<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>p-Nitroaniline
Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Gezondheidsraad                                          Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : Aanbieding advies p-Nitroaniline
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-5134/JR/pg/246-G12
Bijlagen                :1
Datum                   : 1 april 2008
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van p-nitroaniline.
Het maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen worden
geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan
mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Het advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is voorgelegd aan de Commissie GBBS en vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en
Milieubeheer.
Hoogachtend,
prof. dr. J.A. Knottnerus
Bezoekadres                                                                 Postadres
Parnassusplein 5                                                            Postbus 16052
2 5 11 V X D e n          Haag                                              2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1                                      Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : j o l a n d a . r i j n k e l s @ g r. n l                    w w w. g r. n l
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<pre></pre>

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<pre>p-Nitroaniline
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the classification of carcinogenic substances of the
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2008/08OSH, The Hague, April 1, 2008
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues...” (Section
22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Housing, Spatial Planning & the Environment, Social
Affairs & Employment, and Agriculture, Nature & Food Quality. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to gov-
ernment policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. p-Nitroaniline; Evaluation of the carcinoge-
nicity and genotoxicity. The Hague: Health Council of the Netherlands, 2008;
publication no. 2008/08OSH.
all rights reserved
ISBN: 978-90-5549-694-5
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedures 13
1.3 Data 14
2   General information 15
2.1 Identity and physico-chemical properties 15
2.2 IARC classification 16
3   Carcinogenicity studies 17
3.1 Observations in humans 17
3.2 Carcinogenicity studies in animals 17
3.3 Additional information 19
4   Mutagenicity and genotoxicity 21
4.1 In vitro assays 21
4.2 In vivo assays 21
4.3 Additional information 22
    Contents                                    7
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<pre>5   Classification 25
5.1 Evaluation of data on carcinogenicity and genotoxicity 25
5.2 Recommendation for classification 25
    References 27
    Annexes 31
A   Request for advice 33
B   The committee 35
C   Comments on the public review draft 37
D   In vitro genotoxicity data 39
E   Carcinogenic classification of substances by the committee 41
F   Guideline 93/21/EEG of the European Union 43
8   p-Nitroaniline
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie p-nitroaniline
onder de loep. p-Nitroaniline wordt gebruikt als intermediair bij de productie van
verschillende stoffen, zoals antioxidanten en kleurstoffen.
Op basis van de beschikbare gegevens leidt de commissie af dat p-nitroaniline
onvoldoende is onderzocht. Hoewel de gegevens het niet toelaten de stof te clas-
sificeren als kankerverwekkend voor de mens of als moet beschouwd worden als
kankerverwekkend voor de mens, is waakzaamheid is geboden. De commissie
adviseert daarom p-nitroaniline te classificeren als verdacht kankerverwekkend
voor de mens. Dit is vergelijkbaar met een classificatie in categorie 3 volgens de
richtlijnen van de Europese Unie. Binnen deze categorie komt de situatie het
meest overeen met subcategorie b.
Samenvatting                                                                       9
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<pre>10 p-Nitroaniline</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of sub-
stances to which workers are occupationally exposed. The evaluation is per-
formed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council, here-
after called the committee. In this report, the committee evaluated p-nitroaniline.
p-Nitroaniline is used as an intermediate in the production of different sub-
stances, including antioxidants and dyes.
Based on the available information, the committee is of the opinion that p-nitro-
aniline has been insufficiently investigated. While the available data do not war-
rant a classification as carcinogenic to humans or as should be regarded as
carcinogenic to humans, they indicate that there is cause for concern for man.
Therefore, the committee recommends classifying p-nitroaniline as a suspected
human carcinogen. This recommendation is comparable to the EU classification
in category 3. The situation is, furthermore, comparable with subcategory b of
this category.
Executive summary                                                                   11
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<pre>12 p-Nitroaniline</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a classifica-
        tion (see Annex A). The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see Annex E). The criteria used for
        classification are partly based on an EU-directive (see Annex F). In addition to
        classifying substances, the Health Council also assesses the genotoxic properties
        of the substance in question.
        This report contains the evaluation of the carcinogenicity of p-nitroaniline.
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the committee. The members of the committee
        are listed in Annex B. The first draft was prepared by I.A. van de Gevel and M.I.
        Willems, from the Department of Occupational Toxicology of the TNO Nutrition
        Scope                                                                               13
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<pre>    and Food Research, by contract with the Ministry of Social Affairs and Employ-
    ment.
         In 2007 the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex C. The committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the committee is standardly based on sci-
    entific data, which are publicly available. The starting points of the committees’
    reports are, if possible, the monographs of the International Agency for Research
    on Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the committee when
    these are considered most relevant in assessing the carcinogenicity and genotox-
    icity of the substance in question. In the case of p-nitroaniline, such an IARC-
    monograph is not available.
