<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>Pentan-2-one
(CAS No: 107-87-9)
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/136 The Hague, November 9, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Pentan-2-one; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/136.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of pentan-2-
      one 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, Academic
      Medical Centre, Amsterdam, the Netherlands).
           In May 1998, literature was searched in the databases Medline, Embase, and
      Chemical Abstracts, starting from 1966, 1988, and 1970, respectively, and using
      the following key words: 2-pentanone, methyl propyl ketone, MPK, and 107-87-
      9. Current Contents and Poltox, HSELINE, CISDOC, MHIDAS, and
      NIOSHTIC, databases available on CD-ROM, were consulted as well.
           In July 2000, the President of the Health Council released a draft of the
      document for public review. No comments were received.
           An additional search in Toxline and Medline in September 2004 did not
      result in information changing the committee’s conclusions.
2     Identity
      name                       :  pentan-2-one
      synonyms                  :   2-pentanone; methyl propyl ketone; ethyl acetone
      molecular formula          :  C5H10O
      structural formula         :  CH3-CH2-CH2-CO-CH3
      CAS number                 :  107-87-9
136-3 Pentan-2-one
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<pre>3     Physical and chemical properties
      molecular weight            :   86.1
      boiling point               :   102oC
      melting point               :   -78oC
      flash point                 :   7oC (closed cup)
      vapour pressure             :   at 25oC: 2.1 kPa
      solubility in water         :   slightly soluble (at 25oC: 4 g/100 mL)
      log Poctanol/water          :    0.91 (experimental); 0.75 (estimated)
      conversion factors          :   at 20oC, 101.3 kPa: 1 mg/m3 = 0.28 ppm
                                                             1 ppm = 3.59 mg/m3
      Data from ACG98, NLM04, http://www.syrres.com/esc/est_kowdemo.htm.
      Pentan-2-one is a colourless liquid with characteristic odour (ACG98). Odour
      thresholds between 28 and 46 mg/m3 (8-13 ppm) (Amo83, Rut86) and of about
      110 mg/m3 (30 ppm) have been reported (Com95)*. In anosmic subjects (n=4),
      the nasal pungency threshold was about 11,100 mg/m3 (3100 ppm) (Com95)*.
4     Uses
      Pentan-2-one is used as a solvent, as a flavouring agent, and in organic synthesis
      (ACG98).
5     Biotransformation and kinetics
      The respiratory uptake defined as (Cinhaled air – Cmixed exhaled air)/Cinhaled air x 100% for
      pentan-2-one was determined by exposing 4 resting, healthy male volunteers to a
      single concentration of 100 ppm (360 mg/m3) for 10 minutes. The percentage
      solvent in end-exhaled air and in mixed-exhaled air increased after the start of
      the exposure and reached a quasi-steady-state level within a few minutes. The
      mean respiratory uptake for the last 5 minutes of pentan-2-one respiration was
      ca. 53% (Kum99).
           Old data indicated that secondary ketones, such as pentan-2-one, were slowly
      oxidised and eliminated, and it was anticipated that considerable quantities
      would be found in the blood and expired air following exposure (Hag45).
*     The committee estimated the data from figures in which Cometto-Muñiz et al. had plotted the
      thresholds on a logarithmic scale.
136-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      In a brief review, Henson described that ketones are irritating to the mucous
      membranes of the eyes and nasal passages and have measurable toxicities and
      narcotic effects. Without documentation, he stated that concentrations of 2000 to
      4000 ppm (7160-14,320 mg/m3) pentan-2-one vapour were very irritating and
      that concentrations of 1500 ppm (5370 mg/m3) had a strong odour and caused
      irritation of the eyes and nose. When applied to the skin, the solvent has a
      defatting activity, which may increase the skin’s susceptibility to infections
      (Hen59). Besides the odour threshold (see Chapter 3), Cometto-Muñiz and Cain
      determined the eye irritation threshold of pentan-2-one in 10 subjects (6 males, 4
      females, with ages between 19 and 30 years). They found an eye irritation
      threshold of about 10,000 ppm (35,900 mg/m3) (see footnote previous page)
      (Com95).
