<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>                  Health Council of the Netherlands
          5-Nitroacenaphthene
          Health-based calculated occupational cancer risk values
2014/17
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>5-Nitroacenaphthene
     Health-based calculated occupational cancer risk values
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre></pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : Aanbieding advies 5-Nitroacenafteen
Uw kenmerk             : DGV/BMO/U-932542
Ons kenmerk            : U-8165/BvdV/cn/459-F70
Bijlagen               :1
Datum                  : 1 juli 2014
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
5-nitroacenafteen.
Dit advies maakt deel uit van een uitgebreide reeks, waarin concentratieniveaus in lucht
worden afgeleid die samenhangen met een extra kans op overlijden aan kanker van 4 per
1.000 en 4 per 100.000 door beroepsmatige blootstelling. De conclusies van het genoemde
advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige blootstelling aan
stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid
en omgeving.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. W.A. van Gool,
voorzitter
Bezoekadres                                                      Postadres
Rijnstraat 50                                                    Postbus 16052
2515 XP Den Haag                                                 2500 BB Den Haag
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre></pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>5-Nitroacenaphthene
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2014/17, The Hague, July 1, 2014
</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<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 & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, and Education, Culture & Science. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to
government policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. 5-Nitroacenaphthene - Health-based
calculated occupational cancer risk values. The Hague: Health Council of the
Netherlands, 2014; publication no. 2014/17.
all rights reserved
ISBN: 978-94-6281-007-5
</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 14
.3 Data 14
   Identity, toxicity profile and classification 15
.1 Identity and physical and chemical properties 15
.2 Classification as a carcinogenic substance 16
.3 Genotoxicity 16
.4 Non-carcinogenic effects 17
.5 Existing occupational exposure limits 17
   Carcinogenicity studies 19
.1 Human studies 19
.2 Animal experiments 19
.3 Selection of the suitable study for risk estimation in the occupational situation 22
.4 Calculation of the health-based occupational cancer risk values 23
   Contents                                                                             7
</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>   References 27
  Annexes 29
A Request for advice 31
B The Committee 33
C The submission letter (in English) 35
D Comments on the public review draft 37
E Animal studies 39
F Evaluation by the Subcommittee on the Classification of carcinogenic substances 43
G Carcinogenic classification of substances by the Committee 49
H BMD-analysis: Diet study on carcinogenic effects by 5-nitroacenaphtene 51
  5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>Samenvatting
Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid, leidt de
Commissie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van
de gezondheidsraad, de concentraties van een stof in de lucht af die samenhangen
met een vooraf vastgesteld extra risico op sterfte aan kanker (4 per 1000 en 4 per
100.000 individuen) door beroepsmatige blootstelling gedurende het arbeidzame
leven. Het gaat om kankerverwekkende stoffen die door de Gezondheidsraad of
de Europese Unie geclassificeerd zijn in categorie 1A of 1B en die kankerver-
wekkend zijn via een stochastisch genotoxisch mechanisme. Voor de schatting
maakt de commissie gebruik van de Leidraad berekening risicogetallen voor
carcinogene stoffen van de Gezondheidsraad.1 In dit advies doet de commissie
zo’n schatting voor 5-nitroacenafteen. 5-Nitroacenafteen wordt gebruikt bij de
productie van kleurstoffen, plastics en pesticiden.
Naar schatting van de commissie is de concentratie van 5-nitroacenafteen in de
lucht, die samenhangt met een extra kans op overlijden aan kanker van
• 4 per 1 000 (4x10-3), bij 40 jaar beroepsmatige blootstelling, gelijk aan
    1.5 mg/m3
• 4 per 100 000 (4x10-5), bij 40 jaar beroepsmatige blootstelling, gelijk aan
    0.015 mg/m3.
Samenvatting                                                                       9
</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>0 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>Executive summary
At the request of the Minister of Social Affairs and Employment, the Dutch
Expert Committee on Occupational Safety (DECOS), a committee of the Health
Council of the Netherlands, derives so-called health-based calculated
occupational cancer risk values (HBC-OCRVs) associated with excess mortality
levels of 4 per 1,000 and 4 per 100,000 as a result of working life exposure to
substances. It concerns substances which are classified by the Health Council or
the European Union in category 1A or 1B, and which are considered stochastic
genotoxic carcinogens. For the estimation, the Committee uses the Guideline
for the calculation of occupational cancer risk values of the Health Council.2 In
this report the Committee presents such estimates for 5-nitroacenaphtene.
5-Nitroacenaphtene is used in the production of dyes, plastics, and pesticides.
The Committee estimated that the concentration of 5-nitroacenaphtene in the air,
which corresponds to an excess cancer mortality of
• 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to
    1.5 mg/m3
• 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
    0.015 mg/m3.
Executive summary                                                                 11
</pre>

====================================================================== Einde pagina 12 =================================================================

