<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-Chloroacetophenone
(CAS No: 532-27-4)
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/097 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-Chloroacetophenone; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/097.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      2-chloroacetophenone by the Committee on Updating of Occupational Exposure
      Limits, a committee of the Health Council of the Netherlands. The first draft of
      this document is prepared by N. Smits, M.Sc. (Wageningen University and
      Research Centre, Wageningen, the Netherlands)*.
           The evaluation of the toxicity of 2-chloroacetophenone 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, in December 1999, literature was
      searched in the databases Medline, Toxline, and Chemical Abstracts, covering
      the periods 1966, 1985, and 1950, respectively, until December 1999, and using
      the following key words: chloroacetophenone, chloroacetophenon, and
      532-27-4. The Hazardous Substances Data Bank (HSDB) was consulted as well
      (NLM03). The final literature search was carried out in Toxline and Medline in
      September 2003.
           In October 2003, the President of the Health Council released a draft of the
      document for public review. No comments were received.
2     Identity
      name                          :    2-chloroacetophenone
      synonyms                      :    chloroacetophenone; α-chloroacetophenone; ω-chloroacetophenone;
                                         1-chloroacetophenone; chloromethyl phenyl ketone; 2-chloro-1-
                                         phenylethanone; phenacyl chloride; phenyl chloromethyl ketone
      molecular formula             :    C8 H7ClO
      structural formula            :
      CAS number                    :    532-27-4
      Data from ACG99, NLM03.
*     Current address: Institute of Risk Assessment Sciences, University of Utrecht, Utrecht, the Netherlands.
097-3 2-Chloroacetophenone
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<pre>3     Physical and chemical properties
       molecular weight            :      154.6
       boiling point               :      247oC
       melting point               :      58-59oC
       flash point                 :      117.8oC (closed cup; solutions only)
       vapour pressure             :      at 20oC: 0.7 Pa
       solubility in water         :      insoluble (at 20oC: 0.07 g/100 mL)
       log Poctanol/water          :      1.93 (estimated)
       conversion factors          :      not applicable
      Data from ACG99, Ola01, http://esc.syrres.com.
      2-Chloroacetophenone is a colourless to grey crystalline solid with a pungent
      odour (ACG99). An air odour threshold (v/v) of ca. 0.2 mg/m3 has been reported
      (Amo83). When heated, vapours may form explosive mixtures with air
      (NLM03).
4     Uses
      Because of its strong lachrymating capacity, chloroacetophenone is used in tear
      gas formulations for riot-control and personal-protection devices, under the name
      of MACE, Chemical Mace®, or CN (ACG99, NLM03).
5     Biotransformation and kinetics
      The committee did not find data on the biotransformation and kinetics of
      2-chloroacetophenone.
           2-Chloroacetophenone is an alkylating agent that reacts directly with
      nucleophilic compounds in a bimolecular fashion, i.e., of the SN2 type. Some
      toxic effects of 2-chloroacetophenone, particularly following parenteral
      administration, are probably due to alkylation of SH-containing enzymes
      (Bal77).
097-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>6     Effects and mechanism of action
      Human data
      2-Chloroacetophenone is potently and severely irritating to the eyes, respiratory
      tract, and skin (especially if moist). Signs of eye and respiratory tract irritation
      included burning or stinging sensations in the throat, eyes, and nose, salivation,
      blepharospasm, lachrymation, coughing, sneezing, rhinorrhoea, constricting
      sensations in the chest, and breathing difficulties, and also occasionally nausea,
      vomiting, photophobia, and headache. These harassing effects rapidly developed
      at concentrations of about 10 mg/m3, but usually disappeared within 20 minutes
      of the end of exposure, although conjunctivitis persisted for up to 24 hours. At
      concentrations less than 10 mg/m3, there was usually an inverse relationship
      between concentration and tolerance time. Higher concentrations might have
      caused more severe permanent eye injury such as oedema, erosion, ulceration,
      chemosis, and focal haemorrhages, although this damage might have been due to
      close-range blasts or other foreign particles rather than CN. High inhalation
      doses resulting from use in confined spaces resulted in injuries requiring medical
      attention and death, post-mortem examinations showing oedema and congestion
      of the lungs, alveolar haemorrhage, necrosis of the mucosal lining of the lungs,
      and bronchopneumonia. Skin effects reported included primary and allergic
      contact dermatitis, erythema, oedema, vesication, purpura, and necrosis (Bal77,
      Hu89, Ola01, Sid97).
          Estimates of the human LCt50 (i.e., the concentration x time, lethal to 50% of
      an exposed population) range between 8500 to 22,500 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 0.3-1 and 20-50
      mg·min/m3, respectively (Ola01).
