<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>Azathioprine
Health based calculated occupational cancer risk values
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<pre></pre>

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<pre>Aanbiedingsbrief</pre>

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<pre></pre>

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<pre>Azathioprine
Health based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to
the Minister and State Secretary of Social Affairs and Employment
No. 1999/04OSH, The Hague, 20 December 1999
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<pre>Preferred citation:
Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards
(DECOS). Azathioprine. The Hague: Health Council of the Netherlands, 1999;
publication no. 1999/04OSH.
all rights reserved
ISBN: 90-5549-290-6
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<pre>    Contents
    Samenvatting 9
    Executive Summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 14
2   Azathioprine 15
2.1 Introduction 15
2.2 Carcinogenicity studies and selection of study suitable for
    risk estimation in the occupational situation 15
2.3 Carcinogenic activity in experimental animals, life-time low-dose exposure 16
2.4 Health risk to humans 17
2.5 Health risk to workers, calculation of the HBC-OCRV 18
2.6 Existing occupational exposure limits 18
2.7 Toxicity profile of azathioprine 18
    References 21
7   Contents
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<pre>  Annexes 23
A Request for advice 25
B The committee 27
C Comments on the public draft 29
D Animal studies 31
8 Azathioprine
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<pre>  Samenvatting
  Op verzoek van de Minister van Sociale Zaken en Werkgelegenheid schat de Commissie
  WGD van de Gezondheidsraad het extra kankerrisico bij beroepsmatige blootstelling aan
  stoffen die door de Europese Unie of door de Commissie WGD als genotoxisch
  kankerverwekkend zijn aangemerkt. In dit rapport maakt zij zo’n schatting voor
  azathioprine. Zij heeft daarbij gebruik gemaakt van de methode die is beschreven in het
  rapport ‘Berekening van het risico op kanker’ (1995/06WGD) (Hea95).
  Naar schatting van de commissie is de extra kans op kanker voor azathioprine:
       4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0.005 mg/m3
       4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 0.5 mg/m3
9 Samenvatting
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<pre>10 Azathioprine</pre>

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<pre>   Executive summary
   On request of the Minister of Social Affairs and Employment the Dutch Expert
   Committee on Occupational Standards (DECOS), a committee of the Health Council of
   the Netherlands, estimates the additional cancer risk associated with occupational
   exposure to substances that have been classified by the European Union or the DECOS
   as genotoxic carcinogen. In this report the committee presents such estimates for
   azathioprine. It has used the method described in the report ‘Calculating cancer risks due
   to occupational exposure to genotoxic carcinogens’ (1995/06WGD) (Hea95).
   The committee estimated that the additional lifetime cancer risk for azathioprine
   amounts to:
       4 x 10-5 for 40 years of occupational exposure to 0.005 mg/m3
       4 x 10-3 for 40 years of occupational exposure to 0.5 mg/m3
11 Executive summary
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<pre>12 Azathioprine</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for chemical substances are set using a
        three-step procedure. In the first step, a scientific evaluation of the data on the toxicity of
        the substance is made by the Dutch Expert Committee on Occupational Standards
        (DECOS), a committee of the Health Council of the Netherlands, on request of the
        Minister of Social Affairs and Employment (annex A). This evaluation should lead to a
        health-based recommended exposure limit for the concentration of the substance in air.
        Such an exposure limit cannot be derived if the toxic action cannot be evaluated using a
        threshold model, as is the case for substances with genotoxic carcinogenic properties.
             In this case an exposure-response relationship is recommended for use in regulatory
        standard setting, ie. the calculation of so-called health-based calculated occupational
        cancer risk values (HBC-OCRVs). The committee calculates HBC-OCRVs for
        compounds which are classified as genotoxic carcinogens by the European Union or by
        the present committee.
             For the establishment of the HBC-OCRV’s the committee generally uses a linear
        extrapolation method, as described in the committee’s report ‘Calculating cancer risk
        due to occupational exposure to genotoxic carcinogens’ (1995/06WGD). The linear
        model to calculate occupational cancer risk is used as a default method, unless scientific
        data would indicate that using this model is not appropriate.
             In the next phase of the three-step procedure, the Social and Economic Council
        advises the Minister of Social Affairs and Employment on the feasibility of using the
13      Scope
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<pre>    HBC-OCRVs as regulatory occupational exposure limits. In the final step of the
    procedure the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present document contains the derivation of HBC-OCRVs by the committee for
    azathioprine. The members of the committee are listed in Annex B. The first draft of this
    report was prepared by H Stouten and MI Willems, from the TNO Nutrition and Food
    Research Institute in Zeist, by contract with the Ministry of Social Affairs and
    Employment.
