<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>Hexachlorocyclopentadiene
(CAS No: 77-47-4)
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/081, The Hague, 22 October 2003
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Hexachlorocyclopentadiene; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2003; 2000/15OSH/081.
all rights reserved
</pre>

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<pre>1     Introduction
      The present document contains the assessment of the health hazard of
      hexachlorocyclopentadiene (HEX) 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 he toxicity of HEX has been based on reviews published
      by the American Conference of Governmental Hygienists (ACG99), Agency for
      Toxic Substances and Disease Registry (ATSDR) (ATS99), the Advisory
      Committee on Existing Chemicals of Environmental Relevance of the German
      Chemical Society (BUA88), the German MAK-committee (Gre01), and the
      World Health Organization (International Programme on Chemical Safety)
      (WHO91). Where relevant, the original publications were reviewed and
      evaluated as will be indicated in the text. In addition, in August 2000, literature
      was searched in the databases Toxline, Medline, and Chemical Abstracts
      covering the period of 1989 until August 2000, and using the following key
      words: hexachlorocyclopentadiene, perchlorocyclopentadiene, and 77-47-4. The
      final search was carried out in Toxline and Medline in January 2003.
          In April 2003, the President of the Health Council released a draft of the
      document for public review. Comments were received by the following
      individuals and organisations: A Aalto (Ministry of Social Affairs and Health,
      Tampere, Finland). These comments were taken into account in deciding on the
      final version of the document.
081-3 Hexachlorocyclopentadiene
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<pre>2     Identity
      name                     :   hexachlorocyclopentadiene
      synonyms                 :   1,2,3,4,5,5'-hexachloro-1,3-cyclopentadiene; perchlorocyclopentadiene;
                                   hexachloro-1,3-cyclopentadiene; 1,2,3,3,4,5-hexachloro-1,4-cyclopentadiene;
                                   HCCP
      molecular formula        :   C5Cl6
      structural formula       :
      CAS number               :   77-47-4
      Data from BUA88, WHO91.
3     Physical and chemical properties
      molecular weight       :   272.77
      boiling point          :   239oC
      melting point          :   -9oC to -11oC
      flash point            :   not available
      vapour pressure        :   at 25oC: 10 Pa
      solubility in water    :   insoluble (at 22oC: 0.1 mg/100 mL)
      log Poctanol/water     :   5.04-5.51 (experimental); 4.30-4.63 (estimated)
      conversion factors     :   at 20oC and 101.3 kPa:1 ppm = 11.4 mg/m3
                                                         1 mg/m3 = 0.09 ppm
      Data from: BUA88, WHO91, http://esc.syrres.com.
      HEX is a faint yellow to greenish-yellow, non-flammable liquid with a pungent
      odour (ACG99, BUA88). HEX is a highly reactive compound that readily
      undergoes addition and substitution reactions, for example in Diels-Alder
      reactions (BUA88, WHO91). The compound dissociates in a flame or when in
      contact with a hot surface, forming toxic and corrosive vapours (phosgene,
      hydrochloric acid and chlorine gas). In contact with air, the compound forms
      corrosive fumes that can spread over the floor (Che99). Odour thresholds of
081-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      0.002 (0.17 ppb) (WHO91), 0.34 (0.03 ppm) (Amo83), and 1.5-3.3 mg/m3 (1.4-3
      ppm) (Rut86) have been reported.
4     Use
      HEX is an intermediate used in the manufacture of organochlorine pesticides
      (e.g., endosulfan) and of flame-retardants for resins and polymers (ACG99,
      BUA88).
5     Biotransformation and kinetics
      Human data
      One human volunteer received a dose of 1.3 mg 14C-labelled HEX following
      exposure to its vapour (exposure concentration of 14C-HEX and duration of
      exposure not given). Excretion of radioactivity in the urine started 30 minutes
      after the end of exposure, and most of the radioactivity was excreted within 5
      days. No unchanged HEX was detected in urine. Radioactivity comprised polar
      metabolites, which could not be identified (Kha81).
      Animal data
      Groups of female Sprague-Dawley rats were exposed ‘nose-only’ to vapours of
      [14C]-HEX (radiochemical purity: >95%) for 30 to 120 min, at air concentrations
      ranging from 0.11 to 0.56 mg/m3. The percent retention of HEX increased with
      the time of exposure, being 77% after 30 min of exposure and 95% after 120 min
      exposure to the vapour. Retained doses received by the rats ranged from 1 to 40
      µg/kg bw, but the retention was not influenced by the quantity received within
      this range of doses. At a retained dose of 24 µg/kg bw following 1-hour
      exposure, the maximum concentration of radioactivity in blood was achieved at
      the end of the exposure period. At 72 hours after the end of exposure, 33.1% of
      the dose was excreted in the urine, 23.1% in the faeces, and less than 1% in
      expired air. Most of the urinary radioactivity (29.7 % of the dose) was already
      excreted within 24 hours. The amount of radioactivity retained in the body was
      12.9%, most of it in the trachea, lungs, and kidneys (Law81, Law82). In another
      inhalation study, 2 groups of Fischer rats were exposed to [14C]-HEX in air
      (radiochemical purity: >95%; exposure times and air concentrations not given).
      The average absorbed doses were 1.3 and 1.8 mg/kg bw, respectively. At 6 and
      72 hours after the end of exposure, 28.7% and 47.5% of the dose were excreted
081-5 Hexachlorocyclopentadiene
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<pre>      in the faeces, 41.0 and 40.0% in the urine, and 1.4% and 1.0% in expired air (as
      14
         CO2), respectively. Radioactivity retained in the body amounted to 11.5% of the
      dose at 72 hours post-exposure, most of it in the kidneys, the lungs, and the blood
      (ElD83). In either inhalation study, no unchanged HEX or metabolites were
      found in excreta or tissues; the majority of the radiolabel comprised water-
      soluble, polar material (ElD83, Law82).
