<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-Chlorotoluene
(CAS No: 95-49-8)
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/099 The Hague, March 30, 2004
</pre>

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

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

<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. 2-Chlorotoluene; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/099.
all rights reserved
</pre>

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

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

<pre>1     Introduction
      The present document contains the assessment of the health hazard of 2-
      chlorotoluene 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 MA Maclaine Pont, M.Sc. (Wageningen University
      and Research Centre, Wageningen, the Netherlands).
           The evaluation of the toxicity of 2-chlorotoluene has been based on the
      reviews by the American Conference of Governmental Industrial Hygienists
      (ACG99) and the German GDCh-Advisory Committee on Existing Chemicals of
      Environmental Relevance (BUA) (BUA92, BUA96). Where relevant, the
      original publications were reviewed and evaluated as will be indicated in the text.
      In addition, in May 1999, literature was searched in the databases Toxline,
      Medline, and Chemical Abstracts, starting from 1981, 1966, and 1937,
      respectively, and using the following key words: 2-chlorotoluene, o-
      chlorotoluene, o-tolylchloride, 1-chloro-2-methylbenzene, and 95-49-8. 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. No comments were received.
2     Identity
      name                     :  2-chlorotoluene
      synonyms                 :  o-chlorotoluene; 1-chloro-2-methylbenzene; 2-chloro-1-
                                  methylbenzene; o-tolyl chloride
      molecular formula        :  C7H7Cl
      structural formula       :
      CAS number               :  95-49-8
099-3 2-Chlorotoluene
</pre>

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

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

<pre>3     Physical and chemical properties
      molecular weight            :    126.59
      melting point               :    -36oC
      boiling point               :    159oC
      flash point                 :    46oC
      vapour pressure             :    at 20oC: 0.36 kPa
      solubility in water         :    insoluble (at 20oC: 5 mg/100 mL)
      log Poctanol/water          :    3.4 (experimental); 3.18, 3.50 (estimated)
      conversion factors          :    at 20oC, 101.3 kPa: 1 mg/m3 = 0.19 ppm
                                                             1 ppm = 5.27 mg/m3
      Data from BUA92, NLM03, http://esc.syrres.com.
      2-Chlorotoluene is a colourless liquid with an odour resembling that of
      chlorobenzene (ACG99). Odour thresholds of 1.7 mg/m3 (0.3 ppm) in air and of
      0.98 mg/L in water have been reported (San89, You96).
           As a consequence of its low conductivity, the liquid can be electrostatically
      charged. Under certain conditions, toxic and corrosive vapours can be formed
      upon heating and combustion (Che99).
4     Uses
      2-Chlorotoluene is widely used as a solvent and intermediate in the synthesis of
      other organic chemicals, dyes, pharmaceuticals, and synthetic rubber compounds
      (ACG99).
           Commercially produced monochlorotoluene consists of 60% ortho- and 40%
      para-isomers (ACG99).
5     Biotransformation and kinetics
      Within 24 hours after giving male Harlan rats (n=3) single oral (gavage) doses of
      14
         C-labelled 2-chlorotoluene of 320 mg/kg bw, 81 and 3% of the radioactivity
      were excreted in urine and faeces, respectively, while only minor amounts of
      radioactivity (1.1 and 0.5%, respectively) were excreted in the subsequent 24
      hours. In expired air, ca. 10% of the radiolabel was excreted in the first 6 hours,
      followed by an additional 1.5% during the next 18 hours. While only unchanged
      parent compound was identified in expired air, it was not found in urine or
      faeces. Metabolites found in the urine included 2-chlorobenzyl alcohol
099-4 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>      glucuronide (41% of the radioactivity administered), chloro-methyl-
      phenylmercapturic acid (22%), and 2-chlorohippuric acid (19%), and minor
      amounts (1% each) of 2-chlorobenzyl alcohol, 2-chlorobenzoic acid, 2-
      chlorobenzoic acid glucuronide, and unidentified metabolites (Wol74).
           Four days after rats (Sprague-Dawley; n=4/sex) were given single oral doses
      of 2-chloro[U-ring-14C]toluene of 1 mg/kg bw, 85-92% of the radioactivity
      administered was excreted in the urine and 5-8% in the faeces, most of it in the
      first 24 hours after dosing. The major urinary metabolites were a glycine
      conjugate of 2-chlorobenzoic acid (2-chlorohippuric acid) and a ß-glucuronide
      and mercapturic acid of 2-chlorobenzylalcohol, representing 20-23, 35-42, and
      21-28% of the urinary 14C, respectively. One to 4% of the administered dose was
      eliminated as volatile 14C, at least 84% of which was identified as unmetabolised
      2-chlorotoluene. 2-Chlorotoluene was rapidly absorbed and metabolised. Two
      hours after dosing, radioactivity reached a peak level in plasma, 2-chlorobenzyl
      alcohol mercapturic acid and glucuronide being the 2 major components
      accounting for 38 and 25% of plasma radioactivity, respectively. Within 4 days
      after dosing, virtually all of the administered quantity had been eliminated from
      the rats (<1% remained in the carcass). No significant metabolic differences were
      found between males and females. Similar qualitative and quantitative
      distribution of metabolites was found when single oral doses of about 100 mg/kg
      bw were given to female rats (n=2) (Qui83).
           In an unpublished study performed by the same institute, rats (sex and
      number not specified) were intravenously injected with a single dose of 0.7 mg
      14
         C-labelled 2-chlorotoluene. The amount of radiolabel excreted in expired air,
      urine, and faeces amounted to 14-18% (almost all parent compound), 69-81%,
      and 1-3%, respectively. The urinary metabolites identified were 2-chlorobenzyl
      alcohol mercapturic acid (22-23%), 2-chlorobenzyl alcohol glucuronide (13-
      20%), and 2-chlorohippuric acid (7-11%). Unidentified polar metabolites
      accounted for 11%. Nearly 100% of the dose was eliminated within 4 days
      (BUA92).
           Daily oral (gavage) administration of doses of 2-chlorotoluene (purity:
      96.4%; see Wor74) of 20, 80, or 320 mg/kg bw, 7 days/week, for 14 days or 3
      months to rats (Harlan; n=5/sex/group) or of 5, 20, or 80 mg/kg bw to dogs
      (Beagle; n=4/sex/group), 7 hours/day, for 3 months, did not have a significant
      effect on the rate of hepatic O-demethylation of p-nitroanisole to p-nitrophenol,
      assuming the increases observed in the male rats of the mid- and high-dose
      groups at day 14 were due to the unusual low rates on the control animals
      (Hof74).
099-5 2-Chlorotoluene
</pre>

