<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>Dicyclopentadienyl iron (ferrocene)
(CAS No: 102-54-5)
Health-based reassessment of Administrative
Occupational Exposure Limit
Committee on Updating of Occupational Exposure Limits,
a committee of the Health Council of the Netherlands
No. 2000/15OSH/047, The Hague, 31 October 2002
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Dicyclopentadienyl iron (ferrocene); Health-based
reassessment of current administrative occupational exposure limits in the
Netherlands. The Hague: Health Council of the Netherlands, 2002;
2000/15OSH/047.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      dicyclopentadienyl iron, in this document referred to as ferrocene, by the
      Committee on Updating of Occupational Exposure Limits, a committee of the
      Health Council of the Netherlands. The first draft of this document was
      prepared by MA Maclaine Pont, M.Sc. (Wageningen University, Wageningen,
      the Netherlands).
           Literature was retrieved from the databases Medline, Toxline, and Chemical
      Abstracts, covering the periods 1966 until May 1999, 1981 until April 1999 and
      1937 until April 1999, respectively, and using the following key words:
      ferrocene, iron dicyclopentadienyl-, and 102-54-5.
           In December 1998, the President of the Health Council released a draft of
      the document for public review. Comments were received by the following
      individuals and organisations: P Wardenbach, Ph.D. (Bundesanstalt für
      Arbeitsschutz und Arbeitsmedizin, Dortmund, Germany). These comments
      were taken into account in deciding on the final version of the document.
           An additional literature search in May 2002 did not result in information
      changing the committee’s conclusions.
2     Identity
       name                     :     dicyclopentadienyl iron
       synonyms                 :     biscyclopentadienyl iron; di-2,4-cyclopentadien-1-yl iron;
                                      iron bis(cyclopentadiene); iron dicyclopentadienyl; ferrocene
       molecular formula        :     C10H10Fe
       structural formula       :
       CAS number               :     102-54-5
      Data from How92.
047-3 Dicyclopentadienyl iron (ferrocene)
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<pre>3     Physical and chemical properties
       molecular weight         :     186.04
       melting point            :     173-174oC
       boiling point            :     249oC
       flash point              :     -
       vapour pressure                at 20oC: 0.32 - 1.23 Pa
       solubility in water      :     insoluble
       log Poctanol/water       :     3.28 (estimated)
       conversion factors       :     1 mg/m3 = 0.13 ppm
       (20oC, 101.3 kPa)              1 ppm = 7.8 mg/m3
      Data from Che98, Lid96, NLM02, Pel81, http://esc.syrres.com.
      Ferrocene consists of orange-coloured crystals with a camphor-like odour
      (NLM02). Dust explosion is possible, if the compound is finely dispersed in air.
      When dry, it can be electrostatically charged. Ferrocene reacts vigorously with
      oxidants like ammonium chlorate with a chance of fire and explosion (Che98).
4     Uses
      Ferrocene is a good combustion catalyst, because of its excellent solubility in
      hydrocarbons, its high iron content (30%), excellent stability, high vapour
      pressure, and low toxicity. It is also used as an antiknock additive for gasoline
      (ACG91).
5     Biotransformation and kinetics
      After a single oral dose of 59Fe-ferrocene, the compound was well absorbed via
      the gastrointestinal tract by mice, rats, and guinea pigs. Six hours after the
      administration, 13% of the label was found in the liver and 6% in the large
      intestine of rats. Only 40% of the dose was accounted for. One day after the
      administration, 21% of the label was found in the rat liver, 5 to 9% in the guinea
      pig liver, and 40% in the mouse liver. For stomach and intestines together, these
      numbers were 10% (rat), 1.6% (guinea pig), and 5.2% (mouse), respectively.
      Faecal excretion amounted to 10% (rats), 2.0% (guinea pigs), and 7.7% (mice)
      after 3 days. Urinary excretion amounted to 11% (rats), 36% (guinea pigs),
047-4 Health-based Recommended Occupational Exposure Limits
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<pre>      1.9% (mice), 0.7% (anaemic pigs), and 30% (man) of the 59Fe-label in the first
      day. The percentage label excreted after 3 days was 17% (rats), 38% (guinea
      pigs), 5.7% (mice), 10% (anaemic pigs), and 30% (man). When rats, guinea
      pigs and rabbits were given diets containing ferrocene for up to 24 weeks, the
      liver iron content rose progressively. The utilisation of ferrocene iron in
      anaemic rats was 37%, in anaemic pigs 35%, and in man 25% (Gol64).