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>2 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for genotoxic chemical
        substances are set using a three-step procedure. In the first step, a scientific
        evaluation of the data on the toxicity of the substance is made by the Dutch
        Expert Committee on Occupational Safety (DECOS), a committee of the Health
        Council of the Netherlands, at request of the Minister of Social Affairs and
        Employment (Annex A). This evaluation should lead for genotoxic substances
        with a non-stochastic mechanism to a health-based recommended exposure limit
        for the concentration of the substance in air. Such an exposure limit cannot be
        derived if the toxic action cannot be evaluated using a threshold model, as is the
        case for substances with stochastic genotoxic carcinogenic properties. In that
        case, an exposure-response relationship is recommended for use in regulatory
        standard setting, i.e., the calculation of so-called health-based calculated
        occupational cancer risk values (HBC-OCRVs). The Committee calculates HBC-
        OCRVs for compounds, which are classified as genotoxic carcinogens by the
        European Union or by the Committee.
            For the establishment of the HBC-OCRVs, the Committee generally uses a
        linear extrapolation method, as described in the Committee's reports Calculating
        cancer risk and Guideline for the calculation of occupational cancer risk
        values.2,3 The linear model to calculate occupational cancer risk is used as a
        Scope                                                                              13
</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>    default method, unless scientific data would indicate that using this model is not
    appropriate.
        In the next phase of the three-step procedure, the Social and Economic
    Council advises the Minister of Social Affairs and Employment on the feasibility
    of using the HBC-OCRVs as regulatory occupational exposure limits. In the final
    step of the procedure, the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present document contains the evaluation of the DECOS, hereafter called the
    Committee. The members of the Committee are mentioned in Annex B. The
    Committee requested the DECOS Subcommittee on the Classification of
    Carcinogenic Substances to evaluate the genotoxic mechanism of 5-nitroacena-
    phthene (see Annex F and G). The recommendations of the Subcommittee were
    used by DECOS to decide on the appropriate approach to risk assessment. The
    submission letter (in English) to the Minister can be found in Annex C.
        In January 2014, the president of the Health Council released a draft of the
    report for public review. The individuals and organizations that commented on
    the draft are listed in Annex D. The Committee has taken these comments into
    account in deciding on the final version of the advisory report. The received
    comments, and the replies by the Committee, can be found on the website of the
    Health Council.
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,
    Medline and Chemical Abstracts, using carcinogenic properties, carcino*,
    cancer, neoplastic, 5-nitroacenaphthene and CAS registry number as key words.
    In addition, in preparing this report the following reviews were consulted:
    • Review by the Commission of the European Communities4
    • IARC Review.5
    The last search was performed in May 2014 and covered the period 1997-2014
    (a previous search was conducted in 1997 and covered the period 1985 to 19
    February 1997).
 4  5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre> hapter 2
        Identity, toxicity profile and
        classification
2.1     Identity and physical and chemical properties
        5-Nitroacenaphthene is used in the production of dyes, plastics and pesticides.
        Physical and chemical data shown below are from IARC 19785, Richardson6 and
        http://toxnet.nlm.nih.gov (HSDB and ChemIDplus data bases, accessed May 22,
        2014).
        Chemical name                           : 5-nitroacenaphthene
        CAS number                              : 602-87-9
        EINECS number                           : 210-025-0
        EEC number                              : 609-037-00-2
        IUPAC name                              : 5-nitroacenaphthene
        Synonyms                                : 1,2-dihydro-5-nitro-acenaphtylene
        Physical description and colour         : solid, yellow
        Molecular formula                       : C12H9NO2
        Structure                               :
        Identity, toxicity profile and classification                                   15
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>    Molecular weight                                : 199.2
    Melting point                                   : 102-103 °C
    Boiling point (101.3 kPa)                       : 279 °C
    Density                                         : no data
    Solubility                                      : 0.91 mg/L at 25°C in water;
                                                      soluble in ethanol, ethyl ether, ligroin
    Octanol/water partition coefficient, Log Poct/w : 3.85
    Vapour pressure (25°C)                          : 2.65E-5 mm Hg
    Relative vapour density (air = 1)               : no data
    Flash point                                     : no data
    Odour threshold                                 : no data
    Conversion factor (20 °C, 101.3 kPa)            : no data
    EU classification                               : H350 - may cause cancer
2.2 Classification as a carcinogenic substance
    The European Union has classified 5-nitroacenaphtene as a category 1B
    carcinogen (may cause cancer). IARC has classified the compound as a 2B
    carcinogen (possibly carcinogenic to humans).5 In this present evaluation, the
    Committee (DECOS) follows the recommendation of the DECOS Subcommittee
    on the Classification of Carcinogenic Substances and classified 5-nitroace-
    naphthene in category 1B (presumed to be carcinogenic to man) (see Annex F
    and G).
2.3 Genotoxicity
    5-Nitroacenaphthene was mutagenic in the Salmonella typhimurium strains
    TA100 and TA98 without metabolic activation and, to a larger extent (2 or
    5-fold increase, respectively) with metabolic activation.7 Mutagenicity of
    5-nitroacenaphthene in Salmonella typhimurium strains TA100 and TA98 with
    and without metabolic activation was confirmed by McCoy et al..8 Further,
    5-nitroacenaphthene was positive in an umu test system using Salmonella
    typhimurium strain NM3009.9 In a DNA-repair test 5-nitroacenaphthene elicited
    a positive DNA-repair response in vitro in both rat and mouse hepatocytes.10
         Since 5-nitroacenaphthene is positive for bacterial mutagenicity and for
    genotoxicity in the DNA-repair test, the Committee follows the recommendation
    of the DECOS Subcommittee on the Classification of Carcinogenic Substances
    (see Annex F) and concludes that 5-nitroacenaphthene is a genotoxic carcinogen
    with a stochastic mechanism.
 6  5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>2.4 Non-carcinogenic effects
    Limited data on effects other than carcinogenicity are reported for
    5-nitroacenaphthene. In the specific carcinogenicity studies reported in Chapter 3
    a number of toxicological effects were observed and will be discussed there.
2.5 Existing occupational exposure limits
    Worldwide, there are no occupational exposure limits for 5-nitroacenaphthene
    (http://www.ser.nl, accessed May 22, 2014).
    Identity, toxicity profile and classification                                      17
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>8 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre> hapter 3
        Carcinogenicity studies
        Available data have been summarized and evaluated by working groups of
        IARC.5 IARC concluded that there was sufficient evidence for carcinogenicity
        to animals and that no case reports or epidemiological studies were available to
        the working group. The Committee found a NCI/NTP long-term animal
        study not included in the IARC evaluation.11 No epidemiological data on
        5-nitroacenaphthene were found by the Committee.
3.1     Human studies
        No human data were available.
3.2     Animal experiments
        Table 1 (Annex E) summarizes the available carcinogenicity studies in
        experimental animals. These studies comprise an oral study in rats and hamsters
        by Takemura et al., an oral study in rats and mice by NCI/NTP and an
        intraperitoneal study in mice described by IARC.5,11,12 No long-term inhalation
        or dermal studies were available. The design and carcinogenicity results of the
        oral studies are presented below. The results on non-cancer endpoints examined
        in these studies (mortality, body weight, non-neoplastic histopathological
        lesions) will also be discussed in this section.
        Carcinogenicity studies                                                          19
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>      In the NCI/NTP study, Fischer 344 rats (50/sex/dose) were given
  5-nitroacenaphthene in their diet at concentrations of 0.12% (low dose) or
  0.24% (high dose) for 78 weeks (after week 70, there were no surviving male rats
  in the high-dose group).11 Following the treatment period, the animals were
  observed for an additional 22 weeks (low-dose) or 9 weeks (high-dose females).
  The study included two control groups kept on the basal diet. The daily intake of
  5-nitroacenaphthene was calculated by the Committee to be 48 and 96 mg/kg
  bw/day for male rats, and 60 and 120 mg/kg bw/day for female rats (based on
  standard food intake values of 40 and 50 g/kg bw/day for male and female rats,
  respectively, as stated by Gold et al.13). 5-Nitroacenaphthene was carcinogenic to
  male and female rats. In both sexes the incidence of carcinomas in the region of
  the ear canal was increased markedly from none in controls to 49% in low-dose
  males, 43% in high-dose males, 55% in low-dose females and 73% in high-dose
  females. The incidences of alveolar/bronchiolar adenomas and carcinomas were
  also increased in both sexes. The incidences of these lung tumours were 1%,
  17% and 6% in control, low- and high-dose animals (both sexes), respectively.
  The response was not dose-related, possibly because high-dose rats did not
  survive long enough to be at risk for these lung tumours. In addition, in female
  rats the incidences of mammary gland adenocarcinomas and of clitoral gland
  carcinomas were increased from 0% in controls to 10% (mammary gland
  tumours in both dosed groups, clitoral gland carcinomas in high-dose females) or
  12% (clitoral gland carcinomas in low-dose females). The above tumours are
  considered to be relevant for humans.
      As to the non carcinogenic effects: In male rats of both dose groups, severe
  body weight depression was evident after week 20 (up to 27% and 45% lower
  than controls in the low dose and high dose group respectively). In female rats
  body weight depression, although not as extreme, was also observed in both dose
  groups. Accelerated mortality was observed at both dose levels in male rats after