      Holland and White compared cutaneous irritant reactions produced by
      2-chloroacetophenone and (2-chlorobenzylidene)malononitrile (CS), another riot
      control agent, applied dry or moistened on 4 cm diameter skin for 1 hour.
      Amounts as little as 0.5 mg of moistened 2-chloroacetophenone produced
      erythema and vesication in more than 50% of the subjects, compared with faint
      erythema with quantities in excess of 10.0 mg of CS (Hol72).
          There are several case reports on dermal irritation and, confirmed by patch
      testing, allergic contact dermatitis following to accidental or deliberate exposure
      of law enforcement personnel or civilians to 2-chloroacetophenone (see e.g.,
097-5 2-Chloroacetophenone
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<pre>      Bra95, Cal79, Fra76, Goh87, Kan94, Lee89, Mau86, Pen69, Pen71, Tre99). In
      one of these case reports, no reactions were observed in 30 ‘normal’ controls
      tested to a concentration of 0.009% of 2-chloroacetophenone under occlusion for
      48 hours. However, several volunteers experienced primary irritant dermatitis
      from high 2-chloroacetophenone concentrations in range-finding studies to
      obtain a proper concentration for patch testing. Generally, these reactions
      resolved within 1 week, leaving an area of hyperpigmentation, but vesicular
      dermatitis developed at the primary irritant site 14-21 days after the initial
      exposure in 2 of these volunteers who appeared to have allergic contact
      sensitivity to 2-chloroacetophenone by additional appropriate patch testing. To
      evaluate this sensitising potential, 8 volunteers with negative patch-test results to
      dilute solutions were treated under occlusion with a 0.9% solution of 2-
      chloroacetophenone in acetone, 14 or 21 days later followed by a challenge
      application with 0.09%. All subjects developed primary irritant reactions and 5/8
      allergic contact sensitivity, showing erythema, oedema, and vesiculation at the
      patch-test site (Pen69, Pen71). In another, brief communication, Maibach and
      Marzulli reported a brief sensitising reaction in 5/9 male volunteers in a modified
      Draize test after uncovered application of 5 drops of a 1% solution of
      2-chloroacetophenone in acetone. Most of those subjects sensitised to the 1%
      concentration had skin reactions when treated with a 0.1% concentration, but not
      with 0.01%. Most subjects cross-reacted to CS, although at a significantly
      decreased intensity (Mai71).
      Four human volunteers were exposed to concentrations of 2-chloroacetophenone
      up to 350 mg/m3 until they could no longer tolerate the effects or until a
      maximum of 4 minute exposure was attained. 2-Chloroacetophenone was
      primarily a lachrymator. The subjects mainly complained of tingling of the nose
      and rhinorrhoea, burning of the throat, eyes, and skin around the eyes,
      lachrymation, and some degree of blurred vision. Less frequent, but more severe
      symptoms included burning in the chest with difficulties in breathing and slight
      gagging with nausea. At post-exposure examinations, the only constant sign was
      a mild to moderate conjunctivitis. There was not any chest congestion or sign of
      obstruction at any time, and all signs had usually disappeared within 10 minutes.
      Concentrations as low as 20-30 mg/m3 produced irritation within 2-3 minutes.
      The ECt50 (i.e., the concentration that produces a 50% response - acute irritation)
      was 213 mg x min/m3 (mg·min/m3) for 1 minute, 119 mg·min/m3 for 2 minutes,
      and 93 mg·min/m3 for 3 minutes (Pun62b).
          When 2-chloroacetophenone was released into 44 prisoner cells (crude
      estimation of 0.50 to 1.75 g), 28 prisoners required treatment from a physician.
097-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      Eight inmates, all complaining of malaise and lethargy, were admitted to the
      hospital because of laryngotracheobronchitis (in 3) and of first and second
      degree chemical burns (in 1), chemical facial burns (in 1), apparent allergic
      reaction including severe systemic illness (in 1), uncontrollable emesis (in 1),
      and syncope (in 1). The 20 prisoners receiving outpatient physician care had
      primarily ocular (conjunctivitis, with marked conjunctival oedema, in 10) and
      dermal (first and second degree chemical burns, mainly on the lower extremities,
      in 10; papulovesicular rashes in 6) injuries (Tho82). Twelve patients sprayed into
      the faces and eyes with 2-chloroacetophenone (i.e., Mace) from a distance of 15-
      30 cm had skin burns and corneal and conjunctival epithelial injuries (necrosis).
