Carbon Tetrachloride: Environmental Health Criteria 208

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.
Environmental Health Criteria 208
CARBON TETRACHLORIDE
First draft prepared by Ms J. de Fouw, National Institute of Public
Health and the Environment, Bilthoven, the Netherlands
The layout and pagination of this pdf file and the printed
EHC are not identical
Corrigenda published by November 2004 are
incorporated in this file.
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
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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
ISSN 0250-863X
(NLM Classification: QD 305.H5)
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR CARBON
TETRACHLORIDE
PREAMBLE
ABBREVIATIONS
ix
xviii
1.
SUMMARY
2.
IDENTITY, PHYSICAL AND CHEMICAL

PROPERTIES, AND ANALYTICAL METHODS
2.1
2.2
2.3
2.4
3.
Identity
Physical and chemical properties
Conversion factors
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
SOURCES OF HUMAN AND ENVIRONMENTAL

EXPOSURE
3.1
3.2
Natural occurrence
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
6
7
8
8
13
13
14
14
14
14
14
16
16
16
16
16
17
18
18
iii
EHC 208: Carbon Tetrachloride

________________________________________________________
4.
ENVIRONMENTAL TRANSPORT, DISTRIBUTION

AND TRANSFORMATION
4.1
4.2
4.3
4.4
5.
CONCENTRATIONS IN THE ENVIRONMENT

AND EXPOSURE
5.1
5.2
5.3
iv
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
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
Biotic degradation
4.3.1 Aerobic
4.3.2 Anaerobic
Bioaccumulation
Environmental levels
5.1.1 Air
5.1.2 Water
5.1.3 Soil and sediment
5.1.4 Biota
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
Occupational exposure
19
19
19
19
21
22
22
22
22
22
23
23
24
24
24
24
25
26
28
28
28
28
30
30
30
30
30
32
33
34
34
________________________________________________________
6.
KINETICS AND METABOLISM IN LABORATORY

ANIMALS AND HUMANS
6.1
6.2
6.3
7.
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
Biotransformation and covalent binding of
metabolites
Human studies
6.3.1 Uptake
6.3.1.1 Dermal
6.3.1.2 Inhalation
6.3.2 Elimination
EFFECTS ON LABORATORY MAMMALS AND

IN VITRO TEST SYSTEMS
7.1
7.2
7.3
7.4
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
Short-term exposure
7.2.1 Oral exposure
7.2.2 Inhalation exposure
7.2.3 Intraperitoneal exposure
Long-term exposure
Irritation
7.4.1 Skin irritation
7.4.2 Eye irritation
36
36
36
36
37
37
38
40
42
43
48
48
48
49
49
50
50
50
50
50
55
57
59
59
59
62
66
68
70
70
70

________________________________________________________
7.5
Toxicity to the reproductive system,

embryotoxicity, teratogenicity
71
7.5.1 Reproduction
71
7.5.2 Embryotoxicity and teratogenicity
71
7.5.2.1 Oral exposure
72
7.5.2.2 Inhalation exposure
72
7.6
Mutagenicity
73
7.7
Carcinogenicity
83
7.7.1 Mice
83
7.7.2 Rats
85
7.8
Special studies
86
7.8.1 Immunotoxicity
86
7.8.2 Influence of oxygen levels
87
7.9
Factors modifying toxicity
88
7.9.1 Dosing vehicles
88
7.9.2 Diet
89
7.9.3 Alcohol
90
7.9.4 Enhancement of carbon tetrachlorideinduced hepatotoxicity by various
compounds
93
7.9.5 Reduction of carbon tetrachloride-induced
hepatotoxicity by various compounds
97
7.10 Mode of action
100
8.
EFFECTS ON HUMANS
105
8.1
Controlled studies
8.1.1 Inhalation
8.1.2 Dermal
Case reports
Epidemiology
8.3.1 Non-cancer epidemiology
8.3.2 Cancer epidemiology
105
105
105
106
108
108
109
EFFECTS ON OTHER ORGANISMS IN THE

LABORATORY AND FIELD
113
8.2
8.3
9.
9.1
9.2
vi
Toxicity to microorganisms
Aquatic toxicity
9.2.1 Algae
113
113
113
________________________________________________________
9.3
9.2.2 Invertebrates
9.2.3 Vertebrates
Terrestrial toxicity
9.3.1 Earthworms
10. EVALUATION OF HUMAN HEALTH RISKS AND

EFFECTS ON THE ENVIRONMENT
10.1
10.2
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
Evaluation of effects on the environment
113
118
118
118
120
120
120
121
122
122
123
124
124
125
11. FURTHER RESEARCH
128
12. PREVIOUS EVALUATION BY INTERNATIONAL

BODIES
129
REFERENCES
130
RSUM
166
RESUMEN
172
vii
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This publication was made possible by grant number

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support from the European Commission.
viii
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xiii
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xiv
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
xv

________________________________________________________
Secretariat
Dr J. de Fouw, Centre for Substances and Risk Assessment,
National Institute of Public Health and the Environment,
Bilthoven, The Netherlands
Professor F. Vali, IPCS Scientific Adviser, Andrija tampar
School of Public Health, Zagreb University, Zagreb, Croatia
(Responsible Officer and Secretary of Meeting)
xvi
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. Vali 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 Vali, 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.
xvii
ABBREVIATIONS
ALAT
AP
ASAT
ATPase
ATSDR
CNS
CPK
CYP
Hb
Ht
ip
LDH
LOAEL
MPV
NADPH
NIOSH
NOAEL
PBB
PCB
RBC
SDH
SRBC
TC
TDI
xviii
alanine aminotransferase
alkaline phosphatase
aspartate aminotransferase
adenosine triphosphatase
Agency for Toxic Substances and Disease Registry
central nervous system
creatine phosphokinase
cytochrome P-450
haemoglobin
haematocrit
intraperitoneal
lactate dehydrogenase
lowest-observed-adverse-effect level
mean packed volume
reduced nicotinamide adenine dinucleotide phosphate
National Institute for Occupational Safety and Health
(USA)
no-observed-adverse-effect level
polybrominated biphenyl
polychlorinated biphenyl
red blood cell
sorbitol dehydrogenase
sheep red blood cells
tolerable concentration
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 19801990, atmospheric levels
were around 0.51.0 :g/m3. Estimates of atmospheric lifetime are
variable, but 4550 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 :g/litre in fresh water, but much
higher values close to release sites. Levels of up to 60 :g/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 :g/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 :g/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.
Summary
________________________________________________________
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-observedadverse-effect level (NOAEL) was 1 mg/kg body weight. The lowestobserved-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-Hodgkins 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
4
Summary
________________________________________________________
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 :g/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
:g/m3 was calculated using the factors 7/24 and 5/7 to convert to
continuous exposure and an uncertainty factor of 1000 (100 for interand intraspecies variation and 10 for the duration of the study). This
TC corresponds to a TDI of 0.85 :g/kg body weight.
Comparing the estimated upper limit of prevailing human daily
intake of 0.2 :g/kg body weight with the lowest TDI value (0.85
:g/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:
Cl
Cl
Cl
Cl
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
Identity, Physical and Chemical Properties, and Analytical Methods
______________________________________________________
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
Density of solid at !186 /C
1831 kg/m3
!80 /C
Refractive index at 20 /C
Vapour pressure at 20 /C
at 0 /C
1809 kg/m3
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
1.4607
91.3 mmHg; 12.2 kPa
32.9 mmHg; 4.4 kPa
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.
7

________________________________________________________
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.
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

optical path: 20 m
MIRAN infrared
spectrometry
400 :g/m
Air
direct injection
GC with 2 ECDs
in series
0.4 :g/m 3
(estimated)
8 ml injected
Lillian & Singh,

1974
Air
direct injection
GC ECD
0.2 :g/m 3
2 ml injected
BIT-SC, 1976
Air
direct injection
GC ECD
0.06 :g/m 3
5 ml injected
Lasa et al.,
1979
Air
direct injection, methane

added
GC ECD
0.01 :g/m 3
12 ml injected
thorough purification of
carrier gas and apparatus
required
Makide &
Yokohata,
1983
Air
adsorption on Porapak-N liquid GC ECD

desorption (methanol)
1 :g/m 3
20 litres
advantage of using
methanol over CS2 is the
absence of a background
signal in the ECD
Van Tassel et
al., 1981
Air
adsorption on activated
charcoal, liquid desorption
(ethanol) trichloroethylene
used as IS
0.2 :g
up to 30 litres
can be
sampled
activated charcoal shown

to be more efficient
trapping material than
XADs, Tenax or
Chromosorbs
Morele et al.,
1989
GC ECD
GC FID
charcoal liquid desorption
(CS2) methylcyclohexane used
as IS
Air
charcoal, liquid desorption
(CS2)
GC FID
Lioy & Lioy,

1983
ca. 0.15 mg
(detector
sensitivity)
0.01 mg
515 litres
NIOSH, 1977,
1984
Medium
Sampling method
Analytical method
Detection limit
Sample size
Comments
Reference
Air
adsorption on Chromosorb 102 GC ECD

or Silicone OV 101 (at
!35 /C), thermal desorption
0.003 :g/m
Air
adsorption on Porapak-N,
thermal desorption at 200 /C
GC ECD
0.005 :g/m 3
0.33 litres
Air
adsorption on Chromosorb
102, thermal desorption at
200 /C
GC ECD
(collection tube
already connected
to GC)
0.01 :g/m 3
(estimated)
1 litre
Air
adsorption on Carbopak-B at
78 /C, thermal desorption
GC ECD
0.01 :g/m 3
1 litre
Air
adsorption on Chromosorb-102 GC ECD FID

and activated charcoal,
(2 detectors in
parallel)
ca. 0.06 :g/m 3 13 litres
Air
adsorption on Tenax-GC,
GC MS
0.2 :g/m 3
20 litres
Air
adsorption on Carbopak-C,
GC MS
0.1 :g/m 3
300 ml
Crescentini et
al., 1983
Air
GC ECD followed 0.7 :g/m 3
charcoal, liquid desorption (5% by a PID
CS2 in methanol)
24 h sample
Coutant &
Scott, 1982
Air
cold trap (liquid oxygen),

heating
GC ECD
0.006 :g/m 3
20 ml
30 ml aliquot
in trap
Makide et al.,
1979
confirmation of results by
use of GC MS
Russell &
Shadoff, 1977
Elias, 1977
calibration with permeation Crescentini et

tubes
al., 1981
Heil et al.,
1979
compounds were
cryofocused
measurement of air
samples from the
stratosphere
Krost et al.,
1982
Harsch &
Cronn, 1978
0.04 :g/m 3
100 ml
cold trap (!173 /C), heating to GC PID ECD

257 /C
FID (3 detectors in
series)
0.006 :g/m 3
0.51.7 litres
Water
dibromomethane used as IS
GC ECD
0.001 :g/litre
500 :l injected suitable for routine analysis Herzfeld et al.,

of river waters
1989
Water
direct aqueous injection
GC MS (SIM)
2 :g/litre
10 :l injected
Water
direct aqueous injection
GC ECD
0.015 :g/litre
2 :l injected
Water
direct aqueous injection, water GC ECD

removal by permeaselective
membrane
0.05 :g/litre
520 :l
injected
Simmonds &
Kerns, 1979
Water
liquid-liquid extraction (using

hexane)
GC ECD
0.10 :g/litre
1020 ml
Van Rensburg
et al., 1978
Water

xylene)
GC ECD
0.2 :g/litre
Inoko et al.,
1984
Water

pentane)
GC ECD
0.05 :g/litre
Kroneld, 1985
Water
purge and trap technique,

thermal desorption,
fluorobenzene as IS
GC ITD
0.1 :g/litre
Air
injection in cold trap, heating
Air
GC MS (SIM)
5 ml
Cronn &
Harsch, 1979
column is kept at !103 /C
(cryofocusing)
Rudolph &
Jebsen, 1983
Fujii, 1977
suitable for halocarbons
in water in the 0.01 to
10 :g/litre range
Grob, 1984
Eichelberger et
al., 1990
Medium
Sampling method
Analytical method
Detection limit
Sample size
Comments
Reference
GC ECD
1 :g/kg
Adipose purge and trap technique

tissue
(Tenax-silica gel), thermal
desorption
GC MS
< 1.3 :g/litre
200500 mg
liquefied fat
samples
Peoples et al.,
1979
Blood
purge and trap technique

(Tenax-silica gel), thermal
desorption
GC MS
< 1.3 :g/litre
0.5 ml waterserum sample
Peoples et al.,
1979
Blood
warming and passing an inert

gas, vapours trapped on
Tenax-GC, thermal desorption
GC MS
3 :g/litre
10 ml sample
Pellizzari et al.,
1985
Urine
liquid-liquid extraction using

pentane (adding 2.6 g
ammonium carbonate)
GC ECD (20%
SP-2100/0.1%
Carbowax 1500
column)
< 1 :g/litre
10 ml sample
Youssefi et al.,
1978
Fish
extraction with pentane and

isopropanol, with bromotrichloromethane used as IS
GC ECD
0.1 :g/kg in
fresh material
Grain
codistillation of carbon
tetrachloride in food sample
and mixture of 1,2dichloropropane and 1,2dibromopropane as IS in
hexane
De Vries et al.,
1985
Baumann
Ofstad et al.,
1981
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.
______________________________________________________
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.
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.
13
2.4.3
2.4.3.1
Sampling and analysis in biological samples

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 TenaxGC 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 tetrachloride 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
(610 :l) 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 12000
:g/kg. A food sample is mixed with water and an internal standard
14
______________________________________________________
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 :l) into
the GC column.
15
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
3.2.1
3.2.1.1
Anthropogenic sources
Production
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 19801988. 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 19982000 average level (or a calculated consumption level of
16
Sources of Human and Environmental Exposure

________________________________________________________
0.2 kg per capita, whichever is lower) by 2005 and completely stopped

by 2010 (UNEP, 1996).
Table 3. Past production and production capacity of carbon tetrachloride
Country
Year
Production
(in kilotonnes)
Capacity
(in kilotonnes)
France
1988
90
Italy
1987
1988
95
130
Germany (former FRG)
1985
1987
1988
150
180
170
180
520
EEC
1985
1987
480
1988
478
540
1985
72
1987
52
1988
70
United Kingdom
1988
75
USA
1986
286
1987
340
1988
281
1991
143
1985
1200
1987
960
1988
1100
Japan
World
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.
17

________________________________________________________
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 19801987. 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).
18
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION

AND TRANSFORMATION
4.1
4.1.1
Transport and distribution between media

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
13% 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
19

________________________________________________________
compound is found in this compartment explains the relatively even

distribution over the globe as is recorded in Table 4.
Table 4. Levels of carbon tetrachloride in air
Location
Northern
hemisphere
Southern
hemisphere
Year
Mean level (:g/m3)

(range in parentheses)
Reference
1974
0.71
Cox et al. (1976)
1976
0.73
Singh et al. (1977)
1977
0.78
Singh et al. (1979)
19791981
0.87
Singh et al. (1983)
1974
0.44
Cox et al. (1976)
1977
0.76
Singh et al. (1979)
19791981
0.82
Singh et al. (1983)
North-West Pacific 19751980
0.91
(0.830.99)
Rasmussen et al.
(1981)
19751985
0.77
(0.670.83)
Rasmussen & Khalil

(1986)
1976
Antarctica
0.78
Cronn et al. (1977)
19751980
0.8
(0.770.87)
Rasmussen et al.
(1981)
19751985
0.69
(0.620.76)
Rasmussen & Khalil

(1986)
Arctic
1982
0.97
Rasmussen & Khalil

(1983)
North Atlantic
1983
0.56
von Dszeln &

Thiemann (1985)
North America
1976
0.86
(0.330.99)
Pierotti et al. (1980)
California, USA
1976
0.760.86
(0.661.85)
Singh et al. (1977)
Bochum, Germany 1978
0.8 (0.11.2)
Bauer (1981)
Germany (cities)
19801981
0.6
South-West
Germany
19861988
0.50.6
The Netherlands
1980
20
0.831.0
(max. 2.23.2)
von Dszeln &

Thiemann (1985)
Frank & Frank
(1990)
Guicherit &
Schulting (1985)
Environmental Transport, Distribution and Transformation

________________________________________________________
Table 4 (contd).
Location
Turin, Italy
Japan
Year
b
c
Reference
1988
0.96 (0.171.94)a
Gilli et al. (1990)
1988
0.47
(0.191.17)b
Gilli et al. (1990)
1979
0.69
(0.620.72)
Makide et al. (1979)
19941995
a
Mean level (:g/m3)

0.53c
Sugama et al.
(1995)
cold months
warm months
concentrations were higher in winter than during summer
Only a very small proportion of carbon tetrachloride will remain

in water and soil.
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 4550 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
21

________________________________________________________
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 0.33 days and in lakes and groundwaters of 30300 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 halflife 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
4.2.1
4.2.1.1
Abiotic degradation
Degradation in atmosphere
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
22

________________________________________________________
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 1880
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 ClOC groups (Singh et al., 1975). The chlorine
atoms and ClOC 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< 6 CCCl3 + CCl
C
CCl3 + O2 6 6 COCl2 + ClOC
C
Cl + O3 6 ClOC + O2
ClOC + O 6 CCl + O2
23

________________________________________________________
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).
Gb 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
4.3.1
Biotic degradation
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.
24

________________________________________________________
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 523% 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 :g/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 :g/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 :g/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
25

________________________________________________________
dehalogenation of carbon tetrachloride to chloroform was found to

occur, and 700 :g 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 compounds 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 :g/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).
26

________________________________________________________
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 917 and 90400, respectively (Frank & Frank, 1986;
Brown et al., 1998).
27
5. CONCENTRATIONS IN THE ENVIRONMENT AND

EXPOSURE
5.1
5.1.1
Environmental levels
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 0.51.0 :g/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 :g/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
23 :g/m3 (several hundred measurements) with maximum levels up
to 6 :g/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
:g/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 0.00050.0008 :g/litre. As sites nearer to
effluent sources are examined, higher levels are observed. Thus in
28
Concentrations in the Environment and Exposure

________________________________________________________
Table 5. Levels of carbon tetrachloride in surface water

Area
Mean level (:g/litre)

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, The
Netherlands
0.010.02a
(max. 0.29)
Mersey Estuary, UK
2.7
van Zoest & van Eck

(1991)
Edwards et al.
(1982a)
Freshwater
Lake Zurich, Switzerland
0.025 (0.020.035)
Giger et al. (1978)
Lake Ontario, Canada
(< 0.00020.005)
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
River Rhine, Lobith, Germany
1.5 (0.42.8)
Bauer (1981)
Manchester Ship Canal, UK
3.8
Edwards et al.
(1982a)
Manchester Ship Canal, UK
24.2
Groundwater
Zurich (industrial area)
(< 0.053.6)
Birmingham aquifer, UK
(0.021)
Coventry aquifer, UK
4.9 (max. 80)
Giger et al. (1978)

Rivett et al.
(1990a,b)
Burston et al. (1993)
Washington, New Jersey, USA
(ND34)
Suffet et al. (1985)
Gibbstown, New Jersey, USA
(1.41.8)
Rosen et al. (1992)
range of medians
estuaries, levels from 0.01 to 2.7 :g/litre have been observed, and in
remote freshwater sites from 0.0002 to 0.025 :g/litre, while nearer to
industrial facilities mean levels in the range of < 0.124.2 :g/litre
have been recorded.
29

________________________________________________________
Even higher values, e.g., 1601500 :g/litre in the River Rhine

and a mean of 75 :g/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 :g/litre.
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 :g/litre (Staples et al., 1985).
Rain water and snow concentrations of carbon tetrachloride are
generally in the range of 0.3 to 2.8 :g/litre (Su & Goldberg, 1976),
but a level as high as 300 :g/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
30
Table 6. Levels of carbon tetrachloride in biota

Organism
Location
Plankton
Molluscs
Liverpool Bay, UK
Firth of Forth, UK
Liverpool Bay, UK
Thames Estuary, UK
Irish Sea
Crustaceans
Firth of Forth, UK
Liverpool Bay, UK
Thames Estuary, UK
Liverpool Bay, UK
Fish
Thames Estuary, UK
Irish Sea
ND = not detected.
Organ
whole body
whole body
whole body
whole body
muscle
digestive tissue
gill
ovary
mantle
whole body
whole body
whole body
flesh
liver
flesh
brain
gill
gut
liver
muscle
skeletal tissue
heart
Level (:g/kg)
0.040.09 wet weight
2 wet weight
0.41 wet weight
0.10.9 wet weight
528 dry weight
820 dry weight
14 dry weight
16 dry weight
2114 dry weight
13 wet weight
35 wet weight
0.2 wet weight
2 wet weight
ND0.3 wet weight
0.36 wet weight
15191 dry weight
3209 dry weight
944 dry weight
451 dry weight
783 dry weight
722 dry weight
1040 dry weight
Reference
Pearson & McConnell (1975)
Dickson & Riley (1976)

________________________________________________________
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 :g/m3 for various types of dwellings, which is in
agreement with the maximum indoor concentration of 1.2 :g/m3
reported by Clark (1981) and the range of 0.91.8 :g/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 :g/m3. The
highest concentration, 10 :g/m3, was found in a dry-cleaning
establishment.
Wallace (1986) reported typical concentrations in homes in
several cities in the USA of about 1 :g/m3; a maximum value of
9 :g/m3 was found. Shah & Heyerdahl (1988) found an average
carbon tetrachloride level of 2.6 :g/m3, based on 2120 indoor
samples. It should be noted, however, that carbon tetrachloride was
not detected in more than half the samples.
5.2.3
Drinking-water
The National Organics Monitoring Survey (NOMS) in the USA

detected carbon tetrachloride (range of 2.46.4 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 :g/litre while
maximum concentrations reached 16 :g/litre (Westrick et al., 1984).
Bauer (1981) reported that drinking-water in Germany contained an
average of less than 0.1 :g/litre although a maximum level of 1.4
:g/litre was found (average of 100 towns in 1977). Lahl et al. (1981)
reported a carbon tetrachloride concentration less than 0.1 :g/litre in
the drinking-water of 50 cities in Germany. In the United Kingdom,
< 0.012.3 :g/litre was measured in drinking-water (Reynolds et al.,
1982; Reynolds & Harrison, 1982).
Values as high as a median of 3 :g/litre and a maximum of 39.5
:g/litre were reported in Galicia, Spain (Freiria-Gndara et al.,
1992).
32

________________________________________________________
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 :g/litre or :g/kg.
The following concentrations of carbon tetrachloride in
foodstuffs in the United Kingdom in 1973 were reported: meat, 79
:g/kg; edible oils, 1618 :g/kg; tea, 4 :g/kg; and fruits and
vegetables, 38 :g/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 1,1,1trichloroethane could not be separated (McConnell et al., 1975).
According to a study conducted in Germany, carbon tetrachloride
can be present in decaffeinated coffee (4.960 :g/kg), milled cereal,
flour and starch products (levels in 21 samples ranged from less than
0.1 to 26 :g/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 :g/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
:g/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 :g/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
:g/kg), fish (0.6 :g/kg) and juice (0.3 :g/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 :g/kg in four sorts of
cheese, 0.100.34 :g/kg in cereals, 1.75.7 :g/kg in fish sticks and
up to 6.0 :g/kg in butter.
33

________________________________________________________
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 :g/kg (with a range of 2 to 210 :g/kg).
5.2.5
Intake averages
The daily average intake of carbon tetrachloride in Japan by

inhalation was calculated to be 7.7 :g/day (based on a daily
inhalation volume of 15 m3/day and assuming a 100% absorption) and
by ingestion less than 0.1 :g/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 :g/day or 0.18
:g/kg per day.
The ATSDR (1994) estimated the daily intake by inhalation to
be 0.1 :g/kg body weight based on ambient air level of about 1 :g/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
:g/kg body weight based on a typical carbon tetrachloride concentration of 0.5 :g/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 :g/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 :g/person (0.27
:g/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
34

________________________________________________________
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 0.010.23 mg/m3; Clark (1981) reported concentrations 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 :g/m3 (Deer et al., 1987). Use of carbon
tetrachloride in open beakers resulted in exposure levels of 290620
mg/m3 at a United Kingdom quartz crystal processing plant. Levels
were reduced to 5060 mg/m3 by closing the beakers (Kazantzis &
Bomford, 1960).
35
6. KINETICS AND METABOLISM IN LABORATORY

ANIMALS AND HUMANS
6.1
6.1.1
Pharmacokinetics
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, a polyethoxylated oil, at concentrations up to
10%, as an aqueous vehicle for carbon tetrachloride. Aqueous
solutions of carbon tetrachloride in Emulphor 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 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.
36
Kinetics and Metabolism in Laboratory Animals and Humans

________________________________________________________
6.1.1.2
Dermal
Liquid carbon tetrachloride on the intact mouse skin was

absorbed at a rate of 8.3 :g/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 cm 2) 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 :g/100 g and the
expired air contained 0.8 :g/litre. After exposure to 7230 mg/m3 for
3.5 h the blood of the male contained a carbon tetrachloride level of
30 :g/100 g and the expired air contained 3 :g/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).
37

________________________________________________________
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 nonvolatile 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
38

________________________________________________________
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 radioactivity), 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 36 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.
39

________________________________________________________
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 :g/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 (7090% 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
40

________________________________________________________
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
41

________________________________________________________
[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 :l 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).
42

________________________________________________________
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 25%
to CO2, eliminate 48% in the urine, and eliminate 4050%
unchanged in the breath.
6.2
Biotransformation and covalent binding of metabolites

Metabolism of carbon tetrachloride is initiated by cytochrome
P-450-mediated transfer of an electron to the C-Cl bond, forming an
anion radical that eliminates chloride, thus forming the
trichloromethyl radical. This radical may undergo both oxidative and
reductive biotransformation (see Fig. 1). The isoenzymes implicated
in this process are CYP2E1 and CYP2B1/2B2 (Raucy et al., 1993;
Gruebele et al., 1996). Some isoforms may be preferentially
susceptible to degradation by carbon tetrachloride (Tierney et al.,
1992). Evidence that carbon tetrachloride inactivates CYP2E1 and
reduces total CYP2E1 protein in a cell line that constitutively
expresses human CYP2E1 has been obtained by Dai & Cederbaum
(1995). When protein synthesis was blocked, inactivation and
degradation of CYP2E1 by carbon tetrachloride was more
pronounced. Free radical scavengers were unable to prevent CYP2E1
degradation, suggesting that carbon tetrachloride metabolites react at
the active site of CYP2E1. Antioxidants prevented carbon
tetrachloride-induced lipid peroxidation, but not CYP2E1
degradation, suggesting that these processes are disassociated.
The formation of the radical has been demonstrated convincingly
in vitro as well as in vivo in electron spin resonance experiments and
43

________________________________________________________
Cl3COCl
(P450)
+O
CCl4
- Cl-
(P450)
Cl3C .
Cl3CCCl3
Hexachloroethane
H2O
(P450)
- Cl-
Cl2C :
CO
RH
Binding to tissue
components
+ O2
Cl3CH
Chloroform
HCl
R.
PFUA
Cl3COO .
Lipid peroxidation
RH
R.
Cl3COOH
2GSH
GSSG + H2O
Cl3COH
- HCl
GS
SG
O
Diglutathionyl
dithiocarbonate
+ GSH
Binding to
tissue components
COCl2
Phosgene
+ H2O
+ cys
CO2 + HCl
2-Oxo-thiazolidine4-carboxylic acid
Fig. 1. Biotransformation of carbon tetrachloride