  week 45 and in female rats after week 33. Median survival of high-dose males
  was 61 weeks while low-dose males had a median survival of 83 weeks. The
  male control groups lived for at least 100 weeks. Median survival of female rats
  of the high-dose group was 56 weeks and 76 weeks low-dose females. Most
  control females lived for at least 100 weeks. Rats showed no treatment-related
  non-neoplastic lesions. The accelerated mortality in the treated rats may have
  been related to tumour development.
      In the mouse study by NCI/NTP, B6C3F1 mice (50/sex/dose) received diet
  containing 0.06% (low dose) 5-nitroacenaphthene (in females the concentration
  was reduced to 0.03% after 51 weeks because of high mortality in high-dose
  females) or 0.12% (high dose) 5-nitroacenaphthene for 78 weeks.11 Hereafter,
0 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre>the mice were observed an additional 18 weeks. The study included a
control group (50 mice/sex) kept on the basal diet. The daily intake of
5-nitroacenaphthene was calculated by the Committee to be 72 and 144 mg/kg
bw/day for male mice, and 65 and 156 mg/kg bw/day for female mice (based on
standard food intake values of 120 and 130 g/kg bw/day for male and female
mice, respectively, as stated by Gold et al.13; for low-dose females, a time-
weighted average dietary concentration of 0.05% was used in the calculation).
5-Nitroacenaphthene was carcinogenic to female mice, causing hepatocellular
carcinomas (the incidences were 4%, 49% and 40% in control, low- and high-
dose females, respectively) and ovarian tumours (the combined incidences of
tubular cell adenomas, granulosa-cell tumours and luteomas were 10% at the
low-dose and 18% at the high-dose versus 0% in controls). The induction of
ovarian tumours is considered relevant for humans. An increase in the incidence
of liver tumours in a mouse carcinogenicity study is generally considered to have
little relevance to man.
     At study termination in week 96, mean body weight of low-dose male mice
was about 20% lower compared to controls and the mean weight of the few
surviving high-dose males was about 30% lower. Accelerated mortality was
observed in male mice at both dose levels and in female mice at the high-dose.
Mortality of male high dose mice was very high (median survival was 20 weeks).
The death of male high-dose mice was not due to cancer because no tumours
were found in these decedents. Survival in male controls was 86%. In the high-
dose group of female mice 24 deaths (48%) occurred in week 50, apparently due
to toxicity. At scheduled termination, 36% of the high-dose, 76% of the low-dose
and 72% of the control female mice were still alive. Treatment-related non-
neoplastic lesions, namely fatty metamorphosis of the liver and calcification of
the renal papilla, were observed in male mice at both dose levels and in female
mice at the high-dose level.
     Overall, though there are some deficiencies in the experimental design of the
rat and mice study by NCI/NTP (see Table 1 in Annex E), the study is adequate
for derivation of occupational cancer risk values. The other carcinogenicity
studies summarized in Table 1 of Annex E are less adequate for this purpose but
provide supportive evidence that 5-nitroacenaphthene is carcinogenic in
experimental animals. A short description of these studies is given below
(see Table 1 of Annex E for details).
     In the study of Takemura et al. Wistar rats (30 females, 20 males) and
Syrian hamsters (24 females, 10 males) were exposed for up to 6 months to 1%
5-nitroacenaphthene in the diet (see Table 1 in Annex E for daily substance
intake per kg body weight).12 Treatment of female rats was interrupted twice
Carcinogenicity studies                                                            21
</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<pre>    because of toxicity. After the treatment period, regular diet was given until death
    (animals in moribund condition and those showing a grossly visible tumour were
    killed) or scheduled necropsy 500 days after initiation of treatment. Eleven
    treated female rats developed malignant tumours between days 280 and 500,
    namely: one rhabdomyosarcoma, two sebaceous, squamous cell carcinomas in
    the ear duct, five intraductal carcinomas in the breast, and ten adenocarcinomas
    in the small intestine. These tumours are considered to be relevant for humans.
    No tumours were observed in the 29 surviving control female rats or in the
    treated male rats. Seven of the 13 female hamsters which were still alive 270
    days after initiation of treatment developed cholangiomas. As this type of tumour
    is benign (and was not accompanied by malignant tumours), it is not relevant for
    the determination of cancer risk values. No tumours were observed in the treated
    male hamsters and the controls.
        Eighteen out of 30 treated female rats died, probably due to toxicity, within
    200 days without developing a tumour. Weight gain of female rats was
    significantly impaired (no quantitative information reported) and their treatment
    had to be interrupted twice because of toxicity. Male rats grew normally and
    showed no toxic effects. Eleven out of 24 treated female hamsters and 3 out of
    10 treated male hamsters died within 270 days. Female hamsters showed reduced
    body weight compared with the controls (body weight results of male hamsters
    were not reported).
        A third study was described in the report of IARC.5 In this study, 20 female
    mice were treated with 5-nitroacenaphthene by intraperitoneal injection (6 mg/kg
    bw) twice a week for 18 months. In the 15 surviving mice, myeloid leukaemia
    (4/15), reticulum-cell sarcoma (2/15), and mammary carcinoma (1/15) were
    observed.
3.3 Selection of the suitable study for risk estimation in the
    occupational situation
    The study by NCI/NTP in rats and mice is considered to be the most suitable
    study available for estimation of the potential cancer risk in humans under
    occupational exposure conditions, since the exposure and experimental period
    covered the largest part of the lifespan of the experimental animals.11 Moreover,
    adequate numbers of animals were used in this study. As the highest incidences
    of treatment-related malignant tumours were observed in female rats, the data
    from this species and strain were used as starting point. Since the report of the
    NCI/NTP study did not include individual animal data, the tumour incidences as
    reported by Gold et al.13 (See Table 1 Annex E), who had access to the individual
 2  5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>      animal pathology results of the NCI/NTP study, were used to calculate the
      health-based occupational cancer risk values.
          The Committee considers the study of Takemura et al. not suitable for the
      derivation of the occupational cancer risk values because of the considerably
      shorter exposure time, the low numbers of animals used and several other
      limitations in experimental design and reporting.12 The original report of the
      mouse study (using intraperitoneal injection) as described by IARC was not
      available, the study was reported only in an abstract.5 Because of the lack of
      additional information on methods and results, and because the study is not
      published in a peer-reviewed journal, the Committee cannot evaluate the quality
      of this study and considers it not suitable for derivation of cancer risk values.
3.4   Calculation of the health-based occupational cancer risk values
3.4.1 Calculation of carcinogenic activity in experimental animals, life-time
      low-dose exposure
      The Committee considered female rats particularly sensitive to the development
      of tumours in the region of the external ear canal. To calculate the carcinogenic
      activity expressed as the incidence per unit daily dose (mg per kg body weight per
      day) of 5-nitroacenaphtene, the number of female rats with carcinomas in the
      region of the external ear canal was used as starting point (0/99, 28/49 and 35/48
      for control, low dose and high dose group respectively, see Table 1 in Annex E).13
      Since the actual values for daily food or substance intake per kg body weight
      were not given in the available publications, the standard value for daily food
      intake per kg body weight (namely, 50 g/kg body weight/day for female rats,
      taken from Gold et al.13) was used to calculate the daily dose of the test
      substance.3 Hence, the dietary concentration of 0.12% was calculated to provide
      a dose of 60 mg of 5-nitroacenaphthene/kg bw/day (while the dietary
      concentration of 0.24% resulted in a dose of 120 mg/kg bw/day).
      Next, the Committee applied the benchmark dose (BMD) approach to describe
      mathematically the dose-response relationship and for deriving a reference dose
      (BMD10) for further cancer risk calculations (see Annex H for BMD analysis).
      The BMD method aims to describe the best possible dose-response relationship
      for a set of toxicity data using a set of different mathematical models. In the case
      of the ear canal tumours a log-logistic model provided the best fit on the data and
      Carcinogenicity studies                                                              23
</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>      resulted in the lowest BMD10. Using this model a BMD10 equal to 4.85 mg/kg
      bw was chosen (see Annex H).
      Then, the incidence per mg/kg bw/day was calculated as follows:
                                               BMR
      Idose =                                                                             =
               BMD×(Xpo/L)×(Xpe/L)×(exposure hours per day/24)×(exposure days per week/7)
                                 0.10
            =                                            =
               (4.85 mg/kg bw)×(546/1,000)×(700/1,000)
           = 5.4 × 10-2 [mg/kg bw]-1
      Where:
      • Idose is the carcinogenic activity attributable to the exposure to the substance
           per unit daily dose under lifespan conditions, assuming a linear dose response
           relationship, usually expressed per mg/m3 or per mg/kg bw/day
      • BMR is the benchmark response, expressed as 10% extra risk
      • BMD is the benchmark dose, the dose corresponding to the BMR expressed
           in mg per kg body weight per day
      • Xpo and Xpe are the exposure and experimental periods, respectively
      • L is the standard lifespan for the animals in question (L rat is assumed
           to be 1,000 days).
3.4.2 Health risk to humans, life-time low-dose exposure
      To estimate the additional lifetime risk of cancer in humans under lifespan
      conditions on the basis of results in animal experiments, it was assumed that
      no difference exists between experimental animals and man with respect
      to toxicokinetics, mechanism of tumour induction, target, susceptibility etc.,
      unless specific information is available which justifies a different approach.
      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. It is
      also assumed that biological availability of 5-nitroacenapthene is 100%.
 4    5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 25 =================================================================