      In 9 patients, with mild exposure, these areas of fluorescein staining disappeared
      after 72 hours. However, in 3 cases of intense exposure, widespread confluent
      punctate corneal staining persisted for 14-21 days, and in one of these cases, a
      peripheral superficial corneal stromal opacity persisted for 5 months. In 2 cases
      of intense exposure, the corneal sensitivity, which is decreased during the period
      of staining, remained decreased and corneal epithelial breakdown with scattered
      punctuate staining recurred 3 and 4 months, respectively, after exposure (Ros69).
      Animal data
      Irritation and sensitisation
      Application of 12.5% solution of 2-chloroacetophenone in acetone or corn oil to
      the clipped dorsal skin of female rabbits and guinea pigs and male rats for 6
      hours caused, depending on the species, slight to moderate erythema and slight to
      marked oedema at the end of the contact period. The effects gradually subsided
      and disappeared completely between 7 and 14 days post-exposure. At days 4-7,
      mild to marked desquamation was observed in rats and guinea pigs. Between day
      1 and 7, rabbits developed variable sized ecchymoses and scattered necrotic
      areas, followed by scar tissue formation. In all species, lesions extended beyond
      the original area of application (Bal78). Following application of 0.5 mL of
      solutions of 2-chloroacetophenone 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 4.0 (treated skin not washed) for a 1% solution and of
      5.5 (unwashed), 5.2 (skin washed with water), or 2.9 (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).
097-7 2-Chloroacetophenone
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<pre>          Rothberg studied the skin-sensitising potential of 2-chloroacetophenone in
      guinea pigs. Solutions (in acetone) of 0.1 and 1% were injected intradermally or
      applied topically, respectively, (in)to guinea pigs (n=8/group), 3 times a week,
      for 4 weeks. After a 2-week rest period, all animals were both intradermally and
      topically challenged with a 0.1% solution. The challenge doses caused erythema
      in 13/16 animals. No evidence of skin damage was seen in the vehicle-treated
      controls (Rot70). Chung and Giles obtained similar results. Topical (0.2 mL of
      1% or 0.5% solutions in acetone) or intradermal (0.5 mL containing 10-25 g 2-
      chloroacetophenone) administration 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. Skin reactions
      of sensitised guinea pigs to high doses of 2-chloroacetophenone included
      erythema, oedema, induration, necrosis, and eschar formation (Chu72).
          Instillation of doses of 2-chloroacetophenone of about 0.5 and 1 mg into the
      eyes of rabbits caused lachrymation and severe conjunctivitis, which gradually
      disappeared within 2 weeks (Pun62a). Direct instillation of liquid Mace,
      obtained by discharging an aerosol weapon, into the eyes of anaesthetised rabbits
      and monkeys produced lasting opacities and melanosis. Similar effects were
      observed when Mace was sprayed into the eyes of monkeys from a distance of
      4 cm for 2 seconds. Less marked, transient effects were observed following
      instillation in conscious animals, with protective reflexes, or when sprayed from
      a distance of ca. 2 meters (Mac69). The corneal injury that 2-chloroacetophenone
      may produce was studied by applying filter paper squares (area: 9 mm2)
      containing amounts of 2-chloroacetophenone of 10 to 400 µg to the cornea of
      rabbits. Higher doses caused more severe lesions initially. The more severe
      lesions tended to remain unchanged while the lesser ones improved. At day 56,
      the end of the experiment, the percentages of eyes with permanent corneal
      damage amounted to 0, 40, 90, and 100% at doses of 10, 25, 50, and 100 µg or
      more, respectively (Mac70). Instillation of 1-4% solutions of 2-
      chloroacetophenone in 1,1,1-trichloroethane into the eyes of rabbits resulted in
      transient conjunctival redness while solutions of 10 or 20% caused permanent
      corneal damage. When testing commercial formulations, permanent damage was
      observed for a sample containing 4.3% but not for samples containing up to 2%
      2-chloroacetophenone (Gas72). Ballantyne et al. investigated the effects of 2-
      chloroacetophenone in solutions (1-10% in polyethylene glycol 300 - PEG 300 -
      and 5% in different solutions), as a solid (0.1-5 mg), and as aerosols (15 min
      exposure to 719 mg/m3) on the eye of rabbits. The most notable feature following
      a 15-minute exposure to a mean aerosol concentration of 719 mg/m3 was a mild
      blepharitis that lasted for 5 days. Other effects, just detectable, were transient
097-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            lachrymation (lasting for 4 hours) and conjunctival congestion (lasting for 1
            day). Cornea and iris were not affected. In 1-10% PEG 300 solutions,
            2-chloroacetophenone produced inflammatory effects on the eyelids,
            conjunctivae, and nictitating membrane, severity and duration being
            concentration related. Marked and persistent corneal injury was observed at
            concentrations of 5 and 10%, while 2% was the lowest concentration that
            induced transient just detectable keratitis in a small proportion of the treated
            rabbits. Comparative testing using 5% solutions clearly showed the solvent
            influence. Generally, 2-chloroacetophenone produced more marked and longer
            lasting eye effects when tested in PEG 300 or corn oil than in 1,1,1-
            trichloroethane or tri(2-ethylhexyl) phosphate. Solid test compound was
            generally more damaging to the eyes inducing lesions at lower amounts and
            more severe than similar amounts in solution. The no-effect level for keratitis of
            solid 2-chloroacetophenone was estimated between 0.1 and 0.25 mg and for
            solution 1% (Bal75).