(From Harris & Anders, 1981; Anders & Jakobson, 1985; McGregor & Lang, 1996)
44

________________________________________________________
is mediated by a particular cytochrome P-450, of which the haem

moiety is destroyed after carbon tetrachloride exposure (Reiner et
al., 1972; Sipes et al., 1977; Poyer et al., 1978, 1980; Lai et al., 1979;
Tomasi et al., 1980; Fernndez et al., 1982; Noguchi et al., 1982a,b;
McCay et al., 1984). The formation of carbon tetrachloride/
cytochrome P-450 complexes has been demonstrated by Uehleke et
al. (1973), Wolf et al. (1977), Ahr et al. (1980) and Fernndez et al.
(1982).
The most important pathway in the elimination of
trichloromethyl radicals is the reaction with molecular oxygen,
resulting in the formation of trichloromethylperoxyl radicals
(CCl3OOC), as proposed by Packer et al. (1978), Shah et al. (1979),
Mico & Pohl (1983), Pohl et al. (1984) and McCay et al. (1984). This
intermediate, which is even more reactive than the trichloromethyl
radical (Dianzani, 1984), may interact with lipids, causing lipid
peroxidation along with the production of 4-hydroxyalkenals
(Benedetti et al., 1982; Comporti et al., 1984). Radical-induced lipid
peroxidation is also a presumed source of a variety of metabolites,
such as acetone, propanal, butanal and malondialdehyde, which
appear in rat urine 24 h after exposure to carbon tetrachloride (de
Zwart et al., 1997).
It is supposed that the trichloromethylperoxyl radical will react
further to produce phosgene, which again may interact with tissue
macromolecules or with water, finally producing hydrochloric acid
and carbon dioxide (Pohl et al., 1984). Carbon tetrachloride has been
reported to be metabolised to carbon dioxide in liver homogenates by
Rubinstein & Kanics (1964). The biotransformation of carbon
tetrachloride to carbon dioxide in vivo has been reported by Reynolds
et al. (1984).
Condensation of phosgene with cysteine leads to the formation
of 2-oxothiazolidine-4-carboxylic acid (Shah et al., 1979; Kubic &
Anders, 1980). The condensation of phosgene with glutathione
(GSH), resulting in diglutathionyl dithiocarbonate, has been
demonstrated by Pohl et al. (1981) in in vivo experiments.
Formation of chloroform and CCl2-carbene occur under
O2-deficient circumstances (Reiner et al., 1972; Shah et al., 1979;
Pohl et al., 1984). Under in vivo conditions CCl2-carbene is of minor
importance as an intermediate. Castro et al. (1990) examined the
45

________________________________________________________
biotransformation of carbon tetrachloride to chloroform by liver

nuclear preparations of three different species: C3H mice, SpragueDawley rats and Syrian golden hamsters. All species were able to
transform carbon tetrachloride to chloroform. This ability was not
NADPH dependent and proceeded to an equal extent under nitrogen
and air. The relative transforming intensity was mice > hamsters >
rats under anaerobic and hamsters >> mice > rats under aerobic
conditions, respectively. More detailed experiments with preparations
of C3H mice suggested the presence of enzymatic and non-enzymatic
pathways of carbon tetrachloride transformation, as revealed by their
heat susceptibility and the inhibitory effects of EDTA.
Many studies on covalent binding of carbon tetrachloride
metabolites to tissue macromolecules have been carried out, but most
of them have measured only radioactivity and not identified the
adduct formed. Many studies ignored the radioactive impurities
present in the carbon tetrachloride used as well as the possible
incorporation of 14C-radioactivity via carbon dioxide riginating from
carbon tetrachloride. For these reasons, the binding of carbon
tetrachloride should be considered as an association of radioactivity,
unless further information is provided.
According to Shertzer et al. (1988), the active radical metabolic
intermediate of carbon tetrachloride may covalently bind to macromolecules, produce lipid peroxidation, and result in the loss of
intrahepatic calcium homoeostasis.
Cambon-Gros et al. (1986) showed that the fetal rat liver during
the last days of pregnancy, as well as the mother liver, can metabolize
carbon tetrachloride into a free radical: CCl3C. This radical may bind
covalently to the microsomal membranes and cause the destruction of
cytochrome P-450 as well as the inhibition of one of the main microsomal activities, the ability to store Ca2+. Contrary to the situation in
adults, these radicals do not provoke a membrane phospholipid
peroxidation in the fetus. The animals used in the study were
nulliparous pregnant female Sprague-Dawley rats (twentieth day of
gestation).
Tjlve & Lfberg (1983) showed that covalent binding (probably
due to metabolic activation) occurred in many tissues of exposed rats
46

________________________________________________________
(liver, kidney cortex, mucosae of the respiratory tract, the mouth

cavity and the oesophagus).
The non-extractable part of non-volatile radioactivity in liver and
kidney may indicate covalent binding to tissue components (Bergman,
1984). Association of radioactivity to tissue components also appeared
to occur in the testis, the uterine and vaginal mucosa and in the nasal
mucosa.
A similar pattern of association with tissue components to that
observed by Bergman (1984) has been found by Tjlve & Lfberg
(1983) after intravenous and intraperitoneal administration,
indicating that the tissue binding in the nasal mucosa is not specific
to the route of administration.
Daz Gmez et al. (1975a) investigated the relations between
liver carbon tetrachloride levels, lipid peroxidation, the covalent
binding to liver lipids and hepatic centrilobular necrosis after in vivo
administration of equimolar doses of carbon tetrachloride in different
animal species. The results support the hypothesis that carbon
tetrachloride-induced lipid peroxidation is not the only mechanism of
its toxic action. In fact, there seems to be a better correlation between
irreversible association with tissue components and carbon tetrachloride toxicity than between lipid peroxidation and carbon
tetrachloride toxicity.
According to Villarruel et al. (1977) association of carbon tetrachloride metabolites with lipids occurs mostly in the liver and kidney
cortex and medulla. Ansari et al. (1982) demonstrated the binding of
trichloromethyl radicals originating from carbon tetrachloride to
cholesterol. Binding to membrane lipids, eventually leading to crosslinking, has been demonstrated by Link et al. (1984).
Association of carbon tetrachloride derivatives with macromolecules in vitro has been found mainly in microsomal systems, but
binding to lipids and proteins also occurs in purified nuclear
preparations (Daz Gmez & Castro, 1980b).
The covalent binding of carbon tetrachloride reactive metabolites
to different nuclear and microsomal lipids was studied by Fanelli &
Castro (1995) in male Sprague Dawley and Osborne Mendel rats,
47

________________________________________________________
strains with a marked difference in the carcinogenic response to

carbon tetrachloride, the Sprague-Dawley being non-susceptible and
the Osborne-Mendel being responsive. The intensity of covalent
binding to microsomal lipids in vivo and in vitro was higher in the
Osborne Mendel rats. Most of the covalent binding of carbon
tetrachloride reactive metabolites in both rat strains occurs in the
phospholipid and in the cholesterol/cholesterol ester fractions. The
covalent binding to phospholipids is higher in the Sprague Dawley
strain, while binding to cholesterol and cholesterol ester is more
intense in the Osborne Mendel rat.
After administration of [14C]carbon tetrachloride to rats and mice
(9 :mol/kg body weight), the quantities of label associated with DNA
at 6 h post-dosing were 0.52 and 0.72 pmol/mg DNA, respectively. In
this study binding also occurred to nuclear proteins and lipids,
especially to phospholipids (diphosphatidylglycerol) and diglycerides
(Daz Gmez & Castro, 1980a).
The results of the study of Oraumbo & Van Duuren (1989)
indicated that under aerobic incubation conditions, carbon tetrachloride is metabolized to one or more electrophilic metabolites,
which bind covalently to chromatin DNA in a dose- and timedependent manner. In this study chromatin was isolated from male
B6C3F1 hybrid mice and incubated with [14C]carbon tetrachloride in
the presence of hepatic microsomes from the same animals and a
NADPH-regenerating system. The study was carried out with various
carbon tetrachloride concentrations and incubation times.
6.3
Human studies
6.3.1
Uptake
6.3.1.1
Dermal
Immersion of a thumb in liquid carbon tetrachloride for 30 min

produced a maximum alveolar carbon tetrachloride concentration of
about 3.8 mg/m3 air 30 min after the end of exposure (Stewart &
Dodd, 1964). The concentration declined with a half-life of about
2.5 h.
48

________________________________________________________
6.3.1.2
Inhalation
Lehmann & Schmidt-Kehl (1936) reported that 60% of the

quantity of carbon tetrachloride inhaled was retained in an experiment
involving a 30-min exposure of a volunteer to 4200 mg/m3.
6.3.2
Elimination
The pulmonary excretion of 33% of the absorbed quantity of

[38Cl] carbon tetrachloride occurred during the first hour after a single
breath by a volunteer (Morgan et al., 1970). Erickson (1981) found
carbon tetrachloride in mothers milk (concentration and exposure not
specified).
49
7. EFFECTS ON LABORATORY MAMMALS AND IN

VITRO TEST SYSTEMS
7.1
7.1.1
Single exposure
Lethality
LD50 values of carbon tetrachloride for various mammalian

species are represented in Table 7.
For female OF1 mice a LC50 of 7176 ppm (45 998 mg/m3) was
reported after a 6-h inhalation exposure to carbon tetrachloride
(14 days observation period) (Gradiski et al., 1978). Svirbely et al.
(1947) reported a LC50 of 50 000 mg/m3 after a 7-h inhalation
exposure (8-h observation period) for male and female Swiss mice.
A 100% death rate of Wistar rats due to anaesthesia was
observed by Adams et al. (1952) after inhalation exposure to carbon
tetrachloride at concentrations of 121 600 mg/m3 for 2.2 h or 46 700
mg/m3 for 8 h.
Roudabush et al. (1965) reported that the acute dermal LD50
values of carbon tetrachloride for rabbits and guinea-pigs were in
excess of 15 g/kg body weight. Data on mortality and observation
period were not given.
Wahlberg & Boman (1979) applied carbon tetrachloride in
quantities of 800 and 3200 mg (approximately 2100 and 8500 mg/kg
body weight) to the skin of guinea-pigs. After 21 days 5/20 and 13/20
of the animals had died in the 800 mg and 3200 mg groups,
respectively.
7.1.2
7.1.2.1
Non-lethal effects
Oral exposure
Effects on the liver with changes in several enzyme levels are

reported to be the major effects resulting from an acute oral exposure
to carbon tetrachloride. In addition to the effects on the liver, effects
have also been reported in other organs such as lungs and kidneys.
50
Table 7. LD50 values (mg/kg body weight) for mammals

Species/strain
Sex
Route
Vehicle
Observed period
LD50a
Reference
Mice
Swiss Webster
male
intraperitoneal
corn oil
24 h
4144
Klaassen & Plaa (1967a)
female
intraperitoneal
corn oil
24 h
4463
Klaassen & Plaa (1967a)
oral
unknown
not reported
12 10014 400
Strain and sex

unknown
IARC (1979)
Swiss Webster
female
intraperitoneal
corn oil
24 h
4676
Gehring (1968)
OF1 (SPF)
female
intraperitoneal
olive oil
14 days
3350
Gradiski et al. (1974)
Wistar
female
oral
unknown
14 days
2821
Smyth et al. (1970)
Sprague-Dawley
male
intraperitoneal
corn oil
48 h
4463
Klingensmith et al. (1983)
Sprague-Dawley
male
intraperitoneal
corn oil
24 h
3029
Klaassen & Plaa (1969)
Sprague-Dawley
female
intraperitoneal
peanut oil
24 h
6603
Lundberg et al. (1986)
14 days
2824
Lundberg et al. (1986)

Kennedy et al. (1986)
Rats
Charles River
male
oral
corn oil
14 days
10 054
male/female
intraperitoneal
corn oil
24 h
2391
Dogs
Mongrel
a
Most of the values are calculated values because they were reported as ml/kg body weight
Klaassen & Plaa (1967b)

________________________________________________________
a)
Mice
Akahori et al. (1983) examined the biochemical alterations in

liver and blood, and the histological findings in the liver of female
C57BL/6J mice after a single oral administration of carbon
tetrachloride in liquid paraffin at doses of 0.02, 0.5 or 1.5 ml/kg body
weight (calculated to be 32, 797 or 2391 mg/kg body weight) at
various times from 15 to 327 h after administration. The biochemical
changes in the liver (decreases in protein, glucose, phospholipids,
DNA and RNA concentrations; increases in triglycerides, glycogen,
and free and esterified cholesterol concentrations) and in blood (an
increase in serum aspartate aminotransferase (ASAT) activity and free
and esterified cholesterol concentration; a decrease in glucose
concentration) were generally dose-related but occurred more slowly
in the highest dose groups. The biochemical alterations were reflected
in the histological findings in the liver (centrilobular necrosis in the
low-dose and a mild midzonal necrosis in the mid- and high-dose
groups). These histological findings occurred later in the high-dose
group.
A dose-related increase in the serum angiotensin converting
enzyme level, indicative of pulmonary endothelial cell injury, was
reported by Hollinger (1982), who administered carbon tetrachloride
in vegetable oil at doses of 0.1 to 2.8 ml/kg body weight (159 to 4463
mg/kg body weight) to male Swiss-Webster mice.
Boyd et al. (1980) found morphological effects on the pulmonary
Clara cells of mice, including severe dilations of endoplasmic
reticulum and occasional cellular necrosis, after administration of 2.5
ml/kg body weight (3985 mg/kg body weight) of carbon tetrachloride
in sesame oil. Oral doses of less than 1 ml/kg body weight (1594
mg/kg body weight) failed to produce visible pulmonary lesions.
b)
Rats
Murphy & Malley (1969) reported dose-related increases in liver

and serum alanine aminotransferase (ALAT), liver tyrosine transaminase and alkaline phosphatase activities after a single oral dose of
0.5 to 2 ml/kg body weight (797 to 3188 mg/kg body weight) of
undiluted carbon tetrachloride in male Holtzman rats.
52
Effects on Laboratory Mammals and In Vitro Test Systems

________________________________________________________
In a study by Korsrud et al. (1972), fasted male Wistar rats

received carbon tetrachloride at a dose ranging from 0 to 2.5 ml/kg
body weight (0 to 3985 mg/kg body weight) in corn oil. The rats were
killed 18 h later. At a dose of 0.0125 ml/kg body weight (19.9 mg/kg),
there was histopathological evidence of toxic effects on the liver. At
0.025 ml/kg body weight (39.9 mg/kg), liver fat and weight, serum
urea and the activities of sorbitol dehydrogenase, fructose-l-Paldolase, isocitrate dehydrogenase, ALAT and aspartate
aminotransferase (ASAT) were increased.
According to Teschke et al. (1984), liver enzymes such as ALAT,
ASAT and glutamate dehydrogenase measured in serum reached
maximal activities 1248 h following a single intragastric dose of
carbon tetrachloride (1.5 ml/kg body weight) to female Wistar rats.
A maximum increase of ASAT and ALAT after 48 h was
reported by Nakata et al. (1985) after administration of 5 ml/kg body
weight (7970 mg/kg body weight) of carbon tetrachloride in corn oil
to male Wistar rats. Regeneration of the liver was characterized by a
normalization of the ASAT and ALAT levels and an increase in
hepatic thymidylate synthetase and thymidine kinase levels, two
enzymes that are believed to be indicative of tissue regeneration.
A single oral bolus of carbon tetrachloride (17.5 or 179 mg/kg)
to male Sprague-Dawley rats induced a dose-dependent increase in
serum sorbitol dehydrogenase and ALAT activities, and a decrease in
the hepatic cytochrome P-450 content and glucose-6-phosphatase
activity. When the same dose was given as a gastric infusion for 2 h,
or by inhalation exposure, the effects were much smaller (Sanzgiri et
al., 1995). No statistically significant difference was observed in the
toxicity of carbon tetrachloride administered orally in either corn oil,
Emulphor, or Tween-85 (Raymond & Plaa, 1997).
Significant increases in "-GSH, a cytosolic enzyme of short halflife found in high concentration throughout the liver, were detected
2 h after gavage dosing of male Sprague-Dawley rats (Clarke et al.,
1997). It was concluded that "-GST is a more sensitive and accurate
measure of carbon tetrachloride hepatotoxicity than ASAT.
Lowrey et al. (1981) reported a dose-dependent decreased
capacity of rat liver microsomes to sequester calcium 5 min after the
53

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administration of carbon tetrachloride to fasted male Sprague-Dawley

rats at doses ranging from 0.025 to 5 ml/kg body weight (40 to 7970
mg/kg body weight). At 10 min after a carbon tetrachloride dose of
2.5 ml/kg body weight (3985 mg/kg body weight), the microsomal
calcium uptake was reduced to 15% of the control levels.
Chen et al. (1977) observed marked decreases in cytochrome
P-450 content and P-450-related N-demethylation of dimethylaniline
in the microsomes of the lungs of male Sprague-Dawley rats after an
oral carbon tetrachloride dose in mineral oil of 2.5 ml/kg body weight
(3985 mg/kg body weight).
Shinozuka (1971) found alterations of the rough endoplasmic
reticulum membranes of rat hepatic cells, such as detachment of
ribosomes, narrowing of cisternal spaces, fusion of membranes and
eventual collapse, within 30 min after an administration of 5 ml/kg
body weight (7970 mg/kg body weight) of carbon tetrachloride in
mineral oil to Wistar rats.
Boyd et al. (1980) found lesions in the lungs of male SpragueDawley rats that were similar to the lesions found in mice (enlarged
pulmonary Clara cells with dilations of the endoplasmic reticulum,
occasional cellular necrosis) after carbon tetrachloride administration
at doses of 2.4, 3.2 or 4.5 ml/kg body weight (3825, 5100 or 7173
mg/kg body weight) in sesame oil. These lesions, however, were less
pronounced and less frequent than in mice.
Striker et al. (1968) observed reversible lesions limited to the
proximal tubules in the kidneys of male Sprague-Dawley rats after
administration of 0.25 ml/kg body weight (400 mg/kg body weight)
of carbon tetrachloride in mineral oil. The earliest morphological
change was seen in the mitochondria, followed by cellular swelling,
loss of basilar interdigitations and swollen microvilli. Proliferation of
the smooth endoplasmic reticulum occurred later. Serum parameters,
such as creatinine, blood urea nitrogen and bilirubin, temporarily
increased. Furthermore, a decrease in the ability to preserve sodium
ions and water was observed, accompanied by a reduction of succinate
dehydrogenase activity.
54

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Rats administered carbon tetrachloride in corn oil as a single

intraperitoneal dose had significantly prolonged clotting times that
appeared prior to liver necrosis (Pritchard et al., 1987).
c)
Rabbits
Rabbits (strain unspecified), given an intragastric dose of 0.15

ml/kg body weight of a 33% carbon tetrachloride solution in liquid
paraffin (equivalent to 239 mg/kg body weight) showed an abnormal
electrophoretic lipoprotein pattern. This correlated with the degree of
liver injury as measured by ASAT and ALAT activities and plasma
lipid levels (Kanaghinis et al., 1982).
d)
Monkeys
Centrilobular hepatocellular necrosis was observed in two out of

four monkeys 24 h after administration of a single oral dose of carbon
tetrachloride (1590 mg/kg).
e)
Dogs
Dogs were administered single oral doses of 159, 318 and 477
mg/kg. Increased serum ALAT and ASAT activities were observed at
318 mg/kg or more.
7.1.2.2
Inhalation exposure
a)
Mice
Boyd et al. (1980) exposed male Swiss mice to carbon

tetrachloride concentrations of 0.46 or 0.92 mmol/litre air for 1 h,
1.84 mmol/litre air for 12 min, and 3.68 mmol/litre air for 2 min
(70 750, 141 500, 283 000 and 566 000 mg/m3 air). All exposures
produced marked Clara cell lesions, similar to those caused by oral
exposure, and hepatic necrosis.
b)
Rats
Brondeau et al. (1983) exposed male Sprague-Dawley rats (IFFA

CREDO; 8 males/group) to carbon tetrachloride at concentrations of
259, 531, 967 and 1459 ppm (1660, 3404, 6198 and 9352 mg/m3 air)
55

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for 4 h and examined the ASAT, ALAT, SDH and glutamate

dehydrogenase activities in the serum 24 h post-exposure. At the
lowest exposure level only the glutamate dehydrogenase activity was
increased, whereas at the higher exposure levels increases were
observed in all enzyme activities. Similar increases in serum activities
of liver enzymes have been reported in other rat strains (Magos et al.,
1982 (Porton-Wistar and Fischer rats); Jaeger et al., 1975 (Holtzman
rats); Siegers et al., 1985 (Wistar rats)).
When male Sprague-Dawley rats were exposed to carbon
tetrachloride under conditions of various combinations of concentration (; 1350 to 6900 ppm) and exposure time, it appeared that the
concentration had more influence on the hepatotoxicity than the
exposure time (Uemitsu et al., 1985).
Chen et al. (1977) observed a decrease in the cytochrome P-450
content and P-450-related demethylation of dimethylaniline in the
microsomes of lungs of male Sprague-Dawley rats exposed for 30 min
to air containing 4.38% carbon tetrachloride (280 758 mg/m3).
Morphological analysis of the lungs revealed focal changes in
pulmonary architecture consisting of alveolar collapse, septal
thickening and atypical type II pneumocyte configuration.
c)
Cats
Wong & DiStefano (1966) exposed cats to carbon tetrachloride

at a concentration of 10 000 ppm (64 100 mg/m3) for 15, 30, 60 and
240 min. After 15 min the renal lipid content reached maximal levels.
An increase of kidney weight occurred within 60 min and was
maintained throughout the 24-h observation period. The total lipid
content of the liver had increased significantly at 3, 12 and 24 h after
the 4-h exposure period. Increased liver weight was observed 24 h
after the withdrawal of carbon tetrachloride. According to the authors,
the early increases in both the weight and fat content of the kidney
suggests that the renal changes precede the liver damage.
56

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7.1.2.3
Subcutaneous and intraperitoneal exposure
a)
Mice
A subcutaneous dose of 28 mg/kg body weight of carbon

tetrachloride in olive oil to male Swiss mice (10/group) appeared to
be the ED50 for causing prolongation of pentobarbital-induced
sleeping time. Histological examination showed changes in the liver
after administration of 77 mg/kg body weight. (Kutob & Plaa, 1962).
Intraperitoneal administration of carbon tetrachloride in corn oil
induced an elevation of the ALAT activity at calculated dose levels of
11.2 to 15.9 mg/kg body weight in female Swiss mice and at 14.4 to
15.9 mg/kg body weight in male Swiss mice (Klaassen & Plaa,
1967a).
Bhathal et al. (1983) reported striking differences in the degree
of hepatic cell injury among four different strains of mice upon
histological examination after subcutaneous injection of 0.3 ml/mouse
of olive oil containing 5, 10 and 20% carbon tetrachloride. The SJL/J
strain appeared to be the least susceptible and the BALB/c strain the
most susceptible one. The hepatic lesions in the C3H and C57BL/6
strains were intermediate.
b)
Rats
The study of mejkalov et al. (1985) showed the existence of

sex differences in the sensitivity of the liver to carbon tetrachloride,
including a difference in the rate and quality of liver regeneration. It
appeared that in male Wistar rats the biochemical changes occurred
earlier (as early as 6 h after intraperitoneal administration of 1200
mg/kg body weight) and persisted longer (reaching a maximum after
12 h and persisting for more than 72 h) than in females. In females
these changes reached a maximum after 24 h, and after 72 h the levels
were identical to the control values. Whereas in females the liver
regeneration started sooner than in males and led to complete healing
of the liver tissue, the regeneration in males started more slowly and
healing followed a different course, showing the development of
fibrosis.
Carbon tetrachloride dissolved in olive oil was injected intraperitoneally to male Fischer rats at doses of 30 to 1000 mg/kg body
57

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weight. Free and esterified cholesterol, triglycerides, phospholipids

and total lipids in plasma were reduced in a dose-dependent manner.
Cholesterol, triglyceride, phospholipid and total lipid concentrations
in the plasma were significantly lower in rats given 30 mg/kg body
weight than in control rats (p < 0.01) (Honma, 1990).
When male Wistar rats received carbon tetrachloride as an
intraperitoneal injection of 16 or 96 mg/kg body weight in olive oil,
the calcium ion (Ca2+) content of liver microsomes was significantly
increased by 20% in rats treated with 96 mg/kg body weight. The
mitochondrial Ca2+ content was increased in both the 16 and 96
mg/kg body weight group (600% and 1100%, respectively, 3 h after
administration) (Yamamoto, 1990).
c)
Guinea-pigs
Divincenzo & Krasavage (1974) administered intraperitoneally

5, 25, 50, 75 or 150 mg/kg body weight to guinea-pigs. At 25 mg/kg
or more, increased ornithine decarboxylase activity in the serum was
found, an effect that was reflected by histological changes in the liver.
d)
Hamsters
Carbon tetrachloride produced injury to ciliated and non-ciliated

tracheal cells (swollen, loss of staining capacity, diluted nuclei) of
adult male Syrian golden hamsters that received carbon tetrachloride
intraperitoneally at a dose of 2.5 ml/kg body weight (3985 mg/kg body
weight). Groups of three hamsters were killed 1, 4, 12 or 24 h after
treatment. The number of damaged cells increased markedly after 1 h
in the lower trachea, but not until after 4 h in the upper trachea. By
24 h the number of injured cells approached normal values. Effects
were consistent within each group (Ahmadizadeh et al., 1990).
e)
Dogs
When five mongrel dogs were given carbon tetrachloride at

different intraperitoneal doses, increases in ALAT were observed. The
calculated ED50 24-h after exposure was 32 mg/kg (Klaassen & Plaa,
1967b).
58

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De Zwart et al. (1997) have identified eight urinary degradation

products of carbon tetrachloride-induced lipid peroxidation as
potentially useful biomarkers of in vivo hepatocellular damage. Male
Wistar rats were injected intraperitoneally with single doses of 38, 77
and 154 mg/kg body weight and the following substances were
identified in urine 12 to 48 h later: formaldehyde, acetaldehyde,
acetone, propanol, butanol, pentanal, hexanal and malondialdehyde.
A dose-dependent increase in histological and clinical chemistry
evidence of hepatocellular damage, along with these degradation
products, was observed. Increases in urinary concentrations of all
eight products were statistically significant at doses of 77 and 154
mg/kg. At 38 mg/kg, acetaldehyde and propanol were the only urinary
markers to exhibit a statistically significant increase.
7.1.2.4
Dermal exposure
The histopathology of the skin, liver, and kidney in the guineapig (weighing 440 to 570 g) was studied by Kronevi et al. (1979) at
15 min and 1, 4 and 16 h after occlusive epicutaneous administration
of 1 ml of carbon tetrachloride. After 15 min, some degenerative
changes in the epidermis, such a moderate karyopyknosis, marked
spongiosis and perinuclear oedema was observed. These changes
became more obvious with time, and at 16 h a slight karyolysis also
was seen. A junctional separation and cellular infiltration in the
dermis was observed after 4 and 16 h. Carbon tetrachloride exposure
caused hepatic centrilobular hydropic changes and, in addition, a
tendency to necrotic lesions after 16 h. Kidney histology was normal
for all exposed guinea-pigs.
7.2
7.2.1
Short-term exposure
Oral exposure
a)
Mice
Hayes et al. (1986) administered carbon tetrachloride in corn oil

to CD-1 ICR mice (20/sex/group) for 14 consecutive days at dose
levels of 0, 625, 1250 or 2500 mg/kg body weight and for 90
consecutive days at dose levels of 0, 12, 120, 540 or 1200 mg/kg body
weight. No compound-related deaths were seen in the 90-day study
whereas, in the 14-day study, 6, 8 and 12 males and 0, 1 and 2
59