           The committee did not find information on systemic effects of pentan-2-one
      in humans.
      Animal data
      Irritation and sensitisation
      Following instillation into the eyes of rabbits (n=5), pentan-2-one scored an
      injury grade of 3 (i.e., 0.1 mL of undiluted test substance gives injury up to 5.0
      points, or 0.5 mL over 5 points) on a scale from 1 to 10 (Smy62; see also Car46).
      In guinea pigs, exposure to vapour concentrations of 2500 and 5000 ppm (i.e., ca.
      9000 and 17,900 mg/m3) immediately caused eye and nose irritation, while no
      such signs were seen at 1500 ppm (5370 mg/m3) (Spe40, Yan36; see NIO78).
           Application of 0.01 mL undiluted pentan-2-one to the clipped skin of rabbits
      (n=5) caused an injury grade of 1 (i.e., no irritation*) on a scale from 1 to 10
      (Smy62).
           The committee did not find data from sensitisation studies on pentan-2-one.
           With respect to the respiratory tract, de Ceaurriz et al. studied the sensory
      irritation of pentan-2-one in the upper part of the respiratory tract by determining
      the concentration associated with a 50% decrease in the respiratory rate (RD50).
*     Grade 1 was also characterised as giving rise to ‘the least visible capillary injection’ (Smy54).
136-5 Pentan-2-one
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<pre>      Using male Swiss OF1 mice, the RD50 for pentan-2-one was calculated to be
      5915 ppm (i.e., 21,235 mg/m3) (DeC84). Using male Ssc:CF1 mice, Hansen and
      Nielsen estimated the RD50 from a 10-minute period to be 12,832 ppm (ca.
      46,100 mg/m3); the RD0 values, i.e., the mean threshold level causing a decrease
      in respiration rate, from the periods 0-2 and 11-20 minutes were 970 and 564
      ppm (2405 and 2025 mg/m3), respectively (Han94).
      Acute toxicity
      Rats could tolerate exposure to a concentrated, probably saturated*,
      concentration of pentan-2-one without mortality occurring for a maximum of 30
      minutes. Exposure to 2000 or 4000 ppm (71,800 or 143,600 mg/m3), for 4 hours,
      caused mortality in 1/6 and 6/6 (male Carworth-Wistar) rats, respectively
      (observation time: 14 days) (Smy62).
           De Ceaurriz et al. examined the neurobehavioral properties of pentan-2-one
      in mice (male Swiss OF1) using the ‘behavioural despair’ swimming test. This
      bioassay is based on the finding that rodents that are forced to swim in a
      restricted space exhibit vigorous escape-directed activity during the first minute,
      then a transient period of swimming activity and mobility, and, after 3 minutes, a
      state of complete immobility. Exposure to concentrations of 976, 1180, 1549, and
      1965 ppm (ca. 3500-7000 mg/m3), for 4 hours, caused a dose-dependent decrease
      in the duration of immobility measured over a 3-minute period being statistically
      significant at 1180 ppm (ca. 4240 mg/m3). The ID50, i.e., the concentration
      responsible for a 50% decrease in immobility (compared to control values), was
      calculated to be 1348 ppm (ca. 4840 mg/m3; 95% confidence interval: 1243-1454
      ppm) (DeC84).
