<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>(2-Chlorobenzylidene)malononitrile
(CAS No: 2698-41-1)
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/098 The Hague, March 30, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. (2-Chlorobenzylidene)malononitrile; Health-based
Reassessment of Administrative Occupational Exposure Limits. The Hague:
Health Council of the Netherlands, 2004; 2000/15OSH/98.
all rights reserved
</pre>

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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      (2-chlorobenzylidene)malononitrile (CS) 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 N. Smits, M.Sc.
      (Environmental and Occupational Health Group, Wageningen University and
      Research Centre, Wageningen, the Netherlands)*.
           The evaluation of the toxicity of CS has been based on the review by the
      American Conference of Governmental Industrial Hygienists (ACGIH)
      (ACG99). Where relevant, the original publications were reviewed and evaluated
      as will be indicated in the text. In addition, in December 1999, literature was
      searched in the databases Medline, Toxline, and Chemical Abstracts, starting
      from 1966, 1985, and 1950, respectively, and using the following key words:
      chlorobenzylidenemalononitrile, chlorobenzylidene malononitrile, and
      2698-41-1. The final literature search was carried out in Toxline and Medline in
      October 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. Comments were received by the following
      individuals and organisations: TML Scheffers (DSM Chemelot, Geleen, the
      Netherlands). These comments were taken into account in deciding on the final
      version of the document.
2     Identity
      name                    :      (2-chlorobenzylidene)malononitrile
      synonyms                :      (o- chlorobenzal)malononitrile; o-chlorobenzylidene
                                     malononitrile; 2-chlorobenzylidene malononitrile; ß,ß-dicyano-
                                     o-chlorostyrene;
                                     [(2-chlorophenyl)methylene)]propanedinitrile; CS
      molecular formula       :      C10H5ClN2
      structural formula      :
      CAS number              :      2698-41-1
*     Current address: Institute of Risk Assessment Sciences, University of Utrecht, Utrecht, the Netherlands.
098-3 (2-Chlorobenzylidene)malononitrile
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<pre>3     Physical and chemical properties
       molecular weight       :     188.62
       boiling point          :     310-315oC
       melting point          :     95-96oC
       flash point            :     not available
       vapour pressure        :     at 20oC: 0.005 Pa
       solubility in water    :     not soluble (4 mg/100 mL)
       log Poctanol/water     :     2.76 (estimated)
       conversion factors     :     not applicable
      Data from ACG99, NLM03, http://esc.syrres.com.
      CS is a white crystalline solid with a pepper-like odour. It is rapidly hydrolysed
      following contact with water (half-life at pH 7.4 and 25oC: approximately 14
      minutes) (ACG99).
4     Uses
      CS came into widespread use as a tear gas in the 1960s and, because of its greater
      effectiveness and lower potential for toxicity, largely replaced the tear gas
      chloroacetophenone (CN) as the agent of choice for military and police crowd
      control missions. Lower concentrations of CS are required to achieve an
      equivalent response. It can be disseminated as a fine dust via an aerosol or, when
      mixed with a pyrotechnic compound, as a smoke or fog of minute particles from
      a grenade or canister. Sprays currently used by UK police forces contain a
      solution of CS in methyl isobutyl ketone. Methylene chloride and acetone are or
      have been used as well (ACG99, Bal77, Wor99).
5     Biotransformation and kinetics
      Human data
      Human volunteers exposed by inhalation to CS aerosols at concentrations of 0.03
      to 9.0 mg·min/m3, had no elevated thiocyanate levels in their urines (Swe70).
      One out of 6 human volunteers exposed to CS aerosol at a concentration of 90
      mg·min/m3 had trace amounts of the metabolite 2-chlorobenzylmalononitrile
      (see below) in his urine (Lea73).
098-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Animal data
      Following inhalation exposure of mice to CS aerosol (3500 mg/m3, 6 min),
      thiocyanate was excreted in the urine within 24 hours at concentrations that were
      about 7 times higher compared to background levels. After an intraperitoneal
      injection of 146 µmoles/kg bw (27.5 mg/kg bw; 0.5 LD50), about 50% of the CS
      dose was excreted as thiocyanate in the urine, more than 90% in the first 24
      hours. It was suggested that CS is biotransformed into thiocyanate via
      malononitrile and subsequent release of cyanide. Cyanide concentrations in
      blood, following intraperitoneal administration, peaked between 4 and 16
      minutes and the half-life of elimination was about 16 min. The time course of
      toxic symptoms was related to that of blood cyanide concentrations (Fra73).
      Following inhalation exposure of cats to CS aerosol (750 mg/m3 for 60 min), CS
      and two of its metabolites, 2-chlorobenzylmalononitrile and 2-
      chlorobenzaldehyde, were detected in the blood. The half-life of CS in blood of
      5.5 sec. was found after intra-arterial injection (Lea73). CS reacts with plasma
      proteins and glutathione in vivo (Cuc71). The latter was demonstrated by reduced
      sulphydryl concentrations in the plasma of dogs after intravenous doses of CS
      (Cuc71) and by excretion of the metabolite 2-chlorobenzylmercapturic acid in
      the urine of rats (4% of dose) following intraperitoneal administration of CS
      (Rie83). The fate of 3H-ring-labelled, 14C-cyanide labelled, and (14C=C)-side-
      chain-labelled CS was studied in Porton rats by intravenous injections of doses
      of 0.08 to 80 µmol/kg bw (0.015-15 mg/kg bw) or giving oral (gavage) doses of
      80 to 159 µmol/kg bw (15-30 mg/kg bw). The recovery of radioactivity in urine
      up to 96 hours after dosing was 44-74 and 55-100% after intravenous and oral
      administration, respectively. Following oral dosing, the principal urinary
      metabolites were 2-chlorohippuric acid (49% of dose), 1-O- (2-chlorobenzyl)
      glucuronic acid (9.8%), 2-chlorobenzyl cysteine (8.2%), and 2-chlorobenzoic
      acid (8.2%). Minor metabolites identified were 2-chlorophenyl acetyl glycine, 2-
      chlorobenzyl alcohol, and 2-chlorophenyl-2-cyanopropionate. It was also found
      that the proportion of urinary thiocyanate excretion increased with increasing
      oral CS doses (29.9 % of dose at 212 µmol/kg bw or 40 mg/kg bw) (Bre87). The
      principal pathways of the CS metabolism are shown in Figure 1 (see Annex I).