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females died within 2-4 days in the 625, 1250 and 2500 mg/kg body
weight groups, respectively. Dose-dependent effects in the 14-day
study consisted of decreased fibrinogen and lymphocyte levels,
increased LDH, ALAT and ASAT levels, increased absolute and
relative liver weights in both sexes, and decreased lung, thymus and
kidney weights in males. In the 90-day study LDH, ASAT, ALAT and
AP, cholesterol and bilirubin levels in the blood were increased in a
dose-dependent manner while blood glucose levels were decreased at
all dose levels. In both sexes and in all 90-day dose groups absolute
and relative liver, spleen and thymus weights were increased and liver
damage was observed.
The results of a 90-day oral study in CD-1 mice by Condie et al.
(1986), indicated that the no-observed-adverse-effect level (NOAEL)
for hepatotoxic effects after administration of carbon tetrachloride in
corn oil was 1.2 mg/kg body weight (see also section 7.9).
b)
Rats
Four groups of weanling rats (six males and six females per
group) were fed diet containing 0, 150, 225 or 520 mg/kg; estimated
daily doses were 0, 713, 1324, 2127 mg/kg body weight. The fat
content of liver was increased significantly in two higher dose groups
in both males (exposed for 6 weeks) and females (exposed for 5
weeks); the difference compared to the control group was 50 to 200%
(Alumot et al., 1976).
Carbon tetrachloride treatment for 5 consecutive days at a dose
level of 400 mg/kg body weight in corn oil to male Fischer-344 rats
(CD F/CrlBr) increased the relative liver weight, decreased the CYP
enzyme concentration and activity in the liver, and increased the
ALAT levels (Dent & Graichen, 1982).
Bruckner et al. (1986) administered carbon tetrachloride in corn
oil to male Sprague-Dawley rats (5/group) for 5 consecutive days
for 12 weeks, then 2 days without dosing followed by another
4 consecutive days of dosing. Groups of rats weighing 300 to 350 g
received 0, 20, 40 or 80 mg/kg body weight, whereas groups of rats
weighing 200 to 250 g received 0, 20, 80 or 160 mg/kg body weight.
In rats weighing 300350 g, 20 mg/kg body weight caused vacuolization of hepatocytes adjacent to the central vein of most liver lobules.
60

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The other dose levels in this group produced comparable increases in

SDH and ALAT activities, and vacuolization of 25 to 35% of the
hepatocytes in each liver lobule. Carbon tetrachloride appeared to be
more toxic to the rats weighing 200250 g with regard to necrotic
cells, which were rarely seen in livers of the 300350 g rats, while in
each 200250 g rat given 80 mg/kg body weight necrosis was
observed.
Groups of 1516 male Sprague-Dawley rats weighing 200 to
250 g were given carbon tetrachloride in corn oil at doses of 0, 1, 10
and 33 mg/kg body weight for 5 days a week. The rats were dosed
during the dark part of their light cycle. After 12 weeks, 7 to 9
rats/group were killed. The remaining animals were killed 13 days
after exposure. At 10 mg/kg body weight a slightly but significantly
increased SDH activity and mild hepatic centrilobular vacuolization
was seen. Administration of 33 mg/kg body weight caused elevated
serum levels of SDH, ornithine-carbamyl transferase (OCT) and
ALAT, which returned to normal during the recovery period except
for the OCT. Histopathology of the livers of the 33 mg/kg body weight
group revealed cirrhosis, characterized by bile duct proliferation,
fibrosis, lobular distortion, parenchymal regeneration, hyperplastic
nodules and single-cell necrosis. According to the authors (Bruckner
et al., 1986), a NOAEL of 1 mg/kg body weight of carbon
tetrachloride could be established.
Allis et al. (1990) administered carbon tetrachloride in corn oil
to male Fischer-344 rats by gavage at dose levels of 0, 20 or 40 mg/kg
body weight for 12 weeks. At both dose levels ALAT, ASAT and
LDH levels were elevated and hepatic CYP protein concentrations
were reduced. Histopathology showed cirrhotic livers, vacuolar degeneration and hepatocellular necrosis at both dose levels, but this was
more severe in the higher dose group. At day 8 and 15 after exposure,
all serum indicators and CYP protein concentration had returned
to normal levels. In both dose groups, hepatocellular necrosis
disappeared by day 8 and vacuolar degeneration decreased in severity
but was still present at day 15. Cirrhosis persisted in the high-dose
group, although it was less severe. Furthermore the relative liver
weight in animals receiving 40 mg/kg body weight remained elevated.
Several tests on renal function were conducted on adult male
Fischer-344 rats treated for 15 days with carbon tetrachloride in corn
61

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oil at doses of 50, 150, 450 or 1350 mg/kg body weight. At 1350
mg/kg body weight, kidney injury could be observed, as indicated by
haematuria, enzymeuria and decreases in kidney weight and serum
glucose concentration. At 450 mg/kg body weight, a lower body
weight and a reduction in the maximum urine-concentrating ability
were observed (Kluwe, 1981).
c)
Dogs
Young adult Beagle dogs of the Alderly Park strain (6/sex) that
received carbon tetrachloride (in gelatin capsules) as a daily dose of
0.05 ml/kg body weight (80 mg/kg body weight) for 28 days, showed
elevated ALAT and ornithine carbamyl transferase activities, whereas
no effects were observed on ASAT and alkaline phosphatase.
Furthermore there were changes in the livers of all dogs characterized
histologically by fatty vacuolation of centrilobular cells. In 3 of the 12
dogs, the vacuolation also occurred mid-zonally and periportally.
There was some evidence of individual cell necrosis, and in some
cases the sinusoids were mildly congested. No changes in plasma
enzyme activities and no histological changes in the liver were
observed when three females received a daily dose of 0.02 ml/kg body
weight (32 mg/kg body weight) of carbon tetrachloride for 8 weeks.
(Litchfield & Gartland, 1974).
7.2.2
Inhalation exposure
a)
Mice
As reported in a translated, extensive summary, BDF1 mice

(10/sex/group) were exposed (whole-body) to atmospheres of 0, 10,
30, 90, 270 or 810 ppm carbon tetrachloride (0, 64, 192, 577, 1731 or
5192 mg/m3, respectively) for 6 h a day, 5 days a week for 13 weeks.
Mice were observed daily for clinical signs, behavioural changes and
mortality and were weighed each week. Urinalysis, haematology,
blood chemistry and microscopy were performed at the scheduled end
of the experiment. No compound-related deaths occurred. Body
weight gain was depressed in males at 30 ppm or more. Slight, but
statistically significant, changes in haematology were observed in
males at 810 ppm (decreased Hb and increased MPV) and in females
at the two highest dose levels (decreased Hb, Ht and RBC). Increased
liver enzymes in blood were observed in both sexes at the three
62

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highest dose levels. Urinalysis showed a decrease in pH at the highest

dose level in females only. Microscopic examination showed slight to
moderate dose-related changes in the liver including cytological
alterations, even at the lowest dose level in males. At higher dose
levels there were more severe changes described as collapse, deposit
of ceroid, proliferative ducts, increase in mitosis, pleomorphism and
foci (Japan Bioassay Research Centre, 1998). A NOAEL cannot be
established on the basis of these results.
b)
Rats
Exposure (whole body) of Sprague-Dawley rats (IFFA CREDO;

8 males/group) to a carbon tetrachloride atmosphere of 3308 mg/m3
(516 ppm) for 6 h a day for 2 or 4 consecutive days resulted in
increased serum activities of glutamate dehydrogenase, ASAT, ALAT
and SDH after 4 days exposure. After 2 days only the SDH level was
significantly increased (Brondeau et al., 1983).
When male hooded rats were exposed (whole body) 8 h a day for
12 days to carbon tetrachloride levels of 68 or 680 ppm (436 or 4360
mg/m3) increased ASAT levels were found at low- and high-dose
levels after 4 and 2 days, respectively. At both doses the level of liver
lipids reached a maximum after 8 days, the level being related to
the dose. Additional exposure resulted in a decrease (Kanics &
Rubinstein, 1968).
An increased liver triglyceride content was also reported by
Shimizu et al. (1973) who exposed (whole body) female SpragueDawley rats to 10, 50 and 100 ppm of carbon tetrachloride vapour
(64, 320 and 641 mg/m3) for 3 h a day for 6 to 8 weeks. Exposures to
320 and 641 mg/m3 resulted in striking increases in the hepatic triglycerides to a maximum during the first 3 weeks. Afterward this level
was nearly maintained in both groups. At 64 mg/m3 the rise in
triglycerides was minimal and was maintained for 2 weeks.
David et al. (1981) compared the serum enzyme activities and
liver lesions in rats exposed to various concentrationtime combinations. After four exposures to 50 ppm (320 mg/m3) for 6 h per day,
the enzyme activities were significantly increased by 50 to 70%, and
steatosis and hydropic changes were found in the liver. The changes
were significantly more intensive in rats exposed to 250 ppm
63

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(1600 mg/m3) for 72 min per day, not withstanding that the
concentrationtime product was equal. The same was true for two-fold
concentrations and 18 exposures.
Bogers et al. (1987) performed 4-week studies in male Wistar
rats by exposing (whole body) them to 63 or 80 ppm (404 or 513
mg/m3) carbon tetrachloride in three different concentration profiles:
1) continuous exposure of 6 h/day for 5 days/week; 2) exposure of
2 3 h/day (1.5 h interruption) for 5 days/week; and 3) peak loads of
382 ppm (2450 mg/m3) for 5 min (4 peaks for 3 h) with and without
the 1.5-h interruption. The interruption of the daily 6-h exposures did
not result in less severe but rather in slightly more severe hepatotoxic
effects, such as changes in enzyme levels, fat accumulation, increased
relative liver weight, lower microsomal protein content and hydropic
degeneration of liver cells. Peak loads did not affect the severity of the
hepatotoxic effects.
Plummer et al. (1990) exposed (whole body) male black-hooded
Wistar rats (36/group) for 4 weeks to carbon tetrachloride both
continuously (24 h per day, 7 days per week) to 32 ppm (205 mg/m3)
or intermittently (6 h per day, 5 days per week) to 176 ppm (1128
mg/m3). The concentrationtime products were similar for both
groups. The-carbon tetrachloride-induced hepatotoxicity appeared to
be similar in the two exposure profiles. However, when rats received
the enzyme-inducing agents phenobarbitone or 1,3-butanediol during
the study via their drinking-water, the liver injury appeared to be
exacerbated in 1,3-butanediol-treated rats, especially in the intermittent exposure profile.
Groups of male Sprague Dawley rats were exposed (whole body)
to 100 ppm (641 mg/m3) of [14C]carbon tetrachloride for either 8 or
11.5 h/day for periods of 1 to 10 days, and examined with and without
recovery in a tissue distribution study (see section 6.1.3 and 6.1.4).
The only significant difference between rats exposed to the two
different schedules was the serum SDH activity, which was almost
always significantly greater for rats exposed to the 11.5 h/day
schedule than for the comparable groups exposed to the 8 h/day
schedule, except when measured after a recovery period. (Paustenbach
et al., 1986b).
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F-344 rats (10/sex/group) were exposed (whole-body) in a

13-week inhalation study to 10, 30, 90, 270 or 810 ppm carbon
tetrachloride (64.1, 192.3, 576.9, 1730.7 or 5192.1 mg/m3,
respectively) for 6 h a day, 5 days a week. Control groups were
included. Animals were observed for clinical signs, behavioural
changes and mortality once a day, and they were weighed once a
week. Urinalysis was performed at the end of the dosing period, and
haematology, blood biochemistry and microscopy were performed at
the scheduled sacrifice. At 810 ppm the body weight gain was
depressed in both sexes. Haematological changes were observed at 90
ppm or more in both sexes, and at 30 ppm in females. Increased liver
enzymes in blood and urinalysis changes were observed in males at
270 ppm or more and in females at 90 ppm or more. Increased
creatine phosphokinase (CPK) was seen at 30 ppm in females.
Microscopic examination showed slight to marked changes in the
liver described as fatty change, cytological alterations, deposition of
ceroid, proliferative ducts, increase in mitosis, pleomorphism,
cirrhosis and foci. Furthermore, vacuolic change of tubule, hyaline
degeneration of glomerulus and protein cast of the kidney were noted
at the two highest dose levels (Japan Bioassay Research Centre,
1998). An NOAEL could not be established on the basis of these
results.
c)
Comparisons between species
Adams et al. (1952) exposed (whole body) rats, guinea-pigs,

albino rabbits and rhesus monkeys to various concentrations of carbon
tetrachloride in air. Histological data were not reported for the control
groups; these groups were, however, used for comparison with dose
groups. Dose-related effects were seen in Wistar rats (15/sex/group)
after exposure to carbon tetrachloride at concentrations of 5, 10, 25,
50, 100, 200 and 400 ppm (32, 63, 160, 320, 630, 1282 and 2520
mg/m3) for 7 h a day, 5 days a week, during approximately 5.56.5
months. Increased liver weight, increased liver fat content (especially
neutral fat and esterified cholesterol) and fatty degeneration of the
liver were observed after 2 to 3 weeks of exposure to concentrations
of 63 mg/m3 or more. Cirrhotic livers were found from 630 mg/m3
upwards. At a concentration of 320 mg/m3, kidney tubular epithelium
was affected and death rate seemed to be increased, especially in the
males. At the two highest exposure levels testicular weights were
decreased. At the 32 mg/m3 level, no adverse effects were seen. After
exposure for 5 days a week during 13 weeks to 2520 mg/m3 for 3 min
65

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a day or to 630 mg/m3 for 18 min a day, no effects could be observed.

Similar results were obtained in guinea-pigs from 63 mg/m3 upwards.
Rabbits developed slight to moderate fatty degeneration and cirrhosis
of the liver at 160 mg/m3 or more; there was no reported effect at
63 mg/m3. Rhesus monkeys developed slight-to-moderate fatty
degeneration of the liver 630 mg/m3 (2 monkeys); there was no
reported effect at 320 mg/m3 (2 monkeys).
Prendergast et al. (1967) studied the effects of continuous and
repeated exposure to carbon tetrachloride vapour in rats, guinea-pigs,
New Zealand rabbits, beagle dogs and squirrel monkeys (see Table 8).
After repeated exposure to 515 mg/m3, all species showed pulmonary
interstitial fibrosis or pneumonitis. Mottled livers were seen in all
species except in the dog. Histological examination revealed fatty
changes in the livers of all species. In addition, fibrosis, bile duct
proliferation, hepatocyte degeneration and regeneration, focal
inflammatory infiltration and portal cirrhosis were observed in the
guinea-pigs. After continuous exposure to 61 mg/m3 all species
showed growth retardation and all squirrel monkeys showed alopecia
and emaciation. Histopathological examination showed liver changes
similar to those reported after repeated exposures. After continuous
exposure to 6.1 mg/m3 carbon tetrachloride in 61 mg/m3 n-octane (as
a carrier) no visible signs of toxicity were noted in any of the species
and no animals died. At termination, all species except the rat showed
less body weight gain than the controls. Histopathological
examination revealed non-specific inflammatory changes in the lungs
of all species and in the liver, kidney and heart of several animals, but
no specific pathological changes attributable to the exposure were
noted.
7.2.3
Intraperitoneal exposure
Biochemical and morphological characterization of carbontetrachloride-induced lung fibrosis were investigated in rats after
intraperitoneal administration of 1.0 ml/kg body weight (1600 mg/kg
in paraffin oil) twice a week for 2 or 5 weeks, and examined after the
end of the exposure. The third group (5 rats) was treated for 2 weeks
and examined after 3 weeks of recovery. Acute haemorrhagic
interstitial pneumonia resulted from the 2 week exposure, while
chronic interstitial pneumonia was observed in rats exposed for
5 weeks and in the third group after 3 week of recovery (Pkk et al.,
1996).
66
Table 8. Mortality in animals exposed to carbon tetrachloride (from Prendergast at al., 1967).
a
b
c
Concentration
(mg/m3)
Type of
studyb
Ratc
Guinea-pig
(Hartley)
Rabbit
(New Zealand)
Dog
(Beagle)
Monkey
(Squirrel)
515
0/15
3/15
0/3
0/2
1/3
61
0/15
3/15
0/2
0/2
0/3
6.1a
0/15
0/15
0/3
0/2
0/3
in 61 mg/m3 n-octane (as a carrier)

R = 30 exposures, 8 h/day, 5 days/week for 6 weeks; C = continuous 90-day exposure.
Long-Evans or Sprague-Dawley rats

________________________________________________________
7.3
Long-term exposure
In a carcinogenicity study described in section 7.7 (Reuber &
Glover, 1970), young male rats were administered 1.3 ml/kg by
subcutaneous injection twice a week. Severe cirrhosis was observed in
all (16/16) Sprague-Dawley rats by 5 to 16 weeks (the time of death
of the animals) and in 13/17 Black rats by 7 to 18 weeks. In Wistar
rats, 6/12 rats developed moderate and 6/12 severe cirrhosis by 1768
weeks, while the cirrhosis was mild in 2/13, moderate in 7 and severe
in 4 Osborne Mendel rats by 10105 weeks; in Japanese rats, the
cirrhosis was mild in 9/15, moderate in 5 and severe in one rat by 8
to 78 weeks.
Alumot et al. (1976) exposed rats (strain unknown) to carbon
tetrachloride in feed at measured levels of 0, 80 and 200 mg/kg feed
for 2 years. The highest concentration corresponded to a daily dose of
10 to 18 mg/kg body weight. Because of chronic respiratory disease
in all animals beginning at 14 months, which resulted in increased
mortality, the results reported upon necropsy at 2 years were
inadequate for a health risk evaluation.
Muos Torres et al. (1988) administered carbon tetrachloride to
female Wistar rats (150 g initial body weight) as weekly
intraperitoneal injections at a dose of 0.2 ml in mineral oil for 46
weeks. The hepatic lesions were macroscopically and microscopically
evaluated after 8, 16, 22, 30 and 46 injections. After 8 injections,
changes in the hepatic architecture due to an increase in the
collagenous component accompanied by formation of fibrous bridges
were seen. After 46 injections a clearly established cirrhosis with
nodules of different sizes was seen.
BDF1 mice (50/sex/group) were exposed (whole-body) in a 2-year
inhalation study to 0, 5, 25 or 125 ppm carbon tetrachloride (0, 32.05,
160.25 or 801.25 mg/m3) for 6 h a day, 5 days a week. Animals were
observed for clinical signs, behavioural changes and mortality once a
day, and they were weighed once a week for the first 13 weeks and
every 4 weeks thereafter. Urinalysis was performed at the end of the
dosing period, and haematology, blood biochemistry and microscopy
were performed at the scheduled sacrifice. No compound-related
effects were observed at 5 ppm in female mice. The results from male
mice could not be evaluated due to anomalous control group liver
68

________________________________________________________
enzyme data. A significant decrease in survival was observed at 25

and 125 ppm. Liver tumours were the main cause of death at the
highest dose level. Body weight gain was depressed at 25 and 125
ppm. Changes in haematology, blood biochemistry including liver
enzymes, and urinalysis were observed at 25 ppm or more.
Microscopic examination showed changes of the liver (deposit of
ceroid, cyst and degeneration), the kidney (protein cast) and the
spleen (increased deposit of haemosiderin at 25 ppm and increased
extramedullary haematopoiesis at 125 ppm) at the two highest dose
levels in male mice. In female mice changes in the liver included
deposit of ceroid, thrombus, necrosis, degeneration and cyst at 25 and
125 ppm. At 25 ppm an increased deposit of haemosiderin of the
spleen was observed while at 125 ppm deposit of ceroid of the ovary
was seen (Japan Bioassay Research Centre, 1998). A NOAEL could
not be established on the basis of these results.
F-344 rats (50/sex/group) were exposed (whole-body) in a 2-year
inhalation study to 0, 5, 25 or 125 ppm carbon tetrachloride (0, 32.05,
160.25 or 801.25 mg/m3, respectively) for 6 h a day, 5 days a week.
Animals were observed for clinical signs, behavioural changes and
mortality once a day. They were weighed once a week for the first
13 weeks and every 4 weeks thereafter. Urinalysis was performed
at the end of the dosing period, and haematology, blood biochemistry
and microscopy were performed at the scheduled sacrifice. A
significant decrease in survival was observed at 125 ppm, with liver
tumours and/or chronic nephropathy being the main cause of death.
Body weight gain was depressed at 25 and 125 ppm. Changes in
haematology, blood biochemistry including liver enzymes, and
urinalysis were observed at 25 ppm and even at 5 ppm for the nitrate
and protein level in the urine of the rats. At the 125 ppm level, only
one male and three female rats survived, so no statistical test was
performed. Microscopic examination showed changes of the liver
(including fatty change, deposit of ceroid, fibrosis, granulation and
cirrhosis) at the two highest dose levels in both sexes. An increased
deposit of haemosiderin in the spleen was observed in males at all
dose levels. An eosinophilic change of the nasal cavity was observed
in females at all dose levels and in males at 25 and 125 ppm. A
chronic nephropathy (progressive glomerulonephrosis) developed in
females at 25 ppm and in both sexes at 125 ppm. At 125 ppm deposit
of ceroid and granulation of the lymph node were observed in both
69

________________________________________________________
sexes (Japan Bioassay Research Centre, 1998). A NOAEL could not

be established on the basis of these results.
7.4
7.4.1
Irritation
Skin irritation
Epicutaneous administration of 1 ml of carbon tetrachloride has

been demonstrated to induce degenerative changes in the epidermis
15 min to 16 h after application (Kronevi et al., 1979; see section
7.1.2.4).
Moderate dermal irritation was observed after application of
0.5 ml carbon tetrachloride (under occlusion) onto the shaven skin of
rabbits (only abraded skin) and male Hartley guinea-pigs (normal and
abraded skin) (Roudabush et al., 1965).
In a study conducted according to Draize protocol, 0.5 ml carbon
tetrachloride was applied under an occlusive dressing for 24 h to the
intact and abraded skin of rabbits. Irritation was assessed at 24 and
72 h. Carbon tetrachloride was classified as a medium skin irritant.
Histopathology of skin samples taken from the application site on day
3 after exposure confirmed the irritant reaction (Duprat et al., 1976).
Undiluted carbon tetrachloride (10 :l) was applied to the open
skin of guinea-pigs 3 times daily for 3 days. A skin reaction (no
further details provided) was observed on day 2 and an average score
described as redness was seen on day 4 (Anderson et al., 1988).
Wahlberg (1984a) rubbed 0.1 ml (159 mg) of carbon
tetrachloride into the skin of rabbits and guinea-pigs for ten
consecutive days and observed oedema and erythema.
7.4.2
Eye irritation
In a study conducted according to Draize protocol, 0.1 ml of

carbon tetrachloride caused a mild irritant response in rabbits. The
response was evident at 24, 48 and 72 h after exposure and recovery
was complete by day 14 (Duprat et al., 1976).
70

________________________________________________________
7.5
7.5.1
Toxicity to the reproductive system, embryotoxicity,

teratogenicity
Reproduction
Groups of six male rats received a single intraperitoneal injection

of coconut oil or carbon tetrachloride in coconut oil (1:1 mixture) as
3 ml/kg rat weight (2378 mg/kg body weight) After 15 days, a
significant increase in the weight of the pituitary and a decrease in the
weights of the testes and seminal vesicles were observed. Histological
examination showed testicular atrophy and some abnormality in the
process of spermatogenesis in the experimental animals (Chatterjee,
1966).
In a study of similar design with female rats, effects on the
reproductive system were seen 10 days after dosing. The effects
reported were: inhibition of estrous rhythm, reduction in ovarian and
uterine weights and vascularization, an increase in adrenal weight and
a marked reduction in pituitary gonadotrophin potency (Chatterjee
(1968).
Kalla & Bansal (1975) injected male rats with a mixture of
3 ml/kg body weight carbon tetrachloride in coconut oil (1:1, v/v)
(2378 mg carbon tetrachloride/kg body weight) through an intraperitoneal route for 10, 15 or 20 consecutive days. All dosing periods
resulted in decreased weights of testicles and accessory sex organs and
impairments in spermatogenesis. Dosing for 20 days resulted in an
entire deterioration of testicular tissue accompanied by an absence of
spermatids. The study was not reported adequately; number and strain
of rats were not reported.
7.5.2
Embryotoxicity and teratogenicity
The available data suggest that the fetus is not preferentially

sensitive to carbon tetrachloride, and effects of carbon tetrachloride
on fetal development and post-natal survival are likely to be secondary
to maternal toxicity.
71

________________________________________________________
7.5.2.1
Oral exposure
When carbon tetrachloride was administered by gavage to F-344

rats on gestation days 615 at 0, 25, 50 and 75 mg/kg per day in
either corn oil or in an aqueous vehicle containing 10% Emulphor,
it was more maternally toxic when administered in corn oil,
particularly at the highest dose. Full litter resorption (FLR) occurred
at 50 and 75 mg/kg with both vehicles. At 75 mg/kg, dams receiving
carbon tetrachloride in corn oil had a significantly higher rate of FLR
(67%) than those given the aqueous vehicle counterpart (8%)
(Narotsky et al., 1997a). Ammonium sulfide staining was used to
detect the resorption sites (Narotsky et al., 1997b).
Thiersch (1971) dosed pregnant rats with carbon tetrachloride (in
corn oil) at a level of 1000 mg/kg body weight on days 7, 7 and 8, 11,
or 11 and 12 of gestation. No malformations in the offspring were
reported, but the litters of the dams that had received two doses
showed more resorptions than the litters of those receiving one dose.
Clear information on a control group was not provided.
Hamlin et al. (1993) examined the effect on B6D2F1 mice of oral
administration of carbon tetrachloride (in corn oil) at concentrations
of 82.6 or 826.3 mg/kg body weight for five consecutive days
beginning on day 1, 6 or 11 of gestation. No effects were seen on
maternal or various neonatal parameters such as weight and crown
rump length. No malformations were detected in any pup on day 1
post-partum and the pups developed normally.
7.5.2.2
Inhalation exposure
When Schwetz et al. (1974) exposed pregnant Sprague-Dawley

rats to measured carbon tetrachloride concentrations of 334 or 1004
ppm (214 or 6435 mg/m3) for 7 h a day on days 6 to 15 of gestation,
the dams showed a dose-related decrease in food consumption (and
body weight gain). Signs of hepatotoxicity (increased ALAT activity)
were observed at both dose levels, but were not dose-related. Fetal
body weight and crown-rump length were significantly decreased. No
anomalies were seen upon gross examination of the fetuses. In both
exposure groups the incidence of fetuses with subcutaneous oedema
was increased but was statistically significant only in the lower dose
group. The incidence of sternebral anomalies (bipartite and delayed
72

________________________________________________________
ossification) was significantly increased in the fetuses of rats exposed

to the higher dose.
In an inhalation study by Gilman (1971), exposure of pregnant
rats to carbon tetrachloride at 1575 mg/m3 for 8 h a day on days 10 to
15 of gestation decreased the lactation index (83% compared to 98%
in the controls) and the viability index (83% as compared to 99% in
the controls).
7.6
Mutagenicity
The data from genotoxicity assays conducted with carbon
tetrachloride are summarized in Table 9. Since carbon tetrachloride
is a volatile compound that partitions preferentially in the
hydrophobic phase, the conditions adopted for in vitro experiments
are important to the outcome, but these conditions are often not
reported in sufficient detail. Carbon tetrachloride was not mutagenic
to Salmonella typhimurium in a large number of studies. It did,
however, induce DNA damage and mutations in single studies with
Escherichia coli. In fungi it induced intrachromosomal and mitotic
recombination. However, it did not induce aneuploidy in one study on
the yeast Saccharomyces cerevisiae, although aneuploidy was induced
in another single study with Aspergillus nidulans. In the only study
with Drosophila melanogaster, sex-linked recessive lethal mutations
were not induced by carbon tetrachloride.
In mammalian in vitro assays, carbon tetrachloride induced
cell transformation in a single study with Syrian hamster cells and
centromere-positive-staining micronuclei in human cell lines expressing cDNAs for CYP1A2, CYP2A6, CYP3A4, epoxide hydrolase or
CYP2E1. The AHH-1 cell line constitutively expressing CYP1A1
showed no increase in either total micronucleus frequency or
centromere-staining micronucleus frequency. There is little evidence
for the induction in vitro of DNA damage, unscheduled DNA
synthesis, sister-chromatid exchange or chromosomal aberrations.
In mammalian in vivo tests, carbon tetrachloride did induce
DNA strand breakage in one study but not in four others and did not
induce: a) unscheduled DNA synthesis in rat hepatocytes; b)
micronuclei in mouse hepatocytes, bone marrow cells or peripheral
blood erythrocytes; c) chromosomal aberrations in mouse bone
73
Table 9. Mutagenicity studies with carbon tetrachloride