         More recently published data were retrieved from the online databases Med-
    line, Toxline, Chemical Abstracts, and RTECS. The last updated online search
    was in June 2007. The new relevant data were included in this report.
14  p-Nitroaniline
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<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        p-Nitroaniline is used as an intermediate in the production of antioxidants, antio-
        zonants, gasoline additives, and various dyes and pigments.1,2
             Below is given the identity and some of its physical and chemical proper-
        ties.1,3,4
        Chemical name          :  1-amino-4-nitrobenzene
        CAS registry no.       :  100-01-6
        EINECS no.             :  202-810-1
        Synonyms               :  p-nitroaniline; 4-nitroaniline; azoic diazo component 37 (C.I. 37035);
                                  developer 17; Fast Red GG Base; benzeneamine, 4-nitro
        Description            : bright yellow powder
        Molecular formula      : C6H6N2O2
        Molecular structure    :
        Molecular weight       :  138.12
        Boiling point          :  332°C
        Melting point          :  148°C
        Vapour pressure        :  0.00047 Pa at 25°C
        Vapour density         :  4.8 (air = 1)
        Solubility             :  0.8 g/L at 18.5°C (in water)
        General information                                                                              15
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<pre>    Octanol/water partition  : 2.66 (log Pow)
    coefficient
    Stability and reactivity : may explode on heating. On combustion, forms toxic fumes of nitro-
                               gen oxides. The substance is a strong oxidant and reacts with com-
                               bustible and reducing materials. Reacts with organic materials in
                               presence of moisture causing fire hazard.
    EU classification        : R23/24/25: Toxic by inhalation, in contact with skin and if swal-
                               lowed.
                               R33: Danger of cumulative effects.
                               R52/53: Harmful to aquatic organisms, may cause long-term adverse
                               effects in the aquatic environment.
                               (Based on the Annex I entry 612-012-00-9, the p-nitroaniline, m-
                               nitroaniline and o-nitroaniline)
2.2 IARC classification
    IARC did not evaluate p-nitroaniline.
16  p-Nitroaniline
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<pre>Chapter 3
        Carcinogenicity studies
3.1     Observations in humans
        No data were available to evaluate the carcinogenicity of p-nitroaniline in
        humans.
3.2     Carcinogenicity studies in animals
        The National Toxicology Program (NTP) published a long-term animal study on
        the carcinogenic effects of p-nitroaniline.2 Groups of 70 male and 70 female
        B6C3F1 mice were given p-nitroaniline by gavage at doses of 0, 3, 30 or 100 mg/
        kg bw, daily for five days a week for up to 103 weeks. In addition, ten animals
        per group were designated for interim evaluations at 9 and 15 months.
            Survival and body weights in all dosed groups were comparable to controls.
        During the study, haematological effects were observed in mice given 30 or 100
        mg p-nitroaniline/kg bw. These effects included: increased methaemoglobin con-
        centration and reticulocytosis; a slight regenerative anaemia at 100 mg/kg bw
        only; extramedulary haematopoiesis and haemosiderin containing macrophages
        in the spleen; and, the presence of haemosiderin containing Kupffer cells in the
        liver.
            Regarding tumour development, no treatment-related development of
        tumours was found, except for haemangiomas or haemangiosarcomas in male
        mice (see Table 3.1). In summary, significant increases in hepatic haemangiosar-
        Carcinogenicity studies                                                          17
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<pre>   comas were found in male animals given 100 mg p-nitroaniline/kg bw. Further-
   more, in this group, an increase in haemangiomas or haemangiosarcomas
   (combined) at other sites of the body were observed, with a significant positive
   trend; according to NTP, the incidence of these neoplasms exceeded the range for
   NTP historical control groups of male mice, but the incidence were not statisti-
   cally significant greater than controls by pair-wise comparisons. In female mice,
   the incidence of haemangioma or haemangiosarcoma (combined) at all sites was
   slightly increased, but did not reach significance.
        The investigators of the NTP study remarked that an increase in vascular
   tumours of the liver in male mice is seen with several other substances inducing
   haemolytic anaemia. Therefore, they assume that the vascular tumours observed
   in this study are related to p-nitroaniline exposure. Finally, it is unknown why
   female mice are less susceptible for p-nitroaniline exposure than male mice, but
   the difference might be hormone-related.5
   Nair et al. (1990) studied the toxicity of p-nitroaniline in Sprague-Dawley rats.6
   Groups of 60 male and 60 female rats were daily fed (by gavage) p-nitroaniline
   at doses of 0, 0.25, 1.5 or 9.0 mg/kg bw, for 7 days a week for 24 months.
