Chloroform
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS number |
| 1.4.2 Other numbers |
| 1.5 Main brand names, main trade names |
| 1.6 Main manufacturers, main importers |
| 2. SUMMARY |
| 2.1 Main risks and target organs |
| 2.2 Summary of clinical effects |
| 2.3 Diagnosis |
| 2.4 First-aid measures and management principles. |
| 3. PHYSICO-CHEMICAL PROPERTIES |
| 3.1 Origin of the substance |
| 3.2 Chemical structure |
| 3.3 Physical properties |
| 3.3.1 Colour |
| 3.3.2 State/Form |
| 3.3.3 Description |
| 3.4 Hazardous characteristics |
| 4. USES |
| 4.1 Uses |
| 4.1.1 Uses |
| 4.1.2 Description |
| 4.2 High risk circumstance of poisoning |
| 4.3 Occupationally exposed populations |
| 5. ROUTES OF EXPOSURE |
| 5.1 Oral |
| 5.2 Inhalation |
| 5.3 Dermal |
| 5.4 Eye |
| 5.5 Parenteral |
| 5.6 Others |
| 6. KINETICS |
| 6.1 Absorption by route of exposure |
| 6.2 Distribution by route of exposure |
| 6.3 Biological half-life by route of exposure |
| 6.4 Metabolism |
| 6.5 Elimination by route of exposure |
| 7. TOXICOLOGY |
| 7.1 Mode of Action |
| 7.2 Toxicity |
| 7.2.1 Human data |
| 7.2.1.1 Adults |
| 7.2.1.2 Children |
| 7.2.2 Relevant animal data |
| 7.2.3 Relevant in vitro data |
| 7.2.4 Workplace standards |
| 7.2.5 Acceptable daily intake (ADI) and other guideline levels |
| 7.3 Carcinogenicity |
| 7.4 Teratogenicity |
| 7.5 Mutagenicity |
| 7.6 Interactions |
| 8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material sampling plan |
| 8.1.1 Sampling and specimen collection |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gas analysis |
| 8.1.1.4 Haematological analyses |
| 8.1.1.5 Other (unspecified) analyses |
| 8.1.2 Storage of laboratory samples and specimens |
| 8.1.2.1 Toxicological analyses |
| 8.1.2.2 Biomedical analyses |
| 8.1.2.3 Arterial blood gas analysis |
| 8.1.2.4 Haematological analyses |
| 8.1.2.5 Other (unspecified) analyses |
| 8.1.3 Transport of laboratory samples and specimens |
| 8.1.3.1 Toxicological analyses |
| 8.1.3.2 Biomedical analyses |
| 8.1.3.3 Arterial blood gas analysis |
| 8.1.3.4 Haematological analyses |
| 8.1.3.5 Other (unspecified) analyses |
| 8.2 Toxicological Analyses and their Interpretation |
| 8.2.1 Tests on toxic ingredient(s) of material |
| 8.2.1.1 Simple Qualitative Test(s) |
| 8.2.1.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.1.3 Simple Quantitative Method(s) |
| 8.2.1.4 Advanced Quantitative Method(s) |
| 8.2.2 Tests for biological specimens |
| 8.2.2.1 Simple Qualitative Test(s) |
| 8.2.2.2 Advanced Qualitative Confirmation Test(s) |
| 8.2.2.3 Simple Quantitative Method(s) |
| 8.2.2.4 Advanced Quantitative Method(s) |
| 8.2.2.5 Other Dedicated Method(s) |
| 8.2.3 Interpretation of toxicological analyses |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood, plasma or serum |
| 8.3.1.2 Urine |
| 8.3.1.3 Other fluids |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.3.4 Interpretation of biomedical investigations |
| 8.4 Other biomedical (diagnostic) investigations and their interpretation |
| 8.5 Overall Interpretation of all toxicological analyses and toxicological investigations |
| 8.6 References |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning |
| 9.1.1 Ingestion |
| 9.1.2 Inhalation |
| 9.1.3 Skin exposure |
| 9.1.4 Eye contact |
| 9.1.5 Parenteral exposure |
| 9.1.6 Other |
| 9.2 Chronic poisoning |
| 9.2.1 Ingestion |
| 9.2.2 Inhalation |
| 9.2.3 Skin exposure |
| 9.2.4 Eye contact |
| 9.2.5 Parenteral exposure |
| 9.2.6 Other |
| 9.3 Course, prognosis, cause of death |
| 9.4 Systematic description of clinical effects |
| 9.4.1 Cardiovascular |
| 9.4.2 Respiratory |
| 9.4.3 Neurological |
| 9.4.3.1 Central Nervous System (CNS) |
| 9.4.3.2 Peripheral nervous system |
| 9.4.3.3 Autonomic nervous system |
| 9.4.3.4 Skeletal and smooth muscle |
