skin. Recovery in the receptor fluid was negligible. The     absorption rate. As 4,4’-methylene bis (2-chloroaniline) is a lipophilic
 distribution of radioactivity in the skin and membrane was between            substance, artificial retention of this substance in the skin may occur when
 45-73% and 26-53%, respectively, when expressed as proportion of the          using receptor fluids in which it dissolves poorly. In such situations, the
 amount of radioactivity recovered from the skin, membrane plus medium.        OECD guidance recommends to determine total skin absorption based on
 The latter amount showed large inter-individual variation: values ranged      both skin and receptor fluid levels of the test substance. Neither of the
 from about 15% to 90% of total recovery (from coverglass, skin,               above studies provided data on the solubility of 4,4’-methylene bis
 membrane and medium). Based on the absorption rates measured in this          (2-chloroaniline) in the receptor fluid. As aqueous receptor fluids were
 study, the uptake of 4,4’-methylene bis (2-chloroaniline) on 2,000 cm2 per    used, and absorption was calculated from receptor fluid or supporting
 hour ranges between 135 - 645 µg.                                             membrane data alone, the absorption rates from these studies may
 Hotchkiss et al. (1993) exposed fresh, full-thickness human breast skin to    underestimate in vivo absorption.
 a solution of 4,4’-methylene bis (2-chloroaniline) in ethanol for 72 hours in
 flow-through diffusion cells, on four occasions.40 The absorption rates       Assuming that a volume of 10 m3 is inhaled in eight hours and that a
 through unoccluded skin ranged from 0.0031 to 0.041 µg/cm2/hour, based        fraction (by default assumed to be 0.5 by ECETOC) of the atmospheric
 on the recovery of radioactivity in the receptor fluid at 72 hours. The       4,4’-methylene bis (2-chloroaniline) is absorbed by inhalation, the
 percentage of absorption through the skin was low. At 72 hours, 1.4-4.7%      maximum uptake by inhalation upon exposure for eight hours at the
 of the applied dose was recovered from the receptor fluid. Considerable       HBC-OCRV is
 amounts of residual radioactivity remained within the skin (or adhered to     • 2.6 mg/m3 (HBC-OCRV, 4x10-3) x 10 m3 x 0.5 = 13 mg (10% hereof is
 it) and on the skin surface (on average 31% and 42%, respectively).              1,300 µg)
 Based on the absorption rates measured in this study, the uptake of           • 0.026 mg/m3 (HBC-OCRV, 4x10-5) x 10 m3 x 0.5= 0.13 mg (10% hereof
 4,4’-methylene bis (2-chloroaniline) on 2,000 cm2 per hour ranges                is 13 µg).
 between 6-82 µg.
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<pre> chapter 03 | Carcinogenicity studies                                                                   4,4’-Methylene bis (2-chloroaniline) | page 24 of 40
 Based on the above calculations, the Committee concludes that dermal         Different countries have established biological monitoring guidance values
 exposure can considerably contribute to the systemic exposure to             for urinary 4,4’-methylene bis (2-chloroaniline) based on values that can
 4,4’-methylene bis (2-chloroaniline) and that a skin notation for            be reached using good working practises at the workplace, but not on
 4,4’-methylene bis (2-chloroaniline) is required.                            health effects (the values below refer to urinary concentrations of total
                                                                              4,4’-methylene bis (2-chloroaniline) unless indicated otherwise):
 3.6 Health-based biological limit value                                      • 15 µmol/mol creatinine in Great Britain (Health and Safety Executive)42
 The Committee is aware that in industrial practice exposure assessment       • 5 µmol/mol creatinine in Finland (Finnish Institute of Occupational
 of workers to 4,4’-methylene bis (2-chloroaniline) is routinely carried out     Health)43
 by biological monitoring (post-shift measurement in urine) rather than by    • 100 µg free 4,4’-methylene bis (2-chloroaniline)/L in California
 ambient air monitoring. 4,4’-Methylene bis (2-chloroaniline) has a low          (California Occupational Safety and Health Administration)44
 vapour pressure and the main route of systemic exposure is dermal            •  15 µmol/mol creatinine in Australia (Workcover NSW Biological
 penetration.4,7                                                                 Occupational Exposure Limit (BOEL) Committee)45
 Several regulatory authorities assigned a skin notation to their             •  50 µg/g creatinine (about 20 µmol/mol creatinine) in Japan (Japan
 occupational exposure limit for 4,4’-methylene bis (2-chloroaniline) (see       Society for Occupational Health)46
 section 2.4). Exposure of workers manufacturing33 or using41                 • 5 µmol/mol creatinine recommended by SCOEL4.
