<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>Phenacetin
   Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Phenacetin
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7412/BvdV/fs/246-C17
Bijlagen               :1
Datum                  : 13 november 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
fenacetine.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
      Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Het advies is getoetst door de Beraadsgroep Gezondheid en omgeving
van de Gezondheidsraad.
Ik heb het 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
Parnassusplein 5                                                 Postbus 16052
2 5 11 V X D e n          Haag                                   2500 BB Den     Haag
E - m a i l : b . v. d . v o e t @ g r. n l                      w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Phenacetin
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of
the Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/21, The Hague, November 13, 2012
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<pre>The Health Council of the Netherlands, established in 1902, is an independent
scientific advisory body. Its remit is “to advise the government and Parliament on
the current level of knowledge with respect to public health issues and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, 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.
                  The Health Council of the Netherlands is a member of the International Network
                  of Agencies for Health Technology Assessment (INAHTA), an international
                  collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Phenacetin. Evaluation of the carcinogenicity
and genotoxicity. The Hague: Health Council of the Netherlands, 2012;
publication no. 2012/21.
all rights reserved
ISBN: 978-90-5549-920-5
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedures 13
.3 Data 14
   General information 15
.1 Identity and physicochemical properties 15
.2 IARC classification 16
   Carcinogenicity 17
.1 Observations in humans 17
.2 Carcinogenicity studies in animals 22
   Mode of action 27
.1 Genotoxic mode of action 27
   Contents                                   7
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<pre>    Classification 31
 .1 Evaluation of data on carcinogenicity and genotoxicity 31
 .2 Recommendation for classification 32
    References 33
    Annexes 39
A   Request for advice 41
B   The Committee 43
C   The submission letter 45
D   Comments on the public review draft 47
E   IARC Monograph 49
F   Human data 51
G   Animal data 57
H   Genotoxicity data 59
    Carcinogenic classification of substances by the Committee 61
    Phenacetin
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de raad, hierna kortweg aangeduid
als de commissie. In het voorliggende rapport neemt de Commissie fenacetine
onder de loep. Fenacetine werd vanaf 1887 tot ongeveer 1980 gebruikt als pijn-
stiller. Omdat er steeds meer aanwijzingen kwamen dat chronisch gebruik van
fenacetine vormen van nierproblemen kan veroorzaken, is de stof niet meer als
geneesmiddel geregistreerd. Fenacetine wordt vaak versneden aangetroffen in
illegaal verkrijgbare cocaïne.
     Op basis van de beschikbare gegevens leidt de commissie af dat fenacetine
kankerverwekkend is voor de mens. Zij beveelt aan om de stof te classificeren in
categorie 1A.* De commissie concludeert verder dat de stof een stochastisch
genotoxisch werkingsmechanisme heeft.
Volgens het classificatiesysteem van de Gezondheidsraad (zie bijlage I).
Samenvatting                                                                     9
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<pre>0 Phenacetin</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of
substances to which workers are occupationally exposed. The Evaluation is
performed by the subcommittee on the Classification of Carcinogenic
Substances of the Dutch Expert Committee on Occupational Standards of the
Health Council, hereafter called the Committee. In this report, the Committee
evaluated phenacetin. Phenacetin was after the introduction in 1887 up to the
early 1980s used as an analgesic drug. Because chronic use of phenacetin is
suspected to cause renal problems the registration of the drug has been
discontinued. Phenacetin is being used as a cutting agent to adulterate illegally
supplied cocaïne.
    Based on the available information, the Committee is of the opinion that
phenacetin is carcinogenic to humans and recommends to classify the substance
in category 1A.* The Committee is furthermore of the opinion that phenacetin
acts by a stochastic genotoxic mechanism.
According to the classification system of the Health Council (see Annex I).
Executive summary                                                                 11
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<pre>2 Phenacetin</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a
        classification (see Annex A). In addition to classifying substances, the Health
        Council also assesses the genotoxic properties of the substance in question. The
        assessment and the proposal for a classification are expressed in the form of
        standard sentences (see Annex I).
        This report contains the evaluation of the carcinogenicity of phenacetin
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on the Classification of
        Carcinogenic Substances of the Dutch Expert Committee on Occupational
        Standards of the Health Council, hereafter called the Committee. The members
        of the Committee are listed in Annex B. The submission letter (in English) to the
        State Secretary can be found in Annex C.
            In June 2012, the President of the Health Council released a draft of the
        report for public review. No comments were received on the draft document.
        Scope                                                                             13
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<pre>1.3 Data
    The evaluation and recommendation of the Committee is based on scientific
    data, which are publicly available. The starting points of the Committees’ reports
    are, if possible, the monographs of the International Agency for Research on
    Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the Committee when
    these are considered most relevant in assessing the carcinogenicity and
    genotoxicity of the substance in question. The evaluation of the carcinogenicity
    of phenacetin has been based on IARC evaluations (IARC volume 13 (1977),
    IARC volume 24 (1980), IARC supplement 7 (1987) and IARC volume 100A
    (2011))1-4 (in Annex E a summary is given of the IARC data) and additional
    scientific data, which are publicly available. Additional data were obtained from
    the online databases Toxline, Medline and Chemical Abstracts covering the
    period 1978 to September 2012 using phenacetin and CAS no 62-44-2 as key
    words in combination with key words representative for carcinogenesis and
    mutagenesis. The new relevant data were included in this report.
 4  Phenacetin
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<pre> hapter 2
        General information
2.1     Identity and physicochemical properties
        Chemical name            : N-(4-ethoxyphenyl)acetamide1
        CAS registry number      : 62-44-2
        EINECS-number            : 200-533-05
        EEC-number               :
        RTECS-number             :
        Synonyms                 : N-(4-ethoxyphenyl), acetyl-phenetidine, 1-acetamido-4-ethoxybenzene
        Appearance               : odorless, white, glistening crystals, usally scales or as fine white,
                                   crystalline powder6
        Occurrence               :
        Use                      : analgesic and antipyretic drug in human and veterinary medicine.2;
                                   registration in the Netherlands was discontinued in 1984 because of
                                   serious side effects on the kidney;
                                   illegal use as adulterant in cocaine powder
        Molecular formula        : C10-H13-N-O26
        Structural formula       :
        Molecular weight         : 179.226
        Boiling point            : 242-245°C6
        Melting point            : 134-135°C6
        Vapour pressure          : -
        Vapour density (air = 1) : -
        Solubility               : Slightly soluble in water (1 in 1,300)2
        Stability and reactivity : Unstable to oxidizing agents, iodine and nitrating agents2
        EU Classification        : Not classified in Annex I of Directive 67/548/EEC
        General information                                                                              15
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<pre>2.2 IARC classification
    In 2011, IARC concluded :
        There is sufficient evidence in humans for the carcinogenicity of analgesic
    mixtures containing phenacetin. Analgesic mixtures containing phenacetin cause
    cancer of the renal pelvis, and of the ureter.
        There is limited evidence in experimental animals for the carcinogenicity of
    analgesic mixtures containing phenacetin.
        There is sufficient evidence in humans for the carcinogenicity of phenacetin.
    Phenacetin causes cancer of the renal pelvis, and of the ureter.
        There is sufficient evidence in experimental animals for the carcinogenicity
    of phenacetin.
        Analgesic mixtures containing phenacetin are carcinogenic to humans
    (Group 1). Phenacetin is carcinogenic to humans (Group 1).
 6  Phenacetin
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<pre> hapter 3
        Carcinogenicity
3.1     Observations in humans
        Many case report studies showed the existence of renal pelvic and other
        urothelial tumours in patients who have used large amounts of phenacetin-
        containing analgesics.7-16, 17-22
            A vast amount of case-control studies23-28, 29-44 have been published. These
        studies show that phenacetin-containing analgesics are part of the etiology of
        renal pelvic, urothelial and bladder cancer. Most of the exposed individuals in
        these case-control studies are exposed to phenacetin-containing analgesics,
        which makes it difficult to investigate the effect of exposure to phenacetin only.
        Most of the studies were published 15-20 years ago, due to the fact that
        phenacetin-containing products had been off the market in most countries for
        decades now. Recent studies were not published because the lack of long-time
        phenacetin users. The case-control studies have been summarized in the
        following paragraphs and in Annex F.
        Renal pelvis cancer
        McCredie et al. (1986) conducted a hospital based case-control study in New
        South Wales, Australia to investigate the risk factors for renal cancer. Sixty six
        cases of renal pelvis cancer, 86 cases of renal parenchyma cancer and 751
        controls were collected between 1970 and 1982 in Sidney, Australia. Information
        Carcinogenicity                                                                    17
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<pre>  on consumption of phenacetin-containing analgesics was obtained through
  completion of a structured questionnaire at interview. Pathologists classified the
  tumours according to their histological appearances and sought evidence of
  ‘intermediate’ or ‘advanced’ renal papillary necrosis (RPN). Cases were
  excluded if the presence or absence of RPN could not be established. RPN and
  regular consumption of phenacetin both increased the risk for renal pelvis cancer.
