INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
Environmental Health Criteria 208
CARBON TETRACHLORIDE
This report contains the collective views of an international group
of experts and does not necessarily represent the decisions or the
stated policy of the United Nations Environment Programme, the
International Labour Organisation, or the World Health
Organization.
First draft prepared by Ms J. de Fouw, National Institute of Public
Health and the Environment, Bilthoven, the Netherlands
Published under the joint sponsorship of the United Nations
Environment Programme, the International Labour Organisation, and the
World Health Organization, and produced within the framework of the
Inter-Organization Programme for the Sound Management of Chemicals.
World Health Organization
Geneva, 1999
The International Programme on Chemical Safety (IPCS),
established in 1980, is a joint venture of the United Nations
Environment Programme (UNEP), the International Labour Organisation
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a prerequisite for the promotion of chemical safety, and to provide
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Development to strengthen cooperation and increase coordination in the
field of chemical safety. The purpose of the IOMC is to promote
coordination of the policies and activities pursued by the
Participating Organizations, jointly or separately, to achieve the
sound management of chemicals in relation to human health and the
environment.
WHO Library Cataloguing in Publication Data
Carbon tetrachloride.
(Environmental health criteria ; 208)
1.Carbon tetrachloride - toxicity 2.Environmental exposure
I.International Programme on Chemical Safety II.Series
ISBN 92 4 157208 6 (NLM Classification: QD 305.H5)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CARBON TETRACHLORIDE
PREAMBLE
ABBREVIATIONS
1. SUMMARY
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND ANALYTICAL
METHODS
2.1. Identity
2.2. Physical and chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.4.1. Sampling and analysis in air
2.4.2. Sampling and analysis in water
2.4.3. Sampling and analysis in biological samples
2.4.3.1 Blood and tissues
2.4.3.2 Urine
2.4.3.3 Fish
2.4.4. Sampling and analysis in foodstuffs
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production
3.2.1.1 Direct production and procedures
3.2.1.2 Indirect production
3.2.1.3 Emissions
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Transport
4.1.2. Distribution
4.1.3. Removal from the atmosphere; global
warming potential
4.1.4. Removal from water
4.1.5. Removal from soil
4.2. Abiotic degradation
4.2.1. Degradation in atmosphere
4.2.1.1 Photodegradation
4.2.1.2 Photolysis
4.2.1.3 Ozone-depletion potential
4.2.2. Degradation in water
4.2.3. Other degradation processes
4.3. Biotic degradation
4.3.1. Aerobic
4.3.2. Anaerobic
4.4. Bioaccumulation
5. CONCENTRATIONS IN THE ENVIRONMENT AND EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.1.3. Soil and sediment
5.1.4. Biota
5.2. General population exposure
5.2.1. Outdoor air
5.2.2. Indoor air
5.2.3. Drinking-water
5.2.4. Foodstuffs
5.2.5. Intake averages
5.3. Occupational exposure
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Pharmacokinetics
6.1.1. Absorption
6.1.1.1 Oral
6.1.1.2 Dermal
6.1.1.3 Inhalation
6.1.2. Distribution
6.1.3. Elimination and fate
6.1.4. Physiologically based pharmacokinetic modelling
6.2. Biotransformation and covalent binding of metabolites
6.3. Human studies
6.3.1. Uptake
6.3.1.1 Dermal
6.3.1.2 Inhalation
6.3.2. Elimination
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Single exposure
7.1.1. Lethality
7.1.2. Non-lethal effects
7.1.2.1 Oral exposure
7.1.2.2 Inhalation exposure
7.1.2.3 Subcutaneous and intraperitoneal
exposure
7.1.2.4 Dermal exposure
7.2. Short-term exposure
7.2.1. Oral exposure
7.2.2. Inhalation exposure
7.2.3. Intraperitoneal exposure
7.3. Long-term exposure
7.4. Irritation
7.4.1. Skin irritation
7.4.2. Eye irritation
7.5. Toxicity to the reproductive system, embryotoxicity,
teratogenicity
7.5.1. Reproduction
7.5.2. Embryotoxicity and teratogenicity
7.5.2.1 Oral exposure
7.5.2.2 Inhalation exposure
7.6. Mutagenicity
7.7. Carcinogenicity
7.7.1. Mice
7.7.2. Rats
7.8. Special studies
7.8.1. Immunotoxicity
7.8.2. Influence of oxygen levels
7.9. Factors modifying toxicity
7.9.1. Dosing vehicles
7.9.2. Diet
7.9.3. Alcohol
7.9.4. Enhancement of carbon tetrachloride-induced
hepatotoxicity by various compounds
7.9.5. Reduction of carbon tetrachloride-induced
hepatotoxicity by various compounds
7.10. Mode of action
8. EFFECTS ON HUMANS
8.1. Controlled studies
8.1.1. Inhalation
8.1.2. Dermal
8.2. Case reports
8.3. Epidemiology
8.3.1. Non-cancer epidemiology
8.3.2. Cancer epidemiology
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Toxicity to microorganisms
9.2. Aquatic toxicity
9.2.1. Algae
9.2.2. Invertebrates
9.2.3. Vertebrates
9.3. Terrestrial toxicity
9.3.1. Earthworms
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.1.1. Exposure
10.1.2. Health effects
10.1.3. Approaches to health risk assessment
10.1.3.1 Calculation of a TDI based
on oral data
10.1.3.2 Calculation of a TC based on inhalation
data
10.1.3.3 Summary of the results of risk
assessment
10.1.3.4 Conclusions based on exposure and health
risk assessment
10.2. Evaluation of effects on the environment
11. FURTHER RESEARCH
12. PREVIOUS EVALUATION BY INTERNATIONAL BODIES
REFERENCES
RÉSUMÉ
RESUMEN
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
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This publication was made possible by grant number 5 U01
ES02617-15 from the National Institute of Environmental Health
Sciences, National Institutes of Health, USA, and by financial support
from the European Commission.
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WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR CARBON
TETRACHLORIDE
Members
Dr D. Anderson, British Industry Biological Research Association
(BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom
(Chairperson)
Dr E. Elovaara, Finnish Institute for Occupational Health, Helsinki,
Finland
Dr E. Frantik, National Institute of Public Health, Center of
Industrial Hygiene and Occupational Diseases, Prague, Czech Republic
Dr B. Gilbert, Ministry of Health, Far-Manguinhas-FIOCRUZ,
Rio de Janeiro, Brazil (Co-Rapporteur)
Mr M. Greenberg, National Center for Environmental Assessment, Office
of Research and Development, US Environmental Protection Agency,
Research Triangle Park, North Carolina, USA
Mr P. Howe, Institute of Terrestrial Ecology, Monks Wood, Abbots
Ripton, Huntingdon, Cambridgeshire, United Kingdom
Professor H. Kappus, Virchow Klinikum der Humboldt Universitat,
Berlin, Germany
Dr D. McGregor, Unit of Carcinogen Identification and Evaluation,
International Agency for Research on Cancer, Lyon, France
(Co-Rapporteur)
Dr P. Parsons, Health and Safety Executive, Bootle, Merseyside, United
Kingdom
Professor J.A. Sokal, Institute of Occupational Medicine and
Environmental Health, Sosnowiec, Poland
Secretariat
Dr J. de Fouw, Centre for Substances and Risk Assessment, National
Institute of Public Health and the Environment, Bilthoven, The
Netherlands
Professor F. Valic, IPCS Scientific Adviser, Andrija Stampar School
of Public Health, Zagreb University, Zagreb, Croatia (Responsible
Officer and Secretary of Meeting)
ENVIRONMENTAL HEALTH CRITERIA FOR CARBON TETRACHLORIDE
A Task Group on Environmental Health Criteria for Carbon
Tetrachloride met at the British Industrial and Biological Research
Association (BIBRA), Carshalton, United Kingdom, from 2 to 6 March
1998. Dr D. Anderson, welcomed the participants on behalf of the host
institution, and Professor F. Valic opened the Meeting on behalf of
the heads of the three cooperating organizations of the IPCS
(UNEP/ILO/WHO). The Task Group reviewed and revised the draft
monograph and made an evaluation of the risks for human health from
exposure to carbon tetrachloride.
The first draft of this monograph was prepared by Ms J. de Fouw,
Centre for Substances and Risk Assessment, National Institute of
Public Health and the Environment, Bilthoven, the Netherlands.
Professor Valic, Zagreb University, Croatia, was responsible for
the overall scientific content of the monograph and for the
organization of the Meeting, and Dr P.G. Jenkins, IPCS Central Unit,
for the technical editing of the monograph.
The efforts of all who helped in the preparation and finalization
of the monograph are greatfully acknowledged.
ABBREVIATIONS
ALAT alanine aminotransferase
AP alkaline phosphatase
ASAT aspartate aminotransferase
ATPase adenosine triphosphatase
ATSDR Agency for Toxic Substances and Disease Registry
CNS central nervous system
CPK creatine phosphokinase
CYP cytochrome P-450
Hb haemoglobin
Ht haematocrit
ip intraperitoneal
LDH lactate dehydrogenase
LOAEL lowest-observed-adverse-effect level
MPV mean packed volume
NADPH reduced nicotinamide adenine dinucleotide phosphate
NIOSH National Institute for Occupational Safety and Health (USA)
NOAEL no-observed-adverse-effect level
PBB polybrominated biphenyl
PCB polychlorinated biphenyl
RBC red blood cell
SDH sorbitol dehydrogenase
SRBC sheep red blood cells
TC tolerable concentration
TDI tolerable daily intake
1. SUMMARY
Carbon tetrachloride is a clear, colourless, volatile liquid with
a characteristic, sweet odour. It is miscible with most aliphatic
solvents and is itself a solvent. The solubility in water is low.
Carbon tetrachloride is non-flammable and is stable in the presence of
air and light. Decomposition may produce phosgene, carbon dioxide and
hydrochloric acid.
The source of carbon tetrachloride in the environment is likely
to be almost exclusively anthropogenic in origin. Most of the carbon
tetrachloride produced is used in the production of
chlorofluorocarbons (CFCs) and other chlorinated hydrocarbons. The
global production of carbon tetrachloride amounted to 960 000 tonnes
in 1987. However, since the Montreal Protocol on Substances that
Deplete the Ozone Layer (1987) and its amendments (1990 and 1992) have
established a timetable for the phase-out of the production and
consumption of carbon tetrachloride, manufacture has dropped and will
continue to drop.