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

<pre>3.4.3 Health risk to workers, establishment of additional life-time cancer risk
      To estimate the additional lifetime risk of cancer in humans under workplace
      exposure conditions it was assumed that the average man is exposed for 40 years,
      8 hours per day, 5 days per week, 48 weeks per year and inhales 10 m3 air per
      8-hour-working day.
      Using as starting point the estimated incidence of 5.4 x 10-2 per mg/kg bw (Idose),
      the additional life-time cancer risk per mg/m3 under occupational exposure
      conditions (= HBC-OCRV) amounts to:
                             40 years    48 weeks 5 days 10 m3
      HBC-OCRV = Idose ×              ×            ×         ×          = 2.6 × 0-3[mg/m3]-1
                             75 years 52 weeks 7 days 70 kg
      The Committee estimated that the concentration of 5-nitroacenaphtene in the air,
      which corresponds to an excess cancer mortality of
      • 4 per 1,000 (4x10-3), for 40 years of occupational exposure, equals to
          1.5 mg/m3
      • 4 per 100,000 (4x10-5), for 40 years of occupational exposure, equals to
          0.015 mg/m3.
      The toxicity data as summarized in this report are too limited to allow a
      conclusion with regard to risk of adverse effects other than carcinogenicity at the
      concentration levels associated with the referential cancer risk levels.
      Carcinogenicity studies                                                                25
</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>6 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>  References
Health Council of the Netherlands. Guideline for the calculation of risk values for carcinogenic
compounds. The Hague: Health Council of the Netherlands, 2012; publication no. 2012/16E.
Health Council of the Netherlands. Guideline for the calculation of risk values for carcinogenic
compounds. The Hague: Health Council of the Netherlands, 2012; publication no. 2012/16E.
Health Council of the Netherlands. Calculating cancer risk. The Hague: Health Council of the
Netherlands, 1995; publication no.
1995/06WGD.
Roi R, Berlin A, raper M, Krug E. 5-Nitroacenaphthene. In: The toxicology of chemicals 1:
Carcinogenicity.Volume 1, Summary reviews of the scientific evidence. 1989: 125-126.
Some aromatic amines and related nitro compounds (hair dyes, colouring agents and miscellaneous
industrial chemicals). IARC Monog Eval Carcinog Risk Chem Human 1978; 16: 319-323.
5-Nitroacenaphthene. In: Richardson S, Gangollis S, editors. The dictionary of substances and their
effects.vol 6. 1994: 111-112.
Yahagi T, Shimizu H, Nagao M, Takemura N, Sugimura T. Mutagenicity of 5-nitroacenaphthene in
salmonella. Gann 1975; 66(5): 581-582.
McCoy EC, De MG, Rosenkranz EJ, Anders M, Rosenkranz HS, Mermelstein R. 5-Nitroacenaphthene:
a newly recognized role for the nitro function in mutagenicity. Environ Mutagen 1983; 5(1): 17-22.
Oda Y, Yamazaki H, Watanabe M, Nohmi T, Shimada T. Highly sensitive umu test system for the
detection of mutagenic nitroarenes in Salmonella typhimurium NM3009 having high O-
acetyltransferase and nitroreductase activities. Environ Mol Mutagen 1993; 21(4): 357-364.
References                                                                                          27
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>0 Mori H, Sugie S, Yoshimi N, Kinouchi T, Ohnishi Y. Genotoxicity of a variety of nitroarenes and
  other nitro compounds in DNA-repair tests with rat and mouse hepatocytes. Mutat Res 1987; 190(2):
  159-167.
1 National Toxicology Program. Bioassay of 5-nitroacenaphthene for possible carcinogenicity (CAS
  No. 602-87-9). Natl Cancer Inst Carcinog Tech Rep Ser 1978; 118: 1-129.
2 Takemura N, Hashida C, Terasawa M. Carcinogenic action of 5-nitroacenaphthene. Br J Cancer
  1974; 30(5): 481-483.
3 Gold LS, Sawyer CB, Magaw R, Backman GM, de VM, Levinson R et al. A carcinogenic potency
  database of the standardized results of animal bioassays. Environ Health Perspect 1984; 58: 9-319.
4 Klimisch HJ, Andreae M, Tillmann U. A systematic approach for evaluating the quality of
  experimental toxicological and ecotoxicological data. Regul Toxicol Pharmacol 1997; 25(1): 1-5.
5 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague: Health Council of the Netherlands, 2010; publication no. A10/07E.
8 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>A Request for advice
B The Committee
C Submission letter (in English)
D Comments on the public review draft
E Animal studies
F Evaluation of the Subcommittee on the Classification of carcinogenic
  substances
G Carcinogenic classification of substances by the Committee
H BMD-analysis: Diet study on carcinogenic effects by 5-nitroacenaphthene
  Annexes
                                                                          29
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>0 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>====================================================================== Pagina 32 ======================================================================

<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the
     governmental advisory structure, to improve the integration of the development of recommendations
     for health based occupation standards and the development of comparable standards for the general
     population. A consequence of this policy proposal is the initiative to transfer the activities of the
     Dutch Expert Committee on Occupational Standards (DECOS) to the Health Council. DECOS has
     been established by ministerial decree of 2 June 1976. Its primary task is to recommend health based
     occupational exposure limits as the first step in the process of establishing Maximal Accepted
     Concentrations (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     follows:
     The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
     aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
     report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
     quality at the work place. This implies:
     •    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                                                                                        31
</pre>

====================================================================== Einde pagina 32 =================================================================

<br><br>====================================================================== Pagina 33 ======================================================================