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

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

<pre>6     Effects
      Human data
      Two separate industry communications stated that their production workers
      never had skin irritation, dermatitis, or any other form of poisoning from
      exposure to 2-chlorotoluene (no more data presented) (ACG99).
      Animal data
      Irritation and sensitisation
      All experimental animal data on the potential irritation and sensitisation were
      from unpublished studies. Since the original reports were mostly not available to
      the committee, the findings presented below are from the brief information cited
      in the ACGIH (ACG99) and BUA (BUA92, BUA96) reviews.
      A single, 24-hour-occlusive application of 1 mL (1083 mg/kg bw) 2-
      chlorotoluene to the shaven skin of rats (n=5/sex) caused intense pain for up to 2
      hours after the start of the exposure. After the end of the exposure, the skin
      appeared normal (BUA92). The shaven back skin of 3 female rats were treated
      with 0.2 mL of 2-chlorotoluene under occlusion on alternate days for 5
      applications, while occlusive dressings were removed and skins cleaned on the
      intervening days. After the second application, hyperkeratinisation occurred. At
      histological examination, necrosis of the epidermis, superficial dermis with
      adjacent hyperplasia of the epidermis, and marked fibroblastic reaction of the
      dermis were observed. In a separate experiment, 0.2 mL was applied to the skin
      of 3 animals for 6 non-occluded applications. Hyperkeratinisation was seen after
      the second application, which developed to ulceration in one animal. At
      histological examination, similar, but less severe skin lesions were seen as in the
      occluded animals (Bar70). Moderate skin irritation was observed in rabbits in a
      24-hour patch test on abraded and intact skin (ACG99). 2-Chlorotoluene was
      found to be slightly irritating in rabbits in a test performed according to relevant
      OECD guidelines (BUA96). Topical treatment with 0.5 mL (540 mg) caused
      intense erythema and deep erosions on the rabbit ear after 24 hours of exposure
      under occlusive conditions. Not until 6 days after the application, the erythema
      became slight and the erosions merely superficial. Within 2 hours of exposure,
      the animals exhibited slight erythema and superficial erosion of the skin during
099-6 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>      the entire follow-up period. A 1-hour exposure led to low-grade erythema that
      lasted up to 2 days (BUA92). Repeated - 5 days/week, for 4 weeks - dermal
      application of 0.1, 0.3, or 1 mL/kg bw (ca. 100, 300, or 1000 mg/kg,
      respectively) caused moderate to severe dermal irritation in rabbits, due to
      defatting of the tissues. The area and severity of the injury were directly
      proportionate to the volume of the dose (Art74b). In guinea pigs (n=1/dose),
      moderate to intense skin irritation was found after a 24-hour occlusive
      application of 1 or 10 mL of undiluted material (1083 or 10,835 mg/kg bw)
      (ACG99).
          Female guinea pigs (n=10/group) were dermally treated with 0.1 mL of
      emulsions of 10 or 25% of 2-chlorotoluene in 5% acacia solutions, 3 times
      weekly, for 3 weeks, followed by a challenge after a 10-day exposure-free
      period. After treatment, sites were maintained under occlusion for 6 hours, and
      dermal responses were recorded 24 hours post-treatment using the standard
      Draize scale. Application of the 10 and 25% emulsions caused moderate and
      severe irritation, respectively (maximum mean irritation ratings of 2.7 and 7.2,
      respectively; maximum score possible: 8.0), but there were no indications for a
      sensitising potential (Art74d). The application of undiluted 2-chlorotoluene on 3
      consecutive days to the inner surface of the ears of 4 guinea pigs was followed on
      day 7 after the first administration by the application of a 10% or 1% emulsion to
      the shaven flanks. While this brought about slight erythema, there was no
      indication of a sensitising effect (Bar70).
          However, in a Magnusson and Kligman maximisation test, performed
      according to relevant OECD and EEC guidelines, there was no indication of a
      skin-sensitising potential in male guinea pigs upon topical application of
      undiluted test substance and intradermal induction of a 5% solution, followed by
      a challenge with undiluted material (BUA96).
      Instillation of one drop of undiluted 2-chlorotoluene into the eye of a rabbit
      caused delayed moderate conjunctival erythema. After 24 hours, the anterior
      portion of the cornea was opaque having returned to normal 14 days later
      (ACG99). Instillation of 0.1 mL of undiluted material into the eyes of albino
      rabbits produced moderate conjuctival irritation that disappeared by the fifth day.
      No evidence of corneal damage was seen upon fluorescein staining on day 7
      (ACG99). In another study, instillation of 0.1 mL into the conjunctival sac of the
      eye of a rabbit caused immediate, slight to moderate conjunctival erythema
      lasting for up to 24 hours (BUA92). Instillation of a similar amount into the eyes
      of 3 rabbits caused immediate blinking and slight mucopurulent discharge in 2
      animals and redness round the rim of the eye of the third animal. All eyes were
099-7 2-Chlorotoluene
</pre>