Several sufficiently sensitive and accurate analytical methods
for determining carbon tetrachloride in air, water and biological
samples have been developed. The majority of these methods are based
on direct injection into a gas chromatograph or adsorption on
activated charcoal, then desorption or evaporation and subsequent gas
chromatographic detection.
Nearly all carbon tetrachloride released to the environment will
ultimately be present in the atmosphere, owing to its volatility.
Since the atmospheric residence time of carbon tetrachloride is long,
it is widely distributed. During the period 1980-1990, atmospheric
levels were around 0.5-1.0 µg/m3. Estimates of atmospheric lifetime
are variable, but 45-50 years is accepted as the most reasonable
value. Carbon tetrachloride contributes both to ozone depletion and to
global warming. It is in general resistant to aerobic biodegradation
but less so to anaerobic. Acclimation increases biodegradation rates.
Although the octanol-water partition coefficient indicates moderate
potential for bioaccumulation, short tissue lifetime reduces this
tendency.
In water, reports have indicated levels of less than 10 ng/litre
in the ocean and generally less than 1 µg/litre in fresh water, but
much higher values close to release sites. Levels of up to 60 µg/kg
have been recorded in foods processed with carbon tetrachloride, but
this practice has now ceased.
The general population is exposed to carbon tetrachloride mainly
via air. On the basis of the reported concentrations in ambient air,
foodstuffs and drinking-water, a daily carbon tetrachloride intake of
around 1 µg/kg body weight has been estimated. This estimate is
probably rather high for the present day, because the use of carbon
tetrachloride as a fumigant of grain has stopped and the carbon
tetrachloride values reported for food and used in the calculation
were especially those found in fatty and grain-based foods. Values of
0.1 to 0.27 µg/kg body weight for daily exposure of the general
population have been reported elsewhere. Exposure to higher levels of
carbon tetrachloride can occur in the workplace as a result of
accidental spillage.
Carbon tetrachloride is well absorbed from the gastrointestinal
and respiratory tract in animals and humans. Dermal absorption of
liquid carbon tetrachloride is possible, but dermal absorption of the
vapour is slow.
Carbon tetrachloride is distributed throughout the whole body,
with highest concentrations in liver, brain, kidney, muscle, fat and
blood. The parent compound is eliminated primarily in exhaled air,
while minimal amounts are excreted in the faeces and urine.
The first step in the biotransformation of carbon tetrachloride
is catalysed by cytochrome P-450 enzymes, leading to the formation of
the reactive trichloromethyl radical. Oxidative biotransformation is
the most important pathway in the elimination of the radical, forming
the even more reactive trichloromethylperoxyl radical, which can react
further to form phosgene. Phosgene may be detoxified by reaction with
water to produce carbon dioxide or with glutathione or cysteine.
Formation of chloroform and dichlorocarbene occurs under anaerobic
conditions.
Covalent binding to macromolecules and lipid peroxidation occur
via metabolic intermediates of carbon tetrachloride.
The liver and kidney are target organs for carbon tetrachloride
toxicity. The severity of the effects on the liver depends on a number
of factors such as species susceptibility, route and mode of exposure,
diet or co-exposure to other compounds, in particular ethanol.
Furthermore, it appears that pretreatment with various compounds, such
as phenobarbital and vitamin A, enhances hepatotoxicity, while other
compounds, such as vitamin E, reduce the hepatotoxic action of carbon
tetrachloride.
Moderate irritation after dermal application was seen on the
skins of rabbits and guinea-pigs, and there was a mild reaction after
application into the rabbit eye.
The lowest LD50 of 2391 mg/kg body weight (14-day period) was
reported in a study on dogs involving intraperitoneal administration.
In rats the LD50 values ranged from 2821 to 10 054 mg/kg body weight.
In a 12-week oral study on rats (5 days/week), the
no-observed-adverse-effect level (NOAEL) was 1 mg/kg body weight. The
lowest-observed-adverse-effect level (LOAEL) reported in this study
was 10 mg/kg body weight, showing a slight, but significant increase
in sorbitol dehydrogenase (SDH) activity and mild hepatic
centrilobular vacuolization. A similar NOAEL of 1.2 mg/kg body weight
(5 days/ week) was found in a 90-day oral study on mice, with a LOAEL
of 12 mg/kg body weight, where hepatotoxicity occurred.
When rats were exposed to carbon tetrachloride by inhalation for
approximately 6 months, 5 days/week, 7 h/day, a NOAEL of 32 mg/m3 was
reported. The LOAEL, based on changes in the liver morphology, was
reported to be 63 mg/m3. In another 90-day study on rats, a NOAEL of
6.1 mg/m3 was found after continuous exposure to carbon
tetrachloride. The lowest exposure level of 32 mg/m3 (the lowest
concentration studied) in a 2-year inhalation study on rats caused
marginal effects.
The only oral long-term toxicity study available was a 2-year
study in rats, which were exposed to 0, 80 or 200 mg carbon
tetrachloride/kg feed. Owing to chronic respiratory disease in all
animals beginning at 14 months, which resulted in increased mortality,
the results reported upon necropsy at 2 years are inadequate for a
health risk evaluation.
It was concluded that carbon tetrachloride can induce embryotoxic
and embryolethal effects, but only at doses that are maternally toxic,
as observed in inhalation studies in rats and mice. Carbon
tetrachloride is not teratogenic.
Many genotoxicity assays have been conducted with carbon
tetrachloride. On the basis of available data, carbon tetrachloride
can be considered as a non-genotoxic compound.
Carbon tetrachloride induces hepatomas and hepatocellular
carcinomas in mice and rats. The doses inducing hepatic tumours are
higher than those inducing cell toxicity.
In humans, acute symptoms after carbon tetrachloride exposure are
independent of the route of intake and are characterized by
gastrointestinal and neurological symptoms, such as nausea, vomiting,
headache, dizziness, dyspnoea and death. Liver damage appears after 24
h or more. Kidney damage is evident often only 2 to 3 weeks following
the poisoning.
Epidemiological studies have not established an association
between carbon tetrachloride exposure and increased risk of mortality,
neoplasia or liver disease. Some studies have suggested an association
with increased risk of non-Hodgkin's lymphoma and, in one study, with
mortality and liver cirrhosis. However, not all of these studies
pinpointed specific exposure to carbon tetrachloride, and the
statistical associations were not strong.
In general carbon tetrachloride appears to be of low toxicity to
bacteria, protozoa and algae; the lowest toxic concentration reported
was for methanogenic bacteria with an IC50 of 6.4 mg/litre. For
aquatic invertebrates acute LC50 values range from 28 to > 770
mg/litre. In freshwater fish the lowest acute LC50 value of 13
mg/litre was found in the golden orfe (Leuciscus idus melanotus),
and for marine species an LC50 value of 50 mg/litre was reported for
the dab (Limanda limanda). Carbon tetrachloride appears to be more
toxic to embryo-larval stages of fish and amphibians than to adults.
The common bullfrog (Rana catesbeiara) is the most susceptible
species, the LC50 being 0.92 mg/litre (fertilization to 4 days after
hatching).
The available data indicate that hepatic tumours are induced by a
non-genotoxic mechanism, and it therefore seems acceptable to develop
a tolerable daily intake (TDI) and a tolerable daily concentration in
air (TC) for carbon tetrachloride.
On the basis of the study of Bruckner et al. (1986), in which a
NOAEL of 1 mg/kg body weight was observed in a 12-week oral study on
rats, and incorporating a conversion factor of 5/7 for daily dosing
and applying an uncertainty factor of 500 (100 for inter- and
intraspecies variation, 10 for duration of the study, and modifying
factor 0.5 because it was a bolus study), a TDI of 1.42 µg/kg body
weight is obtained.
On the basis of a 90-day inhalation study on rats (Prendergast et
al., 1967), in which a NOAEL of 6.1 mg/m3 was reported, a TC of 6.1
µg/m3 was calculated using the factors 7/24 and 5/7 to convert to
continuous exposure and an uncertainty factor of 1000 (100 for
inter- and intraspecies variation and 10 for the duration of the
study). This TC corresponds to a TDI of 0.85 µg/kg body weight.
Comparing the estimated upper limit of prevailing human daily
intake of 0.2 µg/kg body weight with the lowest TDI value (0.85 µg/kg
body weight), the conclusion can be drawn that the currently
prevailing exposure of the general population to carbon tetrachloride
from all sources is unlikely to cause excessive intake of the
chemical.
In general, the risk to aquatic organisms from carbon
tetrachloride is low. However, it may present a risk to embryo-larval
stages at, or near, sites of industrial discharges or spills.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1 Identity
Chemical formula: CCl4
Chemical structure:
Common name: carbon tetrachloride
Common synonyms: Carbona, carbon chloride, tetrachloromethane,
carbon tet, methane tetrachloride,
perchloromethane, tetrachlorocarbon
Trade names: Benzinoform, Fasciolin, Flukoids, Freon 10,
Halon 104, Necatorina, Necatorine,
Tetrafinol, Tetraform, Tetrasol, Univerm,
Vermoestricid
CAS chemical name: tetrachloromethane
CAS registry number: 56-23-5
RTECS registry number: FG 4900000
2.2 Physical and chemical properties
The most important physical properties of carbon tetrachloride
are given in Table 1.
Table 1. Physical properties of carbon tetrachloridea
Colour colourless
Relative molecular mass 153.8
Boiling point at 101.3 kPa, 20°C 76.72 °C
Melting point at 101.3 kPa, 20°C -22.92 °C
Density (25°C) 1.594 g/ml
Table 1. (Continued)
Density of solid at - 186 °C 1831 kg/m3
- 80 °C 1809 kg/m3
Refractive index at 20 °C 1.4607
Vapour pressure at 20 °C 91.3 mmHg; 12.2 kPa
at 0 °C 32.9 mmHg; 4.4 kPa
Autoignition temperature > 1000 °C
Critical pressure 4.6 MPa
Critical temperature 283.2 °C
Solubility in water at 25 °C 785 mg/litre
Solubility of water in carbon
tetrachloride at 25 °C 0.13 g/kg
Henry's law constant at 24.8 °C 2.3 × 10-2 atm-m3/mol
Heat of evaporation 194.7 kJ/kg
Log Kow 2.64
Log Koc 2.04
a From Kenaga (1980); US EPA (1984b); Huiskamp et al. (1986);
ATSDR (1994).
