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<pre>Carbon tetrabromide
(CAS No: 558-13-4)
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/114, The Hague, June 8, 2004
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<pre>Preferred citation:
Health Council of the Netherlands: Committee on Updating of Occupational
Exposure Limits. Carbon tetrabromide; Health-based Reassessment of
Administrative Occupational Exposure Limits. The Hague: Health Council of the
Netherlands, 2004; 2000/15OSH/114.
all rights reserved
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<pre>1     Introduction
      The present document contains the assessment of the health hazard of carbon
      tetrabromide 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 carbon tetrabromide has been based on the
      review by the American Conference of Governmental Industrial Hygienists
      (ACG98). Where relevant, the original publications were reviewed and evaluated
      as will be indicated in the text. In addition, in December 1999, literature was
      searched in the databases Toxline, Medline, and Chemical Abstracts, starting
      from 1981, 1961, and 1937, respectively, and using the following key words:
      carbon tetrabromide, tetrabromomethane, and 558-13-4.
           In February 2001, the President of the Health Council released a draft of the
      document for public review. No comments were received.
           An additional search in Toxline and Medline in January 2004 did not result in
      information changing the committee’s conclusions.
2     Identity
      name                       :  carbon tetrabromide
      synonyms                   :  tetrabromomethane; methane tetrabromide; carbon bromide
      molecular formula          :  CBr4
      CAS number                 :  558-13-4
3     Physical and chemical properties
      molecular weight           :  331.63
      boiling point              :  189.5oC (slight decomposition)
      melting point              :  ß-form: 90.1oC; α-form: 48.4oC (slight decomposition)
      flash point                :  not available
      vapour pressure            :  at 25oC: 96 Pa
      solubility in water        :  not soluble (at 30oC: 24 mg/100 mL)
      log Poctanol/water         :  3.42 (experimental); 2.80 (estimated)
      conversion factors         :  at 20oC, 101.3 kPa: 1 mg/m3 = 0.07 ppm
                                                         1 ppm = 13.8 mg/m3
      Data from NLM04, Tor94, http://esc.syrres.com.
114-3 Carbon tetrabromide
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<pre>      At room temperature, pure carbon tetrabromide is a colourless, non-flammable
      solid. However, samples are generally yellow-brown in colour (ACG98).
          All 8 human volunteers were able to detect carbon tetrabromide at a
      concentration of ca. 5 ppm (ca. 69 mg/m3), while none of them was able to detect
      the compound at concentrations of 0.3-0.5 ppm (ca. 4-7 mg/m3) (Wuj62).
4     Uses
      Not widely used, carbon tetrabromide finds some employment in organic
      synthesis (ACG98).
          Carbon tetrabromide occurs naturally in small amounts in the alga
      Asparagopsis taxiformis (Bur76).
5     Biotransformation and kinetics
      The committee did not find adequate data on the biotransformation and kinetics
      of carbon tetrabromide.
          Data from skin testing suggested that carbon tetrabromide was not absorbed
      by the skin in amounts resulting in overt toxic signs (Wuj62).
          Torkelson stated that either hydrolysis or metabolism might produce some
      bromide ion but that carbon tetrabromide would not be expected to produce
      physiologically significant quantities of bromide ion in the blood at levels of
      exposure considered acceptable by inhalation (Tor94).
          Wolf et al. reported that in vitro incubation of carbon tetrabromide with
      induced rat liver microsomal preparations resulted in cytochrome P450 complex
      formation and in metabolic formation of carbon monoxide (Wol77).
6     Effects and mechanism of action
      Human data
      The committee did not find data on effects on humans following (occupational)
      exposure to carbon tetrabromide.
      Animal data
      Instillation of unknown amounts of the solid compound into the eyes of rabbits
      caused severe conjunctival irritation, oedema with moderate pain, and permanent
114-4 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>      corneal damage. Instillation for 15 seconds followed by washing with water
      resulted in pain, conjunctival irritation, and temporary corneal damage (Wuj62).
          Occluded application of unknown amounts of carbon tetrabromide to the
      shaven skin of rabbits caused severe hyperaemia, oedema, and moderate
      necrosis. Repeated application of a 10% solution of carbon tetrabromide in
      Dowanol 50B resulted in very slight scaliness after 10 applications to the ear and
      moderate to severe hyperaemia, oedema, and slight necrosis to the shaven
      abdomen of rabbits. Very faint hyperaemia to the ear and slight to moderate
      hyperaemia and scaliness of the abdomen were observed following application
      of a 1% solution (Wuj62).