           Yant et al. exposed guinea pigs to concentrations of pentan-2-one of 0, 1500,
      5000, 13,000, or 50,000 ppm (0, 5370, 17,900, 46,540, or 179,000 mg/m3)** for
      up to 13.5 hours. No abnormal signs or symptoms were observed in controls and
      animals exposed to 1500 ppm (5370 mg/m3). At 5000 ppm (17,900 mg/m3), nasal
      and eye irritation occurred within 3 minutes, lachrymation within 5 minutes,
      incoordination within 4.5 hours, and unconsciousness within about 8 to 12 hours,
      followed closely by dyspnoea, but all animals survived. The time of onset for all
      symptoms decreased rapidly with increasing pentan-2-one concentration, and
      mortality was observed at exposure to 13,000 and 50,000 ppm (46,540 and
*     Theoretically (at 25oC), the concentration in saturated atmosphere can amount to 21,000 ppm or 73,920 mg/m3
      (calculated from: vapour pressure in Pa/105 Pa x 106 ppm).
**    Since the saturated concentration of pentan-2-one at 25oC is 21,000 ppm (73,920 mg/m3), animals may have been
      exposed to aerosols/particulates at the higher levels.
136-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      17,9000 mg/m3) for 300 and 50 minutes, respectively. Animals that died during
      exposure exhibited slight congestion of the brain and marked congestion of the
      systemic organs, including the lungs, which were also emphysematous and
      oedematous, while in the animals with marked incoordination, dyspnoea, and
      narcosis, only little or no and slight to moderate congestion were seen in the
      brain and in the lungs, liver, and kidneys, respectively, at post-mortem
      examinations immediately after the end of exposure. No gross abnormalities
      were found in animals exposed for 30 and 90 minutes and 4.5 hours to 5000 ppm
      (17,900 mg/m3) or for 4.5 and ca. 8 hours to 1500 ppm (5370 mg/m3) and killed
      for necropsy 4-8 days after ending exposure (Yan36; see NIO78).
          A dermal LD50 of 8 mL/kg bw (6,472 mg/kg bw) was estimated in rabbits
      (Smy62). Oral LD50 values of 3730 and 3018 mg/kg bw were reported in rats
      (Hen59, Smy62).
      Repeated-dose toxicity
      The committee did not find data on the toxic effects (including carcinogenicity
      and reproduction toxicity) of pentan-2-one following repeated inhalation or oral
      exposure.
          In rats subcutaneously injected with pentan-2-one doses of 344 mg/kg
      bw/day and equimolar doses of hexan-2-one, 5 days/week, for 20 weeks,
      decreases in body weight were greater, weakness of the hind legs more severe,
      and alertness and resistance on handling less than in a group treated with hexan-
      2-one only. The maximum motor fibre conduction velocity and the motor distal
      latency period, measured in the tail nerves every 2 weeks, were increased and
      decreased, respectively, to a statistically significantly greater extent than in the
      hexan-2-one group (Mis85). This experiment indicated that combined exposure
      of pentan-2-one and hexan-2-one may induce aggravation of the effects on the
      peripheral nervous system and probably also on the central nervous system.
      Mutagenicity and genotoxicity
      Pentan-2-one induced mitotic chromosomal malsegregation (aneuploidy), but no
      mitotic recombination or point mutations when tested in S. cerevisiae strain
      D61.M (Zim85, Zim89).
          The committee did not find data from other in vitro or in vivo mutagenicity or
      genotoxicity assays.
136-7 Pentan-2-one
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<pre>7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for pentan-2-one
      in the Netherlands is 700 mg/m3 (200 ppm), 8-hour TWA.
          Existing occupational exposure limits for pentan-2-one in various countries
      are summarised the annex.
8     Assessment of health hazard
      In human volunteers, the threshold for eye irritation was about 35,900 mg/m3
      (10,000 ppm). The committee did not find information on systemic effects of
      pentan-2-one in humans.
