<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-3-one
(CAS No: 96-22-0)
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/107, The Hague, March 30, 2004
</pre>

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

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

<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Pentan-3-one; Health-based Reassessment of Administrative
Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
2004; 2000/15OSH/107.
all rights reserved
</pre>

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

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

<pre>1     Introduction
      The present document contains the assessment of the health hazard of pentan-3-
      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 December 1997, literature was searched in the databases Medline and
      Chemical Abstracts (starting from 1966 and 1970, respectively), as well as
      Poltox (from 1994 backwards), HSELINE, CISDOC, MHIDAS, and NIOSHTIC
      (from 1997 backwards), and using the following key words: diethyl ketone,
      pentanone, dimethylacetone, and 96-22-0.
           In March 2000, the President of the Health Council released a draft of the
      document for public review. The committee received comments by the following
      individuals and organisations: A Aalto (Ministry of Social Affairs and Health,
      Tampere, Finland), P Wardenbach, Ph.D. (Bundesanstalt für Arbeitsschutz and
      Arbeitsmedizin. Dortmund, FRG), and L Whitford (Health and Safety Executive,
      London, England). These comments were taken into account when deciding on
      the final version of the document.
           An additional search in Toxline and Medline in September 2003 did not
      result in information changing the committee’s conclusions.
2     Identity
      Name                     :   pentan-3-one
      synonyms                 :   3-pentanone; pentanone-3; diethyl ketone; dimethylacetone;
                                   methacetone
      molecular formula        :   C5H10O
      Structure                :   CH3-CH2-CO-CH2-CH3
      CAS number               :   96-22-0
107-3 Pentan-3-one
</pre>

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

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

<pre>3     Physical and chemical properties
      molecular weight           :   86.1
      boiling point              :   102oC
      melting point              :   -42oC
      flash point                :   13oC (open cup)
      vapour pressure            :   at 25oC : 2.0 kPa
      solubility in water        :   slightly soluble (at 20oC: 4.7 g/100 mL)
      log Poctanol/water         :   0.99 (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 NLM03, http://esc.syrres.com.
      Pentan-3-one is a colourless, mobile liquid, with a acetone-like odour (ACG96).
      Odour thresholds of 7 (2 ppm) (Amo03) and ranging between 3 and 49 mg/m3
      (0.8 and 14 ppm) (Rut86) were reported.
4     Uses
      Pentan-3-one is used as a solvent and in organic synthesis (ACG96).
5     Biotransformation and kinetics
      The committee did not find data on the biotransformation and kinetics of pentan-
      3-one in humans or experimental animals
6     Effects and mechanism of action
      Human data
      Threshold concentrations for eye (subjectively) and lung (objectively by
      plethysmograph) response were determined by applying various concentrations
      of pentan-3-one to the eyes of (an unknown number of) subjects through close-
      fitting goggles and, in separate experiments, to the lungs via mouthpiece. No
      numbers were presented, but from a graph, the committee estimates that the
      thresholds for respiratory and eye irritation were roughly 400 and 800 ppm (ca.
      1440 and 2870 mg/m3), respectively (Dou87).
107-4 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>           The committee did not find other human data on effects from (occupational)
      exposure to pentan-3-one.
      Animal data
      Irritation and sensitisation
      Following instillation into the eyes of rabbits (n=5), pentan-3-one scored an
      injury grade of 4 (i.e., 0.02 mL of undiluted test substance gives injury up to 5.0
      points, or 0.1 mL over 5 points) on a scale from 1 to 10 (Smy54; see also Car46).
      Moderate irritation was reported when 50 mg or 100 mg (for 24 hours) was
      instilled into the eyes of rabbits (no details presented) (NIO03).
           Application of 0.01 mL undiluted pentan-3-one to the clipped skin of rabbits
      (n=5) caused an injury grade of 2 (i.e., ‘the least visible capillary injection from
      undiluted compound’) on a scale from 1 to 10 (Smy54; see also Smy62). Mild
      irritation was reported following application of 410 mg in an open irritation test
      or of 500 mg for 24 hours (no details presented) (NIO03).
      Acute toxicity
      Rats could tolerate exposure to a concentrated, probably saturated*,
      concentration of pentan-3-one without mortality occurring for a maximum of 15
      minutes. When exposed to 28,700 mg/m3 (8000 ppm) for 4 hours, 4/6 (male
      Carworth-Wistar) rats died within 14 days (Smy54). Dermal LD50 values were 20
      mL/kg bw (i.e., 16,300 mg/kg bw) in rabbits (Smy54) and 2100 mgkg bw in rats
      (NIO03). Oral LD50 values in rats and mice were 2140 (95% confidence limits:
      1540-2990 mg/kg bw; observation time: 14 days) (Smy54) and 3200 mg/kg bw
      (no details) (NIO03), respectively. Following intravenous injections into mice,
      LD50 and LD100 values of 514 and 1149 mg/kg bw, respectively, were estimated
      (Jep75).
           In a study to explore the relationship between lipophilicity (log Poctanol/water)
      and biological activity (anaesthetic - AD100 - and lethal - LD50, LD100 - doses) of
      classes of compounds (aliphatic hydrocarbons, ethers, ketones), continuous
      intravenous infusion of pentan-3-one into mice resulted in a mean AD100 (i.e., the
      dosis needed for complete loss of righting reflex) of 390 mg/kg bw (95%
      confidence limits: 338-445 mg/kg bw) (Jep75).
*     Theoretically, the concentration in saturated atmosphere can amount to 20,000 ppm or 71,800 mg/m3 (calculated
      from: vapour pressure in Pa/105 Pa x 106 ppm).
107-5 Pentan-3-one
</pre>