        No clear decrease in survival was observed in any of the treated groups com-
   pared to controls. However, the average body weight was increased in the highest
   dosed female group, but not in other groups, nor in male groups. Regarding non-
   carcinogenic effects, in the high dosed groups, heamatological effects were
   observed, such as increased methaemoglobin levels, haemoglobin levels, red
   blood cell counts, and haematocrit. Furthermore, an indication of reticulocytosis
   was seen at the highest dose level but no increase in extramedulary haematopoie-
   sis. In addition, dose related increases in iron pigmentation were seen in the liver
   sinusoidal macrophages and the reticuloendothelial cells of the spleen.
   Table 3.1 p-Nitroaniline induced tumour development in B6C3F1 mice.2
                                matched     historic   exposure (mg/kg bw)
                                controls    controls   3          30       100
   males
     hepatic haemangiosarcoma 0/50          2.1%       1/50       2/50     4/50 (p=0.06,
                                            (0-6%)                         Fisher)
     all organ haemangioma or 5/50          6.6%       3/50       4/50     10/50 (p=0.137,
     haemangiosarcoma                       (0-12%)                        Fisher)
   females
     all organ haemangioma or 1/52          3.0%       3/50       3/51     4/51
     haemangiosarcoma                       (0-12%)
18 p-Nitroaniline
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<pre>        The investigators did not find increased incidences of tumour-bearing ani-
    mals, nor were there any increase in certain types of tumours observed. The com-
    mittee noted that the dose applied to the animals was very low (below the MTD).
    This could explain the absence of vascular tumours in the liver or spleen of rats
    in this study. It might also explain the marginal increase in reticulocytes, and lack
    of increase in extramedulary haematopoiesis, compared to other methaemoglo-
    bin inducers. Therefore, the committee is of the opinion that this study is of lim-
    ited value for cancer risk assessment.
        Fifty male and fifty female mice were given p-nitroaniline by gavage at doses
    of 0, 2, 21 or 70 mg/kg bw for 2 years. Tumour incidences of treated animals did
    not differ from controls.7 No further details on study design and examinations
    were given.
3.3 Additional information
    p-Nitroaniline presents a class of single aromatic agents bearing a nitro and
    amino group, several of which are known carcinogens. Some of the aniline
    agents were, therefore, investigated on carcinogenicity as well.2 Only p-chloro-
    aniline and o-toluidine hydrochloride caused marginal increases in heamangio-
    sarcomas in the liver and spleen of mice. Other type of tumours found after expo-
    sure to aniline-like agents included splenic sarcomas in rats (absent in mice).2
    Carcinogenicity studies                                                               19
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<pre>20 p-Nitroaniline</pre>

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<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        The outcomes of the individual in vitro assays are summarized in Annex D.
            Overall, bacterial mutagenicity assays showed that p-nitroaniline caused
        frame shift mutations, in the presence and in the absence of an exogenous meta-
        bolic system. However, other mutagenicity assays were negative.
            In mammalian cells and in the presence and absence of a metabolic system,
        p-nitroaniline also induced chromosomal aberrations, although one negative out-
        come was reported as well. In one assay, the agent induced sister chromatid
        exchanges in the presence of an activation system, but negative or equivocal out-
        comes were found by other investigators using the same assay.
4.2     In vivo assays
        In the sex-linked recessive lethal mutation assay, using Drosophila melanogaster
        flies, no increased frequency of mutations in male germ cells was detected when
        p-nitroaniline was administered by feed (up to 5,000 ppm; larvae up to 100 ppm),
        or injections (up to 1,000 ppm).2,8,9
            In addition, p-nitroaniline did not increase the frequency of unscheduled
        DNA synthesis in liver cells of male F344 rats.10 The committee noted the limited
        reporting.
        Mutagenicity and genotoxicity                                                     21
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<pre>    Regarding clastogenic effects, no increased frequency of micronuclei in bone
    marrow cells of treated CD-1 mice were found.11 In this study, groups of five to
    six male and female animals received intraperitoneal injections of 0, 80, 400 or
    800 mg p-nitroaniline/kg bw, two times on two consecutive days. Twenty-four
    hours after the last injection, and forty-eight hours for control and highest dosed
    animals, bone marrow cells were harvested and prepared for analysis. One of the
    animals of the highest dose group died during the study. Furthermore, in all
    treated animals clinical signs of toxicity were observed.
    Topham studied sperm-head abnormalities using (CBAxBALB/c)F1 mice, which
    are known to be sensitive for these kind of abnormalities.12 Groups of five mice
    received intraperitoneal injections of p-nitroaniline at doses of 25 up to 500 mg/
    kg bw (dissolved in 0.5% Tween 80 in water), five times on five consecutive
    days. Five weeks after the last injection, the mice were killed and sperm was col-
    lected from the cauda epididymis.