                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). Using male Swiss-Webster mice, an RD50 of 0.96
            ppm (ca. 6 mg/m3) was obtained (Kan79).
            Acute toxicity
            Results of acute lethal toxicity tests with 2-chloroacetophenone in are
            summarised in Table 1.
Table 1 Summary of acute lethal toxicity studies in experimental animals.
exposure route     species                                          LC50, LCt50a, or LD50     reference
inhalation         mouse                                            59 mg/m3 b                NIO03
                   rat                                              23000 mg·min/m3 c         Ola01
                   rabbit                                           15800 mg·min/m3 c         Ola01
                   rat                                              3700-18800 mg·min/m3 d    Ola01
                   mouse                                            18200-73500 mg·min/m3 d   Ola01
                   rabbit                                           5840-11480 mg·min/m3 d    Ola01
                   guinea pig                                       3500-13140 mg·min/m3 d    Ola01
                   dog                                              7033 mg·min/m3 e          Ola01
dermal             guinea pig                                       >1000 mg/kg bw            NIO03
oral               rat (Osborne-Mendel; male, female)               52-258 mg/kg bw f         Gas72
                   rat (Porton-Wistar; male)                        127 mg/kg bw              Bal78
                   mouse                                            139 mg/kg bw              NIO03
                   rabbit (New Zealand; female)                     118 mg/kg bw              Bal78
                   guinea pig (Dunkin Hartley; female)              158 mg/kg bw              Bal78
097-9       2-Chloroacetophenone
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<pre>intravenous          rat (Porton-Wistar; female)                   41 mg/kg bw                               Bal78
                     mouse (Porton albino; male)                   81 mg/kg bw                               Bal78
                     rabbit (New Zealand; male)                    31 mg/kg bw                               Bal78
                     rabbit (New Zealand; female)                  30 mg/kg bw                               Bal78
                     rabbit                                        20 mg/kg bw                               Pun62a
intraperitoneal      rat (Porton-Wistar; male)                     36 mg/kg bw                               Bal78
                     mouse                                         60 mg/kg bw                               NIO03
                     guinea pig (Dunkin Hartley; female)           17 mg/kg bw                               Bal78
a
     Inhalation exposure dose (function of concentration and exposure duration) causing mortality in 50% of the animals.
b
     Exposure duration unknown; not known whether aerosol or smoke was tested.
c
     Pyrotechnically generated.
d
     Aerosol; range of values from several literature sources.
e
     Aerosol.
f
     Depending on vehicle.
              Generally, the cause of death following inhalation was from the injurious action
              of 2-chloroacetophenone on the pulmonary system. Post-mortem examination of
              the animals that died from exposure to aerosols showed pulmonary congestion,
              oedema, emphysema, tracheitis, bronchitis, and bronchopneumonia in dogs and
              pulmonary congestion, oedema, and bronchopneumonia in rats, mice, and guinea
              pigs. Effects observed during exposure consisted of lachrymation, conjunctivitis,
              copious nasal secretions, salivation, hyperactivity, dyspnoea, and lethargy. Post-
              exposure, the most salient finding was dyspnoea while ocular (conjunctivitis)
              and dermal (erythema) effects, lasting for 3 to 7 days, were noted as well
              (Ola01).
                  Following inhalation to sublethal aerosol concentrations of
              2-chloroacetophenone aerosols for 60 minutes - 62.6 mg/m3 (0.1 LC50) -, there
              was a significant increase in compliance in lung function in rats. Total lung
              phospholipids and sphingomyelin contents decreased significantly following
              exposure to 2-chloroacetophenone. Histological observations indicated cellular
              degeneration in the epithelium of the bronchioles and alveolar septal-wall
              thickening due to the presence of an increased number of mononuclear cells
              (Kum95).