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

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

<pre>      normal 48 hours later (Bar70). 2-Chlorotoluene was found to be not irritating in
      rabbits in a test performed according to relevant OECD guidelines (BUA96).
      In 2 separate reports concerning respiratory tract (sensory) irritation,
      concentrations that reduced the respiratory rate in mice by 50% (RD50) were
      reported to be about 3000 mg/m3 (570 ppm) (Ala95, Mul84).
      Acute toxicity
      Data on the acute lethal toxicity of 2-chlorotoluene in experimental animals are
      summarised in Table 1. Generally, the primary toxic effects observed in these
      experiments consisted of effects on the nervous system (BUA92).
      Table 1 Summary of acute lethal toxicity studies for 2-chlorotoluene in experimental animals.
      exposure route species (sex)                 LC50/LD50                        reference
      inhalation      rat (male)                   >20,583 mg/m3 (1 hour)           BUA92
                      rat (male, female)           >63,900 mg/m3 (1 hour)           Art74a
                      mouse (male)                 >20,583 mg/m3 (1 hour)           BUA92
      dermal          rat (male, female)           >1083 mg/kg bw                   BUA92
                      rabbit (male, female)        >2165 mg/kg bw                   Art74a
      oral            rat                          >1600 mg/kg bw                   ACG99
                      rat (male, female)a          1659 mg/kg bw                    Art74b
                      rat (male)                   3227 mg/kg bw                    BUA92
                      rat (female)                 3860 mg/kg bw                    BUA92
                      rat (male)                   3464 mg/kg bw                    Art74a
                      rat (female)                 3031 mg/kg/bw                    Art74a
                      rat                          3900 mg/kg bw                    NIO03
                      rat                          5700 mg/kg bw                    Pis81
                      mouse                        2500 mg/kg bw                    NIO03
                      mouse (male)                 3776 mg/kg bw                    Art74a
                      mouse (female)               3902 mg/kg bw                    Art74a
                      mouse                        4400 mg/kg bw                    Pis81
                      guinea pig                   3000 mg/kg bw                    Pis81
      a
           48-72-hours-old animals.
      No effects were seen in rats (Harlan; n=10/sex) exposed to 63,900 mg/m3
      (12,141 ppm) for 1 hour (Art74a). However, when rats, mice, and guinea pigs
      were exposed to 22,200 mg/m3 (4218 ppm), breathing difficulties, ataxia, and
      convulsions were seen in mice after 30 minute of exposure and in rats and guinea
      pigs 15 minutes later. All animals were comatose within 60 minutes. All rats and
      mice and 7/10 guinea pigs died during exposure and 1 guinea pig during the
099-8 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>      14-day observation period (ACG99, BUA92). When male rats (n=5/group) and
      mice (n=10/group) were exposed to 9333 or 20,583 mg/m3 (1733, 3910 ppm) for
      1 hour, the general condition of the animals was impaired for up to 4-hour post-
      exposure, remaining normal thereafter through the remainder of the 14-day
      observation period, at the higher level. No effects were seen at 9333 mg/m3
      (BUA92). In rats (n=3/group; sex unknown) exposed to 0, 21,000, 73,000,
      900,000 mg/m3 (3990, 13,870, 171,000 ppm) for 6 hours, the signs of toxicity
      observed in the low-concentration animals included coordination loss (after 1.5
      hours), prostration (after 1.75 hours), and tremors (at 2 hours), as well as and
      marked vasodilation. Exposure to 73,000 mg/m3 induced coordination loss,
      vasodilation, laboured respiration, and narcosis. All rats in these 2 exposure
      groups survived the14-day observation period. In the high-concentration group,
      one animal died while severe prostration was seen in the other 2 surviving
      animals (ACG99).
      Repeated-dose toxicity
      When rats (Alderley Park; n=4/sex/group) were exposed to vapour
      concentrations of 2-chlorotoluene of 0, 2635, 5270, 210,800 mg/m3 (0, 500,
      1000, 4000 ppm), 6 hours/day, for 3 weeks, no effects were seen in the low-
      concentration group. In mid-concentration group, there were lethargy,
      diminished response to noise, traces of blood around the nostrils, and low body
      weight gain. No changes were observed in haematology and urinalysis
      parameters. There were no abnormal macroscopic or microscopic findings upon
      post-mortem examinations of the liver, kidneys, spleen, thymus, and ileum,
      while some isolated foamy macrophages were seen in the alveoli. Exposure to
      210,800 mg/m3 was lethal to all animals within 3 minutes (Bar70).
          Head-only exposure of rats (Harlan; n=10/sex/group) to aerosol
      concentrations of 2-chlorotoluene (purity: 96.4%; see Wor74) 0, 33,000, or
      62,000 mg/m3, 1 hour/day, 5 days/week, for 3 weeks, resulted mortality in 2
      males and 3 females of the high-concentration group (5 dying from ‘respiratory
      embarrassment’ while being held in the holding chamber; 1 female from
      suffocation in the holding chamber) and 1 female of the low-concentration group
      (cause of death: acute necrotising pneumonia). In high-concentration animals,
      severe ataxia followed each exposure, about half of the animals becoming
      prostrate for 15 to 30 minutes, and body weight gain was decreased, especially in
      females. In low-concentration animals, slight ataxia was observed, but body
      weight gain was similar to that in controls. Evaluation of haematology and
      clinical chemistry parameters (haematocrit, haemoglobin, red blood cell
099-9 2-Chlorotoluene
</pre>