         In treated animals, exposure did not increase the incidence of sperm-head
    abnormities compared to control animals. The investigators also reported on
    lethality in the highest dose group.
4.3 Additional information
    The carcinogenic mechanism through which p-nitroaniline may induce vascular
    tumours is not completely understood yet. Below is given the state of the art.
         p-Nitroaniline is a methaemoglobin inducing agent.1,2 Similar agents, such as
    aniline and substituted aniline compounds show comparable responses as those
    observed by p-nitroaniline. These responses are caused by reaction of the agent
    or its metabolites with haemoglobin, resulting in the net accumulation of methae-
    moglobin (an oxidized form ferrohaemoglobin).
         This process may also lead to local or systemic iron overload in the body. In
    addition, it is hypothesized that excess of iron may promote the production of
    reactive oxygen species (which ultimately may lead to oxidative damage to
    DNA), suppression of the tumoricidal functioning of macrophages, and/or
    immunosuppression.5 Related to this hypothesis are numerous reports, which
    suggest an association between iron overload and higher risk of cancer.5 In case
    of the NTP carcinogenicity study, it is possible that there was question of iron
    overload, since in high-dosed male mice an increased incidence of Kupffer cell
    (liver macrophages) pigmentation (haemosiderosis) was observed, which is asso-
    ciated with iron overload.2,5
22  p-Nitroaniline
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<pre>    However, at the moment it is unclear whether there exists an association
between iron overload, the presence of haemosiderosis and haemangiosarcomas,
because data from other animal carcinogenicity studies indicate that certain other
hemolytic agents, such as o-nitroaniline, caused increases in Kupffer cell pig-
mentation, but no increases in incidence of haemangiosarcomas, whereas for
other agents it was the other way round.5 No other data on the carcinogenic
mechanism of p-nitroaniline is available. Therefore, it is still unclear what carci-
nogenic mechanism may have caused haemangiosarcomas in male mice of the
NTP study.
Mutagenicity and genotoxicity                                                        23
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<pre>24 p-Nitroaniline</pre>

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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data on the carcinogenicity of p-nitroaniline in humans were available.
            In male mice, p-nitroaniline induced small increases in hepatic haemangiosa-
        rcomas. It furthermore increased haemangiomas and haemangiosarcomes else-
        where in the body. However, female mice showed to be less susceptible for
        developing p-nitroaniline-induced tumours as seen in male mice. Another carci-
        nogenicity study on rats was of limited value for cancer risk assessment, due to
        low exposure levels. Overall, the available data on the carcinogenicity of p-
        nitroaniline is limited, but the committee is concerned about the findings in male
        mice.
            Overall, p-nitroaniline caused mutations and clastogenic effects in some in
        vitro assays, but in other in vitro assays the outcomes were negative. No genotox-
        icity was found in in vivo assays. It is furthermore unclear what carcinogenic
        mechanism may have caused tumours as found in male mice.
5.2     Recommendation for classification
        Based on the available information, the committee is of the opinion that p-nitro-
        aniline has been insufficiently investigated. While the available data do not war-
        rant a classification as carcinogenic to humans or as should be regarded as
        carcinogenic to humans, they indicate that there is cause for concern for man.
        Classification                                                                     25
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<pre>   Therefore, the committee recommends classifying p-nitroaniline as a suspected
   human carcinogen. This recommendation is comparable to the EU classification
   in category 3. The situation is, furthermore, comparable with subcategory b of
   this category.
26 p-Nitroaniline
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<pre>  References
1 Gesellschaft Deutscher Chemiker [Advisory Committee on Existing Chemicals of Environmental
  Relevance] (BUA). p-Nitroaniline (4-nitrobenzeneamine). S. Hirzel Verlag, Stuttgart, Germany,
  BAU report 19; 1995.
2 National Toxicology Program. Toxicology and carcinogenesis studies of p-nitroaniline (Cas no. 100-
  01-6) in B6C3F1 mice (gavage studies). NTP, National Institute of Health, NC, USA, NTP technical
  report no. TR 418 (NIEH publication no. 93-3149): 1993.
3 European Chemicals Bureau. 4-Nitroaniline. International Chemical Safety Cards; 1993.
4 European Chemicals Bureau. 4-Nitroaniline. IUCLID Datasheet. European Commission - European
  Chemicals Bureau; 2000.
5 Nyska A, Haseman JK, Kohen R, Maronpot RR. Association of liver hemangiosarcoma and
  secondary iron overload in B6C3F1 mice--the National Toxicology Program experience. Toxicol
  Pathol 2004; 32(2): 222-228.