<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
      calculated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6
      per year.
  •   The evaluation of documents review the basis of occupational exposure limits that have been
      recently established in other countries.
  •   Recommending classifications for substances as part of the occupational hygiene policy of the
      government. In any case this regards the list of carcinogenic substances, for which the
      classification criteria of the Directive of the European Communities of 27 June 1967 (67/548/
      EEG) are used.
  •   Reporting on other subjects that will be specified at a later date.
  In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
  Social Affairs and Employment the President of the Health Council agreed to
  establish DECOS as a Committee of the Health Council. The membership of the
  Committee is given in Annex B.
2 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 33 =================================================================

<br><br>====================================================================== Pagina 34 ======================================================================

<pre>nnex B
     The Committee
     •  R.A. Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life and Professor of
        Translational toxicology, Wageningen University and Research Centre,
        Wageningen
     •  P.J. Boogaard
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders (NECORD), Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht, and
        National Institute for Public Health and the Environment, Bilthoven
     •  T.M. Pal
        Occupational Physician, Netherlands Center for Occupational Diseases,
        Amsterdam
     •  A.H. Piersma
        Professor of Reproductive and Developmental Toxicology, Utrecht
        University, and National Institute for Public Health and the Environment,
        Bilthoven
     The Committee                                                                33
</pre>

====================================================================== Einde pagina 34 =================================================================

<br><br>====================================================================== Pagina 35 ======================================================================

<pre>  •   H.P.J. te Riele
      Professor of Molecular Biology, VU University Amsterdam, and Netherlands
      Cancer Institute, Amsterdam
  •   I.M.C.M. Rietjens
      Professor of Toxicology, Wageningen University and Research Centre,
      Wageningen
  •   F. Russel
      Professor of Pharmacology and Toxicology, Radboud University Medical
      Centre, Nijmegen
  •   G.M.H. Swaen
      Epidemiologist, Maastricht University, Maastricht
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
  •   P.B. Wulp
      Occupational Physician, Labour Inspectorate, Groningen
  •   B.P.F.D. Hendrikx, advisor
      Social and Economic Council, The Hague
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of the Netherlands, The Hague
  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless important, both for the chairperson and members of a Committee
  and for the President of the Health Council. On being invited to join a
  Committee, members are asked to submit a form detailing the functions they
  hold and any other material and immaterial interests which could be relevant for
  the Committee’s work. It is the responsibility of the President of the Health
  Council to assess whether the interests indicated constitute grounds for non-
  appointment. An advisorship will then sometimes make it possible to exploit the
  expertise of the specialist involved. During the inaugural meeting the
  declarations issued are discussed, so that all members of the Committee are
  aware of each other’s possible interests.
4 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 35 =================================================================

<br><br>====================================================================== Pagina 36 ======================================================================

<pre>nnex C
     The submission letter (in English)
     Subject          : Submission of the advisory report 5-Nitroacenaphthene
     Your Reference   : DGV/MBO/U-932342
     Our reference    : U-8165/BvdV/cn/459-F70
     Enclosed         :1
     Date             : July 01, 2014
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     5-nitroacenaphthene.
     This advisory report is part of an extensive series in which carcinogenic
     substances are evaluated for the possibility to establish health-based calculated
     occupational cancer risk values in accordance with European Union guidelines.
     This involves substances to which people can be exposed while pursuing their
     occupation.
     The present advisory report was prepared by the Dutch Expert Committee on
     Occupational Safety (DECOS) of the Health Council of The Netherlands. The
     report has been assessed by the Health Council’s Standing Committee on Health
     and the Environment.
     The submission letter (in English)                                                35
</pre>

====================================================================== Einde pagina 36 =================================================================

<br><br>====================================================================== Pagina 37 ======================================================================

<pre>  I have today sent copies of this advisory report to the State Secretary of
  Infrastructure and the Environment and to the Minister of Health, Welfare and
  Sport, for their consideration.
  Yours sincerely,
  (signed)
  Professor W.A. van Gool,
  President
6 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 37 =================================================================

<br><br>====================================================================== Pagina 38 ======================================================================

<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in January 2014 for public review. The
     following organization and person has commented on the draft document:
     • Dr. T.J. Lentz, National Institute for Occupational Safety and Health
         (NIOSH), Cincinnati (OH), USA.
     Comments on the public review draft                                               37
</pre>

====================================================================== Einde pagina 38 =================================================================

<br><br>====================================================================== Pagina 39 ======================================================================

<pre>8 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 39 =================================================================

<br><br>====================================================================== Pagina 40 ======================================================================

<pre> nnex        E
             Animal studies
 able 1 Carcinogenicity studies with 5-nitroacenapththene.
 tudy design and        Data on exposure and       Results                                      Remarks
 nimal species          effect endpoints
 emale DD mouse5        Intraperitoneal injection, Of 15 surviving treated mice,                Klimisch score: 4
 0 treated              twice weekly, 6 mg/kg bw 4 developed myeloid leukaemia,                 Only abstract available. Low
 0 control              in arachis oil             2 developed reticulum-cell sarcomas, and 1   number of animals, no data
                        Xpo = 18 months            developed mammary carcinoma.                 on effects other than those
                        Xpe = unknown              No tumours were observed in controls.        mentioned under results.
 ischer F344 rat11      0, 0.12% (low dose) and Adverse effects: Body weight depression at      Klimisch score: 2
 ow dose control: 50 0.24% (high dose) in the both dose levels, severely in males after week    Adequate for
ats/sex                 diet                       20, moderately in females.                   carcinogenicity assessment.
High dose control:      (48 and 96 mg/kg bw/day Mortality: accelerated at both dose levels in   Deficiencies: some controls
 9 males and 50         for male rats, 60 and 120 males from week 45 and in females from        improperly matched,
emales                  mg/kg bw/day for female week 33 (dose-related response).                maximum tolerated dose
 reated:                rats)a                     Tumour incidences in control, low- and high- exceeded, individual animal
 0/sex/dose             Xpo = Males 78 (low dose) dose groups, respectively:                    data not reported.
                        or 70 (high dose) weeks. Lung (alveolar/bronchiolar adenomas and
                        Females: 78 weeks (low carcinomas) : Male: 1/96, 7/41, 3/47; Female:
                        and high dose)             1/99, 8/48, 3/48;
                        Xpe = 100 weeks (low       Carcinomas in the region of the external ear
                        dose males and females), canal: Male: 0/96, 21/43, 20/47; Female: 0/
                        87 weeks (high-dose        99, 28/49, 35/48;
                        females), or 70 weeks      Clitoral gland carcinomas:
                        (high dose males).         Female: 0/99, 6/49, 5/48
                        Appropriate statistical    Mammary gland adenocarcinomas:
                        analysis performed (for    Female: 0/99, 5/49, 5/48
                        tumours: based solely on Treatment-related tumour sites combined
                        rats surviving 52 wk or,   (from Gold et al.13)
             Animal studies                                                                                               39
</pre>

====================================================================== Einde pagina 40 =================================================================

<br><br>====================================================================== Pagina 41 ======================================================================