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

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

<pre>       morphology, erythrocyte and total and differential leukocyte counts,
       prothrombin times, blood glucose, blood urea nitrogen, and serum alanine
       aminotransferase) only showed statistically significantly increased red blood cell
       counts in males of the low- and high-concentration groups (by 4.5 and 8%,
       respectively). Exposure did not affect mean relative organ weights (liver,
       kidneys, heart, spleen, thyroid, adrenals, prostate, testes, uterus, ovaries). Post-
       mortem macroscopic and microscopic evaluations did not demonstrate
       compound-related, toxicologically relevant effects (Art74c).
           When rats (Crl:COBS CD®(SD) BR; n=10/sex/group) were exposed to actual
       vapour concentrations of 2-chlorotoluene (purity: 96.5%) of 0, 4000, 7700,
       11,400, or 15,300 mg/m3 (760-2907 ppm), 6 hours/day, for 14 consecutive days,
       mortality occurred in 1/10 males and 1/10 females exposed to 15,300 mg/m3 and
       in 1/10 females exposed to 11,400 mg/m3. Clinical signs observed included dose-
       related salivation, lachrymation, CNS depression, and ataxia at concentrations of
       7700 mg/m3 and higher, and slight irritation and CNS depression at 4000 mg/m3.
       Other signs included increased incidences of alopecia and brown-stained fur,
       occurring in males at 11,400 mg/m3 and higher and in females at 7700 mg/m3 and
       higher. Body weight gain was significantly, dose-relatedly decreased in all male
       dose groups. Post-mortem observations included increased liver and kidney
       weights in all male dose groups and the 3 highest female dose groups. The effect
       was dose-related for liver, and for kidney in females only. There was a dose-
       related decrease in spleen weight in males at 7700 mg/m3 and higher and in
       females at 11,400 mg/m3 and higher. Macroscopic and microscopic findings only
       included increased incidences of alopecia and stained fur in males at 11,400
       mg/m3 and higher and in females at 7700 mg/m3 and higher, and centrilobular
       hepatocyte enlargement in 6/9 females of highest dose group (Ros83).
           When rabbits (New Zealand white; n=5/sex/group) were exposed to actual
       vapour concentrations of 2-chlorotoluene (purity: 96.5%) of 0, 4000, 7800,
       11,500, or 15,600 mg/m3 (760-2964 ppm), 6 hours/day, for 23 consecutive days,
       no mortality occurred. After each exposure, animals exhibited increased
       respiration. Salivation and lachrymation were seen at 15,600 and 11,500 mg/m3
       and slight salivation at 7800 mg/m3. Food consumption was less in all dose
       groups, being statistically significant at the high level only; there were dose-
       related decreases in body weight gain in all dose groups and weight loss at
       15,600 mg/m3. At post-mortem gross examinations (no microscopy), there were
       no abnormal treatment-related findings in any of the groups (Ros83).
       No systemic toxicity and only moderate to severe irritation at the application site
       was found in rabbits (New Zealand; n=4/sex/group) following repeated - 5
099-10 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

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

<pre>       days/week, for 4 weeks - dermal application of doses of 2-chlorotoluene (purity:
       96.4%; see Wor74) of 0.1, 0.3, or 1 mL/kg bw (ca. 100, 300, or 1000 mg/kg,
       respectively) (Art74b).
           Rats (strain: unknown; n=7/sex) were given daily oral (gavage)
       2-chlorotoluene doses of 270 mg/kg bw, for 14 days. Two animals/sex were
       killed 24 hours after the last dose and the remaining 6 days later. Animals
       exhibited normal appearance and behaviour throughout the study. There were no
       changes in body and liver weights and haematology findings. Macroscopic and
       microscopic examination of the animals killed 24 hours after the last dose
       showed pale enlarged kidneys without accompanying histological changes in one
       male and one female and 2 animals (sex not indicated) with stomach lesions
       (inflammation, oedema). The livers of these animals were investigated by
       electron microscopy and showed dilation of the smooth and rough endoplasmatic
       reticulum and evidence of slight mitochondrial damage and hypertrophy of the
       Golgi apparatus. Of the animals killed 6 days post-exposure, 2 males had
       enlarged kidneys without histological lesions and 3 males minimal signs of
       stomach inflammation (Bar70).
           In white rats, daily intragastric administration of 550 mg/kg bw in oily
       solution (= 0.1 LD50), for 2 months, caused stimulation of haematopoiesis, CNS
       depression, and impaired function of liver, kidneys, and immune system. With
       the same dosing regimen, 55 mg/kg bw led to considerably less marked
       symptoms (no more data or details presented) (BUA92).
           Rats (Harlan; n=20/sex/group) were given daily oral (gavage) doses of
       2-chlorotoluene (purity: 96.4%; see Wor74) of 0, 20, 80, or 320 mg/kg bw, 7
       days/week, for 3 months. At day 14, 5 rats/sex/group were killed for
       determination of the effect on the rate of hepatic O-demethylation of p-
       nitroanisole while similar determinations were performed in another 5 rats/sex/
       group at study termination (see Section ‘Biotransformation and kinetics’). Prior
       to necropsy, blood samples were obtained from each rat for haematology and
       clinical chemistry determinations (haematocrit, haemoglobin, red and white
       blood cell counts; prothrombin times on the serum of half of the animals, and
       blood urea nitrogen, alanine aminotransferase, and glucose on the serum of the
       other half of the animals). Post-mortem, weights of liver, kidneys, heart, spleen,
       thyroid, adrenals, prostate, testes, uterus, and ovaries were determined and liver,
       kidneys, heart, spleen, thyroid, adrenals, prostate, testes, uterus, ovaries colon,
       duodenum, ileum, jejunum, lungs, lymph nodes, mammary, pancreas,
       parathyroid, salivary glands, skin, stomach, striated muscle, thymus, and urinary
       bladder histologically examined. Apart from notations on the protocol of
       ‘increased urine output’ (which was not based on actual volumetric data), ‘nasal
099-11 2-Chlorotoluene
</pre>