6 Nair R, Auletta C, Schroeder R, Johannsen F. Chronic toxicity, oncogenic potential, and reproductive
  toxicity of p-nitroaniline in rats. Fundam Appl Toxicol 1990; 153: 607-621.
7 The Carcinogenicity Potency Project. p-Nitroaniline (CAS 100-01-6). Berkely Lab, University of
  California, the USA; http://potency.berkeley.edu/; 2008.
8 Valencia R, Mason JM, Woodruff RC, Zimmering S. Chemical mutagenesis testing in Drosophila.
  III. Results of 48 coded compounds tested for the National Toxicology Program. Environ Mutagen
  1985; 7: 325-348.
9 Zimmering S, Mason JM, Valencia R. Chemical mutagensis testing in Drosophila. VII. Results of 22
  coded compounds tested in larval feeding studies. Environ Mol Mutagen 1989; 14: 245-251.
  References                                                                                           27
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<pre>10 Mirsalis J, Tyson K, Beck J, Loh E, Steinmetz K, Contreras C et al. Induction of unscheduled DNA
   synthesis (UDS) in hepatocytes following in vitro and in vivo treatment. Environ Mutagen 1983; 5:
   482.
11 Monsanto Co. Initial submission: micronucleus study with p-nitroaniline. EPA document, Doc #88-
   920009095.NTIS/OTS0546378; 1992.
12 Topham JC. The detection of carcinogen-induced sperm head abnormalities in mice. Mutat Res 1980;
   69: 149-155.
13 Chiu CW, Lee LH, Wang CY, Bryan GT. Mutagenicity of some commercially available nitro
   compounds for Salmonella typhimurium. Mutat Res 1978; 58: 11-22.
14 Corbett MD, Wei C, Corbett BR. Nitroreductase-dependent mutagenicity of p-
   nitrophenylhydroxylamine and its N-acetyl and N-formyl hydroxamic acids. Carcinogenesis 1985;
   6(5): 727-732.
15 Dellarco VL, Prival MJ. Mutagenicity of nitro compounds in Salmonella typhimurium in the
   presence of flavin mononucleotide in a preincubation assay. Environ Mol Mutagen 1989; 13(2): 116-
   27.
16 Haworth S, Lawlor T, Mortelmans K, Speck W, Zeiger E. Salmonella mutagenicity test results for
   250 chemicals. Environ Mutagen 1983; 5(Suppl. 1): 3-142.
17 Kawai A, Goto S, Matsumoto Y, Matsushita H. Mutagenicity of aliphatic and aromatic nitro
   compounds. Jpn J Ind Hlth 1987; 29: 34-54.
18 Chung KT, Murdock CA, Zhou Y, Stevens SEJ, Li YS, Wei CI et al. Effects of the nitro-group on the
   mutagenicity and toxicity of some benzamines. Environ Mol Mutagen 1996; 27(1): 67-74.
19 Monsanto Co. Salmonella mutagenicity assay of p-nitroaniline, DA-79-257. EPA document, No.
   878211039, fiche No. OTS0206222; 1980.
20 Pai V, Bloomfield SF, Gorrod JW. Mutagenicity of N-hydroxylamines and N-hydroxycarbamates
   towards strains of Escherichia coli and Salmonella typhimurium. Mutat Res 1985; 151: 201-207.
21 Shimizu M, Yano E. Mutagenicity of mononitrobenzene derivates in the Ames test and rec assay.
   Mutat Res 1986; 170: 11-22.
22 Shahin MM. Mutagenicity of nitroanilines and nitroaminophenols in Salmonella typhimurium. Intl J
   Cosmet Sci 1985; 7: 277-289.
23 Assmann N, Emmrich M, Kampf G, Kaiser M. Genotoxic activity of important nitrobenzenes and
   nitroanilines in the Ames test and their structure-activity relationship. Mutat Res 1997; 395(2-3):
   139-144.
24 Shah MJ, Andrews AW. Mutagenic evaluation of oxidation products of p-phenylenediamine - a hair
   dye component. Toxicol Appl Pharmacol 1979; 48: A49.
25 Topham JC. Interlaboratory variations of test results. In: Norpoth K, Garncer RC, editors. Short term
   mutagenicity test systems for detecting carcinogens. Berlin, Heidelberg, New York: Springer; 1980:
   302-311.
26 Thompson CZ, Hill LE, Epp JK, Probst GS. The induction of bacterial mutation and hepatocyte
   unscheduled DNA synthesis by monosubstituted analines. Environ Mutagen 1983; 5: 803-811.
28 p-Nitroaniline
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<pre>27 Garner RC, Nutman CA. Testing of some azo dyes and their reduction products for mutagenicity
   using Salmonella typhimurium TA1538. Mutat Res 1977; 44: 9-19.