 4,4’-methylene bis (2-chloroaniline) was monitored by measuring both         In France, Robert et al. (1999) proposed a biological guiding value of 20
 personal air exposure levels and urinary excretion. The measured urinary     µg sulfamic acid-labile 4,4’-methylene bis (2-chloroaniline)/L (about 30 µg
 excretion of 4,4’-methylene bis (2-chloroaniline) was much higher than the   total 4,4’-methylene bis (2-chloroaniline)/L).47 The ACGIH has listed total
 urinary excretion estimated from the personal air exposure levels,           4,4’-methylene bis (2-chloroaniline) in urine as adopted biological
 suggesting that a significant amount of 4,4’-methylene bis (2-chloroaniline) exposure determinant, but has refrained from providing a numerical
 is absorbed by other routes than inhalation. This implies that               Biological Exposure index due to insufficient data.4
 measurement of airborne 4,4’-methylene bis (2-chloroaniline) alone is
 likely to underestimate systemic exposure to this substance.                 Considering the relevance of systemic exposure to 4,4’-methylene bis
                                                                              (2-chloroaniline) via absorption through the skin and the current industrial
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<pre> chapter 03 | Carcinogenicity studies                                                                        4,4’-Methylene bis (2-chloroaniline) | page 25 of 40
 practice of worker exposure assessment by biomonitoring, the Committee              39% of that of total urinary 4,4’-methylene bis (2-chloroaniline).47 Dividing
 calculated a health-based biological limit value (BLV) corresponding with           the dog value of 0.54% for excretion of the unchanged compound by
 the HBC-OCRV of 2.6 mg/m3 for an additional life time cancer risk of                39% yields a value of 1.4% for the excretion of total 4,4’-methylene bis
 4x10-3 for 40 years of occupational exposure to 4,4’-methylene bis                  (2-chloroaniline).
 (2-chloroaniline).                                                               • F is the biological availability (by inhalation). A default value of 50% was
 Applying the general formula for urinary excretion of a substance in the            applied since a value in humans or animals has not been determined.
 urine, the cumulative amount of 4,4’-methylene bis (2-chloroaniline),            • r is the maximum absorption, which equals the ventilation rate
 including parent compound and metabolites, excreted at time t is                    multiplied by the exposure concentration.
 calculated as:                                                                   • k is the elimination constant.
                                                                                  • t is the time.
 U = f x F x {(r x t) – [(r/k) x (1-e- k x t)]}
                                                                                  Assuming an hourly ventilation rate of 1.25 m3 for an operator and an
 Where:                                                                           8-hour working day, the totally inhaled volume per day is 10 m3. With the
 • U is the cumulative amount of substance excreted into the urine at time        average amount of creatinine excreted during the day in the urine denoted
    t.                                                                            by “cr”, A BLV (in mg/g creatinine) can be calculated from the following
 • f is the fraction of the absorbed amount of total 4,4’-methylene bis           formula:
    (2-chloroaniline) that is excreted into the urine. The value applied was
    1.4%, based on the urinary excretion of unchanged 4,4’-methylene bis          BLV = [(f x F)/cr] x {(10 x OEL) – [[(10 x OEL)/(8 x k)] x (1 – e(-8 x k))]} or,
    (2-chloroaniline) in dogs and the ratio unchanged/total 4,4’-methylene bis    considering k equals (ln 2)/t½,
    (2-chloroaniline) in the urine of humans. In dogs 0.54% of systemically
    available 4,4’-methylene bis (2-chloroaniline) was excreted unchanged         BLV = [(f x F)/cr] x (10 x OEL) x (1 – {[(ln2)/(8 x t½)] x (1 – e[(-8 x (ln2))/
    into the urine in 24 hours.48 This value closely resembles that in rats.49 In t½])}, with ln 2 = 0.693 and cr = 1.5 g,
    workers potentially exposed to 4,4’-methylene bis (2-chloroaniline), the
    geometric mean urinary concentration of the unchanged compound was            BLV = 6.7 x f x F x OEL x {1 – 0.18 x t½ x (1 – e(-5.54/t½))}
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<pre> chapter 03 | Carcinogenicity studies                                                                   4,4’-Methylene bis (2-chloroaniline) | page 26 of 40
 Using a urinary half-life of 4,4’-methylene bis (2-chloroaniline) of        adenocarcinomas in male rats, observed in the study by Kommineni et al.
 approximately 23 hours13, and an OEL of 2.6 mg/m3, this leads to the        (1979)14, as the critical effect for cancer hazard quantification.
 following value for the BLV:
                                                                             The Committee estimated that the concentration of 4,4’-methylene bis
 BLV = 6.7 x 0.014 x 0.5 x 2.6 x {1 – 0.18 x 23 x (1 - e(-5.54/23))} = 0.014 (2-chloroaniline) in the air, which corresponds to an excess cancer risk of:
 mg/g creatinine.                                                            • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to
                                                                                2.6 mg/m3
 The value of 14 μg/g creatinine is equivalent to 6 μmol/mol creatinine      •  4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
 (based on molecular weights of 267.15 for 4,4’-methylene bis                   0.026 mg/m3.
