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<pre>      Ketene
      (CAS reg no: 463-51-4)
      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/024, The Hague, 13 November 2001
024-1
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<pre>      Preferred citation:
      Health Council of the Netherlands: Committee on Updating of Occupational
      Exposure Limits. Ketene; Health-based Reassessment of Administrative
      Occupational Exposure Limits. The Hague: Health Council of the Netherlands,
      2001; 2000/15OSH/024.
      all rights reserved
024-2
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of ketene 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 H Stouten, M.Sc. (TNO Nutrition and Food Research, Zeist, the Netherlands).
           The evaluation of the toxicity of ketene has been based on the review by the
      American Conference of Governmental Industrial Hygienists (ACG99). Where
      relevant, the original publications were reviewed and evaluated as will be
      indicated in the text. In addition, literature was retrieved from the online data
      bases Medline, Toxline, and Chemical Abstracts covering the period 1966 until
      26 April 1999 (19990426/UP), 1965 until 29 January 1999 (19990129/ED), and 1967
      until 24 April 1999 (19990424/ED; vol 130, iss 18), respectively, and using the
      following key words: ketene, carbomethene, and 463-51-4. HSDB and RTECS,
      data bases available from CD-ROM, were consulted as well (NIO99, NLM99). The
      final literature search has been carried out in April 1999.
           In April 2001, the President of the Health Council released a draft of the
      document for public review. The committee received no comments.
2     Identity
       name                           :     ketene
       synonyms                       :     carbomethene; ethenone; keto-ethylene
       molecular formula              :     C2H2O
       structural formula             :     H2C=C=O
       CAS reg no                     :     463-51-4
      Data from ACG99, NLM99.
024-3 Ketene
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<pre>3     Physical and chemical properties
      molecular weight             :     42.02
      boiling point                :     -56 oC
      melting point                :     -151 oC
      flash point                  :     -
      vapour pressure              :     at 25 oC: 1.4 x 103 kPa ('calculated from
                                         experimentally derived coefficients')
      solubility in water          :     reacts forming acetic acid
      log P octanol/water          :     -0.52 (estimated)
      conversion factors           :     1 ppm = 1.8 mg/m 3
      (20 oC, 101.3 kPa)                 1 mg/m 3 = 0.57 ppm
      Data from ACG99, NLM99, http://esc.syres.com.
      Ketene is a colourless gas with a sharp, penetrating odour. It is an unstable,
      readily polymerising compound, and cannot be stored in the gaseous state.
4     Uses
      Ketene is used as an acetylating agent in chemical synthesis, especially of acetic
      acid and acetate esters (ACG99).
5     Biotransformation and kinetics
      The committee did not find data on the kinetics of ketene.
6     Effects and mechanism of action
      Human data
      Ketene was one out of 21 chemicals selected as a suspect chemical in a nested
      case-control study of non-Hodgkin’s lymphoma (52 cases), multiple myeloma (20
      cases), and lymphocytic and nonlymphocytic leukaemias (18 and 39 cases, resp)
      among a cohort of approximately 29,000 men employed at two chemical
      manufacturing facilities and one research and developmental centre. Based on
      only one case each, odds ratios of 1.3, 2.6, and 1.7 were calculated for
024-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      non-Hodgkin’s lymphoma, multiple myeloma, and nonlymphocytic leukaemia,
      respectively. However, due to this limited number of cases and potential
      exposure to other compounds, no conclusions can be drawn with respect to an
      aetological role of ketene (Ott89).
          The committee did not find other data on workers occupationally exposed to
      ketene.
      Animal data
      Single exposure
      For male mice, a 10-minute inhalation LC50 of 30 mg/m3 (16.5 ppm) has been
      estimated (observation time: 10 days) (Men59).