      The kinetics of HEX in rats following oral dosing has been reported in several
      studies. Rats given a single oral (gavage) dose of 5.5 mg/kg bw of [14C]-HEX
      excreted 35 and 10% of the dose in the urine and the faeces, respectively, within
      7 days. At day 7, only 0.5% of the dose was found in the kidneys and the liver
      (Meh77). In an unpublished study, groups of Sprague-Dawley rats received oral
      doses ranging from 8.5 to 25.6 mg/kg bw. The concentration of radioactivity in
      the blood reached a maximum at 4 hours after administration. Within 48 hours,
      16 and 70% of the radioactivity were excreted in the urine and faeces,
      respectively. At 48 hours after dosing, 2.8% of the radioactivity was retained in
      the organs (liver, kidneys, adipose and muscle tissue, brain, and heart). No
      unchanged HEX was detected in urine or faeces, and most of the radiolabel
      comprised polar products (Yu81). In another study, groups of female Sprague-
      Dawley rats were given single oral doses of 5 to 10 µg/kg bw of [14C]-HEX
      (radiochemical purity: >95%). The maximum blood level of radioactivity was
      reached at 2 to 5 hours after dosing. About 24 and 68% of the dose were excreted
      in the urine and faeces, respectively, within 72 hours after administration. More
      than 90% of the dose was already excreted within the first 24 hours. Biliary
      excretion accounted for 18% of the administered dose, indicating that the
      majority of the dose excreted in faeces comprised unabsorbed material. Bile and
      faeces contained predominantly polar or unextractable material. At 72 hours after
      administration, only 0.2% of the dose was retained in the organs. When the rats
      received a much higher dose (6 mg/kg bw), the amounts of radioactivity excreted
      in urine or faeces were comparable to those excreted at the low dose (about 15%
      of the dose in the urine and 64% in the faeces). However, the retention of
      radioactivity in tissues was appreciably higher (2.8%), most of it in the kidneys
      (1.9%) (Law82). Similar results were obtained in Fischer rats, dosed with 61
      mg/kg bw of [14C]-HEX. Within 72 hours, about 65% of the dose was excreted in
      faeces, 29% in urine, and 0.9% in expired air, while 2.4% of the dose was
      retained in the tissues (ElD83). Groups of rats and mice were given [14C]-HEX,
      either as a single oral (gavage) dose of 2.5 or 25 mg/kg bw, or as daily dietary
      doses of approximately 0.07 to 1.7 mg/kg bw/day for rats and 0.18 to 4.6 mg/kg
      bw/day for mice for 30 days. In the repeated study, the animals were returned to a
081-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      normal diet for up to 30 days. In the single dose study, in either species or sexes,
      the majority of radioactivity (73-96% of the dose) was excreted within 2 days,
      most of it in the faeces. In the repeated dose study, the total excretion of
      radioactivity ranged from 63 to 79% of the dose, on average about 64% in the
      faeces and 8.4% in the urine. In all cases, the kidneys, the liver, and the fat
      contained the highest amounts of radioactivity. Steady state levels of
      radioactivity in these tissues were reached after 15 days of feeding. In a separate
      experiment male rats, in which the bile duct was cannulated, received a single
      oral dose of 25 mg/kg bw of [14C]-HEX. About 16% of the dose was excreted in
      the bile over a 24-hour period confirming poor absorption of orally administered
      HEX. No unchanged HEX was detected in either bile or faeces. The radioactivity
      comprised polar metabolites formed in all probability in the intestine, and most
      of these were not resorbed (Dor84).
          When given intravenously, rats given a single dose of 0.73 mg of [14C]-HEX,
      excreted 21% of the dose via the faeces and 18% via the urine within 48 hours,
      while some 28% of the radioactivity remained in the tissues (Yu81). In another
      study, 34% of the dose was excreted in the faeces and 16.8% in the urine within
      72 hours after administering 0.59 mg/kg bw. Radioactivity retained in tissues
      amounted to 39% of the dose (ElD83). Female Sprague-Dawley rats excreted
      about 31% of the radioactivity in the faeces and 22% in the urine within 72 hours
      after administration of 10 µg/kg bw. Radioactivity in tissues amounted 31% of
      the dose, most of it in the kidneys and the lungs (Law82).
      In vitro studies
      When incubated with [14C]-HEX in vitro, HEX bound to components of liver,
      intestinal contents, and faecal homogenates, as well as to components of whole
      blood and plasma (ElD83).
          In summary, following inhalation or intravenous administration, HEX was
      completely metabolised and rapidly excreted. In case of inhalation, 95% of the
      vapour inhaled was retained and approximately equal fractions of this dose were
      excreted in the faeces and in the urine (ca. 36%) and ca. 1% in expired air.
      Significant amounts (ca. 12%) were retained in the body (especially trachea,
      lungs, and kidneys). Orally administered HEX was poorly absorbed, probably
      due to its reactivity with the contents of the gastrointestinal tract, and
      considerably more of orally dosed HEX was excreted in the faeces when
      compared to HEX administered by inhalation or intravenous injection. The polar
      faecal and urinary metabolites have been isolated but not identified. The failure
      to identify metabolites represents a major difficulty in assessing the
      pharmacokinetics and potential mechanisms of action of HEX.
081-7 Hexachlorocyclopentadiene
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<pre>           After inhalation exposure, HEX can bind to epithelial lung tissue and
      extracellular lining in the lung and to bronchiolar Clara cells in rats (Ran82b).
           No studies on the kinetics of HEX following dermal application were found,
      but toxic responses reported after dermal application suggest that HEX is
      absorbed via the dermal route (WHO91).
6     Effects and mechanism of action
      Human data
      In March 1977, a municipal sewage treatment plant was illegally contaminated
      with a large volume of HEX and related chlorinated hydrocarbons, e.g.,
      octachlorocyclopentene (OCCP), for several days. A number of 193 plant
      employees had worked at the sewage plant for 2 or more days from the beginning
      of the dumping, which was detected by an objectionable odour, until closure of
      the plant when analysis showed the wastewater to be contaminated with HEX,
      and to a lesser extent with OCCP. Although the airborne concentrations of HEX
      at the time of exposure were not known, concentrations in the primary treatment
      areas (screen and grit chambers) ranged between 3 and 11 mg/m3 (0.27-0.97
      ppm), 4 days after the plant closed. A questionnaire was sent to each of the 193
      plant workers and 145 (75%) responded. Most of the workers were men (85%).
      They were generally healthy and had an average age of 35 years. The most
      common symptoms reported were eye irritation (59%), headache (45%), and
      throat irritation (27%). Furthermore, nausea, skin irritation, cough, chest pain,
      difficult breathing, nervousness, abdominal cramps, decreased appetite,
      decreased memory, and increased saliva were reported (19-21 %). Even 6 weeks
      after the episode, a follow-up questionnaire of 177 plant workers showed
      residual symptoms, i.e., headache (18%), fatigue (15%), respiratory tract (9%)
      and eye irritation (9%). Informal follow-up indicated that complaints of
      persistent symptoms slowly declined over 6 months. Of the 41 workers who
      received a medical examination 27% had increased serum LDH activity and 27%
      proteinuria. Three weeks later, these abnormalities had disappeared. Similar
      complaints were noticed in a group of workers (n=97) who were engaged in the
      clean-up of the plant. No abnormalities were seen in haematology parameters,
      urinalyses, or biochemical renal function tests. However, in 18 workers, slight
      abnormalities were recorded in one or more liver function tests, i.e., serum
      aspartate aminotransferase (in 11 workers), serum alkaline phosphatase (in 5),
      serum bilirubin and aspartate aminotransferase (in 1), or serum LDH (in 1); 8
      persons had abnormalities on more than one occasion. Seven workers showed an
081-8 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      increased aspartate aminotransferase activity, probably related to exposure to
      contaminated sewage (Kom80, Mor79).
          In a cross-sectional study, hepatic and renal functions were measured of a
      group of 73 male operators employed in a chemical plant producing chlorinated
      hydrocarbons for on average 8.2 years (range: 0.5-23 years). Exposure data were
      given over the period 1980 to 1993 for allyl chloride, HEX, epichlorohydrin, and
      1,3-dichloropropene. Air concentrations of allyl chloride and HEX occasionally
      exceeded the occupational exposure limits of 3 and 0.11 mg/m3, respectively.
      Biochemical liver function tests (serum ALAT, ASAT, alkaline phosphatase,
      LDH, GGT, and total bile acids) were not statistically significantly different
      compared to a control group. Nor were differences found in biochemical tests for
      renal tubular damage (urinary alanine aminopeptidase, N-acetyl-β-D-
      glucosaminidase, retinol binding protein, and total protein). However, urinary
      albumin concentrations were significantly higher in the exposed group, but this
      (small) increase was not related to exposure. It was concluded that long-term
      exposure to the above chemicals at air levels below or near the respective MAC-
      values does not lead to clinically significant effects on kidney and liver (Boo93).