098-5 (2-Chlorobenzylidene)malononitrile
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<pre>6     Effects and mechanism of action
      Human data
      Most studies on human health effects of CS are from CS application in riot
      control. When detonated outside, a CS grenade generates a cloud 6 to 9 meters in
      diameter; at the centre, a concentration of 2,000 to 5,000 mg/m3 can be produced,
      with concentrations rapidly tapering off at the periphery (Wei69). Marked
      harassment occurred at exposures to 4 mg/m3, with an almost immediate onset of
      effects on the eyes, the skin, and the respiratory tract, such as a burning sensation
      in the eye, excess lachrymation, blepharospasm, conjunctivitis, and photophobia,
      stinging or burning sensations of the skin, particularly in moist areas and often
      accompanied by erythema, and sneezing, coughing, soreness and tightness of the
      chest, difficulty with breathing, and voluntary holding of the breath. CS caused
      primary and allergic contact dermatitis (confirmed by patch testing) and skin
      burns, and factors influencing their severity included duration and degree of
      exposure, heat, humidity, and the material used as solvent. Other sighs and
      symptoms included increased salivation, irritation of the throat, nausea and
      occasionally vomiting and apprehension. In a few cases, CS induced symptoms
      of lung injury indicative of reactive airways dysfunction syndrome (RADS).
      Usually, recovery is complete within 15 to 30 minutes after the end of an
      exposure, although a few signs (like erythema of the lid margins and
      photophobia) may persist slightly longer. Delayed reactions, appearing hours to
      days after exposure, are extremely unlikely after brief outdoor or other low
      exposures. However, they may occur at unusually high doses and medically
      important injury may result from conditions such as excessive application of the
      agent, delivery in enclosed spaces, prolonged exposure (no way to flee), a high
      minute ventilation (during a fight), and (for skin reactions) high temperature and
      relative humidity. Despite reports on alleged fatal cases, mortality in humans
      following CS application has not been authenticated (Bal77, Hil00, Ola01).
      Histories of asthma, chronic obstructive pulmonary disease (COPD), or cardiac
      disease may exacerbate effects (Wor99).
          Estimates of the human LCt50 (i.e., the concentration x time, lethal to 50% of
      an exposed population) range between 25,000 to 150,000 mg·min/m3; estimates
      of the minimal irritant concentration and the ICt50 (i.e., the concentration x time,
      incapacitating/irritating to 50% of an exposed population) were 0.004 and 5
      mg·min/m3, respectively (Ola01).
098-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Human volunteers (n=7) were exposed to CS aerosols dispersed from a 10%
      solution in methylene chloride or from the pure molten compound. The mass
      median aerodynamic diameters (MMAD) were 1.0 and 0.5 µm, respectively.
      Responses were measured in tolerance time, which was defined as the time a
      subject could no longer remain in an atmosphere containing CS. There were no
      differences in response between subjects exposed to aerosols obtained from the
      solution or from the molten compound. When 4 men were exposed to a
      concentration of 1.5 mg/m3 for 90 minutes, 4 subjects developed slight eye
      irritation, 1 slight eye irritation, and 3 headache, which lasted for 24 hours in 2 of
      them. When after a 40-minute exposure to 1.5 mg/m3, concentration was raised
      - without informing the subjects - to 11 mg/m3 within about 10 minutes, all 4
      volunteers left the exposure room within 2 minutes because of respiratory
      irritation. The first and last men left the room at estimated concentrations of ca. 4
      and 7 mg/m3, respectively. Exposure to 6 mg/m3, attained in 10 minutes, induced
      eye, nose, throat, and skin irritation, sneezing, and chest burning, the latter being
      the cause of leaving the chamber by 3 out of 4 subjects within 18 to 29 minutes.
      In contrast, 3 out of 4 sustained a 60-minute exposure to 6.6 mg/m3 gradually
      attained in 30 minutes, having the usual signs but to a lesser degree. The fourth
      person left the room after 2 minutes, at an estimated concentration of ca. 1
      mg/m3, because of a violent cough, voluntarily re-entered the chamber after a
      few minutes (estimated level: ca. 2 mg/m3) until the end of the experiment. When
      5 individuals were exposed to concentrations of 4 to 5 mg/m3, the time to
      complete a set of simple mathematical problems was significantly affected, but
      accuracy was not impaired. When the 7 men received 10 exposures to CS
      concentrations ranging from 1-13 mg/m3 over a 20-day period, no clinical
      abnormalities were observed, except for one person who had an abnormal thymol
      turbidity value, indicating an effect on the liver. The predominated symptom
      experienced by a subject in the initial exposure remained the dominant symptom
      upon repeated exposures. No volunteer developed a tolerance to CS (Pun63).
      Bestwick et al. studied the effects of acute exposure to CS aerosols on 35 healthy
      male volunteers by investigating eye irritation, pain and discomfort in the upper
      respiratory tract and chest, haematology and blood chemistry parameters,
      cardiology (electrocardiogram), and respiratory function (peak flow, tidal
      volume, vital capacity). There were 10 separate trials in which 2 to 6 volunteers
      were exposed for 1 hour to relatively low and constant concentrations of ca. 0.8
      mg/m3 (3 trials) or to concentrations progressively rising over the exposure
      period to final values of ca. 2 mg/m3. Apart from changes that could be ascribed
      to emotional stress and discomfort of the experiment, no abnormalities were
      observed in the haematology, blood chemistry, cardiology, and respiratory
098-7 (2-Chlorobenzylidene)malononitrile
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<pre>      function tests. Two men left the inhalation chamber untimely: one at 8 minutes
      with severe stinging of the eyes, irritation of the throat, cough, dyspnoea,
      salivation, and complaining of nausea, the other at 55 minutes to vomit. All
      subjects experienced effects of exposure to CS instantaneously as unpleasant, but
      most of them found them tolerable after 4 to 5minutes even at about 4-foldly
      rising concentrations. Most prominent symptoms, observed in 50% of the
      volunteers, were watering and stinging eyes, running and stinging nose, stinging
      face, salivation, dry and irritating throat, and cough. In addition, nausea and
      burning and tight chest were frequently reported. Generally, severity of
      symptoms did not increase over the exposure period. However, in 2 trials, 4
      subjects were exposed unprotectedly for the full hour to increasing
      concentrations and the other 4 wore respirators until 5 minutes from the end
      when concentrations were ca. 2 mg/m3 while roles changed in the other trial.