28 Levi BZ, Kuhn JC, Ulitzur S. Determination of the activity of 16 hydrazine derivatives in the
   bioluminescence test for genotoxic agents. Mutat Res 1986; 173: 233-237.
29 Ulitzur S, Weiser ILBZ, Barak M. Determination of 100 chemicals by the improved bioluminescence
   test for mutagenic agents. In: Kircka LJ, editor. Anal. Appl. Biolumin. Chemolumin. (Proc. 3. Int.
   Symp.). London, UK: Academic; 1984: 533-536.
30 Wecher RA, Scher S. Bioassay procedures for identifying genotoxic agents using light emitting
   bacteria as indicator organisms. In: serio M, Pazzagli M, editors. Luminescent assays: Perspectives in
   endocrinology and clinical chemistry. New York: Raven press; 1982: 109-113.
31 Pai V, Bloomfield SF, Jones J, Gorrod JW. Mutagenicity testing of nitrogenous compounds and their
   N-oxidized products using trp+ reversion in E. coli. Biological oxidation of nitrogen 1978; Proc. Int.
   Symp. 2nd: 375-382.
32 Standford Research Institute International. An evaluation of mutagenic potential of p-nitroaniline
   employing the L5178Y TK +/- Mouse lymphoma assay. EPA document, No. 878211853 Fiche no.
   OTS0206222: 1982.
33 Pharmakon Research International Inc. CHO/HGPRT Mammalian cell forward gene mutation assay.
   EPA document, No. 878214479, Fiche No. OTS0206580; 1984.
34 Galloway SM, Armstrong MJ, Reuben C, Colman S, Brown B, Cannon C et al. Chromosome
   aberrations and sister chromatid exchanges in Chinese hamster ovary cells: Evaluations of 108
   chemicals. Environ Mol Mutagen 1987; 10(suppl. 10): 1-175.
35 Huang Q, Wang L, Han S. The genotoxicity of substituted nitrobenzenes and the quantitative
   structure-activity relationship studies. Chemosphere 1995; 30(5): 915-923.
36 Pharmakon Research International Inc. Rat hepatocyte primary culture/DNA repair test. EPA
   document, No. 878214478, Fiche no. OTS0206580; 1983.
   References                                                                                             29
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<pre>A Request for advice
B The committee
C Comments on the public review draft
D In vitro genotoxicity data
E Carcinogenic classification of substances by the committee
F Guideline 93/21/EEG of the European Union
  Annexes
                                                             31
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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
      Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
      and Employment wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
      tal advisory structure, to improve the integration of the development of recommendations for health
      based occupation standards and the development of comparable standards for the general population.
      A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
      by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
      exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
      (MAC-values) for substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as fol-
      lows:
      The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
      aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
      report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
      quality at the work place. This implies:
      •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
           criteria-document that will be made available to the Health Council as part of a specific request
      Request for advice                                                                                        33
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<pre>       for advice. If possible this evaluation should lead to a health based recommended exposure limit,
       or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calcu-
       lated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6 per
       year.
   •   The evaluation of documents review the basis of occupational exposure limits that have been
       recently established in other countries.
   •   Recommending classifications for substances as part of the occupational hygiene policy of the
       government. In any case this regards the list of carcinogenic substances, for which the classifica-
       tion criteria of the Directive of the European Communities of 27 June 1967 (67/548/EEG) are
       used.
   •   Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
   Social Affairs and Employment the President of the Health Council agreed to
   establish DECOS as a Committee of the Health Council.
34 p-Nitroaniline
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<pre>Annex B
      The committee
      •   G..J. Mulder, chairman
          emeritus professor of toxicology, Leiden University, Leiden
      •   P.J. Boogaard
          toxicologist, SHELL International BV, The Hague
      •   Ms. M.J.M. Nivard
          molecular biologist and genetic toxicologist, Leiden University Medical Cen-
          ter, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Quality of Life, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis, Uni-
          versity Medical Center, Leiden
      •   E.J.J. van Zoelen
          professor of cell biology, Radboud University Nijmegen, Nijmegen
      •   J.M. Rijnkels, scientific secretary
          Health Council of the Netherlands, The Hague
      The committee consulted an additional expert, Prof. dr. G. Mohn, working at
      Department of Radiation Genetics and Chemical Mutagenesis of the University
      of Leiden, with respect to the genotoxic data.
      The committee                                                                    35
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<pre>   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health Coun-
   cil Committee. Transparency regarding possible conflicts of interest is nonethe-
   less important, both for the President and members of a Committee and for the
   President of the Health Council. On being invited to join a Committee, members
   are asked to submit a form detailing the functions they hold and any other mate-
   rial and immaterial interests which could be relevant for the Committee’s work.
