<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>Gezondheidsraad                               Voorzitter
Health Council of the Netherlands
Aan de Staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp            : Aanbieding adviezen herevaluatie bestuurlijke MAC-waarden
Uw kenmerk           : ARBO/AMIL/97/00648
Ons kenmerk          : U 2706/CB/MP/563-O3
Bijlagen             : 18
Datum                : 14 december 2000
Mijnheer de staatssecretaris,
Op verzoek van uw ambtsvoorganger bied ik u hierbij de eerste adviezen aan van een
reeks over de gezondheidskundige basis van uit het buitenland overgenomen
grenswaarden voor beroepsmatige blootstelling aan stoffen. Het verzoek om deze
adviezen is in algemene zin vervat in brief nr ARBO/AMIL/97/00648 en in latere stadia
door uw departement toegespitst op afzonderlijke stoffen. De adviezen zijn opgesteld
door een daartoe door mij geformeerde internationale commissie van de Gezondheidsraad
en beoordeeld door de Beraadsgroep Gezondheid en Omgeving.
     De beoogde reeks van in het Engels gestelde adviezen zal losbladig worden
gepubliceerd onder ons publicatienummer 2000/15OSH en, conform de aan de
Gezondheidsraad voorgelegde toespitsingen van de adviesaanvraag, betrekking hebben
op 168 stoffen. Het u thans aangeboden eerste pakket bestaat uit een Algemene Inleiding
(publicatienummer 2000/15OSH/000) en uit de adviezen genummerd 2000/15OSH/001
tot en met 2000/15OSH/017, respectievelijk betrekking hebbend op:
cesiumhydroxide, cyclopentaan, diboraan, dimethoxymethaan, dipropylketon,
fenylfosfine, germaniumtetrahydride, hexachloornaftaleen, methaanthiol,
methylcyclohexanol, methylisopropylketon, mica, natriumhydroxide,
octachloornaftaleen, silaan, tetrachloornaftaleen, en yttrium en yttriumverbindingen.
     Bij afronding van de werkzaamheden van de hierboven bedoelde commissie ontvangt
u een Nederlandstalige samenvatting van de in de gehele reeks van adviezen neergelegde
bevindingen.
Bezoekadres                                                                  Postadres
Parnassusplein 5                                                             Postbus 16052
2511 VX Den Haag                                                             2500 BB Den Haag
Telefoon (070) 340 75 20                                                     Telefax (070) 340 75 23
email: GR@gr.nl
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<pre>Gezondheidsraad
Health Council of the Netherlands
Onderwerp            : Herevaluatie uit het buitenland overgenomen grenswaarden
Ons kenmerk          :U
Pagina               :2
Datum                : 14 december 2000
    De u thans aangeboden adviezen heb ik vandaag ter informatie doen toekomen aan
de Minister van Volksgezondheid, Welzijn en Sport en aan de Minister van
Volkshuisvesting, Ruimtelijke Ordening en Milieubeheer.
Hoogachtend,
prof. dr JJ Sixma
Bezoekadres                                                                   Postadres
Parnassusplein 5                                                              Postbus 16052
2511 VX Den Haag                                                              2500 BB Den Haag
Telefoon (070) 340 75 20                                                      Telefax (070) 340 75 23
email: GR@gr.nl
</pre>

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<pre>      Methylcyclohexanol (mixed isomers)
      (CAS Reg. nr: 25639-42-3)
      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/010, The Hague, 14 December 2000
010-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Methylcyclohexanol (mixed isomers); Health-based
      Reassessment of Administrative Occupational Exposure Limits. The Hague:
      Health Council of the Netherlands, 2000; 2000/15OSH/010.
      all rights reserved
010-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      methylcyclohexanol (mixed isomers) 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 AAE Wibowo,
      Ph.D. (Coronel Institute of the Academic Medical Centre, Amsterdam, the
      Netherlands).