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

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

<pre>       discharge’, or ‘bloody nasal discharge’, there were no treatment-related changes
       in behaviour, survival rate, haematology, clinical chemistry, or histological
       organ findings. In the male animals of the mid- and high-dose groups,
       statistically significantly decreased body weights were observed while mean
       body weights in the low-dose groups and in the females of the mid- and high-
       dose groups were similar to that in controls. Changes in relative organ weights
       were seen in male animals only and included increased adrenal weights in the
       mid- and high-dose group (by 27 an 24%, respectively) and increased heart
       weights (by 14%) in the high-dose group (Gib74a). From this 3-month oral
       study, the committee concludes that 20 mg/kg bw/day is a NOAEL in rats based
       on the decreased body weights observed in male animals at 80 mg/kg bw/day.
           When dogs (Beagle; n=4/sex/group) were given daily oral (by capsule) doses
       of 0, 5, 20, and 80 mg/kg bw of 2-chlorotoluene (purity: 96.4%; see Wor74), 7
       days/week, for 3 months, no treatment-related effects on behaviour, survival,
       eyes, haematology, clinical chemistry, urinalysis, bone marrow, and organs
       (weight, macroscopic and microscopic evaluation) were observed in any of the
       dose groups (Gib74b). From this 3-month oral study, the committee concludes
       that 80 mg/kg bw/day, the highest level tested is a NOAEL in dogs.
       Mutagenicity and genotoxicity
       In vitro, 2-chlorotoluene did not induce mutations or was negative:
       • a mutation assay, using S. typhimurium strains TA98, TA100, TA1535,
           TA1537, and TA1538, with and without induced rat liver metabolic
           activation (Lit82d)
       • a forward mutation assay in mouse lymphoma L5178Y cells, with and
           without rat liver metabolic activation (Lit82c)
       • a chromosome aberration assay in Chinese hamster ovary cells, with and
           without rat liver metabolic activation (Lit82a)
       • the umu test, to detect the induction of error-prone DNA repair, using S.
           typhimurium TA1535/pSK1002 with and without rat liver metabolic
           activation (Ono92)
       in vivo in:
       • a chromosome aberration assay in bone marrow of rats, after 1 or 5 daily oral
           doses (Lit82b)
099-12 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

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

<br><br>====================================================================== Pagina 13 ======================================================================