Carbon tetrachloride is a volatile colourless clear heavy liquid
with a characteristic sweet non-irritant odour. The odour threshold in
water is 0.52 mg/litre and in air is > 10 ppm. Carbon tetrachloride
is miscible with most aliphatic solvents and it is a solvent for
benzyl resins, bitumen, chlorinated rubber, rubber-based gums, oils
and fats. The chemical is non-flammable and fairly stable in the
presence of air and light. Upon heating by a flame or hot metal
surface in air, toxic phosgene is produced. Thermal dissociation in
the absence of air proceeds slowly at about 400°C and is extensive at
temperatures ranging from 900 to 1300°C with the formation of
perchloroethylene, hexachloroethane and some molecular chlorine. A
mixture of carbon tetrachloride and excess of water vapour decomposes
at 250°C to carbon dioxide and hydrochloric acid. When the amount of
water in the mixture is limited, phosgene will be formed too. This
decomposition also occurs when moist or wet carbon tetrachloride is
exposed to UV radiation (253.7 nm). Like other chloromethanes, carbon
tetrachloride reacts (sometimes explosively) with aluminium and its
alloys. Similar violent reaction may occur with metals, such as
barium, magnesium and zinc, boranes and silanes, and, in the presence
of peroxides or light, with unsaturated compounds (such as ethene).
Carbon tetrachloride may be reduced to chloroform when treated with
zinc and acid, and to methane when treated with potassium amalgam and
water (Huiskamp et al., 1986).
2.3 Conversion factors
1 mg carbon tetrachloride/m3 air = 0.156 ppm at 20°C and 101.3
kPa (760 mmHg)
1 ppm = 6.41 mg carbon tetrachloride/m3
2.4 Analytical methods
Procedures used for the sampling and determination of carbon
tetrachloride in different media are summarized in Table 2.
The preferred analytical technique is gas chromatography (GC)
using either electron capture detection (ECD), ion trap detection,
flame or photo ionisation detection or mass spectrometry. Only one
method, reported by Lioy & Lioy (1983), depends on the use of
MIRAN-infrared spectrometry, a method of very poor sensitivity.
2.4.1 Sampling and analysis in air
Methods reported in Table 2 for detecting carbon tetrachloride in
air are of four types.
a) Direct measurement
These methods are simple, because the air is aspirated or
injected directly into the measuring instrument, but they can only be
used when carbon tetrachloride is present in the air at relatively
high levels.
b) Adsorption - liquid desorption
In this type of method, air samples are passed through an
activated adsorbing agent. The adsorbed carbon tetrachloride is
desorbed with an appropriate solvent and then passed through the gas
chromatograph. Activated carbon has been described as superior to
other adsorbents for adsorption. Elution from the carbon is achieved
with carbon disulfide (Morele et al., 1989; ATSDR, 1994).
c) Adsorption - thermal desorption
After adsorption on an activated adsorbing agent, the carbon
tetrachloride is thermally desorbed and driven into the gas
chromatograph.
Table 2. Sampling and analysis of carbon tetrachloridea
Medium Sampling method Analytical method Detection limit Sample size Comments Reference
Air aspiration velocity: 28 l/min MIRAN infrared 400 µg/m3 Lioy & Lioy,
optical path: 20 m spectrometry 1983
Air direct injection GC with 2 ECD's 0.4 µg/m3 8 ml injected Lillian &
in series (estimated) Singh, 1974
Air direct injection GC - ECD 0.2 µg/m3 2 ml injected BIT-SC, 1976
Air direct injection GC - ECD 0.06 µg/m3 5 ml injected Lasa et al.,
1979
Air direct injection, methane GC - ECD 0.01 µg/m3 12 ml injected thorough purification of Makide &
added carrier gas and apparatus Yokohata, 1983
required
Air adsorption on Porapak-N GC - ECD 1 µg/m3 20 litres advantage of using Van Tassel et
liquid desorption (methanol) methanol over CS2 is the al., 1981
absence of a background
signal in the ECD
Air adsorption on activated GC - ECD 0.2 µg up to 30 litres activated charcoal shown Morele et al.,
charcoal, liquid desorption can be sampled to be more efficient 1989
(ethanol) trichloroethylene trapping material than
used as IS XADs, Tenax or
Chromosorbs
adsorption on activated GC - FID ca. 0.15 mg
charcoal liquid desorption (detector
(CS2) methylcyclohexane sensitivity)
used as IS
Table 2. (Continued)
Medium Sampling method Analytical method Detection limit Sample size Comments Reference
Air adsorption on activated GC - FID 0.01 mg 5-15 litres NIOSH, 1977,
charcoal, liquid desorption 1984
(CS2)
Air adsorption on Chromosorb GC - ECD 0.003 µg/m3 20 ml Makide et al.,
102 or Silicone OV 101 (at 1979
-35 °C), thermal desorption
Air adsorption on Porapak-N, GC - ECD 0.005 µg/m3 0.3-3 litres confirmation of results by Russell &
thermal desorption at 200 °C use of GC - MS Shadoff, 1977
Air adsorption on Chromosorb GC - ECD 0.01 µg/m3 1 litre Elias, 1977
102, thermal desorption at (collection tube (estimated)
200 °C already connected
to GC)
Air adsorption on Carbopak-B at GC - ECD 0.01 µg/m3 1 litre calibration with Crescentini et
78 °C, thermal desorption permeation tubes al., 1981
Air adsorption on Chromosorb-102 GC - ECD - FID ca. 0.06 µg/m3 1-3 litres Heil et al.,
and activated charcoal, (2 detectors in 1979
thermal desorption at 150 °C parallel)
Air adsorption on Tenax-GC, GC - MS 0.2 µg/m3 20 litres compounds were Krost et al.,
thermal desorption at 270 °C cryofocused 1982
Air adsorption on Carbopak-C, GC - MS 0.1 µg/m3 300 ml Crescentini et
thermal desorption at 100 °C al., 1983
Air adsorption on activated GC - ECD followed 0.7 µg/m3 24 h sample Coutant &
charcoal, liquid desorption by a PID Scott, 1982
(5% CS2 in methanol)
Table 2. (Continued)
Medium Sampling method Analytical method Detection limit Sample size Comments Reference
Air cold trap (liquid oxygen), GC - ECD 0.006 µg/m3 30 ml aliquot measurement of air Harsch &
heating in trap samples from the Cronn, 1978
stratosphere
Air injection in cold trap, heating GC - MS (SIM) 0.04 µg/m3 100 ml Cronn &
Harsch, 1979
Air cold trap (-173 °C), heating to GC - PID - ECD - 0.006 µg/m3 0.5-1.7 litres column is kept at -103 °C Rudolph &
257 °C FID (3 detectors (cryofocusing) Jebsen, 1983
in series)
Water dibromomethane used as IS GC - ECD 0.001 µg/litre 500 µl injected suitable for routine Herzfeld et al.,
analysis of river waters 1989
Water direct aqueous injection GC - MS (SIM) 2 µg/litre 10 µl injected Fujii, 1977
Water direct aqueous injection GC - ECD 0.015 µg/litre 2 µl injected suitable for halocarbons Grob, 1984
in water in the 0.01 to
10 µg/litre range
Water direct aqueous injection, GC - ECD 0.05 µg/litre 5-20 µl Simmonds &
water removal by injected Kerns, 1979
permeaselective membrane
Water liquid-liquid extraction GC - ECD 0.10 µg/litre 10-20 ml Van Rensburg
(using hexane) et al., 1978
Water liquid-liquid extraction GC - ECD 0.2 µg/litre Inoko et al.,
(using xylene) 1984
Water liquid-liquid extraction GC - ECD 0.05 µg/litre Kroneld, 1985
(using pentane)
Table 2. (Continued)
Medium Sampling method Analytical method Detection limit Sample size Comments Reference
Water purge and trap technique, GC - ITD 0.1 µg/litre 5 ml Eichelberger
thermal desorption, et al., 1990
fluorobenzene as IS
Grain codistillation of carbon GC - ECD 1 µg/kg De Vries et al.,
tetrachloride in food sample 1985
and mixture of
1,2-dichloropropane and
1,2-dibromopropane as IS in
hexane
Adipose purge and trap technique GC - MS < 1.3 µg/litre 200-500 mg Peoples et al.,
tissue (Tenax-silica gel), thermal liquefied fat 1979
desorption samples
Blood purge and trap technique GC - MS < 1.3 µg/litre 0.5 ml water- Peoples et al.,
(Tenax-silica gel), thermal serum sample 1979
desorption
Blood warming and passing an inert GC - MS 3 µg/litre 10 ml sample Pellizzari
gas, vapours trapped on et al., 1985
Tenax-GC, thermal desorption
Urine liquid-liquid extraction using GC - ECD (20% < 1 µg/litre 10 ml sample Youssefi et al.,
pentane (adding 2.6 g SP-2100/0.1% 1978
ammonium carbonate) Carbowax 1500
column)
Fish extraction with pentane and GC - ECD 0.1 µg/kg in Baumann
isopropanol, with fresh material Ofstad et al.,
bromotrichloromethane used as IS 1981
a Abbreviations: GC = gas chromatography; MS = mass spectrometry; ECD = electron capture detector; SIM = single (selected) ion monitoring;
FID = flame ionisation detector; ITD = ion trap detector; PID = photo ionisation detector; IS = internal standard.
d) Cold trap - heating
In this type of procedure, air samples are injected into a cold
trap. The trap is then heated and the carbon tetrachloride content
transferred into the column of a gas chromatograph.
2.4.2 Sampling and analysis in water
Several methods for sampling analysing the carbon tetrachloride
content in water are included in Table 2. Most of these methods are
based on direct injection techniques or on liquid-liquid extraction by
means of a non-polar non-halogenated solvent.
2.4.3 Sampling and analysis in biological samples
2.4.3.1 Blood and tissues
Peoples et al. (1979) developed a method to determine carbon
tetrachloride in adipose tissue and blood. In both cases the carbon
tetrachloride is purged and trapped on Tenax-silica gel and determined
by mass spectrometry after thermal desorption.