          Several epidemiological studies have been reported on workers engaged in
      the manufacture of HEX or chlorinated ‘cyclodiene’ pesticides. Only one of
      these studies dealt with workers who had been engaged in the manufacture of
      HEX. This unpublished mortality study comprised 341 workers (27 males and 54
      females) who had worked in the plant for at least 3 months between 1953 and
      1974. The standardised mortality ratio (SMR) for all causes of death was 69.
      Deaths caused by specific cancers, all cancers, and diseases of the circulatory
      and digestive systems were fewer compared to the overall USA population. No
      data were provided on HEX exposures during the above period. The authors
      noted that the time that had elapsed since the initial exposure (25 years at most)
      reduced the power of the study to detect cancers that may have a 10-40 year
      latent period (Bun80). The other reported epidemiological studies dealt with
      workers who might have been exposed to HEX during the production of
      ‘cyclodiene’ pesticides chlordane, heptachlor, and aldrin and dieldrin. However,
      in none of the reports, information on HEX exposure was given.
          In an unpublished study, the mortality was examined of a cohort of 783
      workers who had been involved in the manufacture of chlordane for 3 months or
      more between 1946 and 1979. There were no significant differences in mortality
      rates between these employees and the overall USA population. The observed
      value for death from all causes, including heart disease and cancer, was less than
      the expected value in the overall USA population (Shi80). In another
      unpublished report, the examination of 1115 workers who had worked for 3
081-9 Hexachlorocyclopentadiene
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<pre>       months or more in a heptachlor production facility between 1952 and 1979
       likewise showed no differences in mortality compared to the overall USA
       population (Shi81). A retrospective study using the combined data of 1403
       workers of both plants revealed a SMR for all causes of death of 72. Among the
       various causes of death, the 2 highest SMRs were 134 for lung cancer (not
       significant) and 183 for cerebrovascular disease (statistically significant). There
       was one death from liver cancer. The excess mortality due to cerebrovascular
       disease was not related to the duration of employment (Wan79, Shi86).
           Another epidemiological study was conducted on a cohort of 570 workers
       who had been engaged in the production of aldrin and dieldrin for 1 year or more
       between 1954 and 1970. The vital status was determined through 1987. There
       was no statistically significant increase in the SMR of all cancers (103.6). The
       incidence of primary liver cancer was 1 out of 570 workers (Jon91).
       Animal data
       Irritation and sensitisation
       HEX was extremely irritating to the skin of rabbits following an occluded single
       application of 430 mg/kg bw. A purplish-black local discolouration and
       subcutaneous oedema was observed. About 12 days later, the skin was hard,
       encrusted, and fissured. Single applications of diluted HEX solutions, at
       concentrations ranging from 0.001% to 90%, to the skin of a monkey caused
       prompt discolouration of the skin at a concentration of 10% and above, the
       colour ranging from a very light to a dark tan as the concentration increased. In
       another monkey, daily 2-hour applications of 0.05 mL of a 10% HEX solution/kg
       bw for 3 consecutive days produced severe skin irritation and necrosis. Five days
       after the application, the skin was hard, encrusted, fissured, necrotic, and
       haemorrhagic. At 13 months after the application, a scar was visible on the
       injured area, with atrophy and complete absence of hair. In a guinea pig, no effect
       on the skin was seen following single applications of 0.05 mL of a 0.01% to 1%
       solution. At concentrations ranging from 40% to 90%, discolouration and
       necrosis was observed (Tre55).
           HEX was a skin sensitiser in the Magnusson and Kligman guinea pig
       maximisation test. All 24 animals used showed positive responses at both 24 and
       48 hours after the challenge (Pri82).
           Instillation of 0.1 mL of HEX into the eyes of New Zealand white rabbits for
       5 minutes or 24 hours resulted in severe eye irritation and in death of all animals
       within 9 days (IRD72).
081-10 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            Acute toxicity
            Results of acute lethal toxicity tests with HEX are summarised in Table 1.
Table 1 Summary of acute lethal toxicity studies in experimental animals.
exposure route        species             strain ( sex)                   LD50 or LC50 (duration) reference
                                                                                   3
inhalation            rat                 Carworth                        35 mg/m (3.5 h)         Tre55
                      rat                 Sprague-Dawley (male)           18 mg/m3 (4 h)          Ran82a
                                          Sprague-Dawley (female)         40 mg/m3 (4 h)
                      rat                 albino                          41.2 mg/m3 (4 h)        Jac87
                                                                                   3
                      guinea pig                                          80 mg/m (3.5 h)         Tre55
dermal                rabbit              (female)                        430-610 mg/kg bwa       Tre55
                      rabbit              (male)                          <200 mg/kg bw
                                          (female)                        340 mg/kg bw            IRD72
oral                  rat                 Carworth (male)                 505 mg/kg bw            Tre55
                      rat                 Charles River (male, female)    926 mg/kg bw            IDR68
                      rat                 Sprague-Dawley (male, female)   651 mg/kg bw            Dor79
                      rat                 Fischer 344 (male)              425 mg/kg bw            SRI80
                                          Fischer 344 (female)            315 mg/kg bw
                      rat                 Sprague-Dawley (male)           1500 mg/kg bw           Gar86
                                          Sprague-Dawley (female)         1300 mg/kg bw
                      mouse               Charles River (male, female)    679 mg/kg bw            Dea77
                      mouse               Unspecified (male, female)      600 mg/kg bw            Dor79
                      mouse               B6C3F1 (male, female)           680 mg/kg bw            SRI80
                      rabbit              (female)                        420-640 mg/kg bwa       Tre55
a
     Minimum lethal dose.
            The committee remarks that HEX is much more toxic by the inhalation route of
            exposure than by the dermal or oral routes.
                The vapours caused serious irritation of the mucous and respiratory
            membranes. Signs of intoxication after inhalation exposure included
            lachrymation, salivation, gasping, and irregular breathing. Pathology revealed
            diffuse degeneration of the brain, heart, and adrenal glands, and degeneration and
081-11      Hexachlorocyclopentadiene
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<pre>       necrosis of the liver and kidney tubules, together with severe pulmonary
       hyperaemia and oedema, acute bronchitis, and interstitial pneumonitis (Tre55).
       In another study, lachrymation, salivation, ataxia, loss of weight, and pulmonary
       abnormalities, characterised by red focal or diffuse consolidation that progressed
       to generalised haemorrhage and hepatisation, were reported (Ran82a). After oral
       administration, clinical signs and symptoms were: diarrhoea, lethargy, retarded
       respiration, decreased limb tone, ataxia, and ptosis (Dea77, Tre55).
       Short-term toxicity
       • Inhalation toxicity
       In an old inhalation study, small groups of rats (n=4), mice (n=5), rabbits (n=6),
       and guinea pigs (n=2) were exposed to concentrations of 3.9 mg/m3 (0.34 ppm),
       7 hours/day, 5 days/week. Guinea pigs survived 30 exposures. Four rabbits died
       before the 25th and all rats and mice between the 6th and 20th exposure. When
       exposed for 30 weeks to 1.7 mg/m3 (0.15 ppm) all species, except 4 of 5 mice,
       survived. Pathology revealed mild degenerative changes in the livers and kidneys
       of all species. The mice were found to have pulmonary oedema and bronchitis,
       and some of the guinea pigs and rats had developed pneumonia (Tre55).
