<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>      Tricarbonyl(eta-cyclopentadienyl)-
      manganese
      (CAS reg no: 12079-65-1)
      Health-based Reassessment of Administrative
      Occupational Exposure Limits
      Committee on Updating of Occupational Exposure Limits,
      a committee of the Health Council of the Netherlands
      No. 2000/15OSH/042, The Hague, 7 March 2002
042-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Tricarbonyl(eta-cyclopentadienyl)manganese; Health-based
      Reassessment of Administrative Occupational Exposure Limits. The Hague:
      Health Council of the Netherlands, 2002; 2000/15OSH/042.
      all rights reserved
042-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      tricarbonyl(eta-cyclopentadienyl)manganese 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 RN Hooftman,
      M.Sc. and H Stouten, M.Sc. (TNO Nutrition and Food Research, Zeist, the
      Netherlands).
           The evaluation of the toxicity of
      tricarbonyl(eta-cyclopentadienyl)manganese has been based on the review by
      ACGIH (ACG91). Where relevant, the original publications were reviewed and
      evaluated as will be indicated in the text. In addition, literature was retrieved from
      the on-line data bases Medline, Toxline, and Chemical Abstracts covering the
      period 1966 to 24 October, 1997 (19971024/UP), 1965 to 20 October 1997
      (19971020/ED), and 1967 to 28 October, 1997 (971028/ED); vol 127 iss 18),
      respectively, and using the following key words: manganese
      cyclopentadienyltricarbonyl (excluding manganese methylcyclopentadienyl
      tricarbonyl with CAS Registry Number 12108-13-3) and 12079-65-1. HSDB (no
      record) and RTECS, data bases available from CD-ROM, were consulted as well
      (NIO98, NLM98). The final literature search has been carried out in October 1997,
      followed by an additional search in May 2001.
           In July 2001, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
042-3 Tricarbonyl(eta-cyclopentadienyl)manganese
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<pre>2     Identity
       name                   :      tricarbonyl(eta-cyclopentadienyl)manganese (TCM)
       synonyms               :      tricarbonyl (η5--2,4-cyclopentadien-1-yl)-manganese
                                     tricarbonyl-pi-cyclopentadienylmanganese
                                     tricarbonyl-π-cyclopentadienylmanganese
                                     cyclopentadienyl manganese tricarbonyl
                                     manganese cyclopentadienyl tricarbony
                                     manganese, tricarbonyl-pi-cyclopentadienyl
       molecular formula      :      C8H5MnO3
       structure              :
       CAS reg no             :      12079-65-1
      Data from ACG91, Ric94.
3     Physical and chemical properties
       molecular weight    :    204,1
       boiling point       :    232 - 233 0C
       melting point       :    75 - 77 0C (sublimes)
       flash point         :    -
       vapour pressure     :    -
       solubility in water :    sparingly soluble
       Log P octanol/water :    -0.57 (estimated)
       conversion factors  :    not applicable
       (20 0C, 101.3 kPa)
      Data from ACG91, Ric94.
      TCM is a bright yellow crystalline substance with camphoraceous odour
      (ACG91).
4     Uses
      TCM is used as an octane enhancement additive for unleaded gasoline (ACG91).
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<pre>5     Biotransformation and kinetics
      There is only some limited information on the toxicokinetics of TCM available.
          Twenty-four hours after a single subcutaneous administration of 0.5-2.5 mg
      Mn/kg bw as TCM to male rats, there was a significant increase in the amount of
      manganese in the lungs. Since this manganese was in a nonlipid soluble form,
      metabolites rather than parent compound may have been accumulated.
      Treatment did not affect blood and hepatic nonprotein sulphydryl levels
      measured in animals sacrificed at 1.5, 6, or 24 hours after administration.
      Pulmonary levels were statistically significantly increased (twofold) over control
      levels, but at t=24 h only. Pretreatment with piperonyl butoxide partially
      prevented this increase after a dose of 0.5 mg Mn/kg (as TCM), but had no effect
      on a dose of 1.0 mg Mn/kg. Since TCM treatment did not alter pulmonary levels
      of thiobarbituric acid reactive materials, it was concluded that there were no
      indications for detectable lipid peroxidation (Cla89).