  The risk of renal pelvis cancer increased nearly 4 times for regular consumers of
  phenacetin without RPN (RR: 3.6, 95% CI: 1.6-8.1) and 20 times for regular
  consumers of phenacetin with RPN (RR: 20, 95% CI: 12-34), compared to non-
  consumers without RPN.36
       McCredie et al. (1988) also conducted a population-based case control study
  in New South Wales, Australia to investigate the risk of developing renal cancer
  papillary necrosis and cancer of the renal pelvis, ureter or bladder associated with
  consumption of either phenacetin or paracetamol. Data were acquired from 381
  cases (identified between 1978 and 1982) and 808 controls. The risk of cancer of
  the renal pelvis was statistically significantly increased nearly 6 and 8-fold with a
  lifetime consumption of respectively, > 0.1 kg (OR: 5.7, 95% CI: 3.2-10.0) and
  > 1 kg (OR: 7.9, 95% CI: 4.6-13.8) phenacetin.37
       In another population-based case control study in New South Wales,
  Australia, McCredie et al. (1993) investigated the consumption of phenacetin
  and paracetamol and the risk of cancer of the kidney and renal pelvis, using data
  of 489 cases of renal-cell cancer and 147 cases of renal pelvic cancer diagnosed
  in 1989 and 1990, together with 523 controls from the electoral rolls. A dose-
  related increase in the risk of cancer of the renal pelvis was observed in
  consumers of phenacetin/aspirin compounds. When used according to the
  definition of “taken at least 20 times in lifetime” phenacetin/aspirin compounds
  increased the risk of renal pelvic cancer more than a 12-fold (RR: 12.2, 95% CI:
  6.8-22.2).39
       McLaughlin et al. (1985) conducted a population-based case-control study of
  renal cancer (495 cases of renal cell cancer, 74 cases of renal pelvis cancer and
  697 controls) in Minneapolis, USA. Patients were collected in the period 1974-
  1979. Patients and the control group were interviewed in 1980 about the use of
  analgesic drugs. Information of different variables was obtained, including the
  use of analgesic drugs (phenacetin-containing, acetaminophen-containing and
  aspirin). A drug was considered phenacetin-containing if phenacetin was
  included in the formulation from 1955 to 1974. Exposures after 1973 were
  excluded for analysis. The groups were divided in male/female and in never,
  ever, irregular and regular (subdivided in ≤ 36 months and > 36 months) users.
  Long-term regular use of phenacetin-containing drugs was associated with an
8 Phenacetin
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<pre>increase in risk for renal pelvic cancer among males (OR: 8.1, 95% CI: 1.2-62),
but not among females (4.2, 95% CI: 0.4-42).41
     Pommer et al. (1999) conducted a case-control study in the area of the former
West Berlin, including 647 new diagnosed cases of urethelial cancer (571
bladder, 25 ureter and 51 renal pelvis cancer cases) from eight hospitals of the
study area between 1990 and 1995 and 647 population-based controls. Intake of
more than 1 kg phenacetin in analgesic mixtures was associated with an
increased risk (not significantly) of renal pelvic cancer (OR of 5.3, 95% CI:
0.3-81).43
Ureter cancer and/or renal pelvis cancer
Several of the case-control studies (including two studies which are already
described above by McCredie et al.,1988, Pommer et al., 199937,43) also analysed
the risk of phenacetin-containing analgesics consumption for the development of
ureter cancer (alone or together with renal pelvic cancer). In the population-
based case-control study in New South Wales, Australia by McCredie et al.
(1988)37 no association was found between ureter cancer and a lifetime
consumption of > 0.1 kg (OR: 0.7, 95% CI: 0.3-2.2) or > 1 kg phenacetin (OR:
1.2, 95% CI: 0.5-3.0).
     In the case-control study in the area of the former West Berlin by Pommer et
al. (1999)43 no association was found between the number of renal pelvis cancer
and ureter cancer combined and a lifetime intake of more than 1 kg phenacetin in
analgesic mixtures (OR of 1.8, 95% CI: 0.2-13).
     Jensen et al. (1989)33 conducted a case-control study (96 cases and 294
controls, identified between 1979 and 1982) in Denmark to investigate the risk of
analgesic intake (phenacetin and/or aspirin) and cancer of the renal pelvis and
ureter. Seventy nine percent of the tumours were located in the renal pelvis
(including calyces). There was an indication of a dose-effect relationship for
phenacetin-containing analgesics and cancer of the renal pelvis and ureter. A
statistically significant increase in relative risk (RR) was seen for female users of
phenacetin-containing analgesics (RR: 4.2, 95% CI: 1.5-12.3), but not for male
users (RR: 2.4, 95% CI: 0.9-6.8).33
     Linet et al. (1995) investigated 502 cases (308 renal pelvis cancer and 194
ureter cancer, identified between 1983 and 1986) and 496 controls in a
population-based case-control study in New Jersey, Iowa and Los Angeles, USA.
Neither cumulative lifetime ingestion nor duration of regular use of phenacetin,
whether alone or in combination with acetaminophen or aspirin, was associated
with significantly increased risk of renal pelvis and ureter cancer. Although this
Carcinogenicity                                                                       19
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<pre>  study contained a large amount of cases, it only contained small number of
  regular analgesic users.35
  Renal cell cancer
  Three case-control studies on renal pelvis cancer, which are already described
  above, also analysed the risk of phenacetin-containing analgesics consumption
  for the development of renal cell cancer.36,41.
      In the population-based case-control study in Minneapolis, US of
  McLaughlin et al. (1985)41 (described above), long-term regular use of
  phenacetin-containing drugs was associated with a statistically significant
  increase in risk for renal cell cancer in women (OR: 1.7, 95% CI: 1.1-2.7 for
  ever-users and OR: 1.7, 95% CI: 1.1-2.6 for irregular-users compared to never
  users).
      In another population-based case-control study by McLaughlin et al.(1992)42
  in Shanghai, China (154 cases and 157 controls) regular use of phenacetin-
  containing analgesics (at least 2 times a week for a period of at least 2 weeks)
  was not associated with renal cell cancer (OR: 2.3, 95% CI: 0.7-7.0).
      In the hospital based case-control study in New South Wales, Australia of
  McCredie et al. (1986)36 (described above), regular use of phenacetin-containing
  analgesics increased the risk of cancer of the renal parenchyma (RR: 2.5, 95%
  CI: 1.3-4.9.), but was not increased by the presence of renal papillary necrosis
  (RPN). Thus, unlike renal pelvis cancer, the relationship between consumption
  of phenacetin-containing analgesics and renal parenchyma appears to be a direct
  one without any intervening effect of RPN.
      In the population-based case-control study in New South Wales, Australia by
  McCredie et al. (1993) (described above), no association was found between the
  number of renal-cell cancers and consumption of phenacetin/aspirin compounds
  (RR: 1.4, 95% CI: 0.9-2.3).39
      In another study McCredie et al. (1995)40 pooled data from 1,313 cases and
  1724 controls from Australia, Denmark, Germany, Sweden and the US,
  identified between 1989 and 1991. The role of phenacetin-containing and other
  types of analgesics in the development of renal-cell cancer was studied. Relative
  risks, adjusted for the effects of age, sex, body-mass index, tobacco smoking and
  study centre, were not statistically significantly increased with a lifetime
  consumption of > 0.1 kg phenacetin (or when subjects were subdivided further
  by amount). According to the authors, these findings do not support the
  hypothesis that analgesics containing phenacetin increase the risk, although the
0 Phenacetin
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<pre>number of ‘regular’ users and the amount of analgesics consumed were too small
to confidently rule out a minor carcinogenic effect of phenacetin.
    Kreiger et al. (1993) performed a population-based case-control study in
Ontario, Canada of risk factors for renal cell carcinoma. Data were collected on
518 case and 1,381 controls identified between 1986 and 1987. In this large
study different risk factors for renal cell carcinoma were observed. No
association was found between phenacetin-only use (5 cases, 9 controls) and the
risk of renal cell carcinoma (OR: 2.5, 95% CI: 0.3-18.5 for males and OR: 1.8,
95% CI: 0.5-7.3 for females) or between acetaminophen-only use and the risk of
renal cell carcinoma (OR: 0.8, 95% CI: 0.3-1.7 for males and OR: 0.9, 95% CI:
0.5-2.0 for females), although few subjects used either compound.34
    Gago et al. (1999) conducted a population-based case-control study in Los
Angeles, US (1,204 cases and equal number controls) to investigate the
relationship between sustained use of analgesics and the risk of renal cell
carcinoma. Regular use of analgesics (2 or more times a week for 1 months or
longer) was a significant risk factor for renal cell carcinoma for all four major
classes of analgesics (aspirin, non-steroidal anti-inflammatory agents other than
aspirin, acetaminophen and phenacetin). Regular use of phenacetin containing
analgesics was associated with an OR of 1.9 (95% CI: 1.3-2.7). A dose-related
increase in risk of renal cell carcinoma was observed after further subdivision
into different amounts of the maximum weekly dose.32
Bladder cancer
Several epidemiological studies 23,25,27,29-31,43 have examined phenacetin and
bladder cancer. Two of the case-control studies on renal pelvis and ureter cancer
which are already described above, also analysed the risk of phenacetin-
containing analgesics consumption for the development of bladder cancer
(McCredie et al., 1988; Pommer et al., 1999).37,43
    In the population-based case-control study in New South Wales, Australia by
McCredie et al. (1988)37(described above), risk for cancer of the bladder was
doubled by the consumption of phenacetin (OR: 2.0, 95% CI: 1.1-3.5 for subjects
with a lifetime consumption of > 1 kg phenacetin and OR: 2.1, 95% CI: 1.3-3.5
for subjects with a lifetime consumption of > 0.1 kg phenacetin).