 (2-chloroaniline) and of 113.12 for creatinine.
                                                                             The Committee concludes that applying these exposure values provides
 The calculated BLV of 6 µmol/mol creatinine (corresponding to the           sufficient protection against the non-carcinogenic effects of 4,4’-methylene
 HBC-OCRV of 2.6 mg/m3 for an excess cancer risk of 4 per 1,000) is close    bis (2-chloroaniline). Taking into account an exposure level of 2.6 mg/m3,
 to the value of 5 µmol/mol creatinine noted by SCOEL4 and the Finnish       the Committee considers a skin notation warranted because dermal
 Institute of Occupational Health43, and somewhat lower than the values      penetration may contribute significantly to the body burden of
 established in Great Britain42, Australia45 and Japan46 (15-20 µmol/mol).   4,4’-methylene bis (2-chloroaniline).
                                                                             The Committee calculated a health-based biological limit value based on
 3.7 Groups with increased risk                                              this exposure level of 2.6 mg/m3. This value, a concentration of total
 No groups with increased risk were identified by the Committee.             4,4’-methylene bis (2-chloroaniline) in the urine, corresponds to a value of
                                                                             14 μg/g creatinine (6 μmol/mol creatinine).
 3.8 Conclusions and recommendation
 The Committee considers 4,4’-methylene bis (2-chloroaniline) to be a
 carcinogenic substance acting by a stochastic genotoxic mechanism.
 The Committee considers the increased incidence of lung
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<pre> Literature                                             4,4’-Methylene bis (2-chloroaniline) | page 27 of 40
 literature
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<pre> Literature                                                                                           4,4’-Methylene bis (2-chloroaniline) | page 28 of 40
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    rat and human skin in vitro. Toxicol In Vitro 1993; 7(2): 141-8.           48
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    monitoring for workers exposed to 4,4’-methylenebis(2-chloroaniline).         4,4’-methylenebis(2-chloroaniline) in dogs. Environ Res 1984; 33(1):
    Am Ind Hyg Assoc J 1990; 51(1): 5-7.                                          234-45.
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    limits (Second edition, published 2011).                                      4,4’-methylene-bis-ortho-chloro-aniline (MBOCA): absorption and
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    Finnish Institute of Occupational Health (FIOH). 4,4’-Metyleenibis(2-         excretion after skin application and gavage. Environ Res 1984; 34(1):
    kloorianiliini), MOCA. Perustelumuistio MOCAn biologisen                      38-54.
    altistumisindikaattorin raja-arvolle. [4,4’-Methylenebis(2-chloroaniline), 50
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    MOCA: Background documentation for MOCA biological limit value].              diaminodiphenylmethan bei Ratten. Naturwissenschaften 1971; 58:
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<pre> Annexes                                              4,4’-Methylene bis (2-chloroaniline) | page 32 of 40
 annexes
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<pre> Annexes                                                                                                                                                       4,4’-Methylene bis (2-chloroaniline) | page 33 of 40
 A            epidemiological studies
 Reference         Study design and population                        Data on exposure and health assessment                 Results                                                       Remarks
 Dost et al.       Type of study: Retrospective cohort study          No information on exposure levels.                     Mortality all causes of death combined: Obs 9, SMR 46         Well performed, except size of cohort is
 (2009)29          Country: UK                                        Duration of exposure: at least 12 months.              (21-88)                                                       small, no data on exposure levels are
                   Type of industry: Rubber industry                  Mortality rates and cancer registrations of the        Mortality all causes excluding neoplasms: Obs 5, SMR 37       available, follow-up period may be too short,
                   Participants: 308 male production workers using    workers for the period 1979-2007 were compared         (12-87)                                                       possible co-exposure to other (bladder)
                   4,4′-methylene bis (2-chloroaniline) in the        with expected values, and SMR and SRR were             Mortality neoplasms: Obs 4, SMR 68 (19-174)                   carcinogens not addressed
                   manufacture of polyurethane elastomers; first      calculated by applying sex-, age- and period-specific  Mortality bladder cancer: Obs 1, SMR 560 (14-3122)
                   employed between 1973-2000                         mortality rates for UK to corresponding person-        Cancer incidence all neoplasms: Obs 9, SRR 77 (35-147)
                   Control: expected values based on national         years-at-risk                                          Cancer incidence bladder cancer: Obs 2, SRR 328 (40-1184)
                   rates                                              Appropriate statistical analysis was performed, but
                                                                      work histories and smoking status were not taken
                                                                      into account
 Chen et al.       Type of study: Retrospective cohort study          Exposure measurement: Air concentration were           One case of proved bladder cancer (transitional cell          Study contains several flaws.