          Groups of male and female Fischer 344 rats were exposed nose-only to
      ferrocene vapour labelled with 59Fe and tritium. The exposure duration was 17
      minutes and the average ferrocene concentration was 88 mg/m3. Serial sacrifices
      were performed up to 117 days following exposure. Internal deposition was
      61.4 ± 3.7 µg per rat, corresponding to 36.6 ± 2.2% of the total inhaled vapour.
      At the earliest sacrifice time, 55% of the internally deposited ferrocene was in
      the nasopharyngeal region, and 30% was in the bronchopulmonary region. The
      remaining 15% was associated with the gastrointestinal tract or other organs.
      Over 75% of the tritium label was excreted within the first day but the 59Fe label
      largely remained in the bronchopulmonary and nasopharyngeal regions over the
      duration of the experiment. The remaining 10% of the iron was primarily
      associated with the liver (Dah80).
          The olfactory tissue of the rat had 7-fold more ferrocene oxidase activity
      (this is an isoenzyme of cytochrome P450, which one is not mentioned), than
      liver on nmol/min per g tissue basis; respiratory tissue had 3-fold more activity
      (Dah91).
6     Effects and mechanism of action
      Human data
      The committee did not find data on health effects of exposure of humans to
      ferrocene.
      Animal data
      Irritation and sensitisation
      The committee did not find data from irritation or sensitisation studies in
      experimental animals.
047-5 Dicyclopentadienyl iron (ferrocene)
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<pre>      Acute toxicity
      The following LD50s have been found: rat (oral) 1320 mg/kg bw; mouse (oral)
      832 mg/kg bw; mouse (intravenous) 178 mg/kg bw (Lew92).
          The main signs of toxicity in rats before they died were: apathy,
      lachrymation, respiratory dyspnoea, and salivation. Autopsy findings of all
      animals (mice and rats) were cachexia (a combination of wasting, weakness,
      and anaemia), wet contents and haemorrhages of the gastrointestinal tract, and
      yellow subcutaneous and mesenteric fat (Sch92).
      Repeated-dose toxicity
      Exposure to ferrocene vapour concentrations of 0, 2.5, 5.0, 10, 20, and 40
      mg/m3 (i.e., 0, 0.32, 0.65, 1.3, 2.6, and 5.2 ppm), 6 hours/day, 5 days/week, for
      2 weeks, did not induce any clinical signs of ferrocene-related toxicity in
      F344/N rats (n=5/sex/group) and B6C3F1 mice (n=5/sex/group). The highest
      exposure level represented the highest concentration of ferrocene vapour that
      could be generated without producing condensation aerosols. No
      exposure-related gross lesions were seen in any of the rats or mice at necropsy.
      Histological examination was done only on the nasal turbinates, lungs, liver,
      and spleen. The only exposure-related findings were histopathological lesions in
      the nasal turbinates of both species. These lesions were primarily centered in the
      olfactory epithelium and were morphologically diagnosed as subacute,
      necrotising inflammation. Nasal lesions were observed in all ferrocene-exposed
      animals and differed only in severity, which was dependent on the exposure
      concentration. The lesions were minimal at the lowest concentration and
      minimal to mild at 5 and 10 mg ferrocene/m3 (Sun91).