              Short-term toxicity
              In 14-day inhalation studies, preceding 13-week and 2-year studies, F344/N rats
              and B6C3F1 mice (n=5/sex/group/species) were exposed to vaporised
097-10        Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>       2-chloroacetophenone* at concentrations of 0, 4.8, 10, 19, 43, or 64 mg/m3 ** (0,
       0.8, 1.6, 3.0, 6.9, 10.2 ppm), 6 hours/day, 5 days/week, for 2 weeks. All rats
       exposed to 19 mg/m3 or higher and 1/5 male rats exposed to 10 mg/m3 died
       before study termination. Rats exposed to 10 mg/m3 lost weight while the final
       mean body weights of male or female rats exposed to 4.8 mg/m3 were 23% and
       15%, respectively, lower than those of controls. During exposure, rats exhibited
       excessive lachrymation and dyspnoea. Erythema was seen in all rats at
       concentrations of 10 mg/m3 and higher, and partial closure of the eyelids at 19
       mg/m3 and higher. Bleeding of the nose was present in 2 exposed males and 7
       exposed females (concentration group not indicated). Data from post-mortem
       examinations in rats were not presented. In mice, all animals exposed to 10
       mg/m3 or higher died before the end of the study. Excessive lachrymation was
       seen during exposure. Final mean body weights of the animals exposed to 4.8
       mg/m3 were similar to those of controls. In 7 exposed males and 2 exposed
       females that died, reddened lungs were observed. No compound-related lesions
       were seen in mice exposed to 4.8 mg/m3 (no more data presented) (Mel90).
            In the subsequent 13-week studies, rats and mice (same strains; n=10/sex/
       group/species) were exposed to concentrations of 0, 0.25, 0.5, 1, 2, and 4 mg/m3
       (0, 0.04, 0.08, 0.16, 0.32, 0.64 ppm) (6 hours/day, 5 days/week). In rats, no
       mortality was observed. During exposure, compound-related clinical signs
       observed included eye irritation at levels of 0.5 mg/m3 and higher. The final
       mean body weights were affected only in male and female rats exposed to
       4 mg/m3 and were 9% lower than those of controls. Apart from slightly increased
       relative liver weights in female animals exposed to 4 mg/m3, no effects were seen
       at post-mortem evaluations. In mice, one female died in both the 0.5- and
       4-mg/m3 concentration group. During exposure, there was eye irritation in
       animals exposed to 0.5 mg/m3 and higher. Final mean body weights were - not
       dose-relatedly - decreased in all exposure groups (by 7-12% and 12-15% in
       males and females) when compared to controls. No compound-related lesions
       were observed at post-mortem evaluations (Mel90). Based on eye irritation
       observed during exposure to the next higher concentration of 0.5 mg/m3, the
       committee concludes that 0.25 mg/m3 is a NOAEL in rats and mice.
*      The formulation used to generate 2-chloroacetophenone vapour was 85% pure, with impurities of insoluble
       material identified as primarily magnesium oxide with traces of silicon dioxide and iron in methylene chloride
       (11.2%), water (2.2%), and unidentified substances (approximately 1.7%). The 2-chloroacetophenone was
       volatilised leaving behind the magnesium oxide.
**     The chamber atmospheres in the 14-day, 13-week, and 2-year studies were not evaluated for the presence of
       aerosolised test substance. Because the saturation concentration at 20oC is about 50 mg/m3, the presence of
       aerosolised material was thought to be unlikely.
097-11 2-Chloroacetophenone
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<pre>           2-Chloroacetophenone has been found to react irreversibly with free
       sulphydryl groups of proteins and enzymes. This reaction was observed to be the
       main cause of denaturation associated with sensory nerve activity (Chu72).
       Long-term toxicity and carcinogenicity
       In the 2-year toxicology and carcinogenicity studies, F344/N rats and B6C3F1
       mice (n=60/sex/group/species) were exposed to 0, 1, and 2 mg/m3 (0, 0.16, 0.32
       ppm) (rats) or to 0, 2, and 4 mg/m3 (0, 0.32, 0.64 ppm) (mice), 6 hours/day, 5
       days/week. During month 15, up to 10 animals/group were sacrificed for blood
       analysis and organ weight (brain, liver, kidney) determination and for complete
       histological examinations (in controls and high-concentration group only). In
       rats, no mortality, compound-related clinical signs, and body weight changes
       were observed. In the interim sacrificed animals, effects observed were limited to
       increased incidences of minimal-to-mild squamous metaplasia and hyperplasia
       of the respiratory epithelium in rats exposed to 2 mg/m3. In the animals killed at
       the end of the study, there was no compound-related increase in the incidence of
       any neoplastic lesion in any of the male exposure groups. In female animals,
       incidences of (benign) fibroadenomas - but not of (malignant) adenocarcinomas
       or carcinomas - of the mammary gland were increased with positive trends, being
       statistically significant in the 2-mg/m3 group (1 mg/m3: 19/50; 2 mg/m3: 23/50;
       controls: 12/50). Non-neoplastic effects were limited to those of the nose. In the
       male animals of the high-concentration, there was a statistically significant
       increase in the incidence of minimal-to-mild suppurative inflammation of the
       nasal mucosa. Further, hyperplasia and squamous metaplasia of the nasal
       respiratory epithelium were observed at dose-dependently increased incidences
       and severity in exposed male and female rats (see Table2).
