<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>Cyanogen chloride
(CAS No: 506-77-4)
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/116, The Hague, June 8, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Cyanogen chloride; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/116.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of cyanogen
      chloride 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 cyanogen chloride has been based on the
      review by the American Conference of Governmental Industrial Hygienists
      (ACGIH) (ACG91). Where relevant, the original publications were reviewed and
      evaluated as will be indicated in the text. In addition, in October 1997, literature
      was searched in the on-line databases Medline, Toxline, and Chemical Abstracts,
      starting from 1965, 1965, and 1967, respectively, and using the following key
      words: cyanogen chloride and 506-77-4.
           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 November 2003 did not
      result in information changing the committee’s conclusions.
2     Identity
      name                   :   cyanogen chloride
      synonyms               :   chlorcyan; chlorine cyanide; chlorocyan; chlorocyanide;
                                 chlorocyanogen
      molecular formula      :   CClN
      structural formula     :   Cl-CN
      CAS number             :   506-77-4
3     Physical and chemical properties
      molecular weight       :  61.5
      boiling point          :  13.8oC
      melting point          :  -6oC
      flash point            :  not available
      vapour pressure        :  at 25oC: 164 kPa
      solubility in water   :   soluble (at 20oC: 2500 mL in 100 mL water)
      log Poctanol/water     :  -0.39 (estimated)
      conversion factors     :  at 20oC, 101.3 kPa: 1 ppm = 2.56 mg/m3
                                                     1 mg/m3 = 0.39 ppm
      Data from ACG91, NLM03, http://esc.syrres.com.
116-3 Cyanogen chloride
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<pre>      Cyanogen chloride is a colourless liquid or gas with a pungent odour (ACG91).
      An odour threshold of 2 mg/m3 (0.8 ppm) has been reported (Rut86).
           It tends to form polymers upon storage.
4     Uses
      Cyanogen chloride is used in organic synthesis, as a poison (tear) gas by the
      military, and as a warning agent in fumigant gases and pesticides (ACG91,
      NLM03).
           According to the database of the Dutch Pesticide Authorisation Board
      (CTB)*, cyanogen chloride is at present not permitted in the Netherlands for use
      in pesticides.
5     Biotransformation and kinetics
      Based on its physico-chemical properties, it can be expected that cyanogen
      chloride will be readily absorbed after respiratory, dermal, and oral exposure.
           Cyanogen chloride reacts with haemoglobin and glutathione eventually
      liberating the CN ion. A two-step mechanism was postulated. In the first step,
      cyanogen chloride should react with a compound having vicinal amino and
      sulphydryl groups (e.g., glutathione, N-acetylcysteine, haemoglobin,
      carboxyhaemoglobin) to a cyclic compound. In the second step, reaction with
      glutathione should release HCN. Both in vitro and in vivo experiments showed
      that cyanogen chloride is very rapidly converted into HCN although not
      quantitatively. The fate of the remaining fraction has not been determined
      (Ald46, Ald51).
           Another committee of the Health Council, viz., the Dutch Expert Committee
      on Occupational Standards (DECOS), has reviewed the metabolism of cyanide in
      a criteria document on HCN, NaCN, and KCN. In summary, cyanide is
      distributed to many organs and the blood. At lethal or nearly lethal doses of these
      cyanides, relatively high concentrations were found in the liver, lungs, kidneys,
      brain, and blood. Various biotransformation pathways have been identified for
      cyanide. The most important way is the formation of thiocyanate by the
      acceptance of a sulphane-sulphur of thiosulphate or other sulphane-sulphur-
      containing compounds (transsulphurisation), the key enzyme being rhodanese.
      The rate-limiting factor of this pathway is the lack of sulphane-sulphur sources in
      the body. Cyanide is largely eliminated from the body via the urinary excretion
*     At: http://www.ctb-wageningen.nl.
116-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      of thiocyanates in the case of high exposure levels. Other minor elimination
      routes include the exhalation of carbon dioxide and traces of hydrogen cyanide.
      The relative importance of various biotransformation and elimination routes is
      unknown for lower, clearly sublethal exposure levels (Hea02).
          Cyanogen chloride was stated to be detoxified at rates of 0.03-0.06 and 0.02-
      0.04 mg/kg/min by rabbits and dogs, respectively depending on the injection
      rate. For man, the detoxification rate should be 0.02-0.1 mg/kg/min (Moo46).