          When given a single oral (gavage) dose of 50 mg/kg bw to rats after a 3-day
      pretreatment with phenobarbital, a decrease in urine volume and a sharp rise in
      urinary manganese excretion was found on day 1 and 2 after TCM
      administration, amounting to approximately 16% of the dose administered. The
      majority of the urinary manganese was concluded to be in the organometallic
      form. Although metabolites were not identified, the authors considered it
      conceivable that TCM may have undergone ring hydroxylation followed by
      conjugation and excretion of at least some of the hydroxylated material. Toxicity
      studies in which phenobarbital was shown to prevent the occurrence of toxic
      effects (convulsions, oedema) in rats (see also next section) suggested
      (enhancement of) biotransformation to more polar and less toxic metabolites
      (Pen85).
          The in vitro metabolism of TCM has been studied using nasal, pulmonary,
      and hepatic microsomes isolated from rats sacrificed 2, 12, or 24 hours after a
      intraperitoneal injection of 0.5 or 1.0 mg m-xylene/kg bw. Pretreatment with
      m-xylene (known to differently alter cytochrome P450 activation in rodent
      pulmonary vs hepatic tissues) inhibited nasal and pulmonary, but not hepatic
      microsomal metabolism of TCM at all time points. Comparison with the results of
      concomitantly performed experiments suggested the involvement of the
      pulmonary cytochrome P450 IIB1 isozyme (Bla94).
          Further in vitro studies showed that TCM was metabolis ed by rat lung and
      liver homogenates or microsomes, but not by the cytosol. For TCM, the apparent
042-5 Tricarbonyl(eta-cyclopentadienyl)manganese
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<pre>      Km was estimated to be 1.0 and 20 µg/mL, the Vmax to be 4.8 and 89 µg/min/g, in
      lung and liver tissue, respectively. Thus, the intrinsic pulmonary and hepatic
      clearance of TCM as calculated from the in vitro Vmax /Km ratio ( 4.5 mL/min) were
      similar. In the experiments, no metabolites were detected in the incubation
      medium by HPLC analysis, but gas chromatographic analysis of headspace air
      showed the presence of an unidentified, volatile metabolite with a low boiling
      point. This metabolite was cytochrome P450 mediated. Phenobarbital
      pretreatment induced hepatic, but not pulmonary TCM metabolism, while both
      3-methylindole and m-xylene pretreatment inhibited pulmonary but not hepatic
      metabolism. In microsomes of freshly prepared alveolar type II cells, no
      TCM-metabolis ing capacity could be detected. From these in vitro data together
      with the results of toxicity studies both with and without adding
      metabolism-interfering compounds, the authors summarised that in situ
      activation of TCM within the lungs is necessary to induce its alveolar toxicity.
      However, since the alveolar type II cells did not exhibit metabolically activating
      capacity, it was suggested that a volatile, active metabolite was produced in the
      bronchiolar Clara cells and from there transported to the alveolar region (Bla96).
6     Effects and mechanism of action
      Human data
      There were no data on workers occupationally exposed to TCM.
      Animal data
      TCM was stated to cause a certain degree of irritation (not further specified)
      when applied as an oil emulsion to selected areas of the skin of rabbits (Ark65).
      When the tails of mice (n=10/group) were exposed to a solution of 1 g TCM/100
      mL gasoline, 2 hours/day, for 5 days, first petechial and then confluent
      haemorrhages were seen after 4 to 5 applications. The greater part of the tail was
      subsequently lost by necrosis. Since similar effects were observed to the
      gasoline-alone exposed controls, these effects were attributed to gasoline rather
      than to TCM (Ark65).