<pre>                       when tumour of interest       Male (carcinomas in the region of the ear
                       was seen earlier, at least as canal, and/or alveolar/bronchiolar carcinomas
                       long as the time at which     and adenomas in the lungs): 1/99, 25/50,
                       the first tumour of interest  21/50; Female (carcinomas in the region of
                       was seen.)                    the ear canal, in clitoral gland, mammary
                                                     gland, and/or alveolar/bronchiolar
                                                     carcinomas and adenomas in the lungs):
                                                     1/100, 37/50, 38/50
B6C3F1 mouse11         0, 0.06% (low dose) and       Adverse effects: Body weight depression in     Klimisch score: 2
 ontrol: 50/sex        0.12% (high dose) in the      male mice of both dose groups.                 Adequate for
reated: 50/sex/ dose   diet (72 and 144 mg/kg        Mortality: accelerated in low- and high-dose   carcinogenicity assessment,
                       bw/day for male mice,         males (dose-dependently) and in high-dose      except in high-dose males
                       65 and 156 mg/kg bw/day       females.                                       (due to poor survival).
                       for female mice)a             Non-neoplastic lesions: fatty metamorphosis    Deficiencies: some controls
                       Xpo = 78 weeks;               of liver and calcification of renal papilla in improperly matched,
                       low-dose females received     males at both dose levels and in high-dose     maximum tolerated dose
                       0.06% in the diet for         females.                                       exceeded, individual animal
                       51 weeks and then 0.03%       Tumours:                                       data not reported.
                       in the diet for 27 weeks      Males: No treatment-related tumours
                       (level lowered because of     observed at low-dose (survival at high-dose
                       high mortality in week        too low for carcinogenicity assessment).
                       50 at the high dose).         Females: Tumour incidences in control, low-
                       Xpe = 96 weeks                and high-dose groups, respectively (no
                       Appropriate statistical       statistical analysis was conducted on these
                       analysis performed (for       total incidences):
                       tumours: based solely on      Hepatocellular carcinomas:
                       mice surviving 52 wk or,      Female: 2/47, 23/47, 18/45;
                       when tumour of interest       Ovaries (tubular cell adenomas, granulosa-
                       was seen earlier, at least as cell tumours, luteomas):
                       long as the time at which     Female: 0/45, 4/41, 7/39;
                       the first tumour of interest  Treatment-related tumour sites combined
                       was seen;                     (from Gold et al.13)
                       high-dose males excluded      Female (hepatocellular carcinomas and/or
                       because of high early         granulosa-cell tumours, luteomas, tubular
                       mortality)                    adenomas in ovaries): 2/50, 23/50, 19/50
 emale Wistar rat12    1% in diet (500 mg/kg         Adverse effects: Debilitation during           Klimisch score: 3
 0 treated,            bw/day)a                      treatment and impaired body weight gain.       Supportive study.
 0 control             Xpo = 4 months                Mortality: 18 treated rats died within 200     Only one dose tested; high
                       (with 2 interruptions         days; one control died during the observation  mortality; no statistical
                       of 3 weeks)                   period.                                        analysis performed;
                       Xpe = max 500 days            Tumours: 11 treated rats developed malignant   exposure period only 4
                       (animals were left to die     tumours between days 280-500: 4 rats had       months and interrupted
                       or killed when moribund       adenocarcinoma in small intestine, 3 had       because of toxicity; only
                       or having a grossly visible   intraductal carcinoma in the breast and        macroscopically observed
                       tumour)                       adenocarcinoma in small intestine, 1 had       tumours were examined
                                                     intraductal carcinoma in the breast, 1 had     microscopically; effect on
                                                     squamous cell carcinoma in the ear duct,       growth not quantified; no
                                                     1 had squamous cell carcinoma in the ear duct  data on non-carcinogenic
                                                     and adenocarcinoma in small intestine, and     effects other than those
                                                     1 had rhabdomyosarcoma, squamous cell          mentioned under results.
                                                     carcinoma in the ear duct, and
                                                     adenocarcinoma in small intestine. Controls:
                                                     no malignant tumours observed
 0            5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 41 =================================================================

<br><br>====================================================================== Pagina 42 ======================================================================

<pre>Male Wistar rat12       1% in diet (400 mg/kg       No malignant tumours observed.               Klimisch score: 3
 0 treated              bw/day)a                    Growth not affected.                         Supportive study
                        Xpo = 6 months              No toxic effects seen during treatment       Only one dosed tested;
                        Xpe = max 500 days          (criteria for toxicity not specified).       exposure period only 6
                        (animals were left to die                                                months; only
                        or killed when moribund                                                  macroscopically observed
                        or having a grossly visible                                              tumours were examined
                        tumour)                                                                  microscopically; no data on
                                                                                                 survival; no information on
                                                                                                 control group; low number
                                                                                                 of animals; no data on non-
                                                                                                 cancer effects other than
                                                                                                 those mentioned under
                                                                                                 results.
 yrian Golden           1% in diet                  Adverse effects: Body weight reduced in      Klimisch score: 3
 amster12               (920 and 1045 mg/kg         females.                                     Supportive study
 4 treated females      bw/day for males and        Mortality: 11 treated females and 3 treated  Only one dosed tested; high
 0 treated males        females, resp.)a            males died within 270 days.                  mortality in treated females;
 0 control females      Xpo = 6 months              Tumours: cholangiomas were observed          no data on mortality in
                        Xpe = max 500 days          histologically in 7 of 13 surviving treated  control females; no
                        (animals were left to die females; no tumours were observed in control statistical analysis
                        or killed when moribund females and in the 7 surviving treated males. performed; exposure period
                        or having a grossly visible                                              only 6 months; only
                        tumour)                                                                  macroscopically observed
                                                                                                 tumours were examined
                                                                                                 microscopically; low
                                                                                                 number of animals; no data
                                                                                                 on non-carcinogenic effects
                                                                                                 other than those mentioned
                                                                                                 under results.
     Calculated by the Committee using standard values for body weight and food intake from Gold et al. (g food/kg body
     weight/day: 40 in male and 50 in female rat, 120 in male and 130 in female mouse, 92 in male and 104.5 in female
     hamster).13
     Xpo= duration of exposure; Xpe= duration of the experiment.
     Klimisch scores were based on Klimisch et al.14
             Animal studies                                                                                                41
</pre>

====================================================================== Einde pagina 42 =================================================================

<br><br>====================================================================== Pagina 43 ======================================================================

<pre>2 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 43 =================================================================

<br><br>====================================================================== Pagina 44 ======================================================================

<pre>nnex F
     Evaluation by the Subcommittee on
     the Classification of carcinogenic
     substances
     The European Union has classified 5-nitroacenaphthene as a category 1B
     carcinogen (may cause cancer). IARC (1978) has classified the compound as a
     2B carcinogen (possibly carcinogenic to humans).1
         In the present update (October 2013) the DECOS Subcommittee on the
     Classification of Carcinogenic Substances evaluated the existing and new
     information regarding human, animal and in vitro studies on carcinogicity and
     genotoxicity of 5-nitroacenaphthene.
     Human studies
     No human data were available to the Subcommittee.
     Animal studies
     These studies comprise an oral study in rats and hamsters by Takemura et al., an
     oral study in rats and mice by NCI/NTP and an intraperitoneal study in mice
     described by IARC.1-3 No long-term inhalation or dermal studies were available.
         In the NCI/NTP study, Fischer 344 rats (50/sex/dose) were given
     5-nitroacenaphthene in their diet at concentrations of 0.12% (low dose) or 0.24%
     (high dose) for 78 weeks (after week 70, there were no surviving male rats in the
     high-dose group).3 Following the treatment period, the animals were observed
     for an additional 22 weeks (low-dose) or 9 weeks (high-dose females). The study
     Evaluation by the Subcommittee on the Classification of carcinogenic substances   43
</pre>