Pellizzari et al. (1985) similarly passed an inert gas over a
warmed plasma sample with adsorption of the vapour on a Tenax-GC
cartridge, and then recovered the carbon tetrachloride by thermal
desorption.
2.4.3.2 Urine
The only method listed in Table 2 for measuring carbon tetra
chloride concentrations in urine is based on an extraction technique
with pentane and direct gas chromatographic analysis of the pentane
extract (Youssefi et al., 1978).
2.4.3.3 Fish
Baumann Ofstad et al. (1981) developed a method for the analysis
of volatile halogenated hydrocarbons in biological samples and used
this method for the analysis of fish samples. It should be noted that
the identification and quantification of carbon tetrachloride is
especially vulnerable to contamination, so the practical usefulness of
this method is very limited.
2.4.4 Sampling and analysis in foodstuffs
A method for the determination of 22 compounds (including carbon
tetrachloride) in a variety of foods was described by Daft (1988). In
this method the samples are extracted with isooctane, and cleaned up
according to fat content and food type. Most samples (6-10 µl) are
injected for GC with ECD and Hall-electron conductivity detection
immediately following the initial extraction or dilution.
De Vries et al. (1985) provided a method for analysis of carbon
tetrachloride in grain and grain-based products containing 1-2000
µg/kg. A food sample is mixed with water and an internal standard
mixture of 1,2-dichloropropane and 1,2-dibromopropane is added. The
water is then distilled until 1 ml has been collected under hexane.
The hexane is then separated, dried and injected (2 µl) into the GC
column.
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
It has been suggested that carbon tetrachloride can be formed in
the troposphere by the solar-induced photochemical reactions of
chlorinated alkenes (Singh et al., 1975). However, so far this
reaction has only been demonstrated in the laboratory, and, even if it
could happen in nature, it is not certain that it would be a major
source of environmental carbon tetrachloride. Carbon tetrachloride has
been detected in volcanic emission gases (Isidorov et al., 1990).
Several studies have shown that global atmospheric levels of carbon
tetrachloride can be explained by anthropogenic sources alone (Singh
et al., 1976).
3.2 Anthropogenic sources
3.2.1 Production
3.2.1.1 Direct production and procedures
Production of carbon tetrachloride began in about 1907 in the
USA. It can be produced by chlorination of methane, methanol, carbon
disulfide, propane, 1,2-dichloroethane and higher hydrocarbons.
The world production of carbon tetrachloride ranged from 850 to
960 kilotonnes over the years 1980-1988. Table 3 provides some data on
past production and production capacities of carbon tetrachloride.
These data are based on information in the ECDIN database (ECDIN,
1992) and BUA-Stoffbericht 45 (BUA, 1990).
Since 1990 the production of carbon tetrachloride has dropped.
The Montreal Protocol of 1990 and its subsequent amendments
established the phase-out by 1996 of production and use of carbon
tetrachloride and of chlorofluorocarbons (CFCs) by major manufacturing
countries. Special conditions were allowed for developing countries,
where consumption of controlled substances under Annex B (including
carbon tetrachloride) was required to be reduced by 85% of its
1998-2000 average level (or a calculated consumption level of 0.2 kg
per capita, whichever is lower) by 2005 and completely stopped by 2010
(UNEP, 1996).
3.2.1.2 Indirect production
Carbon tetrachloride can be produced as a by-product during the
manufacture of other products and compounds (US EPA, 1984a) and during
wood pulp bleaching.
Table 3. Past production and production capacity of carbon
tetrachloride
Country Year Production Capacity
(in kilotonnes) (in kilotonnes)
France 1988 - 90
Italy 1987 95 -
1988 - 130
Germany (former FRG) 1985 150 -
1987 180 -
1988 170 180
EEC 1985 - 520
1987 480 -
1988 478 540
Japan 1985 - 72
1987 52 -
1988 - 70
United Kingdom 1988 - 75
USA 1986 286 -
1987 340 -
1988 - 281
1991 143 -
World 1985 - 1200
1987 960 -
1988 - 1100
3.2.1.3 Emissions
According to US EPA (1991), in 1989 approximately 2000 tonnes of
carbon tetrachloride were released during manufacturing and processing
to the air in the USA. US EPA (1984a) reported emission factors for
carbon tetrachloride arising during the chlorination of hydrocarbons
ranging from 0.9 kg/tonne of carbon tetrachloride (controlled) to 2.8
kg/tonne of carbon tetrachloride (uncontrolled). Furthermore,
emissions may result from industrial water treatment or from old
landfill sites.
3.2.2 Uses
Most of the carbon tetrachloride produced is used in the
production of CFCs, which were primarily used as refrigerants,
propellants, foam-blowing agents and solvents and in the production of
other chlorinated hydrocarbons.
The use of carbon tetrachloride increased in the EEC as well as
in the USA during the years 1980-1987. However, this use has decreased
in recent years due to the Copenhagen Amendment to the Montreal
Protocol (1992) (UNEP, 1996). A survey in Japan could detect no use of
carbon tetrachloride in small to medium scale industries in 1996 (Ukai
et al., 1997).
Carbon tetrachloride has been used as a grain fumigant,
pesticide, solvent for oils and fats, metal degreaser, fire
extinguisher and flame retardant, and in the production of paint, ink,
plastics, semi-conductors and petrol additives. It was previously also
widely used as a cleaning agent. All these uses have tended to be
phased-out as production has dropped (ECDIN, 1992; ATSDR, 1994).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
4.1.1 Transport
Carbon tetrachloride introduced into water resources is
transported by movement of surface water and groundwater. Because of
its volatility, evaporation is considered to be the main process for
the removal of carbon tetrachloride from aquatic systems. The amount
of carbon tetrachloride dissolved in the oceans is reported to be less
than 1-3% of that in the atmosphere (Galbally, 1976; Singh et al.,
1976). Practically all the carbon tetrachloride released to the
environment is thus present in the atmosphere (US EPA, 1991). Because
carbon tetrachloride does not degrade readily in the atmosphere,
significant global transport is expected.
Following releases to soil, most carbon tetrachloride is expected
to evaporate rapidly due to its high vapour pressure. A small fraction
of carbon tetrachloride may adsorb to organic matter, based on a
calculated soil adsorption coefficient of 100 (log Koc = 2.04)
(Kenaga, 1980).
Walton et al. (1992) studied the adsorption of carbon
tetrachloride from solution onto two soils, a silt loam (1.49% organic
carbon) and a sandy loam (0.66% organic carbon). The soil was shaken
with several concentrations of carbon tetrachloride (100 to 650 mg/kg
soil) for 18 h. The Koc values determined were 143.6 for the silt
loam and 48.9 for the sandy loam. Duffy et al. (1997) studied the
downward movement of carbon tetrachloride in 3 horizons of a fine
montmorillonitic soil. Koc values of 55, 77.6 and 269 were calculated
for the modern A, buried A and loess C soil horizons. However, the
authors point out that Koc values are unreliable in soils with low
organic carbon and high clay content. Therefore, the highest Koc
value should be treated with some caution.
4.1.2 Distribution
The evidence that the residence time of carbon tetrachloride in
the atmosphere is long (see section 4.1.3) and that nearly all of the
compound is found in this compartment explains the relatively even
distribution over the globe as is recorded in Table 4.
Only a very small proportion of carbon tetrachloride will remain
in water and soil.
Table 4. Levels of carbon tetrachloride in air
Location Year Mean level (µg/m3) Reference
(range in
parentheses)
Northern 1974 0.71 Cox et al. (1976)
hemisphere 1976 0.73 Singh et al. (1977)
1977 0.78 Singh et al. (1979)
1979-1981 0.87 Singh et al. (1983)
Southern 1974 0.44 Cox et al. (1976)
hemisphere 1977 0.76 Singh et al. (1979)
1979-1981 0.82 Singh et al. (1983)
North-West 1975-1980 0.91 Rasmussen et al.
Pacific (0.83-0.99) (1981)
1975-1985 0.77 Rasmussen & Khalil
(0.67-0.83) (1986)
1976 0.78 Cronn et al. (1977)
Antarctica 1975-1980 0.8 Rasmussen et al.
(0.77-0.87) (1981)
1975-1985 0.69 Rasmussen & Khalil
(0.62-0.76) (1986)
Arctic 1982 0.97 Rasmussen & Khalil
(1983)
North Atlantic 1983 0.56 von Düszeln &
Thiemann (1985)
North America 1976 0.86 Pierotti et al.
(0.33-0.99) (1980)
California, USA 1976 0.76-0.86 Singh et al.
(0.66-1.85) (1977)
Bochum, Germany 1978 0.8 (0.1-1.2) Bauer (1981)
Germany (cities) 1980-1981 0.6 von Düszeln &
Thiemann (1985)
Table 4. (Continued)
Location Year Mean level (µg/m3) Reference
(range in
parentheses)
South-West 1986-1988 0.5-0.6 Frank & Frank
Germany (1990)
The Netherlands 1980 0.83-1.0 Guicherit &
(max. 2.2-3.2) Schulting (1985)
Turin, Italy 1988 0.96 (0.17-1.94)a Gilli et al. (1990)
1988 0.47
(0.19-1.17)b Gilli et al. (1990)
Japan 1979 0.69
(0.62-0.72) Makide et al. (1979)
1994-1995 0.53c Sugama et al. (1995)
a cold months
b warm months
c concentrations were higher in winter than during summer
4.1.3 Removal from the atmosphere; global warming potential
The troposphere to stratosphere turnover time has been estimated
at around 30 years (Versar Inc., 1979). This is a shorter period of
time than is estimated for the degradation processes of carbon
tetrachloride in the troposphere (see section 4.2). Therefore
tropospheric carbon tetrachloride will attain significant
concentration in the stratosphere.
Cupitt (1980) calculated that deposition of carbon tetrachloride
from the atmosphere will be very slow.
Estimates of the atmospheric lifetime (the overall persistence of
carbon tetrachloride in the troposphere and the stratosphere combined)
are variable, but most values range from 25 to 100 years (Molina &
Rowland, 1974; Galbally, 1976; Singh et al., 1979; Edwards et al.,
1982a,b; Simmonds et al., 1983, 1988; Rowland, 1985; Huiskamp et al.,
1986; Howard, 1990; IPCC, 1990, 1995; WMO, 1991) with 45-50 years
generally being accepted as the most reasonable value.