          Generally, higher inhalation concentrations were found to induce mortality in
      experiments conducted in the thirties and fourties, probably because analytical
      measurement methods were less accurate (Men59) or even not available (Tre49)
      in those days. All mice (number not reported) exposed by inhalation to 180
      mg/m3 (100 ppm), for 5 minutes, died within 1 to 4 hours. Five-minute exposures
      to 360-540 mg/m3 (200-300 ppm) killed all mice, rats, and guinea pigs (numbers not
      reported), within ca. 1/2-1, 2, and 2-4 hours, respectively (Cam37). When exposed
      for 10 minutes, inhalation concentrations of 210 and 430 mg/m3 (120, 245 ppm)
      were lethal to 0/4 and 4/4 rats, respectively (observation time: 10 days). In mice,
      mortality rates were 20/20 and 18/20 following exposures to 120 and 210 mg/m3
      (68, 120 ppm), respectively; in guinea pigs, these rates were 3/4 and 4/4 at 630
      and 1070 mg/m3 (359, 610 ppm), respectively (observation time: 3 days) (Woo47).
      Using exposure periods of 10 minutes as well, Treon et al. found inhalation
      concentrations of 45, 90, 450, 675, 360, and 1350 mg/m3 (25, 50, 250, 375, 200, 750
      ppm) to be non-lethal in mice (n=10), monkeys (n=1), rats (n=2), guinea pigs
      (n=2), cats (n=1), and rabbits (n=2), respectively; corresponding minimum lethal
      concentrations were 90, 360, 675, 900, 1350, and 1800 mg/m3 (50, 200, 375, 500,
      750, 1000 ppm), respectively (Tre49).
          Generally, there were only minor signs of irritation, and - mostly after a
      latency period of variable duration - laboured breathing, jerky clonic movements,
      and coma were seen; the animals died from respiratory failure with intense
      pulmonary oedema and marked capillary ingestion (Cam37, Tre49, Woo47).
          Pre-exposure to non-lethal levels of ketene (in excess of 9 mg/m3 or 5 ppm) for
      10 minutes or to ozone protected mice against otherwise lethal concentrations of
      ketene or ozone at exposure 3 to 14 days later (Men59).
024-5 Ketene
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<pre>      Repeated exposure
      Following two 4-hour inhalation exposures to 41 mg/m3 (23 ppm) mortality rates
      were 0/2, 0/1, 10/10, 2/2, and 4/4 in rats, monkeys, mice, guinea pigs, and rabbits,
      respectively, while two 6.5-hour exposures to this level were lethal to 2/2 rats and
      2/4 rabbits (other species not tested). When exposed to 22 mg/m3 (12 ppm), 6
      hours/day (except for day 1 and 2 with 4.5 and 5.5 hours, resp), 5 days/week, for
      3 weeks, 4/7 mice, 1/2 rats, and 4/4 rabbits died. Rats (n=2/group), guinea pigs
      (n=2/group), and monkeys (n=1/group) survived exposure to 1.8 mg/m3 (1 ppm),
      7 hours/day, 5 days/week, for 14 or 55 days. In mice, survival rates were 9/10
      each for both exposure periods, and in rabbits, 4/4 and 2/5 for the 14- and 55-day
      period, respectively. No apparent injury was observed in the surviving animals
      (Tre49). In view of the limited number of animals exposed and the statement of
      the authors that they did not have an analytical method at their disposal to
      determine actual concentrations, the significance of the results of these
      experiments cannot be assessed.
      Mutagenicity and genotoxicity
      Ketene did not induce back-mutations in Neurospora (Jen52).
          Referring to a paper published in 1947, ketene was stated to produce positive
      results when tested in Drosophila (no details presented) (Jen52).
      No data on carcinogenicity or reproduction toxicity of ketene have been found.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for ketene in the
      Netherlands is 0.9 mg/m3 (0.5 ppm), 8-hour TWA.
          Existing occupational exposure limits for ketene in some European countries
      and in the USA are summarised in the annex.
8     Assessment of health hazard
      From acute inhalation data from animal experiments (10-min LC50 in mice: 30
      mg/m3 or 16.5 ppm), the committee concludes that ketene is a very toxic
      compound. Acute exposures caused respiratory tract irritation and animals died
      from respiratory failure with severe pulmonary oedema.
024-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>           Ketene was found to be negative in an in vitro mutagenicity test in fungi and
       positive in a Drosophila-test.
           The committee did not find data from valid repeated exposure toxicity studies
       (including the potential carcinogenicity and reproduction toxicity) or from
       genotoxicity tests in bacterial and mammalian cell systems in vitro or in mammals
       in vivo.