 (2005) 30
                   Country: Taiwan, China                             measured and ranged between less than 0.02 and         carcinoma; 14 years exposure, non-smoker, had not worn        No specific data on exposure levels are
                   Type of industry: 4,4′-methylene bis               0.41 mg/m3 depending on area in the factory            any personal protective equipment).                           available, follow-up period may be too short,
                   (2-chloroaniline) manufacturing                    Duration of exposure: unknown                          Additionally, one worker with suspected malignant cells on    no information on duration of exposure,
                   Participants: 76 4,4′-methylene bis                Type of examination: Urine occult blood, urine         urine cytology (suspected bladder cancer) and one worker      number of participants is small, no statistical
                   (2-chloroaniline)-exposed workers                  cytology, nuclear matrix proteins, and abdominal       with atypical cytology combined with gross hematuria. Both    analysis performed on tumour incidence, no
                   Control:92 non-exposed workers from the same       ultrasonography in all participants. Intravenous       workers refused additional cystoscopic examination            clear defined study population, possible
                   factory                                            urography cystoscopy, and physical examination as      Positive rates for occult blood, matrix proteins and atypical co-exposure to other (bladder) carcinogens
                                                                      follow-up in workers with positive screening result    cells were similar in exposed and non-exposed groups          not addressed
 Ward et al.       Type of study: Retrospective cohort study          No information on exposure levels                      Three cases of bladder cancer (non-invasive papillary         Study contains several flaws.
 (1988, 1990)31,32 Country: USA                                       Duration of exposure: median duration of               tumours) identified (two non-smokers between 28-29 years of No specific data on exposure levels are
                   Type of industry: 4,4′-methylene bis               employment being 3.2 months                            age, the third patient was 44 years and ex-smoker; exposure   available, follow-up period may be too short,
                   (2-chloroaniline) manufacturing                    Follow-up period: maximally 11.5 years                 duration: 12, 9 and 1.5 months respectively). None of the     no specific information on duration of
                   Participants: 540 exposed workers                  Type of examination: Urine cytology and dipstick       cases had abnormal cytology or hematuria                      exposure and probably too short, no control
                                                                      analysis in all participants, cytoscopy in 200                                                                       group used, no valid comparison rate
                                                                      participants                                                                                                         available, no clear defined study population,
                                                                                                                                                                                           possible exposure to other (bladder)
                                                                                                                                                                                           carcinogens not known
 Linch et al.      Type of study: Retrospective cohort study          No information on exposure levels (exposure was        No deaths and no malignancies were observed in exposed        Study contains several flaws.
 (1971)33          Country: USA                                       confirmed by urinalysis)                               workers and controls                                          No specific data on exposure levels are
                   Type of industry: 4,4′-methylene bis               Duration of exposure: between 6 months and 16                                                                        available, no useful information on duration
                   (2-chloroaniline) manufacturing                    years                                                                                                                of exposure, no information on follow-up
                   Participants: 31 exposed workers and 31            Follow-up period: unknown                                                                                            period, number of participants is small,
                   controls                                           Type of examination: Urine cytology, medical records                                                                 possible exposure to other (bladder)
                                                                                                                                                                                           carcinogens not known
  Obs: Observed, SMR: Standardized mortality ratio (ratio of observed to expected death), SRR: Standardized registration ratio (ratio of observed to expected cancer morbidity).
32         Health Council of the Netherlands | No. 2018/25                                                                                                                             2                                                 34
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<pre> Annexes                                                                                                                                     4,4’-Methylene bis (2-chloroaniline) | page 34 of 40
 B           animal studies
 Reference         Study design and       Data on exposure and effect         Results                                                                                       Remarks
                   animal species         endpoints
 Kommineni et al. ChR CD (SD) male        Diet (27% protein)                  Mortality: Average survival 89, 87, 80 (p<0.01), 65 (p<0.001) for the 0, 250, 500 and 1000    Klimisch score: 2
 (1979)14          rats                   0, 250, 500,                        ppm groups, resp.                                                                             Well-performed study, adequate
                   100, 100, 75, 50       1000 ppm (mg/kg diet), equivalent   Adverse effects: Mean body weight gain markedly lower in high dose group compared to          for carcinogenicity assessment
                   animals at 0, 250,     to 10, 20 and 40 mg/kg body         control. Slight decrease in haemoglobin and haematocrit in high dose group.                   and derivation of cancer risk
                   500 and 1000 ppm,      weight/day (based on default food   Tumours: For 0, 250, 500 and 1000 ppm groups, resp.                                           values.