====================================================================== Einde pagina 44 =================================================================

<br><br>====================================================================== Pagina 45 ======================================================================

<pre>  included two control groups kept on the basal diet. The daily intake of
  5-nitroacenaphthene was calculated by the Committee to be 48 and 96 mg/kg
  bw/day for male rats, and 60 and 120 mg/kg bw/day for female rats (based on
  standard food intake values of 40 and 50 g/kg bw/day for male and female rats,
  respectively, as stated by Gold et al.4). 5-Nitroacenaphthene was carcinogenic to
  male and female rats. In both sexes the incidence of carcinomas in the region of
  the ear canal was increased markedly from none in controls to 49% in low-dose
  males, 43% in high-dose males, 55% in low-dose females and 73% in high-dose
  females. The incidences of alveolar/bronchiolar adenomas and carcinomas were
  also increased in both sexes. The incidences of these lung tumours were 1%,
  17% and 6% in control, low- and high-dose animals (both sexes), respectively.
  The response was not dose-related, possibly because high-dose rats did not
  survive long enough to be at risk for these lung tumours. In addition, in female
  rats the incidences of mammary gland adenocarcinomas and of clitoral gland
  carcinomas were increased from 0% in controls to 10% (mammary gland
  tumours in both dosed groups, clitoral gland carcinomas in high-dose females) or
  12% (clitoral gland carcinomas in low-dose females). The above tumours are
  considered to be relevant for humans.
      In the mouse study by NCI/NTP, B6C3F1 mice (50/sex/dose) received diet
  containing 0.06% (low dose) 5-nitroacenaphthene (in females the concentration
  was reduced to 0.03% after 51 weeks because of high mortality in high-dose
  females) or 0.12% (high dose) 5-nitroacenaphthene for 78 weeks.3 Hereafter, the
  mice were observed an additional 18 weeks. The study included a control group
  (50 mice/sex) kept on the basal diet. The daily intake of 5-nitroacenaphthene was
  calculated by the committee to be 72 and 144 mg/kg bw/day for male mice, and
  65 and 156 mg/kg bw/day for female mice (based on standard food intake values
  of 120 and 130 g/kg bw/day for male and female mice, respectively, as stated by
  Gold et al.4; for low-dose females, a time-weighted average dietary concentration
  of 0.05% was used in the calculation). 5-Nitroacenaphthene was carcinogenic to
  female mice, causing hepatocellular carcinomas (the incidences were 4%,
  49% and 40% in control, low- and high-dose females, respectively) and ovarian
  tumours (the combined incidences of tubular cell adenomas, granulosa-cell
  tumours and luteomas were 10% at the low-dose and 18% at the high-dose
  versus 0% in controls). The induction of ovarian tumours is considered relevant
  for humans. An increase in the incidence of liver tumours in a mouse
  carcinogenicity study is generally considered to have little relevance to man.
  In the study of Takemura et al. Wistar rats (30 females, 20 males) and Syrian
  hamsters (24 females, 10 males) were exposed for up to 6 months to 1%
  5-nitroacenaphthene in the diet (see Table 1 in annex D for daily substance intake
4 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 45 =================================================================

<br><br>====================================================================== Pagina 46 ======================================================================

<pre>per kg body weight).2 Treatment of female rats was interrupted twice because of
toxicity. After the treatment period, regular diet was given until death (animals in
moribund condition and those showing a grossly visible tumour were killed) or
scheduled necropsy 500 days after initiation of treatment. Eleven treated female
rats developed malignant tumours between days 280 and 500, namely: one
rhabdomyosarcoma, two sebaceous, squamous cell carcinomas in the ear duct,
five intraductal carcinomas in the breast, and ten adenocarcinomas in the small
intestine. These tumours are considered to be relevant for humans. No tumours
were observed in the 29 surviving control female rats or in the treated male rats.
Seven of the 13 female hamsters which were still alive 270 days after initiation
of treatment developed cholangiomas. As this type of tumour is benign (and was
not accompanied by malignant tumours), it is not relevant for the determination
of cancer risk values. No tumours were observed in the treated male hamsters
and the controls.
     A third study was described in the report of IARC.1 In this study, 20 female
mice were treated with 5-nitroacenaphthene by intraperitoneal injection (6 mg/kg
bw) twice a week for 18 months. In the 15 surviving mice, myeloid leukaemia
(4/15), reticulum-cell sarcoma (2/15), and mammary carcinoma (1/15) were
observed.
     The Subcommittee concludes that 5-nitroacenaphthene is carcinogenic to
experimental animals.
Mechanism of genotoxicity (see Table 2)
5-Nitroacenaphthene was mutagenic in the Salmonella typhimurium strains
TA100 and TA98 without metabolic activation and, to a larger extent (2 or
5-fold increase, respectively) with metabolic activation.5 Mutagenicity of
5-nitroacenaphthene in Salmonella typhimurium strains TA100 and TA98 with
and without metabolic activation was confirmed by McCoy et al.6 Further,
5-nitroacenaphthene was positive in an umu test system using Salmonella
typhimurium strain NM3009.7 In a DNA-repair test 5-nitroacenaphthene elicited
a positive DNA-repair response in vitro in both rat and mouse hepatocytes.8
     Since 5-nitroacenaphthene is positive for bacterial mutagenicity and for
genotoxicity in the DNA-repair test, the Subcommittee concludes that
5-nitroacenaphthene is a stochastic genotoxic carcinogen.
Evaluation by the Subcommittee on the Classification of carcinogenic substances      45
</pre>

====================================================================== Einde pagina 46 =================================================================

<br><br>====================================================================== Pagina 47 ======================================================================

<pre>  Table 2 Genotoxic effects of 5-nitroacenaphthene.
  Test system                   Concentration                           Resulta           Reference
                                                                        -S9 +S9
  Salmonella typhimurium,       0-100 µg/plate                          +        ++       Yahagi et al.
  strains TA98, TA100,                                                                    19755
  reverse mutation
  Salmonella typhimurium,       0-100 µg/plate                          +        ++       McCoy et
  strains TA98, TA100,                                                                    al. 19836
  reverse mutation
  Salmonella typhimurium,       Minimal concentration 25 ng/ml           +                Oda et al.
  strain NM3009, umu gene                                                                 19937
  expression
                                                                        Rat      Mouse
  DNA-repair tests with rat or 0.2 µg/ml- 0.2 mg/ml                     +        +        Mori et al.
  mouse hepatocytes in                                                                    19878
  primary culture
  a    + = positive; – = negative
  Recommendation
  Epidemological studies are not available regarding carcinogenicity of
  5-nitroacenaphthene. However, sufficient evidence is available that
  5-nitroacenaphthene is carcinogenic to animals. Therefore, the Subcommittee
  recommends to classify 5-nitroacenaphthene in category 1B (‘substance
  presumed to be carcinogenic to humans’). Moreover , the Subcommittee is of the
  opinion that a stochastic genotoxic mechanism may underly carcinogenicity. The
  Subcommittee recommends health-based calculated occupational cancer risk
  values (HBC-OCRVs) to be calculated for regulatory standard setting.
  References
  Some aromatic amines and related nitro compounds (hair dyes, colouring agents and miscellaneous
  industrial chemicals). IARC Monog Eval Carcinog Risk Chem Human 1978; 16: 319-323.
  Takemura N, Hashida C, Terasawa M. Carcinogenic action of 5-nitroacenaphthene. Br J Cancer
  1974; 30(5): 481-483.
  National Toxicology Program. Bioassay of 5-nitroacenaphthene for possible carcinogenicity (CAS
  No. 602-87-9). Natl Cancer Inst Carcinog Tech Rep Ser 1978; 118: 1-129.
  Gold LS, Sawyer CB, Magaw R, Backman GM, de VM, Levinson R et al. A carcinogenic potency
  database of the standardized results of animal bioassays. Environ Health Perspect 1984; 58: 9-319.
  Yahagi T, Shimizu H, Nagao M, Takemura N, Sugimura T. Mutagenicity of 5- 15 nitroacenaphthene
  in salmonella. Gann 1975; 66(5): 581-582.
6 5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 47 =================================================================