14  Azathioprine
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<pre>Chapter 2
        Azathioprine
2.1     Introduction
        Azathioprine (CAS-no: 446-86-8) has been classified as a genotoxic carcinogen by
        DECOS (DECOS95).
             The carcinogenicity of azathioprine has been evaluated by IARC (IARC81;
        IARC87). IARC concludes that there is sufficient evidence for carcinogenicity to
        humans and limited evidence for carcinogenicity to animals. This evaluation of the
        carcinogenicity was based on reviews by IARC (IARC81; IARC87). In addition,
        literature was retrieved from online databases Medline, Toxline and Chemical Abstracts,
        covering the period 1966 to January 1996.
2.2     Carcinogenicity studies and selection of study suitable for risk estimation
        in the occupational situation
        Main tumours in humans after treatment with azathioprine in renal transplant patients
        include non-Hodgkin’s lymphoma, squamous cell cancers of the skin, hepatobiliary
        carcinomas and mesenchymal tumours. In other groups of patients who have received
        azathioprine as an immunosuppressant for treatment of diseases like rheumatoid
        arthritis, systemic lupus, inflammatory bowel disease etc. the same array of
        malignancies was found to be in excess, although to a lesser extent. For these patients,
        however, the picture is still not completely clear. Patients with rheumatoid arthritis
        constituted the largest category in the latter study, and some, but not all studies have
15      Azathioprine
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<pre>    found that this disease conveys a risk for non-Hodgkin’s lymphoma in the absence of
    treatment (IARC87). Therefore, it is concluded that the available epidemiological studies
    are not suitable for quantitative cancer risk estimation in workers, because it is not clear
    to what extent the health status of the examined groups of patients interferes with the
    carcinogenic activity of azathioprine.
         Azathioprine was tested by intraperitoneal, subcutaneous and/or intramuscular
    administration in mice and by oral and intraperitoneal administration in rats. Suggestive
    evidence was obtained for the induction of lymphomas after intraperitoneal,
    subcutaneous or intramuscular injection in mice and for ear-duct carcinomas in rats after
    oral administration (IARC81; IARC87). Because of limitations in design and reporting,
    the results were considered to be inconclusive (IARC81, IARC87).
         Table 1 summarizes the oral carcinogenicity studies with experimental animals
    (Annex D). Despite their limitations, these animal studies are used for quantitative risk
    assessment in workers, because the available epidemiological studies do not allow
    quantitative risk assessment in workers as pointed out above. In the absence of animal
    inhalation studies, oral study are used to calculate the carcinogenic activity in
    experimental animals.
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure
    Below the carcinogenic activity is calculated for the study of Frankel et al (Fra70) and
    for the two experiments reported by Cohen et al. (Coh83). The committee is of the
    opinion that the available data do not indicate that the use of the linear model is not
    appropriate.
    Frankel et al., 1970
    To calculate the carcinogenic activity, expressed as the incidence per mg azathioprine
    per kg bw/day, the incidence of male and female rats with a squamous cell carcinoma of
    the ear-duct was used as starting point. Assuming that the daily food intake amounts to
    40 and 50 g/kg bw/day for males and females, respectively, the intake of the test
    substance is calculated to be 6.75 mg/kg bw/day, taken males and females together
    (Fra70).
    The incidence of tumour bearing animals per mg/kg bw/day (lifespan conditions,
    assuming a linear dose response relationship), Idose, is calculated as follows:
16  Azathioprine
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<pre>                                                      Ie - Ic
    I*dose =    C x (X po /L) x (Xpe /L) x exposure hours per day/24 x exposure days per week
                                                                                              =
                                  6/42 - 0/20
    =                                                                      = 1.6*10-1 [mg/kg bw/d]-1
        (6.75 mg/kg/d) x (364 d /1000 d ) x (364 d /1000 d ) x 24/24 x 7/7
    Cohen et al. 1983
    The incidence of female rats with malignant tumours (squamous cell carcinoma of the
    ear-duct, thymic lymphomas) was used as starting point to calculate the incidence per
    mg/kg bw/day. Assuming a mean body weight of 275 g (see Coh83, Charts 1 and 2), the
    intake of the test substance is calculated to amount to 16.2 mg/kg bw/day (Xpo 336
    days) and 17.3 mg/kg bw/day (Xpo = 294 days) for the first and second experiment,
    respectively (Coh83).