6     Effects and mechanism of action
      Human data
      Limited data on human exposure are reported. They mostly originate from its use
      as a poison gas during World War I.
          The lowest irritant concentration to man was reported to be 1 ppm (2.6
      mg/m3) for a 10-minute exposure period. Exposures to 2 ppm (5.2 mg/m3) for 10
      minutes and to 20 ppm (52 mg/m3) for 1 minute were reported to be unbearable.
      Exposure to 40 ppm (104 mg/m3) should immediately induce irritation of the
      eyes and respiratory tract with blepharospasms, strong lachrymation, and tickling
      cough. Levels of 48 ppm (125 mg/m3) and 159 ppm (410 mg/m3) were stated to
      be fatal after 10 and 30 minutes exposure, respectively (cited by ACG91, Gre97,
      Har94 from probably poorly documented literature from the 1920s and 1930s;
      see e.g., Flu31).
          Unpublished information submitted to the ACGIH TLV Committee (in 1977)
      said that under occupational conditions, people had to leave work because of
      severe eye and nose irritation at concentrations of 0.7 ppm (1.8 mg/m3)
      (ACG91). From a case of chronic exposure (daily for 8 months to an unknown
      concentration), it is known that cyanogen chloride causes muscular weakness,
      lung congestion, skin irritation, hoarseness, conjunctivitis, oedema of the eyelids,
      significant weight loss, and burning urine. In a group of 10 workers with long-
      term occupational exposure to unknown levels, there were complaints of chronic
      vomiting, diarrhoea, cough, cold sensation, chronic headache, and weight loss
      (cited by ACG91 and Gre97 from a report published in 1920).
          Generally, cyanogen chloride possesses the same general type of toxicity and
      mode of action as hydrogen cyanide, but it is more irritating (Har94).
116-5 Cyanogen chloride
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<pre>            Animal data
            Cyanogen chloride was stated to cause marked irritation of the respiratory tract
            with haemorrhagic exudate from the bronchi and trachea and pulmonary oedema,
            but no exposure levels were presented (ACG91).
                 Concentrations of approximately 260 mg/m3 (100 ppm) were reported to be
            lethal to dogs, rats, and mice after 20, 37, and 60 minutes, respectively (Gre97).
            These data suggested that dogs are more sensitive than rats or mice.
                 Some toxicity data concerning acute exposure by inhalation are presented in
            Table 1.
Table 1 Summary of effects of cyanogen chloride following single exposure by inhalation (data from Flu31).
speciesa concentrationb duration     response                 species    concentration      duration    response
                         (min)                                                              (min)
         mg/m3 ppm                                                       mg/m3 ppm
                                                                                            c
mouse    200     80      5           tolerated by some        cat        1000     400                   fatal
                                     animals
         300     120     3.5         fatal to some animals    dog         50      20        20          tolerated
         1000    400     3           fatal                                120     48        360         fatal
rabbit   3000    1200    2           fatal                                300     120       8           severe injury,
                                                                                                        recovery
cat      100     40      18          fatal after 9 days                   800     320       7.5         fatal
         300     120     3.5         fatal                    goat       2500     1000      3           fatal after 70 hours
a
    Sex and number not reported.
b
    Conversion by Flury and Zernik.
c
    A ‘few inhalations’.
             For rabbits and dogs, intravenous LD50 values of 3.15 and 3.30 mg/kg bw,
            respectively, have been reported. Based on comparison with hydrogen cyanide,
            Moore and Gates felt that cyanogen chloride was as toxic by inhalation as by
            intravenous injection (Moo46).
                 The oral LD50 was 6 mg/kg for cats, with deaths occurring at about 30
            minutes (Moo46).
                 Subcutaneous doses of 5 and 20 mg/kg bw were reported to be lethal to dogs
            and rabbits, respectively (NIO03).
                 Daily exposure of dogs and swine (0.5-2 hours/day, for 2 weeks) to
            unspecified, sublethal concentrations resulted in vomiting, diarrhoea, irritation of
            eyes and upper respiratory tract, tachycardia, polypnoea, and weight loss. Severe
            lung congestion was observed (Gre97).