Speciesa
Strain
Measured end-pointb
Test conditions
Activationc Inductiond Resultse
Reference
Bacterial systems
S. typhimurium
TA 100
TA 1535
base-pair substitution
not reported
+ rat
PCB
McCann et al.,
1975
S. typhimurium
G 46
not reported
+ mouse
i.n.r.
Kraemer et al.,
1974
S. typhimurium
TA 1950
G 46
concentrations:
10, 20 and 40 mg/ml
unknown
Braun &
Schneich,
1975
S. typhimurium
TA 1535
TA 1538
frameshift mutation
test performed in
desiccators
+ rabbit
i.n.r.
i.m.
Uehleke et al.,
1977
S. typhimurium
TA 100
TA 1535
TA 98
TA 1537
TA 1538
test performed in
desiccators
+ rabbit
PCB
Simmon et al.,
1977
S. typhimurium
TA 1535
TA 1538
frameshift mutation
concentration: 8 mM,
incubation in closed
containers
(survival > 90%)
+ mouse
PB
i.m.
Uehleke et al.,
1977
S. typhimurium
TA 100
TA 1535
test performed in
desiccators
!/+
sp. n.r.
i.n.r.
Simmon &
Tardiff, 1978
S. typhimurium
TA 100
TA 1535
TA 98
TA 1537
TA 1538
concentrations: 4, 5.7,
7, 10.2, 12.3, 18.4
:moles/plate; test for
volatile liquids
Barber et al.,
1981
frameshift mutation
frameshift mutation
!
+ rat
PCB
Table 9 (contd).
S. typhimurium
TA1535/pSK1002
SOS induction
open
Nakamura et al.,
1987
S. typhimurium
TA1535/pSK 1002
SOS induction
open
Brams et al.,
1987
S. typhimurium
TA1535/pSK 1002
forward mutation
open
Roldn-Arjona et
al., 1991
S. typhimurium
TA1535/pSK 1002
forward mutation
open
Roldn-Arjona &
Pueyo, 1993
S. typhimurium
TA100
TA1535
TA1537
TA97
TA98
reverse mutation
open
Zeiger et al.,
1988
S. typhimurium
TA100
TA98
TA97
reverse mutation
open
Brams et al.,
1987
S. typhimurium
TA 100
TA 1535
TA 98
TA 1537
TA 1538
concentration: below
toxicity limit
De Flora, 1981;
De Flora et al.,
1984
E. coli
K 12
gene mutations
not reported
+ mouse
i.n.r.
i.m.
Kraemer et al.,
1974
E. coli
K 12
gene mutations
not reported
+ rabbit
i.n.r.
i.m.
Uehleke et al.,
1976
E. coli
uvrA
back-mutation to trp
concentration:
0.01% v/v
+ mouse
i.n.r.
Norpoth et al.,
1980
frameshift mutation
Table 9 (contd).
Speciesa
E. coli
Strain
WP2 uvrA
Measured end-pointb
Test conditions
Reference
reverse mutation
2.5% atmosphere
(+)
Norpoth et al.,
1980
Non-mammalian eukaryotic systems

A. nidulans
unknown
somatic segregation
(crossing-over and
non-disjunction)
spot test technique
n.r.
Bignami, 1977
A. nidulans
unknown
induction of 8-azaguanine resistance
spot test technique
n.r.
Bignami, 1977
A. nidulans
35 (haploid)
P1 (diploid)
forward mutation
somatic segregation
concentration:
0.5% v/v
n.r.
n.r.
(+)
+
Gualandi, 1984
Benigni et al.,
1993
Callen et al.,
1980
A. nidulans
aneuploidy
S. cerevisiae
D7
gene conversion at
trps-locus; mitotic
recombination at ade-2;
gene conversion at ilv-1
S. cerevisiae
AGY31DEL
intrachromosomal
recombination
Schiestl et al.,
1989
S. cerevisiae
AGY31DEL
intrachromosomal
recombination
Galli & Schiestl,

1995
S. cerevisiae
D61.M
mitotic chromosome loss
Whittaker et al.,
1989
mitotic recombination
Galli & Schiestl,

1996
S. cerevisiae
concentration: 21, 28,

34 mM; test performed
in screw-capped glass
tubes
Table 9 (contd).
Drosophila
melanogaster
SLRL mutation
feeding
Foureman et al.,
1994
Drosophila
melanogaster
SLRL mutation
injection
Foureman et al.,
1994
Chinese hamster
lung
V79
aneuploidy
2500 :g/ml
nfelt, 1987
Cell line
AHH1 (expressing
CYP1A1)
aneuploidy
(centromere staining)
10 mM
Doherty et al.,
1996
Cell line
MCL-5 (cDNAs for aneuploidy

CYP1A2, CYP2A6, (centromere staining)
CYP3A4, CYP2E1
and epoxide
hydrolase)
2 mM
Doherty et al.,
1996
Cell line
h2E1 (cDNAs for

CYP2E1)
aneuploidy
(centromere staining)
2 mM
Doherty et al.,
1996
Cell line
AHH1 (expressing
CYP1A1)
micronucleus
10 mM
Doherty et al.,
1996
Cell line
MCL-5 (cDNAs for micronucleus

CYP1A2, CYP2A6,
CYP3A4, CYP2E1
and epoxide
hydrolase
2 mM
Doherty et al.,
1996
Cell line
h2E1 (cDNAs for

CYP2E1)
2 mM
Doherty et al.,
1996
micronucleus
Table 9 (contd).
Speciesa
Strain
Measured end-pointb
Test conditions
Reference
In vitro mammalian systems

Chinese hamster
ovary cells
anaphase analysis
for chromosomal
rearrangements
concentration: 5 :l/ml
Chinese hamster
ovary cells
chromosomal
aberrations + SCE
highest concentration:
3000 :g/ml
+ rat
concentration: 0.005,
0.01, 0.02 :l/ml in
sealed flasks; toxicity
observed
cells posses
intrinsic
activity
Rat
liver epithelium
metaphase analysis
for chromosomal
abnormalities
Human
lymphocyte
chromosomal aberrations concentration:

+ SCE
3.876 :g/ml
PCB
+ sp.n.r.
i.n.r
(+)
Coutino, 1979
!
!
!
Loveday et al.,
1990
!
!
Garry et al.,
1990
Dean & HodsonWalker,

1979
Host-mediated assays
S. typhimurium
TA 1950
mice NMRI;
subcutaneous
4 ml/kg body weight
Braun &
Schneich,
1975
S. typhimurium
TA 1950
mice CBA*C57Bl/6;
subcutaneous 20%
solution in sunflower oil
Shapiro &
Fonshtein, 1979
Syrian hamster
embryo cells
cell transformation
(clonal assay)
3 :g/ml
(+)
Amacher &
Zelljadt, 1983
Rat hepatocytes
in vivo
UDS
100 mg/kg 1 p.o. or

14 p.o.
Doolittle et al.,
1987
Table 9 (contd).
Sawada et al.,
1991
chromosomal aberrations 8000 mg/kg 1
Lilp, 1983
Mouse bone
marrow and
peripheral
erythrocytes
in vivo
micronucleus
Suzuki et al.,
1997
Mouse liver
in vitro
binding to DNA
Diaz-Gomez &
Castro, 1980a
Mouse, rat, Syrian

hamster liver in
vivo
binding to DNA
Castro et al.,
1989
Nath et al., 1990
Wang & Liehr,

1995
Rat hepatocytes
in vivo
SCE and chromosomal

aberrations and
micronucleus
Mouse bone
marrow in vivo
Mouse liver
in vivo
Syrian hamster
liver and kidney in
vivo
a
b
c
d
e
ICR
I-compound reduction
(32P-post-labelling)
binding to DNA
1600 mg/kg 1 p.o.
2000 mg/kg and

3000 mg/kg
1600 mg/kg 1 p.o.
S. typhimurium = Salmonella typhimurium; A. nidulans = Aspergillus nidulans; S. cerevisiae = Saccharomyces cerevisiae

SCE = sister chromatid exchange; UDS = unscheduled DNA synthesis
+ = with metabolic activation; ! = without metabolic activation; sp.n.r. = species not reported; n.r. = not reported whether metabolic
activation was used
i.n.r. = inducer not reported; i.m. = intact microsomes added; PCB = polychlorinated biphenyls; PB = phenobarbital
! = negative; + = positive; (+) = weakly positive
Table 10. Indicator tests with carbon tetrachloride

Species
Strain
Measured end-point
Test conditions
Activationa Inducationb Resultsc
Reference
Bacterial systems
Escherichia coli
WP2 (repair proficient DNA repair

WP67 (uvrA polA-)
CM871 (uvrAa, recA-,
lexA-)
variation 1: liquid
micro method
+ rat
variation 2: 24 h
preincubation and
plating out
+
PCB
!
+ rat
De Flora et al.,
1984
+
+
PCB
In vitro mammalian cells

Chinese hamster
ovary cells
SCE
0.1, 1 mM; solvent
DMSO
Chinese hamster
ovary cells
SCE
!S9: toxic at 1490

:g/ml; +S9: 2930
:g/ml highest dose
Human
lymphocyte
SCE
concentration: 3.876
:g/ml
Human
lymphocyte
UDS
concentration: 2.5,
5 :g/ml; solvent
DMSO
+d
Athanasiou &
Kyrtopoulos,
1981
+ rat
PCB
!
!
Loveday et al.,
1990
+ sp.n.r.
i.n.r.
Garry et al.,
1990
+ rat
!
!
!
!
Sina et al., 1983
tested
Rat
hepatocyte
DNA single strand

breaks
0.3, 3 mM
!
!
PB
Perocco & Prodi,

1981
Table 10 (contd).
In vivo mammalian systems
Mouse
NMRI
DNA single strand

breaks
2.5 mg/kg body

weight; single oral
dose, undiluted or in
corn oil
Schwartz et al.,
1979
Mouse
CBA*BALB/c
sperm head
abnormalities
0.1, 0.25, 0.5, 1.0,

1.5 mg/kg body
weight (i.p.) for 5
days; solvent corn oil
Topham, 1980
Mouse
CDI
DNA damage in 3H- 0.020.1 ml/kg body

labelled liver cells
weight; single oral
dose in corn oil
Gans & Korson,

1984
Rat
Wistar
UDS in liver cells
4000 mg/kg body

weight; single oral
dose, 2 and 17 h
exposure
ee
Craddock &
Henderson, 1978
Rat
Fischer-344
UDS in liver cells
10 or 100 mg/kg
body weight; single
oral dose in corn oil,
2 h exposure
Mirsalis &
Butterworth,
1980
Rat
(hepatectomized)
Wistar
DNA damage
single oral dose of

200800 mg/kg body
weight in corn oil,
3 weeks after
hepatectomy
Stewart, 1981
Rat
Fischer-344
DNA single strand

breaks
400 mg/kg body

weight; single oral
dose in corn oil
Bermudez et al.,
1982
Table 10 (contd).
Species
Strain
Measured end-point
Test conditions
Activationa Inducationb Resultsc
Reference
Rat
Fischer-344
UDS in liver cells
40 or 400 mg/kg
body weight; single
oral dose up to 48 h
of exposure
Mirsalis et al.,
1982
Rat
Sprague-Dawley
DNA damage
200 mg/kg body

weight; single i.p.
dose
Brambilla et al.,
1983
a
b
c
d
e
+ = with metabolic activation; ! = without metabolic activation; sp.n.r.= species not reported
PCB = polychlorinated biphenyls; PB = phenobarbital; i.n.r.; = inducer not reported
! = negative; + = positive; e = equivocal
chromosome aberrations occurred, but no details on this finding were reported
increase in DNA associated with tissue regeneration, but no increase in unscheduled DNA synthesis

________________________________________________________
marrow; or d) aneuploidy in mouse hepatocytes. Binding of carbon

tetrachloride to liver cell DNA has been observed in rats, mice and
Syrian hamsters treated in vivo. There has been a report of a reduction
in I-compounds (species- and tissue-specific DNA adducts) in mouse
liver.
The only clear evidence for genotoxicity comes from a number
of fungal cell experiments involving mutation and recombinational
events. Effects in mammalian cells indicate damage during
cytokinesis. This type of damage could result from interactions with
proteins, rather than DNA, e.g., of the trichloromethyl radical, and
could be induced secondarily to the toxicity of carbon tetrachloride
(McGregor & Lang, 1996). Thus, no carbon-tetrachloride-DNA
adduct identification has been made, while the polar adducts observed
in Syrian hamster liver DNA appear to be derived from lipid
peroxidation products (Wang & Liehr, 1995). Consequently, strandbreakage and aneuploidy could arise from the effects of lipid peroxidation products rather than carbon tetrachloride or its metabolites;
linoleic acid hydroperoxide, for example, can induce single-strand
breaks in DNA of cultured fibroblasts (Nakayama et al., 1986). No
resolved DNA damage has been observed in vivo. It is concluded that
although carbon tetrachloride has some effects upon genetic material
and these could be due to a direct effect of carbon tetrachloride, no
supporting evidence is available; the effects are explicable in terms of
nuclear protein or DNA damage induced secondarily to carbon
tetrachloride toxicity.
7.7
7.7.1
Carcinogenicity
Mice
After administration of 0.1 ml of a 40% solution of carbon

tetrachloride in olive oil (64 mg/mouse) by stomach tube to male C3H
mice, female C mice, and male and female A and Y mice 2 or 3 times
a week for 8 to 16 weeks (23 to 58 treatments), hepatomas developed
in 126/143 (88%), 34/41 (83%), 63/64 (98%) and 9/15 (60%) of the
C3H, C, A and Y mice, respectively. No concurrent control data were
reported. Historical control data indicated the following incidence of
hepatomas (%) at one year or more: male C3H, 27%; female C, 0%;
male and female A, 1.5%; male and female Y, 1.6% (Edwards, 1941;
Edwards & Dalton, 1942). In 34 of 73 male and female mice of the
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L strain that received 0.04 ml carbon tetrachloride per treatment by

stomach tube 2 or 3 times a week for 46 treatments and were killed 3
to 3.5 months following treatment, hepatomas were found that were
similar to those found in the other strains (Edwards et al., 1942).
Eschenbrenner & Miller (1944) administered 30 doses (each
0.005 ml) of 32%, 16%, 8%, 4% and 2% solutions of carbon
tetrachloride in olive oil (2540, 1270, 635, 318 or 160 mg/kg body
weight) at 1- to 5-day intervals to mice of the A strain. Control group
animals were administered olive oil. All animals were examined for
hepatomas 150 days after the first dose. Hepatomas were found in
33/60, 32/60, 25/60, 23/60 and 23/60 mice of the 32, 16, 8, 4 and 2%
dose groups. A variation in the numerical incidence of hepatomas at
a given time was observed to be related both to the total amount
administered and to the interval elapsing between successive doses.
The incidence of hepatomas increased with the interval between
dosing from 1 to 4 days.
Weisburger (1977) reported that, in B6C3F1 mice dosed by
gavage with carbon tetrachloride in corn oil at levels of 1250 or 2500
mg/kg body weight 5 days/week for 78 weeks and killed at 90 weeks,
hepatomas were found in 47/48 males and 43/45 females receiving the
higher dose and in 49/49 males and 40/40 females receiving the lower
dose. Control incidences of hepatomas were 3/18 in males and 1/18
in females. An increase in adrenal tumours was also reported in the
treated mice.
Groups of 50 male and 50 female BDF1 mice, 6 weeks of age,
were exposed by whole-body inhalation to 0, 5, 25 or 125 ppm (0, 32,
160 or 800 mg/m3) carbon tetrachloride (purity > 99.8%) for 6 h per
day on 5 days a week for 104 weeks. Survival of the mid- and highdose groups in both sexes (35/50, 36/50, 25/50 and 1/50 males; 26/50,
24/49, 10/50 and 1/49 females) was decreased due to liver tumours.
Significantly increased incidences of hepatocellular adenomas (9/50,
10/50, 27/50 and 16/50 males; 2/50, 8/49, 17/50 and 5/49 females)
were observed in mid- and high-dose males (p < 0.01, Chi-square test)
and in low- and mid-dose females (low dose, p < 0.05; mid-dose,
p < 0.01), hepatocellular carcinomas (17/50, 12/50, 44/50 and 47/50
males; 2/50, 1/49, 33/50 and 48/49 females) in mid- and high-dose
males and females (p < 0.01) and pheochromocytomas of the adrenal
gland (0/50, 0/50, 16/50 and 31/50 males; 0/50, 0/49,0/50 and 22/49
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females) in mid- and high-dose males (p < 0.01) and high-dose

females (p < 0.01) (Nagano et al., 1998).
7.7.2
Rats
In a study reported by Reuber & Glover (1970) male rats of the

Osborne-Mendel, Japanese, Wistar, Black and Sprague-Dawley
strains received twice a week a subcutaneous injection (1.3 ml/kg
body weight) of a 50% solution of carbon tetrachloride in corn oil
(1036 mg/kg body weight). The Japanese rats survived for 47 weeks
and Osborne-Mendel rats for 44 weeks. Wistar rats lived for 33 weeks
and Black and Sprague-Dawley rats lived only for 11 and 33 weeks,
respectively. Hepatocellular carcinomas developed in 8/13 OsborneMendel rats and in 12/15 Japanese rats, and hyperplastic nodules were
also found in these strains. The hepatocellular carcinomas found in
4/12 Wistar rats were smaller. Nodules and hyperplasia were also
observed in Wistar rats, as well as moderate to severe cirrhosis. The
Black rats and Sprague-Dawley rats died with severe cirrhosis before
they developed carcinomas. No hepatocellular carcinomas developed
in the controls of any strain.
Weisburger (1977) reported increases in the incidence of neoplastic nodules and hepatocellular carcinomas after oral
administration of carbon tetrachloride in corn oil to Osborne-Mendel
rats at doses of 47 and 94 mg/kg body weight (males) and 80 and 160
mg/kg body weight (females) for 78 weeks. The rats were killed at
110 weeks. The incidences of hepatocellular carcinomas in the
controls were 0/20 in males and 1/20 in females, and the incidences
of liver neoplastic nodules were 0/20 in males and 1/20 in females.
Groups of 50 male and 50 female F-344 rats, 6 weeks of age,
were exposed by whole-body inhalation to 0, 5, 25 or 125 ppm (0, 32,
160, 800 mg/m3) carbon tetrachloride (purity > 99.8%) for 6 h per day
on 5 days a week for 104 weeks. Survival of the high-dose groups in
both sexes (22/50, 29/50, 19/50 and 3/50 males; 39/50, 43/50, 39/50
and 1/50 females) was decreased due to liver tumours and chronic
nephropathy (progressive glomerulonephrosis). There were significantly increased incidences of hepatocellular adenomas (0/50, 1/50,
1/50 and 21/50 males; 0/50, 0/50, 0/50 and 40/50 females) and
hepatocellular carcinomas (1/50, 0/50, 0/50 and 32/50 males; 0/50,
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0/50, 3/50 and 15/50 females) in high-dose rats of each sex (p < 0.01,
Chi-square test) (Nagano et al., 1998).
7.8
7.8.1
Special studies
Immunotoxicity
Carbon tetrachloride treatment of B6C3F1 female mice resulted

in marked suppression of both humoral and cell-mediated immune
functions. Humoral immunity, as measured by the T-dependent
antibody response to sheep red blood cells (SRBC), proved to be the
most sensitive indicator of carbon-tetrachloride-induced immunotoxicity. Carbon tetrachloride was immunotoxic in female B6C3F1
mice at all doses tested (5005000 mg/kg body weight) and there were
no significant differences in the magnitude of immunosuppression
between oral and intraperitoneal routes of exposure. There was no
doseresponse relationship with respect to SRBC antibody responses;
all dose levels resulted in approximately 50% suppression of the
control response. To determine whether a doseresponse relationship
could be attained, female mice were treated at lower carbon
tetrachloride levels (25, 50 and 100 mg/kg body weight) for 30
consecutive days. It appeared that doses as low as 50 mg/kg body
weight produced the maximum attainable inhibition of SRBC
response (50%); 25 mg/kg body weight caused a 20% reduction
(Kaminsky et al., 1989; 1990).
Delaney & Kaminski (1994) studied the immunomodulatory
activity of serum isolated from carbon tetrachloride-treated B6C3F1
mice on T-cell-independent humoral immune responses. The results
of the study suggested that carbon tetrachloride has bifurcating
immunological effects. Exposure to carbon tetrachloride appears to
suppress T-cell-dependent immune responses but enhance the activity
of B-cells. Both effects appear to be mediated by blood-borne factors.
Incubation of sera from carbon-tetrachloride-treated mice with
neutralizing monoclonal antibodies toward transforming growth
factor $1 reversed the immunosuppression, indicating that TGF $1
at least in part mediates the immunosuppression induced by carbon
tetrachloride.
In contrast to the results found in mice by Kaminsky et al. (1989,
1990), Smialowicz et al. (1991) found no consistent alterations in
humoral or cell-mediated immune function in male Fischer-344 rats
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at dosages that clearly resulted in body weight decreases and hepatotoxicity. However, the dose levels used in this study (up to 40 mg/kg
body weight) were much lower than those reported by Kaminsky et al.
(1989, 1990).
Mice (A/PhJ) were administered carbon tetrachloride (about 300
mg/kg per day intraperitoneally in olive oil) for 2, 7, 14 and 23 days.
A variety of immunological parameters were evaluated.
Morphological examination by light microscopy revealed significant
activation of lymphoid tissues in T-cell-dependent areas and only
slight activation in B-cell-dependent areas (Jirova et al., 1996).
Thymus weights (after exposure for 2, 14 and 23 days) and spleen
weights (after exposure for 2 and 23 days) decreased significantly
when weights at 23 days were compared to those of controls. The
response of SRBC was permanently suppressed from the beginning of
exposure.
7.8.2
Influence of oxygen levels
It is known that under normal atmospheric conditions carbon

tetrachloride initiates lipid peroxidation in mice and rat liver microsomes and in mice and rats in vivo (Sagai & Tappel, 1979; Kornbrust
& Mavis, 1980; Gee et al., 1981; Lee et al., 1982). At reduced oxygen
concentrations the carbon-tetrachloride-induced lipid peroxidation is
greatly enhanced in in vivo experiments and in microsomal
preparations, but in these in vitro systems, the process is entirely
blocked under anoxic conditions (Kieczka & Kappus, 1980; Noll &
De Groot, 1984).
Covalent binding to RNA and DNA was enhanced in the absence
of oxygen when male rat (Sprague-Dawley) hepatocytes were treated
with carbon tetrachloride (Cunningham et al., 1981). DiRenzo et al.
(1984) observed that the enhanced covalent binding to protein or
lipid, caused by carbon tetrachloride in cultured male rat (SpragueDawley) hepatocytes, at decreased oxygen tension was most evident
for the binding to lipids.
Shen et al. (1982) studied the effect of oxygen concentrations on
carbon-tetrachloride-induced hepatotoxicity in male Long-Evans rats
exposed to differing oxygen concentrations combined with different
carbon tetrachloride concentrations. In this in vivo experiment, carbon
tetrachloride appeared to be more toxic when oxygen concentrations
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were reduced, as shown by increased ALAT activity, more severe

centrilobular necrosis, and increased covalent binding to hepatic
microsomal lipids and proteins.
An increased metabolism of carbon tetrachloride under hypoxic
conditions, and consequently an aggravated hepatotoxicity, was
reported in male Wistar rats by Siegers et al. (1985). In agreement
with the reports of Kieczka & Kappus (1980) and Noll & De Groot
(1984), a more pronounced lipid peroxidation was observed, as shown
by exhaled ethane, than in animals kept under normal oxygen
conditions and treated with the same dose of carbon tetrachloride.
Male Sprague-Dawley rats were used in a study by Burk et al.
(1988) to examine the effect of hyperbaric oxygen on carbon
tetrachloride metabolism by different isoenzymes of cytochrome P450. The authors concluded that under low oxygen tensions the rate
of carbon tetrachloride metabolism depended largely on the amount
of cytochrome P-450 present, while under higher oxygen tensions the
major determinant was the type of cytochrome P-450.
7.9
7.9.1
Factors modifying toxicity