The Global Warming Potential (GWP) of carbon tetrachloride,
relative to CO2, is estimated (IPCC, 1995) to be 2000, 1400 and 500
at integration time horizons of 20, 100 and 500 years. Its
contribution to total warming may be 0.3% as integrated effect over a
time horizon of 100 years (IPCC, 1995). Relative to CFC 12, the GWP of
carbon tetrachloride has been estimated to be 0.12 (UNEP, 1989).
4.1.4 Removal from water
The major removal process from water is volatilization to the
atmosphere. This was indicated by laboratory tests performed by
Dilling et al. (1975). These tests showed that a 1 ppm concentration
of low-molecular-weight chlorinated hydrocarbons will not persist in
agitated natural water bodies due to evaporation. In 29 min 50% of the
amount of carbon tetrachloride was evaporated, and in 97 min 90% was
evaporated. Zoeteman et al. (1980) calculated a half-life of carbon
tetrachloride in rivers of 0.3-3 days and in lakes and groundwaters of
30-300 days.
4.1.5 Removal from soil
Anderson et al. (1991) studied the loss of carbon tetrachloride
from two different soil types, a silt loam (1.49% organic carbon) and
a sandy loam (0.66% organic carbon). Carbon tetrachloride was applied
to the soil at a concentration of 100 mg/kg (dry weight) and the soil
was incubated in the dark at 20°C for 7 days. The mean half-life for
disappearance of carbon tetrachloride was 5 days. There was no
significant difference between the loss from sterile and non-sterile
systems indicating that volatilization was the likely removal process.
Jury et al. (1984) predicted that carbon tetrachloride would have
a volatilization half-life of 0.2 days at a depth of 1 cm and 0.8 days
at a depth of 10 cm in soil, based on volatilization tests and
assuming a uniform distribution of the chemical with depth.
4.2 Abiotic degradation
4.2.1 Degradation in atmosphere
4.2.1.1 Photodegradation
Carbon tetrachloride is very stable in the troposphere (Lillian
et al., 1975; Cox et al., 1976; Singh et al., 1980). This is primarily
because carbon tetrachloride, in contrast to most other volatile
halocarbons, has low reactivity towards hydroxyl radicals. This is
evident from rate constants determined by several authors (Howard
Carleton & Evenson, 1976; Cox et al., 1976; Clyne & Holt, 1978). Based
on these rate constants, half-lives of > 3.9 to 137 years can be
calculated for the decomposition of carbon tetrachloride in the
troposphere (Lyman et al., 1982).
Cox et al. (1976) found an even higher tropospheric half-life of
> 330 years.
4.2.1.2 Photolysis
Edwards et al. (1982b) estimated a lifetime in the troposphere
due to photolysis of the order of 500 years.
The principal degradation process for carbon tetrachloride occurs
in the stratosphere, where it is dissociated by short wave length
(190- 220 nm) UV radiation to form the trichloromethyl radical and
chlorine atoms. Simmonds et al. (1983) estimated a half-life of 18-80
years for this photodissociation process.
4.2.1.3 Ozone-depletion potential
The chlorine atoms in carbon tetrachloride interact with oxygen
or ozone to produce ClO* groups (Singh et al., 1975). The chlorine
atoms and ClO* groups attack the surrounding ozone in a reaction in
which they act as catalysts until scavenged by some other chemical
reaction (Isaksen & Stordal, 1981; Rowland, 1985; Ember et al., 1986).
This effect is reflected in an ODP (ozone depletion potential) of 1.08
(WMO, 1991) and 1.1 (UNEP, 1996), compared with the chlorofluorocarbon
CFC-11, and was responsible for the inclusion of carbon tetrachloride
in the amended Montreal Protocol of 1990 (UNEP, 1996).
Catalytic breakdown of ozone by chloride-containing radicals:
CCl4 + h nu -> *CCl3 + *Cl
*CCl3 + O2 -> -> COCl2 + ClO*
*Cl + O3 -> ClO* + O2
ClO* + O -> *Cl + O2
4.2.2 Degradation in water
Carbon tetrachloride dissolved in water does not photodegrade or
oxidize in any measurable amount (Howard et al., 1991). The rate of
hydrolysis was thought to be second order with respect to carbon
tetrachloride with a calculated half-life of 7000 years at a
concentration of 1 ppm (Mabey & Mill, 1978). However, Jeffers et al.
(1996) found that the rate of hydrolysis for dilute solutions of
carbon tetrachloride was first-order and estimated the half-life to be
40 years. The authors reanalysed data previously stated as
second-order kinetics and found it to be consistent with a first-order
rate of hydrolysis.
4.2.3 Other degradation processes
Photodissociation of carbon tetrachloride adsorbed on to
silicates has been observed in the laboratory by Ausloos et al.
(1977).
Gäb et al. (1980) found experimentally that carbon tetrachloride
degraded over sand, silica gel and Al2O3. The degradation rate
depended, among other factors, on the laboratory conditions. Under the
conditions representative for deserts, degradation was about 4.5%
after exposure for 115 days.
4.3 Biotic degradation
4.3.1 Aerobic
Carbon tetrachloride has been shown to be resistant to aerobic
biodegradation by mixed bacterial cultures growing on methane as the
carbon source. No degradation of carbon tetrachloride was observed in
a mixed culture of methane-utilizing bacteria isolated from soil and
incubated in the dark for 6 days (Cochran et al., 1988). Oldenhuis et
al. (1989) reported no degradation of carbon tetrachloride by the
methanotrophic bacterium Methylosinus trichlosporium in the presence
of formate and oxygen.
Vannelli et al. (1990) found that carbon tetrachloride was not
degraded by the ammonia-oxidizing bacterium
Nitrosomonas europea when incubated at 1 mg/litre for 24 h.
In contrast, Tabak et al. (1981) found carbon tetrachloride to be
significantly degradable under aerobic conditions, with rapid
adaptation. Carbon tetrachloride (5 and 10 mg/litre) was incubated at
25°C for 7 days in static culture containing yeast extract inoculated
with settled domestic wastewater. Eighty to eighty-seven per cent of
the initial concentration disappeared within 7 days in the first
culture. An abiotic control showed that 5-23% of this loss could be
due to volatilization. In three subsequent cultures, carbon
tetrachloride was degraded to concentrations below the detection limit
(< 0.1 mg/litre) in the same period.
4.3.2 Anaerobic
The biodegradation of carbon tetrachloride has been studied under
methanogenic conditions. In batch cultures, carbon tetrachloride at a
concentration of 200 µg/litre was incubated in the dark at 35°C with
mixed methanogenic bacteria derived from a laboratory-scale digester
fed with activated sludge. Carbon tetrachloride was found to be
degraded to below the detection limit (< 0.1 µg/litre) within 16
days; carbon dioxide was the only degradation product identified. In a
continuous-flow column study, columns were initially seeded with an
inoculum of methanogenic bacteria from rum distillery wastewater.
Acetate (100 mg/litre) was fed to the column as primary growth
substrate and carbon tetrachloride was fed as a secondary substrate.
The column had a 2 day retention time, and it was found that carbon
tetrachloride was 99% degraded in the column; carbon dioxide being the
major degradation product (Bouwer & McCarty, 1983a).
Bouwer & McCarty (1983b) studied the biodegradation of carbon
tetrachloride under denitrifying conditions. Using batch cultures
seeded with primary sewage effluent and containing nitrate as an
electron acceptor, carbon tetrachloride (75 µg/litre) was found to be
degraded rapidly with no detectable lag period when incubated in the
dark at 25°C for 8 weeks. Chloroform and carbon dioxide were the
degradation products identified.
The biodegradation of carbon tetrachloride using aquifer material
has been studied (Parsons et al., 1985). Microcosms were constructed
containing groundwater and sediment contaminated with trichloroethene.
The concentration of carbon tetrachloride was 4 mg/litre and
incubation was carried out in the dark at 25°C. Reductive
dehalogenation of carbon tetrachloride to chloroform was found to
occur, and 700 µg chloroform/litre was detected after 8 weeks.
Egli et al. (1987) observed that pure cultures of
Desulfobacterium autotrophicum dechlorinated carbon tetrachloride to
trichloromethane and dichloromethane within 6 days.
Klecka & Gonsior (1984) provided evidence that reductive
dehalogenation of carbon tetrachloride in aqueous solution under
anaerobic conditions could be achieved with naturally occurring iron
porphyrins and other reducing agents. Carbon tetrachloride (1
mg/litre) was rapidly degraded to chloroform when incubated at 25°C
with an iron porphyrin (haematin) and sulfide.
Bioremediation studies have shown that anaerobic biodegradation
is enhanced by increasing the concentration of primary substrates
(such as glucose and acetate) and by lowering the redox potential
(providing a relatively higher electron activity which facilitates
dechlorination) (Doong & Wu, 1995, 1996; Doong et al., 1996; Jin &
Englarde, 1996).
4.4 Bioaccumulation
The log octanol-water partition coefficient (Kow) of carbon
tetrachloride is 2.64 indicating a moderate potential for
bioaccumulation under conditions of constant exposure. However,
studies have shown that the compound's short tissue lifetime reduces
this tendency. Barrows et al. (1980) reported a bioconcentration
factor of 30 for bluegill sunfish (Lepomis macrochirus) with a
tissue half-life of less than one day. A similar bioconcentration
factor of 30 (whole body; fresh weight) was reported by Veith (1978)
in bluegill. Neely et al. (1974) found a bioconcentration factor of
17.7 for muscle tissue of rainbow trout (Oncorhynchus mykiss). A
higher bioconcentration factor of 300 (wet weight) has been measured
for carbon tetrachloride in the green alga Chlorella fusca exposed
to 50 µg/litre for at least 24 h (Geyer, 1984). No significant
bioaccumulation in marine food chains was found in an extensive study
by Pearson & McConnell (1975) (see Table 6, section 5.1.4).
Some plants, due to their lipid content, take up carbon
tetrachloride from the air. Thus studies of the equilibrium
partitioning of carbon tetrachloride between the gas phase and conifer
needles (Pinus sylvestris and Picea abies) on the one hand and
hexane-extractable leaf waxes on the other hand showed partition
ratios (g/m3 needle; g/m3 air) of 9-17 and 90-400, respectively
(Frank & Frank, 1986; Brown et al., 1998).