          Exposure to vapour concentrations of 0, 3.0, 10, and 30 mg/m3 (i.e., 0, 0.39,
      1.3, and 3.9 ppm), 6 hours/day, 5 days/week, for 13 weeks, did not induce any
      clinical signs of ferrocene-related toxicity in F344/N rats (n=10/sex/group) and
      B6C3F1 mice (n=10/sex/group). The mean iron lung burden in rats exposed to
      30 mg/m3 for 90 days was 4 times greater than the burden in control rats. The
      relative liver weight of rats showed a dose-related increase, which was
      significant (p<0.05) at the highest dose level for the males and at the 2 highest
      dose levels for the females. The relative liver weight of female mice was
      decreased at 3.0 mg/m3, but there was no dose-response relationship. On the
      other hand, the absolute liver weight of female mice showed a dose-related
      decrease, which was significant at all dose levels (p<0.05). The effects of
047-6 Health-based Recommended Occupational Exposure Limits
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<pre>      ferrocene exposures on organ weights may indicate a secondary response to the
      loss of appetite from the severe nasal lesions or may indicate that these are
      target organs for chronic toxicity (particularly the liver), according to the
      authors. No exposure-related changes in respiratory function, lung
      biochemistry, bronchoalveolar lavage cytology, total lung collagen clinical
      chemistry, and haematological parameters were observed. There were neither
      indications of developing pulmonary fibrosis nor of any haematological
      toxicity. Exposure-related histological alterations, primarily pigment
      accumulations, were observed in the nose, larynx, trachea, lung, and liver of
      both species, and in the kidneys of mice. Lesions were most severe in the nasal
      olfactory epithelium, where pigment accumulation, necrotising inflammation,
      metaplasia, and epithelial regeneration occurred. Nasal lesions were observed in
      all ferrocene-exposed animals and differed only in severity which was
      dependent on the exposure concentration. The results suggest that the
      mechanism of ferrocene toxicity may be the intracellular release of ferrous ion
      through ferrocene metabolism, followed by either iron-catalysed lipid
      peroxidation of cellular membranes or the iron-catalysed Fenton reaction to
      form hydroxyl radicals that directly react with other key cellular components,
      such as protein or DNA (Nik93).
           When rats were given oral doses of 50 mg ferrocene daily for 15 days, there
      was an increase in leukocyte, erythrocyte, and thrombocyte count as well as in
      haemoglobin content (Pap63). It seems that the effects were reversible within 15
      days, but the text is not clear.
           Daily oral administration of ferrocene at doses of 30, 100, or 300 mg/kg bw,
      for 6 months, and 1000 mg/kg bw, for 3 months, produced haemosiderosis with
      unusually high, dose-related accumulation of iron in the liver of dogs. The
      doses of 300 and 1000 mg/kg bw resulted in cirrhosis, which was considered by
      the authors to be an effect of the hydrocarbon moiety (Yea69).
      The committee did not find data from carcinogenicity or reproduction toxicity
      studies.
      Mutagenicity and genotoxicity
      Ferrocene was negative in:
           a bacterial mutation assay (preincubation), using S. typhimurium strains
           TA98, TA100, TA1535, and TA1537, with and without metabolic
           activating systems from induced rat and hamster livers (Haw83),
047-7 Dicyclopentadienyl iron (ferrocene)
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<pre>          a bacterial mutation assay (plate incubation), using S. typhimurium strains
          TA97a, TA98, TA100, TA102, TA1535, TA1537, and TA1538, with and
          without metabolic activating systems from induced rat and hamster livers
          (Dun99),
          a sex-linked recessive lethal assay in D. melanogaster after feeding
          (Zim85),
          a mouse lymphoma L5178Y TK+/- mutation assay in the presence of a
          induced rat liver S9 mix (Dun99),
          a chromosome aberration assay in Chinese Hamster ovary (CHO) cells, with
          and without metabolic activation (Gal85).
      Ferrocene was positive in:
          a sex-linked recessive lethal assay in D. melanogaster after injection
          (Zim85),
          a heritable translocation asssay in D. melanogaster in which reciprocal
          translocation were induced in the offspring of after injection of the fathers
          (Zim85),
          a mouse lymphoma L5178Y TK+/- mutation assay in the absence of a
          induced rat liver S9 mix (Dun99),
          a sister chromatid exchange (SCE) assay in CHO cells, with and without
          metabolic activation (Gal85).
      The committee did not find data from genotoxicity studies in intact mammals.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) in the
      Netherlands is 10 mg/m3, 8-hour TWA.
          Existing occupational exposure limits for ferrocene in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      The committee did not find data from studies on the effects of ferrocene in
      humans or from experimental animal irritation and sensitisation,
      carcinogenicity, reproduction toxicity, or in vivo genotoxicity studies.
          In a 13-week inhalation study in which rats and mice were exposed to
      ferrocene vapour concentrations of 3, 10, and 30 mg/m3 (0.39, 1.3, and 3.9
047-8 Health-based Recommended Occupational Exposure Limits
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<pre>       ppm) (Nik93), the most prominent findings were olfactory epithelial lesions
       which were seen in all animals and which showed a dose-dependent severity.