      Exposure to a saturated atmosphere at 25oC* for 1.3 or 0.5 hours was lethal to all
      rats, the rats exposed for 0.5 hours dying within 1-2 days after exposure. All rats
      survived exposure to a saturated atmosphere at 26oC for 0.2 hours, showing eye
      and nasal irritation and retarded weight gain subsequent to exposure (Wuj62).
          The oral LD50 in rats was 1800 mg/kg bw (5.4 mmol/kg bw) (Wuj62),
      compared with 2350 mg/kg bw (15.3 mmol/kg bw) for carbon tetrachloride
      (NIO04b).
          The subcutaneous LD50 in mice was estimated to be 298 mg/kg bw (0.9
      mmol/kg bw), compared with 30,768 mg/kg bw (200 mmol/kg bw) for carbon
      tetrachloride (Kut62a).
          An intravenous LD50 of 56 mg/kg bw has been listed for mice (NIO04a).
          Single intraperitoneal injections did not cause changes in hepatic function or
      serum enzymes in rats in one study at doses up to 125 µL/kg bw (Aga83), but in
      another study, it increased the relative liver weight of rats at 10 µL/kg bw
      (Kli81).
          After a single subcutaneous injection into mice, liver function damage was
      observed 24 hours later in the form of a decreased plasma clearance of
      bromosulphalein in 1 out of 10 mice at 0.05 mmol/kg bw (16.6 mg/kg). At 0.3
      mmol/kg bw (100 mg/kg bw), 40% of the animals had liver function damage and
      2 out of 5 animals had histological changes in the liver. The type of changes was
      not described (Kut62b).
      After exposure to a concentration of 4-8 ppm (ca. 55-110 mg/m3) for 1 or 2
      weeks, rats showed mild eye and nasal irritation. Gross pathology yielded slight
*     The (theoretic) concentration in saturated air can be calculated using the formula: (vapour pressure in Pa x 106
      ppm)/105 Pa. Using a vapour pressure at 25oC of 96 Pa, the committee estimates that these animals could have
      been exposed to 960 ppm or 1325 mg/m3.
114-5 Carbon tetrabromide
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<pre>      lung, liver, and kidney damage. Microscopic examination showed mild to
      advanced degenerative changes in the liver of all female rats and most of the
      male rats. Further, cloudy swelling, necrosis, and fatty changes were observed in
      the livers. The kidney damage was not further described (Wuj62).
      Groups of 5 male and 5 female rats, 4 male guinea pigs, and 1 female rabbit were
      exposed to 0.3-0.5 ppm CBr4 (ca. 4-7 mg/m3), 7 hours/day, 5 days/week, for 5
      weeks. The concentration was determined by combustion and analysed for
      bromide. The authors estimated the actual concentration to have been 1 ppm
      (13.8 mg/m3) when compared with results of a polarographic analysis that gave a
      30% higher concentration. Only the tissues of the male rats were examined
      microscopically. No effects were observed in the lungs, spleen, pancreas, adrenal
      gland, testicle, and heart. In the livers, there was dilation of the sinusoids, cloudy
      swelling of the cells, and usually small areas of necrosis. Degenerative changes
      were observed in the renal epithelium of the kidneys characterised by necrosis of
      the convoluted tubules, glomerular degeneration, and sometimes shrinkage of the
      glomerular tufts and proliferation of the interstitial tissue (Wuj62).
          Groups of 10 male and 10 female rats, 5 male and 5 female guinea pigs, and
      2 male and 2 female rabbits were exposed to 0.3-0.5 ppm CBr4 (ca. 4-7 mg/m3),
      presumably 7 hours/day, 5 days/week, for 6 months. The concentration was
      measured by a polarographic method. Control groups of rats and guinea pigs
      were either not exposed, or sham exposed. Growth, general appearance, and
      mortality records showed no evidence of adverse effects in the rats or female
      guinea pigs. The final body weight of the male guinea pigs was depressed, but
      not statistically significant (p>0.05). All organ weights and clinical values were
      within normal limits. No adverse effects were observed either grossly or
      microscopically in the various species and sexes (Wuj62). The committee
      concludes that under the circumstances of the study, intermittent exposure to
      carbon tetrabromide concentrations of 4-7 mg/m3 (0.3-0.5 ppm) was a NOAEL
      for rats, guinea pigs, and rabbits.