Dosing vehicles
Several studies have demonstrated that carbon-tetrachlorideinduced hepatotoxicity, like absorption (see section 6.1.1.1), can be
influenced by the dosing vehicle.
In order to evaluate the effect of vehicle on the hepatotoxicity in
mice, Condie et al. (1986) treated male and female CD-1 mice with
oral doses of carbon tetrachloride (0, 1.2, 12 or 120 mg/kg body
weight) in either corn oil or 1% Tween-60 vehicle, 5 times/week for
90 days. Differences between the vehicles were observed in mice at
the 12 mg/kg dose level. Hepatomegaly and more fat accumulation
were observed when carbon tetrachloride was administered in corn
oil. At the highest dose level the usage of corn oil as vehicle caused
a greater hepatotoxic effect, as shown by necrosis and fatty infiltration
in the mice. The data indicated that the NOAEL for hepatotoxic
effects after carbon tetrachloride exposure in corn oil was 1.2 mg/kg
body weight, while the NOAEL for the Tween-60 groups was 12
mg/kg body weight.
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When pregnant F-344 rats were dosed by gavage with carbon

tetrachloride in corn oil or an aqueous vehicle containing 10%
Emulphor during gestation, corn oil was associated with a full litter
resorption (FLR) rate of 67%, compared to 8% in those dosed with
Emulphor (Narotsky et al., 1997a). Further details regarding this
study are described in section 7.5.2.1.
Koporec et al. (1995) determined the vehicle effects on the
subchronic toxicity of carbon tetrachloride in male Sprague-Dawley
rats. Carbon tetrachloride was administered at dose levels of 0, 25 or
100 mg/kg body weight by gavage in either corn oil or a 1%
Emulphor aqueous emulsion 5 days/week for 13 weeks. It was
concluded that there was no difference in the subchronic
hepatotoxicity of carbon tetrachloride in rats when given in corn oil
or as an aqueous emulsion. This result contrasts with the result found
in mice described by Condie et al. (1986), and with the result of the
study in male Sprague-Dawley rats by Kim et al. (1990b), who
reported that the hepatotoxicity in male Sprague-Dawley rats was less
pronounced at each dose level when corn oil was used as a vehicle.
Administration of undiluted carbon tetrachloride or of an aqueous
emulsion produced comparable toxicity.
Szende et al. (1994) dosed male F-344 rats with carbon tetrachloride (0.2 ml/kg body weight) dissolved in various oils (sunflower,
corn, fish or olive oil) by gastric intubation 3 times/week for 8 weeks.
The increase of collagen fibres in the liver was only 24% when olive
oil was used as a vehicle, instead of the 68% increase when the other
oils were used.
7.9.2
Diet
In male NMRI mice, fasted for 24 h before receiving an

intraperitoneal injection (0.1 ml/kg body weight) of carbon
tetrachloride (159.4 mg/kg body weight) in olive oil, higher hepatic
carbon tetrachloride and chloroform levels were found (Pentz &
Strubelt, 1983).
Fed male Sprague-Dawley rats appeared to be more resistant to
the toxic action of carbon tetrachloride than rats starved overnight.
Contrary to findings in mice, the carbon tetrachloride concentrations
were similar in the livers of fed and fasted rats (Daz Gmez et al.,
1975b).
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Male Wistar rats were fed various test diets in order to assess the
nutritional effects on the liver mixed-function oxidases (MFO) and
consequently on the carbon tetrachloride metabolism. The MFO
activity increased almost linearly with decreasing food intake.
Furthermore it was shown that a diet deficient in carbohydrate
enhanced the metabolism and thus the toxic action of carbon
tetrachloride, irrespective of the protein or fat content of the diet
(Nakajima et al., 1982; Sato & Nakajima, 1985).
Cervinkov et al. (1987) investigated the effect of long-term
intake of high or low protein diet on liver repair processes after the
administration of carbon tetrachloride. Rats were fed for 21 days on
a low-protein diet (LPD), a standard diet (SD) and a high-protein diet
(HPD) and were then given a single intraperitoneal injection (0.75
ml/kg body weight) of carbon tetrachloride (calculated to be 1196
mg/kg body weight). The HPD was found to increase sensitivity to
carbon tetrachloride, but it also promoted liver repair processes. The
LPD raised liver resistance to carbon tetrachloride, but the
development of liver repair activity differed from the process after the
SD and HPD, since polyploidy of the hepatocytes predominated and
there was also an increase in the number of binuclear hepatocytes.
Cell hypertrophy was expressed less in rats fed on the LPD. As far as
liver repair was concerned, the HPD showed no explicit advantage
over the SD.
7.9.3
Alcohol
Several studies have demonstrated that ethanol, methanol and

other alcohols potentiate the hepatic toxicity of carbon tetrachloride
(Traiger & Plaa, 1971; Cantilena et al., 1979; Harris & Anders, 1980;
Ray & Mehendale, 1990; Simko et al., 1992). Dietary ethanol (2 g/80
ml liquid diet for 3 weeks) potentiated carbon tetrachloride
(inhalation exposure to 10 ppm (64.1 mg/m3) for 8 h) hepatotoxicity,
measured by serum aminotransferases and liver malonaldehyde
concentrations, in male Wistar rats. Potentiation did not occur upon
exposure to 5 ppm (32 mg/m3) for 8 h (Ikatsu et al., 1991; Ikatsu &
Nakajima, 1992). Only a minor potentiating effect on weight gain, but
no effect on carbon-tetrachloride-induced hepatotoxicity was
observed, when rats were simultaneously treated with ethanol (# 0.5
ml/kg) and carbon tetrachloride (20 mg/kg) by gavage for 14 days
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(Berman et al., 1992). Micronodular cirrhosis was observed in all

treated rats after 10 weeks of inhalation exposure to carbon
tetrachloride (513 mg/m3, 6 h/day, 5 days/week) when the animals
were simultaneously given ethanol as a part of a liquid diet, while no
animal treated with either ethanol or carbon tetrachloride alone
developed cirrhosis (Hall et al., 1991). Similar cirrhosis was also
observed in Porton rats treated with carbon tetrachloride and ethanol
(Hall et al., 1994). Inhalation exposure to methanol (10 000 ppm for
6 h) increased the liver toxicity of carbon tetrachloride (a single dose
of 0.075 ml/kg after 24 h) (Simmons et al., 1995). Similar exposure
to methanol also increased the toxicity of inhaled carbon tetrachloride
(100, 250 to 1000 ppm (641, 1602 to 6410 mg/m3) for 6 h at 2627
h after the beginning of the methanol exposure). This potentiation
subsided when the interval between methanol and carbon tetrachloride
exposures was increased by 24 h (Evans & Simmons, 1996).
Malonaldehyde generation induced by carbon tetrachloride in vitro
was enhanced by prior exposure of the rats to methanol (10 000 ppm
for 6 h); this enhancement coincided with an increased microsomal
activity of para-nitrophenol hydroxylase, used as a marker of
cytochrome P-450 2E1; inhibition of CYP 2E1 by allyl sulfone
abolished the carbon-tetrachloride-induced lipid peroxidation (Allis
et al., 1996).
Sato & Nakajima (1985) reported that the metabolism of carbon
tetrachloride in the rat was enhanced by pretreatment with ethanol. It
was found that the increase in carbon tetrachloride hepatotoxicity was
related to the degree of the enhancement. Similar observations were
made by Sato et al. (1980), Teschke et al. (1984), Strubelt (1984) and
Reinke et al. (1988).
In a study by Wang et al. (1997), before exposure to carbon
tetrachloride, rats were kept either on an ethanol-containing (2 g/80
ml per rat per day) liquid diet for 3 weeks, to obtain a maximal
induction of the alcohol-inducible CYP 2E1 isoenzyme, or on a liquid
diet with no alcohol. Both groups were exposed to carbon
tetrachloride by inhalation (0, 320 or 3205 mg/m3 for 6 h), or by oral
or intraperitoneal administration (0, 0.105 or 1.675 mmol/kg).
Ethanol-pretreatment increased significantly the metabolism of carbon
tetrachloride as indicated by the carbon tetrachloride concentrations
in blood samples. Plasma ALAT and ASAT levels, assayed 24 h after
carbon tetrachloride treatment, were highly significantly increased in
a
l
l
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carbon tetrachloride-dosed rats pretreated with ethanol, whereas in

control diet groups only a slight elevation of transaminases was
observed after the high-dose carbon tetrachloride treatment.
Shibayama (1988) compared the hepatotoxicity of carbon
tetrachloride (intraperitoneal administration in olive oil) in male
Wistar rats fed a standard diet and 5 or 20% ethanol solution with the
hepatotoxicity of carbon tetrachloride in control rats, which received
water instead of ethanol for a period of 1 to 100 weeks. The results
indicated that the effect of ethanol on the hepatotoxicity is dependent
on the daily amount of alcohol intake and is not affected by the
duration of the alcohol consumption. Kniepert et al. (1990), however,
reported that an increased duration (30 or 52 weeks instead of 1 or 10)
of ethanol pretreatments (10% in drinking water) caused a decrease
in ethanol potentiation of carbon-tetrachloride-induced toxicity in
male Wistar rats.
Ray & Mehendale (1990) studied the effect caused by a single
dose of carbon tetrachloride after pretreatment with various homologous alcohols in male Sprague-Dawley rats. A combination of the
alcohols methanol, ethanol, isopropanol and decanol with carbon
tetrachloride potentiated liver injury but did not affect lethality. A
combination of t-butanol, pentanol, hexanol and octanol potentiated
liver injury and decreased animal survival significantly. Eicosanol
potentiated neither liver injury nor lethality.
Hall et al. (1994) observed that chronic administration of alcohol
and low-dose carbon tetrachloride vapour caused cirrhosis in all
male Porton rats receiving this treatment for 57 weeks. A possible
mechanism for the interaction between alcohol and carbon tetrachloride is the alcohol-dependent induction of cytochrome P-450 2E1,
resulting in enhanced production of toxic metabolites of carbon
tetrachloride. These in turn are responsible for the initiation of lipid
peroxidation and impaired conjugation of carbon tetrachloride
metabolites with glutathione.
To determine the doseresponse relationships in the production
of hepatic fibrosis and cirrhosis, the livers of male Porton rats (4
animals/group) were examined after combined exposure to carbon
tetrachloride and alcohol (Plummer et al., 1994). Carbon tetrachloride
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was administered by inhalation 6 h/night for 5 nights/week at concentrations of 10, 20 or 40 ppm (actual values of 60, 120.1 or 240.1
mg/m3, respectively). Ethanol was administered orally at levels of 75,
150, or 300 kcal/litre liquid diet, leading to mean daily intakes of
2.29, 4.61 and 8.16 g ethanol/kg body weight, respectively. It was
proposed to continue administration of alcohol and carbon
tetrachloride until animals became cirrhotic, as diagnosed by liver
biopsy, or for a maximum of 20 weeks. However, the alcohol
consumption declined gradually, approximately to half that at the
beginning. Results of the study show that both alcohol and carbon
tetrachloride contribute to the liver injury in a dose-related manner.
All four rats that received the high dose of both carbon tetrachloride
and alcohol, and one of four rats that received the medium alcohol
and high-dose carbon tetrachloride treatments, showed liver cirrhosis
after 10 weeks of exposure. Two of four rats that received the low
alcohol in combination with the high-dose of carbon tetrachloride
showed cirrhosis after 20 weeks. Although cirrhosis was observed
only at the highest carbon tetrachloride dose, some degree of hepatic
fibrosis was observed in all treated rats in a dose-related manner.
Daniluk et al. (1994) reported that acute liver injury due to
intraperitoneal carbon tetrachloride administration combined with a
long-term alcohol consumption may act synergistically in depressing
interferon production in C3H/He mice.
Strain differences in response to carbon tetrachloride have been
described for both mice (see section 7.1.2.3) and rats (see section 7.3).
7.9.4
Enhancement of carbon tetrachloride-induced hepatotoxicity by

various compounds
According to Klingensmith et al. (1983) the LD50 of carbon

tetrachloride after oral administration dropped by a factor of 14 after
pretreatment with chlordecone. The potentiation of carbon tetrachloride toxicity by chlordecone appears to be related to a chlordeconedependent increase in the biotransformation rate of carbon
tetrachloride and a chlordecone-dependent reduction of the liverregenerating capacity (Mehendale, 1984).
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Mehendale (1989) described a mechanism for the potentiation of

carbon tetrachloride hepatotoxicity by chlordecone. The mechanism
underlying the highly unusual amplification of carbon tetrachloride
toxicity relates to the suppression of the initial hepatocellular
regeneration, ordinarily stimulated by low doses of carbon
tetrachloride.
Pretreatment with phenobarbital enhanced the metabolism of
carbon tetrachloride in rats, and consequently the toxicity (Bechtold
et al., 1982; Fander et al., 1982; Sato & Nakajima, 1985), whereas
pretreatment with PCBs or 3-methylcholanthrene for a few days
hardly influenced the carbon tetrachloride metabolism and carbon
tetrachloride toxicity (Sato & Nakajima, 1985). Prolonged
pretreatment with hexachlorobenzene, PBBs or PCBs, however, made
male rats considerably more susceptible to the toxic effects of carbon
tetrachloride (Kluwe et al., 1982).
The reaction of the liver to carbon tetrachloride was studied in
the adaptive stage of organic solvent poisoning. Rats were pretreated
daily with benzene, toluene, xylene, phenobarbital or oil for 4 days.
On day 4, carbon tetrachloride was given orally and 24 h later the rats
were killed. Histological, histochemical and electron microscopic
examination revealed a potentiating interaction between the solvents
and carbon tetrachloride, similar to the potentiation of carbon
tetrachloride toxicity by simultaneous phenobarbital administration.
Centrilobular necrosis caused by carbon tetrachloride became
confluent and turned submassive in the livers of pretreated animals,
and it appeared that in the rats treated with solvent and carbon
tetrachloride, the amount of damaged area was twice that induced by
carbon tetrachloride alone (Ttrai et al., 1979).
Qazi & Alam (1988) reported that phenobarbitone treatment in
drinking-water together with carbon tetrachloride (by intraperitoneal
injection) induced severe liver cirrhosis with marked proliferation
of the bile ducts in female rats. Females receiving only carbon
tetrachloride showed moderate cirrhosis whereas the females
receiving only phenobarbitone remained healthy, showing only an
increased liver weight.
ElSisi et al. (1993a,b) studied the effect of retinol (vitamin A) on
carbon-tetrachloride-induced hepatoxicity in a timeresponse and a
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doseresponse study. In the timeresponse study, male SpragueDawley rats were given 75 mg/kg body weight retinol for 1 or 3 days,
or 1,2,3 or 5 weeks. In the doseresponse study, retinol was given at
daily doses of 30 to 75 mg/kg body weight for 3 weeks. At 24 h after
the last dose of retinol, 0.15 ml carbon tetrachloride/kg body weight
(239 mg/kg body weight) in corn oil was given by intraperitoneal
injection and another 24 h later the animals were killed. All treatment
durations with retinol, except 1 day, resulted in equivalent
potentiation of carbon tetrachloride hepatotoxicity. All rats pretreated
with retinol and subsequent administration of carbon tetrachloride had
more extensive liver injury than those given carbon tetrachloride
alone. As the daily dose of retinol increased, so did the degree of
potentiation of carbon tetrachloride hepatotoxicity.
Pretreatment with ketonic or ketogenic compounds (e.g., hexane,
acetone, isopropanol) potentiated the liver injury in Sprague-Dawley
rats produced by an intraperitoneal carbon tetrachloride injection
(Charbonneau et al., 1985).
The hepatotoxicity of the liver to carbon tetrachloride is considerably enhanced in alloxan-diabetic rats. This potentiation effect can be
reversed by an additional insulin treatment before the carbon
tetrachloride administration (Villarruel et al., 1982).
Intraperitoneal treatment of male Sprague-Dawley rats with
pyrazole increased the sensitivity of these rats to carbon tetrachloride
hepatotoxicity as assessed by significant loss of cytochrome P-450 and
increases in ASAT and ALAT levels. As stated by the author (Ebel,
1989), these observations are consistent with the hypothesis that only
certain forms of P-450 (and in this case the alcohol-inducible form)
are capable of activation of hepatotoxins and potentiate the toxicity.
Imidazole and pyrazole, inducers of CYP 2E1, caused 3- to 25fold enhanced rates of carbon-tetrachloride-induced lipid
perioxidation (and chloroform production from carbon tetrachloride);
the increase was directly related to the amount of this cytochrome in
the microsomes (Johansson & Ingelman-Sundberg, 1985).
Acetone, methyl ethylketone and methyl isobutylketone (6.8
mmol/kg body weight for 3 days) increased the hepatotoxicity of
carbon tetrachloride (Raymond & Plaa, 1995a); this enhanced toxicity
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was coincident with an increased microsomal aniline hydroxylase

activity (Raymond & Plaa, 1995b). In addition to the effect on
cytochrome P-450, acetone, but not the other ketones, increased basal
canalicular membrane fluidity, as measured by fluorescence
polarization of 1,6-diphenyl-1,3,5-hexatriene or 1,4-(trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene (Raymond & Plaa, 1996).
Treatment of male athymic nude rats, male and female SpragueDawley rats, and male Fischer-344 rats with retinol (75 mg/kg/day for
7 days) greatly enhanced the hepatotoxicity of carbon tetrachloride in
F-344 rats (0.2 or 0.1 mg/kg i.p.), while it protected Balb/C, C3H/HeJ,
athymic nude and Swiss-Webster mice against carbon tetrachloride
hepatotoxicity (0.0125 to 0.02 ml/kg, respectively) (Hooser et al.,
1994). In male Sprague-Dawley rats retinol ($ 100 000 IU/kg per day
for 3 weeks or 250 000 IU/kg per day for $ 1 week) greatly increased
the hepatotoxicity of carbon tetrachloride (0.15 ml/kg intraperitoneally) (ElSisi et al., 1993a). There was a simultaneous six- to
eight-fold increase in the amount of exhaled ethane and a less than
two-fold increase in covalent binding to liver proteins in rats treated
with retinol (250 000 IU or 75 mg/kg per day for 1 week) and carbon
tetrachloride (0.15 ml/kg), in comparison with rats treated with
carbon tetrachloride alone. However, there was no increase in the
exhaled 14CO2, exhaled organics or metabolites excreted in the urine,
or covalent binding to hepatic lipids from 14C-carbon tetrachloride.
Aminobenzotriazole (50 mg/kg intraperitoneally, 2 h before carbon
tetrachloride), an inhibitor of cytochrome P-450, blocked the retinolinduced potentiation of the hepatotoxicity of carbon tetrachloride
(ElSisi et al., 1993b). A single dose of retinol ($ 75 mg/kg orally) 24
h before carbon tetrachloride also very significantly potentiated
carbon tetrachloride hepatotoxicity (Badger et al., 1996). While the
total cytochrome P-450 content of the liver was not affected by the
retinol treatment, the concentration (Western blot analysis) and
activity (aniline hydroxylase) of CYP 2E1 were both elevated. Isolated
hepatocytes from retinol-treated rats also exhibited enhanced
susceptibility to carbon tetrachloride (Badger et al., 1996).
Concomitant administration of a single, non-hepatotoxic dose of
6 mmol dichloromethane (DCM)/kg and 308 mg carbon tetrachloride
intraperitoneally potentiated carbon tetrachloride-induced hepatotoxicity, as measured by SDH and ALAT. When a radiolabelled tracer
dose of carbon tetrachloride was included in the treatment, DCM was
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found to significantly increase the covalent binding of [14C]-carbon

tetrachloride metabolites to microsomal lipids. However, DCM did
not affect lipid peroxidation induced by carbon tetrachloride (Kim,
1997).
Potentiation of carbon tetrachloride hepatotoxicity was studied
after inhalation exposure at concentrations of 0, 5 or 10 ppm (0, 160
or 320 mg/m3) for 8 h and simultaneous exposure to chloroform (0, 25
or 50 ppm for 8 h). While carbon tetrachloride exposure had no effect
on plasma ALAT or ASAT levels, co-exposure to chloroform resulted
in a slight increase of the transaminase activity in blood (Ikatsu &
Nakajima, 1992).
7.9.5
Reduction of carbon tetrachloride-induced hepatotoxicity by

various compounds
Vitamin E reduces the carbon-tetrachloride-induced lipid peroxidation in rat liver and kidney slices (Gavino et al., 1984), but in an
in vivo experiment in rats only limited protection by vitamin E against
this process was seen (Gee et al., 1981). A protective action of
vitamin E against liver cell membrane damage in Wistar rats was
reported in several studies (Ozeki et al., 1982; Martnez-Calva et al.,
1984). This protective action could be reinforced by co-administration
of vitamin E and riboflavin tetrabutyrate (Miyazawa et al., 1984).
When male Wistar rats were given vitamin E 15 h before carbon
tetrachloride administration, a partial or complete protection against
the necrogenic effect of carbon tetrachloride was induced, depending
on the concentration of carbon tetrachloride used. Furthermore, the
vitamin supplementation prevented the carbon-tetrachloride-induced
increase in total hepatic calcium content (Biasi et al., 1991).
Protection, apparent as a decrease in mortality, less pronounced
histological damage and lower serum aminotransferase levels was
afforded by intravenous administration of "-tocopherol as a suspension or in liposomes, which are accumulated in Kupffer cells (Yao et
al., 1994; Liu et al., 1995). Where incorporated into liposomes, other
antioxidants, such as butylated hydroxytoluene and ascorbic acid
palmitate, also protected mice against carbon tetrachloride toxicity
(Yao et al., 1994).
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Preventive effects on hepatotoxicity in rats were also reported for

vitamin D3 and vitamin C by Fander et al. (1982) and Ademuyiwa et
al. (1994), respectively.
In contrast to the results of ElSisi et al. (1993a,b), who reported
a potentiation in hepatotoxicity when retinol was given to rats prior
to carbon tetrachloride administration, Rosengren et al. (1995)
observed a protective effect on the liver when retinol was given to
mice prior to carbon tetrachloride administration.
Studies reported by Bishayee & Chatterjee (1993) and Mandal et
al. (1993) indicated a possible hepatoprotective role of carrot (Daucus
carota) aqueous extract and Mikania cordata root extract in male
Swiss mice. The increased lipid peroxidation and decreased glutathione levels, resulting from carbon tetrachloride treatment, were
significantly reversed in a dose-related way after pretreatment of the
mice with the carrot extract. According to authors this protective role
of carrot extract could be attributed to its antioxidant properties.
Pretreatment of rats with SKF-525 A (inhibitor of drugmetabolizing enzymes), cysteine (in particular in combination with
tryptophan) or reduced glutathione decreased the carbontetrachloride-induced hepatotoxicity (Bechtold et al., 1982; de
Ferreyra et al., 1983; Gorla et al., 1983).
Administration of 6,6'-methylene-bis(2,2,4-trimethyl-1,2dihydroquinoline), tert-butyl-4-hydroxyanisole, oltipraz or anethol
dithiolthione protects mice against the acute toxic effects of carbon
tetrachloride (Fehr et al., 1982; Toncsev et al., 1982; Ansher et al.,
1983; Benson, 1993). A preventive effect was also observed when
diethyldithiocarbamate and carbon disulfide were administered to
mice. Diethyldithiocarbamate was most effective when given orally,
while the action of carbon disulfide was less dependent on the route
of administration (Masuda & Nakayama, 1982).
Rao & Mehendale (1989) reported that administration of fructose
1,6-diphosphate decreased the toxicity of carbon tetrachloride in rats
(as shown by a 5070% decrease in the activity of serum
transaminases). This decrease was accompanied by elevated activities
of enzymes involved in the polyamine metabolism (important for
hepatocellular regeneration and recovery).
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It appears that nicotinamide administered to male SpragueDawley rats at late stages of carbon tetrachloride poisoning (e.g., 6 or
10 h after the hepatotoxin) significantly prevents the liver necrogenic
effects of carbon tetrachloride at 24 h. A study by de Ferreyra et al.
(1994) did not reveal any relevant effect when nicotinamide was given
30 min before the hepatotoxin.
Simultaneous treatment of carbon-tetrachloride-intoxicated rats
with zinc (227 mg/litre in drinking-water) resulted in improved serum
and liver enzyme levels and attenuated histological abnormalities as
well as NADPH-dependent lipid peroxidation (Dhawan & Goel,
1994).
Studies of Kaminski et al. (1989, 1990) demonstrated that carbon
tetrachloride administration in mice results in a marked suppression
of humoral and cell-mediated immune functions. Ahn & Kim (1993)
observed that PMC (diphenyl dimethyl dicarboxylate) had a significant preventive effect on carbon-tetrachloride-induced immunotoxic
status in ICR mice that were immunized and challenged with sheep
red blood cells (SRBC) and were subsequently given PMC (3 or 6
mg/kg body weight; oral administration) once a day for 28 days in
combination with carbon tetrachloride (1 ml/kg body weight, 25%,
oral administration) twice a week, 2 h after PMC administration.
Gadolinium chloride (10 mg/kg), given intravenously 24 h prior
to an intragastric dose of carbon tetrachloride (4 g/kg), nearly
completely protected rats from hepatic necrosis, as measured by serum
ASAT levels and trypan blue exclusion, without an effect on CYP 2E1
(Edwards et al., 1993). This was interpreted to indicate a role of
Kupffer cells in carbon-tetrachloride-induced hepatic damage, since
gadolinium chloride at this concentration strongly inhibits Kupffer
cell phagocytosis (Hustzik et al., 1980). Similar dosage of gadolinium
chloride was, however, also reported to decrease the total amount of
hepatic cytochrome P-450 in rats, as well as the activity of aniline
para-hydroxylase (Badger et al., 1997). In support of the role of
Kupffer cells in carbon-tetrachloride-induced hepatic damage, it was
reported that gadolinium chloride (10 mg/kg given intravenously 24 h
before carbon tetrachloride administration) prevented and methyl
palmitate, another Kupffer cell inhibitor, attenuated the periportal
oedema observed using proton magnetic imaging 12 h after carbon
tetrachloride administration (0.8 ml/kg given intraperitoneally)
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(Towner et al., 1994). In vivo pin trapping using "-phenyl-N-tertbutylnitrone and a subsequent electron paramagnetic resonance study
of the liver indicated that gadolinium chloride did not affect the
generation of trichloromethyl radicals from carbon tetrachloride
(Towner et al., 1994). Gadolinium chloride (10 mg/kg given intravenously), methyl palmitate, polyethylene-glycol-coupled superoxide
dismutase and polyethylene-glycol-coupled catalase protected
Sprague-Dawley rats against retinol-induced potentiation of carbon
tetrachloride hepatotoxicity, both after a single dose and daily dosing
for seven days of retinol (ElSisi et al., 1993a; Sauer & Sipes, 1995;
Badger et al., 1996). Dietary "-tocopherol (250 mg/kg diet) partly
protected male Wistar rats against carbon-tetrachloride-induced (0.15
ml 3 times a week for 5 weeks) hepatic damage (Parola et al., 1992).
In an acute experiment, "-tocopheryl hemisuccinate (0.19 mmol,
100 mg/kg by gavage) afforded a partial protection against the
hepatotoxicity of carbon tetrachloride (1.0 g/kg) administered 18 h
later (Tirmenstein et al., 1997).
7.10 Mode of action