5. CONCENTRATIONS IN THE ENVIRONMENT AND EXPOSURE
5.1 Environmental levels
5.1.1 Air
Reported concentrations of carbon tetrachloride measured in
ambient air are presented in Table 4.
As seen in Table 4, mean global levels of atmospheric carbon
tetrachloride usually lie in the range of 0.5-1.0 µg/m3. Based on an
analysis of 4913 ambient air samples (including remote, rural,
industrial and source-dominated sites in the USA), the average
concentration of carbon tetrachloride was 1.1 µg/m3 (Shah &
Heyerdahl, 1988). Urban atmospheric carbon tetrachloride levels and
levels in industrial areas can be considerably higher as shown by the
measurements by Lillian et al. (1975), Singh et al. (1980, 1982) and
Bozzelli & Kebbekus (1982). These authors reported mean levels of 2-3
µg/m3 (several hundred measurements) with maximum levels up to 6
µg/m3. Near a production facility in the United Kingdom, Pearson &
McConnell (1975) recorded levels an order of magnitude higher.
It has been estimated that concentrations of carbon tetrachloride
were increasing worldwide until recently (Simmonds et al., 1988;
Howard, 1990). The Intergovernmental Panel on Climate Change (IPCC)
has estimated the atmospheric concentration to be about 0.94 µg/m3
and the annual rate of increase to be 1.5% (IPCC, 1990). However, the
accumulation of the substance in the atmosphere seems to have stopped
(Fraser et al., 1994) and even started to decline (Fraser & Derek,
1994).
5.1.2 Water
Some reported aquatic concentrations of carbon tetrachloride are
summarized in Table 5.
As seen in Table 5, remote oceanic levels of carbon tetrachloride
are usually in the range of 0.0005-0.0008 µg/litre. As sites nearer to
effluent sources are examined, higher levels are observed. Thus in
estuaries, levels from 0.01 to 2.7 µg/litre have been observed, and in
remote freshwater sites from 0.0002 to 0.025 µg/litre, while nearer to
industrial facilities mean levels in the range of < 0.1-24.2 µg/litre
have been recorded.
Even higher values, e.g., 160-1500 µg/litre in the River Rhine
and a mean of 75 µg/litre in the River Main, recorded in 1976 in
Germany, were the result of direct waste release (BUA, 1990).
Groundwater levels range from undetectable to a maximum of 80
µg/litre.
Table 5. Levels of carbon tetrachloride in surface water
Area Mean level (µg/litre)
(range in parentheses) Reference
Marine
East Pacific ocean 0.0005 Su & Goldberg
(1976)
East Pacific ocean 0.0007 Singh et al. (1983)
Arctic ocean 0.0008 Fogelqvist (1985)
Estuarine
Scheldt Estuary, 0.01-0.02a van Zoest & van
The Netherlands (max. 0.29) Eck (1991)
Mersey Estuary, UK 2.7 Edwards et al.
(1982a)
Freshwater
Lake Zurich, Switzerland 0.025 (0.02-0.035) Giger et al. (1978)
Lake Ontario, Canada (< 0.0002-0.005) Kaiser et al. (1983)
Niagara River, Canada 0.0029 (max. 0.018) Kaiser et al. (1983)
River Weaver, UK < 0.1 Rogers et al. (1992)
River Gowry, UK 0.9 Rogers et al. (1992)
River Rhine, Lobith, 1.5 (0.4-2.8) Bauer (1981)
Germany
Manchester Ship Canal, UK 3.8 Edwards et al.
(1982a)
Manchester Ship Canal, UK 24.2 Rogers et al. (1992)
Groundwater
Zurich (industrial area) (< 0.05-3.6) Giger et al. (1978)
Birmingham aquifer, UK (0.02-1) Rivett et al.
(1990a,b)
Coventry aquifer, UK 4.9 (max. 80) Burston et al.
(1993)
Washington, New Jersey, (ND-34) Suffet et al. (1985)
USA
Gibbstown, New Jersey, (1.4-1.8) Rosen et al. (1992)
USA
a range of medians
Based on analysis of data from STORET database, carbon
tetrachloride was detectable in 1063 of 8858 ambient water samples,
with a median concentration of 0.1 µg/litre (Staples et al., 1985).
Rain water and snow concentrations of carbon tetrachloride are
generally in the range of 0.3 to 2.8 µg/litre (Su & Goldberg, 1976),
but a level as high as 300 µg/litre was observed in rainwater
collected near a production site in the United Kingdom (Pearson &
McConnell, 1975).
5.1.3 Soil and sediment
Carbon tetrachloride might occur in soil due to spills, runoff
and leaching. However, only 0.8% of 361 measured soil/sediment samples
appeared to contain carbon tetrachloride. The concentration was
reported to be less than 5.0 mg carbon tetrachloride/kg dry weight
soil or sediment (Staples et al., 1985).
5.1.4 Biota
Levels of carbon tetrachloride in biota are summarized in Table
6.
5.2 General population exposure
The general population can be exposed to carbon tetrachloride
through air, foodstuffs and drinking-water.
5.2.1 Outdoor air
Levels in ambient air to which the general population may be
exposed are recorded in Table 4.
5.2.2 Indoor air
Because of its volatility, carbon tetrachloride tends to
volatilize from tap water. Although, human exposure by inhalation of
carbon tetrachloride transferred to the indoor air from showers and
baths, toilets, washing and cooking is conceivable, no experimental
data have been reported (McKone, 1987).
Several reports on carbon tetrachloride levels in dwellings have
been published. Taketomo & Grimsrud (1977) found values ranging
between 0.6 and 1.3 µg/m3 for various types of dwellings, which is in
agreement with the maximum indoor concentration of 1.2 µg/m3 reported
by Clark (1981) and the range of 0.9-1.8 µg/m3 found in a US EPA
study. In addition, several measurements have been made in garages,
shops, supermarkets, swimming pools, restaurants, etc. (Taketomo &
Grimsrud, 1977; Ullrich, 1982). The observed concentrations usually
ranged between 0.6 and 2.0 µg/m3. The highest concentration, 10
µg/m3, was found in a dry-cleaning establishment.
Wallace (1986) reported typical concentrations in homes in
several cities in the USA of about 1 µg/m3; a maximum value of 9
µg/m3 was found. Shah & Heyerdahl (1988) found an average carbon
tetrachloride level of 2.6 µg/m3, based on 2120 indoor samples. It
should be noted, however, that carbon tetrachloride was not detected
in more than half the samples.
Table 6. Levels of carbon tetrachloride in biota
Organism Location Organ Level (µg/kg) Reference
Plankton Liverpool Bay, UK whole body 0.04-0.09 wet weight Pearson & McConnell (1975)
Molluscs Firth of Forth, UK whole body 2 wet weight Pearson & McConnell (1975)
Liverpool Bay, UK whole body 0.4-1 wet weight Pearson & McConnell (1975)
Thames Estuary, UK whole body 0.1-0.9 wet weight Pearson & McConnell (1975)
Irish Sea muscle 5-28 dry weight Dickson & Riley (1976)
digestive tissue 8-20 dry weight Dickson & Riley (1976)
gill 14 dry weight Dickson & Riley (1976)
ovary 16 dry weight Dickson & Riley (1976)
mantle 2-114 dry weight Dickson & Riley (1976)
Crustaceans Firth of Forth, UK whole body 1-3 wet weight Pearson & McConnell (1975)
Liverpool Bay, UK whole body 3-5 wet weight Pearson & McConnell (1975)
Thames Estuary, UK whole body 0.2 wet weight Pearson & McConnell (1975)
Fish Liverpool Bay, UK flesh 2 wet weight Pearson & McConnell (1975)
liver ND-0.3 wet weight Pearson & McConnell (1975)
Thames Estuary, UK flesh 0.3-6 wet weight Pearson & McConnell (1975)
Irish Sea brain 15-191 dry weight Dickson & Riley (1976)
gill 3-209 dry weight Dickson & Riley (1976)
gut 9-44 dry weight Dickson & Riley (1976)
liver 4-51 dry weight Dickson & Riley (1976)
muscle 7-83 dry weight Dickson & Riley (1976)
skeletal tissue 7-22 dry weight Dickson & Riley (1976)
heart 10-40 dry weight Dickson & Riley (1976)
ND = not detected.
5.2.3 Drinking-water
The National Organics Monitoring Survey (NOMS) in the USA
detected carbon tetrachloride (range of 2.4-6.4 ng/litre) in public
drinking-water systems in 10% of the 113 samples surveyed (US EPA,
1984b). In 30 out of 954 drinking-water samples from various cities in
the USA carbon tetrachloride could be detected. Median concentrations
in different groups ranged from 0.3 to 0.7 µg/litre while maximum
concentrations reached 16 µg/litre (Westrick et al., 1984). Bauer
(1981) reported that drinking-water in Germany contained an average of
less than 0.1 µg/litre although a maximum level of 1.4 µg/litre was
found (average of 100 towns in 1977). Lahl et al. (1981) reported a
carbon tetrachloride concentration less than 0.1 µg/litre in the
drinking-water of 50 cities in Germany. In the United Kingdom,
< 0.01-2.3 µg/litre was measured in drinking-water (Reynolds et al.,
1982; Reynolds & Harrison, 1982).
Values as high as a median of 3 µg/litre and a maximum of 39.5
µg/litre were reported in Galicia, Spain (Freiria-Gándara et al.,
1992).
5.2.4 Foodstuffs
According to investigations carried out in Europe and USA between
1973 and 1989, many foodstuffs contained carbon tetrachloride at
concentrations of a few µg/litre or µg/kg.
The following concentrations of carbon tetrachloride in
foodstuffs in the United Kingdom in 1973 were reported: meat, 7-9
µg/kg; edible oils, 16-18 µg/kg; tea, 4 µg/kg; and fruits and
vegetables, 3-8 µg/kg (McConnell et al., 1975). Values in a similar
range were found for dairy products, other edible oils, fats,
beverages, other fruits and bread, but here carbon tetrachloride and
1,1,1-trichloroethane could not be separated (McConnell et al., 1975).