           Groups of Sprague-Dawley rats (n=10/sex/group) were exposed to
       concentrations of HEX (purity: 97.7%) of 0, 0.25, 1.25, or 5.7 mg/m3 (0, 0.022,
       0.11, 0.5 ppm), 6 hours/day, 5 days/week, for 2 weeks. In the high-exposure
       group, 9 male and 2 female animals died during the exposure period. In the low-
       and mid-exposure groups, no mortality or treatment-related clinical signs were
       observed. Males had a significant dose-related decrease in mean body weight
       compared to controls. In the animals of the high-exposure group, clinical signs
       observed were dark red eyes, laboured respiration, and paleness of the
       extremities. Haematological examination revealed increases in haematocrit,
       haemoglobin level, and erythrocyte count and decreased lymphocyte counts. In
       the mid-exposure group, males showed a decrease in haematocrit, but an increase
       in haemoglobin level. In all male exposure groups, there was a dose-dependent
       increase of serum total protein levels. Absolute liver weights were reduced in
       males of the low-exposure group and in females of the low- and mid-exposure
       group. In animals exposed to 5.7 mg/m3, absolute lung weights were increased
       and the absolute weights of kidneys, adrenals, and ovaries were decreased,
       compared with the controls. Data on relative organ weights were not given.
       Microscopic examination on rats of the 5.7 mg/m3 group revealed lung changes
       mainly confined to the bronchioles, characterised by epithelial erosion, focal
       areas of hyperplastic cuboidal and columnar epithelium, inflammatory cell
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<pre>       infiltration and/or exudate in the lumen. Minimal atrophy of olfactory epithelium
       occurred in the nasal passages. There were no significant treatment-related
       microscopic changes in the mid- and low-exposure groups compared with the
       controls. These nasal and lung changes in the high-exposure group were
       consistent with observed impaired respiratory function, confirming the lung as
       the main target organ, according to Rand et al. In a parallel experiment, groups of
       rats (n=5/sex/group) were treated similarly, but served as separate recovery
       groups to observe effects during a 14-day (control, low- and mid-exposure
       groups) or 21-day (high-exposure group) period without exposure. Rats in the
       high-exposure group received only 5 exposures, because of the high mortality in
       the main study (see above). All animals survived during the exposure period, but
       3 males in the high-exposure group died within 7 days after the end of exposure.
       A decrease in mean body weight was observed for both sexes in the high-
       exposed group. Haematological abnormalities in the high- and mid-exposure
       group were reversible during the recovery period, except increased haemoglobin
       levels in the males of both groups. Changes in absolute organ weights were not
       observed in any of the groups at 14 or 21 days after the end of exposure.
       Microscopic changes of the lung and the nasal area observed in the high-
       exposure group recovered 2 to 3 weeks after termination of exposure. According
       to Rand et al., the NOAEL was 1.25 mg/m3 (Ran82a).
           The same authors conducted a 14-week inhalation study with groups of rats
       (n=40/sex/group) receiving whole-body exposure to HEX at concentrations 0,
       0.11, 0.57, or 2.28 mg/m3 (0, 0.01, 0.05, 0,2 ppm), 6 hours/day, 5 days/week. No
       treatment-related mortality was observed, but rats in the high- and mid-exposure
       groups displayed a transient dark red colouring of the eyes. However,
       ophthalmoscopic examination did not reveal chemical induced abnormalities. No
       treatment-related changes were seen in body weight gain, food consumption, or
       clinical chemical parameters. A small, but occasionally statistically significant
       increase in haemoglobin level and erythrocyte count was measured in males
       exposed to 0.11 mg/m3, females exposed to 0.57 mg/m3, and males and females
       exposed to 2.28 mg/m3. These changes were probably related with impaired
       respiratory function, according to Rand et al. In males and females of all
       treatment groups, absolute mean liver weights were statistically significantly
       reduced by 3 to 15%, relative to controls, and in all treated males absolute kidney
       weights were reduced by 10 to 11%. Upon macroscopic and microscopic
       examination, no treatment-related abnormalities were observed. Rand et al. set
       the NOAEL at 2.28 mg/m3 (Ran82a). In a further study, dose-dependent
       abnormalities were found in the Clara cells of the lungs at 0.11 mg/m3 and above.
       These abnormalities comprised an increase in the mean number of inclusions in
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<pre>       the apex and base of the Clara cells, the biological significance of which is
       unclear (Ran82b).
           In a 90-day inhalation study, groups of F344 rats (n=10/sex/group) were
       exposed to concentrations of HEX of 0, 0.46, 1.7, 4.6, 11.4, or 22.8 mg/m3
       (0, 0.04, 0.15, 0.4, 1, 2 ppm), 6 hours/day, 5 days/week. All rats in the 2 highest
       exposure groups died within the first 4 weeks. Clinical signs were eye irritation
       and respiratory distress in all rats at 11.4 mg/m3 and above, listlessness in all rats
       at 4.6 mg/m3 and above, and posterior paresis in all rats at 1.7 mg/m3. At 4.6
       mg/m3, male animals showed decreased body weights and increased absolute and
       relative lung weights, compared to controls. No abnormalities in haematology,
       clinical chemistry, or urinalysis parameters were observed in male or female rats
       of any exposure group. Macroscopic and microscopic examination revealed
       inflammation and necrosis of the nose, larynx, trachea, and lungs, as well as
       metaplasia of the nasal epithelium in males and females exposed to 4.6 mg/m3
       and above. No compound-related changes were observed in any organ of male
       and female animals exposed to 0.46 mg/m3 (NTP94).
           Groups of Wistar rats (n=27/sex/group) were exposed to concentrations of
       HEX of 0, 0.57, 1.14, or 5.7 mg/m3 (0, 0.05, 0.1, 0.5 ppm), 6 hours/day, 5
       days/week, for 30 weeks. At the end of the exposure period, the animals, 9 males
       and 9 females of each group, were retained for a 14-week recovery period. In the
       high-exposure group, 3 males and 2 females died during the exposure period and
       1 male during the recovery period. Most animals of the high-exposure group
       were sneezing and lethargic at some time during the exposure period, but such
       signs were absent in the low- and mid-exposure groups. Significant decreased
       body weights compared to control animals were observed in males at the high-
       exposure level from week 7 to the end of exposure and in females of the high-
       and mid-exposure groups at the end of the recovery period. Haematological
       examination of samples collected at the end of week 30 revealed a statistically
       significant increase in haematocrit, haemoglobin level, and erythrocyte and
       neutrophil count, and a significantly lower lymphocyte count in male rats of the
       high-exposure group, compared to controls. No abnormalities were observed in
       clinical chemical and urinalysis parameters. At the end of the exposure period,
       absolute and relative kidney weights were significantly increased in females at
       the high exposure. The changes in absolute heart weights (significantly
       decreased in high-exposure males), testes weights (significantly increased at the
       mid-exposure level), and relative kidney weights (significantly increased in high-
       and low-exposure males) were judged as ‘probably not of biological
       significance’. Microscopic examination of tissues of high-exposure animals
       collected at the end of week 30 revealed pulmonary degenerative changes
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<pre>       ranging from epithelial hyperplasia, oedema, and sloughing of the bronchiolar
       epithelium of males and females to epithelial ulceration and necrosis in the
       males. Such changes were absent in the mid- and low-exposure groups and in the
       recovery groups. Mild degenerative changes were seen in the liver and kidney of
       a few high-exposure rats after 30 weeks. The NOAEL was 1.14 mg/m3 (Cla82).