<pre>       and further in:
       • an in vitro cell transformation assay using Balb/3T3 cells, with and without
           rat liver metabolic activation (Lit83)
       Reproduction toxicity
       Pregnant rats (Crl:COBS CD®(SD) BR; n=25/group) were exposed to 2-
       chlorotoluene concentrations of 0, 1000, 3000, or 9000 mg/m3 (190, 570, 1710
       ppm), 6 hours/day, on gestational days 6 to 19. During exposure to 9000 and
       3000 mg/m3, the rats showed slight to moderate and slight ataxia, respectively.
       At 9000 mg/m3, food consumption was significantly reduced (p<0.05), while
       mean water consumption was significantly increased at 9000 and 3000 mg/m3.
       Maternal body weight gains were markedly and slightly reduced at 9000 and
       3000 mg/m3, respectively. At 9000 mg/m3, significantly reduced litter and fetal
       weights (p<0.01 and p<0.001, respectively) and increased incidences of
       malformations, skeletal anomalies, and skeletal variants were seen. At 1000 and
       3000 mg/m3, the offspring did not show any treatment-related effects (Edw83a).
           Pregnant New Zealand white rabbits (n=16/group) were exposed to 2-
       chlorotoluene concentrations of 0, 1500, 4000, and 10,000 mg/m3 (285, 760,
       1900 ppm), 6 hours/day, on gestational days 6 to 28. At 10,000 mg/m3,
       lachrymation, salivation, and ptosis were observed during initial exposures. At
       10,000 and 4000 mg/m3, there was a significant dose-related reduction in food
       consumption during the treatment period, which resulted in retardation of mean
       maternal body weight gain between the onset of treatment and day 9 of gestation.
       The treatment had no significant effect on litter size, pre- and post-implantation
       loss, litter or fetal weight, or incidence of skeletal anomalies and variants
       (Edw83b).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for
       2-chlorotoluene in the Netherlands is 50 ppm (250 mg/m3), 8-hour TWA, with a
       skin notation.
           Existing occupational exposure limits for 2-chlorotoluene in some European
       countries and in the USA are summarised in the annex.
099-13 2-Chlorotoluene
</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>8      Assessment of health hazard
       The committee did not find human data on the toxicokinetics or on the effects
       following exposure to 2-chlorotoluene.
            The committee did not find experimental animal data on the toxicokinetics
       following inhalation of 2-chlorotoluene. When given intravenously or orally
       (gavage) to rats, 2-chlorotoluene was rapidly absorbed and metabolised, and
       almost completely excreted within 24 hours. 2-Chlorotoluene was oxidised at the
       methyl group to chlorobenzyl alcohol and chlorobenzoic acid, and excreted
       mainly in the urine (ca. 70-90%) as the glucuronide or mercapturic acid of the
       alcohol or as chlorohippuric acid, and in small amounts in expired air (ca.
       5-15%; basically parent compound) and faeces (ca. 2-7%).
            Data on skin and eye irritation are conflicting. On one hand, they indicate
       that 2-chlorotoluene is corrosive to the skin and irritating to the eyes while on the
       other hand, unpublished studies (not available to the committee) performed
       according to OECD guidelines should lead to the conclusion that the compound
       is slightly irritating to the skin and not irritating to the eyes. There were no
       indications for a skin-sensitising potential.
            Acute inhalation, dermal, and oral lethal toxicity data included 1-hour LC50
       values in rats and mice of higher than ca. 21,000 mg/m3, dermal LD50 values of
       higher than ca. 1100 and 2200 mg/kg bw in rats and rabbits, respectively, and
       oral LD50 values of 2500 mg/kg bw and above in mice, rats, and guinea pigs. The
       primary effects observed in the inhalation studies consisted of symptoms such as
       laboured breathing, loss of coordination, prostration, and narcosis.
            The committee found only limited information from repeated inhalation
       studies, in which animals were either exposed intermittently (5 days/week) for 3
       weeks (rats) or for 14 or 23 consecutive days (rats and rabbits, respectively).
       Intermittent exposure - 6 hours/day, 5 days week, for 3 weeks - of rats to vapour
       concentrations of 2635 mg/m3 (500 ppm) did not induce any effects while
       lethargy, diminished response to noise, blood around the nostrils, and decreased
       body weight were seen at the next higher concentration of 5270 mg/m3 (1000
       ppm). Consecutive exposure - 6 hours/day, for 14 (rats) or 23 (rabbits) days - to
       vapour concentrations of 4000 mg/m3 (760 ppm), the lowest level tested, caused
       slight irritation, CNS depression, and increased liver weights (males only) in rats
       and decreased body weight gain in rabbits.
            In 3-month oral studies in rats and dogs, which included a limited number of
       haematology and clinical chemistry findings and adequate post-mortem
       examinations (Gib74a, Gib74b), daily doses of 80 mg/kg bw caused non-specific
099-14 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<pre>       effects like depressed growth and increased relative adrenal weights in male rats
       only while no effects were observed at 20 mg/kg bw or in female rats up to
       320 mg/kg bw, the highest dose tested. In dogs, no effects were seen at doses up
       to 80 mg/kg bw, the highest dose tested. The committee did not find data from
       long-term repeated-dose toxicity studies, including carcinogenicity, on
       2-chlorotoluene.
           In in vitro assays, 2-chlorotoluene did not induce mutations or DNA damage
       in bacteria or mutations or chromosome aberrations in mammalian cell systems.
       In vivo, the compound did not induce an increase in the incidence of
       chromosome aberrations in bone marrow from rats following single or repeated
       oral administration.
           No developmental toxicity was observed in rats after inhalation exposure to
       3000 mg/m3 (570 ppm), 6 hours/day, on gestational days 6 to 19, a concentration
       that induced slight ataxia and slightly reduced maternal body weight gains. At
       the next higher concentration of 9000 mg/m3 (1710 ppm), there was
       developmental toxicity (reduced litter and fetal weights, increased incidences of
       malformations, skeletal anomalies, and skeletal variants) accompanied by
       marked maternal toxicity (slight to moderate ataxia; markedly reduced body