| 9.4.4 Gastrointestinal |
| 9.4.5 Hepatic |
| 9.4.6 Urinary |
| 9.4.6.1 Renal |
| 9.4.6.2 Others |
| 9.4.7 Endocrine and reproductive systems |
| 9.4.8 Dermatological |
| 9.4.9 Eye, ears, nose, throat: local effects |
| 9.4.10 Haematological |
| 9.4.11 Immunological |
| 9.4.12 Metabolic |
| 9.4.12.1 Acid-base disturbances |
| 9.4.12.2 Fluid and electrolyte disturbances |
| 9.4.12.3 Others |
| 9.4.13 Allergic reactions |
| 9.4.14 Other clinical effects |
| 9.4.15 Special risks |
| 9.5 Others |
| 9.6 Summary |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Life supportive procedures and symptomatic treatment |
| 10.3 Decontamination |
| 10.4 Enhanced elimination |
| 10.5 Antidote treatment |
| 10.5.1 Adults |
| 10.5.2 Children |
| 10.6 Management discussion |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 12. ADDITIONAL INFORMATION |
| 12.1 Specific preventive measures |
| 12.2 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS (ES) |
CHLOROFORM
International Programme on Chemical Safety
Poisons Information Monograph 121
Chemical
1. NAME
1.1 Substance
Trichloromethane
1.2 Group
Organochlorine solvent
1.3 Synonyms
chloroform (Dutch, German, Polish),
chloroform (IUPAC),
chloroforme (French),
chloroformium anaestheticum,
chloroformum,
chloroformum pro narcosi,
cloroformio,
formyl trichloride,
methane trichloride,
methenyl chloride,
methenyl trichloride,
methyl trichloride,
trichloormethaan (Dutch),
trichlormethan (Czech),
trichloroform,
triclorometano (Italian),
1.4 Identification numbers
1.4.1 CAS number
67-66-3
1.4.2 Other numbers
1888 (UN)
FS9100000 (NIOSH)
UN Hazard class: 6.1 (poisonous substances)
1.5 Main brand names, main trade names
Freon 20, NCI-C02686, R20, R20 (refrigerant)
1.6 Main manufacturers, main importers
Produced by many manufacturers and widely
imported.
2. SUMMARY
2.1 Main risks and target organs
Acutely, CNS depression and respiratory arrest; late
onset liver and kidney damage.
2.2 Summary of clinical effects
Acute poisoning with chloroform is uncommon. The main
route of exposure is inhalation but in some cases poisoning
is due to ingestion; skin absorption is limited. Central
nervous system depression is the most prominent sign after
acute exposure. Death may occur within few minutes of heavy
exposure from respiratory arrest or from ventricular
fibrillation (cardiac arrest). The prognosis is favourable if
consciousness is recovered but liver and kidney damage may
then develop. Less severe exposure causes dizziness, dilated
pupils, nausea, vomiting.
2.3 Diagnosis
Headache, impaired consciousness, convulsions,
respiratory paralysis, dizziness, abdominal pain, nausea,
vomiting and diarrhoea are the feature of chloroform
poisoning following ingestion There may be dizziness and
short of breath following inhalation.
Later, symptoms of liver and kidney may develop. The main
features of acute poisoning do not depend on the route of
entry but rather on the amount of chloroform absorbed by the
body.
Analysis of biological fluids plays no role in the diagnosis
of acute poisoning.
2.4 First-aid measures and management principles.
Management consists of early decontamination, supportive
treatment with respiratory and cardiac monitoring, avoidance
of catecholamine drugs and treatment of hepatic and or kidney
failure if they occur.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Although negligible amounts of chloroform may be
produced naturally in the atmosphere (Ross et al., 1978) and
in soil and water (Clayton & Clayton, 1981), manufacturing is
the main source.
Chloroform is usually manufactured by two processes -
hydrochlorination and then further chlorination of methanol
or chlorination of methane (GCA Corporation, 1984). Both
processes yield a mixture of chloromethanes. Chloroform is
then separated by sequential distillation.
