<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>Aziridine (ethylene imine)
Health based calculated occupational cancer risk values
</pre>

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

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

<pre></pre>

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

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

<pre>Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp           : Aanbieding advies
Uw kenmerk          : DGV/BMO-U-932542
Ons kenmerk         : U 1888/AB/jt/459-H31
Bijlagen            :1
Datum               : 6 september 2000
Bij brief van 3 december 1993, nr DGV/BMO-U-932542, verzocht de Staatssecretaris
van Welzijn, Volksgezondheid en Cultuur namens de Minister van Sociale Zaken en
Werkgelegenheid om gezondheidskundige advieswaarden af te leiden ten behoeve van de
bescherming van beroepsmatig aan stoffen blootgestelde personen.
Per 1 januari 1994 heeft mijn voorganger daartoe een commissie ingesteld die de
werkzaamheden voortzet van de Werkgroep van Deskundigen (WGD). De WGD was
een door genoemde minister ingestelde adviescommissie.
Hierbij bied ik u - gehoord de Beraadsgroep Gezondheid en Omgeving - een publicatie
van de commissie aan over aziridine (ethyleen imine).
Deze publicatie heb ik heden ter kennisname aan de Minister van Volksgezondheid
Welzijn en Sport en aan de Minister van Volkshuisvesting Ruimtelijke Ordening en Mi-
lieubeheer gestuurd.
w.g.
prof. dr JJ Sixma
</pre>

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

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

<pre></pre>

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

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

<pre>Aziridine (ethylene imine)
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. 2000/13OSH, The Hague, 6 September 2000
</pre>

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

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

<pre>Preferred citation:
Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards
(DECOS). Aziridine (ethylene imine); Health-based calculated occupational cancer risk
values. The Hague: Health Council of the Netherlands, 2000; publication no.
2000/13OSH.
all rights reserved
ISBN: 90-5549-335-x
</pre>

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

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

<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedure 14
2   Aziridine (ethylene imine) 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, lifetime low-dose exposure 16
2.4 Health risk to humans 16
2.5 Calculation of the HBC-OCRV 17
2.6 Existing occupational exposure limits 17
    References 19
7   Contents
</pre>

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

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

<pre>  Annexes 21
A Request for advice 23
B The Committee 25
C Comments on the public draft 27
D Animal studies 29
8 Aziridine (ethylene imine)
</pre>

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

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

<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 kank-
  erverwekkend zijn aangemerkt. In dit rapport maakt zij zo’n schatting voor aziridine. Zij
  heeft daarbij gebruik gemaakt van de methode die is beschreven in het rapport ‘Bereken-
  ing van het risico op kanker’ (1995/06WGD) (Dec95).
  Naar schatting van de commissie is de extra kans op kanker voor aziridine:
       4 x 10-5 bij 40 jaar beroepsmatige blootstelling aan 0.9 µg/m3
       4 x 10-3 bij 40 jaar beroepsmatige blootstelling aan 90 µg/m3
9 Samenvatting
</pre>

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

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

<pre>10 Aziridine (ethylene imine)</pre>

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

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

<pre>   Executive summary
   On request of the Minister of Social Affairs and Employment the Dutch Expert Commit-
   tee on Occupational Standards (DECOS), a committee of the Health Council of the
   Netherlands, estimates the additional lifetime 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 az-
   iridine. It has used the method described in the report ‘Calculating cancer risks due to
   occupational exposure to genotoxic carcinogens’ (1995/06WGD) (Dec95).
   The committee estimated that the additional lifetime cancer risk for aziridine amounts to:
        4 x 10-5 for 40 years of occupational exposure to 0.9 µg/m3
        4 x 10-3 for 40 years of occupational exposure to 90 µg/m3
11 Executive summary
</pre>

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

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

<pre>12 Aziridine (ethylene imine)</pre>

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

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

<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 Min-
        ister 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 com-
        pounds 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 ex-
        trapolation 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 ad-
        vises the Minister of Social Affairs and Employment on the feasibility of using the
13      Scope
</pre>

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

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

<pre>    HBC-OCRVs as regulatory occupational exposure limits. In the final step of the proce-
    dure the Minister sets the official occupational exposure limits.
1.2 Committee and procedure
    The present document contains the derivation of HBC-OCRVs for aziridine by the com-
    mittee. The members of the committee are listed in Annex B. The first draft of this re-
    port was prepared by MI Willems, from the TNO Nutrition and Food Research Institute
    in Zeist, by contract with the Ministry of Social Affairs and Employment.
        In 1998, the President of the Health Council released a draft of the report for public
    review. The individuals and organisations that commented on the draft are listed in an-
    nex C. The committee has taken these comments into account in deciding on the final
    version of the report.
14  Aziridine (ethylene imine)
</pre>