                   resp.                  intake of 40 g/kg body weight/day)  Lung adenocarcinomas in 0/100, 14/100 (p<0.001), 20/75 (p<0.001), 31/50 (p<0.001)             Deficiencies: only one sex used,
                                          Xpo = 18 months                     Mammary adenocarcinomas in 1/100, 5/100, 8/75 (p<0.01), 14/50 (p<0.001).                      exposure less than life-span,
                                          Xpe = 24 months                     Zymbal gland carcinomas in 1/100, 8/100 (p<0.05), 5/75, 11/50 (p<0.001)                       statistical method used is
                                          Statistical analysis: method        Hepatocellular carcinomas in 0/100, 3/100, 3/75, 18/50 (p<0.001)                              unknown
                                          unknown
 Kommineni et al. ChR-CD (SD) male        Diet: low protein (8%)              Mortality: Average survival 87, 81, 79, 77 (p<0.05) for the 0, 125, 250 and 500 ppm groups,   Klimisch score: 2
 (1979)14          rats                   0, 125, 250, 500 ppm (mg/kg diet),  resp.                                                                                         Well-performed study, adequate
                   100, 100, 75, 50       equivalent to 5, 10 and 20 mg/kg    Adverse effects: Mean body weight gain markedly lower in high dose group compared to          for carcinogenicity assessment.
                   animals at 0, 125, 250 body weight/day (based on default   controls. Slight decrease in haemoglobin and haematocrit in high dose group.                  Deficiencies: statistical method
                   and 500 ppm, resp.     food intake of 40 g/kg body weight/ Tumours: For 0, 125, 250 and 500 ppm groups, resp.                                            used is unknown, protein level in
                                          day)                                Lung adenocarcinomas in 0/100, 3/100, 7/75 (p<0.01), 8/50 (p<0.001)                           diet is considerably below the
                                                                              Mammary adenocarcinomas in 0/100, 1/100, 3/75, 3/50 (p<0.05).                                 required amount for rats, only
                                          Xpo = 18 months                     Zymbal gland carcinomas in 0/100, 0/100, 4/75 (p<0.05), 6/50 (p<0.001)                        one sex used, exposure less than
                                          Xpe = 24 months                     Hepatocellular carcinomas in 0/100, 0/100, 0/75, 9/50 (p<0.001)                               life-span
                                          Statistical analysis: method        Hemangiosarcomas in 1/100, 2/100, 4/75, 4/50 (p<0.05)
                                          unknown
 Stula et al.      ChR-CD (SD) rats       Diet (23% protein):                 Mortality: Average survival (range) 564 (63-731), 628 (306-733), 560 (152-733), 548 (224-719) Klimisch score: 2
 (1971, 1975)16,35 (50/sex/group)         0, 1000 ppm (mg/kg diet),           days for control male, control female, exposed male and exposed female rats, resp.            Well-performed study, adequate
                                          equivalent to 40 (males) and 50     Adverse effects: liver changes including hepatocytomegaly, fatty change, necrosis, bile duct  for carcinogenicity assessment.
                   Sacrificed for interim (females) mg/kg body weight/day     proliferation, fibrosis                                                                       Deficiencies: limited (only liver)
                   evaluation at 1 year:  (based on default food intake of 40 Tumours: (for control male, control female, exposed male and exposed female rats, resp.)      information on non-cancer
                   6/sex/group            and 50 g/kg body weight/day in      Lung: Adenomatosis (preneoplastic lesion) in 1/44, 1/44, 14/44 (p<0.05), 11/44 (p<0.05) and   effects, only one dose tested
                                          males and females, respectively)    adenocarcinoma in 0/44, 0/44, 21/44 (p<0.05), 27/44 (p<0.05). Squamous cell carcinoma in
                                          Xpo: 2 years                        one exposed male and one exposed female.
                                          Xpe: 2 years                        Pleural biphasic tumour: 0/44, 0/44, 4/44, 2/44.
                                          Statistical analysis: Chi-square    Liver: hepatocellular adenoma: 0/44, 0/44, 3/44, 2/44, hepatocellular carcinoma: 0/44, 0/44,
                                                                              3/44, 3/44
                                                                              Mammary adenocarcinoma: 0/44, 3/44, 3/44, 5/44
                                                                              The following malignant tumours were observed in a single treated animal and were absent in
                                                                              controls: vagina fibrosarcoma, kidney adenocarcinoma, peritoneal mesothelioma, duodenum
                                                                              adenocarcinoma
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<pre> Annexes                                                                                                                                   4,4’-Methylene bis (2-chloroaniline) | page 35 of 40
 Reference         Study design and       Data on exposure and effect        Results                                                                                         Remarks
                   animal species         endpoints
 Stula et al.      ChR-CD (SD) rats       Diet: low protein (7%) 0, 1000 ppm Mortality: Average survival (range) 384 (44-495), 466 (371-498), 400 194-475), 423 (287-475)    Klimisch score: 3
 (1971, 1975)16,35 (25/sex/group)         (mg/kg diet), equivalent to 40     days for control male, control female, exposed male and exposed female rats, resp.              Supportive study.