    In the case-control study in Berlin, Germany by Pommer et al. (1999)43
(described above), no association was observed between a lifetime intake of
more than 1 kg phenacetin in analgesic mixtures and bladder cancer (OR: 0.75,
95% CI: 0.39-1.43).
Carcinogenicity                                                                   21
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<pre>        In a population-based case-control study conducted in Los Angeles,
    California, US by Castelao et al. (2000), 1,514 cases of bladder cancer and an
    equal number of controls, identified between 1987-1996 were investigated.
    Regular use of analgesics was not associated with an increased risk of bladder
    cancer in either man or women. The intake of phenacetin-containing analgesics
    was positively related to bladder cancer risk in a dose-dependent manner, while
    the intake of its major metabolite in humans, acetaminophen, was unrelated to
    risk. Regular use of phenacetin-containing analgesics was not associated with an
    increased risk of bladder cancer (OR: 1.5, 95% CI: 0.85-2.73).29
        In a hospital based case-control study conducted in Spain by Fortuny et al.
    (2006), the use of non-aspirin non-steroidal anti-inflammatory drugs (NSAID),
    aspirin, paracetamol (acetaminophen), phenacetin, and metamizol (dipyrone) and
    risk of bladder cancers was assessed. Data on 958 cases and 1,029 controls,
    identified between 1997 and 2000 was analysed. A significant reduction in
    bladder cancer risk was observed for regular users of non-aspirin NSAIDs
    compared with never users. No evidence of an overall effect for regular use
    paracetamol or aspirin was observed. Regular use of phenacetin was not
    associated with an increased risk of bladder cancer (OR: 1.3, 95% CI: 0.3-4.5).
    However, this estimate was based on only 7 cases and 12 controls.30
        In a population-based case-control study conducted in New Hampshire, UK
    by Fortuny et al. (2007), the influence of phenacetin, other analgesics and
    NSAID use on the risk of bladder cancer was investigated. Data from 376 cases
    and 463 controls, identified between 1998 and 2001 was analysed. Elevated
    OR’s were associated with reported use of phenacetin-containing medications
    (OR: 2.2, 95% CI: 1.3-3.8 for ever compared to never users), especially with
    longer duration of use (OR: 3.0, 95% CI: 1.4-6.5 for > 8 years of use).31
3.2 Carcinogenicity studies in animals
    A group of 30 BD I and BD III rats (age, 100 d) received phenacetin (40-50 mg)
    daily in the diet (average total, dose 22g). One rat died after a total dose of 10 g
    and was found to have an osteochondroma. The mean age of death of the treated
    animals was 770 days, the control animals 750 days. No tumours related to
    treatment were observed.45
        Four groups of 15, 20, 20, and 24 male albino rats were fed with diets
    containing 0, 0.05, 0.1 or 0.5 % N-hydroxyphenacetin (metabolite of phenacetin)
    during 73 weeks. Assuming a body weight of 400 grams and a daily food intake
    of 20 grams, the exposure of N-hydroxyphenacetin was 25, 50, and 250 mg/kg
    bw/day respectively. Of treated animals 11, 13 and 15 rats were still alive at the
 2  Phenacetin
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<pre>time of appearance of the first tumour after 45, 45 and 38 weeks. Of these
animals 8/11, 13/13 and 15/15 developed liver tumours (described as
hepatocellular carcinomas). None of the control group animals developed
tumours. One of the animals fed with 0.1% diet developed a transitional cell
carcinoma of the renal pelvis.46
    Female SD rats were given 0 or 0.535% phenacetin in the diet for 86 or 110
weeks. Assuming a body weight of 400 grams and a daily food intake of 20
grams the exposure of phenacetin was 268 mg/kg bw/day. In the 86-week study,
epithelial hyperplasia of renal papillae was found in 2/24 controls and 21/38
treated animals. In the 110 week study the following changes were observed:
Urothelial hyperplasia of the renal papillae in 26 animals, dilatation of vasa recta
in 28, and epithelial hyperplasia in 1 animal. In addition, carcinomas of the
mammary gland (5/30) and ear duct (4/30; P>0.05) were found in the treated
group. In the control group, uroepithelial hyperplasia was found in 5 animals,
dilatation of vasa recta in 8 and mammary carcinoma in 1 animal.47
    Two groups of SD rats (50 male, 50 female, age 9 wks) were fed a diet
containing 1.25 or 2.5% phenacetin for 18 months, followed by a basal diet for 6
months. Assuming a body weight of 400 grams and a daily food intake of 20
grams the exposure of phenacetin was 625 and 1,250 mg/kg bw/day respectively.
The control group (65 male and 65 female) were fed with the same basal diet.
Among animals surviving for 24 months or dying within 24 months with
tumour(s), neoplasms were detected in 27/27 males and 21/27 females fed 2.5%,
in 20/22 males and 19/25 females fed 1.25% and in 1/19 males and 6/25 females
in the control group. Tumours (benign and malignant) of the nasal cavity were
found in 16/27 males and 7/27 females fed 2.5% and in 16/22 males and 6/25
females fed 1.25%. Malignant tumours of the urinary tract were detected in
13/27 males and 4/27 females fed with the high dose and in 1/22 males and 0/25
females fed with the low dose; 2 papillomas were found in females given the
high dose. No nasal cavity or urinary tract tumours were seen in controls.48
    Two groups of B6C3F1 mice (52 male and female, age 6 weeks) were fed for
96 weeks a diet containing 1.25 or 0.6% phenacetin followed by a basal diet for 8
weeks. Assuming a body weight of 20 grams and a daily food intake of 3 grams
the exposure of phenacetin was 1,875 and 900 mg/kg bw/day respectively. The
control group of animals (50 mice of each sex) was fed the same basal diet for
104 weeks. All animals were killed at the end of the experiment. The organs
were examined histopathologically. Mice that died during the experiment were
also autopsied.
    Phenacetin at a dose of 0.6% induced a significant increased incidence of
renal cell adenoma in male mice only. A dose of 1.25% was induced a significant
Carcinogenicity                                                                      23
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<pre>  increase in both renal cell adenoma and carcinoma in male mice. A clear dose-
  response relationship was seen between the doses of phenacetin and the
  induction of renal cell carcinoma. A statistically significant increased incidence
  of tumours was found in the liver, lung, skin, hematopoietic system (leukaemia
  or lymphoma) and occasionally in some other organs.49
      Four groups of twenty rats (male Sprague-Dawley, age 6 weeks) were given
  phenacetin (0, 0.5, 1.0 or 1.5 %) in the diet for 6 or 12 weeks. The 0.5, 1.0 and
  1.5 % groups had a real phenacetin intake of 0.78, 1.28 and 1.77 g/kg bw (at
  week 2 of the experiment) and this intake decreased to 0.31, 0.65 and 1.18 g/kg
  bw (at week 12).Ten rats of each group were killed at 6 and 12 weeks. One hour
  before killing a single i.p injection of labelled thymidine was given. To
  determine to which extent the labelled thymidine was incorporated in the DNA
  of various tissues, the labelling index was measured. A high labelling index
  indicates a high cell proliferation. There was a dose-related increase in the
  labelling index in the urothelium of the bladder and kidney (especially after 6
  weeks and 1.0% and 1.5% dose). After 6 weeks the labelling indices were
  increased in the bladder. After 12 weeks the labelling indices in the bladder were
  only increased numerically but not statistically significant. In the renal pelvic the
  labelling index was significantly increased at doses of 1.0 and 1.5 %. At week 12
  the majority of rats treated with 1.5% had labelling indices ≥ 2-fold than the
  control both in kidney and bladder. The increased labelling indices were
  associated with urothelial hyperplasia (in particular after 6 weeks).50
      Twenty male Crl:CDBR rats were treated by gavage with phenacetin during
  7 or 14 days. The rats were divided in 4 groups: a control, a low-dose (100 mg/kg
  bw/day), an intermediate (625 mg/kg bw/day) and a high-dose group (1,250
  mg/kg bw/day). One week of phenacetin treatment resulted in dose-related
  increases in DNA synthesis in both respiratory and olfactory mucosa. The
  increase observed in the respiratory mucosa was due to inflammatory cells in the
  lamina propria and not to proliferation of the respiratory epithelial cells. One or
  two weeks of daily phenacetin treatment resulted in degenerative changes in the
  olfactory epithelium and necrosis of Bowman’s glands. These changes were
  associated with increases in cell proliferation in the olfactory epithelium only.