116-6       Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Since it is reasonable to ascribe the (possible) systemic toxicity due to exposure
      to cyanogen chloride to cyanide, the findings as presented in the aforementioned
      criteria document on HCN, NaCN, and KCN will be summarised here. In
      humans, exposure to lethal or nearly lethal doses leads to a series of respiratory,
      cardiovascular, and neurological symptoms. Death is preceded by coma, and is
      caused by respiratory failure or cardiac arrest. Acute toxicity is characterised by
      a rather steep dose-response/effect relationship: exposure to 20 mg/m3 for several
      hours may lead to slight effects only, while exposure to 120 mg/m3 may be fatal.
      Survival of serious acute poisoning may be followed by severe
      neurotoxicological sequelae. Some case studies suggested that human cyanide
      toxicity is not restricted to acute effects and their sequelae, but that effects may
      gradually develop upon repeated exposure, in particular neurotoxicity and goitre.
      However, it was not possible to link these effects to exposure levels.
          In one epidemiological study in which exposure levels were 5.9 to 12.4 ppm
      (6.5-13.8 mg CN/m3), higher incidences of a number of symptoms (headache;
      weakness; changes in taste, smell; giddiness; throat irritation; vomiting,
      dyspnoea; lachrymation; precordial pain; salivation; disturbances of
      accommodation; psychosis) were reported in occupationally exposed workers
      when compared to not-exposed controls, as well as enlarged thyroids, pointing to
      goitre, in most of the exposed workers. In experimental animals, similar
      respiratory, cardiovascular, and neurological effects are observed following
      single exposures.
          Depending on species, compound, and exposure duration, the respiratory
      LC50 ranged between 134 and 410 ppm (149-455 mg/m3). Repeated exposures
      (12 exposures of 1/2 hour, 1 exposure per 8 days or 14 or 19 exposures of 1/2
      hour, 1 exposure per 2 days) to 50 mg HCN/m3 resulted in severe histological
      brain lesions in dogs; no histological effects were observed in hearts, lungs, and
      adjacent arteries of rabbits continuously exposed to 0.5 mg HCN/m3 for 4 weeks.
      A wide variety of effects, among others on the CNS and the male reproduction,
      were reported from short-term oral experiments in experimental animals at daily
      doses of about 0.5 mg/kg bw. No effects were seen in rats orally exposed to
      about 3.5 mg/kg bw/day, for 2 years. No indications for a carcinogenic or
      genotoxic potential were found. However, because of flaws in design of the long-
      term studies and the limited number of genotoxicity endpoints examined, no
      definitive conclusions could be drawn.
          Cyanides were embryotoxic and teratogenic at maternally toxic doses. Since
      lower doses were not tested, a definitive conclusion concerning reproduction
      toxicity cannot be drawn either. Finally, DECOS concluded that the most
      important primary effect of cyanide is the inhibition of the enzyme cytochrome C
116-7 Cyanogen chloride
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<pre>      oxidase in the respiratory chain, thus blocking the utilisation of oxygen and the
      production of ATP by oxidative phosphorylation. Cyanides can inhibit other
      metallo enzymes as well; however, the effects of this inhibition are assumed to
      be overshadowed by the effects of the inhibition of cytochrome C oxidase, at
      least at the high doses investigated (Hea02).
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for cyanogen
      chloride in the Netherlands is 0.6 mg/m3 (0.3 ppm), which is a ceiling value.
          Existing occupational exposure limits for cyanogen chloride in some
      European countries and in the USA are summarised in the annex.
          In its criteria document on HCN, NaCN, and KCN, DECOS recommended a
      health-based occupational exposure limit of 1 mg/m3, 8-hour TWA, and a ceiling
      limit of 10 mg/m3 as CN- from any combination of these 3 compounds (Hea02).
8     Assessment of health hazard
      Cyanogen chloride has the same general type of toxicity and mode of action as
      hydrogen cyanide, but it is considered to be much more irritating to the
      respiratory tract and the eyes, even at very low concentrations. According to data
      from the 1920’s and 1930’s, the lowest concentration inducing irritation in
      humans should be 1 ppm (2.6 mg/m3) at a 10-minute exposure period. Other
      symptoms observed in humans exposed to unknown concentrations include
      muscular weakness, lung congestion, skin irritation, hoarseness, conjunctivitis,
      oedema of the eyelids, cold sensation, weight loss, chronic headache, and
      burning urine.
          Inhalation data for experimental animals are limited to acute exposures, from
      which it is clear that cyanogen chloride should be classified as very toxic by
      inhalation.