          Eighty percent of the rats exposed to 120 mg/m3, for 2 hours, died, while there
      was no mortality following a 2-hour exposure to 20 or 40 mg/m3. The authors
      stated that they did not succeed in obtaining a concentration that killed all
      animals. Although guinea pigs and rabbits were involved in the experiments as
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<pre>      well, no data regarding these species were presented. Acute effects reported to
      be observed following inhalation exposure were vascular changes (increased
      permeability of vessels, oedema, haemorrhages, decreased blood pressure),
      effects on the nervous system (atrophic changes in the nerve cells), and
      haematological changes (erythrocytosis, decreased osmotic pressure of the
      erythrocytes) (Ark65).
          Following immersing of the tails of mice (n=10/group) in a solution of 1 g
      TCM/100 mL gasoline, 2 hours/day, for 5 days, no differences were seen in
      effects found in animals exposed to gasoline with and without TCM. Inhalation
      was prevented by placing the animals at the edge of a fume cupboard with their
      muzzles towards its door. However, tetrahydrofuran solutions of TCM were
      found to be more toxic than solutions in oil. All animals whose tails had been
      immersed in tetrahydrofuran solutions died within 1 hour, while no mortality
      occurred in the group exposed to tetrahydrofuran alone (Ark65).
          When injecting single subcutaneous doses of 0, 0.5, 1.0, and 2.5 mg Mn/kg
      bw as TCM (vehicle: propylene glycol) to male rats, 5/9 animals of the high-dose
      group died within 24 hours most likely due to pulmonary oedema and/or
      inflammation. There were no changes in plasma lactate dehydrogenase, sorbitol
      dehydrogenase, and blood urea nitrogen levels (measured at t=24 h) in any of
      the treatment groups suggesting the absence of marked hepatic or renal damage.
      Lung lavages (performed only in the animals surviving for 24 hours) showed
      dose-dependent lung damage (small increase in the LDH level, large increase in
      albumin and protein content). Piperonyl butoxide diminished pneumotoxicity
      suggesting that this effect may be caused by the formation of mono-oxygenase
      metabolites (Cla89).
          In a follow-up study, 3.76 mg TCM/kg bw was administered subcutaneously
      to male rats. At histological examination of the lungs and trachea, pulmonary
      lesions were observed in all animals sacrificed 48 or 96 hours after injection, but
      in none of the animals killed after 24 hours. The lesions were found in the
      alveolar region only and consisted of areas of thickened alveolar septa
      containing mononuclear cells, distended perivascular lymphatics, and alveolar
      haemorrhage; there were neither overt signs of necrosis nor infiltration of
      neutrophils. In additional experiments, the pulmonary toxicity of TCM was
      quantified by bronchoalveolar lavage fluid protein, albumin, and lactate
      dehydrogenase levels in rats treated with TCM alone or with TCM following
      pretreatment with m-xylene, 3-methylindole, and phenobarbital. Pretreatment with
      each of these compounds considerably or completely reduced pneumotoxicity as
      estimated by the lavage parameters (Bla96).
042-7 Tricarbonyl(eta-cyclopentadienyl)manganese
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<pre>          Following oral administration, LD 50 values of 22 (95% C.I.: 19-26 mg/kg) and
      80 mg/kg bw in rats and of 150 mg/kg bw in mice have been reported (Ark63,
      Pen85). Furthermore, there was an intraperitoneal LD 50 of 14 mg/kg bw (95% C.I.:
      10 - 20 mg/kg) in rats (Pen85) and there were intravenous LD 50s of 0.7 (NIO98)
      and 3.2 mg/kg bw (Str64) in mice.
      Single oral or intraperitoneal administration of 15.9-40 and 8.0-31.7 mg/kg bw,
      respectively, to male rats (n=4/group) produced convulsions, pulmonary
      oedema, and increased relative lung weights. The ED 50s for convulsion were 32
      (95% C.I.: 24-42 mg/kg) and 20 mg/kg (95% C.I.: 15-26 mg/kg) following oral and
      intraperitoneal administration, respectively. Lethal effects were not directly
      related to convulsions: some animals died without ever showing convulsions.