According to a study conducted in Germany, carbon tetrachloride
can be present in decaffeinated coffee (4.9-60 µg/kg), milled cereal,
flour and starch products (levels in 21 samples ranged from less than
0.1 to 26 µg/kg). The origin in the first case is the
caffeine-extraction procedure, and in the second case in all
probability fumigation of the raw cereals. The use of carbon
tetrachloride for fumigation of stored foodstuffs and decaffeination
of coffee appears to have generally ceased and it is unlikely that its
occurrence in food stuff will be of significance. Less than 1 µg/kg
was found in sugar, fruit, vegetables, beverages, bread, toast,
potatoes, olives, oils, milk, butter, eggs, yoghurt, (cream) cheese,
meat and fish. In cough mixtures 0.1 to 1.8 µg/kg was found (Bauer,
1981).
Entz et al. (1982) and Entz & Hollifield (1982), in analyses of
various foods for a series of volatile halogenated hydrocarbons, did
not find carbon tetrachloride at a detection limit of 0.5 to 3 µg/kg,
depending on the type of product. Decaffeinated coffee and flour
products were not included in the studies.
Kroneld (1989) detected carbon tetrachloride in meat (0.9 µg/kg),
fish (0.6 µg/kg) and juice (0.3 µg/kg) in Finland in 1987.
Carbon tetrachloride levels in table-ready foods in the USA were
reported by Heikes (1987). He found up to 2.2 µg/kg in four sorts of
cheese, 0.10-0.34 µg/kg in cereals, 1.7-5.7 µg/kg in fish sticks and
up to 6.0 µg/kg in butter.
In a survey by Daft (1989, 1991) carbon tetrachloride was
detected in 44 out of 549 food items from the USA, most often in fatty
and grain-based foods. The mean level in food items with detectable
levels was 31 µg/kg (with a range of 2 to 210 µg/kg).
5.2.5 Intake averages
The daily average intake of carbon tetrachloride in Japan by
inhalation was calculated to be 7.7 µg/day (based on a daily
inhalation volume of 15 m3/day and assuming a 100% absorption) and by
ingestion less than 0.1 µg/day (Yoshida, 1993). If adjusted to a daily
inhalation volume of 22 m3/day, an absorption of 40% and a body
weight of 64 kg, the daily intake would be 11.4 µg/day or 0.18 µg/kg
per day.
The ATSDR (1994) estimated the daily intake by inhalation to be
0.1 µg/kg body weight based on ambient air level of about 1 µg/m3
(assuming inhalation of 20 m3/day, a body weight of 70 kg and an
absorption of 40% based on measurements in monkeys and humans). The
daily intake via drinking-water was estimated to be about 0.01 µg/kg
body weight based on a typical carbon tetrachloride concentration of
0.5 µg/litre (assuming a water consumption of 2 litres/day and a body
weight of 70 kg).
In an earlier study of about 500 foodstuffs, an average daily
intake via foods and drinks of 8.63 µg/person per day was calculated
for inhabitants of Germany (Lahl, 1983). Because the intake by
inhalation is expected to be at least as much (BUA, 1990), the total
daily average intake would be estimated to be 17.26 µg/person (0.27
µg/kg body weight for a person of 64 kg). This calculation refers to a
period when carbon tetrachloride was still used in food processing or
in fumigation of grain.
5.3 Occupational exposure
The most likely route of exposure in the workplace is by
inhalation. Workers may be exposed to carbon tetrachloride during, for
example, the production of carbon tetrachloride itself, the synthesis
of compounds using carbon tetrachloride as a starting material and the
use of carbon tetrachloride as a solvent. Furthermore, workers have
been exposed to carbon tetrachloride at grain (due to fumigation) and
water treatment facilities. The National Institute for Occupational
Safety and Health estimated that in the USA around 58 000 workers were
potentially exposed to carbon tetrachloride, based on a national
survey conducted from 1981 to 1983 (National Library of Medicine,
1992).
A few studies on concentrations of carbon tetrachloride in
factories, and grain and water treatment facilities have been
reported. For water treatment facilities, Lurker et al. (1983)
reported exposure concentrations of 0.01-0.23 mg/m3; Clark (1981)
reported concen trations ranging from 0 to 1.1 mg/m3.
A peak exposure to an inspector during handling of grain at a
facility in the USA reached 277 mg/m3. Few employees, however, had a
mean exposure above 641 µg/m3 (Deer et al., 1987). Use of carbon
tetrachloride in open beakers resulted in exposure levels of 290-620
mg/m3 at a United Kingdom quartz crystal processing plant. Levels
were reduced to 50-60 mg/m3 by closing the beakers (Kazantzis &
Bomford, 1960).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Pharmacokinetics
6.1.1 Absorption
Carbon tetrachloride is absorbed readily from the
gastrointestinal and respiratory tract. Dermal absorption of carbon
tetrachloride, either in vapour or in liquid phase, is possible, but
the dermal absorption of the vapour appears to be very low.
6.1.1.1 Oral
Carbon tetrachloride is relatively insoluble in water, a source
of exposure relevant to environmental scenarios and human health risk.
As a result, many studies examining the hepatotoxicity of carbon
tetrachloride used corn oil as a dosing vehicle for laboratory animals
(Paul & Rubinstein, 1963; Larson & Plaa, 1965; Marchand et al., 1970).
Corn oil has been found to delay markedly the absorption of carbon
tetrachloride (Kim et al., 1990a) as well as other halocarbons (Withey
et al., 1983) from the gastrointestinal tract.
In part, because carbon tetrachloride in water is directly
relevant to human exposure studies, recent studies in laboratory
animals employed Emulphor(R), a polyethoxylated oil, at
concentrations up to 10%, as an aqueous vehicle for carbon
tetrachloride. Aqueous solutions of carbon tetrachloride in
Emulphor(R) were administered to Sprague-Dawley rats both as a bolus
and during gastric infusion at a constant rate during a 2-h period
(Sanzgiri et al., 1995). Uptake and tissue levels of carbon
tetrachloride after gastric infusion were less than after bolus
dosing. When the concentration of Emulphor(R) was varied up to 10%,
absorption (and distribution) of carbon tetrachloride was not affected
(Sanzgiri & Bruckner, 1997).
A comparison of the uptake of carbon tetrachloride in corn oil
and aqueous emulsions is discussed in section 7.9. Tissue levels of
carbon tetrachloride associated with bolus dosing, gastric infusion,
and inhalation are discussed in section 6.1.2. The relationship of
dosing vehicle, dose rate, and route of exposure to hepatotoxicity is
discussed in section 7.9.
6.1.1.2 Dermal
Liquid carbon tetrachloride on the intact mouse skin was absorbed
at a rate of 8.3 µg/cm2 per minute (Tsuruta, 1975). Jakobson et al.
(1982) examined the percutaneous uptake of liquid carbon tetrachloride
(1 ml) in guinea-pigs (carbon tetrachloride in a glass depot, covering
3.1 cm2 of clipped skin). A peak blood level of about 1 mg carbon
tetrachloride/litre was reached within 1 h. Despite continuation of
the exposure the blood levels declined during the following h,
possibly due to local vasoconstriction, rapid transport from blood to
adipose tissues or biotransformation processes.
Wahlberg & Boman (1979) applied 0.5 or 2 ml of carbon
tetrachloride in a closed glass container on the skin (3.1 cm2) of
guinea-pigs. The deposits were completely absorbed within a few days.
McCollister et al. (1951), who exposed the clipped skin of one
male and one female monkey to [14C]carbon tetrachloride vapour (whole
body exposure), detected radioactivity in the blood and in the expired
air. After an exposure of 3 h at 3056 mg/m3, the blood of the female
contained a carbon tetrachloride level of 12 µg/100 g and the expired
air contained 0.8 µg/litre. After exposure to 7230 mg/m3 for 3.5 h
the blood of the male contained a carbon tetrachloride level of 30
µg/100 g and the expired air contained 3 µg/litre.
6.1.1.3 Inhalation
In rats exposed by inhalation to carbon tetrachloride
concentrations of 100 or 1000 ppm (641 or 6410 mg/m3) for 2 h, the
total amounts systemically absorbed were 17.5 and 179 mg/kg body
weight. The Cmax values (mg/ml) were approximately 1 and 13,
respectively, and the AUC values (mg.min/ml) were approximately 120
and 1900, respectively (Sanzgiri et al., 1995).
Steady-state carbon tetrachloride concentrations in the blood of
approximately 320 mg/litre were reached within about 5 h when dogs
were exposed to a carbon tetrachloride concentration in air of 15 000
ppm (96 150 mg/m3) for several hours (Von Oettingen et al., 1950).
McCollister et al. (1951) exposed three female rhesus monkeys to
an average [14C]carbon tetrachloride concentration of 46 ppm (295
mg/m3) via air for 139, 244 or 300 min, respectively. Within 300 min,
30% of the inhaled quantity was absorbed but in the blood no
steady-state concentration of radioactivity was reached. The
radioactivity level in the blood at that moment corresponded to 3 mg
carbon tetrachloride/litre blood and was distributed over carbon
tetrachloride (56.2%), "acid volatile" carbonates (16.5%) and
non-volatile material (27.3%).
The US EPA Iris Program uses 40% absorption as a mean for the
calculation of human respiratory intake. The determined values ranged
from 30% to 65% (US EPA, 1991).
6.1.2 Distribution
The tissue distribution of carbon tetrachloride has been
investigated in mice after inhalation (Bergman, 1984), in rats after
oral administration (Marchand et al., 1970; Teschke et al., 1983;
Watanabe et al., 1986) and after inhalation (Paustenbach et al.,
1986a), in rabbits after oral administration (Fowler, 1969), in dogs
after inhalation (Von Oettingen et al., 1950) and in monkeys after
inhalation (McCollister et al., 1951).
Bergman (1984) investigated the distribution of [14C]carbon
tetrachloride in the mouse after a single inhalation exposure (10 min;
256 000 mg/m3 air). Immediately after the exposure, high levels of
radioactivity were found in fat, bone marrow, white matter of the
brain, spinal cord and nerves, liver, kidneys, salivary glands and
gastrointestinal mucosa. The radioactivity in bronchi, liver, kidneys,
salivary glands and the gastrointestinal mucosa (particularly in the
mucosa of the glandular part of the stomach and of the colon and
rectum) was to a large extent non-volatile. A similar pattern of
distribution was observed 30 min after the exposure, except in the
liver where a more pronounced accumulation of non-volatile
radioactivity was seen than observed immediately after inhalation. A
large part of the non-volatile radioactivity in the liver and kidneys
appeared to be non-extractable, which may indicate covalent binding to
tissue components (see section 6.2). Non-extractable radioactivity was
also present in the bronchi and nasal mucosa. Non-volatile and
non-extractable radioactivity was present in the vaginal and uterine
mucosa and interstitially in the testis.