       The authors of the study suggested that these irritant effects may have been
       exacerbated by viral infection, since serologic determinations for sentinel or
       control animals were positive for antibodies to rat coronavirus or
       sialodacryoadenitis virus at months 6, 12, 18, and 24 of the studies.
097-12 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>Table 2 Incidences and severity of nasal lesions in rats exposed to 2-chloroacetophenone, 6 hours/day, 5 days/week, for 2 years
(Mel90).
                                                       males                                        females
                                     0 mg/m3           1 mg/m3        2 mg/m3        0 mg/m3        1 mg/m3        2 mg/m3
                                     (46)a             (50)           (49)           (48)           (50)           (49)
nasal passage
suppurative inflammation             26               36              46**           29             27             33
nasal respiratory epithelium
hyperplasia                          12 (1.5)b         17 (1.3)       44** (1.6)     20 (1.2)       31* (1.5)      38** (2.2)
squamous metaplasia                  2 (1.0)           11* (1.3)      27** (1.8)     1 (1.0)        7* (1.6)       26** (1.7)
a
    Number of animals examined.
b
    Mean severity grade: 1=minimal, 2=mild, 3=moderate, 4=marked.
    * p<0.05.
    ** p<0.01.
                  In mice, there were lower survival rates in female animals (25/50, 32/50 vs.
             40/50 in controls), being statistically significant when compared to controls in
             the low-concentration group after week 98, and decreased mean body weights
             (by 5-12%) in the male animals of the high-concentration group. Clinical signs
             reported included rapid, shallow breathing of mice of the high-concentration
             group during the first 6 month of exposure and of the low-concentration group
             from month 3 through 6. No exposure-related effects were seen in the animals
             killed at month 15. In the animals exposed for 2 years, there were no exposure-
             related, statistically significant increases in the incidences of neoplastic lesions.
             Non-neoplastic lesions were limited to those of the nasal passage and included
             respiratory epithelial squamous metaplasia in 4/49 female and 2/48 male mice of
             the high-concentration group, which was not seen in any animal of the low-
             concentration or control group (Mel90). From this study, the committee
             considers 2-chloroacetophenone not to be a carcinogenic compound following
             exposure by inhalation. Based on the slightly increased incidences of nasal
             respiratory epithelial squamous metaplasia and slightly decreased body weights
             (in males), the committee concludes that 2 mg/m3 is a NOAEL in mice. In rats,
             the committee could not set a NOAEL since nasal lesions were found at 1 mg/m3,
             the lowest level tested.
                  In a study of Gwynn et al., 2-chloroacetophenone showed a co-carcinogenic
             potential since it increased the incidence of epidermal papillomas in skin of mice
             previously given dermal applications of 0.3 mL of 0.15% 9,10-dimethyl-1,2-
             benzanthracene (DMBA) dissolved in acetone. Twenty-one days after
             administration of DMBA, 0.3 mL of 0.4-0.8% 2-chloroacetophenone in acetone
             was applied twice a week for 12 weeks and once a week for the following 15
097-13       2-Chloroacetophenone
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<pre>       weeks. Twenty epidermal neoplasms were found in 9/12 mice treated with
       DMBA and 2-chloroacetophenone, compared to 1/12 in acetone-treated controls
       (Gwy52).
       Mutagenicity and genotoxicity
       2-Chloroacetophenone was negative when tested in a pre-incubation assay in S.
       typhimurium strains TA98, TA100, TA1535, and TA1537 in the presence and
       absence of S9 (hamster liver or rat liver) (dose range: 0.3-333 µg/plate).
       Depending on strain and metabolic activation, doses of 33 µg/plate were
       (slightly) cytotoxic (Zei87; see also Mel90).
           Using in vitro mammalian cell systems, 2-chloroacetophenone did not induce
       sister chromatid exchanges when tested with and without metabolic activation in
       Chinese hamster ovary cells (dose ranges: 0.16-5.0 and 0.016-0.5 µg/mL,
       respectively), but, at the highest dose tested without metabolic activation, i.e.,
       3.0 µg/mL, there was an increase in the percentage of cells with chromosomal
       aberrations along with marked cytotoxicity (Mel90).