          In rabbits, pentan-2-one was slightly irritating to the eyes and not irritating to
      the skin. In mice, mean threshold levels causing decreases in respiration rate
      (RD0), from the periods 0-2 and 11-20 minutes, were 970 and 564 ppm (2405 and
      2025 mg/m3), respectively. Exposure to 2000 or 4000 ppm (71,800 or 143,600
      mg/m3), for 4 hours, caused mortality in 1/6 and 6/6 male rats, respectively
      (observation time: 14 days). When mice were exposed to concentrations of 976,
      1180, 1549, and 1965 ppm (ca. 3500-7000 mg/m3), for 4 hours, there was a dose-
      dependent effect in the ‘behavioural despair’ swimming test being statistically
      significant at 1180 ppm (ca. 4240 mg/m3) and higher. No effects were reported in
      guinea pigs exposed to 5000 ppm (5370 mg/m3) for up to 13.5 hours. Exposure
      to 5000 ppm (17,900 mg/m3) caused nasal and eye irritation (within 3 minutes),
      incoordination (within 4.5 hours), and unconsciousness and dyspnoea (after 8
      hours); concentrations of 13,000 ppm (46,540 mg/m3) were lethal. The dermal
      LD50 was 6472 mg/kg bw for rabbits; the oral LD50 values 3018 and 3730 mg/kg
      bw for rats.
          The committee did not find data on the toxic effects (including
      carcinogenicity and reproduction toxicity) of pentan-2-one following repeated
      inhalation or oral exposure.
          Pentan-2-one induced mitotic chromosomal malsegregation (aneuploidy),
      but no mitotic recombination or point mutations when tested in S. cerevisiae. The
      committee did not find data from other in vitro or in vivo mutagenicity or
      genotoxicity assays.
      The committee considers the toxicological database on pentan-2-one too poor to
      justify recommendation of a health-based occupational exposure limit.
136-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       The committee concludes that there is insufficient information to comment on
       the present MAC-value.
       References
ACG98  American Conference of Governmental Industrial Hygienists (ACGIH). Methyl acetylene. In:TLVs®
       and other occupational exposure values - 1998. [CD-ROM]. Cincinnati OH, USA; ACGIH®, 1998.
ACG04a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2004. Cincinnati OH, USA: ACGIH®, 2004: 112.
ACG04b American Conference of Governmental Industrial Hygienists (ACGIH). 2004 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, 2004: 40.
Amo83  Amoore JF, Hautala E. Odor as an aid to chemical safety: odor thresholds compared with threshold
       limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol
       1983; 3: 272-290.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 34 (At-vejledning C.0.1).
Car46  Carpenter CP, Smyth HF Jr. Chemical burns of the rabbit cornea. Am J Ophthalmol 1946; 29: 1363-
       72.
Com95  Cometto-Muñiz JE, Cain WS. Relative sensitivity of the ocular trigeminal, nasal trigeminal and
       olfactory systems to airborne chemicals. Chem Senses 1995; 20: 191-198.
DeC84  De Ceaurriz J, Micillino JC, Marginac B, et al. Quantitative evaluation of sensory irritating and
       neuro-behavioural properties of aliphatic ketones in mice. Food Chem Toxicol 1984; 22: 545-549.
DFG04  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2004. Maximum
       concentrations and Biological Tolerance Values at the workplace Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2004: 94 (rep no 40).
EC04   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs); http://europe.eu.int/comm/employment_social/health_safety/areas/
       oels_en.htm.
Hag45  Haggard HW, Miller DP, Greenberg LA. The amyl alcohols and their ketones: their metabolic fates
       and comparative toxicities. J Ind Hyg Toxicol 1945; 27: 1-14.
Han94  Hansen LF, Nielsen GD. Sensory irritation and pulmonary irritation of n-methyl ketones: receptor
       activation mechanisms and relationships with threshold limit values. Arch Toxicol 1994; 68: 193-
       202.
Hen59  Henson EV. Toxicology of some aliphatic ketones. J Occup Med 1959; 1: 607-613.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 23.
136-9  Pentan-2-one
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<pre>Kum99  Kumagai S, Oda H, Matsunaga I, et al. Uptake of 10 polar solvents during short-term respiration.
       Toxicol Sci 1999; 48: 255-63.