The tissue distribution in rats (in order of decreasing
radio-activity), 3 h after oral administration, as reported by
Watanabe et al. (1986) was: liver, kidney, brain, muscle and blood.
Carbon tetrachloride tends to accumulate in fat. Maximal fat tissue
carbon tetrachloride concentrations exceeded the maximal blood levels
by a factor of 60 after oral administration to rats (Marchand et al.,
1970).
Peak levels of carbon tetrachloride were observed 3-6 h following
an acute oral carbon tetrachloride dose (1.5 ml/kg body weight
administered in olive oil) in the blood (26 mg/litre), liver and fat
of female Wistar rats. Subsequently, the carbon tetrachloride levels
declined rapidly (Teschke et al., 1983).
Peak blood levels of carbon tetrachloride after a 12-h inhalation
exposure of rats were 12 mg/litre blood at an airborne concentration
of 2 mg/litre (320 ppm), 20 mg/litre blood at 4 mg/litre (640 ppm) and
36 mg/litre blood at 8 mg/litre (1280 ppm). The blood level attained
50% of this value after 60 min. A 4-h exposure to a concentration of
2.6 mg/litre (406 ppm) led to a blood level of 10.5 mg/litre, which
dropped to 50% of this peak value within 30 min after exposure
(Frantik & Benes, 1984).
Paustenbach et al. (1986a) found the highest concentration of
carbon tetrachloride equivalents in the fat, liver, lungs and adrenals
of male Sprague-Dawley rats repeatedly exposed to 100 ppm (641 mg/m3)
of [14C]carbon tetrachloride vapour for 8 or 11.5 h/day for periods
of 1 to 10 days.
Fowler (1969) administered 1 ml carbon tetrachloride/kg body
weight to rabbits by stomach tube as a 20% (v/v) solution in olive
oil. Five rabbits were killed 6, 24 and 48 h after receiving carbon
tetrachloride and the concentration in fat, liver, kidney and muscle
tissue was determined. Two rabbits receiving olive oil were killed as
control animals. The highest carbon tetrachloride concentration after
6, 24 and 48 h was found in fat tissue, but the amount found in the
fat as well as in the other tissues after 6 h diminished rapidly
during the subsequent 42 h.
Von Oettingen et al. (1950) studied the distribution of carbon
tetrachloride in Beagle dogs after exposure to 15 000 ppm (96 150
mg/m3) and reported a lowest concentration in the blood followed in
increasing order by liver, heart and brain.
The pattern of distribution immediately after a 5-h inhalation of
46 ppm (295 mg) [14C]carbon tetrachloride/m3 in monkeys (McCollister
et al., 1951) was (tissues in order of decreasing concentration of
total radioactivity): fat, liver, bone marrow, blood, brain, kidneys,
heart, spleen, muscle, lungs, bone.
Sanzgiri et al. (1995) demonstrated that the tissue
pharmacokinetic profile was influenced by the route and rate of
administration of carbon tetrachloride. Inhalation exposure of rats to
1000 ppm (6410 mg/m3) carbon tetrachloride for 2 h resulted in a
systemic dose of 179 mg/kg body weight. This dose was subsequently
administered as an oral bolus or a constant gastric infusion over 2 h.
In all cases tissue levels were highest in fat with levels in all
tissues being higher after an oral bolus dose than after inhalation
exposure or gastric infusion. For the liver Cmax was higher after an
oral bolus dose (58 mg/g) than after inhalation (20 mg/g) or gastric
infusion (0.5 µg/g). The authors speculate that the capacity of
first-pass metabolism can be exceeded following a large single bolus
oral dose, although not during gastric infusion of the same dose over
2 h.
6.1.3 Elimination and fate
In a study by Reynolds et al. (1984), all routes of elimination
were investigated simultaneously after a single oral administration of
[14C]carbon tetrachloride to fasted rats at dose levels ranging from
15.4 to 4004 mg/kg body weight. The exhalation of unchanged carbon
tetrachloride increased at higher dose levels (70-90% after
administration of 46.2 mg/kg body weight or more). This result might
be explained by a saturation of the first pass metabolism, or by an
impairment of the overall carbon tetrachloride metabolism due to a
breakdown of cytochrome P-450, which is induced by carbon
tetrachloride-metabolites (as reported by Noguchi et al., 1982a,b).
Both the amount of carbon tetrachloride excreted and the time-course
of excretion depended on the dose, tending to become slower as the
dose increased. For example, the half-life for exhalation of carbon
tetrachloride was 1.3 h at 46.2 mg/kg body weight but was 6.3 h at
4004 mg/kg body weight.
Page & Carlson (1994) examined whether faecal excretion, either
biliary or by direct exsorption, contributed significantly to carbon
tetrachloride elimination from the body of rats. It appeared that
biliary and non-biliary mechanisms contributed to the faecal
elimination of [14C]carbon tetrachloride, but that this route
accounted for less than 1% of the administered dose of 1 mmol/kg body
weight in rats. Thus faecal elimination of carbon tetrachloride (as
parent compound) does not significantly contribute to the overall
elimination of carbon tetrachloride.
The carbon tetrachloride levels in blood declined with a
half-life of 4 to 5 h during the first 24 h after oral administration
of 1.25 ml carbon tetrachloride/kg body weight (Larson & Plaa, 1965)
or 2 ml (0.1 mCi) [14C]carbon tetrachloride/kg body weight (Marchand
et al., 1970). Carbon tetrachloride levels in the liver declined with
a half-life of about 7 h after administration by gastric intubation of
2.5 ml carbon tetrachloride/kg body weight (Dingell & Heimberg, 1968).
Kim et al. (1990a) found a half-life for carbon tetrachloride in
the blood of 98 min and a whole body clearance of 0.13 ml/min per g
when 25 mg carbon tetrachloride/kg body weight was orally administered
in four different vehicles to male Sprague-Dawley rats. The
elimination appeared to be the same in all the different vehicle
groups, whereas the absorption differed (see section 6.1.1.1).
According to Paustenbach et al. (1986a) the rate of carbon
tetrachloride clearance in rats after inhalation exposure is biphasic,
with an initial half-life of 7 to 10 h. Exposure for longer periods of
time led to a decreased rate of clearance (and to higher
concentrations in the fat) (Paustenbach et al., 1986a,b, 1988). In the
study of Sanzgiri et al. (1995) (see section 6.1.1.3) the apparent
clearance values after inhalation doses delivering 17.5 or 179 mg/kg
body weight, respectively, were 150 and 100 ml/min per kg and the
half-life value was about 164 min.
Veng-Pedersen et al. (1987) exposed rats repeatedly by inhalation
to 100 ppm [14C]carbon tetrachloride (641 mg/m3) for either 8 h/day
for 5 days or 11.5 h/day for 4 days. The pulmonary excretion of
[14C]activity was clearly biphasic for both dosing regimens, with
mean half-lives for the first and second phase being 84 and 400 min
for the 8-h exposure and of 91 and 496 min for the 11.5-h exposure,
respectively. This indicates that the second phase of the 11.5-h group
was longer than the second phase of the 8-h group. This observation
suggests that during longer exposure periods a greater fraction of the
inhaled carbon tetrachloride is distributed to poorly perfused tissues
like fat, thus altering the elimination.
McCollister et al. (1951) demonstrated in monkeys that, after an
inhalation exposure to [14C]carbon tetrachloride, radioactive
material was excreted in faeces, urine and expired air. According to
the authors the compounds in the urine consisted of urea, bicarbonate
and an acid hydrolysable, non-amino acid substance.
6.1.4 Physiologically based pharmacokinetic modelling
A biphasic kinetic in the biotransformation of carbon
tetrachloride has been observed in several inhalation studies. The
relationship of arterial blood and inhaled carbon tetrachloride
concentrations, as found in male Sprague-Dawley rats, suggested that
carbon tetrachloride metabolism is limited by blood perfusion of the
liver at inhaled concentrations below 100 ppm (641 mg/m3) and that it
is saturated at inhaled concentrations above 100 ppm. The estimated
rate of reaction (Vmax) measured in the blood was 2.7 mg/kg body
weight per hour. This rate gradually decreased during the exposure
period of 5 h, which could be due to rapid loss of cytochrome P-450
content. The Vmax in rats pretreated with 100 µl carbon tetrachloride
(oral administration, 24 h before inhalation exposure) decreased about
57%, which was in good agreement with the decrease of the cytochrome
P-450 content. (Uemitsu, 1986).
Gargas et al. (1986) calculated for carbon tetrachloride a Vmax
of 0.63 mg/kg body weight per hour in an inhalation study in male
Fischer-344 rats.
Applications of pharmacokinetic models for the inhalation
exposure of rats have provided Vmax and Km estimates in rats of 0.63
mg/h per kg and 0.25 mg/litre (Gargas et al., 1986) and 0.37 mg/h/kg
and 1.3 mg/litre (Evans et al., 1994).
Paustenbach et al. (1988) constructed a physiologically based
pharmacokinetic model (PB-PK) for inhaled carbon tetrachloride and
used this model to predict the pharmacokinetics of inhaled
[14C]carbon tetrachloride in male Sprague-Dawley rats exposed for 8
or 11.5 h/day for 1 or 2 weeks. The simulations were compared with
actual laboratory data (Paustenbach et al., 1986a,b). The model
accurately predicted the behaviour of carbon tetrachloride and its
metabolites. Metabolites were partitioned in three compartments: the
amounts to be excreted in the breath (as [14C]CO2), urine and
faeces. Of total carbon tetrachloride metabolites, 6.5, 9.5 and 84%
were formed via the pathways leading to CO2, urinary and faecal
metabolites, respectively.
The PB-PK model suggests that at concentrations up to 100 ppm
(641 mg/m3), rats, monkeys and humans metabolize and eliminate carbon
tetrachloride in a similar manner. Most species convert 2-5% to CO2,
eliminate