      Seven volunteers tolerated exposure unprotectedly (the 8th leaving to vomit; see
      above), while when having worn a respirator, only one man was able to stay for
      longer than one minute and 5 left within 30 seconds. Generally, symptoms
      disappeared readily after removing from exposure (Bes72).
          In a dermal human volunteer study, cutaneous irritant reactions produced by
      CS and CN were compared following application of dry or moistened test
      substance on 4 cm diameter for 1 hour. Application of amounts of dry CS of 20
      and 25 mg caused faint erythema and transient irritation commencing up to 30
      minutes following application in 3/3 and 3/7 volunteers, respectively, while no
      effects were observed in any of the volunteers (n=6/group) treated with doses
      ranging from 2 to 10 mg. Applying moistened CS at amounts of 10, 20, or 30 mg,
      faint to mild erythema and irritation was seen in about 50% or more of the
      volunteers (n=4 or 7/group), while amounts as little as 0.5 mg of dry or
      moistened CN produced erythema and vesication in more than 50% of the
      subjects (Hol72). Concentrations of 14,000 mg/m3 or more for one hour under
      simulated, tropical conditions produced extreme irritation, erythema, and
      vesication of the skin. The dermal effects noted were related to climatic
      conditions, race, and skin qualities (Wei69).
      In a chemical plant manufacturing CS, 25 out of 28 workers gave a history of
      dermatitis involving the arms and neck. Erythema was more likely present if the
      symptomatic site was under partial occlusion such as boots and the collar-gas
      mask area at the posterior part of the neck. Two of the 25 workers showed skin
      reactions consistent with allergic sensitisation to CS (by positive patch test
      reactions when tested with a 1:1000 dilution of CS in olive oil). CS
      concentrations in 3 sampling areas were 12 mg/m3 during filling of plastic bags
098-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      in an open process, 1 mg/m3 in the storage room, and 0.64 mg/m3 during milling.
      In general, 50% of men would develop some degree of erythema at 3,5±1,5
      mg/m3 at moist and warm climatological conditions (Shm73).
          Thomas et al. reported the hospitalisation of 9 U.S. marines, participating in a
      military training event, with a transient pulmonary syndrome (cough and
      shortness of breath in 9, haemoptosis in 5, hypoxia in 4). Symptoms began to
      appear 36 to 84 hours after heavy (‘voluntary’) exposure to CS during which the
      marines had been submitted to strenous physical exercise including a 1.5-mile
      run and several 1000-1500-meter pool or open-ocean swims. All signs and
      symptoms resolved within 3 days of admission, and lung function was normal
      when tested one week after exposure (Tho02). Although Thomas et al. ascribed
      the effects to CS, the committee is in agreement with McDonald and Mahon
      (McD02) of the opinion that they were more likely caused by the swimming. On
      one hand, CS exposure leads to acute, transient effects, mostly of the eyes, but
      sometimes of the respiratory tract. Delayed onset and/or persistent pulmonary
      symptoms are highly unusual, and despite the fact that about 200,000 marines
      have been exposed to CS since 1996 under field conditions, no such cases were
      reported. On the other hand, the symptoms appeared in all marines immediately
      after their swims and are similar to those associated with water aspiration or
      swimming-induced pulmonary oedema (McD02).
          All, but 2 out of 34 young adults who had been exposed to CS spray in a
      confined space during a confrontation with the police (10 directly on the face, the
      others indirectly) still reported ocular symptoms one hour after the event. Other
      major symptoms concerned the respiratory tract (in 23) and the throat. At one
      month, ocular, throat, and respiratory symptoms were still present in 18, 20, and
      14 individuals, respectively. At 10 months, 5 persons still complained of
      respiratory symptoms, but no abnormalities were seen at physical examination or
      lung function tests (Kar03).
      Reproduction toxicity
      In an in-depth inquiry into the adverse health and toxicological effects of CS
      following its use in Londonderry, Northern Ireland, in 1969, no increase in the
      incidence of spontaneous abortions, stillbirths, or congenital abnormalities was
      found, comparing a 9-month period of heavy tear gas exposure with a previous 9-
      month period (Ola01).
          The committee did not find data from other studies.
098-9 (2-Chlorobenzylidene)malononitrile
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<pre>       Animal data
       Irritation and sensitisation
       Following 6-hour unoccluded application of 12.5% solutions of CS in acetone or
       corn oil, CS was found to be moderately irritating to the skin of rabbits
       (n=6/group) and slightly irritating to the skin of rats (n=6/group) and the guinea
       pigs (n=6/group). Within 7 to 14 days, all effects had resolved (Bal78).
       Following application of 0.5 mL of solutions of CS in trioctyl phosphate to the
       intact clipped back skin of rabbits for 30 minutes, primary irritation scores
       (representing mean values from 2 rabbits treated at each of 6 timed intervals
       between 1 and 30 minutes after exposure) of 2.3 (treated skin not washed) for a
       1% solution and of 1.0 (unwashed) or 1.3 (skin washed with water or washed
       with water and soap) for 4% solutions were calculated. Scores of 5.0 or more
       were stated to be required to meet the definition for a skin irritant (Gas72).