  Two-week daily gavage treatment of rats with phenacetin at 100, 625 and 1,250
  mg/kg/day increased olfactory epithelial cell replication by 62.1, 174 and 763%,
  respectively.51
      Phenacetin was mixed in the feed at a concentration of 0.7 or 1.4% and
  administered to transgenic CB6F1-rasH2 mice and non-transgenic, wildtype
  (non-Tg, WT) mice during 24 weeks. Assuming a body weight of 20 grams and a
  daily food intake of 3 grams the exposure to phenacetin was 1,050 and 2,100
4 Phenacetin
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<pre>mg/kg bw/day respectively. Phenacetin induced spleen haemangiosarcoma and
lung adenomas in the rasH2mice but not in the non-Tg mice. Lung adenomas
(12 in exposed versus 2 in control) and spleen hemangiosarcomas (6/0) were
found in male rasH2 treated with 1.4% phenacetin in the feed. This incidence
was significant higher than in the corresponding non-Tg mice.52
    P53+/- transgenic mice were given phenacetin by daily gavage with dose of
100, 200 and 350 mg/kg bw/day suspended in 0.5% methylcellulose during 26
weeks. In a separate study the mice were given a dose of 0.14, 0.7 and 1.4%
phenacetin in the diet. Control and high-dose groups of wild-type mice were
included in both studies. No increase in treatment-related tumour incidence was
found after 26 week of treatment.53
    The transgenic Tg.AC mice strain is able to respond to dermal application
with development of squamous-cell papillomas of the skin. Phenacetin was
administered topically (0, 0.08, 0.4 and 2 mg, daily) and in the diet (0, 12, 60,
300 ppm) during 26 weeks. Phenacetin was negative by both routes of
exposure.54
    Phenacetin was administered in the feed (0, 0.1, 0.25, 0.5, or 0.75% w/w) to
transgenic Xpa-/- mice (15 male, 15 female), to double transgenic Xpa-/-/p53+/-
mice (15 male, 15 female) and to wild type (WT) C57BL/6 mice (15 male, 15
female). Assuming a body weight of 20 grams and a daily food intake of 3 grams
the exposure of phenacetin was 150, 375, 750, 1,125 mg/kg bw/day respectively.
The exposure to phenacetin was 39 weeks for all groups. At the end of the
experiment renal proximal tubular hyperplasia was observed in two high-dose
Xpa-/- males and in one Xpa-/-/p53+/- male mouse. A tubular adenoma was found
in a Xpa-/-/p53+/- female mouse. In all male and female transgenic, but not the
WT mice, multifocal karyomegaly in the proximal renal tubules was found. In
addition, olfactory epithelial degeneration was observed in the nose of most male
and female transgenic and WT mice of the high-dose groups.55
    Phenacetin had the ability to induce morphological transformation in
cultured
    C3H/10T1/2 clone 8 mouse embryo cells (10T1/2 cells). Treatment of the
10T1/2 cells with 0.5, 1.0, and 2.0 mg/ml phenacetin caused a dose-dependent
decrease in plating efficiency and a dose-dependent increase in type II
morphologically transformed foci.56
    Phenacetin tested in the Syrian hamster embryo transformation assay gave
negative results. The highest concentration phenacetin tested was 500 µg/ml
phenacetin. Phenacetin above a concentration level of 500 µg/ml was insoluble
in the medium with DMSO.57
Carcinogenicity                                                                   25
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<pre>      In an initiation-promotion experiment male F344 rats (6 weeks of age) were
  divided in two groups of 20 and one of 10 rats. The two groups of 20 rats were
  pretreated with 0.1% DHPN in drinking water and 3.0% uracil in the diet during
  4 weeks. DHPN (dihydroxy-di-N-propylnitrosamine) is a carcinogen which is
  known to induce tumours of the renal pelvis, renal tubular cells and urinary
  bladder in rats. One week after cessation, one group received basal diet and one
  group received a diet containing 2.0% phenacetin (average intake 1,145 mg/kg/
  day) during the following 35 weeks. The group of 10 animals was given, during
  the same period, a diet with 2.0% phenacetin (average intake 1,068 mg/kg/day)
  without the initial combination treatment of DHPN and uracil. The occurrence of
  renal cell tumours was increased in the group given phenacetin (9/20) as
  compared with the DHPN + uracil alone control (1/19). In the urinary bladder,
  phenacetin treatment was associated with increased incidence of preneoplastic or
  neoplastic lesions. The group of animals, treated with phenacetin alone, without
  the pretreatment, induced simple hyperplasias of the urinary bladder at high
  incidence.58
6 Phenacetin
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<pre> hapter 4
        Mode of action
4.1     Genotoxic mode of action
        More details of these studies have been summarized in Annex H.
4.1.1   Gene mutation assays
        In vitro
        Phenacetin was not mutagenic in several bacterial models in the presence or
        absence of rat or mouse liver microsome preparations: the models included a
        repair test in Bacillus subtillus59 and reverse mutation test in Salmonella
        typhimurium TA1535, TA 1537, TA98 and TA 10060,61, Escherichia coli
        K 12/343/1361, and B. subtilis TKJ 5211.59 Positive bacterial mutagenic results
        have been obtained in S. typhimurium TA 100 in the presence of hamster, but not
        rat, liver post-mitochondrial supernatant of Aroclor-treated animals.62-64
        Phenacetin led to an increase in the mutant frequency in Salmonella typhimurium
        TA 100 in the presence of a hamster liver metabolic activation.65,66
             In the hprt test phenacetin induced an increase in the mutant frequency in
        V79 Chinese hamster cells in vitro in the presence of hamster liver microsome
        preparations.65,67.
        Mode of action                                                                  27
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<pre>      In vivo
      Phenacetin was negative in an intrasanguineous host-mediated assay with E.coli
      K 12 in NMRI mice given 2 mmol/kg intraperitoneally. Phenacetin did not
      induce an increased frequency of sex-linked recessive lethals in Drosophila
      melanogaster.
      Phenacetin was given in the feed of DNA repair deficient (Xpa-/- and Xpa-/-/
      Trp53+/-) mice and wild type (WT) carrying the IacZ (0.75% w/w, during 0, 4, 8,
      or 12 weeks). Xpa-/- mice lack the normal nucleotide excision repair pathway.
      Due to this deficiency, these mice are more sensitive to genotoxic compounds
      than wild type mice. Phenacetin exposure induced an increase in the lacZ mutant
      frequency in the kidney of WT, Xpa-/- and Xpa-/-/Trp53+/- mice as compared with
      concurrent untreated controls of the wild type C57BL/6 mice. The increase in
      Xpa-/- and Xpa-/-/Trp53+/- mice was stronger than in WT mice. A minor and
      negative response was found in the liver and the spleen, respectively. The
      observed phenacetin-induced mutant frequency was higher in male than in
      female mice.68
4.1.2 Cytogenetic assays
      In vitro
      Phenacetin induced DNA fragmentations in an acellulair test-system with λ
      DNA but not with calf thymus DNA.69
      In vivo
      No data were available on the genetic and related effects of phenacetin in
      humans.
          The results of studies on the induction of chromosomal aberrations, sister
      chromatid exchanges and micronuclei in rodents treated with phenacetin in vivo
      were equivocal.61,70 Phenacetin exposure did not result in an enhanced number of
      micronucleated erythrocytes in the bone marrow of NMRI mice given 2 x 5
      mmol/kg bw intraperitoneally.61
          Following in vivo treatment, the alkaline elution assay showed no increase of
      DNA damage in bone-marrow cells of i.p-treated mice or in liver cells of rats
      treated by gavage. However, an increase of DNA damage was observed in liver
      of rats after i.p. administration of phenacetin and in kidney of rats receiving
 8    Phenacetin
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<pre>      phenacetin by gavage.65 Sister chromatid exchanges were seen in mice (i.p, 330
      mg/kg bw) treated with phenacetin. This increase of SCE was weak but
      statistically significant.65
           The micronucleus bone marrow test showed a positive response in mice given
      phenacetin i.p. Phenacetin doses of 37.5, 75, 150, 300, 400 and 600 mg/kg bw/day
      were administered only once or multiple times (2-4) to CD-1 mice. Positive
      responses were seen at 600 mg/kg/day after single and triple dosing and at 400
      and 600 mg/kg/day after double dosing.71,72 A single dose of phenacetin of 0, 2, 5,
      50 and 100 mg/kg given i.p to SJL Swiss mice resulted in a moderate but
      significant increase of cells with micronuclei compared with the control group.73
           The micronucleus assay with peripheral reticulocytes from phenacetin-treated
      mice (CD-1 and MS/Ae strain) was negative after a single dose of 400, 600 and
      800 mg/kg bw(24 h after i.p). Positive results were obtained with 600 and 800
      mg/kg bw after 48 h. Double treatment (24 h between treatments) enhanced the
      responses. A dose response was obtained for all different sample times. In this
      same experiment CD-1 mice treated with phenacetin (i.p, 600 mg/kg bw, single
      and double treatment) gave a positive result in the micronucleus test in bone
      marrow cells.74
           Phenacetin was administered to rats (Sprague-Dawley) with doses of 500,
      1,000 and 2,000 mg/kg bw/day during 2 days or 250, 500, 750, 1,000 mg/kg
      bw/day during 14 days. Blood samples were taken on day 1, 3, 6, 9, 12 and 15 for
      the micronucleus assay with peripheral reticulocytes. In the 14-day test,
      phenacetin increased the frequency of micronucleated reticulocytes in peripheral
      blood at 500 mg/kg bw/day starting from day 9, and at 750 and 1,500 mg/kg
      bw/day starting from day 6. In the test with 2 days application the frequencies of
      micronucleated reticulocytes increased at 1,000 and 2,000 mg/kg bw/day. In the
      test with 14 days application the micronucleus assay in the bone marrow showed
      a positive dose-related response.75
4.1.3 Miscellaneous
      In vitro
      Hepatocytes isolated from mouse, hamster, rat and guinea pig showed no marked
      increase in unscheduled DNA synthesis (UDS) after exposure to phenacetin.76
      After treatment with phenacetin, mouse L-cells gave positive results using a
      DNA-synthesis inhibition test system.77 An increase in DNA damage measured
      by the alkaline elution assay was not observed when human and rat hepatocytes
      were treated with phenacetin in vitro.78
      Mode of action                                                                      29
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<pre>0 Phenacetin</pre>

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<pre> hapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        The Committee is aware that in most of the epidemiological studies described
        above the effect of phenacetin may be influenced by other analgetic
        comedications, by selection bias, especially in the hospital-based case-control
        studies, and recall bias. However, the Committee is also of the opinion that the
        epidemiological evidence cannot exclude that phenacetin-containing analgetics
        are part of the etiology of renal pelvic, urothelial and bladder cancer. However,
        the evidence is considered sufficient by the Committee. For bladder cancer the
        evidence does not support such a relationship. Based on the available
        information the Committee concludes that there is sufficient evidence for
        carcinogenicity of phenacetin to humans.