    According to the above equation, the estimated incidence of tumour bearing animals per
    mg/kg bw/day (lifespan conditions) amounts to:
                           10/14−0/20
                                                                 = 2.8 x 10-1 in the first experiment, and to
    (16.2mg/kg/d)×(462 d /1000)x(336 d /1000)x24/24x7/7
                           9/19−0/30
                                                                 = 1.3 x 10-1 in the second experiment.
    (27.2mg/kg/d)x(462 d /1000)x(294 d /1000)x24/24x7/7
    To calculate the additional risk of cancer at the workplace, the incidence of 1.6x10-1
    calculated from the data of Frankel et al. (Fra70) was used as starting point, since the
    dose administered in the latter study was lower than the dose used in the experiments of
    Cohen and was clearly less toxic (see Table 1, remarks).
2.4 Health risk to humans
    To estimate the additional lifetime risk of cancer in humans under lifespan conditions on
    the basis of results in animal experiments, it is assumed that no difference exists between
    experimental animals and man with respect to toxicokinetics, mechanism of tumour
*   Idose= the carcinogenic activity attributable to the exposure to the substance per unit daily dose under lifespan
    conditions, assuming a linear dose response relationship, usually expressed per mg/m3 or per mg/kg bw/day.
    Ie and Ic = incidence of tumour bearing animals or tumours in exposed and control animals, respectively,
    Xpo = exposure period, Xpe = experimental period
    L = standard lifespan for the animals in question (L rat is assumed to be 1000 days)
17  Azathioprine
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<pre>    induction, target, susceptibility etc, unless specific information is available which
    justifies a different approach. Furthermore, it is assumed that the average man lives 75
    years, weighs 70 kg, and is exposed 24 hours per day, 7 days per week, 52 weeks per
    year, for lifetime.
2.5 Health risk to workers, calculation of the HBC-OCRV
    To estimate the additional lifetime risk of cancer in humans under workplace conditions,
    it is assumed that the average man lives 75 years, is exposed 8 hours per day, five days a
    week, 48 weeks a year, for 40 years, and inhales 10 m3 air per 8 hour-working day.
    Using as starting point the estimated incidence of 1.6 x 10-1 per mg/kg bw/day, the
    additional lifetime cancer risk per mg/m3 under occupational conditions (=HBC-OCRV)
    amounts to:
    HBC-OCRV = 1.6 x 10 −1 x 75y x 48w      x 5d x 10m = 8.0 x 10 −3 [mg/m 3 ] −1
                                     40y              3
                                         52w 7d 70kg
    Based on the HBC-OCRV of 8.0 x 10-3 the additional lifetime cancer risks amount to:
          4 x 10-5 for 40 years of exposure to 0.005 mg/m3
          4 x 10-3 for 40 years of exposure to 0.5 mg/m3
2.6 Existing occupational exposure limits
    The regulatory authorities of the Netherlands, Germany, United Kingdom, Denmark,
    Sweden, and the EU and the USA-ACGIH have not established occupational exposure
    limits for azathioprine (ISZW99; DFG99; HSE99; Arb96, NBO93; ACG99).
2.7 Toxicity profile of azathioprine
    Human data (from IARC81; IARC87)
    Azathioprine is an immunosuppressive agent. Dosage depends upon clinical and
    haematological responses of individual patients. Therapy is usually initiated at a level of
    2 - 5 mg/kg bw per day, orally, with a long-term maintenance dose of 1 - 3 mg/kg bw
    per day (IARC87).
          The major toxic effect of azathioprine is bone-marrow depression. Use of azathi-
    oprine during pregnancy may reduce birth weight significantly. The data were
    insufficient to evaluate the teratogenic potential of this drug to humans.
18  Azathioprine
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<pre>   Animal data (from IARC81; IARC87)
   The single oral LD50 for azathioprine was 2500 mg/kg bw in mice and 400 mg/kg bw in
   rats; and the ip LD50 was 650 mg/kg bw in mice and 310 mg/kg bw in rats. Maximum
   tolerated doses after chronic daily treatment were 20 mg/kg bw in mice; 2 mg/kg bw in
   dogs; 1 mg/kg bw in Patas monkeys; and about 20 mg/kg bw in male rats. The main
   toxic effect of azathioprine after, e.g., 45 mg/kg bw per day in rats or 4 mg/kg bw per
   day in dogs is bone-marrow depression. Azathioprine is embryolethal at doses nontoxic
   to the mother and can induce a variety of severe teratogenic effects irrespective of the
   route of administration in several animal species. A NOAEL for teratogenic effects is
   not reported, the lowest reported teratogenic dose range, orally, is 5 - 15 mg/kg bw per
   day in rabbits. Azathioprine is mutagenic in bacteria, yeast, Drosophila melanogaster
   and in mice in vivo. At high concentrations the drug is clastogenic to human
   lymphocytes in vitro.