Mis85  Misumi J, Nagano M. Experimental study on the enhancement of the neurotoxicity of methyl n-butyl
       ketone by non-neurotoxic aliphatic monoketones. Br J Ind Med 1985; 42: 155-161.
NIO78  US National Institute for Occupational Safety and Health (NIOSH). Criteria for a recommended
       standard. Occupational exposure to ketones. Cincinnati OH, USA : US Dept of Health, Education,
       and Welfare, Public Health Service, Center for Disease Control, NIOSH, 1978; DHEW (NIOSH)
       Publication No 78-173.
NLM04  US National Library of Medicine (NLM), ed. Methyl propyl ketone. In: The Hazardous Substances
       Data Bank (HSDB) (last revision date pentan-2-one file: October 2002; last review date: September
       1997); http://toxnet.nlm.nih.gov.
Rut86  Ruth JH. Odor thresholds and irritation levels of several chemical substances: a review. Am Ind Hyg
       Assoc J 1986; 47: A142-51.
Smy54  Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data. List V. AMA Arch Ind Hyg
       Occup Med 1954; 10: 61-8.
Smy62   Smyth HF Jr, Carpenter CP, Weil CS, et al. Range-finding toxicity data. List VI. Am Ind Hyg Assoc
       J 1962; 23: 95-107.
Spe40  Specht H, Miller JW, Valaer PJ, et al. Acute response of guinea pigs to the inhalation of ketone
       vapours. Cincinnati OH, USA: National Institute of Health, 1940; NIH Bulletin No 176 (cited in
       NIO78).
Swe00  Swedish National Board of Occupational Safety and Health. Occupational exposure limit values and
       measures against air contaminants. Solna, Sweden: National Board of Occupational Safety and
       Health, 2000; Ordinance AFS 2000:3.
SZW04  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2004. The Hague,
       the Netherlands: Sdu Uitgevers, 2004: 37.
TRG04  TRGS 900. Technische Regeln für Gefahrstoffe. Grenzwerte in der Luft am Arbeitsplatz. BArbBl
       2004; (7/8).
Yan36  Yant WP, Patty FA, Schrenk HH. Acute response of guinea pigs to vapors of some new commercial
       organic compounds IX. Pentanone (methyl propyl ketone). Public Health Rep 1936; 51: 392-9; cited
       in NIO78 and NIOSHTIC.
Zim85  Zimmermann FK, Mayer VW, Scheel I, et al. Acetone, methyl ethyl ketone, ethyl acetate, acetonitrile
       and other polar aprotic solvents are strong inducers of aneuploidy in Saccharomyces cerevisiae.
       Mutat Res 1985; 149: 339-51.
Zim89  Zimmermann FK, Scheel I, Resnick MA. Induction of chromosome loss by mixtures of organic
       solvents including neurotoxins. Mutat Res 1989; 224: 287-303.
136-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for pentan-2-one in various countries.
country                            occupational               time-weighted       type of exposure notea      referenceb
- organisation                     exposure limit             average             limit
                                   ppm        mg/m3
the Netherlands
- Ministry of Social Affairs and 200          700             8h                  administrative              SZW04
Employment
Germany
- AGS                              200        710             8h                                              TRG04
                                   800        2840            15 min
- DFG MAK-Kommission               -c         -c                                                              DFG04
Great-Britain
- HSE                              200        716             8h                  OES                         HSE02
                                   250        895             15 min
Sweden                             -          -                                                               Swe00
Denmark                            200        700             8h                  OEL                         Arb02
USA
- ACGIH                            200        -               8h                  TLV                         ACG04b
                                   250        -               15 min              STEL
- OSHA                             200        700             8h                  PEL                         ACG04a
- NIOSH                            150        530             10 h                REL                         ACG04a
European Union
- SCOEL                            -          -                                                               EC04
a
     S = skin notation; which 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
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
136-11        Pentan-2-one
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<pre>136-12 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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