<br><br>====================================================================== Pagina 48 ======================================================================

<pre>McCoy EC, De MG, Rosenkranz EJ, Anders M, Rosenkranz HS, Mermelstein R.
5-Nitroacenaphthene: a newly recognized role for the nitro function in mutagenicity. Environ
Mutagen 1983; 5(1): 17-22.
Oda Y, Yamazaki H, Watanabe M, Nohmi T, Shimada T. Highly sensitive umu test system
for the detection of mutagenic nitroarenes in Salmonella typhimurium NM3009 having high
O-acetyltransferase and nitroreductase activities. Environ Mol Mutagen 1993; 21(4): 357-364.
Mori H, Sugie S, Yoshimi N, Kinouchi T, Ohnishi Y. Genotoxicity of a variety of nitroarenes and
other nitro compounds in DNA-repair tests with rat and mouse hepatocytes. Mutat Res 1987; 190(2):
159-167.
The Subcommittee
•    R.A. Woutersen, chairman
     Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
     Translational
•    Toxicology, Wageningen University and Research Centre, Wageningen J. van
     Benthem Genetic Toxicologist, National Institute for Public Health and the
     Environment, Bilthoven
•    P.J. Boogaard
     Toxicologist, Shell International BV, The Hague
•    G.J. Mulder
     Emeritus Professor of Toxicology, Leiden University, Leiden
•    M.J.M. Nivard
     Molecular Biologist and Genetic Toxicologist, Leiden University Medical
     Center, Leiden
•    G.M.H. Swaen
     Epidemiologist, Dow Benelux NV, Terneuzen (until April 1, 2013);
     Exponent, Menlo Park, USA (from August 15, 2013)
•    E.J.J. van Zoelen
     Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
•    G.B. van der Voet, scientific secretary
     Toxicologist, Health Council of The Netherlands, The Hague
Date meeting: October 25, 2013
Evaluation by the Subcommittee on the Classification of carcinogenic substances                   47
</pre>

====================================================================== Einde pagina 48 =================================================================

<br><br>====================================================================== Pagina 49 ======================================================================

<pre>8 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 49 =================================================================

<br><br>====================================================================== Pagina 50 ======================================================================

<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                67/548/EEC            EC No 1272/2008
                                                                                before                as from
                                                                                12/16/2008            12/16/2008
A            The compound is known to be carcinogenic to humans.                1                     1A
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
B            The compound is presumed to be as carcinogenic to humans.          2                     1B
             • It acts by a stochastic genotoxic mechanism.
             • It acts by a non-stochastic genotoxic mechanism.
             • It acts by a non-genotoxic mechanism.
             • Its potential genotoxicity has been insufficiently investigated.
                Therefore, it is unclear whether the compound is genotoxic.
             The compound is suspected to be carcinogenic to man.               3                     2
3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
             properties of the compound.
4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.15
             Carcinogenic classification of substances by the Committee                                                49
</pre>

====================================================================== Einde pagina 50 =================================================================

<br><br>====================================================================== Pagina 51 ======================================================================

<pre>0 5-Nitroacenaphthene</pre>

====================================================================== Einde pagina 51 =================================================================

<br><br>====================================================================== Pagina 52 ======================================================================

<pre>nnex H
     BMD-analysis: Diet study
     on carcinogenic effects by
     5-nitroacenaphtene
     Software            US EPA BMDS version 2.4.
     Model type          Dichotomous, restricted models.
     BMR, Risk type      10%, extra risk (default value for dichotomous (quantal)
                         animal data.
     BMDL                Lowest 95% confidence interval of the BMD.
     Model fitting       Based on visual inspection of graphs, judgement on
                         BMD-BMDL deviation (model accepted at a deviation of
                         < factor 10), and calculated differences in log-likelihoods.
     Data source         National Toxicology Program. Bioassay of
                         5-nitroacenaphthene for possible carcinogenicity
                         (CAS No. 602-87-9). Natl Cancer Inst Carcinog Tech Rep
                         Ser 1978; 118: 1-129 (a 2-year diet study).11
     Animals             Female F344/N rats.
     Exposure            0, 60 and 120 mg/kg bw/day
                         (see Annex E for specific details)
     Effects             Tumour incidence of ear canal, lung, mammary gland,
                         clitoral gland (see Annex E for specific details).
     BMD-analysis: Diet study on carcinogenic effects by 5-nitroacenaphtene           51
</pre>

====================================================================== Einde pagina 52 =================================================================

<br><br>====================================================================== Pagina 53 ======================================================================

<pre>    Table 3 Results of a BMD-analysis using a loglogistic model.
                          0 mg/kg       60 mg/kg        120 mg/kg                                                                                         BMD10                       BMDL10a
                          bw/day        bw/day          bw/day                                                                                            (mg/kg bw)                  (mg/kg bw)
    Ear canal             0/99          28/49           35/48                                                                                              4.85                        3.36
    (squamous cell and
    ceruminous cell
    carcinomas)
    Lung                  1/99           8/48             3/48                                                                                            89.50                         0.24
    (alveolar/bronchial
    adenomas and
    carcinomas)
    Mammary gland         0/99           5/49             5/48                                                                                            85.69                       51.12
    adenocarcinoma
    Clitoral gland        0/99           6/49             5/48                                                                                            76.92                       46.75
    carcinoma
    a                                  BMDL alleen genoemd als deze minder dan een factor 10 afwijkt van de corresponderende
                                       BMD.
                                                     L o g - L o g is tic M o d e l, w ith B M R o f 1 0 % E x tra R is k fo r th e B M D a n d 0 .9 5 L o w e r C o n fid e n c e L im it fo r th e B M D L
                                                                                          L o g -L o g is tic
                                                    0 .8
                                                    0 .6
        F ra c tio n A ff e c t e d
                                                    0 .4
                                                    0 .2
                                                      0
                                                             BM DL B MD
                                                                  0                  20                         40             60                   80                  100                  12 0
                                                                                                                             dose
                                      1 1 :1 6 1 0 /2 3 2 0 1 3
    Figure 1 Graph BMD-analysis: Ear canal tumours.
2   5-Nitroacenaphthene
</pre>

====================================================================== Einde pagina 53 =================================================================

<br><br>====================================================================== Pagina 54 ======================================================================

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

====================================================================== Einde pagina 54 =================================================================

<br><br>