      Phenobarbital pretreatment prevented the occurrence of both convulsions and
      oedema, presumably by enhancing the biotransformation of TCM to more polar
      and less toxic metabolites. After pretreatment with relatively small intraperitoneal
      doses of 5 mg TCM/kg bw, for 3 days, a single oral dose of 34 mg TCM/kg bw
      induced convulsions (in 4/7 vs 10/10 in not pretreated animals) but no mortality
      (pneumotoxicity) (0/7 vs 10/10); a preceding 3-day fasting period had similar
      effects (convulsions in 1/5, mortality in 1/5) (Pen85).
          Single intraperitoneal doses of 10 and 30 mg/kg bw induced moderate
      necrosis of the nonciliated bronchiolar (Clara) cells in rat and mouse,
      respectively (time of sacrifice: at 24 h) (Has82).
          Rabbits, guinea pigs, and rats (number unknown) were exposed to an
      average concentration of 1 mg/m3, 4 hours/day, for 11 months. In rats, there were
      no visible signs of toxicity, but some effect on the nervous system (i.e., an
      increase in the threshold level of neuromuscular excitability measured by electric
      stimuli) occurred in the course of the experiment. Exposure induced effects on
      the kidneys as was indicated by decreased diuresis and proteinuria (no data
      presented). Especially in guinea pigs and rabbits, there was a decrease in
      resistance to infection. Although it was stated that animals were examined
      histologically, results were not presented (Ark65). The significance of the result
      reported in this study are difficult to assess. No quantitative data or statistical
      analyses were presented. The results of the neuromuscular excitability threshold
      were presented by a graph, but there were some discrepancies between this
      graph and the text. In addition, no standard deviations were included.
          There were no data available from genotoxicity, carcinogenicity, and
      reproduction toxicity studies.
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<pre>7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for TCM in the
      Netherlands is 0.1 mg/m3, 8-hour TWA.
          Existing occupational exposure limits for TCM in some European countries
      and in the USA are summarised in the annex.
8     Assesment of health hazard
      No human data and only limited data from single dose inhalation, oral,
      subcutaneous, or intraperitoneal experiments in animals are available.
          Limitedly reported acute inhalation data (80% mortality in rats exposed to 120
      mg/m3 for 2 hours) suggest that TCM should be considered as very toxic by
      inhalation.
          From acute oral mortality studies (LD50 rat: 22 mg/kg bw), the committee
      considers TCM to be very toxic if swallowed.
          Following single oral, intraperitoneal, or subcutaneous exposure of rats, the
      lung is the target organ, although convulsions have been observed as well.
      The committee considers the toxicological data base on
      tricarbonyl(eta-cyclopentadienyl)manganese too poor to justify recommendation
      of a health-based occupational exposure limit.
      The committee concludes that there is insufficient information to comment on the
      level of the present MAC-value.
      References
ACG91 American Conference of Governmental Industrial Hygienists (ACGIH). Manganese
      cyclopentadienyl tricarbonyl. In: Documentation of the threshold limit values and biological
      exposure indices. 6th ed. Cincinnati OH, USA: ACGIH, 1991: 879-80.
ACG00 American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
      exposure values - 2000. Cincinnati OH, USA: ACGIH® , Inc, 2000: 73.
ACG01 American Conference of Governmental Industrial Hygienists (ACGIH). 2001 TLVs ® and
      BEIs® . Threshold Limit Values for chemical substances and physical agents. Biological
      Exposure Indices. Cincinnati OH, USA: ACGIH® , Inc, 2001: 38.
042-9 Tricarbonyl(eta-cyclopentadienyl)manganese
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<pre>Arb00a Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark:
       Arbejdstilsynet, 2000; (At-vejledning C.0.1).
Arb00b Arbetarskyddstyrelsen. Hygieniska gränsvärden och åtgärder mot luftföroreningar. Solna,
       Sweden: National Board of Occupational Safety and Health, 2000; (Ordinance AFS 2000/3).
Ark63  Arkhipova OG. [On the mechanism underlying the action of cyclopentadienyltricarbonyl
       manganese - a new antiknock compound]. Gig Tr Prof Zabol 1963; 7: 43-9 (in Russian).