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

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

<pre>      Repeated-dose toxicity
      The committee did not find data from repeated inhalation studies on 3-pentanone
      in experimental animals.
      Oral administration (gavage) of doses of 10 mg/kg bw/day of 3-pentanone to
      male Sprague-Dawley rats (n=8) for 16 days caused a decrease in body weight
      (by 7%; p=0.1) when compared to controls. Serum cholesterol values were 104,
      81 (p=0.1), and 93% of control values measured at treatment days 4, 10, and 16,
      respectively (Car75).
          In preliminary studies, pentan-3-one given to female Wistar rats (n=5/group)
      at concentrations of 1.0% (estimated by Homan and Weil to be equivalent to 634
      mg/kg bw/day) for 7 days caused decreased body weight gains (by ca. 80%)
      accompanied by decreased food (by ca. 15%) and water (by ca. 30%)
      consumption. Gross post-mortem examination revealed pale or mottled kidneys
      in both treated and control animals. No effects were seen following
      administration of 0.5 % (estimated to be equivalent to 450 mg/kg bw) (Hom77).
      In the subsequent definitive study, 5 female Wistar rats were given oral (2.4% in
      drinking water) doses of pentan-3-one equivalent to 1860 mg/kg bw/day for 120
      days. After exposure days 46, 57, 80, and 110, rats were submitted to 10
      neurological tests examining balance, strength, coordination, and behaviour.
      Post-mortem examinations included liver and kidney weight determinations and
      gross, histopathological, and neuropathological evaluations. Results were
      compared with those from 2 control groups of 5 animals each, receiving tap
      water only. Pentan-3-one treatment caused a statistically significant decrease in
      body weight gain (by ca. 40%), accompanied by decreased food (by ca. 3-13%)
      and water (by ca. 30-40%) consumption. Performance in neurological testing
      was not impaired at any of the test days. Upon post-mortem examinations, livers
      were not affected, but there were statistically significant increases in relative and
      absolute kidney weights, which were not accompanied by gross or histological
      changes. There were no significant gross lesions in any of the other organs
      examined, and there was no evidence of sciatic nerve neuropathy or skeletal
      muscle atrophy (Hom77, Mar77).
      Mutagenicity and genotoxicity
      Pentan-3-one induced mitotic chromosomal malsegregation (aneuploidy), low
      levels of mitotic recombination, and, possibly, point mutations when tested in S.
      cerevisiae strain D61.M at concentrations of 0.99, 1.23, and 1.48% (Zim85).
107-6 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>      Reproduction toxicity
      Seven female CF1 mice were given daily intraperitoneal injections of 50
      mg/kg bw of 3-pentanone for 28 days. From treatment day 10 onwards, they
      were mated with untreated males (2 females per male; males rotated every 5th
      day). At treatment day 28, females were sacrificed, and the number of
      pregnancies, viable fetuses, reabsorptions, and dead fetuses were recorded. In the
      3-pentanone-treated animals, there were decreases in the number of pregnant
      animals (by 13%) and in the average number of fetuses per litter (by 14%) and an
      increase in the number of reabsorption sites per litter (5.4 fold) when compared
      with controls (n=62) (Car75; see also Hal74).
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for pentan-3-one
      in the Netherlands is 705 mg/m3 (200 ppm), 8-hour TWA
          Existing occupational exposure limits for this substance in some European
      countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      The committee did not find data on the toxicokinetics of pentan-3-one in humans
      or experimental animals.
          From a human volunteer study, the threshold concentrations for eye and
      respiratory irritation were roughly 1440 and 2870 mg/m3 (400 and 800 ppm),
      respectively. The committee did not find other human data on effects from
      (occupational) exposure to pentan-3-one.
          In experimental animals, pentan-3-one was moderately irritating to the eyes
      and mildly irritating to the skin of rabbits. A 4-hour exposure to 28,700 mg/m3
      (8000 ppm) was lethal to 4/6 male rats. Dermal LD50 values were 16,300 and
      2100 mg/kg bw in rabbits and rats, respectively; oral LD50 values were 2140 and
      3200 mg/kg bw in rats and mice, respectively.
          When female rats were orally (2.4% in drinking water) exposed to doses of
      pentan-3-one equivalent to 1860 mg/kg bw/day – the only dose tested - for 120
      days, there were decreases in body weights (by ca. 40%), which was
      accompanied by decreases in food and water consumption, and increases in
      relative and absolute kidney weights, which were not accompanied by gross or
      histological changes, while the livers were not affected. Performance in
107-7 Pentan-3-one
</pre>