           In a 90-day inhalation study, groups of B6C3F1 mice (n=10/sex/group) were
       exposed to HEX concentrations of 0, 0.46, 1.7, 4.6, 11.4, or 22.8 mg/m3 (0, 0.04,
       0.15, 0.4, 1, 2 ppm), 6 hours/day, 5 days/week. All mice in the 2 high-exposure
       groups died during the first week of exposure. Of the animals exposed to 4.6
        mg/m3, 5 males and 2 females died. Final body weights of males exposed to 1.7
       or 4.6 mg/m3 were significantly lower compared to control animals. Treatment-
       related posterior paresis and listlessness were observed at 4.6 mg/m3 and above.
       At these levels, microscopic examination revealed necrosis or inflammation of
       the nose, larynx, or lung. Squamous metaplasia of the larynx or trachea was
       observed in males at 1.7 mg/m3 and above and in females at 4.5 mg/m3 and
       above. The NOAEL was 0.46 mg/m3 (NTP94).
           Cynomolgus monkeys (n=6/sex/group) were exposed to HEX concentrations
       of 0, 0.11, 0.57, or 2.28 mg/m3 (0, 0.01, 0.05, 0.2 ppm), 6 hours/day, 5 days/
       week, for 14 weeks. There were no mortalities or adverse clinical signs. No
       changes in body weight gain and food consumption, pulmonary function,
       haematological, clinical chemical, or urinalyses were found between animals in
       any of the exposed groups, compared with the controls. Furthermore, no
       abnormalities were found upon ophthalmoscopic, macroscopic, or microscopic
       examinations. The NOAEL was 2.28 mg/m3, the highest level tested (Ran82a).
       • Oral toxicity
       Groups of F344 rats (n=10/sex/group) were given HEX (purity: 94-97%) by
       gavage at doses of 0, 10, 19, 38, 75, or 150 mg/kg bw, 5 days/week, for 13
       weeks. A significant increase in mortality was observed at the top dose (7 males
       and 5 females). Clinical signs of toxicity were reduced spontaneous activity and
       ruffled fur in both sexes at 38 mg/kg bw/day and above. Body weights were
       significantly reduced compared with controls in males and females, receiving 38
       mg/kg bw/day and more, and 75 mg/kg bw/day and more, respectively. In female
       rats, relative liver weights were significantly increased at 38 mg/kg bw/day and
       above, and relative kidney weights at 75 mg/kg bw and above. Macroscopic and
       microscopic examination revealed treatment-related lesions in the forestomach,
       including proliferative and inflammatory changes of the epithelia at 38 mg/kg
       bw/day and above in males, and at 19 mg/kg bw/day and above in females. Toxic
081-15 Hexachlorocyclopentadiene
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<pre>           nephrosis, characterised by proximal tubular dilation, was observed at 38 mg/kg
           bw/day in both males and females. The NOAEL was 10 mg/kg bw/day (Abd84).
                 Groups of B6C3F1 mice (n=10/sex/group) received oral (gavage) doses of
           HEX (purity: 94-97%) of 0, 19, 38, 75, 150, or 300 mg/kg bw/day, 5 days/week,
           for 13 weeks. At 300 mg/kg bw/day, all male mice and 3 female mice died.
           Clinical signs of toxicity were ruffled fur and slight inactivity at 300 and 150
           mg/kg bw/day. Body weights were significantly reduced at 300 and 150 mg/kg
           bw/day in females, and at 150 mg/kg bw/day in males. In females, relative lung
           weight was significantly increased at 300 mg/kg bw/day, and relative liver and
           kidney weights were significantly increased in both sexes at 19 mg/kg bw .
           Macroscopic and microscopic examination revealed treatment-related lesions in
           the forestomach, including epithelial hyperplasia, and focal inflammation at 38
           mg/kg bw/day and above (both sexes), and ulceration at 300 mg/kg bw/day
           (males only). Toxic nephrosis, characterised by lesions in the terminal portion of
           the proximal convoluted tubule in the inner cortex was observed in females only
           at 75 mg/kg bw/day and above. The NOAEL and LOAEL were 19 mg/kg bw/day
           in males and females, respectively (Abd84).
           A summary of short-term studies is shown in Table 2.
Table 2 Summary of short-term toxicity studies in experimental animals.
exposure   species               dose level               exposure      critical effect          NOAELa     reference
route      (strain)                                       duration
inhalation rat                   0, 0.25, 1.25, 5.7       2 weeks       nasal and lung injury;   1.25 mg/m3 Ran82
           (Sprague-Dawley)      mg/m3                                  haematological effects
           rat                   0, 0.46, 1.7, 4.6, 11.4, 13 weeks      posterior paresis        0.46 mg/m3 NTP94
           (F344)                22.8 mg/m3
           rat                   0, 0.11, 0.57, 2.28      14 weeks      none                     2.28 mg/m3 Ran82
           (Sprague-Dawley)      mg/m3
           rat                   1.7 mg/m3                30 weeks      liver and kidney injury; LOAEL: 1.7 Tre55
           (Carworth)                                                   pneumonia                mg/m3
           rat                   0. 0.57, 1.13, 5.7       30 weeks      lung, liver, and renal   1.13 mg/m3 Cla82
           (Wistar)              mg/m3                                  injury; haematological
                                                                        effects; reduced body
                                                                        weights
           mouse                 0, 0.46, 1.7, 4.6, 11.4, 13 weeks      effects on respiratory   0.46 mg/m3 NTP94
           (B6C3F1)              22.8 mg/m3                             tract; reduced body
                                                                        weights
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<pre>       mouse              1.7 mg/m3               30 weeks  mortality               LOAEL: 1.7  Tre55
                                                                                    mg/m3
       rabbit             1.7 mg/m3               30 weeks  liver and kidney injury LOAEL: 1.7  Tre55
                                                                                    mg/m3
       monkey             0, 0.11, 0.57, 2.28     14 weeks  none                    2.28 mg/m3  Ran82
       (cynomolgus)        mg/m3
oral   rat                0, 10, 19, 38, 75, 150  13 weeks  forestomach lesions     10 mg/kg bw Abd84
       (F344)             mg/kg bw
       mouse              0, 19, 38, 75, 150, 300 13 weeks  forestomach lesions     19 mg/kg bw Abd84
       (B6C3F1)           mg/kg bw                                                  (males);
                                                                                    LOAEL: 19
                                                                                    mg/kg bw
                                                                                    (females)
       Long-term toxicity and carcinogenicity
       In a 2-year inhalation study, groups of F344/N rats (n=60/sex/group) were
       exposed to HEX concentrations of 0, 0.11, 0.57, or 2.28 mg/m3 (0, 0.01, 0.05, 0.2
       ppm), 6 hours/day, 5 days/week. Survival rates and mean body weights of
       exposed rats were similar to those of the controls. No treatment-related clinical
       findings were observed in male or female rats during the 2-year study. No
       differences in urinalysis parameters were found at the 15-month interim
       evaluation, which could be attributed to exposure to HEX. Macroscopic and
       microscopic examination revealed that no treatment-related increased incidences
       of neoplasms occurred in any of the exposure groups. Toxicity was limited to the
       respiratory tract and included a statistically significantly increased incidence of
       pigmentation of the respiratory epithelium of the nose (all male and female
       groups), the trachea (high-exposure males only), and the bronchioles and bronchi
       of the lung (all male and female groups). At 0.11 mg/m3, significant nasal effects
       were found in both males and females and significant lung effects in females.