                                          (males) and 50 (females) mg/kg     Adverse effects: liver changes including hepatocytomegaly, fatty change, necrosis, bile duct    Deficiencies: limited  (only liver)  
                   Sacrificed for interim body weight/day (based on default  proliferation, fibrosis                                                                         information on non-cancer
                   evaluation at 1 year:  food intake of 40 and 50 g/kg body Tumours: (control male, control female, exposed male and exposed female rats, resp.)            effects, low number of animals
                   4/sex/group            weight/day in males and females,   Lung adenomatosis: 1/21, 1/21, 8/21 (p<0.05), 14/21 (p<0.05)                                    used, exposure period too short,
                                          respectively)                      Lung adenocarcinoma: 0/21, 0/21, 5/21 (p<0.05), 6/21 (p<0.05).                                  maximum tolerated dose
                                          Xpo: 16 months (study terminated   Hepatocellular adenoma: 0/21, 0/21, 5/21 (p<0.05), 2/21.                                        exceeded, protein level in diet is
                                          because of reduced survival on     Hepatocellular carcinoma: 0/21, 0/21, 11/21 (p<0.05), 1/21                                      considerably below the required
                                          protein-deficient diet)            Mammary fibroadenoma: 0/21, 7/21, 0/21, 1/21 (p<0.05)                                           amount for rats, only one dose
                                          Xpe: 16 months                     Mammary adenocarcinoma: 0/21, 0/21, 0/21, 6/21 (p<0.05)                                         tested
                                          Statistical analysis: Chi-square   The following malignant tumours were observed in a single treated animal and absent in
                                                                             controls: skin squamous cell carcinoma, malignant lymphoma, ileum adenocarcinoma.
 Russfield et al.  HaM/ICR mice           Diet                               Mortality: increased early mortality in female mice of the high dose group.                     Klimisch score: 2
 (1975)15          (25/sex/group)         0, 1000 and 2000 ppm (mg/kg diet), Adverse effects: no effects on growth, no treatment-related non-neoplastic changes              Well-performed study, adequate
                                          equivalent to 120 and 240 (males)  Tumours:                                                                                        for carcinogenicity assessment
                                          and 130 and 260 (females) mg/kg    Hepatomas: male: 3/18, 3/13, 4/20; female: 0/20, 9/21 (p<0.01), 7/14 (p<0.01) at 0, 1000 and    Deficiencies: low number of
                                          body weight/day (based on default  2000 ppm, resp. (Liver tumours in mice have little relevance to man)                            animals used, exposure less than
                                          food intake of 120 and 130 g/kg    Vascular tumours (generally subcutaneous hemangiomas and hemangiosarcomas): male:               life-span
                                          body weight/day in males and       0/18, 3/13, 8/20; female: 1/20, 0/21, 6/14 at 0, 1000 and 2000 ppm, resp. (incidence in treated
                                          females, respectively)             animals comparable to historical control)
                                          Xpo = 18 months
                                          Xpe = 24 months
                                          Statistical analysis: Fisher exact
                                          test
 Russfield et al.  ChR CD-1 rats          Diet                               Mortality: At 18 months: 96, 80% of control and treated animals survived, resp. At 20-22        Klimisch score: 3
 (1975)15          (25 males/ group)      0, 500 and 1000 ppm (mg/kg diet),  months: about 55% survival in all groups                                                        Supportive study.
                                          equivalent to 20 and 40 mg/kg body Adverse effects: Body weight: ca. 780, 730 and 680 g at 0, 500 and 1000 ppm, resp., after 18    Deficiencies: only one sex used,
                                          weight/day (based on default food  months. Differences persisted until necropsy.                                                   low number of animals used,
                                          intake of 40 g/kg body weight/day) Tumours:                                                                                        exposure less than life-span
                                          Xpo = 18 months                    Lung adenomatosis: 0/22, 3/22, 4/19 at 0, 500 and 1000 ppm, resp.
                                          Xpe = 24 months                    Hepatomas (without invasion of hepatoma cells in blood vessel walls): 0/22, 1/22, 4/19 at 0,
                                          Statistical analysis: Fisher exact 500 and 1000 ppm, resp.