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

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

<pre>Chapter 2
        Aziridine (ethylene imine)
2.1     Introduction
        The carcinogenicity of aziridine (CAS no. 115-56-4) has been evaluated by IARC
        (IARC75), ACGIH (ACG91) and DFG in 1970 and 1985 (Gre95). IARC has concluded
        that the degree of evidence for carcinogenicity of aziridine to animals is limited
        (IARC87). In addition, aziridine has been classified as a category 2 carcinogen by the
        European Union.
             This evaluation of the carcinogenicity was based on a review by IARC (IARC87).
        In addition, literature was retrieved from online databases Medline, Toxline and Cancer-
        lit covering the period 1975 to 1996*.
2.2     Carcinogenicity studies and selection of study suitable for risk estimation
        in the occupational situation
         No case reports or epidemiological studies were available.
             Table 1 (annex D) summarizes the carcinogenicity studies with experimental ani-
        mals. Aziridine is carcinogenic in two strains of mice after oral administration, produc-
        ing an increased incidence of liver-cell and pulmonary tumours (IARC75, Inn69).
        Subcutaneous injection of single doses in suckling mice produced an increased incidence
*       After completion of the report, IARC concluded in 1999 that aziridine was a IARC group 2B compound. No additional
        animal studies were presented (IARC99).
15      Aziridine (ethylene imine)
</pre>

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

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

<pre>    of lung tumours in males. In one experiment in rats, the incidence of tumours at the in-
    jection site following its subcutaneous injection in oil is increased (IARC75).
           In the absence of inhalation studies, the oral studies of Innes et al (1969) are used
    for the calculation of the potential cancer risk at the workplace. In this study, the inci-
    dences of mice ((C57Bl/6xC3H/Anf)F1) with (mixtures of) different tumours after expo-
    sure to aziridine are 16/17 (male), 15/15 (female) and 31/32 (male and female) (Inn69)
    (for exposure regime see annex D). The committee is of the opinion that the available
    data do not indicate that the use of the linear model is not appropriate.
2.3 Carcinogenic activity in experimental animals, lifetime low-dose exposure
    To calculate the carcinogenic activity expressed as incidence per mg aziridine per kg bw
    per day, the number of tumour-bearing male and female mice of the
    (C57B1/6xC3H/Anf)F1 strain are used as starting point (Inn69). The average dose per
    day amounts to: (4.64 x 22 + 13 x 0.12 x 524)/(78 x 7) = 1.68 mg/kg bw per day.
    The incidence of tumour-bearing mice per mg/kg bw/day (lifespan conditions, assuming
    a linear dose response relationship), Idose, is calculated as follows:
                                                          Ie - Ic
           I*dose = C x (Xpo /L) x (Xpe /L) x exposure hours per day/24 x exposure days per week/7  =
                       31/32 - 30/166
           1.68 x 546/750 x 546/750 x 24/24 x 7/7       = 8.9 x 10-1 [mg/kg/d]-1
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 in-
    duction, target, susceptibility etc, unless specific information is available which justifies
    a different approach. Furthermore, it is assumed that the average man lives 75 years,
    weights 70 kg and is exposed 24 hours per day 7 days/week, 52 weeks per year for life-
    time.
*   Idose = the carcinogenic activity attributable to the exposure to the substance per unit daily dose under lifespan condi-
    tions assuming a linear dose response relationship
    Ie and Ic = incidence of tumour bearing animals or tumours in exposed and control amnimals, respectively,
    Xpo = exposure period, Xpe = experimental period
    and L = standard lifespan for the animals in question (L rat is assumed to be 1000 days)
16  Aziridine (ethylene imine)
</pre>

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

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

<pre>2.5 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. Us-
    ing as starting point the estimated incidence of 8.9 x 10-1 per mg/kg bw/day, the addi-
    tional lifetime cancer risk per mg/m3 under occupational conditions, the HBC-OCRV,
    amounts:
          HBC-OCRV = 8.9x10 −1 x 75y x 52w      x 7d x 70kg = 4.5 x 10 −2 [mg/m 3 ] −1
                                        40y 48w 5d 10m    3
    Based on the HBC-OCRV of 4.5 x 10-2 per mg/m3 the reference additional lifetime can-
    cer risk amounts to:
          4 x 10-5 for 40 years of exposure to 0.9 µg/m 3
          4 x 10-3 for 40 years of exposure to 90 µg/m 3.
2.6 Existing occupational exposure limits
    Table 2 summarizes the occupational exposure limits established by the regulatory
    authorities of United Kingdom, and by the USA-ACGIH. No occupational exposure lim-
    its have been established in The Netherlands, Germany (TRK value) and Sweden. The
    lowest occupational exposure limit (HBR-OEL) set by these countries amounts to 0.88
    mg/m3. This concentration is about a factor 10 higher than the concentration leading to
    an additional cancer risk of 4 x 10-3 (i.e., 90 µg/m 3).
17  Aziridine (ethylene imine)
</pre>