            Ferrocene did not induce mutations in S. typhimurium, D. melanogaster
       after feeding (sex-linked recessive lethal assay), and mouse lymphoma cells
       (with metabolic activation) or chromosome aberrations in CHO cells, but was
       positive in a mutation assay in mouse lymphoma cells in the absence of a
       metabolic activating system, in an SCE assay in CHO cells and, after injection,
       in a sex-linked recessive lethal assay and a heritable translocation assay in D.
       melanogaster.
            The committee considers the lesions in the nasal olfactory epithelium as the
       critical effect, and takes the LOAEL of 3.0 mg/m3 from the 13-week inhalation
       study as a starting point in deriving a health-based occupational exposure limit
       (HBROEL). For the extrapolation to a HBROEL, an overall assessment factor
       of 24 is established. This factor covers the following aspects: the absence of a
       no-adverse-effect level (NOAEL), inter- and intraspecies variation, and
       differences between experimental conditions and the exposure pattern of the
       worker. Thus, applying this factor of 24 and the preferred value approach, a
       health-based occupational exposure limit of 0.1 mg/m3 is recommended.
       The committee recommends a health-based occupational exposure limit for
       dicyclopentadienyl iron (ferrocene) of 0.1 mg/m3, as an 8-hour time-weighted
       average.
       References
ACG91  American Conference of Governmental Industrial Hygienists (ACGIH). Documentation of the
       threshold limit values and biological exposure indices. 6th ed. Cincinnati, Ohio, USA: ACGIH,
       1991: 453-4.
ACG02a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values -2002. Cincinnati OH, USA: ACGIH®, Inc, 2002: 43.
ACG02b American Conference of Governmental Industrial Hygienists (ACGIH). 2002 TLVs® and BEIs®.
       Threshold Limit Values for chemical substances and fysical agents. Biological Exposure Indices.
       Cincinnati OH, USA: ACGIH®, Inc, 2002: 27.
Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2000; At-vejledning C.0.1.
Arb00b Arbetarskyddsstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. Solna, Sweden:
       Arbetarskyddsstyrelsen, 2000; Ordinance AFS 2000:3.
047-9  Dicyclopentadienyl iron (ferrocene)
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<pre>CEC00  Commission of the European Communities (CEC). Commission Directive 2000/39/EC of 8 June
       2000 establishing a first list of indicative occupational exposure limit values in implementation of
       Council Directive 98/24/EC on the protection of the health and safety of workers from the risks
       related to chemical agents at work. Official Journal of the European Communities 2000; L142
       (16/06/2000): 47-50.
Che98  Chemiekaarten: Gegevens voor het veilig werken met chemicaliën/[ed by] Samenwerkingsverband -
       Chemiekaarten (NIA’TNO, VNCI). 14e ed. 1999. The Hague, theNetherlands: Ten Hagen & Stam,
       1998: 551.
Dah80  Dahl AR, Briner TJ. Biological fate of a representative lipophilic metal compound (ferrocene)
       deposited by inhalation in the respiratory tract of rats. Toxicol Appl Pharmacol 1980; 56: 232-9.
Dah91  Dahl AR, Hadley WM. Nasal cavity enzymes involved in xenobiotic metabolism: effects on the
       toxicity of inhalants. Crit Rev Toxicol 1991; 21: 345-72.
DFG02  Deutsche Forschungsgemeinschaft (DFG): Senatskommission zur Prüfung gesundheitsschädlicher
       Arbeitsstoffe. MAK- und BAT-Werte-Liste 2002. Maximale Arbeitsplatzkonzentrationen und
       Biologische Arbeitsstofftoleranzwerte. Weinheim, FRG: Wiley-VCH, 2002; rep no 38.
Dun99  Dunkel VC, San RHC, Seifried HE, et al. Genotoxicity of iron compounds in Salmonella
       typhimurium and L5178Y mouse lymphoma cells. Environ Mol Mutagen 1999; 33: 28-41.
Gal85  Galloway SM, Bloom AD, Resnick M, et al. Development of a standard protocol for in vitro
       cytogenetic testing with chinese hamster ovary cells: comparison of results for 22 compounds in two
       laboratories. Environ Mutagen 1985; 7: 1-51.