       weight gain). Tested similarly in rabbits, no developmental toxicity was seen at
       concentrations up to 10,000 mg/m3 (1900 ppm), the highest level tested.
       Maternal toxicity observed included retarded body weight gain in the first
       3 exposure days at 4000 and 10,000 mg/m3 (760, 1900 ppm) and lachrymation,
       salivation, and ptosis during initial exposures to 10,000 mg/m3.
       The committee is of the opinion that, because of limitations in study design
       (short duration, continuous exposure), the quality of the inhalation studies is
       insufficient to be used as a basis for deriving a health-based recommended
       occupational exposure limit (HBROEL). Therefore, the committee takes the
       NOAEL of 20 mg/kg bw of the better designed 3-month oral rat study (Gib74a)
       as a starting point. Since workers are exposed for 5 days a week, this NOAEL
       from a continuous study (i.e., 7 days a week) is adjusted by multiplying with a
       factor of 7/5 resulting in a no-adverse-effect level (NAEL) of 28 mg/kg bw. For
       the extrapolation to a HBROEL, a factor of 4 for allometric scaling from rats to
       humans, based on caloric demand, and an overall factor of 18, covering inter-
       and intraspecies variation and the differences between experimental conditions
       and the exposure pattern of the worker, are applied, resulting in a NAEL for
       humans of 0.4 mg/kg bw/day. Assuming a 70-kg worker inhales 10 m3 of air
       during an 8-hour working day and a retention of 100%, and applying the
099-15 2-Chlorotoluene
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>       preferred value approach, a HBROEL of 2 mg/m3 is recommended for
       2-chlorotoluene.
       The committee recommends a health-based occupational exposure limit for
       2-chlorotoluene of 2 mg/m3 (0.4 ppm), as an 8-hour time-weighted average
       (TWA).
       The committee did not find kinetic data to evaluate absorption through the skin.
       However, in view of the low acute lethal toxicity following dermal and
       inhalation exposure, an exclusion criterion in the decision scheme to decide on a
       skin notation (ECE98), the committee does not recommend a skin notation.
       References
ACG99  American Conference of Governmental Industrial Hygienists (ACGIH). o-Chlorotoluene. In: TLVs®
       and other occupational exposure values - 1999. [CD-ROM]. Cincinnati OH, USA: ACGIH®, Inc,
       1999.
ACG03a American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values – 2003. Cincinnati OH, USA: ACGIH®, Inc, 2003: 31.
ACG03b American Conference of Governmental Industrial Hygienists (ACGIH). 2003 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, Inc, 2003: 22.
Ala95  Alarie Y, Nielsen GD, Andonian HF, et al. Physicochemical properties of nonreactive volatile
       organic chemicals to estimate RD50: alternatives to animal studies. Toxicol Appl Pharmacol 1995;
       134: 92-9.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 20 (At-vejledning C.0.1).
Art74a Arthur BH, Gibson WR, Griffing WJ, et al. The effects on laboratory animals from single exposures
       to o-chlorotoluene. Greenfield IN, USA: Lilly Research Laboratories, Toxicology Division, 1974
       (available from NTIS, Springfield VA, USA; order no NTIS/OTS0507354).
Art74b Arthur BH, Harris PN, Worth HM. Subacute dermal toxicity of o-chlorotoluene to rabbits. Greenfield
       IN, USA: Lilly Research Laboratories, Toxicology Division, 1974 (available from NTIS, Springfield
       VA, USA; order no NTIS/OTS0507354).
Art74c Arthur BH, Owen NV, Worth HM. Subacute inhalation toxicity of o-chlorotoluene to rats. Greenfield
       IN, USA: Lilly Research Laboratories, Toxicology Division, 1974 (available from NTIS, Springfield
       VA, USA; order no NTIS/OTS0507354).
Art74d Arthur BH, Worth HM. The effects on the guinea pig from multiple dermal applications of o-
       chlorotoluene; a sensitization study. Greenfield IN, USA: Lilly Research Laboratories, Toxicology
       Division, 1974 (available from NTIS, Springfield VA, USA; order no NTIS/OTS0507354).
099-16 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>Bar70  Barry ES. Toxicological report. o-Chlorotoluene. Macclesfield, England: Imperial Chemical
       Industries, Ltd, Industrial Hygiene Research Laboratories, 1970; rep no HO/IH/T/768.
BUA92  GDCh-Advisory Committee on Existing Chemicals of Environmental Relevance (Beratergremium
       für Umweltrelevante Altstoffe) (BUA). Chlorotoluenes (methylchlorobenzenes). Stuttgart, FRG: S.
       Hirzel Verlagsgesellschaft, 1992; BUA Report 38.
BUA96  GDCh-Advisory Committee on Existing Chemicals of Environmental Relevance (Beratergremium
       für Umweltrelevante Altstoffe) (BUA), ed. Chlorotoluene. In: Di(2-ethylhexyl)phthalate (No. 4);
       chloromethane (No. 7); o-nitroanisole (No. 9); p-nitroanisole (No. 10); m-/p-chloronitrobenzene (No.
       11); dinitrotolunene (No. 12); diphenylamine (No. 15); dibutylphthalate (No. 22); chlorotoluene (No.
       38); N-ethylaniline (No. 51); dioxane (No. 80). Stuttgart, FRG: S. Hirzel Verlagsgesellschaft, 1996;
       BUA Report 114 (Supplementary reports I).
Che99  Chemiekaarten: gegevens voor het veilig werken met chemicaliën/[ed by] Samenwerkingsverband-
       Chemiekaarten (TNO Arbeid, VNCI). 15th ed. The Hague, the Netherlands: ten Hagen & Stam,
       1999.
DFG03  Deutsche Forschungsgemeinschaft (DFG): Commission for the Investigation of Health Hazards of
       Chemical Compounds in the Work Area. List of MAK and BAT values 2003. Maximum
       concentrations and Biological Tolerance Values at the workplace Weinheim, FRG: Wiley-VCH
       Verlag GmbH & Co. KGaA, 2003; rep no 39.
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.
ECE98  European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC). Examination of a
       proposed skin notation strategy. Brussels, Belgium: ECETOC, 1998; Special Report No. 15.
Edw83a Edwards JA, Leeming NM, Clark R, et al. Effect of 2-chlorotoluene vapour on pregnancy of the rat.
       Hungtingdon (Cambridgeshire), England: Huntingdon Research Centre plc, 1983; rep no HKR 8/
       821122 (available from NTIS, Springfield VA, USA; order no NTIS/OTS0507458).
Edw83b Edwards JA, Leeming NM, Clark R, et al. Effect of 2-chlorotoluene vapour on pregnancy of the New
       Zealand white rabbit. Huntingdon (Cambridgeshire), England: Huntingdon Research Centre plc,
       1983; rep no HKR7/8369 (available from NTIS, Springfield VA, USA; order no NTIS/
       OTS0507457).
Gib74a Gibson WE, Gossett FO, Koenig GR, et al. The toxicity of daily oral doses of o-chlorotoluene in the