           Rothberg studied the skin-sensitising potential of CS in guinea pigs. Serial
       solutions (in polyethylene glycol) of 0.000001 to 1% were injected intradermally
       into guinea pigs (5 groups; n=2/group), 3 times a week, for 4 weeks. After a 3- to
       4-week rest period, all animals were both intradermally and topically challenged
       with a 0.1% solution. The challenge doses caused erythema in 8/10 animals; the
       remaining 2 died during the sensitisation period. Another group of 6 animals was
       treated topically with a 1% solution of CS in acetone, 3 times a week, for 3
       weeks. After a 2-week rest period, animals were challenged with a topically
       applied 0.1% solution of CS in acetone/olive oil (1:1), which caused a positive
       response in all animals. No evidence of skin damage was seen in the vehicle-
       treated controls (Rot70).
           Topical administration (0.2 mL of 1% or 0.5% acetone solution) or
       intradermal administration (of 0.5 mL containing 10-25 g CS) and topical (0.1
       mL of 0.1 to 1% solutions in acetone) or intradermal (0.1 mL of a solution in
       saline containing 1-10 µg/mL) challenge caused contact sensitisation or delayed
       hypersensitivity, especially when routes of induction and challenge were
       identical (Chu72).
           Instillation of 0.05 of a 10% or of a 50% solution of CS in methylene
       dichloride into the eyes of rabbits resulted almost immediately in severe
       conjunctivitis persisting for 30 to 60 minutes. There also was erythema of the
       eyelids, lasting for a day or 2. No permanent eye damage was observed (Pun62).
           Instillation of 1-4% solutions of CS in 1,1,1-trichloroethane into the eyes of
       rabbits resulted in transient conjunctival redness while solutions of 5 or 10%
       caused chemosis and moderate conjunctivitis, respectively, all eyes being normal
098-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>             within 7 days. Corneal opacity or iritis was not observed (Gas72). Instillation of
             0.1 mL of 0.5-10% solutions of CS in polyethylene glycol 300 into the eye of
             rabbits (n=10/group) caused lachrymation, blepharitis, and chemosis and
             hyperaemia of conjunctivae and nictating membranes at all concentrations, and
             sloughing, iritis, and keratitis at concentrations of 1%. Generally, severity and
             durations of the effects increased with the concentration. All eyes were normal
             within 14 days. Instillation as a solid at amounts of 0.5-5 mg caused similar but
             less severe effects, roughly resolving within 4 to 7 days (Bal74).
                 With respect to the respiratory tract, the sensory irritation in the upper part
             was studied by determining the concentration associated with a 50% decrease in
             the respiratory rate (RD50). In male Swiss-Webster mice, exposed to aerosols for
             1 or 3 minutes, RD50 values of 8.6 and 3.2 mg/m3 (ca. 1.1 and 0.4 ppm) were
             obtained, respectively (Ala72).
             Acute toxicity
             Acute lethal toxicity data (LCt50s/ LD50s) in experimental animals are
             summarised in Table 1.
 Table 1 Summary of acute lethal toxicity studies in experimental animals.
 exposure route        species (strain, sex)                               LCt50a or LD50        reference
 inhalation            mouse                                               74,050 mg·min/m3 b    Bal78
                       rat                                                 68,400 mg·min/m3 b    Bal78
                       rabbit                                              65,600 mg·min/m3 b    Bal78
                       rat (Porton-Wistar; male)                           88,480 mg·min/m3 c    Bal78
                       rat                                                 32,500 mg·min/m3 c    Pun62
                       mouse (Porton albino; male)                         50,010 mg·min/m3 c    Bal78
                       mouse                                               43,500 mg·min/m3 c    Pun62
                       rabbit (New Zealand; female)                        54,090 mg·min/m3 c    Bal78
                       rabbit                                              17,300 mg·min/m3 c    Pun62
                       guinea pig (Dunkin Hartley; female)                 67,200 mg·min/m3 c    Bal78
                       guinea pig                                          8,300 mg·min/m3 c     Pun62
 oral                  rat (Osborne-Mendel; male, female)                  178-358 mg/kg bw d    Gas72
                       rat (Porton-Wistar; male)                           1366 mg/kg bw         Bal78
                       rat (Porton-Wistar; female)                         1284 mg/kg bw         Bal78
                       mouse                                               282 mg/kg bw          NIO03
                       rabbit (New Zealand; male)                          231 mg/kg bw          Bal78
                       rabbit (New Zealand; female)                        143 mg/kg bw          Bal78
                       guinea pig (Dunkin Hartley; female)                 212 mg/kg bw          Bal78
 intravenous           rat (Porton-Wistar; female)                         28 mg/kg bw           Bal78
                       mouse (Porton albino; male)                         48 mg/kg bw           Bal78
                       rabbit (New Zealand; male)                          31 mg/kg bw           Bal78
098-11       (2-Chlorobenzylidene)malononitrile
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<pre>                          rabbit (New Zealand; female)                         28 mg/kg bw                        Bal78
                          rabbit                                               8 mg/kg bw                         Pun62
  intraperitoneal         rat (Porton-Wistar; male)                            48 mg/kg bw                        Bal78
                          mouse                                                32 mg/kg bw                        NIO03
                          guinea pig (Dunkin Hartley; female)                  73 mg/kg bw                        Bal78
a
      Inhalation exposure dose (function of concentration and exposure duration) causing mortality in 50% of the animals.
b
      Pyrotechnically generated smoke.
c
      Aerosol.
d
      Depending on vehicle.
               Animals dying from acute inhalation exposure showed congested and
               oedematous lungs with multiple haemorrhages. Histological examination
               showed moderate to marked congestion of alveolar capillaries and intra-
               pulmonary veins. In addition, congestion of the liver, kidney, spleen, and small
               intestine was demonstrated (Bal78). Ballantyne and Swanston concluded that,
               within the limits of the experimental procedures, CS was similarly toxic in rats,
               mice, rabbits, and guinea pigs when exposed briefly to high concentrations of
               aerosols generated from the pure compound or of grenade smokes (Bal78).
                   Exposure to unreported aerosol concentrations of CS, with 90% of the
               particles having an aerodynamic equivalent diameter between 1.5 and 2 µm, for
               up to 20 minutes affected lung physiology (i.e., decreases in minute ventilation)
               and induced histological lesions in the trachea (cytoplasmic vacuoles in
               epithelial cells) and the lungs (emphysema) of male Wistar rats (Deb99).