Ark65  Arkhipova OG, Tolgskaya MS, Kochetkova TA. Toxicity within a factory of the vapor of
       new antiknock compound, manganese cyclopentadienyltricarbonyl. Hyg Sanit 1965; 30
       (4-6): 40-4 (English translation from Gig Sanit).
Bla94  Blanchard KT, Morris JB. Effects of m-xylene on rat nasal cytochrome P450 mixed
       function oxidase activities. Toxicol Lett 1994; 70: 253-9.
Bla96  Blanchard KT, Clay RJ, Morris JB. Pulmonary activation and toxicity of cyclopentadienyl
       manganese tricarbonyl. Toxicol Appl Pharmacol 1996; 136: 280-8.
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.
Cla89  Clay RJ, Morris JB. Copmparitive pneumotoxicity of cyclopentadienyl manganese
       tricarbonyl and methylcyclopentadienyl manganese tricarbonyl. Toxicol Appl Pharmacol
       1989; 98: 434-43.
DFG01  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health
       Hazards of Chemical Compounds in the Work Area. List of MAK and BAT values 2001.
       Maximum concentrations and biological tolerance values at the workplace. Weinheim, FRG:
       Wiley-VCH, 2001; (rep no 37).
Has82  Haschek WM, Hakkinen PJ, Witschi HP, et al. Nonciliated bronchiolar epithelial (Clara) cell
       necrosis induced by organometallic carbonyl compounds. Toxicol Lett 1982; 14: 85-92.
HSE01  Health and Safety Executive (HSE). EH40/2001. Occupational Exposure Limits 2001.
       Sudbury (Suffolk),England: HSE Books, 2001: 27.
NIO98  US National Institute of Occupational Safety and Health (NIOSH). Registry of Toxic Effects
       of Chemical Substances (RTECS) [CD-ROM], issue April 1998. SilverPlatter International,
       1998 (last update TCM file: December, 1997).
NLM98  US National Library of Medicine (NLM). Hazardous Substances Data Bank (HSDB)
       [CD-ROM], issue April 1998. SilverPlatter International, 1998.
Pen85  Penney DA, Hogberg K, Traiger GJ, et al. The acute toxicity of cyclopentadienyl manganese
       tricarbonyl in the rat. Toxicology 1985, 34: 341-7.
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<pre>Ric94  Richardson ML, Gangioli S, eds. M21, Manganese cyclopentadienyl tricarbonyl. In : The
       dictionary of substances and their effects. Cambridge, UK: Royal Society of Chemistry, 1994:
       331-2 (Vol 5).
Str64  Strohmeier W. Toxizität von Cyclopentadienylmangantricarbonyl- und
       Chromhexacarbonyl-Derivaten. Z Naturforsch 1964; 19: 540.
SZW01  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2001. The
       Hague, the Netherlands: Sdu, Servicecentrum Uitgevers, 2001: 42.
TRG00  TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe.
       BArbBl 2000; 2.
042-11 Tricarbonyl(eta-cyclopentadienyl)manganese
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<pre>             Annex
Occupational exposure limits for tricarbonyl(eta-cyclopentadienyl) manganese in various countries.
country                         occupational             time-weighted     type of exposure notea        lit refb
-organisation                   exposure limit           average           limit
                                ppm        mg/m 3 c
the Netherlands
-Ministry of Social Affairs     -          0.1           8h                administrative    S           SZW01
and Employment                  -          0.3           15 min
Germany
-AGS                            -          0.1           8h                                  S           TRG00
-DFG MAK-Kommission             -          -                                                             DFG01
Great-Britain
-HSE                            -          0.1           8h                OES               S           HSE01
                                -          0.3           15 min
Sweden                          -          -                                                             Arb00b
Denmark                         -          0,1           8h                                  S           Arb00a
USA
-ACGIH                          -          0.1           8h                TLV               S           ACG01
-OSHA                           -          0.1           8h                PEL               S           ACG00
-NIOSH                          -          0.1           10 h              REL               S           ACG00
European Union
-SCOEL                          -          -                                                             CEC00
a
     S = skin notation; this means 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
     In all cases, exposures are measured as manganese
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