           The committee did not find data from other in vitro (including on mutations
       in mammalian cell systems) or in vivo studies.
       Reproduction toxicity
       The committee did not find in vivo studies on the potential reproduction toxicity
       of to 2-chloroacetophenone.
           In vitro experiments were discussed in the NTP report on the toxicology and
       carcinogenity studies (see above). Incubation of chick embryos in the primitive
       streak stage with 0.5-3 mM 2-chloroacetophenone for 15-120 minutes was
       reported to increase the frequency of abnormalities in the nervous system
       including improper differentiation and incomplete closure of the brain. In
       separate studies, well-differentiated closed neural tubes were seen when embryos
       were incubated with 2-chloroacetophenone and subsequently exposed to
       sulphydryl agents. Embryos incubated with 2-chloroacetophenone at the head-
       process showed normal development. The inhibitory effect of
       2-chloroacetophenone on morphogenesis of the nervous system was concluded
       to be reversible (Mel90).
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<pre>       Immunotoxicity
       Kumar et al. evaluated the effects of 2-chloroacetophenone on the immune
       system. Short-term repeated exposure of 22 Swiss albino male mice to
       2-chloroacetophenone vapours at a concentration of 153 mg/m3 for 15 minutes
       daily on 10 consecutive days resulted in increased mortality to L.
       monocytogenes. Significantly elevated bacterial growth was observed in the
       spleen and liver of exposed animals compared to controls. Increased
       susceptibility to infection was considered to be the function of immune alteration
       due to 2-chloroacetophenone exposure. This may be attributed to immunotoxic
       effects on T-cell-mediated macrophage functions (Kum92).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for 2-
       chloroacetophenone in the Netherlands is 0.3 mg/m3 (0.05 ppm), 8-hour TWA.
           Existing occupational exposure limits for 2-chloroacetophenone in some
       European countries and in the USA are summarised in the annex.
8      Assessment of health hazard
       The main occupational routes of exposure to 2-chloroacetophenone are
       inhalation of aerosols and vapours and skin contact, during manufacture and
       packaging operations, during loading of solutions for aerosols, and during
       carrying a canister in a holster. The committee did not find data on occupational
       exposure levels.
           In humans, 2-chloroacetophenone is severely irritating to the eyes
       (lachrymator), respiratory tract, and skin; it is a skin-sensitising compond as
       well. Ocular and dermal harassment rapidly occurs at levels of 10 mg/m3. When
       human volunteers were exposed to 2-chloroacetophenone aerosol concentrations
       of up to 350 mg·min/m3 for up to 4 minutes, they most frequently complained of
       symptoms indicative of eye, nose, and throat irritation and less frequently of
       more severe symptoms such as burning in the chest with breathing difficulties
       and slight gagging with nausea. Post-exposure, mild to moderate conjunctivitis
       was the only constant sign; all signs had usually disappeared within 10 minutes.
       Estimates of the minimal irritant concentration and the ICt50 (i.e., the
       concentration x time, incapacitating/irritating to 50% of an exposed population)
       were 0.3-1 and 20-50 mg·min/m3, respectively. Use in confined spaces can cause
       serious morbidity and mortality, autopsy revealing pulmonary oedema and
097-15 2-Chloroacetophenone
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<pre>       congestion and necrosis of airway mucosa. Estimates of the LCt50 (i.e., the
       concentration x time, lethal to 50% of an exposed population) ranged between
       8500 to 22,500 mg·min/m3
            In experimental animals, 2-chloroacetophenone caused severe primary and
       allergic contact dermatitis and lachrymation, blepharospasm, and severe and
       permanent corneal lesions. During acute inhalation exposure, lachrymation,
       conjunctivitis, copious nasal secretions, salivation, hyperactivity, dyspnoea, and
       lethargy occurred while dyspnoea, conjunctivitis, and erythema were the most
       salient post-exposure findings. In animals that died, pulmonary system injury
       (pulmonary congestion, oedema, bronchopneumonia) was the cause of death. In
       one study, cellular degeneration in the epithelium of the bronchiole and alveolar
       septal-wall thickening were observed in rats exposed to 62.6 mg/m3 for 60
       minutes.