               Short-term toxicity
               In 14-day inhalation studies, preceding 13-week and 2-year studies, F344/N rats
               (n=10/sex/group) and B6C3F1 mice (n=10/sex/group) were exposed to CS
               aerosols, comprising of a mixture of 94% CS, 5%Cab-O-Sil colloidal silica, and
               1% hexamethyldisilazane, at concentrations of 0, 1, 3, 10, 30, and 100 mg/m3,
               6 hours/day, 5 days/week. All rats exposed to 30 and 100 mg/m3 and all mice
               exposed to 10, 30 and 100 mg/m3 died before the end of the study. Compound-
               related clinical signs included erythema, blepharospasm, listlessness, nasal
               discharge, and mouth breathing (NTP90).
                   In the subsequent 13-week study, F344/N rats (n=10/sex/group) and B6C3F1
               mice (n=10/sex/group) were exposed to similar CS aerosols at concentrations of
               0, 0.4, 0.75, 1.5, 3, and 6 mg/m3 (6 hours/day, 5 days/week). One rat exposed to
               6 mg/m3 died before the end of the study. Mean body weights of rats exposed to
               1.5 mg/m3 or more were reduced by 17-44% (males) or 10-24% (females)
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<pre>       compared to controls. The absolute and relative thymus weights were reduced at
       6 mg/m3. Treatment-related nasal lesions in rats included focal erosion with
       regenerative hyperplasia and squamous metaplasia of the respiratory epithelium
       and suppurative inflammation. All mice exposed to 6 mg/m3 and one of each sex
       exposed to 3 mg/m3 died before the end of the study. Treatment-related lesions in
       mice also included squamous metaplasia of the nasal epithelium and
       inflammation (NTP90).
           Wistar rats (n=50/group), Porton mice (n=75/group), and Dunkin-Hartley
       guinea pigs (n=50/group) were exposed to CS aerosols concentrations of 0, 3,
       and 30 mg/m3, one hour/day, 5 days/week, until they had undergone 120, 55, and
       120 exposures, respectively. Initially, groups of animals were also exposed to a
       concentration of 233 mg/m3, but due to high mortality of mice and guinea pigs,
       exposure to this level was stopped after 3-5 days. At the end of the exposure
       periods, the animals were observed daily for 6 months. No statistically
       significant differences in mortality were seen between the control and the groups
       exposed to 3 or 30 mg/m3. Weight gain was reduced in a dose-related fashion in
       mice, but not in rats or guinea pigs. Histological examination showed laryngitis
       and tracheitis in mice exposed to 30 mg/m3, but not in the other species. No
       treatment-related increased incidences of neoplastic lesions at any site in any
       species were observed (Mar83).
           No mortality was observed in male rats (n=56) during or after exposure to
       thermally generated CS aerosol concentrations of 1000-2000 mg/m3, 5
       minutes/day, for 5 days. At post-mortem examinations, performed at various
       time points after the final exposure ranging from 1 hour to 21 days, lung lesions
       were observed in a total of 10 rats, including minimal congestion and a few small
       scattered alveolar haemorrhages in 5 and bronchopneumonia in the other 5 rats.
       Exposure to similarly generated concentrations of 12-15 mg/m3, 80 minutes/day,
       for 9 days resulted in mortality in 5/50 rats due to bronchopneumonia. Post-
       mortem examination of the remaining 45 rats at various time points after the final
       exposure showed minimal congestion or alveolar haemorrhages of the lungs in 7
       and bronchopneumonia in 9 rats (Bal72).
           Rats (n=30) and dogs (n=5) were exposed 5 days/week for 5 weeks to CS
       aerosol (mass median diameter: 1.5 µm) concentrations of ca. 720 mg/m3 for 5
       minutes and 680 mg/m3 for 1 minute, respectively. Dogs reacted vigorously
       during each exposure. The only obvious sign observed was salivation, which
       lasted for ca. 1 minute after exposure. Treatment did not affect haematology and
       blood chemistry parameters during the 5-week period. No other data were
       presented. Rats showed vigorous reactions as well. Visible signs included bloody
       noses. During the exposure period, 6 rats died without having post-mortem gross
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<pre>       pathological changes. The exposed rats lost weight by about 1% compared with
       gain weight in controls by about 20%. at post-mortem examinations of animals
       sacrificed during and after the 5-week period, no effects on relative heart, kidney,
       lung, liver, and spleen weights or macroscopic changes were seen (Pun62).
       The effect of CS on the immune system was studied in mice given daily
       intraperitoneal injections of 8 or 16 mg/kg bw CS in olive oil for 10 days. The
       humoral immune response to sheep red blood cells was suppressed at both doses.
       Increased serum protein and corticosterone levels were also measured.
       Nagarkatti et al. suggested that CS may directly act on the immune system at low
       doses, while at higher doses, in addition to this direct effect, increased
       corticosterone levels may also contribute to immunosuppression (Nag81).
       Long-term toxicity and carcinogenicity
       In the 2-year NTP toxicity and carcinogenicity studies in rats and mice, F344/N
       rats (n=50/sex/group) were exposed to CS aerosol concentrations of 0, 0.075,
       0.25 or 0.75 mg/m3, 6 hours/day, 5 days/week. The CS aerosol was of the same
       composition as in the 2- and 13-week NTP studies (see ‘Short-term toxicity’). No
       increased mortality or clinical signs of intoxication were observed in any of
       treated groups compared to the controls. Final mean body weights of rats
       exposed to 0.75 mg/m3 were about 10-12% lower than those of controls. There
       were no compound-related increases in the incidences of neoplasms at any site.