Recknagel & Glende (1973) suggested that carbon tetrachloride
toxicity requires cleavage of the carbon-chlorine bond and that the
cleavage takes place after binding of carbon tetrachloride to
cytochrome P-450 apoprotein in the mixed-function oxidase system
located in the hepatocellular endoplasmatic reticulum. However,
cytochrome P-450 is encased in lipid, and peroxidative decomposition
of the lipid is initiated by the free radicals formed by the cleavage.
Owing to the decomposition of the lipid and the attack on protein
functional groups by lipid peroxides, the structure and function of the
endoplasmatic reticulum is destroyed.
The carbon-tetrachloride-induced destruction of microsomal
cytochrome P-450 in vitro (De Groot & Haas, 1980, 1981) and in vivo
(Pasquali-Ronchetti et al., 1980; Shen et al., 1982) inhibits the further
biotransformation of carbon tetrachloride, the generation of radicals
and the concomitant peroxidation of endoplasmic reticular lipids.
Burk et al. (1983) proposed a theory in which the toxic action of
carbon tetrachloride in vivo is dependent on either trichloromethyl or
trichloromethylperoxide radical formation, which is controlled by the
oxygen status of the liver cell (peripheral or centrilobular), leading to
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damage to tissue macromolecules. This theory has been supported by

mechanistical arguments as summed up by Slater (1982) and
Dianzani (1984), who proposed the trichloromethyl radical as the
main covalently binding agent (haloalkylation) and the
trichloromethylperoxide radical as the main lipid-peroxidationinducing agent.
Oral dosage of carbon tetrachloride (2.5 ml/kg) decreased the
ATP-dependent calcium uptake of liver microsomes within 30 min in
Sprague-Dawley rats (Moore et al., 1976). The cytosolic concentration
of Ca2+ increased 100-fold in hepatocytes exposed to carbon
tetrachloride (about 1 mmol/litre), and this was paralleled by an
inhibition of the endoplasmic reticulum Ca-Mg ATPase (Long &
Moore, 1986). The inhibition of the ATPase by carbon tetrachloride
exposure has been confirmed in several studies (Srivastava et al.,
1990), and has led to the hypothesis that this is the specific
mechanism by which radical intermediates from carbon tetrachloride
lead to cell death. Calcium chelating agents, Calcion and alizarin
sodium sulfonate, administered 6 or 10 h after a necrogenic
intraperitoneal dose of carbon tetrachloride (1 ml/kg), markedly
decreased the necrotizing effect of carbon tetrachloride on the liver,
and decreased the hepatic calcium concentration but did not affect
carbon-tetrachloride-induced lipid peroxidation in vitro, or lipid
accumulation in the liver (de Ferreyra et al., 1989, 1992). Carbon
tetrachloride (0.010.12 mmol/litre) induced a complete release of
calcium from calcium-loaded microsomes in the presence of NADPH;
this release was blocked by adding the spin trapping agent, phenyltert-butylnitrone (PBN) after a lag period that was dependent on the
concentration of carbon tetrachloride. The lag period was shortened
using microsomes from pyrazole-treated rats, which showed an
elevated activity for para-nitrophenol oxidation, and lengthened in the
presence of the CYP-450 2E1 inhibitor, methylpyrazole, or an antiCYP-450 2E1 antibody. Calcium release was practically complete at
concentrations of carbon tetrachloride that had no effect on the Ca-Mg
ATPase activity. Ruthenium red, a specific ryanodine receptor
inhibitor, completely blocked the carbon-tetrachloride-induced
calcium release at a concentration (0.02 mmol/litre) that had no effect
on para-nitrophenol hydroxylation or formation of PBN-carbon
tetrachloride adducts (Stoyanovsky & Cederbaum, 1996). These
results support the notions that the hepatotoxicity of carbon
tetrachloride requires metabolism to the CCCl3 radical and is mediated
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by calcium release from intracellular stores, most likely from the

ryanodine-sensitive calcium store.
Brattin et al. (1984) stated that the disturbance of the
intracellular Ca2+ balance cannot be regarded as an intracellular toxic
messenger. Recknagel (1983), however, suggested that an early
disturbance in hepatocellular Ca2+ homoeostasis may be involved in
the pathological changes elicited by carbon tetrachloride (Recknagel,
1983). In addition, other authors suggest that the depression of the
Ca2+-sequestration capacity of the endoplasmic reticulum
(microsomes), resulting in a rise in the concentration of Ca2+ in the
cytosol, is an important factor in carbon-tetrachloride-induced
hepatotoxicity (Waller et al., 1983; Srivastava et al., 1990;
Yamamoto, 1990; Glende & Recknagel, 1991). Mehendale (1990,
1991) showed that hepatic microsomes from carbon-tetrachloridetreated rats accumulated progressively greater concentrations of Ca2+
in response to the rise of Ca2+ levels in cytosol.
It is well known that lactic acid plays an important role in
hepatic fibrogenesis. Ayub-Ayala et al. (1993) determined the
relationship between short-term carbon tetrachloride administration
and the rise in lactic acid levels, before the appearance of any signs of
hepatic cirrhosis. After intraperitoneal administration of one single
and three consecutive carbon tetrachloride doses of 2.0 ml/kg body
weight (1:1 dilution in mineral oil) to Sprague-Dawley rats, the blood
lactic acid levels were raised, whereas the administration of mineral
oil did not increase them. Since carbon tetrachloride increases lactic
acid levels prior to cirrhosis development, the authors suggested that
chronic presence of lactic acid is one of the factors in hepatic
fibrogenesis caused by carbon tetrachloride.
Castro et al. (1990) stated that the understanding of the
mechanism of the liver carcinogenic effects of carbon tetrachloride
might be of relevance because there are reasons to believe that carbon
tetrachloride might be one of those carcinogens of a non-genotoxic
nature. The authors showed that liver nuclei from three species tested
(rat, hamster and mouse) were able to promote a lipid peroxidation
process in the presence of carbon tetrachloride, and that NADPH was
only required in part for carbon-tetrachloride-induced lipid peroxidation in the case of the mice. There was no correlation between the
intensity of carbon-tetrachloride-induced lipid peroxidation, either in
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liver nuclear or liver slices preparations, in the three species tested

and their carcinogenic response to carbon tetrachloride. These results
suggest that lipid peroxidation is not determinant or rate-limiting in
the process of liver cancer induction by carbon tetrachloride, but does
not exclude its participation in given stages of the overall process of
cancer development, as is actually believed to occur during chemical
carcinogen insult.
Carbon tetrachloride induced a hepatic cell proliferation,
increasing the frequency of cells in S-phase from < 1% in control
animals to around 10% in B6C3F1 mice (100 mg/kg by gavage 48 h
before sacrifice) (Mirsalis et al., 1985). In rats a similar increase was
observed after a dose of 400 mg/kg (Mirsalis et al., 1985), and the
increase was around 30% in CD mice (50 mg/kg) (Doolittle et al.,
1987). In male Fischer-344 rats, the frequency of S-phase cells was
elevated in one study to 30% 24 h after the only dose tested, 0.4 ml/rat
(Cunningham & Matthews, 1991). In another study with 400 mg/kg
carbon tetrachloride, the frequency was increased to 3% in fed and to
15% in fasting F-344 rats (Asakura et al., 1994). In yet another study
with Fischer rats, an increase to 5% was observed 24 h after an intraperitoneal dose of 400 mg/kg carbon tetrachloride (Mirsalis et al.,
1985). An even lower response, approximately 2%, was observed in
Tif:RAIf rats (400 mg/kg) (Puri & Mller, 1989). An increase in
DNA synthesis was observed 48 h (and the number of ras transcripts
was elevated 3648 h) after an intragastric dose (2.5 ml/kg) of carbon
tetrachloride in Sprague-Dawley rats (Goyette et al., 1983). A rapid
transient increase in c-fos and c-jun mRNA (12 h post-treatment)
was also observed in the liver of male Sprague-Dawley rats after a
single dose of 160 mg/kg carbon tetrachloride (Zawaski et al., 1993).
An increase in the c-fos, c-jun and c-myc nRNA was also observed in
male Wistar rats after a single dose of carbon tetrachloride (2 ml/kg
intragastrically) (Coni et al., 1990, 1993). In rat liver, ras and myc
proteins were observed by immunohistochemical techniques. Their
concentrations peaked in periportal areas 32 h after dosing with
carbon tetrachloride (2.5 ml/kg), and staining throughout the lobule
peaked 96 h after the carbon tetrachloride dose (Richmond et al.,
1992). The sequence of fos, myc and Ha-ras mRNA expression,
followed by hepatocyte proliferation, was also observed in F-344 rats
after a single intraperitoneal dose of 2000 mg/kg carbon tetrachloride
by gavage (Goldsworthy et al., 1994). Injection of a polyclonal
antiserum to murine tumour necrosis factor " one hour before a
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challenge with carbon tetrachloride (0.1 ml/kg) blocked the increase

in c-fos and c-jun mRNA expression and the subsequent increase of
S-phase cells, while at the same time prolonging the elevation of
serum ALAT, ASAT and sorbitol dehydrogenase (SDH) in female
B6C3F1 mice. When recombinant TNF " was injected to mice, rapid
expression of c-jun and c-fos proto-oncogene mRNA was observed,
thus supporting the notion that TNF " has a role in the hepatocellular
regeneration after carbon tetrachloride administration (Bruccoleri et
al., 1997). This idea was originally put forward after the
demonstration of increased expression of TNF " following an
administration of a hepatotoxic dose of carbon tetrachloride (Czaja et
al., 1989). On the other hand, injection of soluble TNF " receptor
preparation to rats had a protective effect against a higher dose of
carbon tetrachloride (0.5 ml/kg), reducing the mortality, serum
aminotransferase levels and the extent of histological liver damage
(Czaja et al., 1995).
104
8. EFFECTS ON HUMANS
8.1
8.1.1
Controlled studies
Inhalation
Six healthy male volunteers were exposed (three times 4 weeks

apart) to carbon tetrachloride vapour at concentrations of 49 ppm (314
mg/m3) for 70 min, 11 ppm (70.5 mg/m3) for 180 min and 10 ppm
(64.1 mg/m3) for 180 min. At the high concentration level, all subjects
smelled a sweetish odour. None of the volunteers reported irritation,
nausea, lightheadedness or disturbance in coordination. No increase
in ASAT activity was observed, but a decrease in serum iron concentration was observed in two out of four subjects at the highest
concentration. No effects were observed at the lower concentrations.
Carbon tetrachloride was detected in exhaled breath at all three
exposure levels (Stewart et al., 1961).
8.1.2
Dermal
Daily treatments for 10 days with carbon tetrachloride did not

cause any increase in skin-fold thickness or erythema on the volar
surface of the forearms of a healthy human volunteer. However, no
occlusion was used, so it is probable that the chemical evaporated
after administration (Wahlberg, 1984a).
When an excess of carbon tetrachloride was applied in a glass
ring to the volar surface of the forearms of a healthy man for 5 min
there was an immediate increase in blood flow. A spontaneous
transient whitening of the skin was observed after 5 min and after 10
to 20 min a slight, transient erythema appeared (Wahlberg, 1984b).
Immersion of the thumbs of three volunteers for 30 min in
carbon tetrachloride caused mild erythema that disappeared in 1 to
2 h after exposure. The volunteers reported a burning sensation in the
thumbs, which subsided within 10 min after the immersion (Stewart
& Dodd, 1964).
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8.2
Case reports
Cases of poisoning with carbon tetrachloride have resulted from
the accidental or suicidal ingestion of carbon tetrachloride, but the
majority resulted from the inhalation of carbon tetrachloride vapour;
the concentration of the saturated vapour at ambient temperature can
reach 800 000 mg/m3. Carbon tetrachloride appears to be toxic to the
liver and kidney. The clinical picture of carbon tetrachloride
poisoning is characterized, independent of the route of intake, in the
first 24 h with gastrointestinal and neurological symptoms, such as
nausea, headache, dizziness, vomiting, diarrhoea and dyspnoea. Liver
damage appears, at the earliest, after 24 h. In serious cases, ascites
and hepatic coma develop, often accompanied by haemorrhages.
Kidney damage is detected later, in 1 to 6 days, but often only 23
weeks following the poisoning (Zimmerman, 1978; Kluwe, 1981;
Monster & Zielhuis, 1983).
Von Oettingen (1964) reviewed the literature on acute carbon
tetrachloride intoxication in humans. He concluded that exposure to
1080 ppm (64.1 to 512.8 mg/m3) for 34 h has no adverse effects. At
higher concentrations nausea, vomiting, headache, rapid pulse, rapid
respiration, sleepiness, dizziness, unconsciousness and immediate
death can occur even after only 1030 min of exposure.
Bagnasco et al. (1978) reported a case in which a 22-year-old
man ingested 355 ml carbon tetrachloride and an equal amount of
water to commit suicide. His liver function deteriorated over the first
24 h, but gradually within the following 3 to 4 days the patient
improved. According to the authors fatal cases have been reported
with as little as 1.5 ml carbon tetrachloride, whereas some patients
have been known to survive after swallowing more than 100 ml.
Smetana (1939) described two cases of carbon tetrachloride
poisoning. One person, who drank an unknown quantity of carbon
tetrachloride, died. Apart from the general symptoms, jaundice,
anuria and malaise were observed. Aside from lesions in the liver
there was clinical evidence of functional damage of the kidneys,
recognized by the presence of albumin in the urine, oliguria, nitrogen
retention, oedema and acute hypertension. The patients had a history
of alcoholism.
106
Effects on Humans
________________________________________________________
Norwood et al. (1950) reported three cases of severe intoxication

arising from use of carbon tetrachloride, two by inhalation and one by
drinking. The two people who inhaled carbon tetrachloride died, and
nephrosis was found to have occurred. All three had a history of heavy
drinking.
Tracey & Sherlock (1968) described a 59-year-old man, with a
history of moderate alcohol consumption, who was exposed to carbon
tetrachloride vapour. Five days later, he developed nausea, vomiting
and diarrhoea, followed by jaundice and acute renal failure. The liver
was found to be enlarged. He recovered uneventfully and liver
functions returned to normal.
McDermott & Hardy (1963) reported three cases of liver cirrhosis
in which repeated exposure to carbon tetrachloride vapour occurred
over a number of years. One of the cases involved mixed solvent
exposure. There was no evidence of significant alcohol intake for any
of the patients.
Ruprah et al. (1985) reported details of 19 patients poisoned with
carbon tetrachloride during the period 19811984. Eight of these
patients were known to have ingested other substances, including
phenothiazine and benzodiazepine tranquillizers, trichloroethane and
trichloroethanol. Carbon tetrachloride exposure was by inhalation
(4 cases) or ingestion (15 cases). In each case the diagnosis was
confirmed by laboratory analysis of blood specimens. The age of the
patients ranged from 3 to 79 years and the whole-blood concentrations
at the time of hospital admission varied from 0.1 to 31.5 mg/litre.
However, actual doses and exposure concentrations were not known
and are difficult to estimate. In none of these cases was the
intoxication associated with occupational use or exposure. The
commonest symptoms found in these patients were vomiting,
abdominal pain, diarrhoea, dizziness, headache and coma. There were
no fatalities.
Norwood et al. (1950) reported 51 very mild and 4 mild intoxications among industrial workers using carbon tetrachloride. The 4
mildly intoxicated patients showed the general symptoms of carbon
tetrachloride intoxication. No data on exposure levels were given.
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Kazantzis & Bomford (1960) examined a group of 17 factory

workers, exposed to carbon tetrachloride atmospheric concentrations
of 45 to 100 ppm (288641 mg/m3). During periods of 24 months to
1 week before the examination, 12 out of 17 workers had experienced
one or more of the following symptoms: nausea, anorexia, vomiting,
flatulence, epigastric discomfort or distention, depressive symptoms,
headache or giddiness. After taking measures to reduce carbon
tetrachloride evaporation, these symptoms disappeared and follow-up
for 6 months revealed no recurrences.
Fourteen workers in an isopropyl alcohol packaging plant
became ill after exposure to unspecified carbon tetrachloride levels
(Folland et al., 1976). The illness was characterized by the gradual
onset of nausea, vomiting, weakness, headache and abdominal pain.
In three heavily exposed subjects renal failure developed. Air
concentrations of isopropanol in the plant were measured 12 and 9
months before and 2 months after the exposure and were about 400
ppm (2564 mg/m3).
Brugnone et al. (1983) investigated 40 workers occupationally
exposed to carbon tetrachloride vapour. After several measurements
it turned out that the alveolar carbon tetrachloride concentration
corresponded to about 53% of the environmental concentration
measured in the breathing zone (mean 3.5 5.9 mg/m3). Among the
40 workers, two suffered accidental carbon tetrachloride intoxication
with acute renal impairment.
Manno et al. (1996) reported that five workers were exposed to
carbon tetrachloride vapour for 2 h and two for 6 h following fire
accidents. Carbon tetrachloride was present in the fire-extinguishing
liquid. Symptoms of carbon tetrachloride poisoning (diarrhoea,
nausea, vomiting, fever and liver and kidney impairment) developed
only in two heavily drinking workers who consumed, respectively,
about 120 and 250 g ethanol daily. The other workers, consuming less
than 50 g ethanol per day, did not develop symptoms. Exposure data
were not available.
8.3
8.3.1
Epidemiology
Non-cancer epidemiology
In a mortality study in a metal fabrication plant (Teta & Ott,

1988) slight increase in mortality from liver cirrhosis was observed.
108
Effects on Humans
________________________________________________________
The highest increase (SMR 2.7) was found in workers potentially

exposed to carbon tetrachloride before the use of this solvent was
discontinued. The authors consider carbon tetrachloride exposure as
a possible contributing risk factor for the cirrhosis findings. However,
exposure data for carbon tetrachloride, data on other exposures and
alcohol consumption were not available, which limit the ability to
draw conclusions regarding carbon tetrachloride.
Volunteers from three plants were divided into four groups on
the basis of estimated exposure to carbon tetrachloride: none (n=262),
low (1 ppm (6.4 mg/m3) or less, n=40), medium (14 ppm (6.425.6
mg/m3), n=54) and high (more than 4 ppm (25.6 mg/m3), n=61). The
alcohol consumption was at the same level in all groups. ALAT,
ASAT, alkaline phosphatase, (-glutamyltransferase, glutamate
dehydrogenase, and other biochemical and haematological variables
were determined. The percentages of values above the normal range
were 2.7% in the non-exposed group and 7.8% in combined exposed
groups for ALAT, and 3% and 10.9% for (-glutamyltransferase,
respectively (both differences statistically significant). The low
exposure group did not differ significantly in any enzymatic activity
test from the non-exposed group (Tomenson et al., 1995).
8.3.2
Cancer epidemiology
A number of epidemiological studies (e.g., cohort mortality,

retrospective cohorts, and case-control) have examined potential
cause-effect relationships between carbon tetrachloride exposure and
incidence of cancer. Because these studies are all characterized by
mixed exposures and a lack of carbon tetrachloride exposure data, any
contribution from carbon tetrachloride cannot be reliably identified.
Thus, information from these studies is not useful for quantitative
health risk evaluation.
Ott et al. (1985) conducted a cohort mortality study of 1919 men
employed for one or more years between 1940 and 1969 at a chemical
manufacturing facility in the USA. This cohort included 226 workers
assigned to a unit that produced chlorinated methanes (methyl
chloride, dichloromethane, chloroform, and carbon tetrachloride) and,
recently, perchloroethylene. Exposure levels were not reported. The
follow-up period was from 1940 to 1979 and follow-up was 94%
complete. Expected numbers of cancer deaths were based on US white
109

________________________________________________________
male cancer rates for the full cohort; the expected numbers in the full
cohort were used for sub-cohort analyses. There were 42 deaths,
including nine cancers, three of which were pancreatic cancers. The
standardized mortality ratios for all deaths and for all cancers were
not elevated.
Blair et al. (1990) performed a study to examine the risk of
cancer and other causes of death among a cohort of 5365 members of
a dry cleaners union in the USA. The cohort consisted of people who
were union members for one or more years before 1978 and had been
employed in dry cleaning establishments. Carbon tetrachloride was
used extensively in dry cleaning between 1930 and 1960, although
other solvents, such as white spirit (Stoddard solvent), were also
widely used. The exposure assessment classified members by level
of exposure to solvents, but not by type of solvent. The mean year at
entry into the cohort was 1956. Follow-up was from 1948 to 1978 and
was 88% complete. There were 294 cancer deaths, including a
significant excess of oesophageal cancer. Non-significant excesses of
several other cancers were found, but only the risk of lymphatic and
haematopoietic cancers appeared to be related to the level of solvent
exposure.
Blair et al. (in press) performed a retrospective cohort mortality
study of 14 457 workers employed for at least one year between 1952
and 1956 at an aircraft maintenance facility in the USA. Among this
cohort were 6737 workers who had been exposed to carbon
tetrachloride (Stewart et al., 1991). Among women, exposure to
carbon tetrachloride was associated with an increased risk of nonHodgkins lymphoma and multiple myeloma, but among men the
corresponding risks were lower. No association was observed with
breast cancer and no other site-specific results for carbon tetrachloride
were presented. Exposure levels for carbon tetrachloride were not
reported, and overlapping exposure to other solvents limits the ability
to draw conclusions regarding carbon tetrachloride.
A nested case-control study within a cohort of rubber workers in
the USA was performed to examine the relationship between exposure
to 24 solvents (levels of exposure not reported) and the risk of cancer
(Checkoway et al., 1984; Wilcosky et al., 1984). The cohort consisted
of 6678 male rubber workers who were either active or retired
between 1964 and 1973. The cases comprised all persons with fatal
110
Effects on Humans
________________________________________________________
stomach cancer (n=30), respiratory system cancer (n=101), prostrate

cancer (n=33), lymphosarcoma (n=9) and lymphocytic leukaemia
(n=10). The control group was a 20% age-stratified random sample
of the cohort (n=1350). Although an association was observed
between exposure for one or more years to carbon tetrachloride and
lymphocytic leukaemia and lymphosarcoma after adjusting for year
of birth, overlapping exposures limit the ability to draw conclusions
regarding carbon tetrachloride.
Bond et al. (1986) conducted a nested case-control study of lung
cancer among a cohort of 19 608 white male chemical workers in the
USA. They were employed for one or more years between 1940 and
1980 at a large facility that produced chlorinated solvents, plastics,
chlorine, caustic soda, ethylene, styrene, epoxy, latex, magnesium
metal, chlor-nitrogen agricultural chemicals and glycols. The cases
were 308 lung cancer deaths that occurred among cohort members
between 1940 and 1981. Two control groups, one consisting of other
deaths (n=308) and the other a living series (n=97), were matched
for race, year of birth, and year of hire. No association was observed
between having been exposed (levels not reported) to carbon
tetrachloride (ever versus never) and lung cancer.
Linet et al. (1987) performed an analysis to compare two
different methods for determining occupational exposure in a
population-based case-control study of chronic lymphocytic
leukaemia. No association between chronic lymphocytic leukaemia
and carbon tetrachloride was observed in either set of analyses.
Heineman et al. (1994) performed a case-control study to
examine the relationship between occupational exposure to six
chlorinated aliphatic hydrocarbons and risk of astrocytic brain cancer.
The study was conducted in three areas of the USA, and 300 cases and
320 controls were included in the analysis. Exposure was assessed
using a semi-quantitative job exposure matrix developed for the study
(Gmez et al., 1994), and probability of exposure, duration of
exposure, average intensity and cumulative exposure were examined.
There were 137 cases and 123 controls classified as having been
exposed at some time. There was an association between the incidence
of astrocytic brain cancer and chlorinated solvent exposure, but not
specifically carbon tetrachloride.
111

________________________________________________________
Cantor et al. (1995) performed a case-control study to examine

the relationship between occupational exposure and female breast
cancer mortality in 24 states in the USA. Probability and level of
workplace exposure to 31 chemical and physical agents were
estimated using a job exposure matrix. No association was found with
probability of exposure to carbon tetrachloride. After adjustment for
age and socioeconomic status, a slightly but significantly elevated risk
was observed at the highest exposure level among white women but
not among black women. However, the designation of the usual
occupation from death certificates in combination with a job-exposure
matrix may be a poor indicator of exposure to carbon tetrachloride.
Holly et al. (1996) performed a case-control study of intraocular
melanoma to examine the role of chemical exposure. Cases were
white male patients referred to the Ocular Oncology Unit at the
University of California San Francisco between 1978 and 1987. Two
white males matched on age and geographic area were selected for
each case using random digit dialling. A total of 221 cases and 447
control (93% and 85% participation rates, respectively) were
interviewed for the study. Although an association with exposure
(ever versus never) to carbon tetrachloride and other cleaning
fluids was observed, the potential for recall bias for exposure history
and the lack of characterization of the exposure atmospheres
precludes the ability to draw conclusions regarding carbon
tetrachloride alone.
In a case-control study carried out in Montreal, the investigators
estimated the associations between 293 workplace substances and
several types of cancer (Siemiatycki, 1991). Carbon tetrachloride was
one of the substances. About 4% of the study subjects had been
exposed to carbon tetrachloride at some time. Among the main
occupations for which carbon tetrachloride was attributed in this study
were fire fighters, machinists and electricians. For most types of
cancer examined (oesophagus, stomach, colon, pancreas, prostrate,
kidney, skin melanoma, non-Hodgkins lymphoma), there was no
indication of an excess risk. There were, however, elevated risks for
rectal cancer and, in the population subgroup of French-Canadians,
bladder cancer.
112
9. EFFECTS ON OTHER ORGANISMS IN THE

LABORATORY AND FIELD
Owing to the volatility of carbon tetrachloride, care must be
taken in interpreting test results, particularly those in open static
systems where no chemical analysis of the actual concentration was
carried out.
9.1
Toxicity to microorganisms
Carbon tetrachloride appeared to be of low toxicity to several
microorganisms (see Table 11).
During studies to determine the toxicity threshold, an initial
reduction of cell multiplication or change in culture turbidity was seen
at 30 mg/litre in aerobic bacteria, but an IC50 as low as 6.4 mg/litre
was found for methanobacteria. The toxicity threshold for protozoa
was much higher (> 300 mg/litre).
Walton et al. (1989) studied the effect of carbon tetrachloride
on the microbial respiration of two slightly acidic soil types, a Captina
silt loam (1.49% organic carbon) from Roane County, Tennessee,
USA, and a sandy loam (0.66% organic carbon) from Stone County,
Mississippi, USA. Carbon tetrachloride was applied at a rate of 1000
:g/g soil (dry weight) and microbial respiration, measured as CO2
efflux, was monitored at 24-h intervals over a 6-day period. Carbon
tetrachloride had no effect on the respiration of the silt loam. The CO2
efflux of the sandy loam decreased relative to the control soil but
recovered within the 6-day exposure period.
9.2
9.2.1
Aquatic toxicity
Algae
Data in Table 11 show the toxicity of carbon tetrachloride to

algae to be low.
9.2.2
Invertebrates
The acute toxicity values for carbon tetrachloride in Daphnia

magna (Table 12) range from 28 to > 770 mg/litre.
113
Table 11. Carbon tetrachloride toxicity to bacteria, protozoa and algae

Organism
Test conditions
End-point
Nominal concentration
(mg/litre)
Reference
Bacteria
Pseudomonas fluorescens
16 h, 25 /C, static
3% reduction of turbidity
threshold, log phase
30
Bringmann, 1973
Pseudomonas putida
16 h, 25 /C, static
threshold, log phase
30
Bringmann & Khn,

1977a
Nitromonas sp.
24 h, 25 /C, static
IC50, 50% reduction in NH3

consumption
51
Blum & Speece,

1991
Methanogens
24 h, 35 /C, static
IC50, 50% reduction in gas

production
Aerobic heterotrophs.
24 h, 35 /C, static
IC50, 50% reduction in oxygen

uptake
Bacteriovorous flagellate
(Entosiphon sulcatum)
72 h, 25 /C, static
5% reduction cell count
> 770
Bringmann, 1978
Bacteriovorous flagellate
(Uronema parduczi)
20 h, 25 /C, static
5% reduction in cell count
> 616
Bringmann & Khn,

1980
Saprozoic flagellate
(Chilomonas paramecium)
48 h, 20 /C, static
5% reduction in cell count
> 300
Bringmann et al.,
1980
6.4
130
Blum & Speece,

1991
Blum & Speece,
1991
Protozoa
Table 11 (contd).
Algae
Blue-green alga
(Microcystis aeroginosa)
192 h, 27 /C, static
threshold
105
Green alga
(Scenedesmus quadricauda)
192 h, 27 /C, static
threshold
> 600
Bringmann & Khn,

1977a
Haematococcus pluvialis
4 h, 20 /C, static
EC10, 10% reduction in oxygen

uptake
> 136
Knie et al., 1983
Bringmann, 1975
Table 12. Carbon tetrachloride toxicity to invertebrates and fish

Organism
Test conditions
Parameter
Concentration
(mg/litre)
Reference
Invertebrates
Daphnia magna
2123 /C
reconstituted
well water; pH 7.49.4;
hardness 173 mg
CaCO3/litre
static
48 h LC50
24 h LC50
35 nominal
35 nominal
LeBlanc, 1980
Daphnia magna
2022 /C
dechlorinated
tap water; pH 7.6;
hardness
173 mg CaCO3/litre
static
24 h LC50
> 770
Bringmann & Khn,

1977b
static
24 h LC50
28
Knie et al., 1983
static
renewal
336 h LC50
67
Knemann, 1981
static
48 h LC50
95 nominala
472 nominala
Juhnke &
Ldemann, 1978
static
48 h LC50
13
Knie et al., 1983
static
96 h LC50
125 nominal
Dawson et al.,
1975/77
Daphnia magna
Fish
Freshwater
Guppy (Poecilia reticulata)
22 /C
Golden orfe
(Leuciscus idus melanotus)
20 /C
hardness 25 mg
CaCO3/litre
Golden orfe
(Leuciscus idus melanotus)
Bluegill sunfish
(Lepomis macrochirus)
23 /C
well water;
pH 7.67.9; hardness
55 mg CaCO3/litre
Table 12 (contd).
Bluegill sunfish
(Lepomis macrochirus)
2123 /C
Fathead minnow
(Pimephales promelas)
Fathead minnow
(Pimephales promelas )
21.7 /C
Dab
(Limanda limanda)
Tidewater silverside
(Menidia beryllina)
pH 6.76.8;
hardness 3248
mg CaCO3/litre
static
96 h LC50
27 nominal
Buccafusco et al.,
1981
flow
LC50
43.1 measured
US EPA, 1984b
pH 6.8; hardness
49.2 mg CaCO3/litre
flow
96 h LC50
41.4 measured
National Library of
Medicine, 1997
natural seawater
flow
96 h LC50
50 measured
Pearson &
McConnell, 1975
20 /C
saltwater;
pH 7.67.9; hardness
55 mg CaCO3/litre
static
96 h LC50
150 nominal
Dawson et al.,
1975/77
Marine
The authors tested 200 selected chemicals with the golden orfe test under comparable conditions in two different laboratories and
found LC50 values of 95 mg/litre (Juhnke) and 472 mg/litre (Ldemann), respectively, for carbon tetrachloride