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

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

<pre>     Table 2 Occupational exposure limits for aziridine.
   country                      level                        time realtion      notations      ref.
                                                 3
                                ppm        mg/m
                     a
   The Netherlands              -          -                 -                  -
   Germanyb                     (0.5)      (0.9)             8-h TWA            -              DFG96
   UKc                          -          -                 8-h TWA            -              HSE95
   Swedend                      -          -                 -                  -              NBO93
   USA-ACGIHe                   0.5        0.88              8-h TWA            skin           ACG96
   a
         Aziridine is listed as a carcinogen
   b
         The DFG classifies aziridine as a category A2 carcinogen; DFG category A carcinogens are not as-
         signed a health-based occupational exposure limit, but a so called TRK-value (TRK = Technische
         Richtkonzentrationen), a concentration feasible with currently available technical means. TRK-
         values are given in brackets.
   c
         In the UK, aziridine has been included in the list of substances defined as carcinogens for the pur-
         pose of the COSHH regulations. Aziridine has been assigned the risk phrase “R45” (may cause
         cancer), and an OEL does not exist anymore.
   d
         In Sweden, aziridine is placed under section 9 (carcinogen) and may only be handled by permis-
         sion of the Labour Inspectorate.
   e
         Classified as A3 carcinogen: animal carcinogen.
   For the committee,
   The Hague, 6 September 2000
   dr ASAM van der Burght,                          Prof. dr GJ Mulder,
   scientific secretary                             chairman
18 Aziridine (ethylene imine)
</pre>

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

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

<pre>       References
ACG91  American Conference of Governmental Industrial Hygienists (ACGIH). Ethylenimine. In: Documentation
       of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Cincinnati OH, USA: ACGIH,
       1991: 628-30.
ACG96  American Conference of Governmental Industrial Hygienists (ACGIH).1996. TLVs(R) and BEIs(R).
       Threshold Limit Valuesfor chemical substances and physical agents.Biological Exposure Indices. Cincin-
       nati OH, USA: ACGIH, 1996: 22.
DEC95  Health Council of the Netherlands: Dutch Expert Committee on Occupational Standards (DECOS). Cal-
       culating cancer risk. The Hague: Health Council of the Netherlands, 1995 publication no 1995/06WGD.
DFG96  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher Arbe-
       itsstoffe. MAK- und BAT-Werte-Liste 1996. Maximale Arbeitsplatzkonzentrationen und biologische Ar-
       beitsstofftoleranzwerte. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1996: 57, 108, 128 (Mitteilung
       32).
Gre95  Greim H, ed. Deutsche Forschungsgemeinschaft (DFG). Äthylenimin/Ethylenimin. In: Gesundheit-
       sschädliche Arbeitsstoffe. Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werte (Maximale
       Arbeitsplatz-Konzentrationen). 1st-21th ed. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1995.
HSE95  Health and Safety Executive (HSE). Occupational exposure limits 1995. Sudbury (Suffolk), UK: HSE
       Books, 1995: 18, 49 (Guidance note 40/95).
IARC75 International Agency for Research on Cancer (IARC). Aziridine. Some aziridines, N-, S-, O-mustards and
       selenium. Lyon, France: IARC, 1975: 37-46. In: IARC monographs on the evaluation of carcinogenic risk
       of chemicals to man, Vol 9.
19     References
</pre>

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

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

<pre>IARC99 International Agency for Research on Cancer (IARC). Re-evalualtion of some organic chemicals, hydra-
       zine and hydrogen peroxide (part two). Lyon, France: IARC, 1999: 337-344. In: IARC monographs on the
       evaluation of carcinogenic risk of chemicals to man, Vol 71.
Inn69  Innes JRM, Ulland BM, Valerio MG, et al. Bioassay of pesticides and industrial chemicals for tumori-
       genicity in mice: a preliminary note. J Natl Cancer Inst 1969; 42: 1101-14.
ISZW95 Inspectiedienst van het Ministerie van Sociale Zaken en Werkgelegenheid (ISZW). De Nationale MAC-
       lijst 1995. The Hague, The Netherlands: Sdu Servicecentrum Uitgeverijen, 1995: 21, 63 (pub no P145).
NBO93  National Board of Occupational Safety and Health (NBOSH). Occupational exposure limits. Solna, Swe-
       den: NBOSH, 1993: 74 (Ordinance AFS 1993/9).
20     Aziridine (ethylene imine)
</pre>