       Non-neoplastic lesions were present in the nasal passage only. In animals
       exposed to 0.75 mg/m3, they consisted of statistically significant increases in the
       incidences of hyperplasia and squamous metaplasia of the respiratory epithelium
       and degeneration of the olfactory epithelium with ciliated columnar and/or
       squamous metaplasia, and of proliferation of the periosteum of the turbinate
       bones; in females, there was an increased incidence of chronic focal
       inflammation and histiocytic cellular infiltrates in the lungs. At 0.25 mg/m3,
       increased incidences of olfactory epithelial metaplasia in males and of
       respiratory epithelial metaplasia in females were observed (NTP90). From this
       2-year rat inhalation study, the committee concludes that 0.075 mg/m3 is a
       NOAEL for rats, based on increased incidences of metaplasia in the olfactory
       and respiratory epithelium in male and female rats, respectively, at the next
       higher concentration of 0.25 mg/m3 (NTP90).
           B6C3F1 mice (n=50/sex/group) were exposed to concentrations of 0, 0.75 or
       1.5 mg/m3. No increased mortality or clinical signs of intoxication were observed
       in any of treated groups compared to the controls. Final mean body weights of
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<pre>       mice were 12-17% lower than those of controls. There were no compound-
       related increases in the incidences of neoplasms at any site. In female mice, there
       were pronounced dose-related decreases in the incidences of adenomas of the
       pituitary pars distalis and of malignant lymphomas. As with rats, non-neoplastic
       lesions were present in the nasal passage only and included statistically
       significant increases in the incidences of suppurative inflammation with
       hyperplasia and squamous metaplasia of the respiratory epithelium in male
       animals exposed to 0.75 and 1.5 mg/m3 and in females exposed to 1.5 mg/m3
       (NTP90). From this 2-year mouse inhalation study, the committee could not
       establish a NOAEL since respiratory epithelial lesions were observed in male
       rats at 0.75 mg/m3, the lowest concentration tested.
       Mutagenicity and genotoxicity
       Mutagenicity assays comprised tests for the detection of gene mutations in
       bacteria, yeast, and mammalian cells (in vitro) and for cytogenicity (in vitro and
       in vivo) and other genotoxicity assays (in vitro and in vivo).
       •   In vitro tests:
           • Gene mutation assays. Tests for reverse mutations in several strains of S.
               typhimurium (TA98, TA100, TA1535, TA1537, TA1538) were negative
               at concentrations ranging from 10 to 2000 µg/plate both with and without
               metabolic activation. Equivocal results were obtained with TA100
               (Dän81). The absence of gene mutations in S. typhimurium was confirmed
               in later studies with strains TA97a, TA98, TA100, TA102, and TA104 at
               doses ranging from 12.5 to 800 µg/plate (Mes92, Zei87) or with strain
               TA100 at doses up to 3500 µg/plate (Rie83, Wil83) with or without S9
               activation.
               In contrast, CS induced forward mutations in cultured mouse lymphoma
               L5178Y cells at concentrations of 2.5 µg/mL in the absence of S9
               activation (McG88). Gene mutations were also induced in V79 Chinese
               hamster cells at concentrations up to 75 µM (Zie89).
           • Cytogenicity assays. CS induced micronuclei in cultured Chinese hamster
               V79 cells at doses up to 75 µM (Zie89). In another study, chromosomal
               aberrations and sister chromatid exchanges (SCE) were induced in V79
               cells in a dose-dependent manner at concentrations ranging from 9.4 to
               37.7 µM, without S9 activation (Bau92). This was confirmed in cultured
               Chinese hamster ovary (CHO) cells in the presence or absence of S9 from
               rat or hamster liver (NTP90).
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<pre>           • Other genotoxicity assays. CS did not induce DNA repair synthesis in
               cultured V79 Chinese hamster cells at concentrations up to 75 µM
               (Zie89). However, CS caused a concentration-dependent c-mitotic effect
               in V79 cells, indicating an interaction of the chemical with the mitotic
               apparatus. The percentage of mitosis with abnormal spindle morphology
               was increased in a dose-dependent manner at CS concentrations up to 18.8
               µM (Sal91, Sch89).
       •   In vivo tests:
           CS did not cause increases in the frequencies of sex-linked recessive lethal
           mutations in sperm of D. melanogaster fed sucrose solutions containing
           2.6x10-3 or 5x10-4 M CS (Wil83).
           No increases in the frequency of micronucleated polychromatic erythrocytes
           was observed in bone marrow cells of mice given single oral and
           intraperitoneal doses of 113 and 226 and of 18,9 and 37.8 mg/kg bw,
           respectively (Wil83).
           CS bound covalently to nuclear proteins but not to DNA in liver and kidney
           of rats given single intraperitoneal injections of 14C-side-chain-labelled CS of
           13 mg/kg bw (Dän81).
           In summary, CS has the potential to induce gene mutations as well as
           clastogenic and aneugenic effects in cultured mammalian cells, mostly in the
           absence of S9-mix. However, no gene mutations could be demonstrated in
           bacterial assays and no clastogenic effects were observed in the bone marrow
           of CS-treated mice.
           The CS metabolites malononitrile, 2-chlorobenzaldehyde, 2-chlorobenzoic
           acid, and 2-chlorobenzyl alcohol did not induce gene mutations in S.
           typhimurium (Rie83, NTP90); malononitrile and 2-chlorobenzaldehyde did
           not induce chromosomal aberrations in cultured V79 cells (Bau92).
       Reproduction toxicity
       Pregnant rats (Porton SPF; n=22/group) and rabbits (New Zealand White;
       n=12/group) were exposed to CS aerosol concentrations of 6, 20, or 60 mg/m3, 5
       minutes/day on gestational days 6-15 and 6-18, respectively. In addition,
       separate groups of 8 to 12 rats received intraperitoneal injections of doses of CS
       of 20 mg/kg on gestational days 6, 8, 9, 10, 12, and 14. There were no
       statistically significant differences in maternal body weight increase, placental
       weight, number of litters, litters size, number of live fetuses, percentage of fetal
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<pre>       loss, and fetal body weight between any of the treatment groups and the controls.
       The number of external, visceral or skeletal abnormalities was not statistically
       significantly different between the groups (Ups73).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for CS in the
       Netherlands is 0.4 mg/m3, as a ceiling value.
           Existing occupational exposure limits for CS in some European countries and
       in the USA are summarised in Annex II.
8      Assessment of the hazard
       CS is absorbed into the body by inhalation of its aerosol and is rapidly
       metabolised into breakdown products, which are mainly excreted in the urine.