   In conclusion, a health-based occupational exposure limit for azathioprine derived from
   data other than on genotoxicity/carcinogenicity would in all likelihood be expected to be
   in between the concentration levels associated with the referential cancer risk levels.
   The Hague, 20 December 1999,
   for the committee
   drASAM van der Burght,                      Prof. dr GJ Mulder,
   scientific secretary                        chairman
19 Azathioprine
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<pre>20 Azathioprine</pre>

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<pre>        References
ACG99   American Conference of Governmental Industrial Hygienists (ACGIH). 1999. TLVs® and BEIs®. Guide
        to Occupational Exposure Values, Cincinnati OH, USA: ACGIH, 1999: 126.
Arb96   Arbejdstilsynet. Exposure Limit value for substances and materials. Copenhagen, Danmark:
        Arbejdstilsynet, 1996:10.
DECOS95 Scientific documentation on the Dutch list of occupational Carcinogens (I). Dutch Expert Committee on
        OCcupational Standards; 1995; RA 1/95.
DFG99   Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher
        Arbeitsstoffe. MAK- und BAT-Werte-Liste 1999. MAK- und BAT-Werteliste 1999. Maximale
        Arbeitsplatzkonzentrationen und biologische Arbeitsstofftoleranzwerte. Weinheim, (Mitteilung 35).
Hea95   Health Council of the Netherlands, Dutch Expert Committee on Occupational Standards (DECOS).
        Calculating cancer risks, THe HAgue, The Netherlands. 1995; pub no 1995/06 WGD.
HSE99   Health and Safety Executive (HSE). Occupational exposure limits 1999. Sudbury (Suffolk), UK: HSE
        Books, 1999; Guidance note EH 40/96.
Hun97   Hunter WJ, Aresini G, Haigh R et al. Occupational exposure limits for chemicals in de European Union.
        Occup. Environ. Med, 1997; 54:217-22.
IARC81  International Agency for Research on Cancer (IARC). In: Some antineoplastic and immunosuppressive
        agents. Lyon, France: IARC, 1981: 47-78 (IARC monographs on the evaluation of carcinogenic risks to
        humans; Vol 26).
IARC87  International Agency for Research on Cancer (IARC). In: Overall evaluations of carcinogenicity: an
        updating of IARC monographs: Volumes 1 to 42. Lyon, France: IARC, 1987: 119-20 ( IARC monographs
        on the evaluation of the carcinogenic risk of chemicals to humans; Suppl 7).
21      References
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<pre>ISZW99 Inspectiedienst van het Ministerie van Sociale Zaken en Werkgelegenheid (ISZW). De Nationale
       MAC-lijst 1999. The Hague, The Netherlands: Sdu Servicecentrum Uitgeverijen, 1999;
NBO93  Noational Board of Occupational Safety and Health (NBOSH). Occupational exposure limits. Solna,
       Sweden: NBOSH, 1993; Ordinance AFS 1993/9.
22     Azathioprine
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<pre>A  Request for advice
B  The committee
C  Comments on the public draft
D  Animal studies
   Annexes
23
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<pre>24 Azathioprine</pre>

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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State Secretary
      of Welfare, Health and Cultural Affairs, the Minister of Social Affairs and Employment
      wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmental
      advisory structure, to improve the integration of the development of recommendations for health based
      occupation standards and the development of comparable standards for the general population. A
      consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established by
      ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational exposure
      limits as the first step in the process of establishing Maximal Accepted Concentrations (MAC-values) for
      substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as follows:
      The Health Council should advice the Minister of Social Affairs and Employment on the hygienic aspects
      of his policy to protect workers against exposure to chemicals. Primarily, the Council should report on
      health based recommended exposure limits as a basis for (regulatory) exposure limits for air quality at
      the work place. This implies:
           A scientific evaluation of all relevant data on the health effects of exposure to substances using a
           criteria-document that will be made available to the Health Council as part of a specific request for
           advice. If possible this evaluation should lead to a health based recommended exposure limit, or, in
25    Request for advice
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<pre>       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.