           Literature was retrieved from the data bases Medline, Toxline, Chemical
      Abstracts and Embase, starting from 1966, 1967, 1970 and 1988, respectively,
      and using the substance name as a keyword. Also the CD roms HSEline,
      Cisdoc, Mhidas and NIOSHtic were consulted (from 1997 backwards). Data
      considered to be critical were evaluated by reviewing the original publications.
      The final literature search has been carried out in October 1997.
           In February 1999, the President of the Health Council released a draft of the
      document for public review. Comments were received by the following
      individuals and organizations: dr P Wardenbach (Bundesanstalt für
      Arbeitsschutz und Arbeitsmedizin, Dortmund, Germany). These comments
      were taken into account in deciding on the final version of the document.
2     Identity
       name                              :    methylcyclohexanol (mixed isomers)
       synonyms                          :    hexahydrocresol
                                              hexahydromethylphenol
                                              methylhexalin
       molecular formula                 :    C7H14O
       structural formula                :
       CAS reg nr                        :    25639 - 42 - 3
010-3 Methylcyclohexanol (mixed isomers)
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<pre>3     Physical and chemical properties
       molecular weight                   :    114.2
       boiling point                      :    155 - 1800C
       melting point                      :    < -210C
       vapour Pressure                    :    0.2 kPa
       solubility in water                :    3.4 g/100 ml
       log Poct/water                     :    not known
       conversion factors                 :    1 mg/m3 = 0.21 ppm
       (20 oC, 101.3 kPa)                      1 ppm = 4.75 mg/m3
      Data from IPC91
      Methylcyclohexanol is a straw-coloured liquid with a weak odour like coconut
      oil (NIO94). The vapour can be detected by its odour at 2375 mg/m3 (500 ppm)
      (Hat91).
4     Uses
      Methylcyclohexanol is used as a solvent for cellulose esters and ethers, a
      lubricant antioxidant, a blending agent of soaps and detergents, in textile and
      artificial silk industry, and as a degreasing agent (ACG96).
5     Biotransformation and kinetics
      Methylcyclohexanol can be absorbed into the body by inhalation of its vapour,
      through the skin, and by ingestion of its liquid (IPC91). There are no
      quantitative data on absorption. Neither is there any information on
      distribution, biotransformation, excretion and biological monitoring methods
      for this compound.
           Methylcyclohexanol is one of the metabolites of methylcyclohexane. Parnell
      et al. (Par88) reported among others trans-3-methylcyclohexanol and
      trans-4-methylcyclohexanol as urinary metabolites after oral administration of
      methylcyclohexane to male Fischer rats.
010-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      According to Hathaway et al. (Hat91), a concentration of methylcyclohexanol
      equivalent to its odour threshold of 2375 mg/m3 (500 ppm) can cause upper
      respiratory irritation. This information was given without further details. There
      are no human data available on possible systemic effects induced by exposure
      to this compound.
      Animal data
      No recent animal data on methylcyclohexanol have been found.
           Treon et al. (Tre43a) exposed young healthy rabbits to methylcyclohexanol
      by inhalation. One or two rabbits from each lot of 12 were set aside as controls.
      Three experiments were carried out, in each of which methylcyclohexanol was
      employed in a concentration of 560, 1060 or 2300 mg/m3 for 6 hours daily, 5
      days per week over a period of 10 weeks. No deaths occurred at any
      concentration. Signs of intoxication, consisting of salivation, conjunctival
      irritation and slight lethargy, were seen only after exposure to the highest
      concentration of 2300 mg/m3. Concentration-related microscopic pathological
      changes in liver and kidneys were observed in all animals. In the lowest
      exposure group, however, these were ‘barely discernible’, according to the
      authors. All rabbits gained weight during the experiment. During the daily
      exposure periods no significant changes in body temperature between exposed
      and control animals were observed. According to the authors,
      methylcyclohexanol does not cause narcosis within the limits of the
      concentrations that can be obtained at ordinary temperatures. They concluded
      that the ‘maximum safe concentration for the prolonged exposure of rabbits’
      would be ‘very slightly below 560 mg/m3.