          Exposure of rats to 10-1000 mg/m3 of CBr4 fumes, 4 hours/day for 4 months,
      was reported to cause metabolic changes in the livers. Even the lowest
      concentration caused irritation of the eyes and respiratory tract (Pau69).
      Mutagenicity and genotoxicity
      Carbon tetrabromide was positive in a forward mutation assay to resistance to L-
      arabinose in S. typhimurium strain BA13; without rat liver metabolic activation,
      the number of mutants was much higher than with metabolic activation (Rol93).
114-6 Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>          Carbon tetrabromide was negative in a test for chromosomal malsegregation
      in the mould A. nidulans (Cre95).
      The committee did not find data from carcinogenicity and reproduction toxicity
      studies on carbon tetrabromide.
7     Existing guidelines
      The current administrative occupational exposure limit (MAC) for carbon
      tetrabromide in the Netherlands is 1.4 mg/m3 (0.1 ppm), 8-hour TWA.
          Existing occupational exposure limits for carbon tetrabromide in some
      European countries and in the USA are summarised in the annex.
8     Assessment of health hazard
      In rabbits, carbon tetrabromide exerted local effects like severe irritation and
      permanent corneal damage to the eyes and slight irritation, hyperaemia, and
      oedema to the skin of rabbits.
          After inhalation exposure, the target organ of toxicity is the liver. Mild to
      advanced degenerative changes, cloudy swelling, necrosis, and fatty changes
      have been observed in the livers of rats after exposure to 55-110 mg/m3 (4-8
      ppm). Also, after exposure to 13.8 mg/m3 (1 ppm), degenerative changes were
      observed in the livers and kidneys of rats. In a 6-month study with rats, guinea
      pigs, and rabbits, intermittent exposure to 4-7 mg/m3 (0.3-0.5 ppm) did not
      induce any effect, and was, therefore, an NOAEL. Given the poor documentation
      of the study and the difficulties in measuring the concentration, the committee
      considers the study insufficient as a starting point to establish a health-based
      occupational exposure limit.
      The committee considers the toxicological database on carbon tetrabromide too
      poor to justify recommendation of a health-based occupational exposure limit.
      The committee concludes that there is insufficient information to comment on
      the level of the present MAC-value.
114-7 Carbon tetrabromide
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<pre>       References
ACG98  American Conference of Governmental Industrial Hygienists (ACGIH). Carbon tetrabromide.
       In:TLVs® and other occupational exposure values -1998. [CD-ROM]. Cincinnati OH, USA;
       ACGIH®, 1998.
ACG03  American Conference of Governmental Industrial Hygienists (ACGIH). Guide to occupational
       exposure values - 2003. Cincinnati OH, USA: ACGIH®, 2003: 23.
ACG04  American Conference of Governmental Industrial Hygienists (ACGIH). 2004 TLVs® and BEIs®
       based on the documentation of the Threshold Limit Values for chemical substances and physical
       agents & Biological Exposure Indices. Cincinnati OH, USA: ACGIH®, 2004: 18.
Aga83  Agarwal AK, Berndt WO, Mehendale HM. Possible nephrotoxic effect of carbon tetrabromide and
       its interaction with chlordecone. Toxicol Lett 1983; 17: 57-62.
Arb02  Arbejdstilsynet. Grænseværdier for stoffer og materialer. Copenhagen, Denmark: Arbejdstilsynet,
       2002: 19 (At-vejledning C.0.1).
Bur76  Burreson BJ, Moore RE Roller PP. Volatile halogen compounds in the alga Asparagopsis taxiformis
       (Rhodophyta). J Agric Food Chem 1976; 24: 856-61.
Cre95  Crebelli R, Andreoli C, Carere A, e.a. Toxicology of halogenated aliphatic hydrocarbons: structural
       and molecular determinants for the disturbance of chromosome segregation and the induction of lipid
       peroxidation. Chem Biol Interact 1995; 98: 113-29.
DFG03  Deutsche Forschungsgemeinschaft (DFG): Commisson 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 & 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/health_safety/areas/
       oels_en.htm.
Kli81  Klingensmith JS, Mehendal HM. Potentiation of brominated halomethane hepatotoxicity by
       chlordecone in the male rat. Toxicol Appl Pharmacol 1981; 61: 378-84.