       CS is a potent sensory irritant. Human beings in contact with CS in air may
       experience effects on the eyes, respiratory tract, and skin. Typical signs and
       symptoms during exposure to aerosols include eye discomfort, excess
       lachrymation, blepharospasm, burning sensations in the nose and throat,
       rhinorrhoea, excess salivation, constricting sensations in the chest, sneezing,
       coughing, and stinging or burning sensations in exposed skin. Characteristic is
       the prompt onset of effects upon exposure and the rapid disappearance of signs
       and symptoms after ending exposure.
           Based on acute lethal toxicity studies in test animals, the committee
       considers the compound as toxic after inhalation and as harmful via the oral
       route. The systemic acute toxicity of CS in experimental species is due to the
       biotransformation of CS to cyanide. In thirteen-week toxicity studies in rats and
       mice, dose-related lesions of the nasal passage including squamous metaplasia of
       the nasal epithelium were observed, with a LOAEL of 0.4 mg/m3 (lowest
       concentration tested) in rats and a NOAEL of 0.75 mg/m3 in mice. Results of
       2-year inhalation studies showed hyperplasia, squamous metaplasia of the
       respiratory epithelium, and degeneration of the olfactory epithelium with ciliated
       columnar and/or squamous metaplasia in rats. The committee feels that these
       effects could be explained from severe tissue irritation by CS. The NOAEL was
       0.075 mg/m3. No evidence was found of carcinogenic activity of CS in rats or
       mice. In vitro mutagenicity assays with CS produced negative results in bacterial
       test systems but positive results when using mammalian cell cultures. In vitro
       cytogenicity tests (SCE, micronucleus) were also positive, but no clastogenic
       effects were observed in CS-treated mice. No covalent binding with DNA could
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<pre>       be demonstrated in rats, following CS administration. The committee considers
       that in view of the negative inhalation carcinogenicity studies, the positive in
       vitro mutagenicity findings are not relevant for workers. One human and one
       animal study produced no evidence for teratogenicity or embryotoxicity.
       The committee considers the hyperplasia and squamous metaplasia of the
       respiratory tract epithelium as the critical effect, and takes the NOAEL of
       0.075 mg/m3 found in the 2-year study in rats as a starting point in deriving a
       health-based recommended occupational exposure limit (HBROEL). For the
       extrapolation to a HBROEL, an overall assessment factor of 4 is established.
       This factor covers the following aspects: intra- and interspecies variation and the
       type of effect. Thus applying this factor and the preferred-value approach, a
       health-based occupational exposure limit of 0.02 mg/m3 is proposed for CS.
       The committee recommends a health-based occupational exposure limit for
       (2-chlorobenzylidene)malonitrile of 0.02 mg/m3, as inhalable dust, as an 8-hour
       time-weighted average (TWA).
       Reference
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ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 27.
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<pre>Bal78  Ballantyne B, Swanston DW. The comparative acute mammalian toxicity of 1-chloroacetophenone
       (CN) and 2-chlorobenzylidene malononitrile (CS). Arch Toxicol 1978; 40: 75-95.
Bau92  Bauchinger M, Schmid E. Clastogenicity of 2-chlorobenzylidene malonitrile (CS) in V79 Chinese
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Bes72  Bestwick FW, Holland P, Kemp KH. Acute effects of exposure to orthochlorobenzylidene
       malononitrile (CS) and the development of tolerance. Br J Ind Med 1972; 29: 298-306.
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Chu72  Chug CW, Giles AL Jr. Sensitization of Guinea Pigs to alpha-Chloroacetophenone (CN) and ortho-
       Chlorobenzylidene Malononitrile (CS) Tear Gas Chemicals. J Immunol 1972; 109: 284-93.
Cuc71  Cucinell SA, Swentzel KC, Biskop R, et al. Biochemical reaction and metabolic fate of riot control
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Deb99  Debarre S, Karinthi L, Delamanche S, et al. Comparative acute toxicity of o-chlorobenzylidene
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DFG03  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
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       concentrations and Biological Tolerance Values at the workplace Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2003; rep no 39.
EC04   European Commission: Directorate General of Employment and Social Affairs. Occupational
       exposure limits (OELs). http://europe.eu.int/comm/employment_social/h&s/areas/oels_en.htm.
Fra73  Frankenberg L, Sörbo B. Formation of cyanide from o-chlorobenzylidene malononitrile and its
       toxicological significance. Arch Toxicol 1973; 31: 99-108.
Gas72  Gaskins JR, Hehir RM, McCaulley DF, et al. Lacrimating agents (CS and CN) in rats and rabbits.
       Acute effects on mouth, eyes and skin. Arch Environ Health 1972; 24: 449-54.
Hil00  Hill AR, Silverberg NB, Mayorga D, et al. Medical hazards of the tear gas CS. A case of persistent,
       multisystem, hypersensitivity reaction and review of the literature. Medicine (Baltimore) 2000; 79:
       234-40.
Hol72  Holland P, White RG. The cutaneous reactions produced by o-chlorobenzyl-idenemalononitrile and -
       chloroacetophenone when applied directly to the skin of human subjects. Br J Dermatol 1972; 86:
       150-4.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
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Kar03  Karagama YG, Newton JR, Newbegin CJR. Short-term and long-term physical effects of exposure to
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Lea73  Leadbeater L. The absorption of ortho-chlorobenzylidene malononitrile (CS) by the respiratory tract.
       Toxicol Appl Pharmacol 1973; 25: 101-10.
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<pre>Mar83  Marrs TC, Colgrave HF, Cross NL, et al. A repeated dose study of the toxicity of inhaled 2-
       chlorobenzylidene malononitrile (CS) aerosol in three species of laboratory animal. Arch Toxicol
       1983; 52: 183-98.
McD02  McDonald EC, Mahon RT. [Letter to the editor]. Mil Med 2002; 167: iii-iv.