            Phenacetin induced tumours of the urinary tract (in mice and rats) and nasal
        cavity (in rat) when given orally. New published data consisted of 9 not standard
        carcinogenicity studies, which support this conclusion. Three of these studies
        with rats gave insight in the mechanism of the damage induced by phenacetin.
        They gave evidence of DNA damage in the bladder or nasal mucosa. Four other
        studies used transgenic mice. In two of these studies, the transgenic mice showed
        increased lung, spleen and kidney tumours compared to wild type mouse. The
        two other studies are transformation tests with mouse-embryo and hamster
        embryo cells, of which only the study in mouse-embryo showed increased
        transformation. Considering the available animal data, the Committee concludes
        Classification                                                                    31
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<pre>    that there is sufficient evidence for carcinogenicity of phenacetin to animals. In
    addition, the Committee is aware that both animal data and the human data show
    a relationship beween phenacetin and cancer of the kidney. This relationship was
    even more supported by the observation that phenacetin increased the lacZ
    mutant frequency in kidney of transgenic mice. Such an analogy in cancer
    development in man and animal on the level of a specific organ supports the role
    of phenacetin as a carcinogen.
        Phenacetin was negative in almost all in vitro bacterial mutagenicity tests. On
    the other hand, DNA damage was observed in mammalian cells in vitro and in
    vivo. Phenacetin induced inhibition of DNA synthesis and an increase in the
    mutant frequency in a gene mutation assay with mammalian cells when hamster
    but not rat S9 mix was used as metabolic activation. The positive findings in
    vitro were confirmed in in vivo genotoxicity tests. Phenacetin was positive in
    several micronucleus tests as well as in a gene mutation test with transgenic
    animals; in several studies a clear dose-response relationship was observed.
    Therefore, it can be concluded that phenacetin is a stochastic genotoxic
    compound.
5.2 Recommendation for classification
    The Committee concludes that phenacetin is carcinogenic to humans and
    recommends classifying the substance in category 1A.*
    Moreover, the Committee concludes that phenacetin has a stochastic genotoxic
    working mechanism.
    According to the classification system of the Health Council (see Annex I).
 2  Phenacetin
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4 Phenacetin
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  References                                                                                           35
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<pre>5 Schmal D, REITER A. [Absence of carcinogenic effect in phenacetin.]. Arzneimittelforschung 1954;
  4(6): 404-405.
6 Calder IC, Goss DE, Williams PJ, Funder CC, Green CR, Ham KN et al. Neoplasia in the rat induced
  by N-hydroxyphenacetin, a metabolite of phenacetin. Pathology 1976; 8(1): 1-6.
7 Johansson S, Angervall L. Urothelial changes of the renal papillae in Sprague-Dawley rats induced
  by long term feeding of phenacetin. Acta Pathol Microbiol Scand [A] 1976; 84(5): 375-383.
8 Isaka H, Yoshii H, Otsuji A, Koike M, Nagai Y, Koura M et al. Tumors of Sprague-Dawley rats
  induced by long-term feeding of phenacetin. Gann 1979; 70(1): 29-36.
9 Nakanishi K, Kurata Y, Oshima M, Fukushima S, Ito N. Carcinogenicity of phenacetin: long-term
  feeding study in B6c3f1 mice. Int J Cancer 1982; 29(4): 439-44.
0 Johansson SL, Radio SJ, Saidi J, Sakata T. The effects of acetaminophen, antipyrine and phenacetin
  on rat urothelial cell proliferation. Carcinogenesis 1989; 10(1): 105-11.
1 Bogdanffy MS, Mazaika TJ, Fasano WJ. Early cell proliferative and cytotoxic effects of phenacetin
  on rat nasal mucosa. Toxicol Appl Pharmacol 1989; 98(1): 100-12.
2 Usui T, Mutai M, Hisada S, Takoaka M, Soper KA, McCullough B et al. CB6F1-rasH2 mouse:
  overview of available data. Toxicol Pathol 2001; 29 Suppl: 90-108.
3 Storer RD, French JE, Haseman J, Hajian G, LeGrand EK, Long GG et al. P53+/- hemizygous
  knockout mouse: overview of available data. Toxicol Pathol 2001; 29 Suppl: 30-50.
4 Eastin WC, Mennear JH, Tennant RW, Stoll RE, Branstetter DG, Bucher JR et al. Tg.AC genetically
  altered mouse: assay working group overview of available data. Toxicol Pathol 2001; 29 Suppl: 60-
  80.
5 Lina BA, Woutersen RA, Bruijntjes JP, van Benthem J, van den Berg JA, Monbaliu J et al. Evaluation
  of the Xpa-deficient transgenic mouse model for short-term carcinogenicity testing: 9-month studies
  with haloperidol, reserpine, phenacetin, and D-mannitol. Toxicol Pathol 2004; 32(2): 192-201.
6 Patierno SR, Lehman NL, Henderson BE, Landolph JR. Study of the ability of phenacetin,
  acetaminophen, and aspirin to induce cytotoxicity, mutation, and morphological transformation in
  C3H/10T1/2 clone 8 mouse embryo cells. Cancer Res 1989; 49(4): 1038-44.
7 Mauthe RJ, Gibson DP, Bunch RT, Custer L. The syrian hamster embryo (SHE) cell transformation
  assay: review of the methods and results. Toxicol Pathol 2001; 29 Suppl: 138-46.
8 Shibata MA, Sano M, Hagiwara A, Hasegawa R, Shirai T. Modification by analgesics of lesion
  development in the urinary tract and various other organs of rats pretreated with dihydroxy-di-N-
  propylnitrosamine and uracil. Jpn J Cancer Res 1995; 86(2): 160-7.
9 Tanooka H. Development and applications of Bacillus subtilis test systems for mutagens, involving
  DNA-repair deficiency and suppressible auxotrophic mutations. Mutat Res 1977; 42(1): 19-31.
0 Shudo K, Ohta T, Orihara Y, Okamoto T, Nagao M, Takahashi Y et al. Mutagenicities of phenacetin
  and its metabolites. Mutat Res 1978; 58(2-3): 367-370.
1 King MT, Beikirch H, Eckhardt K, Gocke E, Wild D. Mutagenicity studies with x-ray-contrast media,
  analgesics, antipyretics, antirheumatics and some other pharmaceutical drugs in bacterial, Drosophila
  and mammalian test systems. Mutat Res 1979; 66(1): 33-43.
6 Phenacetin
</pre>

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<pre>2 Camus AM, Friesen M, Croisy A, Bartsch H. Species-specific activation of phenacetin into bacterial
  mutagens by hamster liver enzymes and identification of N-hydroxyphenacetin O-glucuronide as a
  promutagen in the urine. Cancer Res 1982; 42(8): 3201-8.
3 Dunkel VC, Simmon VF. Mutagenic activity of chemicals previously tested for carcinogenicity in the
  National Cancer Institute bioassay program. IARC Sci Publ 1980;(27): 283-301.
4 Weinstein D, Katz M, Kazmer S. Use of rat/hamster S-9 mixture in the Ames mutagenicity assay.
  Environ Mutagen 1981; 3(1): 1-9.
5 De Flora S, Russo P, Pala M, Fassina G, Zunino A, Bennicelli C et al. Assay of phenacetin
  genotoxicity using in vitro and in vivo test systems. J Toxicol Environ Health 1985; 16(3-4): 355-77.
6 Oldham JW, Preston RF, Paulson JD. Mutagenicity testing of selected analgesics in Ames Salmonella
  strains. J Appl Toxicol 1986; 6(4): 237-43.
7 Fassina G, ABBONDANDOLO A, MARIANI L, TANINGHER M, Parodi S. Mutagenicity in V79
  cells does not correlate with carcinogenicity in small rodents for 12 aromatic amines. J Tox Env
  Health 1990; 29(1): 109-130.