                                          test
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<pre> Annexes                                                                                                                                               4,4’-Methylene bis (2-chloroaniline) | page 36 of 40
 Reference            Study design and            Data on exposure and effect          Results                                                                                          Remarks
                      animal species              endpoints
 Grundmann and        Wistar rats                 Low protein diet (protein level not  Mortality: Survival mean 730, 565, and 535 days for control, exposed male and exposed            Klimisch score: 3
 Steinhoff            (25/sex/group)              specified)                           female rats, resp.                                                                               Supportive study.
 (1970)34                                         0, 0.1% (total 27 g/kg body weight,  Adverse effects:Changes in the livers of treated animals that died without visible tumour (fatty Deficiencies: short exposure
                                                  corresponding to 54 mg/kg body       liver, necrosis and bleedings in two males; necrosis and fatty liver in five females).           period, low number of animals
                                                  weight/day based on 500-day          Tumours: For control males, control females, treated males and treated female, resp.             used, limited information on
                                                  exposure period)                     Total: 0/25, 2/25, 23/25, 20/25                                                                  non-cancer effects,
                                                  Xpo: 500 days                        Liver tumours (multilocular hepatomata; metastases in lung of two males and in brain of one      histopathology limited to liver and
                                                  Xpe: lifespan                        male): 0/25, 0/25, 22/25, 18/25                                                                  organs showing gross lesion, no
                                                                                       Lung tumours (mainly carcinomata): 0/25, 0/25, 8/25, 5/25                                        statistical analysis performed,
                                                                                                                                                                                        protein level in diet is
                                                                                                                                                                                        considerably below the required
                                                                                                                                                                                        amount for rats, only one dose
                                                                                                                                                                                        tested
 Stula et al.         Beagle dogs                 Oral (capsules)                      Mortality: One treated dog died after 3.4 years (death not related to treatment). Other animals  Klimisch score: 3
 (1978)36              (6 females/                0 and 100 mg/day, first six weeks: 3 were killed after 8.3 (one dog) or 9 years of treatment.                                         Supportive study.
                      group)                      days/week, then 5 days/week (8-15    Adverse effects: Increased blood glutamic pyruvic transaminase (GPT) activity in treated         Deficiencies: only one sex used,
                                                  mg/kg bw/day)                        dogs.                                                                                            low number of animals used, only
                                                  Xpo: 9 years                         Increased numbers of erythrocytes, leukocytes and epithelial cells in urine sediment in treated  one dose tested
                                                  Xpe: 9 years                         dogs (some epithelial cells showed changes suggestive of neoplasia in the genitourinary
                                                  Statistical analysis: Fisher exact   tract).
                                                  test, one tail                       Nodular hyperplasia in the liver in 0/6 control and 3/5 treated dogs
                                                                                       Tumours:
                                                                                       Urinary bladder papillary transitional cell carcinoma: 0/5, 4/5 (p<0.025) The fifth treated dog
                                                                                       had a combined transitional cell carcinoma / adenocarcinoma in the urethra.
 Steinhoff and        Wistar rats                 Subcutaneous injection               Mortality: Survival mean: 1040 and 778 days control and exposed rats, resp.                      Klimisch score: 3
 Grundmann            Control and exposed         500 or 1000 mg/kg bw, once a         Tumours:                                                                                         Supportive study.
 (1971)50             groups: 25 and 17           week or longer, total dose: 25 g/kg  In total 13 and 29 malignant tumours in control and exposed group, resp.                         Deficiencies: very limited
                      rats/sex, resp.             bw                                   Hepatocellular carcinoma: 0/50, 9/34                                                             information on study design and
                                                  Xpo = 620 days                       Lung tumours (adenocarcinomas and carcinomas): 1/50, 7/34                                        results (reported as short
                                                  Xpe = lifespan                                                                                                                        communication), low number of
                                                                                                                                                                                        animals used, exposure period
                                                                                                                                                                                        too short, route of exposure not
                                                                                                                                                                                        relevant, no information on
                                                                                                                                                                                        non-cancer effects, no statistical
                                                                                                                                                                                        analysis performed
  Xpo = duration of exposure; Xpe = duration of the experiment.