       Details are shown in Table 3. Exposure to HEX also caused a significant increase
       in the incidence of squamous metaplasia of the laryngeal epithelium in females at
       0.11 and 2.28 mg/m3, but not at 0.57 mg/m3, compared to controls (Table 3). The
       severity of squamous metaplasia was minimal in all exposed and control females.
       The apparent change diagnosed as squamous metaplasia consisted of stratified
       squamous epithelium several cell layers thick and was believed to be located in
       areas usually lined by columnar epithelium. Due to individual variation in
       determining where the transition from squamous to columnar epithelium occurs
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<pre>             as well as difficulties in obtaining consistent sections, the relevance of the higher
             incidences of squamous metaplasia in the 0.11 and 0.57 mg /m3 groups is
             uncertain. In conclusion, there was no evidence of carcinogenic activity of HEX
             in male or female F344/N rats. A NOAEL for toxic effects, however, could not
             be established (NTP94).
Table 3 Summary of respiratory tract effectsa in F344 rats and B6C3F1 mice after inhalation exposure to HEX, 6 hours/day,
5 days/week, for 2 years (NTP94).
                                             male rats (n=48-50)                              female rats (n=48-50)
                                  0          0.11       0.57      2.28b          0           0.11        0.57       2.28b
pigmentation:
nose                              1          46**       48**      48**           0           34**        47**       48**
trachea                           0          0          0         5*             0           0           0          1
lung (bronchioles)                0          0          0         49**           0           25**        42**       50**
lung (peribronchiolar            0           0          2         1**            3           1           4          27**
metaplasia:
larynx                            1          2          6         4              9           20*         15         24**
                                             male mice (n=50)                                female mice (n=50)
mucosal pigmenation:
nose                              0          45**       50**      44**           0           40**        48**       41**
trachea                           0          29**       48**      48**           0           6*          43**       42**
lung                              0          2          42**      45**           0           0           27**       44**
suppurative pigmentation:
nose                              0          0          1         36**           4           0           3          40**
a
     Incidences expressed as number of animals.
b
     Concentrations in mg/m3.
     * p<0.05; ** p>0.01.
             In a similar study, groups of B6C3F1 mice were exposed to HEX concentrations
             of 0, 0.11, 0.57, or 2.28 mg/m3 (0, 0.01, 0.05, 0.2 ppm), 6 hours/day, 5
             days/week, for 2 years. The 2-year survival rate of high-exposure females was
             marginally lower than that of the controls due to a higher incidence of ovarian
             inflammation. Mean body weights of high-exposure males (weeks 62 to 103) and
             females (throughout the study) were lower than those of the controls. No
             treatment-related clinical findings were observed in males or females in any of
             the exposure groups. There were no treatment-related differences in urinalysis
             parameters at the 15-month interim evaluation, compared to the controls. The
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<pre>       site of toxicity of HEX exposure was the respiratory tract. Macroscopic and
       microscopic examination revealed a statistically significant increased incidence
       of treatment-related pigmentation of the respiratory epithelium of the nose (all
       male and female groups), trachea (all male and female groups), and lung (mid-
       and high-exposure males and females), and suppurative inflammation of the nose
       (high-exposure males and females) (see Table 3). No statistically significant
       increased incidences of neoplasms were found in any of the treatment groups,
       compared to the control group. A NOAEL for toxic effects, however, could not
       be established (NTP94).
           In a separate so-called ‘stop-exposure’ study, groups of male mice
       (n=50/group) were exposed to HEX concentrations of 2.28 mg/m3 (0.2 ppm), for
       33 or 66 weeks, or to 5.7 mg/m3 (0.5 ppm), for 26 or 42 weeks, and then
       examined at 2 years after the beginning of exposure. Two-year survival rates and
       mean body weights of ‘stop-exposure’ groups were similar to that of the controls.
       No treatment-related clinical abnormalities were observed. Macroscopic and
       microscopic examination revealed that non-neoplastic respiratory tract lesions
       were similar to those observed in the above 2-year exposure study. Treatment-
       related pigmentation and inflammation of the respiratory epithelium were
       persistent, as indicated by their presence in many mice after recovery periods of
       62 to 78 weeks. The incidence and severity of the lesions were related to
       exposure concentration and duration. This suggests that the pigment could be a
       reaction product between the chemical and an intracellular component of the
       respiratory tissues that has a very slow turnover rate, according to the authors.
       There appears to be a critical burden, below which suppurative inflammation of
       the trachea and lung does not occur. The critical burden, expressed as a
       composite unit (concentration x weeks), was estimated at 226-237 mg/m3
       x weeks (NTP94).
       Mutagenicity and genotoxicity
       •   In vitro tests
           • Gene mutation assays. HEX (purity: 98%) did not induce reverse gene
               mutations in several strains of S. typhimurium (TA98, TA100, TA1535,
               and TA1537) at concentrations up to 3.3 µg/plate without metabolic
               activation, or up to 100 µg/plate after metabolic activation by a rat liver
               microsomal S9 preparation (Haw83). In an unpublished study,
               application of HEX (purity: 98.9%) at concentrations up to 10 µg/mL in
               the absence, or up to 500 µg/mL in the presence of S9 fraction did not
               increase the reverse gene mutation frequency in agar layer cultures of
081-19 Hexachlorocyclopentadiene
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<pre>             S. typhimurium strains TA98, TA100, TA1535, TA1537, or TA1538, or of
             E. coli strains WP2 or WP2 uvrA (Bro83). In E. coli strain K12, HEX did
             not induce reverse mutations at 2.7 mmol/L in the presence or absence of
             S9 (Gog78). In 2 studies, without details of the concentrations tested,
             negative results were reported using S. typhimurium strains TA1535 or
             TA1538 (Gre77) or S. typhimurium strain TA100 (WHO91), both with
             and without metabolic activation. However, in one study, positive results
             were found in S. typhimurium strains TA98 and TA100 and in E.coli strain
             PQ37 with and without metabolic activation. No details were given of the
             concentrations tested (Raa93). HEX, dissolved in DMSO, did not induce
             gene mutations in the thymidine kinase (TK+/-) assay in cultured L5178Y
             mouse lymphoma cells at concentrations of 0.002 to 0.04 µL/L without
             metabolic activation, and 0.4 to 1.25 µL/L with metabolic activation
             (Mat78). HEX at a concentration of 273 µg/L did not increase the gene
             mutation frequency in the HGPRT forward mutation assay carried out in
             rat liver epithelium cells (Wil80). No increased sex-linked recessive lethal
             mutations were found in Drosophila, either by feeding Canton-S wild-
             type males HEX doses of 40 mg/kg feed for 3 days, and then mated, or by
             injection of males with HEX dissolved in 10% alcohol at concentrations
             of 2000 or 3000 mg/L (Zim85). In a later study, the negative results were
             confirmed when feeding males doses of 10 mg/kg feed for 3 days or by
             injection of males with a solution of 900 mg HEX/L (Mas92).