   It is the responsibility of the President of the Health Council to assess whether
   the interests indicated constitute grounds for non-appointment. An advisorship
   will then sometimes make it possible to exploit the expertise of the specialist
   involved. During the establishment meeting the declarations issued are dis-
   cussed, so that all members of the Committee are aware of each other’s possible
   interests.
36 p-Nitroaniline
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2007 for public review. The follow-
      ing organisations and persons have commented on the draft document:
      • E. González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain;
      • R.D. Zumwalde, National Institute for Occupational Safety and Health, the
          USA.
      Comments on the public review draft                                               37
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<pre>Annex        D
             In vitro genotoxicity data
Test system                             Exposure conditions  Result                          Reference
Gene mutations
Salmonella typhimurium strains:                              with and without exogenous met-
                                                             abolic activation
TA97                                    up to 6,666 μg/plate - (without activation)          2,13-17
                                                             - (with activation)
TA98                                    up to 6,666 μg/plate + (without activation)          2,15,18-21
                                                             + (with activation)
                                        up to 1,000 μg/plate - (without activation)          22
                                                             - (with activation)
                                        up to 1,000 μg/plate - (without activation)          12,23-25
                                                             + (with activation)
TA98 FMN                                0.1 – 10 μmol/plate  + (with activation)             15
TA98 NR                                 up to 3,000 μg/plate - (without activation)          14,18
                                                             - (up to 50 μg/plate,
                                                                 with activation)
                                                             + (with activation)
TA100                                   up to 6,666 μg/plate - (without activation)          2,13,16-23,26
                                                             - (with activation)
TA100 FMN                               up to 10 μmol/plate  + (with activation)             15
TA100 NR                                up to 3,000 μg/plate - (without activation)          18,26
                                                             - (with activation)
TA1535                                  up to 6,666 μg/plate - (without activation           2,16,19-22
                                                             - (with activation)
TA1535                                  no data available    - (with activation, aroclor)    24,25
                                                             + (with activation,
                                                                phenobarbitone)
             In vitro genotoxicity data                                                                    39
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<pre>TA1537                            up to 6,666 μg/plate          -   (without activation)   2,16,19,21,22,26
                                                                -   (with activation)
TA1538                            up to 6,666 μg/plate          -   (without activation)   14,22
                                                                -   (with activation)
TA1538                            up to 1,000 μg/plate          -   (without activation)   26,27
                                                                +   (with activation)
TA1538                            up to 10 μg/plate             +   (without activation)   21
TA1538 NR                         up to 50 μg/plate             -   (without activation)   14
                                                                -   (with activation)
G46                               up to 1,000 μg/plate          -   (without activation)   26
                                                                -   (with activation)
C3076                             up to 1,000 μg/plate          -   (without activation)   26
                                                                -   (with activation)
D3052                             up to 1,000 μg/plate          -   (without activation)   26
                                                                +   (with activation)
Photobacterium leiognathi SD 18   up to 100 μg/plate            +   (no data on metabolic  28,29
(forward mutations)                                                  activation)
Photobacterium phophoreum         no data available             +  (no data on metabolic   30
(forward mutations)                                                 activation)
Escherichia coli WPuvrA           up to 1,000 μg/plate          -  (without activation)    20,26,31
                                                                -  (with activation)
Bacillus subtilus                 up to 10 mg/plate             +  (without activation)    21
L5178Y TK+/- mouse lymphoma cells up to 1,000 μg/mL             +  (without activation)    2,32
                                                                -  and + (with activation)
Chinese hamster ovary cells;      up to 800 μg/mL               -  (without activation)    33
HGPRT mutations                                                 -  (with activation)
Chromosomal abberations
Chinese hamster ovary cells       up to 1,600 μg/mL             - and + (without exogenic  2,18,34
                                                                  metabolic activations)
Chinese hamster ovary cells       up to 5,000 μg/mL             + (with metabolic          2,34
                                                                    activation)
human peripheral lymphocytes      up to 0.10 mmol/L             + (without activation)     35
Sister chromatid exchanges
Chinese hamster ovary cells       up to 200 μg/mL               - and equivocal (without   2,34
                                                                  metabolic activation)
Chinese hamster ovary cells       up to 5,000 μg/mL             - and + (with metabolic    2,34
                                                                  activation)
Unscheduled DNA synthesis
primary rat liver cells           up to 1,000 nmol/mL (μg/well) - and equivocal            26,36
40            p-Nitroaniline
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<pre>Annex         E
              Carcinogenic classification of sub-
              stances by the committee
The committee expresses its conclusions in the form of standard phrases:
Judgment of the committee                                                                       Comparable with EU class
This compound is known to be carcinogenic to humans                                             1
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound should be regarded as carcinogenic to humans                                      2
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound is a suspected human carcinogen.                                                  3
•   This compound has been extensively investigated. Although there is insufficient evidence    (A)
    for a carcinogenic effect to warrant a classification as ‘known to be carcinogenic to
    humans’ or as ‘should be regarded as carcinogenic to humans’, they indicate that there is
    cause for concern.