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

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

<pre>A  Request for advice
B  The committee
C  Comments on the public draft
D  Animal studies
   Annexes
21
</pre>

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

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

<pre>22 Aziridine (ethylene imine)</pre>

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

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

<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 conse-
      quence 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 de-
      cree 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
23    Request for advice
</pre>

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

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

<pre>       the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calculated con-
       centration 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 re-
       cently established in other countries.
       Recommending classifications for substances as part of the occupational hygiene policy of the gov-
       ernment. In any case this regards the list of carcinogenic substances, for which the classification cri-
       teria 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 an-
   nex B.
24 Aziridine (ethylene imine)
</pre>

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

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

<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.
25    The Committee
</pre>

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

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

<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)
        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 M Willems, from the De-
   partment of Occupational Toxicology of the TNO Nutrition and Food Research Insti-
   tute, by contract with the Ministry of Social Affairs and Employment.
   Secretarial assistance: J Toet.
   Lay-out: J van Kan.
26 Aziridine (ethylene imine)
</pre>

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

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

<pre>Annex C
      Comments on the public draft
      A draft of the present report was released in 1998 for public review. The following or-
      ganisations and persons have commented on the draft document:
          WF ten Berge, DSM, Heerlen
27    Comments on the public draft
</pre>

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

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

<pre>28 Aziridine (ethylene imine)</pre>

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

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

<pre>Annex D
      Animal studies
      See table on the next page.
29    Animal studies
</pre>

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

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

<pre>Table 1 Carcinogenicity studies with aziridine.
authors  species     exposure     dose                    exposure and ex- findings                                     remark
                     characteris-                         perimental period
                     tics
Inn69    mousea      gavage/      4.6 mg/kg bw/day by     Xpo and Xpe 78    male: number of mice with tumours 16/17
                     diet         gavage daily from the   weeks for male    [control 22/79] (15 with hepatomas [control
                                  7th to 28th day of age. and 77 weeks for  8/79], 15 with pulmonary tumours [control
                                  Subsequently for 78     female.           5/79]).
                                  (male) or 77 (female)                     female: number of mice with tumours 15/15
                                  weeks at a concentra-                     [control 8/87] (11 with hepatomas [control
                                  tion of 13 mg/kg of                       0/87), 15 with pulmonary tumours [control
                                  diet.                                     3/87]).
Inn69    mouseb      gavage/      4.64 mg/kg bw/day by Xpo and Xpe 77       male: number of mice with tumours 16/16 (9
                     diet         gavage daily from the weeks for male      with hepatomas [control 5/90], 12 with pul-
                                  7th to 28th day of age. and female.       monary tumours [control 10/90]).
                                  Subsequently for 77                       female: number of mice with tumours 11/11
                                  weeks at a con-                           (2 with hepatomas [control 1/82], 10 with
                                  centration of 13 mg/kg                    pulmonary tumours [control 3/82], 2 with
                                  of diet.                                  lymphomas).
IARC75 mousea        subcuta-     1 x 4.64 mg/kg bw on Xpe: 80 weeks        male: number of mice with tumours 7/18 (2   number of tumours in
                     neous injec- the 7th day of age.                       hepatomas, 5 pulmonary tumours, 2 lymp-     treated males significantly
                     tion                                                   homas).                                     higher than in control
                                                                            female: number of mice with tumours 1/18 (1 males (P = 0.01).
                                                                            lung tumour)                                control data not available
IARC75 mouseb        subcuta-     4.64 mg/kg bw on the Xpe: 80 weeks        male: number of mice with tumours 6/18 (6   number of tumours in
                     neous injec- 7th day of age.                           pulmonary tumours).                         treated males significantly
                     tion                                                   female: number of mice with tumours 1/18 (1 higher than in control
                                                                            lung tumour)                                males (P = 0.01).
                                                                                                                        control data not available
IARC75 rat           subcuta- ne- twice weekly (total 67 Xpo 33.5 weeks; sarcomas at the injection site 5/6 male (con-
                     ous injec-   injections); total dose Xpe 73 weeks      trol 1/10) and 1/6 female (control 0/9)
                     tion         20 mg/kg bw.
Xpo = exposure period, Xpe = experimental period.
a
     (C57Bl/6xC3H/Anf)F1
b
     (C57Bl/6xAKR)F1
30           Aziridine (ethylene imine)
</pre>

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

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

<pre>31 Animal studies</pre>

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

<br><br>