          • Cytogenicity assays. HEX did induce sister chromatid exchanges (SCE)
             and chromosomal aberrations in cultured Chinese hamster ovary (CHO)
             cells with and without S9 (NTP94). In an unpublished study, no
             statistically significant increase in the frequency of chromosomal
             aberrations in rat liver (RL4) cell cultures exposed to HEX (purity: 98.9%)
             at concentrations up to 0.2 µg/mL was found (Bro83).
          • Other assays. HEX in a concentration of 2.73 mg/L produced no increase
             in the DNA-repair rate in rat hepatocyte primary cultures (Wil80).
             Negative results were also obtained in an additional unscheduled DNA
             synthesis (UDS) assay (Bra83). In another unpublished study, HEX
             (purity: 98.9%) did not induce mitotic gene conversion in S. cerevisiae
             JD1 at concentrations up to 10 µg/mL, either in the presence or absence of
             rat liver S9 (Bro83). However, HEX was positive in the B. subtilis rec-
             assay at concentrations in the range of 20-30 µg/L in the absence, and
             300-500 µg/L in the presence of S9 (Mat89).
       •  In vivo tests
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<pre>       In an unpublished study, no dominant lethal mutations were induced when male
       CD-1 mice (n=10) were given oral (gavage) doses of HEX of 0.1, 0.3, or 1.0
       mg/kg bw/day for 5 days, and then mated with female animals throughout
       spermatogenesis (7 weeks) (WHO91).
           No increase in the frequency of micronucleated erythrocytes was observed in
       male or female B6C3F1 mice, exposed by inhalation to HEX concentrations
       ranging from 0.11 to 2.28 mg/m3 (0.01-0.2 ppm), 6 hours/day, 5 days/week, for
       13 weeks (NTP94).
       • Other tests
       In an unpublished study, no malignant cell transformations were observed in
       cultured BALB/3T3 cells after incubation with HEX at concentrations of 0, 10,
       20, 39, 78, or 156 µg/L (WHO91)
       In summary, in most in vitro tests in microorganisms or mammalian cells, HEX
       has no mutagenic or genotoxic activity. The induction of SCEs and chromosome
       aberrations in CHO cells in vitro could neither be confirmed in a rat liver cell
       culture nor in an in vivo micronucleus assay in mice. The committee concluded
       that HEX is not a mutagenic hazard.
       Reproduction toxicity
       The committee did not find inhalation reproduction toxicity studies on HEX.
       Following dosing by gavage, HEX was evaluated for developmental toxicity in
       rats, mice, and rabbits.
           In pregnant CD-1 rats (numbers not presented) given HEX (purity: 98.2%) in
       corn oil at doses of 0, 3, 10, and 30 mg/kg bw/day on gestational days 6 to 15, no
       significant differences were observed in maternal survival, mean maternal body
       weight gain, mean number of implantations, corpora lutea, or live fetuses, mean
       fetal body weights, or male/female sex ratios comparing dosed and control
       groups. No increased incidences of external, soft tissue, or skeletal abnormalities
       were found in fetuses in any of the exposed groups compared to the controls. The
       NOAEL for both maternal and developmental toxicity was 30 mg/kg bw/day, the
       highest dose tested (IRD78).
           Groups of pregnant CF-1 mice (numbers not given) received HEX (purity:
       98%) at daily oral doses of 0, 5, 25, or 75 mg/kg bw on gestational days 6-15,
       and were sacrificed on gestational day 18. No signs of maternal toxicity were
       observed in any of the groups. Fertility, average numbers of implantations, live
       fetuses per litter, number of resorptions per litter, fetal body weight, or fetal
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<pre>       crown-rump length of the treated mice were not significantly different compared
       to the control group. There was no increase in the incidence of fetal
       malformations examined in 249 to 374 fetuses per group when considered
       collectively or by individual type. The NOAEL for maternal and developmental
       toxicity was 75 mg/kg bw/day (Mur80). In another study, 16 pregnant CD-1 mice
       received HEX doses of 0 or 45 mg/kg bw/day on gestational days 8-12. Neither
       significant effects on maternal body weights nor any changes in either the
       number of live offspring or the average fetal weight on the 1st and 3d day after
       birth were found in the exposed animals compared to controls (Che82). In
       another study, using the same dosing regimen, the observation period of
       offspring of CD-1 mice was extended to 250 days. No treatment-related effects
       were observed on survival rate, and no macroscopic and microscopic
       abnormalities were found in the liver, testes, seminal vesicles, or right kidney of
       male animals compared to controls. The females did not show impairment of
       reproductive functions. The NOAEL for both maternal and developmental
       toxicity was 45 mg/kg bw/day, the highest level tested (Gra84).
           Groups of pregnant New Zealand white rabbits (numbers not given) received
       daily oral doses of HEX (purity: 98.2%) of 0, 5, 25, or 75 mg/kg bw on
       gestational days 6-18, and were sacrificed on gestational day 29. At the high
       dose, mortality, diarrhoea, and body weight loss was observed. Fertility, average
       numbers of implantations, live fetuses per litter, number of resorptions per litter,
       fetal body weight, or fetal crown-rump length of the treated mice were not
       significantly different compared to controls. There was an increase in the number
       of fetuses with one minor skeletal variation, i.e., a 13th rib, which was
       significantly higher at the high dose compared to controls (58/171 or 34%, 33/95
       or 35%, 33/78 or 42%, and 44/77 or 57%, at 0, 5, 25, and 75 mg/kg bw/day,
       respectively) (Mur80). The committee concludes that, in this study, the NOAEL
       for both maternal and developmental toxicity was 25 mg/kg bw (Mur80).
7      Existing guidelines
       The current administrative occupational exposure limit (MAC) for HEX in the
       Netherlands is 0.11 mg/m3 (0.01 ppm), 8-hour TWA.
           Existing occupational exposure limits for HEX in some European countries
       and in the USA are summarised in the annex.
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<pre>8      Assessment of health hazard
       For workers, engaged in the manufacture or use of HEX, the main routes of
       exposure to the chemical are through inhalation of its vapour or by direct skin
       contact with the liquid.
       In rats, following 2-hour inhalation exposure to air concentrations ranging from
       0.11 to 0.57 mg/m3 (0.01-0.05 ppm), 95% of the inhaled vapour is retained in the
       body. No data is available of the percentage of dermal uptake. HEX is very
       reactive, and, following absorption into the body, the compound or its
       metabolites may bind to blood, tissues, and the contents of the gastrointestinal
       tract. The kinetics of HEX have been studied in experimental species following
       the inhalation, oral, or intravenous routes of exposure. In rats, following a 2-hour
       exposure up to 0.57 mg/m3 (0.05 ppm), 95% of the amount inhaled was retained
       and completely metabolised. Approximately equal amounts of the dose were
       excreted in the urine and the faeces (ca. 36% each) within 72 hours after
       exposure. At 72 hours, ca. 12% was retained in the body, principally the trachea,
       lungs, and kidneys. A small amount (ca. 1%) was excreted as CO2. Following
       oral administration, absorption was poor, probably due to its reactivity with the
       contents of the gastrointestinal tract. Most of the dose is excreted in the faeces
       (63-80%) and only 15-35% in the urine, within 72 hours. The percentage of the
       dose retained in the body at 72 hours after application varied from 0.2% to 2.8%,
       principally in the kidneys. Studies on the metabolism of HEX have been
       unsuccessful; the polar faecal and urinary metabolites have been isolated but not
       identified.