8 Luijten M, Speksnijder EN, van Alphen N, Westerman A, Heisterkamp SH, van Benthem J et al.
  Phenacetin acts as a weak genotoxic compound preferentially in the kidney of DNA repair deficient
  Xpa mice. Mutat Res 2006; 596(1-2): 143-150.
9 Adams SP, Laws GM, Storer RD, DeLuca JG, Nichols WW. Detection of DNA damage induced by
  human carcinogens in acellular assays: Potential application for determining genotoxic mechanisms.
  Mutat Res ; 1996; 368(3-4): 235-248.
0 Granberg Ohman I, Johansson S, Hjerpe A. Sister-chromatid exchanges and chromosomal
  aberrations in rats treated with phenacetin, phenazone and caffeine. Mutat Res 1980; 79(1): 13-8.
1 Sutou S, Kondo M, Mitsui Y. Effects of multiple dosing of phenacetin in the micronucleus test. Mutat
  Res 1990; 234(3-4): 183-6.
2 Sutou S, Mitui Y, Toda S, Sekijima M, Kawasaki K, Ando N et al. Effect of multiple dosing of
  phenacetin on micronucleus induction: a supplement to the international and Japanese cooperative
  studies. Mutat Res 1990; 245(1): 11-4.
3 Sicardi SM, Martiarena JL, Iglesias MT. Mutagenic and analgesic activities of aniline derivatives. J
  Pharm Sci ; 1991; 80(8): 761-764.
4 Higashikuni N, Baba T, Nakamura T, Sutou S. The micronucleus test with peripheral reticulocytes
  from phenacetin-treated mice. Mutat Res 1992; 278(2-3): 159-64.
5 Asanami S, Shimono K, Sawamoto O, Kurisu K, Uejima M. The suitability of rat peripheral blood in
  subchronic studies for the micronucleus assay. Mutat Res 1995; 347(2): 73-8.
6 Holme JA, Soderlund E. Species differences in cytotoxic and genotoxic effects of phenacetin and
  paracetamol in primary monolayer cultures of hepatocytes. Mutat Res 1986; 164(3): 167-75.
7 Gotoh S, Higashi K, Miyata Y, Nishi C, Sakamoto Y. Screening for carcinogens by DNA-synthesis
  inhibition test using mouse L-cells. J UOEH 1983; 5(2): 147-53.
  References                                                                                            37
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<pre>8 Robbiano L, Allavena A, Bagarolo C, Martelli A, Brambilla G. Comparison in human and rat
  hepatocytes of the DNA-damaging activity of five chemicals probably carcinogenic to humans.
  Toxicol in Vitro; 1994; 8(1): 131-137.
9 Guideline to the classification of carcinogenic compounds. Health Council of The Netherlands,
  editor. The Hague, The Netherlands: 2010: publication no. A10/07E.
8 Phenacetin
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<pre>A Request for advice
B The Committee
C The submission letter
D Comments on the public review draft
E IARC Monograph
F Human data
G Animal data
H Genotoxicity data
  Carcinogenic classification of substances by the Committee
  Annexes
                                                             39
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<pre>0 Phenacetin</pre>

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<pre>nnex A
     Request for advice
     In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
     Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
     and Employment wrote:
     Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
     tal advisory structure, to improve the integration of the development of recommendations for health
     based occupation standards and the development of comparable standards for the general population.
     A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
     Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
     by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
     exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
     (MAC-values) for substances at the work place.
     In an addendum, the Minister detailed his request to the Health Council as
     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                                                                                        41
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<pre>      for advice. If possible this evaluation should lead to a health based recommended exposure limit,
      or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a
      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 Phenacetin
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<pre>nnex B
     The Committee
     •  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
     •  Ms M.J.M. Nivard
        Molecular Biologist and Genetic Toxicologist, Leiden University Medical
        Center, Leiden
     •  G.M.H. Swaen
        Epidemiologist, Dow Chemicals NV, Terneuzen
     •  E.J.J. van Zoelen
        Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
     •  G.B. van der Voet, scientific secretary
        Health Council of the Netherlands, The Hague
     The Committee                                                              43
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<pre>  The Health Council and interests
  Members of Health Council Committees are appointed in a personal capacity
  because of their special expertise in the matters to be addressed. Nonetheless, it
  is precisely because of this expertise that they may also have interests. This in
  itself does not necessarily present an obstacle for membership of a Health
  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 Phenacetin
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<pre>nnex C
     The submission letter
     Subject           : Submission of the advisory report Phenacetin
     Our reference     : U-7412/BvdV/fs/246-C17
     Your Reference    : DGV/MBO/U-932342
     Enclosed          :1
     Date              : November 13, 2012
     Dear State Secretary,
     I hereby submit the advisory report on the effects of occupational exposure to
     Phenacetin.
     This advisory report is part of an extensive series in which carcinogenic
     substances are classified in accordance with European Union guidelines. This
     involves substances to which people can be exposed while pursuing their
     occupation.
         The advisory report was prepared by the Subcommittee on the Classification
     of Carcinogenic Substances, a permanent subcommittee of the Health Council’s
     Dutch Expert Committee on Occupational Safety (DECOS). The advisory report
     has been assessed by the Health Council’s Standing Committee on Health and
     the Environment.
     The submission letter                                                          45
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<br><br>====================================================================== Pagina 46 ======================================================================

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

<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in June 2012 for public review. No
     comments were received on the draft document.
     Comments on the public review draft                                           47
</pre>

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<pre>8 Phenacetin</pre>

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<pre>nnex E
     IARC Monograph
     Volume 100A, 2011 (excerpt from Phenacetin, pp397-400)
     Phenacetin was considered by previous IARC Working Groups in 1976 and
     1980. Analgesic mixtures containing phenacetin were considered by a previous
     IARC Working Group in 1987. Since that time, new data have become available,
     these have been incorporated in the Monograph, and taken into consideration in
     the present evaluation.
     5          Evaluation
     There is sufficient evidence in humans for the carcinogenicity of analgesic
     mixtures containing phenacetin. Analgesic mixtures containing phenacetin cause
     cancer of the renal pelvis, and of the ureter.
         There is limited evidence in experimental animals for the carcinogenicity of
     analgesic mixtures containing phenacetin.
         There is sufficient evidence in humans for the carcinogenicity of phenacetin.
     Phenacetin causes cancer of the renal pelvis, and of the ureter.
         There is sufficient evidence in experimental animals for the carcinogenicity
     of phenacetin.
         Analgesic mixtures containing phenacetin are carcinogenic to humans
     (Group 1).
         Phenacetin is carcinogenic to humans (Group 1).
     IARC Monograph                                                                    49
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<pre>  For the overall evaluation of phenacetin, the Working Group took into
  consideration that tumours of the renal pelvis and ureter are not known to result
  from the other components of the analgesic mixtures used in most countries;
  namely, aspirin, codeine phosphate, and caffeine.
0 Phenacetin
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<pre>  nnex       F
             Human data
Human case-control studies of phenacetin exposure and different forms of cancer (published after the IARC publication of
 987).