________________________________________________________
Carbon tetrachloride had no effect on the embryonic development

of sea urchin (Paracentrotus lividus) eggs at concentrations up to the
saturated solution concentration (Congiu et al., 1984).
9.2.3
Vertebrates
Acute toxicity data for fish are summarized in Table 12. The
acute LC50 values for fish range from 13 to 472 mg/litre for the
Golden orfe (Leusiscus idus melanotus).
Rainbow trout (Oncorhynchus mykiss) were exposed to carbon
tetrachloride concentrations of between 1 and 80 mg/litre for up to
336 h under semi-static conditions (water was renewed every 48 h).
No mortality was observed and no significant changes in enzyme
activity were found (Statham et al., 1978).
Toxicity data for embryo-larval stages of fish and amphibians
are given in Table 13. Carbon tetrachloride is considerably more toxic
to the embryo-larval stages of several species of fish and amphibians
than it is to the adults (Birge, 1980; Black et al., 1982). The common
bullfrog (Rana catesbeiana) was the most susceptible species. At 60
:g/litre the incidence of teratic larvae was 1%, rising to 17% at 7.8
mg/litre. A more striking effect was found in the hatchability of the
embryos, which declined from 92% at 60 :g/litre to 23% at 7.8
mg/litre (Birge, 1980).
9.3
9.3.1
Terrestrial toxicity
Earthworms
Red earthworms (Eisenia foetida) were exposed to carbon

tetrachloride via filter paper in glass vials. An LC 50 of 160 :g/cm2
was found (Neuhauser et al., 1985).
118
Table 13. Carbon tetrachloride toxicity to embryo-larval stages of fish and amphibians
Organism
Fish
Rainbow trout
(Oncorhynchus mykiss)
Fathead minnow
(Pimephales promelas)
Amphibians
Bullfrog
(Rana catesbeiana)
Pickerel frog
(Rana palustris)
Fowlers toad
(Bufo fowleri)
European common frog
(Rana temporaria)
Leopard frog
(Rana pipiens)
African clawed toad
(Xenopus laevis)
Northwestern salamander
(Ambystoma gracile)
a
b
Test conditions
Exposure period
(days)
Parameter
Measured
concentration
(mg/litre)
Reference
13 /C pH 9.2; hardness
104 mg CaCO3/litre
96 mg CaCO3/litre
flow
27a
LC50
1.97
Black et al., 1982
flow
9b
LC50
4.0
Black et al., 1982
21 /C pH 8; hardness
108 mg CaCO3/litre
104 mg CaCO3/litre
104 mg CaCO3/litre
96 mg CaCO3/litre
96 mg CaCO3/litre
96 mg CaCO3/litre
96 mg CaCO3/litre
flow
8b
LC50
0.9
Birge, 1980
flow
8b
LC50
2.4
Birge, 1980
flow
7b
LC50
2.8
Birge, 1980
flow
9a
LC50
1.2
Black et al., 1982
flow
9a
LC50
1.6
Black et al., 1982
flow
6a
LC50
22.4
Black et al., 1982
flow
9.5a
LC50
1.98
Black et al., 1982
The organisms were exposed from fertilization until 4 days after hatching
The organisms were exposed from 28 h post spawning to 4 days after hatching
10. EVALUATION OF HUMAN HEALTH RISKS AND

EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
10.1.1 Exposure
Carbon tetrachloride can be detected ubiquitously in the environment, mostly in the air due to its volatility and high vapour pressure.
Furthermore it is found in foodstuffs and drinking-water.
Based on the estimates of mean exposure from various media, as
reported in chapter 5, the general population may be exposed via air
at a concentration of 0.51.0 :g/m3 (retention calculated to be 0.068
0.136 :g/kg body weight per day, assuming 40% retention, ATSDR,
1994), and via drinking-water at levels of 0.13 :g/litre (calculated
to be 0.0030.094 :g/kg body weight). Intake via foodstuffs is
estimated to be very small (0.13 :g/day) (Yoshida, 1993), but could
have been larger in the past in individuals who consumed fumigated
or otherwise contaminated foods. These are presumably no longer on
the market since this use of carbon tetrachloride has ceased. This
means for the general population an estimated maximum daily carbon
tetrachloride intake of about 0.23 :g/kg body weight, assuming
(IPCS, 1994):
a body weight of 64 kg;
an inhalation volume of 22 m3/day;
a water consumption of 2 litres/day;
a food consumption of 1.536 kg/day.
According to estimates made by the ATSDR and in Japan and
Germany the general population is considered to be exposed to carbon
tetrachloride via ingestion and inhalation leading to an average daily
intake of 0.1 to 0.27 :g/kg body weight.
Workers involved in the production or use of carbon tetrachloride
are likely to be exposed to higher levels than the general population.
Based on a national survey conducted from 1981 to 1983, NIOSH
estimated that 58 208 workers were potentially exposed to carbon
tetrachloride in the USA during that period.
120
Evaluation of Human Health Risks and Effects on the Environment

_____________________________________________________________
Exposure to higher levels of carbon tetrachloride could occur as a

result of accidental spillage or near hazardous waste sites
contaminated with carbon tetrachloride.
10.1.2 Health effects
Acute symptoms after human exposure to carbon tetrachloride

are characterized by gastrointestinal and neurological symptoms, such
as nausea, vomiting, headache, dizziness and dyspnoea. Liver damage
appears after 24 h or more. Kidney damage is evident often only 2 to
3 weeks following the poisoning. Short-term and long-term exposure
to low concentrations of carbon tetrachloride can also produce hepatic
and renal damage. The toxicity of carbon tetrachloride is associated
with the formation of reactive metabolites, the principal enzyme
involved being CYP 2E1. 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. How these factors affect the CNS and kidney
responses is not known. No adequate long-term oral study on
laboratory animals, suitable for quantitative health risk evaluation of
carbon tetrachloride, was available (section 7.3).
In a 12-week oral study on rats (5 days/week), a NOAEL of
1 mg/kg body weight was reported. The LOAEL reported in this study
was 10 mg/kg body weight, showing a slight, but significant increase
in SDH activity and mild hepatic centrilobular vacuolization
(Bruckner et al., 1986). A NOAEL of 1.2 mg/kg body weight was
reported in a 90-day oral study on mice (5 days/week). On the basis
of hepatotoxicity, the LOAEL was 12 mg/kg body weight (Condie et
al., 1986).
When rats were exposed to carbon tetrachloride by inhalation for
approximately 6 months, 5 days/week, 7 h/day, the NOAEL was 32
mg/m3. The LOAEL, based on changes in the liver morphology, was
63 mg/m3 (Adams et al., 1952). In a 90-day study on rats, a NOAEL
of 6.1 mg/m 3 was found after continuous exposure to carbon
tetrachloride (Prendergast, 1967).
An exposure level of 32 mg/m3 (the lowest concentration studied)
in a 2-year inhalation study on rats caused marginal effects (Japan
Bioassay Research Centre, 1998).
121

________________________________________________________
In experiments with mice and rats, carbon tetrachloride proved

to be capable of inducing hepatomas and hepatocellular carcinomas.
The doses inducing hepatic tumours were higher than those inducing
cell toxicity. It is likely that the carcinogenicity of carbon tetrachloride
is secondary to its hepatotoxic effects.
There is little evidence to suggest that carbon tetrachloride is
genotoxic.
Based on the weight of evidence it can be concluded that the
hepatic tumours are induced by an indirect mechanism and that a
tolerable daily intake or concentration can be derived.
The available data suggest that carbon tetrachloride can induce
embryotoxic and embryolethal effects, but only at doses that are
maternally toxic. Carbon tetrachloride is not teratogenic in rats and
mice.
10.1.3 Approaches to health risk assessment
There is little evidence to suggest that carbon tetrachloride is

genotoxic. A quantitative risk assessment for threshold effects (IPCS,
1994), which includes the effects of non-genotoxic carcinogens, was
therefore adopted.
10.1.3.1
Calculation of a TDI based on oral data
Calculations of tolerable daily intake (TDI) were based on the 12week oral study on rats (Bruckner et al., 1986) and the 90-day oral
study on mice (Condie et al., 1986), where NOAEL values of 1 mg/kg
body weight and 1.2 mg/kg body weight were identified, respectively.
a)
Rat
TDI =
weight
1 mg/kg body weight (5/7)

500
= 1.42 :g/kg body
where:
1 mg/kg body weight is the NOAEL in the 12-week oral study on

rats
122

_____________________________________________________________
b)
(5/7) is the conversion from 5 days/week of dosing to

7 days/week
500 is the uncertainty factor (10 for interspecies variation, 10 for
intraspecies variation and 10 for a less-than-long-term study; a
modifying factor of 0.5 was applied because this was a bolus
study).
Mouse
TDI = 1.2 mg/kg body weight (5/7)

= 1.72 :g/kg body weight
500
where:
1.2 mg/kg body weight is the NOAEL in the 90-day oral study
on mice
(5/7) is the conversion from 5 days/week of dosing to

7 days/week

intraspecies variation and 10 for a less-than-long-term study; a
modifying factor of 0.5 was applied because this was a bolus
study).
10.1.3.2
Calculation of a tolerable concentration based on inhalation data
Calculations of tolerable concentrations (TC) were based on:

(a) the 90-day study of Prendegast (1967) where a NOAEL of 6.1
mg/m3 was identified for continuous exposure; (b) the 6-month study
of Adams et al. (1952) where a NOAEL of 32 mg/m3 was found; and
(c) the 2-year inhalation study by Japan Bioassay Research Centre
(1998) where a LOAEL with a marginal adverse effect was 32 mg/m3.
a)
TC =
6.1 mg/m3
1000
= 6.1 :g/m3
where:
6.1 mg/m3 is the NOAEL in the 90-day inhalation study on rats
1000 is the uncertainty factor (10 for interspecies variation, 10

for intraspecies variation; and 10 for a less-than-long-term study)
b)
TC =
32 mg/m3 (7/24) (5/7)

1000
= 6.7 :g/m3
123

________________________________________________________
where:
32 mg/m3 is the NOAEL in the 6-month inhalation study on rats
(7/24) (5/7) is the conversion from 7 h/day and 5 days/week to

continuous exposure.
1000 is the uncertainty factor (10 for interspecies variation, 10

for intraspecies variation and 10 for a less-than-long-term study).
c)
TC =
= 11.4 :g/m3
32 mg/m3 (6/24) (5/7)

500
32 mg/m3 is the LOAEL in the 2-year inhalation study on rats

(6/24) (5/7) is the conversion from 6 h/day and 5 days/week to
continuous exposure
intraspecies variation and 5 for use of a marginal effect rather
than a no-observed-effect level).
It is noted that the end-point on which the LOAEL is based in

the recent 2-year inhalation bioassay on rats (i.e. proteinuria) was not
investigated in the studies of Adams et al. (1952) and Prendergast
(1967).
10.1.3.3
Summary of the results of risk assessment
TDI
1.42 :g/kg body weight
Oral studies
Inhalation studies
weight
weight
10.1.3.4
TC
6.1 :g/m3
6.7 :g/m3
11.4 :g/m3
TDI (calculated from the TC)

0.85 :g/kg body
0.92
: g/kg body
Conclusions based on exposure and health risk assessment
On the basis of exposure data presented in chapter 5, an

approximate upper-limit estimate of the daily intake of carbon
tetrachloride for long-term exposure of the general population can be
made for prevailing normal exposure and for a worst case scenario.
124

_____________________________________________________________
The following concentration ranges are considered:
ambient air, 0.51.0 :g/m3 (worst case 6 :g/m3 );

indoor air in dwellings, 0.62.0 :g/m3 (worst case 9 :g/m3);
drinking-water, 0.00022.3 :g/litre (worst case 16 :g/litre; the
abnormally high value of 39.5 :g/litre reported in Spain was not
considered);
foodstuffs (particularly table-ready foods) 0.16.0 :g/kg (worst
case 31 :g/kg).
The daily estimates are summarized in Table 14.
As is seen from Table 14, the upper limit of human daily intake
under prevailing conditions is estimated to be 0.2 :g/kg body weight,
well below the lowest tolerable daily intake (0.85 :g/kg body weight)
presented in section 10.1.3.3. This leads to the conclusion that the
currently prevailing exposure of the general population to carbon
tetrachloride from all sources is unlikely to cause excessive intake of
the chemical.
The hypothetical worst case scenario of exposure may bring
about a daily intake of 2.5 :g/kg body weight, more than ten times the
daily intake under currently prevailing conditions, and three times the
lowest tolerable intake. This would indicate a need for caution.
However, conditions similar to those of the worst case scenario are
very unlikely to occur in future, due to the expected fall in the use of
carbon tetrachloride as a consequence of the Amended Montreal
Protocol.
10.2 Evaluation of effects on the environment

Carbon tetrachloride may be released into the environment
during its production, storage, transport and use. Owing to its
volatility, most of the substance emitted into the environment can be
found in the air. The residence time of carbon tetrachloride in the
atmosphere is long, and it can therefore be transported over long
distances from the point of emission. The main degradation site of
carbon tetrachloride is the stratosphere where it is photolytically
degraded by UV radiation. Carbon tetrachloride contributes both to
ozone depletion and to global warming.
125
Table 14. Daily intake of carbon tetrachloride for long-term exposure of the general population
Prevailing upper limits
Worst case scenario
Concentration
Daily intake
Concentration
Daily intake
1 :g/m3
1 :g/m3 22 m3 0.4a = 8.8 :g
9 :g/m3
9 :g/m3 22 m3 0.4a = 79.2 :g
0.1 :g/litre
0.1 :g/litre 2 litres = 0.2 :g
16 :g/litre
16 :g/litres 2 litres = 32 :g
3 :g/kg
3 :g/kg 1.5 kg = 4.5 :g
31 :g/kg
31 :g/kg 1.5 kg = 46.5 :g
Air
Water
Food
Total daily intake
13.5 :g
157 :g
Total daily intake per kg

body weight
0.2 :g
2.5 :g
The value of 0.4 derives from the 40% retention reported by ATSDR (1994)

_____________________________________________________________
Carbon tetrachloride is, in general, resistant to aerobic biodegradation, but less so to anaerobic. Acclimation increases biodegradation rates. Although the octanol-water partition coefficient indicates
a moderate potential for bioaccumulation, the short lifetime in tissues
reduces this tendency.
Carbon tetrachloride is of low toxicity to the algae and microorganisms tested; the lowest toxic concentration of carbon tetrachloride reported was for methanogenic bacteria (IC50 = 6.4 mg/litre).
In aquatic invertebrates, LC50 values range from 28 mg/litre to over
770 mg/litre.
The lowest acutely toxic concentration found for freshwater fish
was an LC50 of 13 mg/litre for the golden orfe (Leuciscus idus
melanotus). The lowest LC50 for a marine species was 50 mg/litre for
the dab (Limanda limanda).
Carbon tetrachloride is toxic to embryo-larval stages of fish and
of amphibians. The most sensitive species tested was the common
bullfrog (Rana catesbeiana) with an LC50 of 0.92 mg/litre for the
period from fertilization to 4 days post-hatching.
Comparing the LC50 value for the most sensitive aquatic species
(0.9 mg/litre) with typical levels of carbon tetrachloride in water (<
1.0 :g/litre) gives a ratio of > 900. Therefore, the general risk to
aquatic organisms is low. However, carbon tetrachloride may present
a risk to embryo-larval stages of aquatic organisms at, or near, sites
of industrial discharges or spills, where much higher levels have been
reported.
127
11. FURTHER RESEARCH

a)
Physiologically based pharmacokinetic models for carbon tetrachloride should be further developed in order to improve their
use in defining target organ doses in human exposure conditions.
b)
Since there is a lack of epidemiological data in those countries

where carbon tetrachloride is still used, epidemiological studies
of exposed populations would be useful.
c)
No further research topics are recommended in view of the

phase-out of the production and use of carbon tetrachloride as a
result of the Montreal Protocol on Substances that Deplete the
Ozone Layer.
128
12. PREVIOUS EVALUATION BY INTERNATIONAL

BODIES
A drinking-water guideline value of 2 :g/litre has been recommended for carbon tetrachloride by the World Health Organization
(WHO, 1993), based on a risk assessment approach for non-genotoxic
carcinogens. A NOAEL of 1 mg/kg body weight and an uncertainty
factor of 1000 were adopted for calculations.
The International Agency for Research on Cancer evaluated
carbon tetrachloride in 1978 (IARC, 1979), and re-evaluated it in
1987 (IARC, 1987) and 1998 (IARC, in press). The conclusions from
the most recent evaluation were that there is inadequate evidence for
carcinogenicity of carbon tetrachloride in humans but sufficient
evidence for its carcinogenicity in experimental animals. The overall
evaluation was that carbon tetrachloride is possibly carcinogenic to
humans (Group 2B).
129
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165
RSUM
Le ttrachlorure de carbone est un liquide limpide, incolore et
volatil qui dgage une odeur doucetre caractristique. Il est miscible
la plupart des solvants aliphatiques et il est lui-mme un solvant. Il
est peu soluble dans leau. Le ttrachlorure de carbone nest pas
inflammable et il est stable lair et la lumire. En se dcomposant,
il peut donner naissance du phosgne, du dioxyde de carbone et
de lacide chlorhydrique.
La prsence de ttrachlorure de carbone dans lenvironnement est
vraisemblablement presque exclusivement dorigine humaine. La
majeure partie du ttrachlorure de carbone produit sert la
prparation de chlorofluorocarbures (CFC) et autres hydrocarbures
chlors. En 1987, la production mondiale de ttrachlorure de carbone
a t de 960 000 tonnes. Toutefois, depuis que le Protocole de
Montral relatif aux substances qui appauvrissent la couche dozone
(1987) et ses amendements de 1990 et de 1992, a tabli un calendrier
pour labandon progressif de la production et de la consommation de
ttrachlorure de carbone, la production a recul et continuera le
faire.
On a mis au point plusieurs mthodes suffisamment sensibles et
prcises pour la recherche et le dosage du ttrachlorure de carbone
dans lair, leau et les milieux biologiques. La plupart dentre elles
sont bases, soit sur linjection directe de lchantillon dans un
chromatographe en phase gazeuse, soit sur une adsorption sur
charbon actif, suivie dune dsorption ou dune vaporation puis
dune dtection par chromatographie en phase gazeuse.
La presque totalit du ttrachlorure de carbone libr dans
lenvironnement finira tt ou tard dans latmosphre en raison de sa
grande volatilit. Comme sa dure de sjour dans latmosphre est
longue, il est largement distribu. Au cours de la priode 19801990,
la concentration atmosphrique du ttrachlorure de carbone tait de
lordre de 0,51,0 :g/m3. Les estimations de sa dure de sjour
atmosphriques sont variables mais on pense que la valeur la plus
raisonnable est de 45 50 ans. Le ttrachlorure de carbone contribue
la fois la destruction de la couche dozone et au rchauffement du
climat. Il est gnralement rsistant la biodgradation arobie, mais
166
Rsum
________________________________________________________
moins la biodgradation anarobie. La vitesse de biodgradation

peut saccrotre par suite dun processus dacclimatation. Bien que le
coefficient de partage octanol-eau indique un potentiel de bioaccumulation moyen, cette tendance est rduite par la brivet de la demi-vie
tissulaire.
Dans leau, on fait tat de concentrations infrieures 10 ng/litre
pour les ocans et de moins de 1 :g/litre pour les eaux douces, mais
de valeurs beaucoup plus fortes proximit des sites de dcharge. On
a mesur des valeurs allant jusqu 60 :g/kg dans des denres
alimentaires qui avaient t traites avec du ttrachlorure de carbone,
mais cette pratique a cess.
Cest essentiellement par lintermdiaire de lair que la population dans son ensemble est expose au ttrachlorure de carbone. Si
lon se base sur les concentrations releves dans lair ambiant, les
denres alimentaires et leau de boisson, on peut estimer environ
1 :g/kg de poids corporel la dose de ttrachlorure de carbone
absorbe. Cette estimation est probablement un peu forte lheure
actuelle, du fait quon nutilise plus de ttrachlorure de carbone pour
la fumigation des crales et que les concentrations annonces pour
les aliments et utilises pour ce calcul, correspondaient tout
particulirement aux matires grasses et aux produits base de
crales. Dautres sources font tat de valeurs comprises entre 0,1 et
0,27 :g/kg p.c. pour lexposition journalire de la population
gnrale. Une exposition plus importante au ttrachlorure de carbone
peut se produire sur le lieu de travail en cas de dversement
accidentel.
Le ttrachlorure de carbone est bien rsorb au niveau des voies
digestives et respiratoires de lHomme et des animaux. Il peut
galement y avoir absorption percutane du produit liquide, mais dans
le cas de la vapeur, cette absorption est lente.
Le ttrachlorure de carbone se rpartit dans tout lorganisme,
mais se concentre surtout dans le foie, le cerveau, les reins, les
muscles, les tissus adipeux et le sang. Le compos initial slimine
principalement dans lair expir et, en proportion minime, dans
lurine et les matires fcales.
167

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La premire tape de la biotransformation du ttrachlorure de

carbone est catalyse par les enzymes du cytochrome P-450 et aboutit
la formation dun radical ractif, le radical trichloromthyl. La voie
de biotransformation la plus importante conduisant llimination de
ce radical consiste dans une oxydation en un radical encore plus
ractif, le radical trichloromthylperoxyl, qui peut ragir son tour
pour donner du phosgne. Le phosgne peut tre dtoxifi par raction
avec leau pour donner du dioxyde de carbone ou par raction avec le
glutathion ou la cystine. En anarobiose, il y a formation de
chloroforme et de dichlorocarbne.
Les intermdiaires mtaboliques du ttrachlorure de carbone
peuvent former des liaisons covalentes avec des macromolcules et
provoquer la peroxydation des lipides.
Laction toxique du ttrachlorure de carbone a pour organes
cibles le foie et le rein. La gravit des effets hpatiques dpend dun
certain nombre de facteurs tels que la sensibilit de lespce, la voie
et le mode dexposition, le rgime alimentaire et une exposition
concomitante ventuelle dautres substances, notamment lthanol.
En outre, il semble quun traitement pralable par divers composs,
comme le phnobarbital ou la vitamine A, accroisse lhpatotoxicit
du ttrachlorure de carbone, alors que dautres, au contraire, la
rduisent, comme la vitamine E.
Aprs application sur lpiderme de lapins et de cobayes, on a
constat une irritation modre et une raction galement modre a
t observe aprs instillation dans loeil du lapin.
La DL50 la plus faible (2391 mg/kg p.c. sur une priode de 14
jours) a t obtenue lissue dune tude sur des chiens qui recevaient
le compos par voie intrapritonale. Chez le rat, on a obtenu des
valeurs comprises entre 2821 et 10 054 mg/kg p.c.
Lors dune tude de 12 semaines sur des rats comportant
ladministration du produit par la voie buccale 5 jours par semaine,
on a obtenu une dose sans effet nocif observable (NOAEL) de 1 mg/kg
p.c. La dose la plus faible produisant un effet nocif observable
(LOAEL) tait de 10 mg/kg p.c., les effets observs tant une
168
Rsum
________________________________________________________
augmentation lgre, mais significative, de lactivit de la sorbitoldshydrognase et une vacuolisation modre des hpatocytes
centrilobulaires. Une NOAEL similaire de 1,2 mg/kg p.c. (5 jours par
semaine) a t obtenue chez des souris lors dune tude de 90 jours
avec administration buccale; dans la mme tude, la LOAEL
(hpatotoxicit) a t trouve gale 12 mg/kg p.c.
En exposant des rats du ttrachlorure de carbone par la voie
respiratoire pendant environ 6 mois, 5 jours par semaine, 7 heures par
jour, on a obtenu une NOAEL de 32 mg/m3 LOAEL, base sur des
anomalies de la morphologie hpatique, a t trouve gale 63
mg/m3. Dans une autre tude de 90 jours sur des rats, on a obtenu une
NOAEL de 6,1 mg/m3 aprs exposition continue du ttrachlorure de
carbone. Lors dune tude dinhalation de 2 ans portant galement sur
des rats, la concentration la plus faible tudie (32 mg/m3) a provoqu
des effets marginaux.
La seule tude toxicologique long terme dont on dispose a
consist faire ingrer du ttrachlorure de carbone des rats pendant
2 ans, aux doses respectives de 0, 80 et 200 mg de produit par kg de
nourriture. En raison dune affection respiratoire chronique qui a
touch tous les animaux partir du 14me mois et a provoqu une
augmentation de la mortalit, les rsultats de lautopsie effectue au
bout de deux ans ne peuvent pas tre utiliss pour une valuation du
risque sanitaire.
Les tudes dinhalation effectues sur des rats et des souris ont
permis de conclure que le ttrachlorure de carbone peut avoir des
effets embryotoxiques pouvant aller jusqu la mort de lembryon.
Toutefois ces effets ne se manifestent quaux doses toxiques pour les
femelles gravides. Le ttrachlorure de carbone nest pas tratogne.
De nombreuses tudes de gnotoxicit ont t effectues sur le
ttrachlorure de carbone. Sur la base des donnes disponibles, on peut
considrer que ce compos nest pas gnotoxique.
Le ttrachlorure de carbone provoque lapparition dhpatomes
et de carcinomes hpatocellulaires chez le rat et la souris. Les doses
169