26 Azathioprine
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<pre>Annex B
      The Committee
         GJ Mulder, chairman
         professor of toxicology; Leiden University, Leiden
         RB Beems
         toxicologic pathologist; National Institute of Public Health and the Environment,
         Bilthoven
         PJ Borm
         toxicologist; Heinrich Heine Universität Düsseldorf (Germany)
         JJAM Brokamp, advisor
         Social and Economic Council, The Hague
         VJ Feron,
         professor of toxicology; TNO Nutrition and Food Research Institute, Zeist
         DJJ Heederik
         epidemiologist; Wageningen University, Wageningen
         LCMP Hontelez, advisor
         Ministry of Social Affairs and Employment, The Hague
         G de Jong
         occupational physician; Shell International Petroleum Maatschappij, The Hague
         J Molier-Bloot
         occupational physician; BMD Akers bv, Amsterdam
         IM Rietjens
         professor in Biochemical toxicology; Wageningen University, Wageningen.
27    The Committee
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<pre>       H Roelfzema, advisor
       Ministry of Health, Welfare and Sport, Den Haag
       T Smid
       occupational hygienist; KLM Health Safety & Environment, Schiphol and professor
       of working conditions, Free University, Amsterdam
       GMH Swaen
       epidemiologist; Maastricht University, Maastricht
       HG Verschuuren
       toxicologist; DOW Europe, Horgen (Switzerland)
       AAE Wibowo
       toxicologist; Coronel Institute, Amsterdam
       F de Wit
       occupational physician; Labour Inspectorate, Arnhem
       CA Bouwman, scientific secretary
       Health Council of the Netherlands, Den Haag
       ASAM van der Burght, scientific secretary
       Health Council of the Netherlands, Den Haag
   The first draft of the present advisory report was prepared by H Stouten and M Willems,
   from the Department of Occupational Toxicology of the TNO Nutritionand Food
   Research Institute, by contract with the Ministry of Social Affairs and Employment.
   Secretarial assistance: E Vandenbussche-Parméus.
   Lay-out: J van Kan.
28 Azathioprine
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<pre>Annex C
      Comments on the public draft
      A draft of the present report was released in 1999 for public review. The following
      organizations and persons have commented on the draft document:
          mr P Ridgeway, Health and Safety Executive, United Kingdom
          mr A Aalto, Tampere, Finland
29    Comments on the public draft
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<pre>30 Azathioprine</pre>

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<pre>Annex D
       Animal studies
      See next page.
31    Animal studies
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<pre>Table 1 Carcinogenicity studies with azathioprinea.
authors  species          exposure    dose               exposure   findings                    remark
                          charac-                        and ex-
                          teristics                      perimental
                                                         period
Fra70    ratb             diet        0, 150 mg/kg       Xpo=Xpe is Squamous-cell ear-duct      The observed increase in
                                      food (= 6.75       52 weeks   carcinomas:                 incidence of carcinomas is not
                                      mg/kg bw/day)                 control: 0/10 , 0/10 ;      statistically significantly diffe-
                                                                    treatment group:            rent from that in the control.
                                                                    3/17, 3/25.
Coh83    ratc(females) diet           In total 1.5 g/rat Xpo= 48    Treatment group: 10/14      It is noted, that the treatment
Exp. 1   control, N=20                In view of the     weeks      effective rats with tumours group started with 36 animals.
         test, N=36                   toxicity, dose     Xpe= 66    (lymphoma in thymus 6/14,   The effective number of rats
                                      levels were        weeks      squamous cell carcinoma in  includes those that survived 10
                                      changed during                ear duct 4/14).             weeks or more of the
                                      the experiment.               Control group: 2/20         experiment. There were no de-
                                                                    fibroadenomas of the        aths in the control group.
                                                                    mammary glands.
Exp. 2   ratc (females) diet          In total 2.2 g/rat Xpo= 42    Treatment group: 9/19       It is noted, that the treatment
         control, N=30                In view of the     weeks      effective rats had tumour   group started with 28 animals.
         test, N=28                   toxicity, dose     Xpe= 66    (lymphoma in thymus 7/19,   The effective number of rats
                                      levels were        weeks      squamous cell carcinoma in  includes those that survived 10
                                      changed during                ear duct 2/19).             weeks or more of the
                                      the experiment.               Control group: 3/30         experiment. There were no de-
                                                                    fibroadenomas of the        aths in the control group.
                                                                    mammary glands.
Xpo: exposure period;
Xpe: experimental period
a
    References with respect to subcutaneous and/or intramuscular administration (mouse) and intraperitoneal admini- stration
    (mouse and rat) are not summarized. IARC (1981) considered the results to be inconclusive, because of limitations in
    design and reporting of the studies.
b
    Fischer 344 rats
c
    Sprague-Dawley rats
32          Azathioprine
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