eference design/population        results                                               confounding       remarks
                                  exposure            cases /      risk ratio(95% CI)   factors
                                  phenacetin          controla
                                  containing drugs
enal pelvic cancer
McLaugh population-based case- never                m 24/232       OR 1                 adjusted for age the separate effects
in et al., control, Minneapolis,                    f 12/147       OR 1                 and cigarette     of the analgesics
 98541     US                     ever              m 26/196       OR 1.2 (0.6-2.4)     smoking.          could not be
                                                    f 9/100        OR 1.3 (0.5-3.4)                       adequately
           (74 cases and 697      irregular         m 21/175       OR 1.1 (0.6-2.3)                       assessed because
           controls, identified                     f 12/122       OR 1.1 (0.4-3.2)                       most long-term
           between 1974-1979)     regular ≤36 mo m 1/17            OR 0.5 (0.02-3.9)                      users took both
                                                    f 1/12         OR 1.8 (0.4-22.0)                      phenacetin and
                                  regular>36 mo m 4/4              OR 8.1 (1.2-62.2)                      acetaminophen-
                                                    f 2/10         OR 4.2 (0.4-42.0)                      containing
                                                                                                          products
McCredie hospital-based case-     no consumption      32/672                            adjusted for sex
 t al.,    control, Sidney, New   (lifetime exposure
 98636     South Wales, Australia < 1kg)
           (66 cases and 751      lifetime exposure > 27/35        RR 20 (12-34)
           controls, identified   1 kg with RPN
           between 1970-1982)     lifetime exposure > 7/44         RR 3.6 (1.6-8.1)
                                  1 kg absence of
                                  RPN
             Human data                                                                                                   51
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<pre>McCredie population-based case-    ≥ 1 kg / lifetime    33/54   OR 7.9 (4.6-13.8)  adjusted for sex most cases were
t al.,     control, New South                                                      and exposure to included in
 98837     Wales, Australia        > 0.1 kg / lifetime  40/636  OR 5.7 (3.2-10.0)  paracetamol and previous studies
           (73 cases and 688                                                       tobacco
           controls, identified
           between 1980-1982)
McCredie population-based case-    non-consumers        76/474  OR 1               adjusted for age,
t al.,     control, New South      < 2.04 kg/ lifetime  12/16   OR 5.2 (2.2-12.4)  sex method of
 99339     Wales, Australia        2.04-6.87 kg/        16/16   OR 8.3 (3.4-20.5)  interview,
           (147 cases and 523      lifetime                                        cigarette
           controls identified in  > 6.88 kg/ lifetime  42/17   OR 18.5 (8.7-39.9) smoking,
           1989-1990)              consumption of                                  paracetamol in
                                   aspirin or                                      any form and
                                   phenacetin                                      educational level
 tewart et “blinded”               < 1 kg / lifetime    20/37   RR 1.0             adjusted for age this study used the
l.,        histopathological       1.0-4.9 kg /         6/5     RR 1.9 (0.5-7.3)   and smoking       same cases as
 99944     review of cases from    lifetime                                                          McCredie et al.,
           population- based case- 5.0-9.9 kg /         5/4     RR 2.1 (0.5-8.9)                     1993
           control study, New      lifetime
           South Wales, Australia ≥ 10.0 kg / lifetime  17/5    RR 5.6 (1.8-18)
 ommer     hospital-based and      no/rare analgesic    20/19   OR 1.0             adjusted for
t al.,     population-based        intake                                          socioeconomic
 99943     case-control, (former)  > 1.0 kg / lifetime  7/2     OR 5.3 (0.3-81)    status, cigarette
           West Berlin, Germany                                                    smoking and
           (51 cases and 647                                                       laxative intake
           controls)
ensen et hospital-based            adjusted never     m 31/113  RR 1.0             adjusted for age, 79% of the tumours
l.,        case-control,           used               f 9/55    RR 1.0             sex, tobacco      were located in the
 98933     Copenhagen, the island  ever used          m 13/12   RR 2.4 (0.9-6.8)   smoking and       renal pelvis
           of Sjaelland, Denmark                      f 17/15   RR 4.2 (1.5-12.3)  occupational      including calyces
           (96 cases and 294       crude: never       m 31/113  RR 1.0             exposures
           controls, identified    used               f 9/55    RR 1.0             known to be
           between 1979 and        ever used          m 13/12   RR 3.9 (1.7-9.1)   associated with
           1982)                                      f 17/15   RR 6.9 (2.7-17.7)  high risks of
                                   1-749 g            m 6/7     RR 3.1 (1.0-9.6)   these cancers
                                                      f 2/3     RR 6.1 (1.5-25.6)
                                   > 750 g            m 5/2     RR 9.1 (2.2-38)
                                                      f 7/7     RR 6.1 (1.9-20.0)
                                   dose unknown       m 4/4     RR 2.4 (0.4-14.5)
                                                      f 6/4     RR 9.2 (2.5-33)
 inet et   population-based        no regular use       385/369 OR 1.0             adjusted for age, 308 cases with
l.,        case-control, New       ≤ 1.0 kg / lifetime  21/23   OR 0.8 (0.4-1.6)   sex, geographic   renal pelvis cancer
 99535     Jersey, Iowa and Los    > 1.0 kg / lifetime  9/12    OR 0.3 (0.3-2.1)   area and          and 194 cases with
           Angeles, US (502 cases                                                  cigarette         ureter cancer
           and 496 controls                                                        smoking           This study only
           identified between                                                                        contained small
           1983-1986)                                                                                number of regular
                                                                                                     analgesic users and
                                                                                                     no analgesic
                                                                                                     abusers.
 2           Phenacetin
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<pre> ommer     hospital-based and       > 1.0 kg / lifetime  7/3     OR 1.8 (0.2-13)   adjusted for      51 cases with renal
 t al.,    population-based                                                        socioeconomic pelvis and 25 cases
 99943     case-control, West                                                      status, cigarette with ureter cancer
           Berlin, Germany (76                                                     smoking and
           cases and 647 controls)                                                 laxative intake.
 reter cancer
McCredie population-based case-     ≥ 1 kg / lifetime    6/54    OR 1.2 (0.5-3.0)  adjusted for sex
 t al.,    control, New South       > 0.1 kg / lifetime  49/636  OR 0.7 (0.3-2.2)  and exposure to
 98837     Wales, Australia                                                        paracetamol and
           (55 cases and 688                                                       tobacco
           controls, identified
           between 1980-1982)
enal cell cancer
McLaugh population-based case-      never              m 188/232 OR 1.0            adjusted for age
in et al., control, Minneapolis,                       f 74/147  OR 1.0            and cigarette
 98541     US                       ever               m 125/196 OR 0.7 (0.5-1.0)  smoking.
           (495 cases and 697                          f 108/122 OR 1.7 (1.1-2.7)
           controls, identified     irregular          m 99/175  OR 0.7 (0.5-0.9)
           between 1974-1979)                          f 86/100  OR 1.7 (1.1-2.6)
                                    regular ≤36 mo m     18/17   OR 1.3 (0.6-2.7)
                                                       f 10/12   OR 1.9 (0.7-5.6)
                                    regular>36 mo m      8/4     OR 2.2 (0.6-8.9)
                                                       f 12/10   OR 2.4 (0.8-6.7)
McCredie hospital-based case-       no consumption       72/672                    adjusted for sex
 t al.,    control, Sidney, New     (lifetime exposure
 98636     South Wales, Australia   < 1kg)
           (86 cases and 751        lifetime exposure > 1/35     RR 2.5 (1.3-4.9)
           controls, identified     1 kg with RPN
           between 1970-1982)
                                    lifetime exposure > 13/44    RR 0.4 ( 0.1-2.7)
                                    1 kg absence of
                                    RPN
McLaugh population-based case- regular use (at least 154/157     OR 2.3 (0.7-7.0)  adjusted for age,
in et al., control, Shanghai,       2 times/week for 2                             sex, education,
 98541     China (154 cases and     weeks or longer)                               BMI and
           157 controls, identified                                                cigarette
           between 1978-1989)                                                      smoking.
McCredie population-based case-     non-consumers        420/474 OR 1              adjusted for age,
 t al.,    control, New South       < 2.04 kg/ lifetime  21/16   OR 1.4 (0.7-2.9)  sex method of
 99339     Wales, Australia         2.04-6.87 kg/        24/16   OR 1.8 (0.9-3.5)  interview,
           (489 cases and 523       lifetime                                       cigarette
           controls identified in   > 6.88 kg/ lifetime  17/17   OR 1.0 (0.5-2.1)  smoking,
           1989-1990)               consumption of                                 paracetamol in
                                    aspirin or                                     any form and
                                    phenacetin                                     obesity
             Human data                                                                                              53
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<pre>Kreiger et population-based case-     no phenacetin or m 265/578   OR 1.0             adjusted for age, this study included
 l.,        control, Ontario,         acetaminophen f 166/580      OR 1.0             active cigarette  only a small
 99334      Canada (490 cases and     phenacetin only m 2/2        OR 2.5 (0.3-18.5)  smoking and       amount of
            1351 controls,                              f 3/7      OR 1.8 (0.5-7.3)   combined          phenacetin users
            identified between        phenacetin and m 3/4         OR 1.4 (0.3-6.7)   Quetelet index
            1986-1987)                acetaminophen f 0/8          -
                                      any phenacetin m 5/6         OR 1.7 (0.5-5.9)
                                                        f 3/15     OR 0.8 (0.2-2.7)
McCredie case-control, data           reference group m 839/1094   RR 1.0             adjusted for      this study only
 t al.,     pooled from studies in                      f 474/630  RR 1.0             centre, age, sex, contained a small
 99540      Australia, Denmark,       < 0.1 kg          m 14/28    RR 0.6 (0.3-1.2)   BMI, cigarette    number of regular
            Germany, Sweden and                         f 17/22    RR 1.1 (0.6-2.3)   smoking           analgesics users
            US (1313 cases and        > 0.1 kg          m 46/67    RR 0.9 (0.6-1.4)   the RR as not     and the amount of
            1724 controls,                              f 51/58    RR 1.4 (0.9-2.1)   changed by        consumed
            identified between         0.1-1.0 kg       m 25/48    RR 0.7 (0.4-1.2)   additional        analgesics was also
            1989-1991)                                  f 26/32    RR 1.3 (0.7-2.3)   adjustment for    small
                                       1.1-5.0 kg       m 16/17    RR 1.3 (0.6-2.7)   consumption of
                                                        f 20/14    RR 2.1 (1.0-4.4)   paracetamol or
                                       > 5 kg           m 5/2      RR 2.6 (0.5-14.2)  other analides
                                                        f 5/12     RR 0.6 (0.2-1.8)
Gago-       population-based case non/irregular use 616/744        OR 1.0             adjusted for
Domin- control, Los Angeles,          analgesics                                      level of
 uez et     California, US (1204      regular use          86/55   OR 1.9 (1.3-2.7)   education, BMI,
 l.,        cases and 1204 controls, max weekly dose 41/37         OR 1.3 (0.8-2.2)   cigarette
 99932      identified between        <2 g                                            smoking,
            1986-1994)                max weekly dose 22/6         OR 4.1 (1.5-10.8)  hypertension,
                                      2-<4 g                                          use
                                      max weekly dose 23/12        OR 2.3 (1.0-5.0)   amphetamines.