________________________________________________________
qui entranent la formation de tumeurs hpatiques sont suprieures

aux doses cytotoxiques.
Chez lHomme, les manifestations aigus qui surviennent aprs
exposition au ttrachlorure de carbone sont indpendants du mode
dabsorption et se caractrisent par des symptmes gastrointestinaux
et neurologiques tels que nauses, vomissements, cphales,
tourdissements, dyspne qui finissent par aboutir la mort. Des
lsions hpatiques apparaissent au bout de 24 h ou davantage. Les
lsions rnales ne se manifestent souvent que 2 ou 3 semaines aprs
lintoxication.
Les tudes pidmiologiques nont pas permis dtablir
lexistence dune association entre lexposition au ttrachlorure de
carbone et un accroissement du risque de mortalit, de cancer ou
daffection hpatique. Certains travaux incitent penser quil pourrait
y avoir augmentation du risque de lymphome non Hodgkinien et,selon
une tude particulire, du risque de mortalit et de cirrhose du foie. Il
faut cependant prciser que toutes ces tudes ne portaient pas
spcifiquement sur lexposition au ttrachlorure de carbone et quil
ny avait pas, en tout cas, de corrlations statistiques fortes.
En gnral, le ttrachlorure de carbone se rvle peu toxique pour
les bactries, les protozoaires et les algues. La concentration toxique
la plus faible a t mesure chez les bactries mthanognes (CI50 =
6,4 mg/litre). Pour les invertbrs aquatiques, les valeurs de la Cl50
aigu varient de 28 > 770 mg/litre. Dans le cas des poissons deau
douce, cest chez lorfe (Leuciscus idus melanotus) que lon a trouv
la valeur la plus faible de la CL50 aigu, avec 13 mg/litre. Chez les
espces marines, cest la limande (Limanda limanda) qui prsente la
plus faible valeur de la CL50, avec 50 mg/litre. Chez les poissons et les
amphibiens, le ttrachlorure de carbone se rvle plus toxique pour les
stades embryo-larvaires que pour les adultes. La grenouille-taureau
commune (Rana catesbeiara) est lespce la plus sensible, avec une
CL50 de 0,92 mg/litre (de la fcondation 4 jours aprs lclosion).
Les donnes disponibles montrent que le mcanisme de
formation des tumeurs hpatiques nest pas de nature gnotoxique et
170
Rsum
________________________________________________________
il est donc admissible de fixer une dose journalire tolrable par

ingestion (TDI) et une concentration journalire tolrable dans lair
(TC).
En sappuyant sur ltude de Bruckner et al. (1986) qui ont
dtermin une dose sans effet nocif observable (NOAEL) de 1 mg/kg
p.c. lors dune tude de 12 semaines sur des rats auxquels on avait fait
ingrer du ttrachlorure de carbone, et en utilisant un facteur de
conversion de 5/7 pour la dose journalire et un coefficient
dincertitude de 500 (100 pour les variations inter- et intraspcifiques,
10 pour la dure de ltude plus un facteur de 0,5 pour tenir compte
du fait que lon avait utilis des boulettes), on parvient une TDI de
1,42 :g/kg de poids corporel.
En sappuyant sur une tude dinhalation de 90 jours pratique
sur des rats (Prendergast et al., 1967), qui a permis daboutir une
NOAEL de 6,1 mg/m3 on a calcul une TC de 6,1 :g/m3 en utilisant
les coefficients de 7/24 et de 5/7 pour passer une exposition en
continu et un coefficient dincertitude de 1000 (100 pour les
variations inter- et intraspcifiques et 10 pour la dure de ltude).
Cette TC correspond une TDI de 0,85 :g/kg de poids corporel.
En comparant la limite suprieure de la dose journalire absorbe
par lHomme, cest--dire 0,2 :g/kg p.c., la valeur la plus faible de
la TDI, soit 0,85 :g/kg p.c., on peut conclure que lexposition actuelle
de la population gnrale au ttrachlorure de carbone de toutes
origines a peu de chances de causer une absorption excessive de ce
compos.
En rgle gnrale, les organismes aquatiques ne courent gure de
risque imputable au ttrachlorure de carbone. Toutefois, il peut y avoir
un danger pour les stades embryo-larvaires sur les sites de dcharge
ou de dversement de produits industriels ou proximit de ces sites.
171
RESUMEN
El tetracloruro de carbono es un lquido voltil transparente,
incoloro, con un olor dulce caracterstico. Es miscible con la mayor
parte de los disolventes alifticos y tiene a su vez propiedades
disolventes. La solubilidad en agua es baja. El tetracloruro de carbono
no es inflamable y se mantiene estable en presencia del aire y de la
luz. Su descomposicin puede producir fosgeno, anhdrido carbnico
y cido clorhdrico.
La fuente de tetracloruro de carbono en el medio ambiente con
toda probabilidad tiene un origen casi exclusivamente antropognico.
La mayor parte del tetracloruro de carbono producido se emplea en la
fabricacin de clorofluorocarbonos y otros hidrocarburos clorados. La
produccin mundial ascendi en 1987 a 960 000 toneladas. Sin
embargo, desde que en el Protocolo de Montreal relativo a las
sustancias que agotan la capa de ozono (1987) y en sus enmiendas
(1990 y 1992) se estableci un calendario para la reduccin progresiva
de la produccin y consumo del tetracloruro de carbono, su
fabricacin ha disminuido y seguir descendiendo.
Se han elaborado varios mtodos analticos suficientemente
sensibles y precisos para la determinacin del tetracloruro de carbono
en muestras de aire, agua y biolgicas. La mayora de estos mtodos
se basan en la inyeccin directa en un cromatgrafo de gases o la
adsorcin en carbn activado, seguida de la desorcin o la
evaporacin y la posterior deteccin por cromatografa de gases.
Casi todo el tetracloruro de carbono que se libera en el medio
ambiente estar en ltimo trmino presente en la atmsfera, debido a
su volatilidad. Dado que su tiempo de permanencia en la atmsfera es
prolongado, tiene una distribucin muy amplia. Durante el perodo
1980-1990, las concentraciones atmosfricas fueron de alrededor de
0,5-1 :g/m3. Las estimaciones de su permanencia en la atmsfera son
variables, pero se aceptan como los valores ms razonables los 45-50
aos. El tetracloruro de carbono contribuye tanto a la reduccin del
ozono como al calentamiento mundial. Es en general resistente a la
biodegradacin aerobia, pero menos a la anaerobia. La aclimatacin
aumenta la velocidad de biodegradacin. Aunque el coeficiente de
172
Rsumen y Conclusiones
________________________________________________________
reparto octanol/agua indica un potencial de bioacumulacin

moderado, el breve perodo de permanencia en los tejidos reduce esta
tendencia.
En el agua, se han notificado concentraciones inferiores a
10 ng/litro en los ocanos y generalmente inferiores a 1 :g/litro en el
agua dulce, pero con valores mucho ms elevados cerca de los lugares
de liberacin. Se han registrado concentraciones de hasta 60 :g/kg en
alimentos elaborados con tetracloruro de carbono, pero esta prctica
se ha suprimido.
La poblacin general est expuesta al tetracloruro de carbono
fundamentalmente a travs del aire. A partir de las concentraciones
notificadas en el aire ambiente, los productos alimenticios y el agua
potable, se ha estimado que la ingesta diaria de tetracloruro de
carbono es de alrededor de 1 :g/kg de peso corporal. En la actualidad
esta estimacin es probablemente demasiado elevada, porque se ha
suprimido el uso del tetracloruro de carbono como fumigante de los
cereales y los valores notificados para los alimentos y utilizados en el
clculo fueron fundamentalmente los obtenidos en alimentos a base
de grasas y cereales. En otras partes se han descrito valores de 0,1 a
0,27 :g/kg de peso corporal para la exposicin diaria de la poblacin
general. Se puede producir una exposicin a concentraciones ms
elevadas de tetracloruro de carbono en el lugar de trabajo debido a un
derrame accidental.
El tetracloruro de carbono se absorbe bien de los tractos
gastrointestinal y respiratorio en los animales y en el ser humano. Es
posible la absorcin cutnea de tetracloruro de carbono lquido, pero
la absorcin cutnea del vapor es lenta.
El tetracloruro de carbono se distribuye por todo el organismo,
alcanzando las concentraciones ms altas en el hgado, el cerebro, el
rin, los msculos, la grasa y la sangre. El compuesto original se
elimina fundamentalmente en el aire exhalado, mientras que se
excretan cantidades mnimas en las heces y la orina.
En la biotransformacin del tetracloruro de carbono, el primer
paso es la catlisis por enzimas del citocromo P-450 para formar un
radical reactivo, el triclorometilo. La biotransformacin oxidativa es
173
EHC 194: Aluminium

________________________________________________________
la ruta ms importante en la eliminacin del radical, produciendo otro

radical incluso ms reactivo, el triclorometilperoxilo, que puede
reaccionar de nuevo para formar fosgeno. ste se puede destoxificar
mediante la reaccin con el agua para producir anhdrido carbnico,
o con el glutatin o la cistena. En condiciones anaerobias se forma
cloroformo y diclorocarbeno.
Se produce la unin a macromolculas mediante enlaces
covalentes y la peroxidacin de lpidos a travs de intermediarios
metablicos del tetracloruro de carbono.
El hgado y el rin son los rganos destinatarios de la toxicidad
de este compuesto. La gravedad de los efectos hepticos depende de
diversos factores, como la susceptibilidad de la especie, la ruta y el
modo de exposicin, la alimentacin o la exposicin simultnea a
otros compuestos, en particular el etanol. Adems, parece que el
tratamiento previo con diversos compuestos, como el fenobarbital y la
vitamina A, aumenta la hepatotoxicidad, mientras que otros
compuestos, como la vitamina E, reducen la accin hepatotxica del
tetracloruro de carbono.
Tras la aplicacin cutnea se ha observado una irritacin
moderada en la piel de conejos y cobayas, y se puso de manifiesto una
reaccin leve despus de aplicar el compuesto en el ojo del conejo.
La DL50 ms baja, de 2391 mg/kg de peso corporal (perodo de
14 das), se notific en un estudio realizado con perros mediante
administracin intraperitoneal. En ratas, los valores de la DL50
oscilaron entre 2821 y 10 054 mg/kg de peso corporal.
En un estudio de administracin por va oral a ratas durante 12
semanas (5 das/semana), la concentracin sin efectos adversos
observados (NOAEL) fue de 1 mg/kg de peso corporal. La
concentracin ms baja sin efectos adversos observados (LOAEL)
notificada en este estudio fue de 10 mg/kg de peso corporal,
registrndose un aumento ligero, pero significativo, de la actividad de
la sorbitol deshidrogenasa y una ligera vacuolacin centrilobular
heptica. En un estudio de 90 das por va oral realizado en ratones,
se encontr una NOAEL semejante de 1,2 mg/kg de peso corporal
174
________________________________________________________
(5 das/semana) con una LOAEL de 12 mg/kg de peso corporal

cuando se produjo hepatotoxicidad.
Cuando se expusieron ratas a tetracloruro de carbono mediante
inhalacin durante unos seis meses, cinco das a la semana, siete
horas diarias, se notific una NOAEL de 32 mg/m3. Se inform de
una LOAEL, basada en cambios en la morfologa del hgado, de 63
mg/m3. En otro estudio de 90 das en ratas se encontr una NOAEL
de 6,1 mg/m3 tras una exposicin continua a tetracloruro de carbono.
El nivel de exposicin ms bajo, de 32 mg/m3 (la concentracin ms
baja estudiada), en un estudio de inhalacin en ratas de dos ao
produjo efectos marginales.
El nico estudio de toxicidad prolongada por va oral fue uno de
dos aos realizado en ratas expuestas a 0, 80 y 200 mg de tetracloruro
de carbono/kg de alimentos. Debido a una enfermedad respiratoria
crnica que contrajeron todos los animales a partir del 14 mes y que
provoc un aumento de la mortalidad, los resultados notificados de la
necropsia a los dos aos son insuficientes para evaluar el riesgo para
la salud.
Se lleg a la conclusin de que el tetracloruro de carbono puede
inducir efectos embriotxicos y embrioletales, pero slo a dosis txicas
para la madre, como se observ en los estudios de inhalacin
realizados en ratas y ratones. El tetracloruro de carbono no es
teratognico.
Se han realizado numerosas valoraciones de la genotoxicidad del
tetracloruro de carbono. Tomando como base los datos disponibles, se
puede considerar que este producto es un compuesto no genotxico.
El tetracloruro de carbono induce la formacin de hepatomas y
carcinomas hepatocelulares en ratones y ratas. Las dosis que inducen
la formacin de tumores hepticos son ms elevadas que las que
producen toxicidad celular.
En el ser humano, los sntomas agudos tras la exposicin a
tetracloruro de carbono son independientes de la ruta de ingestin y
se caracterizan por sntomas gastrointestinales y neurolgicos, como
175
EHC 194: Aluminium

________________________________________________________
nuseas, vmitos, dolor de cabeza, desvanecimiento, disnea y la

muerte. Despus de las 24 horas o ms aparecen lesiones hepticas.
Son evidentes los trastornos renales con frecuencia slo dos o tres
semanas despus de la intoxicacin.
Los estudios epidemiolgicos no han establecido una asociacin
entre la exposicin al tetracloruro de carbono y el aumento del riesgo
de mortalidad, neoplasia o enfermedad heptica. Algunos estudios
han indicado una asociacin con un aumento del riesgo de linfoma
no-Hodgkin y, en un estudio, con la mortalidad y la cirrosis heptica.
Sin embargo, no en todos estos estudios se seal la exposicin
especfica al tetracloruro de carbono y las asociaciones estadsticas no
fueron convincentes.
En general, el tetracloruro de carbono parece tener una toxicidad
baja para las bacterias, los protozoos y las algas; la concentracin
txica ms baja notificada para las bacterias metanognicas
correspondi a una CI50 de 6,4 mg/litro. Para los invertebrados
acuticos, los valores de la CL50 aguda fueron de 28 a >770 mg/litro.
En los peces de agua dulce el valor ms bajos de la CL50 aguda, de 13
g/litro, se encontr en el cachuelo dorado (Leuciscus idus melanotus),
y para las especies marinas se notific un valor de la CL50 de 50
mg/litro para la limanda (Limanda limanda). El tetracloruro de
carbono parece ser ms txico para las fases embrionaria y larvaria de
los peces y anfibios que para los adultos. La rana toro comn (Rana
catesbeiara) es la especie ms susceptible, con una CL50 de 0,92
mg/litro (desde la fecundacin hasta los cuatro das despus de la
eclosin).
Los datos disponibles indican que la induccin de tumores
hepticos se debe a un mecanismo no genotxico, por lo que parece
aceptable el establecimiento de una ingesta diaria tolerable (IDT) y de
una concentracin diaria tolerable (CDT) en el aire para el
tetracloruro de carbono.
Tomando como base el estudio de Bruckner et al. (1986), en el
cual se observ una NOAEL de 1 mg/kg de peso corporal en un
estudio de 12 semanas con administracin por va oral a ratas, e
incorporando un factor de conversin de 5/7 para la dosificacin
176
________________________________________________________
diaria y aplicando un factor de incertidumbre de 500 (100 por la

variacin interespecfica e intraespecfica, 10 por la duracin del
estudio y un factor de modificacin de 0,5 porque se trataba de un
estudio de bolo), se obtiene una IDT de 1,42 :g/kg de peso corporal.
Al comparar el lmite superior estimado de la ingesta diaria
predominante de 0,2 :g/kg de peso corporal con el valor ms bajo de
la IDT (0,85 :g/kg de peso corporal), se puede llegar a la conclusin
de que la exposicin predominante en la actualidad de la poblacin
general al tetracloruro de carbono procedente de todas las fuentes es
poco probable que d lugar a una ingesta excesiva de la sustancia
qumica.
En general, el riesgo del tetracloruro de carbono para los
organismos acuticos es bajo. Sin embargo, puede presentar un riesgo
para las fases embrionaria y larvaria en lugares de vertidos o escapes
industriales o en zonas prximas a ellos.
177
THE ENVIRONMENTAL HEALTH CRITERIA SERIES

Acetaldehyde (No. 167, 1995)
Acetone (No. 207, 1998)
Acetonitrile (No. 154, 1993)
Acrolein (No. 127, 1991)
Acrylamide (No. 49, 1985)
Acrylic acid (No. 191, 1997)
Acrylonitrile (No. 28, 1983)
Aged population, principles for evaluating
the effects of chemicals (No. 144, 1992)
Aldicarb (No. 121, 1991)
Aldrin and dieldrin (No. 91, 1989)
Allethrins (No. 87, 1989)
Aluminium (No. 194, 1997)
Amitrole (No. 158, 1994)
Ammonia (No. 54, 1986)
Anticoagulant rodenticides (No. 175, 1995)
Arsenic (No. 18, 1981)
Asbestos and other natural mineral fibres
(No. 53, 1986)
Barium (No. 107, 1990)
Benomyl (No. 148, 1993)
Benzene (No. 150, 1993)
Beryllium (No. 106, 1990)
Biomarkers and risk assessment: concepts
and principles (No. 155, 1993)
Biotoxins, aquatic (marine and freshwater)
(No. 37, 1984)
Boron (No. 204, 1998)
Brominated diphenylethers (No. 162, 1994)
Butanols four isomers (No. 65, 1987)
Cadmium (No. 134, 1992)
Cadmium environmental aspects
(No. 135, 1992)
Camphechlor (No. 45, 1984)
Carbamate pesticides: a general
introduction (No. 64, 1986)
Carbaryl (No. 153, 1994)
Carbendazim (No. 149, 1993)
Carbon disulfide (No. 10, 1979)
Carbon monoxide (No. 13, 1979)
Carbon tetrachloride (No. 208, 1999)
Carcinogens, summary report on the
evaluation of short-term in vitro tests
(No. 47, 1985)
Carcinogens, summary report on the
evaluation of short-term in vivo tests
(No. 109, 1990)
Chlordane (No. 34, 1984)
Chlordimeform (No. 199, 1997)
Chlordecone (No. 43, 1984)
Chlorendic acid and anhydride
(No. 185, 1996)
Chlorinated paraffins (No. 181, 1996)
Chlorine and hydrogen chloride
(No. 21, 1982)
Chloroalkyl ethers, selected (No. 201, 1998)
Chlorobenzenes other than
hexachlorobenzene (No. 128, 1991)
Chlorofluorocarbons, fully halogenated
(No. 113, 1990)
Chlorofluorocarbons, partially halogenated

(ethane derivatives) (No. 139, 1992)
(methane derivatives) (No. 126, 1991)
Chloroform (No. 163, 1994)
Chlorophenols (No. 93, 1989)
Chlorothalonil (No. 183, 1996)
Chromium (No. 61, 1988)
Chrysotile asbestos (No. 203, 1998)
Copper (No. 200, 1998)
Cresols (No. 168, 1995)
Cyhalothrin (No. 99, 1990)
Cypermethrin (No. 82, 1989)
Cypermethrin, alpha- (No. 142, 1992)
DDT and its derivatives (No. 9, 1979)
DDT and its derivatives
environmental aspects (No. 83, 1989)
Deltamethrin (No. 97, 1990)
Demeton-S-methyl (No. 197, 1997)
Diaminotoluenes (No. 74, 1987)
Diazinon (No. 198, 1997)
1,2-Dibromoethane (No. 177, 1996)
Di-n-butyl phthalate (No. 189, 1997)
1,2-Dichloroethane
(No. 62, 1987, 1st edition)
(No. 176, 1995, 2nd edition)
2,4-Dichlorophenoxyacetic acid
(2,4-D) (No. 29, 1984)
2,4-Dichlorophenoxyacetic acid
environmental aspects (No. 84, 1989)
1,3-Dichloropropene, 1,2-dichloropropane
and mixtures (No. 146, 1993)
Dichlorvos (No. 79, 1988)
Diesel fuel and exhaust emissions
(No. 171, 1996)
Diethylhexyl phthalate (No. 131, 1992)
Diflubenzuron (No. 184, 1996)
Dimethoate (No. 90, 1989)
Dimethylformamide (No. 114, 1991)
Dimethyl sulfate (No. 48, 1985)
Diseases of suspected chemical
etiology and their prevention,
principles of studies on (No. 72, 1987)
Dithiocarbamate pesticides,
ethylenethiourea, and propylenethiourea:
a general introduction (No. 78, 1988)
Electromagnetic fields (No. 137, 1992)
Endosulfan (No. 40, 1984)
Endrin (No. 130, 1992)
Environmental epidemiology, guidelines on
studies in (No. 27, 1983)
Epichlorohydrin (No. 33, 1984)
Ethylbenzene (No. 186, 1996
Ethylene oxide (No. 55, 1985)
Extremely low frequency (ELF) fields
(No. 36, 1984)
Fenitrothion (No. 133, 1992)
Fenvalerate (No. 95, 1990)
Flame retardants: a general introduction
(No. 192, 1997)
continued at end of book
THE ENVIRONMENTAL HEALTH CRITERIA SERIES (continued)
Fluorine and fluorides (No. 36, 1984)

Food additives and contaminants in food,
principles for the safety assessment of
(No. 70, 1987)
Formaldehyde (No. 89, 1989)
Genetic effects in human populations,
guidelines for the study of (No. 46, 1985)
Glyphosate (No. 159, 1994)
Guidance values for human exposure limits
(No. 170, 1994)
Heptachlor (No. 38, 1984)
Hexachlorobenzene (No. 195, 1997)
Hexachlorobutadiene (No. 156, 1994)
Alpha- and beta-hexachlorocyclohexanes
(No. 123, 1992)
Hexachlorocyclopentadiene (No. 120, 1991)
n-Hexane (No. 122, 1991)
Hydrazine (No. 68, 1987)
Hydrogen sulfide (No. 19, 1981)
Hydroquinone (No. 157, 1994)
Immunotoxicity associated with exposure to
chemicals, principles and methods for
assessment (No. 180, 1996)
Infancy and early childhood, principles for
evaluating health risks from chemicals
during (No. 59, 1986)
Isobenzan (No. 129, 1991)
Isophorone (No. 174, 1995)
Kelevan (No. 66, 1986)
Lasers and optical radiation (No. 23, 1982)
Lead (No. 3, 1977)a
Lead, inorganic (No. 165, 1995)
Lead environmental aspects
(No. 85, 1989)
Lindane (No. 124, 1991)
Linear alkylbenzene sulfonates and related
compounds (No. 169, 1996)
Magnetic fields (No. 69, 1987)
Man-made mineral fibres (No. 77, 1988)
Manganese (No. 17, 1981)
Mercury (No. 1, 1976)a
Mercury environmental aspects
(No. 86, 1989)
Mercury, inorganic (No. 118, 1991)
Methanol (No. 196, 1997)
Methomyl (No. 178, 1996)
2-Methoxyethanol, 2-ethoxyethanol, and
their acetates (No. 115, 1990)
Methyl bromide (No. 166, 1995)
Methylene chloride
(No. 164, 1996, 2nd edition)
Methyl ethyl ketone (No. 143, 1992)
Methyl isobutyl ketone (No. 117, 1990)
Methylmercury (No. 101, 1990)
Methyl parathion (No. 145, 1992)
_________________
a
Out of print
Methyl tertiary-butyl ether (No. 206, 1998)

Mirex (No. 44, 1984)
Morpholine (No. 179, 1996)
Mutagenic and carcinogenic chemicals,
guide to short-term tests for detecting
(No. 51, 1985)
Mycotoxins (No. 11, 1979)
Mycotoxins, selected: ochratoxins,
trichothecenes, ergot (No. 105, 1990)
Nephrotoxicity associated with exposure
to chemicals, principles and methods for
the assessment of (No. 119, 1991)
Neurotoxicity associated with exposure to
chemicals, principles and methods for the
assessment of (No. 60, 1986)
Nickel (No. 108, 1991)
Nitrates, nitrites, and N-nitroso compounds
(No. 5, 1978)a
Nitrogen oxides
(No. 4, 1977, 1st edition)a
(No. 188, 1997, 2nd edition)
2-Nitropropane (No. 138, 1992)
Noise (No. 12, 1980)a
Organophosphorus insecticides:
a general introduction (No. 63, 1986)
Paraquat and diquat (No. 39, 1984)
Pentachlorophenol (No. 71, 1987)
Permethrin (No. 94, 1990)
Pesticide residues in food, principles for the
toxicological assessment of (No. 104, 1990)
Petroleum products, selected (No. 20, 1982)
Phenol (No. 161, 1994)
d-Phenothrin (No. 96, 1990)
Phosgene (No. 193, 1997)
Phosphine and selected metal phosphides
(No. 73, 1988)
Photochemical oxidants (No. 7, 1978)
Platinum (No. 125, 1991)
Polybrominated biphenyls (No. 152, 1994)
Polybrominated dibenzo-p-dioxins and
dibenzofurans (No. 205, 1998)
Polychlorinated biphenyls and terphenyls
(No. 2, 1976, 1st edition)a
(No. 140, 1992, 2nd edition)
Polychlorinated dibenzo-p-dioxins and
dibenzofurans (No. 88, 1989)
Polycyclic aromatic hydrocarbons, selected
non-heterocyclic (No. 202, 1998)
Progeny, principles for evaluating health
risks associated with exposure to chemicals
during pregnancy (No. 30, 1984)
1-Propanol (No. 102, 1990)
2-Propanol (No. 103, 1990)
Propachlor (No. 147, 1993)
Propylene oxide (No. 56, 1985)
Pyrrolizidine alkaloids (No. 80, 1988)
THE ENVIRONMENTAL HEALTH CRITERIA SERIES (continued)
Quintozene (No. 41, 1984)

Quality management for chemical
safety testing (No. 141, 1992)
Radiofrequency and microwaves
(No. 16, 1981)
Radionuclides, selected (No. 25, 1983)
Resmethrins (No. 92, 1989)
Synthetic organic fibres, selected
(No. 151, 1993)
Selenium (No. 58, 1986)
Styrene (No. 26, 1983)
Sulfur oxides and suspended particulate
matter (No. 8, 1979)
Tecnazene (No. 42, 1984)
Tetrabromobisphenol A and derivatives
(No. 172, 1995)
Tetrachloroethylene (No. 31, 1984)
Tetradifon (No. 67, 1986)
Tetramethrin (No. 98, 1990)
Thallium (No. 182, 1996)
Thiocarbamate pesticides: a general
introduction (No. 76, 1988)
Tin and organotin compounds
(No. 15, 1980)
Titanium (No. 24, 1982)
Toluene (No. 52, 1986)
Toluene diisocyanates (No. 75, 1987)
Toxicity of chemicals (Part 1), principles and
methods for evaluating the (No. 6, 1978)
Toxicokinetic studies, principles of
(No. 57, 1986)
Tributyl phosphate (No. 112, 1991)
Tributyltin compounds (No. 116, 1990)
Trichlorfon (No. 132, 1992)
1,1,1-Trichloroethane (No. 136, 1992)
Trichloroethylene (No. 50, 1985)
Tricresyl phosphate (No. 110, 1990)
Triphenyl phosphate (No. 111, 1991)
Tris- and bis(2,3-dibromopropyl) phosphate
(No. 173, 1995)
Ultrasound (No. 22, 1982)

Ultraviolet radiation
(No. 160, 1994, 2nd edition)
Vanadium (No. 81, 1988)
Vinylidene chloride (No. 100, 1990)
White spirit (No. 187, 1996)
Xylenes (No. 190, 1997)
THE CONCISE INTERNATIONAL CHEMICAL ASSESSMENT DOCUMENT SERIES

CICADs are IPCS risk assessment documents that provide concise but critical summaries of
the relevant scientific information concerning the potential effects of chemicals upon human
health and/or the environment.
2-Butoxyethanol (No. 10, 1998)
3,3'-Dichlorobenzidine (No. 2, 1998)
1,2-Dichloroethane (No. 1, 1998)
Limonene (No. 5, 1998)
Methyl methacrylate (No. 4, 1998)
N-Phenyl-1-naphthylamine (No. 9,
1998)
1,1,2,2-Tetrachloroethane (No. 3,
1998)
o-Toluidine (No. 7, 1998)
Triglycidyl isocyanurate (No. 8, 1998)
To obtain further copies of monographs in this series, please contact Marketing and
Dissemination, World Health Organization, 1211 Geneva 27, Switzerland (Fax: +41-227914857; E-mail: publications@who.ch)
Price: Sw.fr. 42.ISBN 92 4 157208 6

Price in developing countries: Sw.fr. 29.40

Carbon Tetrachloride: Environmental Health Criteria 208

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This report contains the collective views of an international group of

Environmental Health Criteria 208

Published under the joint sponsorship of the United Nations

World Health Organization

The International Programme on Chemical Safety (IPCS), established in

(NLM Classification: QD 305.H5)

The World Health Organization welcomes requests for permission to reproduce

IDENTITY, PHYSICAL AND CHEMICAL

SOURCES OF HUMAN AND ENVIRONMENTAL

EHC 208: Carbon Tetrachloride

ENVIRONMENTAL TRANSPORT, DISTRIBUTION

CONCENTRATIONS IN THE ENVIRONMENT

Transport and distribution between media

KINETICS AND METABOLISM IN LABORATORY

EFFECTS ON LABORATORY MAMMALS AND

EHC 208: Carbon Tetrachloride

Toxicity to the reproductive system,

EFFECTS ON OTHER ORGANISMS IN THE

10. EVALUATION OF HUMAN HEALTH RISKS AND

Evaluation of human health risks

11. FURTHER RESEARCH

12. PREVIOUS EVALUATION BY INTERNATIONAL

NOTE TO READERS OF THE CRITERIA

This publication was made possible by grant number

Environmental Health Criteria

EHC 208: Carbon Tetrachloride

recognized. The EHC monographs have become widely established,

standard setting. These latter are the exclusive purview of national

Summary a review of the salient facts and the risk evaluation

EHC 208: Carbon Tetrachloride

If an EHC monograph is proposed for a chemical not on the

EHC PREPARATION FLOW CHART

Document preparation initiated

Draft sent to IPCS Responsible Officer (RO)

Responsible Officer, Editor check for coherence of text and

International circulation to Contact Points (150+)

Comments to IPCS (RO)

Review of comments, reference cross-check;

Post-TG draft; detailed reference cross-check

WHO Publication Office

EHC 208: Carbon Tetrachloride

The three cooperating organizations of the IPCS recognize the

WHO TASK GROUP ON ENVIRONMENTAL HEALTH

EHC 208: Carbon Tetrachloride

ENVIRONMENTAL HEALTH CRITERIA FOR CARBON

EHC 208: Carbon Tetrachloride

In water, reports have indicated levels of less than 10 ng/litre in

Covalent binding to macromolecules and lipid peroxidation occur

EHC 208: Carbon Tetrachloride

The only oral long-term toxicity study available was a 2-year

mg/litre. In freshwater fish the lowest acute LC50 value of 13 mg/litre

2. IDENTITY, PHYSICAL AND CHEMICAL

Carbona, carbon chloride,

Benzinoform, Fasciolin, Flukoids,

CAS chemical name:

CAS registry number:

RTECS registry number: FG 4900000

Identity, Physical and Chemical Properties, and Analytical Methods

Physical and chemical properties

Relative molecular mass

Boiling point at 101.3 kPa, 20/C

Melting point at 101.3 kPa, 20 /C

Density (25 /C)