       Case studies in humans showed that acute exposure to HEX, due to an illegal
       contamination of a municipal sewage plant with a large volume of HEX and
       related chlorinated hydrocarbons, resulted in a high incidence of eye, throat, and
       skin irritation, headaches, nausea, respiratory distress, and nervousness in plant
       workers and clean-up workers. These complaints persisted for 3 to 6 weeks. Air
       concentrations, measured 4 days after the plant closed, ranged from 3 to 11
       mg/m3 (0.27-0.97 ppm). In some of the clean-up workers, a slight increase in
       serum aspartate aminotransferase activity was found, probably related with
       exposure. In another study, it was demonstrated that long-term exposure (average
       ca. 8 years) to HEX and other chlorinated hydrocarbons, at air concentrations
       near or below the occupational exposure limits, did not produce abnormal
       biochemical liver and kidney function tests in the workforce. Epidemiological
081-23 Hexachlorocyclopentadiene
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<pre>       studies on workers involved in the production of HEX or in the use of HEX as an
       important precursor of chemical of organochlorine pesticide manufacture, such
       as chlordane, heptachlor, aldrin, or dieldrin, did not give indications for an
       increased mortality rate (all cases, cancer, or diseases of the circulatory system),
       compared to the overall USA population. However, information specific to HEX
       exposure, either qualitative or quantitative, was not available in any of these
       studies. In addition, study populations were relatively small, and observation
       times (25 years at most) relatively short. According to the committee, these data,
       therefore, contribute little to the health hazard assessment of HEX.
       In experimental animal studies, the compound was very irritating to the eyes and
       the skin. In one study, HEX was found to be a skin sensitiser in guinea pigs. HEX
       is much more toxic when inhaled than when ingested or following dermal
       contact. Based on the results of acute lethal toxicity studies in animals, the
       committee considers the compound as very toxic after inhalation exposure, toxic
       after skin contact, and harmful if swallowed.
           Effects of HEX exposure in short- or long-term studies in rats and mice
       included: lung injury and increased erythrocyte, haematocrit, and haemoglobin
       level in a 2-week inhalation study in rats (NOAEL: 1.25 mg/m3 (0.11 ppm)),
       posterior paresis in a 13-week inhalation study in rats (NOAEL: 0.46 mg/m3
       (0.04 ppm)), lung, liver, and kidney injury, and increased erythrocyte and
       haemoglobin level in a 30-week inhalation study in rats (NOAEL: 1.14 mg/m3
       (0.1 ppm)), pigmentation of respiratory epithelium of the nose, the bronchioles,
       and the bronchi, and squamous metaplasia of laryngeal epithelium in a 2-year
       inhalation rat study (LOAEL: 0.11 mg/m3 (0.01 ppm)), squamous metaplasia of
       larynx and trachea in a 13-week inhalation study in mice (NOAEL: 0.46 mg/m3
       (0.04 ppm)), pigmentation of respiratory epithelium of the nose and the trachea
       in a 2-year inhalation mouse study (LOAEL: 0.11 mg/m3 (0.01 ppm)),
       forestomach lesions in rats and mice in a 13-week oral study (NOAEL: 10 mg/kg
       bw/day for the rat and 19 mg/kg bw/day for the male mouse; LOAEL: 19 mg/kg
       bw/day for the female mouse). No adverse effects were found in a 14-week
       inhalation study in monkeys (NOAEL: 2.28 mg/m3 (0.2 ppm)). The brown
       pigment observed in the mucosa and submucosa of the respiratory tract of rats
       and mice in the 2-year inhalation study was not reported when rats and mice
       were exposed to other irritant chemicals, like methyl isocyanate, glutaraldehyde,
       or formaldehyde. The NTP suggested that the pigmentation might have been the
       result of a direct reaction between the chemical or one of its metabolites and the
       respiratory tissues (NTP94).
081-24 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>            HEX did not induce gene mutations in most tests, using bacteria or cultured
       mammalian cells. However, tests for cytogenicity in HEX-treated cultured
       mammalian cells were conflicting. In vivo, HEX did not increase the frequency
       of micronuclei in erythrocytes or of dominant lethal mutations in mice. The
       committee concluded that HEX is not a mutagenic hazard in vivo.
            The 2-year inhalation studies in rats and mice did not show treatment-related
       increased incidences of neoplastic lesions in either species.
            In developmental toxicity studies, oral dosing of HEX did not induce
       maternal or developmental toxicity in rats and mice at 30 and 75 mg/kg bw, the
       highest dose levels tested. In rabbits, there was an increase in the incidence of the
       number of fetuses with a 13th rib at a maternally toxic dose of 75 mg/kg bw,
       while neither maternal nor developmetal toxicity was seen at 25 mg/kg bw.
       From the above-discussed data, the committee takes the well-performed 2-year
       rat inhalation study (NTP94) as a starting point in deriving a health-based
       recommended occupational exposure limit (HBROEL). In this study, the
       committee considered squamous metaplasia of the laryngeal epithelium to be the
       critical effect. A NOAEL could not be established since at 0.11 mg/m3 (0.01
       ppm), the lowest level tested, these laryngeal lesions as well as pigmentation of
       the respiratory epithelium of the nose, the bronchioles, and the bronchi were
       demonstrated. For extrapolation to a HBROEL, the committee establishes an
       overall assessment factor of 12 covering the absence of a NOAEL, intra- and
       interspecies variation, and the type of critical effect. Thus, applying this factor of
       12 and the preferred-value approach, the committee recommends a health-based
       occupational limit of 0.01 mg/m3 (0.0009 ppm) for hexachlorocyclopentadiene.
       The committee recommends a health-based occupational exposure limit for
       hexacyclopentadiene of 0.01 mg/m3 (0.0009 ppm), as an 8-hour time-weighted
       average (TWA). A skin notation is not deemed necessary because of the local
       character of the critical effect.
081-25 Hexachlorocyclopentadiene
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<pre>       References
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<pre>Cla82  Clark DG , Pilcher A, Blair D, et al. Thirty week chronic inhalation study of
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081-29 Hexachlorocyclopentadiene
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<pre>              Annex
Occupational exposure limits for hexachlorocyclopentadiene 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 0.01        0.11             8h                 administrative                    SZW03
Employment
Germany
- AGS                              -         -                                                                     TRG00
- DFG MAK-Kommission               -c        -                                                                     DFG02
Great Britain
- HSE                              -         -                                                                     HSE02
Sweden                             -         -                                                                     Swe00
Denmark                            0.01      0.1              8h                                                   Arb02
USA
- ACGIH                            0.01      -                8h                 TLV                    A4d        ACG03b
- OSHA                             -         -                                                                     ACG03a
- NIOSH                            0.01      0.1              10 h               REL                               ACG03a
European Union
- SCOEL                            -         -                                                                     EC03
a
     S = skin notation, which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
c
     Listed among compounds for which studies of the effects in man or experimental animals have yielded insufficient
     information for the establishment of MAK values.
d
     Classified in carcinogenicity category A4, i.e., not classifiable as a human carcinogen: agents which cause concern that
     they could be carcinogenic for humans but which cannot be assessed conclusively because of a lack of data. In vitro or
     animal studies do not provide indications of carcinogenicity which are sufficient to classify the agent into one of the other
     categories.
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