                                      4-<8 g
 ladder cancer
McCredie population-based case-       ≥ 1 kg / lifetime 27/54     OR 2.0 (1.1-3.5)   adjusted for sex most cases were
 t al.,     control, New South        ≥ 0.1 kg / lifetime 135/636 OR 2.1 (1.3-3.5)   and exposure to included in previous
 98837      Wales, Australia                                                         paracetamol and studies
            (162 cases and 688                                                       tobacco
            controls, identified
            between 1980-1982)
 ommer et hospital-based and         > 1.0 kg / lifetime 23/23    OR 0.7 (0.4-1.4)   adjusted for
 l., 199943 population-based                                                         socioeconomic
            case-control, (former)                                                   status, cigarette
            West Berlin, Germany                                                     smoking and
            (571 cases and 647                                                       laxative intake.
            controls, identified
            between 1990-1994)
Castelao et population-based case-   non/irregular use    961/920 OR 1.0             adjusted for level
 l., 200029 control, Los Angeles,    analgesics                                      of education,
            USA                      regular use          82/64   OR 1.5 (0.9-2.7)   cigarette
            (1514 cases and 1514     < 46 g / lifetime    25/18   OR 1.4 (0.6-3.1)   smoking, NSAID
            controls,                46-250 g / lifetime  27/20   OR 1.6 (0.7-3.7)   use, use other
            1987-1996)               >250 g / lifetime    21/20   OR 1.9 (0.8-4.4)   analgesics,
                                                                                     employment as
                                                                                     hairdresser
  4           Phenacetin
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<pre>ortuny et hospital-based case-      nonusers             848/893   OR 1.0                 adjusted for age,
l., 200630 control, Spain (958 case ever use             59/67     OR 1.1 (0.7-2.0)       sex, region,
           and 1029 controls,       non regular use      52/55     OR 1.1 (0.6-2.0)       cigarette
           identified between       (> 20 times lifelong                                  smoking, use
           1997-2000)               and < 2 times/week                                    other NSAID or
                                    for 1 month)                                          analgesics
                                    regular use (> 2     7/12      OR 1.3 (0.3-4.5)
                                    times/week for ≥ 1
                                    month)
ortuny et population-based case never use                313/421   OR 1.0                 adjusted for age,
l., 200731 control, New             ever use             53/35     OR 2.2 (1.3-3.8)       sex, region,
           Hampshire, UK (376       duration 4 yr        22/14     OR 2.2 (1.0-4.7)       cigarette
           cases and 463 controls, duration 4-8 yr       6/9       OR 1.1 (0.4-3.5)       smoking, use
           identified between       duration > 8 yr      25/12     OR 3.0 (1.4-6.5)       other NSAID or
           1998-2001)                                                                     analgesics
     The number of cases and controls do not necessarily add up to the total number of cases and controls of the whole study (as
     mentioned in the second column), since in many studies also exposure to other (non-phenacetin-containing) analgesics are
     studied.
              Human data                                                                                                     55
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<pre>6 Phenacetin</pre>

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<pre> nnex         G
              Animal data
 nimal species,      dose, route of exposure     duration carcinogenic effects                                  ref.
number, sex, age)
  AT, BD I & III     40-50 mg phenacetin oral    2 yr     no tumours observed                                    2
 0, sex unspecified, (diet) (average total dose,
 00 d                22 g)
  AT, albino, 15-24, 0.05, 0.1 or 0.5 % N-        1.5 yr  hepatocellular carcinomas                              2
male                 hydroxyphenacetin oral
                     (diet)
  AT, S-D, female    0.535% phenacetin oral      1.5-2 y  carcinomas of the mammary gland and ear duct           3
                     (diet)
  AT, S-D, 50 male, 1.25-2.5% phenacetin oral    1.5 yr   tumours in nasal cavity                                3
 0 female, 9 wk      (diet)                               tumours in the urinary tract
                                                          papillomas (only in female)
MICE, B6C3F1,        0.6-1.25 % phenacetin oral  2 yr     renal cell adenoma                                     1
 2 m+f,              (diet)                               kidney, liver, lung, skin and hemapotopoietic tumours
  AT, S-D, 20, m,    0.05, 1.0 and 1.5% oral     6-12 wk  increased labeling index kidney and bladder           50
  wk                 (diet)
  AT, F344,          pretreatment 0.1% DHPN      35 wk    renal cell tumours in the pre-treated rats.           58
 0-20, m, 6 wk       and 3.0% uracil                      no tumours in the non pre-treated rats.
                     +phenacetin 2.0% oral
                     (diet) (1068-1145 mg/kg/d)
  AT, Crl:CDBR       100, 625 and 1250 mg/kg,    7-14 d   increased DNA synthesis in respiratory and olfactory  51
                     oral (gavage)                        mucosa
              Animal data                                                                                            57
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<pre>8 Phenacetin</pre>

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<pre>  nnex        H
              Genotoxicity data
n vitro assays.
est                      cell line/species   concentration          results          remarks          reference
                                                                    - act.  + act.
DNA fragmentation        Calf thymus DNA     0.2-2.5 mM             -                                 Adams et al.,
                         λ DNA               0.1010 mM              -       NT                        199669
                         λ DNA               0.25-2.5 mM            NT      +
 ene mutation test in    S.thyphimurium      sublethal doses        -       -                         De Flora
 acteria                 TA97, TA98, TA100   <10 mg/plate                   + TA100                   et al., 198565
everse mutation test     and TA102
 ene mutation test in    TA98, TA 100,       5,50,500, 1,000, 2,500 -       -                         Oldham et
 acteria                 TA1,535, TA1,537,   and 5,000 µg/plate             + TA100                   al., 198666
everse mutation test     TA1,538
DNA-repair test          E.coli strains:     0.3, 1, 3 mg/plate     -       NT                        De Flora et
                         WP2uvrA, WP67,                                                               al., 198565
                         TM1,080, TM1,080
DNA synthesis inhibition mouse L-cells       1 mM                   NT      +                         Goto et al.,
est                                                                         (rat-S9)                  198377
 lkaline elution assay   rat hepatocytes     0, 1, 1.8, 3.2 mM      -       NT                        Robbiano et
                         human               0, 1, 1.8, 3.2 mM      -       NT                        al., 199478
                         hepatocytes
 nscheduled DNA          liver-              0.1, 0.5, 1, 2.5, 5,   -                UDS measured     Holme et al.,
 ynthesis (UDS) test     hepatocytes, mouse, 10 mM, 18-19 h                          by scintillation 198676
                         rat, guina pig or                                           counting
                         hamster
              Genotoxicity data                                                                                  59
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<pre> ene mutation test in     V79                   0, 1 and 5 mM             -    -                               De Flora
mammalian cells                                                                (rat-S9)                        et al., 198565
Hprt-test                                                                       ±
                                                                               (hamster-S9)
 ene mutation test in     V79                   0, 1, 1.5, 5, 7.5 mM      -    -                               Fassina et
mammalian cells                                                                (rat-S9)                        al., 199067
Hprt-test                                                                      +
                                                                               (hamster-S9)
n vivo mutation assays.
est                       species            route of     dose                       results remarks           reference
                                             admini-
                                             stration
 lkaline elution assay    rat, liver cells   i.p          330 mg/kg                  +                         De Flora et
                                             gavage                                  -                         al., 198565
                          rat, kidney cells  gavage                                  +
                          mouse, bone marrow i.p                                     -
 ister chromatid          mouse              i.p          330 mg/kg                  +                         De Flora et
 xchange test (SCE)                                                                                            al., 198565
micronucleus test in bone CD-1 mice          i.p          37.5, 75, 150, 300, 400    +                         Sutou et al.,
marrow cells                                              and 600 mg/kg; 1, 2, 3                               199071
                                                          or 4 times
micronucleus test in bone SJL Swiss mice     i.p          0, 2, 5, 50, 100 mg/kg,    +                         Sicardi et al.,
marrow cells                                              1 dose                                               199173
micronucleus test in      CD-1 mice          i.p          400, 600, 800 mg/kg        -       single treatment Higashikuni
 eripheral blood cells                       i.p          400, 600, 800 mg/kg        +       double treatment et al., 199274
                                             i.p          400, 600, 800 + 300,       +
                                                          400, 600, 800 mg/kg
micronucleus test in      MS/Ae mice         i.p          400, 600 mg/kg             +       single treatment
 eripheral blood cells
                                             i.p                                     +       double treatment
micronucleus test in bone CD-1 mice          i.p          600 mg/kg                  +       single treatment
marrow cells
                                             i.p                                     +       double treatment
micronucleus test in      Sprague-Dawley     gavage       500, 1,000, 2,000          +                         Asanami et
 eripheral blood cells    rats                            mg/ml during 2 days                                  al., 199575
                                                          250, 500, 750, 1,000       +       sample times on
                                                          mg/ml during 14 days               day 1,3,6,9,12
                                                                                             and 15.
micronucleus test in bone                                 250, 500, 750, 1,000       +
marrow cells                                              mg/ml during 14 days
n vivo gen- mutation      C57BL/6 mice       oral, in     0.75% w/w, 4, 8 and        +       sample times 4, 8 Luijten et al.,
 ssay with lacZ                              feed         12 weeks                           or 12 weeks       200668
ransgenic mice
  0           Phenacetin
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<pre> nnex        I
             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 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.79
             Carcinogenic classification of substances by the Committee                                                61
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<pre>2 Phenacetin</pre>

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<br><br>