McG88  McGregor DB, Brown A, Cattanach P, et al. Responses of the L5178Y tk+/tk- mouse lymphoma cell
       forward mutation assay. II: 18 coded chemicals. Environmental and Molecular Mutagenesis 1988;
       11:91-118
Mes92  Meshram GP, Malini RP, Rao KM. Mutagenicity evaluation of riot control agent o-
       chlorobenzylidene malononitrile (CS) in the Ames Salmonella/ microsome test. J Appl Toxicol 1992;
       12: 377-84.
Nag81  Nagarkatti M, Nagarkatti PS, Raghuveeran CD. Short-term toxicity studies of o-chlorobenzylidene
       malononitrile on humoral immunity in mice. Toxicol Lett 1981; 8: 73-6.
NIO03  US National Institute for Occupational Safety and Health (NIOSH), ed. Malonitrile, o-
       chlorobenzylidene-. In: The Registry of Toxic Effects of Chemical Substances (RTECS) (last update
       CS file: October 2002). http://www.cdc.gov/niosh.
NLM03  US National Library of Medicine (NLM), ed. 2-Chlorobenzalmalonitrile. In: Hazardous Substances
       Data Bank (HSDB) (last revision date CS file: May 14, 2003; last review date: September 14, 2000);
       http://toxnet.nlm.nih.gov.
NTP90  National Toxicology Program (NTP). Toxicology and Carcinogenesis Studies of CS2 (94% 0-
       Chlorobenzylidene Malononitrile) in F344/N Rats and B6C3F1 Mice. NTP Technical Report No.
       377. National Institutes of Health, Research Triangle Park, NC, 1990.
Ola01  Olajos EJ, Salem H. Riot control agents: pharmacology, toxicology, biochemistry, and chemistry. J
       Appl Toxicol 2001; 21: 355-91.
Pun62  Punte CL, Weimer JT, Ballard TA, et al. Toxicologic studies on o-chlorobenzylidene malononitrile.
       Toxicol Appl Pharmacol 1962; 4: 656-662.
Pun63  Punte CL, Owens JE, Gutentag PJ. Exposure to o-chlorobenzylidene malononitrile: controlled human
       exposures. Arch Environ Health 1963; 6: 366-74.
Rie83  Rietveld EC, Delbressine LP, Waegemaekers TH, et al. 2-Chlorobenzylmercapturic acid, a
       metabolite of the riot control agent 2-chlorobenzylidene malononitrile (CS) in the rat. Arch Toxicol
       1983; 54: 139-44.
Rot70  Rothberg S. Skin sensitization potential of the riot control agents BBC, DM, CN and CS in guinea
       pigs. Mil Med 1970; 135: 552-6.
Sal91  Salassidis K, Schmid E, Bauchinger M. Mitotic spindle damage induced by 2-chlorobenzylidene
       malonitrile (CS) in V79 Chinese hamster cells examined by differential staining of the spindle
       apparatus and chromosomes. Mutat Res 1991; 262: 263-6.
Sch89  Schmid E, Bauchinger M, Ziegler-Skylakakis K, Andrae U. 2-Chlorobenzylidenemolononitrile CS
       causes spindle distubances in V79 Chinese hamster cells. Mutat Res 1989; 226: 133-6.
Shm73  Shmunes E, Taylor JS. Industrial contact dermatitis. Effect of the riot control agent ortho-
       chlorobenzylidene malononitrile. Arch Dermatol 1973; 107: 212-6.
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<pre>Swe70  Swentzel KC, Merkey RP, Cucinell SA, et al. Unchanged thiocyanate levels in human subjects
       following exposure to CS aerosol. Edgewood Arsenal MD, USA: Department of the Army, 1970;
       Edgewood Arsenal Technical Memorandum No 100-8; unpublished report, cited in Bal78.
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.
Tho02  Thomas RJ, Smith PA, Rascona DA, et al. Acute pulmonary effects from o-
       chlorobenzylidenemalonitrile ‘tear gas’: a unique exposure outcome unmasked by strenous exercise
       after a military training event. Mil Med 2002; 167: 136-9.
TRG00  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Ups73  Upshall DG. Effects of o-chlorobenzylidene malononitrile (CS) and the stress of aerosol inhalation
       upon rat and rabbit embryonic development. Toxicol Appl Pharmacol 1973; 24: 45-59.
Wei69  Weigand DA. Cutaneous reaction to the riot control agent CS. Mil Med 1969; 134: 437-40.
Wil83  Wild D, Eckhardt K, Harnasch D, et al. Genotoxicity study of CS (ortho-
       chlorobenzylidenemalononitrile) in Salmonella, Drosophila, and mice. Failure to detect mutagenic
       effects. Arch Toxicol 1983; 54: 167-70.
Wor99  Worthington E, Nee PA. CS exposure--clinical effects and management. J Accid Emerg Med 1999;
       16: 168-70.
Zei87  Zeiger E, Anderson B, Haworth S, et al. Salmonella mutagenicity tests III. Results from the testing of
       255 chemicals. Environ Mutagen 1987; 9: 1-110.
Zie89  Ziegler-Skylakakis K, Summer KH, Andrae U. Mutagenicity and cytotoxicity of 2-
       chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells. Arch Toxicol
       1989; 63: 314-9.
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<pre>       Annex I
       Figure 1 Principal pathways of CS metabolism (Bre87; adapted from NTP90).
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<pre>              Annex II
 Occupational exposure limits for (2-chlorobenzylidene)malonitrile 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        0.05       0.4          ceiling              administrative      S         SZW03
 Employment
 Germany
 - AGS                                   -          0.4                               S                             TRG00
 - DFG MAK-Kommission                    -          -                                                               DFG03
 Great-Britain
 - HSE                                   -          -                                                               HSE02
 Sweden                                  -          -                                                               Swe00
 Denmark                                 0.05       0.4          ceiling              S                             Arb02
 USA
 - ACGIH                                 0.05       -            ceiling              TLV                 S, A4c    ACG03b
 - OSHA                                  0.05       0.4          8h                   PEL                           ACG03a
 - NIOSH                                 0.05       0.4          ceiling              REL                 S         ACG03a
 European Union
 - SCOEL                                 -          -                                                               EC04
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.
c
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
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<pre>098-24 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>