          The committee did not find data on toxicity following repeated exposure
      (including those on carcinogenicity and reproduction toxicity) and mutagenicity.
      The committee considers the toxicological database on cyanogen chloride 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.
116-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      References
ACG91 American Conference of Governmental Industrial Hygienists (ACGIH). Documentation of the
      threshold limit values and biological exposure indices. 6th ed. Cincinnati OH, USA: ACGIH®, 1991:
      801-2.
ACG03 American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
      exposure values - 2003. Cincinnati OH, USA: ACGIH®, 2003: 36.
ACG04 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: 22.
Ald46 Aldridge WN, Evans CL. The physiological effects and fate of cyanogen chloride. Quart J Exp
      Physiol 1946; 33: 241-66.
Ald51 Aldridge WN. The conversion of cyanogen chloride to cyanide in the presence of blood proteins and
      sulphydryl compounds. Biochemistry 1951; 48: 271-6.
Arb02 Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
      2002: 21 (At-vejledning C.0.1).
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: 44 (rep no 39).
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.
Flu31 Flury F, Zernike F. Chlorcyan. In: Schädliche Gase. Dämpfe, Nebel, Rauch- und Staubarten. Berlin,
      FRG: Verlag Julius Springer, 1931: 410-1.
Gre97 Greim H., ed. Chlorcyan. In Gesundheidsschädliche Arbeitsstoffe. Toxikologisch-
      arbeitsmedizinische Begründungen von MAK-werten (Maximale Arbeitsplatzkonzentrationen). 1st-
      25st ed. Weinheim, FRG: VCH Verlagsgesellschaft mbH, 1997.
Har94 Hartung, R. Cyanides and nitriles. In: Clayton GD, Clayton, FE. Toxicology. 4th ed. New York,
      USA: John Wiley & Sons, Inc, 1994: 3132-34 (Patty's industrial hygiene and toxicology; Vol 2, Part
      D).
Hea02 Health Council: Dutch Expert Committee on Occupational Standards. Hydrogen cyanide, sodium
      cyanide, and potassium cyanide. Health-based recommended occupational exposure limits. The
      Hague, the Netherlands: Health Council of the Netherlands, 2002; publ no 2002/15OSH.
HSE02 Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
      (Suffolk), England: HSE Books, 2002: 15.
Moo46 Moore S, Gates M. Hydrogen cyanide and cyanogen chloride. In: Renshaw B, ed. Chemical warfare
      agents and related chemical problems - part I-11. Washington DC, USA: National Defense Research
116-9 Cyanogen chloride
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<pre>       Committee, 1946: 7-16 (Vol 1) (available from National Technical Information Service, Springfield
       VA, USA; rep no PB158508).
NIO03  US National Institute for Occupational Safety and Health (NIOSH), ed. Cyanogen chloride. In: The
       Registry of Toxic Effects of Chemical Substances (RTECS) (last update cyanogen chloride file:
       October 2002); http://www.cdc.gov/niosh.
NLM03  US National Library of Medicine (NLM), ed. Cyanogen chloride. In: The Hazardous Substances
       Data Bank (HSDB) (last revision date cyanogen chloride file: February 2003; last review date:
       January 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: A-142-51.
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: 30 (Ordinance AFS 2000:3).
SZW04  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2004. The Hague,
       the Netherlands: Sdu Uitgevers, 2004: 22.
TRG03  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArBl
       2003; (9).
116-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>              Annex
Occupational exposure limits for cyanogen chloride in various countries.
country                             occupational              time-weighted         type of          notea        referenceb
- organisation                      exposure limit            average               exposure limit
                                    ppm        mg/m3
the Netherlands
- Ministry of Social Affairs and    0.3        0.6            ceiling               administrative                SZW04
Employment
Germany
- AGS                               -          0.75           8h                                                  TRG03
- DFG MAK-Kommission                -c         -c                                                                 DFG03
Great-Britain
- HSE                               0.3        0.77           15 min                OES                           HSE02
Sweden                              0.1        0.3            8h                                                  Swe00
                                    0.3        0.8            15 min
Denmark                             0.10       0.30           8h                                                  Arb02
USA
- ACGIH                             0.3        -              ceiling               TLV                           ACG04
- OSHA                              -          -              -                                                   ACG03
- NIOSH                             0.03       0.06           ceiling               REL                           ACG03
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.
116-11        Cyanogen chloride
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<pre>116-12 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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