       The committee considers the toxicological data base on ketene too poor to
       justify recommendation of a health-based occupational exposure limit.
       The committee concludes that in view of the acute toxicity data the present
       MAC-value of 0.9 mg/m3 (0.5 ppm), as an 8-hour TWA, for ketene is too high.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). Ketene. In: TLVs ®
       and other occupational exposure values -1999. [CD-ROM]. Cincinnati OH, USA; ACGIH® ,
       1999.
ACG00  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2000. Cincinnati OH, USA: ACGIH® , Inc, 2000: 70.
ACG01  American Conference of Governmental Industrial Hygienists (ACGIH). 2001 TLVs ® and
       BEIs® . Threshold Limit Values for chemical substances and fysical agents. Biological
       Exposure Indices. Cincinnati OH, USA: ACGIH® , Inc, 2001: 37.
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.
Cam37  Cameron GR, Neuberger A. Ketene as noxious gas. J Pathol Bacteriol 1973; 45: 653-60.
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.
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: 69 (rep no 37).
024-7  Ketene
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<pre>HSE01 Health and Safety Executive (HSE). EH40/2001. Occupational Exposure Limits 2001.
      Sudbury (Suffolk), England: HSE Books, 2001: 20.
Jen52 Jensen KA, Kirk I, Kølmark G, et al. Chemically induced mutations in Neurospora. Cold
      Spring Harbor Symp Quant Biol 1952; 16: 245-61.
Men59 Mendenhall RM, Stokinger HE. Tolerance and cross-tolerance development to atmospheric
      pollutants ketene and ozone. J Appl Physiol 1959; 14: 923-6.
NIO99 National Institute of Occupational Safety and Health (NIOSH). Ketene. In: Registry of Toxic
      Effects of Chemical Substances (RTECS) [CD-ROM], issue July 1999. SilverPlatter
      International, 1999 (last update ketene file: July 1999).
NLM99 US National Library of Medicine (NLM). Ketene. In: Hazardous Substances Data Bank
      (HSDB). [CD-ROM], issue July 1999. SilverPlatter International, 1999 (last update ketene
      file: January 1999).
Ott89 Ott MG, Teta J, Greenberg HL. Lymphatic and hematopoietic tissue cancer in a chemical
      manufacturing environment. Am J Ind Med 1989; 16: 631-43.
SZW01 Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2001. The
      Hague, The Netherlands: Sdu, Servicecentrum Uitgevers, 2001: 31.
Tre49 Treon JF, Sigmon HE, Kitzmiller KV, et al. Physiological response of animals exposed to
      air-borne ketene. J Ind Hyg Toxicol 1949; 31: 209-19.
TRG00 TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe.
      BArbBl; 2000; 2.
Woo47 Wooster HA, Lushbaugh CC, Redemann CE. The inhalation toxicity of ketene and ketene
      dimer. J Ind Hyg Toxicol 1947; 29: 56-7.
024-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            Annex
Occupational exposure limits for ketene in various countries.
country                       occupational                    time-weighted type of exposure    notea    lit refb
-organisation                 exposure limit                  average        limit
                              ppm            mg/m 3
The Netherlands
- Ministry                    -              0.9              8h             administrative              SZW01
Germany
- AGS                         0.5            0.9              8h                                         TRG00
                              0.5            0.9              15 min
- DFG MAK-Kom.                -              -c                                                          DFG01
Great Britain
- HSE                         0.5            0.87             8h             OES                         HSE01
                              1.5            2.6              15 min
Sweden                        -              -                                                           Arb00b
Denmark                       0.5            0.9              8h                                         Arb00a
USA
- ACGIH                       0.5            -                8h             TLV                         ACG01
                              1.5            -                15 min         STEL
- OSHA                        0.5            0.9              8h             PEL                         ACG00
- NIOSH                       0.5            0.9              10 h           REL                         ACG00
                              1.5            3                15 min         STEL
European Union
- SCOEL                       -              -                                                           CEC00
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 substances for which studies of the effects in man or in experimental animals have yielded
     insufficient information for the establishment of MAK values
024-9       Ketene
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