Gol64  Golberg L, Martin LE. The absorption, distribution and utilization of iron in fat-soluble form. Life
       Sci 1964; 3: 1465-74.
Haw83  Haworth S, Lawlor T, Mortelmans K, et al. Salmonella mutagenicity test results for 250 chemicals.
       Environ Mutagen 1983; 5 (suppl 1): 3-142.
How92  Howard PH, Neil M, ed. Dictionary of chemical names and synonyms. Chelsea MA, USA: Lewis
       Publishers, 1992.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 18.
Lew92  Lewis sr. RJ, ed. Sax’s dangerous properties of industrial materials. 8th ed. New York, USA: Van
       Nostrand Reinhold, 1992; 1699.
Lid96  Lide DR, Frederiks HPR, ed. CRC Handbook of chemistry and physics. 77th ed. Boca Raton FL,
       USA: CRC Press, 1996; 3-165.
Nik93  Nikula KJ, Sun JD, Barr EB, et al. Thirteen-week, repeated inhalation exposure of F344/N rats and
       B6C3F1 mice to ferrocene. Fundam Appl Toxicol 1993; 21: 127-39.
NLM02  US National Library of Medicine (NLM), ed. Ferrocene. In: Hazardous Substances Data Bank
       (HSDB) (last review date ferrocene file: 2 March 1994; last revision date: 13 May 2002);
       http://www.toxnet.nlm.nih.gov.
047-10 Health-based Recommended Occupational Exposure Limits
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<pre>Pap63  Papoyan SA, Breivis PV. [Influence of ferrocene on blood-forming organs.] Russian. Vopr
       Rentgenol i Okol, Akad Nauk Arm SSSR, Inst Rentgenol i Onkol 1963; 7: 177-82. Chem Abstr
       62:8295a.
Pel81  Pelino M, Tomassetti M, Piacente V, et al. Vapor pressure measurements of ferrocene, mono- and
       1,1’-diacetylferrocene. Thermochim Acta 1981; 44: 89-99.
Sch92  Schlede E, Mischke U, Roll R, et al. A national validation study of the acute-toxic-class method. An
       alternative to the LD50 test. Arch Toxicol 1992; 66: 455-70.
Sun91  Sun JD, Dahl AR, Gillett NA, et al. Two-week, repeated inhalation exposure of F344/N rats and
       B6C3F1 mice to ferrocene. Fundam Appl Toxicol 1991; 17: 150-8.
SZW02  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2002. The Hague,
       the Netherlands: Sdu, Servicecentrum Uitgevers, 2002: 44.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Yea69  Yeary RA. Chronic toxicity of dicyclopentadienyliron (ferrocene) in dogs. Toxicol Appl Pharmacol
       1969; 15: 666-76.
Zim85  Zimmering S, Mason JM, Valencia R, et al. Chemical mutagenesis testing in Drosophila. II. Results
       of 20 coded compounds tested for the National Toxicology Program. Environ Mutagen 1985; 7:
       87-100.
047-11 Dicyclopentadienyl iron (ferrocene)
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<pre>             Annex
Occupational exposure limits for ferrocene in various countries.
country                              occupational                 time-weighted    type of        notea      referenceb
-organisation                        exposure limit               average          exposure limit
                                     ppm         mg/m3
the Netherlands
-Ministry of Social Affairs          -           10               8h               administrative            SZW02
and Employment
Germany
-AGS                                 -           5c               8h               administrative            TRG00
-DFG MAK-Kommission                  -           -                                                           DFG02
Great-Britain
-HSE                                 -           10               8h               OES                       HSE02
                                     -           20               15 min           STEL
Sweden                               -           -                                                           Arb00b
Denmark                              -           -                                                           Arb00a
USA
-ACGIH                               -           10               8h               TLV                       ACG02b
-OSHA                                -           15d, 5e          8h               PEL                       ACG02a
-NIOSH                               -           10d, 5e          10 h             REL                       ACG02a
European Union
-SCOEL                               -           -                                                           CEC00
a
     S = skin notation; which mean that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     As inhalable fraction of the aerosol.
d
     As total dust.
e
     As respirable fraction.
047-12       Health-based Recommended Occupational Exposure Limits
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