            In repeated inhalation studies, 2-chloroacetophenone did not cause gross or
       microscopic lesions in male and female rats and mice exposed to concentrations
       ranging from 0.25 to 4 mg/m3, 6 hours/day, 5 days/week, for 13 weeks, Effects
       observed were slightly decreased (by 9%) body weights in male and female rats,
       slightly increased relative liver weights in female mice exposed to 4 mg/m3 and
       eye irritation in both species during exposure to concentrations of 0.5 mg/m3 and
       higher. The NOAEL was 0.25 mg/m3. In a 2-year study, at exposure levels of 1
       and 2 (rats) or 2 and 4 (mice) mg/m3, however, no eye irritation or any other
       clinical sign was noticed in any of the treated groups. Apart from increases in the
       incidences of benign mammary gland fibroadenomas in female rats (significant
       positive trend test; increase significant in high-concentration group), there were
       no increases in the incidence of any benign or malignant tumour in any of the
       groups. In rats, the only effects observed were minimal-to-mild nasal passage
       lesions (squamous epithelial metaplasia and hyperplasia) showing dose-
       dependent increases in incidence and severity. Based on these findings, the
       committee concludes that, in this study, 1 mg/m3, the lowest level tested, is a
       minimal-observed-adverse-effect level in rats. In mice, there were very slight
       increases in the incidences of nasal lesions in male and female and slight
       decreases in body weights in male animals exposed to 4 mg/m3, 2 mg/m3 being
       the NOAEL.
            The committee concluded that 2-chloroacetophenone was negative in a
       S. typhimurium mutation assay and in a test for SCEs and chromosome
       aberrations in CHO cells, the only tests available.
            Based on the results of the carcinogenicity and (limited number of)
       genotoxicity studies, the committee is of the opinion that 2-chloroacetophenone
       will not be a carcinogenic risk to occupationally exposed workers.
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<pre>            The committee did not find data from reproduction toxicity studies with 2-
       chloroacetophenone.
       Contrary to the 13-week inhalation study, no eye irritation (or other clinical
       signs) was seen at higher levels in the subsequent 2-year study. Therefore, the
       committee prefers to take the minimal irritation of the nasal passages at 1 mg/m3
       in a 2-year rat inhalation study 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 8 is established. This factor covers the
       following aspects: the absence of a NOAEL, 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 0.1 mg/m3 is proposed
       for 2-chloroacetophenone.
       Based on threshold estimates for eye (lachrymation) and respiratory tract
       irritation in humans, the committee recommends a short-term exposure limit of
       0.3 mg/m3 in order to prevent irritation from peak levels.
       The committee recommends a health-based occupational exposure limit for
       2-chloroacetophenone of 0.1 mg/m3, as inhalable dust, as an 8-hour time-
       weighted average, and a short-term exposure limit of 0.3 mg/m3, as inhalable
       dust, as a 15-minute time-weighted average.
       References
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ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
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097-17 2-Chloroacetophenone
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<pre>Bal75  Ballantyne B, Gazzard MF, Swanston DW, et al. The comparative ophthalmic toxicology of 1-
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Bal78  Ballantyne B, Swanston DW. The comparative acute mammalian toxicity of 1-chloroacetophenone
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Bra95  Brand CU, Schmidli J, Ballmer-Weber B, et al. Lymphozytenstimulationstest, eine mögliche
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Cal79  Calnan CD. Chloracetophenone (CS) dermatitis. Contact Dermatitis 1979; 5: 195-6.
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Hol72  Holland P, White RG. The cutaneous reactions produced by o-chlorobenzylidenemalononitrile and -
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Kan79  Kane LE, Barrow CS, Alarie Y. A short-term test to predict acceptable levels of exposure to airborne
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Kan94  Kanerva L, Tarvainen K, Pinola A, et al. A single accidental exposure may result in a chemical burn,
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<pre>Kum95  Kumar P, Vijayaraghavan R, Pant SC, et al. Effect of inhaled aerosol of 1-chloroacetophenone (CN)
       and dibenz (b,f)-1,4- oxazepine (CR) on lung mechanics and pulmonary surfactants in rats. Hum Exp
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<pre>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
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       the Netherlands: Sdu, Servicecentrum Uitgevers, 2003: 20.
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       Arch Environ Health 1982; 37: 182-6.
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<pre>              Annex
Occupational exposure limits for 2-chloroacetophenone 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           0.3          8h                   administrative                SZW03
Employment
Germany
- AGS                                -              0.3                                                             TRG00
- DFG MAK-Kommission                 -              -                                                               DFG03
Great-Britain
- HSE                                0.05           0.32         8h                   OES                           HSE02
Sweden                               -              -                                                               Swe00
Denmark                              0.05           0.3          8h                                                 Arb02
USA
- ACGIH                              0.05           -            8h                   TLV                 A4c       ACG03b
- OSHA                               0.05           0.3          8h                   PEL                           ACG03a
- NIOSH                              0.05           0.3          10 h                 REL                           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.
097-21        2-Chloroacetophenone
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<pre>097-22 Health-based Reassessment of Administrative Occupational Exposure Limits</pre>

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<br><br>