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

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

<pre>       neurological testing was not impaired and there was no evidence of sciatic nerve
       neuropathy or skeletal muscle atropy.
            The committee did not find relevant data from other repeated-dose toxicity
       studies, including carcinogenicity and reproduction toxicity.
            In an in vitro mutagenicity test, diethyl ketone caused chromosomal
       malsegregation (aneuploidy) and low levels of mitotic recombination and,
       possibly, point mutations. The committee did not find data from other
       genotoxicity studies on pentan-3-one.
       The committee considers the toxicological database on pentan-3-one 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
ACG96  American Conference of Governmental Industrial Hygienists (ACGIH). Diethyl ketone. In: TLVs
       and other occupational exposure values - 1996 [CD-ROM, version 1.7-s4 02/01/95]. Cincinnati OH,
       USA: ACGIH®, Inc, 1996.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 47.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 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®, Inc, 2003: 27.
Amo83  Amoore JE, 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: 272-90.
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.
Car75  Carlson GL, Hall IH, Piantadosi C. Cycloalkanones. 7. Hypocholesterolemic activity of aliphatic
       compound related to 2,8-dibenzylcyclooctanone. J Med Chem 1975; 18: 1024-6.
DFG03  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2003. Maximum
       concentrations and biological tolerance values at the workplace. Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2003; rep no 39.
107-8  Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>Dou87 Douglas RB, Coe JE. The relative sensitivity of the human eye and lung to irritant gases. Ann Occup
      Hyg 1987; 31: 265-7.
EC03  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.
Hal74 Hall IH, Carlson GL, Abernethy GS, et al. Cycloalkanones. 4. Antifertility activity. J Med Chem
      1974; 17: 1253-7.
Hom77 Homan ER, Weil CS. Comparative toxicity to rats of methoxyacetone and five other aliphatic
      ketones in their drinking water. Pittsburgh PA, USA: Carnegie-Mellon University, Carnegie-Mellon
      Institute of Research, 1977; project report 40-37 (available from the National Technical Information
      Service, Springfield VA, USA; order no NTIS/OTS0206068).
HSE02 Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
      (Suffolk), UK: HSE Books, 2002: 23.
Jep75 Jeppsson R. Parabolic relationship between lipophilicity and biological activity of aliphatic
      hydrocarbons, ethers and ketones after intravenous injections of emulsion formulations into mice.
      Acta Pharmacol Toxicol 1975; 37: 56-64.
Mar77 Maronpot RR. Comparative pathology on rats given methoxyacetone and five other aliphatic ketones
      in drinking water (ketone neurotoxicity). Pittsburgh PA, USA: Carnegie-Mellon University,
      Carnegie-Mellon Institute of Research, 1977; project report 40-146 (available from the National
      Technical Information Service, Springfield VA, USA; order no NTIS/OTS0206068).
NIO03 US National Institute for Occupational Safety and Health (NIOSH), ed. 3-Pentanone. In: Registry of
      Toxic Effects of Chemical Substances (RTECS) (last update pentan-3-one file: October 2002); http://
      www.cdc.gov/niosh.
NLM03 US National Library of Medicine (NLM), ed. 3-Pentanone. In: Hazardous Substances Data Bank
      (HSDB) (last revision data pentan-3-one file: January 2003; 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. 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.
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.
SZW03 Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2003. The Hague,
      the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 37.
TRG00 TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
      2000; 2.
107-9 Pentan-3-one
</pre>

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

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

<pre>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.
107-10 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>              Annex
Occupational exposure limits for pentan-3-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         705              8h                  administrative            SZW03
Employment
Germany
- AGS                                  -           700              8h                                            TRG00
- DFG MAK-Kommission                   -           -                                                              DFG03
Great-Britain
- HSE                                  200         716              8h                  OES                       HSE02
                                       250         895              15 min
Sweden                                 -           -                                                              Swe00
Denmark                                200         700              8h                                            Arb02
USA
- ACGIH                                200         -                8h                  TLV                       ACG03b
                                       300         -                15 min              STEL
- OSHA                                 -           -                                                              ACG03a
- NIOSH                                200         705              8h                  REL                       ACG03a
European Union
- SCOEL                                -           -                                                              EC03
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.
107-11        Pentan-3-one
</pre>

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

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

<pre>107-12 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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

<br><br>