           The same authors (Tre43b) also exposed rabbits to methylcyclohexanol by
      oral administration and cutaneous application. The minimum lethal dose of
      methylcyclohexanol for rabbits by oral administration was between 1750 and
      2000 mg/kg bw. Rapid narcosis and convulsive movements resulted. There was
      a decrease in the percentage of inorganic sulphates and an increase in the
      glucuronic acid content of the urine. Rabbits given doses ranging from 1000 to
      1750 mg/kg bw lost body weight in the first 2 to 4 days and regained weight
010-5 Methylcyclohexanol (mixed isomers)
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<pre>      during the following 2 to 4 days. The authors concluded that rabbits when
      given sublethal oral doses of methylcyclohexanol, suffered from rapidly
      developing anaesthesia together with spasmodic jerking of the head and
      rhythmic ‘running’ movements of the forelegs. In some cases there was slight
      salivation, lacrimation and distension of the ear veins.
          The minimum lethal dose of methylcyclohexanol for rabbits by cutaneous
      administration was between 6800 and 9400 mg/kg bw On one rabbit 10 ml
      methylcyclohexanol was applied to the clipped abdominal skin in two-5 ml
      portions at half-hour intervals, for 6 days (a total dose of 21,000 mg/kg bw).
      The residual material was removed after one hour by washing. During the first
      two days general weakness and scattered local petechiae were observed. On
      subsequent days deep anaesthesia, lasting for several hours, developed
      accompanied by convulsive movements and tremors of the forelegs. Thickening
      of the skin and hemorrhagic areas were noted at the site of application. The
      animal died 18.5 hours after the final application.
      No data on long-term toxicity, mutagenicity, genotoxicity, carcinogenicity and
      reproduction toxicity of methylcyclohexanol have been found.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) of
      methylcyclohexanol in the Netherlands is 235 mg/m3 (50 ppm), 8 h TWA.
          Existing occupational exposure limits for methylcyclohexanol in some
      European countries and in the USA are summarized in the annex.
8     Assessment of health hazard
      There are no human data available on exposure to methylcyclohexanol. Studies
      in experimental animals indicated the central nervous system and probably also
      the liver and kidneys as target organs of methylcyclohexanol exposure. This is
      substantiated by the fact that experimental animals exposed to
      methylcyclohexane also showed effects of the central nervous system.
      Methylcyclohexanol is a metabolite of methylcyclohexane*.
          Although the study by Treon et al. (Tre43b) is dated, the committee
      concludes that it has been well performed and sufficiently documented to be
      used as a starting point for the hazard assessment of methylcyclohexanol. The
*     The committee will also reassess the current administrative OEL of methylcyclohexane.
010-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      committee considers the concentration of 560 mg/m3 (118 ppm)
      methylcyclohexanol in rabbits to be the lowest observed adverse effect level
      (LOAEL). After applying an overall assessment factor of 18 to account for
      starting from a LOAEL instead of a NOAEL and for inter- and intraspecies
      variation, the committee recommends a health-based occupational exposure
      limit of 31 mg/m3 which results in a preferred value of 50 mg/m3 (10.5 ppm), 8
      h TWA for methylcyclohexanol (mixed isomers).
      The committee recommends a health-based occupational exposure limit of 50
      mg/m3 (10.5 ppm) for methylcyclohexanol (mixed isomers), as an 8 hour time
      weighted average (TWA).
      References
ACG96 American Conference of Governmental Industrial Hygienists (ACGIH). TLVs and other occupational
      exposure values - 1996 (CD ROM, version 1.7 - s4 02/01/95). Cincinnati OH, USA: ACGIH, 1996.