  Klimisch scores were based on Klimisch et al (1997)
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<pre> Annexes                                                                                                                            4,4’-Methylene bis (2-chloroaniline) | page 37 of 40
 C BMD-analysis                                                                                     Result of BMD-analysis for male rats
                                                                                                      Model            No. Par.  Log-lik      AIC         BMDL     BMDU       BMD  conv  Weight
                                                                                                      Null             1         -162.63      327.26      NA       NA         NA   NA
 Software                 Proast, version 65.7                                                        Full             4         -117.19      242.38      NA       NA         NA   NA
 BMR, risk type           10%, extra risk                                                             two stage        3         -117.35      240.7       5.44     10.9       7.95 Yes   0.1802
 BMDL                     Lowest 95% confidence interval of the BMD                                   log.logist       3         -117.75      241.5       5.88     11.1       8.66 Yes   0.1208
                          The fit of a model is measured by the comparison with the best fitting      Weibull          3         -117.48      240.96      5.44     11         8.32 Yes   0.1582
                          model (the one with the lowest AIC (AICmin)). If [AICmodel < AICmin +       Log.prob         3         -117.92      241.84      6.18     11.1       8.81 Yes   0.1019
                          2] then both models are similar and the tested model provides a fit         gamma            3         -117.56      241.12      5.36     11         8.39 Yes   0.1460
 Model fit and averaging
                          comparable with the best fitting model. The weight of a model depends
                                                                                                      logistic         2         -122.73      249.46      11.7     15.6       13.5 Yes   0.0023
                          on the fit – models with lower fit are attributed lower weights for model
                                                                                                      probit           2         -121.64      247.28      NA       NA         12.6 Yes   0.0067
                          averaging.
                                                                                                      LVM: Expon.
                          Kommineni C, Groth DH, Frockt IJ, Voelker RW, Stanovick RP.                                  3         -117.53      241.06      5.42     11.1       8.36 Yes   0.1505
                                                                                                      M3-
                          Determination of the tumorigenic potential of methylene-bis-
 Data source              orthochloroaniline. J Environ Pathol Toxicol. 1979;2(5):149-171             LVM: Expon.
                                                                                                                       3         -117.65      241.3       5.67     11.1       8.53 yes   0.1335
                          Effect data analysed only when statistical differences between exposed      M3-
                          and control group was p ≤ 0.05.
                          Male ChR CD (SD) rats exposed via the diet (fixed concentrations) for
 Exposure design
                          18 months; experimental period 24 months                                    Final BMDL                       Final BMDU                  Final BMD#
 Effect parameter         Incidence of lung adenocarcinomas                                           5.85                             11.8                        8.3
                                                                                                    #
                                                                                                       The model averaged BMD is calculated using the formula: BMD=exp((LN(BMDL)+LN(BMDU))/2)
 Data on exposure and response
 Dose (mg/kg body weight/      Number of male rats per dose          Number of male rats with lung
 day)                                                                adenocarcinomas
 0                             100                                   0
 10                            100                                   14
 20                            75                                    20
 40                            50                                    31
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<pre> Annexes                                              4,4’-Methylene bis (2-chloroaniline) | page 38 of 40
37    Health Council of the Netherlands | No. 2018/25                2                                   39
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<pre>                                                                                                                                        4,4’-Methylene bis (2-chloroaniline) | page 39 of 40
 The Committee                                                                                        Observers:
                                                                                                      •  H. Stigter, Occupational Physician, Inspectorate SZW, Ministry of Social Affairs and Employment,
 Members of the Committee:                                                                               The Hague
 • F.G.M. Russel, Professor of Pharmacology and Toxicology, Radboud University Medical Center,        •  D. Theodori, Social and Economic Council, The Hague
   Nijmegen, chairman
 • P.J. Boogaard, Professor of Environmental Health and Human Biomonitoring, Wageningen               Scientific secretary:
   University and Research Centre; and toxicologist, Shell International BV, The Hague                •  S.R. Vink, Health Council of the Netherlands, The Hague
 • R. Houba, Occupational Hygienist, Netherlands Expertise Centre for Occupational Respiratory
   Disorders, Utrecht
 • E.D. Kroese, Toxicologist, TNO, Zeist
 • C.F. Kuper, Toxicologic Pathologist, Utrecht
 • H. van Loveren, Professor of Immunotoxicology, Maastricht University, Maastricht
 • I.M.C.M. Rietjens, Professor of Toxicology, Wageningen University and Research Centre,
   Wageningen
 • G.B.G.J. van Rooy, Occupational Physician/toxicologist, Arbo Unie Expert Centre for Chemical Risk
   Management, and Radboud UMC Outpatient Clinic for Occupational Clinical Toxicology, Nijmegen
 • L.A. Smit, Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
 • R.C.H. Vermeulen, Epidemiologist, Institute for Risk Assessment Sciences, University Utrecht,
   Utrecht
 • A.H. Piersma, Professor of Reproductive and Developmental Toxicology, Utrecht University, and
   National Institute for Public Health and the Environment, Bilthoven, structurally consulted expert
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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 Water Management, Social
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 This publiation can be downloaded from www.healthcouncil.nl.
 Preferred citation:
 Health Council of the Netherlands. 4,4’-Methylene bis (2-chloroaniline).
 The Hague: Health Council of the Netherlands, 2018; publication no. 2018/25.
 All rights reserved
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