Kut62a Kutob SD, Plaa GL. A procedure for estimating the hepatotoxic potential of certain industrial
       solvents. Toxicol Appl Pharmacol 1962; 4: 354-61.
Kut62b Kutob SD, Plaa GL. Assessment of liver function in mice with Bromsulphalein. J Appl Physiol 1962;
       17: 123-5.
HSE02  Health and Safety Executive (HSE). EH40/2002. Occupational Exposure Limits 2002. Sudbury
       (Suffolk), England: HSE Books, 2002: 14.
NIO04a US National Institute for Occupational Safety and Health (NIOSH), ed. Carbon tetrabromide. In: The
       Registry of Toxic Effects of Chemical Substances (RTECS) (last update carbon tetrabromide file:
       October 2002); http://www.cdc.gov/niosh.
114-8  Health-based Reassessment of Administrative Occupational Exposure Limits
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<pre>NIO04b US National Institute for Occupational Safety and Health (NIOSH), ed. Carbon tetrachloride. In: The
       Registry of Toxic Effects of Chemical Substances (RTECS) (last update carbon tetrachloride file:
       October 2002); http://www.cdc.gov/niosh.
NLM04  US National Library of Medicine (NLM), ed. Tetrabromomethane. In: The Hazardous Substances
       Data Bank (HSDB) (last revision data carbon tetrabromide file: January 2003; last review date:
       September 2003); http://toxnet.nlm.nih.gov.
Pau69  Pauslovskaya VV, Petrum NM. [Changes in some biochemical indexes in animals following
       inhalation exposure to low concentrations of tetrabromomethane]. In Russian. Farmakol Toksikol
       (Moskow) 1969; 32: 736-8; cited from Chemical Abstracts 72:77902q.
Rol93  Roldán AT, Pueyo C. Mutagenic and lethal effects of halogenated methanes in the Ara test of
       Salmonella typhimurium: quantitative relationship with chemical reactivity. Mutagenesis 1993; 8:
       127-31.
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.
SZW04  Ministerie van Sociale Zaken en Werkgelegenheid (SZW). Nationale MAC-lijst 2004. The Hague,
       the Netherlands: Sdu Uitgevers, 2004: 40.
Tor94  Torkelson TR. Carbon tetrabromide, tetrabromomethane [CAS # 558-13-4]. In: Clayton GD, Clayton
       FE, ed. Toxicology. 4th ed. New York, USA: J. Wiley & Sons, Inc, 1994: 4080-2 (Patty's industrial
       hygiene and toxicology; Vol II, Pt E; Ch 38, Sect 2.11).
TRG03  TRGS 900. Grenzwerte in der Luft am Arbeitsplatz; Technische Regeln für Gefahrstoffe. BArBl
       2003; (9).
Wol77  Wolf CR, Mansuy D, Nastainczyk W, et al. The reduction of polyhalogenated methane by liver
       microsomal cytochrome P450. Mol Pharmacol 1977; 13: 698-705.
Wuj62  Wujkowski TZ. Toxicity of carbon tetrabromide as determined on a laboratory animals. Dow
       Chemical Company, 1962; unpublished report submitted to the committee by Dow Chemical
       company, Horgen, Switzerland.
114-9  Carbon tetrabromide
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<pre>              Annex
Occupational exposure limits for carbon tetrabromide 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      0.1         1.4           8h                 administrative               SZW04
Employment
Germany
- AGS                                 -           1.4           8h                                              TRG03
- DFG MAK-Kommission                  -           -                                                             DFG03
Great Britain
- HSE                                 0.1         1.4           8h                 OES                          HSE02
                                      0.3         4.1           15 min
Sweden                                -           -                                                             Swe00
Denmark                               0.1         1.4           8h                                              Arb02
USA
- ACGIH                               0.1         -             8h                 TLV                          ACG04
                                      0.3         -             15 min             STEL
- OSHA                                -           -                                                             ACG03
- NIOSH                               0.1         1.4           10 h               REL                          ACG03
                                      0.3         4             15 min             STEL
European Union
- SCOEL                               -           -                                                             EC04
a
     S = skin notation; which means that skin absorption may contribute considerably to body burden; sens = substance can
     cause sensitisation.
b
     Reference to the most recent official publication of occupational exposure limits.
114-10        Health-based Reassessment of Administrative Occupational Exposure Limits
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