•   This compound has been insufficiently investigated. While the available data do not war-    (B)
    rant a classification as ‘known to be carcinogenic to humans’ or as ‘should be regarded as
    carcinogenic to humans’, they indicate that there is a cause for concern.
This compound cannot be classified                                                              not classifiable
•   There is a lack of carcinogenicity and genotoxicity data.
•   Its carcinogenicity is extensively investigated. The data indicate sufficient evidence sug-
    gesting lack of carcinogenicity.
              Carcinogenic classification of substances by the committee                                             41
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<pre>Annex F
      Guideline 93/21/EEG of the European
      Union
      4.2            Criteria for classification, indication of danger, choice of risk phrases
      4.2.1          Carcinogenic substances
      For the purpose of classification and labelling, and having regard to the current state of knowledge,
      such substances are divided into three categories:
      Category 1:
      Substances known to be carcinogenic to man.
      There is sufficient evidence to establish a causal association between human exposure to a substance
      and the development of cancer.
      Category 2:
      Substances which should be regarded as if they are carcinogenic to man.
      There is sufficient evidence to provide a strong presumption that human exposure to a substance may
      result in the development of cancer, generally on the basis of:
      •    appropriate long-term animal studies
      •    other relevant information.
      Guideline 93/21/EEG of the European Union                                                             43
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<pre>   Category 3:
   Substances which cause concern for man owing to possible carcinogenic effects but in
   respect of which the available information is not adequate for making a satisfactory assess-
   ment.
   There is some evidence from appropriate animal studies, but this is insufficient to place the substance
   in Category 2.
   4.2.1.1       The following symbols and specific risk phrases apply:
   Category 1 and 2:
   T; R45 May cause cancer
   However for substances and preparations which present a carcinogenic risk only when inhaled, for
   example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with
   skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be
   used:
   T; R49 May cause cancer by inhalation
   Category 3:
   Xn; R40 Possible risk of irreversible effects
   4.2.1.2       Comments regarding the categorisation of carcinogenic substances
   The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into
   Categories 2 and 3 is based primarily on animal experiments.
   For classification as a Category 2 carcinogen either positive results in two animal species should be
   available or clear positive evidence in one species; together with supporting evidence such as geno-
   toxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship
   with other known carcinogens, or data from epidemiological studies suggesting an association.
44 p-Nitroaniline
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<pre>Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is
     insufficient for classification in Category 2. Additional experiments would not be expected to
     yield further relevant information with respect to classification.
b    substances which are insufficiently investigated. The available data are inadequate, but they
     raise concern for man. This classification is provisional; further experiments are necessary
     before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experimental tumour induction in view of possible human exposure. These argu-
ments, especially in combination, would lead in most cases to classification in Category 3, even
though tumours have been induced in animals:
•    carcinogenic effects only at very high levels exceeding the 'maximal tolerated dose'. The maxi-
     mal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go
     along with physical changes such as about 10% retardation in weight gain;
•    appearance of tumours, especially at high dose levels, only in particular organs of certain species
     is known to be susceptible to a high spontaneous tumour formation;
•    appearance of tumours, only at the site of application, in very sensitive test systems (e.g. i.p. or
     s.c. application of certain locally active compounds);
•    if the particular target is not relevant to man;
•    lack of genotoxicity in short-term tests in vivo and in vitro;
•    existence of a secondary mechanism of action with the implication of a practical threshold above
     a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological
     regulation, chronic stimulation of cell proliferation;
•    existence of a species - specific mechanism of tumour formation (e.g. by specific metabolic
     pathways) irrelevant for man.
For a distinction between Category 3 and no classification arguments are relevant which exclude a
concern for man:
•    a substance should not be classified in any of the categories if the mechanism of experimental
     tumour formation is clearly identified, with good evidence that this process cannot be extrapo-
     lated to man;
•    if the only available tumour data are liver tumours in certain sensitive strains of mice, without
     any other supplementary evidence, the substance may not be classified in any of the categories;
•    particular attention should be paid to cases where the only available tumour data are the occur-
     rence of neoplasms at sites and in strains where they are well known to occur spontaneously with
     a high incidence.
Guideline 93/21/EEG of the European Union                                                                 45
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<br><br>