       rat. Greenfield IN, USA: Lilly Research Laboratories, Toxicology Division, 1974 (available from
       NTIS, Springfield VA, USA; order no NTIS/OTS0507354).
Gib74b Gibson WE, Gossett FO, Koenig GR, et al. The toxicity of daily oral doses of o-chlorotoluene in the
       dog. Greenfield IN, USA: Lilly Research Laboratories, Toxicology Division, 1974 (available from
       NTIS, Springfield VA, USA; order no NTIS/OTS0507354).
Hof74  Hoffman DG, Bernhard NR. The effect of o-chlorotoluene (compound 22679) on hepatic p-
       nitroanisole O-demethylation in rats and dogs. Greenfield IN, USA: Lilly Research Laboratories,
       Toxicology Division, 1974 (available from NTIS, Springfield VA, USA; order no NTIS/
       OTS0507354).
099-17 2-Chlorotoluene
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational exposure limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 14.
Lit82a Litton Bionetics, Inc. Mutagenicity evaluation of orthochlorotoluene in an in vitro cytogenetic assay
       measuring chromosome aberration frequencies in Chinese hamster ovary (CHO) cells. Final Report.
       Kensington MD, USA: Litton Bionetics, Inc, 1982 (abstract cited from Toxline) (original report
       available from NTIS, Springfield VA, USA; order no NTIS/OTS0507446)
Lit82b Litton Bionetics, Inc. Mutagenicity evaluation of orthochlorotoluene (OCT) in the rat bone marrow
       cytogenetic assay. Final report. Kensington MD, USA: Litton Bionetics, Inc, 1982 (abstract cited
       from Toxline) (report available from NTIS, Springfield VA, USA; order no NTIS/OTS0507445).
Lit82c Litton Bionetics, Inc. Mutagenicity evaluation of orthochlorotoluene (OCT) in the mouse lymphoma
       forward mutation assay. Final report. Kensington MD, USA: Litton Bionetics, Inc, 1982 (abstract
       cited from Toxline) (report available from NTIS, Springfield VA, USA; order no NTIS/
       OTS0507444).
Lit82d Litton Bionetics, Inc. Mutagenicity evaluation of orthochlorotoluene in the Ames Salmonella/
       microsome plate test. Final report. Kensington MD, USA: Litton Bionetics, Inc, 1982 (abstract cited
       from Toxline) (report available from NTIS, Springfield VA, USA; order no NTIS/OTS0507442).
Litt83 Litton Bionetics, Inc. Evaluation of orthochlorotoluene in the in vitro transformation of Balb/3T3
       cells assay with microsomal enzyme-medicated metabolic activation. Final report. Kensington MD,
       USA: Litton Bionetics, Inc, 1983 (abstract cited from Toxline) (report available from NTIS,
       Springfield VA, USA; order no NTIS/OTS0507430).
Mul84  Muller J, Greff G. Recherche de relations entre toxicité de molécules d'intérêt industriel et propriétés
       physico-chimiques: test d'irritation des voies aériennes supérieures appliqué à quatre familles
       chimiques. Food Chem Toxicol 1984; 22: 661-4.
NIO03  US National Institute of Occupational Safety and Health (NIOSH), ed. Toluene, -o-chloro-. In:
       Registry of Toxic Effects of Chemical Substances (last update 2-chlorotoluene file: October 2002);
       http://www.cdc.gov/niosh/rtecs/xs895440.html.
NLM03  US National Library of Medicine (NLM), ed. 2-Chlorotoluene. In: Hazardous substances data bank
       (HSDB) (last revision date 2-chlorotoluene file: 24 January 2003; last review date: 19 September
       1996); http://toxnet/nlm.nih.gov.
Ono92  Ono Y, Somiya I, Kawaguchi T. Genotoxic evaluation on aromatic organochlorine compounds by
       using umu test. Water Sci Technol 1992; 26: 61-9
Pis81  Pis'ko GT, Tolstopyatova GV, Belyanina TV, et al. [Substantiation of maximum permissible
       concentrations of o- and p-chlorotoluenes in reservoir water]. In Russian. Gig Sanit 1981; 46 (2): 67-
       8.
Qui83  Quistad GB, Mulholland KM, Jamieson GC. 2-Chlorotoluene metabolism by rats. J Agric Food
       Chem 1983; 31: 1158-62.
Ros83  Rose PH, Hardy CJ, Clark GC, et al. 2-Chlorotoluene; a preliminary inhalation study in the rat and
       rabbit. Huntingdon (Cambridgeshire), England: Huntingdon Research Centre, 1983; HRC rep no
       HKR 5/82802.
099-18 Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<pre>San89  Sangster J. Octanol-water partition coefficients of simple organic compounds. J Phys Chem Ref Data
       1989; 18: 1111-229.
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: 21.
TRG00  TRGS 900: Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArbBl
       2000; 2.
Wol74  Wold JS. The metabolism of o-chlorotoluene-14C in the rat. Greenfield IN, USA: Lilly Research
       Laboratories, Toxicology Division, 1974 ((available from NTIS, Springfield VA, USA; order no
       NTIS/OTS0507354).
Wor74  Worth HM, Emmerson JL. The safety evaluation of o-chlorotoluene. Indianapolis IN, USA: Elanco
       Products Company, Lilly Research Laboratories, Toxicology Division, 1974 (available from NTIS,
       Springfield VA, USA; order no NTIS/OTS0507354).
You96  Young WF, Horth H, Crane R, et al. Taste and odor threshold concentrations of potential potable
       water contaminants. Water Res 1996; 30: 331-40.
099-19 2-Chlorotoluene
</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>              Annex
Occupational exposure limits for 2-chlorotoluene 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     50            250           8h                  administrative  S          SZW03
Employment
Germany
- AGS                                -             -                                                            TRG00
- DFG MAK-Kommission                 -             -                                                            DFG03
Great Britain
- HSE                                50            264           8h                  OES                        HSE02
Sweden                               -             -                                                            Swe00
Denmark                              50            285           8h                                  S          Arb02
USA
- ACGIH                              50            -             8h                  TLV                        ACG03b
- OSHA                               -             -
- NIOSH                              50            250           10 h                REL                        ACG03a
                                     75            375           15 min              STEL                       ACG03a
European Union
- SCOEL                              -             -                                                            EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to the body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
099-20        Health-based Reassessment of Administrative Occupational Exposure Limits
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>