ACG00 American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
      exposure values -2000. Cincinnati OH, USA: ACGIH, 2000.
Arb96 Arbejdstilsynet. Exposure limit values for substances and materials. Copenhagen, Denmark: The
      Working Environment Service; Instruction no. 3.1.0.2. 1996.
DFG99 Deutsche Forschungsgemeinschaft. List of MAK and BAT values 1999. Commission for the
      investigations of health hazards of chemicals compounds in the work area. Weinheim, Germany: VCH
      Verlagsgesellschaft mbH, 1999, Report nr. 35.
Hat91 Hathaway GJ, Proctor NH, Hughes JP, Fischman ML, editors. In: Proctor and Hughes’ Chemical
      hazards of the workplace, third edition, 1991, New York: Van Nostrand Reinhold, New York, 1991:
      389.
HSE99 Health and Safety Executive (HSE). Occupational exposure limits 1999. Sudbury, England: HSE
      Books, 1999; Guidance note EH40/99.
IPC91 International Programme on Chemical Safety (IPCS) - European Communities.International Chemical
      Safety Cards. Methylcyclohexanol (mixed isomers), 1991: ICSC 0292.
Lee88 Lee KM, Dahlhauser KF, Plapp BV. Reactivity of horse liver alcohol dehydrogenase with
      3-methylcyclohexanols. Biochemistry 1988; 27: 3528-3532.
NBO96 National Board for Occupational Safety and Health. Occupational exposure limit values. Solna,
      Sweden: NBOSH, 1996; Ordinance AFS1996/2.
NIO94 National Institute for Occupational Safety and Health (NIOSH). NIOSH pocket guide to chemical
      hazards. US Dept Health and Human Services. Washington, 1994.
Par88 Parnell MJ, Henningsen GM, Hixson CJ, Yu KO, McDonald GA, Serve MP. The metabolism of
      methylcyclohexane in Fischer 344 rats. Chemosphere 1988; 17: 1321-1327.
010-7 Methylcyclohexanol (mixed isomers)
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<pre>SZW00  Ministerie van Sociale Zaken en Werkgelegenheid (SZW): Arbeidsinspectie. [De nationale MAC-lijst
       2000]. Dutch. The Hague, the Netherlands: Sdu Servicecentrum Uitgeverijen, 2000.
Tre43a Treon JF, Crutchfield Jr WE, Kitzmiller KV. The physiological response of animals to cyclohexane,
       methylcyclohexane and certain derivatives of these compounds. II. Inhalation. J Ind Hyg Toxicol 1943;
       25: 323-347.
Tre43b Treon JF, Crutchfield Jr WE, Kitzmiller KV. The physiological response of rabbits to cyclohexane,
       methyl-cyclohexane and certain derivatives of these compounds. I. Oral administration and cutaneous
       administration. J Ind Hyg Toxicol 1943; 25: 199-214.
TRG00  TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. B Arb Bl
       2000; 2.
010-8  Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>             Annex
Occupational exposure standards for methylcyclohexanol (mixed isomers) in various countries.
country                               occupational exposure        time-weighted       type of exposure notea lit refb
-organisation                         limit                        average             limit
                                      ppm          mg/m3
The Netherlands
-Ministry                             50           235             8h                  administrative         SZW00
Germany
-AGS                                  50           235             8h                                         TRG00
-DFG MAK-Kom.                         50           240             8h                  MAK                    DFG99
Great-Britain
-HSE                                  50           237             8h                  OES                    HSE99
                                      75           356             15 min              STEL
Sweden                                -            -                                                          NBO96
Denmark                               50           235             8h                                         Arb96
USA
-ACGIH                                50           234             8h                  TLV                    ACG00
-OSHA                                 100          470             8h                  PEL
-NIOSH                                50           235             10 h                REL
European Union
-SCOEL                                -            -
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
010-9        Methylcyclohexanol (mixed isomers)
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<pre>010-10 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>