3.2 Chemical structure
CHCl3
Molecular weight 113.4
3.3 Physical properties
3.3.1 Colour
3.3.2 State/Form
3.3.3 Description
Boiling point: 61.15°C - 61.70°C.
Melting point: -63.2 - -63.5°C at atmospheric
pressure.
Flash point: none.
Relative vapour density (air = 1): 4.1 - 4.36 kg/m at
101 kPa, 0°C.
Vapour pressure: 21.15 kPa at 20°C.
Solubility in water: 10.62g/kg at O°C
8.95g/kg at 10°C
8.22g/kg at 20°C
Specific gravity: 1.483 at 20°C
Chloroform is miscible with acetone, benzene, carbon
disulphide, carbon tetrachloride, ethanol, ether,
petroleum ether, fixed and volatile oils and most
organic solvents.
Concentration Conversion Factors
1 mg/l = 206 ppm 1 ppm = 4.89 mg/m3 at 25°C and
atmospheric pressure (Royal Society of Chemistry,
1986)
3.4 Hazardous characteristics
At normal temperature and pressures, chloroform is a
heavy, very volatile, clear, colourless, highly refractive,
non inflammable liquid. It has a characteristic sweet,
ethereal odour and a sweetish burning taste. The odour is not
irritant. Pure chloroform is light, sensitive and reagent
grade chloroform usually contains 0.75% ethanol as stabilizer
(Merck).
Chloroform reacts vigorously with acetone in the presence of
KOH or CaOH. It may also react explosively with fluorine,
dinitrogen tetraoxide, aluminium, lithium, sodium,
sodium/methanol, NaOH/methanol, sodium methoxide and
triisopropylphosphine (Sax, 1984; Bretherick, 1979).
Mixtures of chloroform and nitromethane are said to be
detonable (Bretherick, 1979).
Chloroform is oxidized by strong oxidizing agents such as
chromic acid with formation of phosgene and chlorine gas.
Chloroform may generate the highly toxic gas phosgene if it
comes into contact with flames or hot metal surfaces (NIOSH,
1979a). When heated to decomposition it emits toxic fumes of
chlorine (Sax, 1984).
Chloroform explodes when in contact with aluminium powder or
magnesium powder.
4. USES
4.1 Uses
4.1.1 Uses
4.1.2 Description
The main use of chloroform is the production of
other materials,principally fluorocarbons (for
example, chlorodifluoromethane) used in the synthesis
of tetrafluoroethylene and polytetrafluoroethylene,
and as a refrigerant and propellant. Chloroform is
also widely employed as an organic solvent in
industryand in analytical laboratories. It has also
been used as an ingredient of pharmaceuticals, drugs,
cosmetics, grain fumigants, dyes and pesticides.
The United States Food and Drug Administration listed
some 1900 human drug products containing chloroform in
1976 (IARC, 1979) but its pharmaceutical use has been
restricted in many countries. Chloroform may be a drug
of abuse.
Worldwide production of chloroform in 1973 was about
2.5 million tonnes (Ross et al., 1978).
4.2 High risk circumstance of poisoning
Exposure may be occupational or by voluntary ingestion
or inhalation for its psychotropic effects (Hutchens 1985;
Storms,1973; Iffland & Ramme, 1983; Beer et al.,
1984).
4.3 Occupationally exposed populations
High risk circumstances of acute and chronic poisoning
occur mostly in chemical plants where chloroform is
manufactured and used and in chemical laboratories which use
chloroform as a solvent. Transport and storage of improperly
closed containers also creates a high risk. Chronic exposure
may occur in farmers using pesticides containing chloroform
(for instance, grain fumigants); in people dealing with drugs
and cosmetics containing chloroform; and in users of such
products.
5. ROUTES OF EXPOSURE
5.1 Oral
Acute poisoning may be due to accidental or deliberate
ingestion. Chloroform is readily absorbed through mucous
membranes (Davidson et al., 1978). Although water, food and
oral drugs contain minute amounts of chloroform, significant
chronic poisoning is unlikely by this route.
5.2 Inhalation
Inhalation is the most frequent and the most important
route of entry of chloroform. Poisoning by this route is also
best understood from experience of its use as a general
anaesthetic until it was replaced by less toxic
compounds.
Up to 64-67% of chloroform from inspired air is retained in
the body. Pulmonary intake is directly related to the
chloroform concentration in the air, the ventilation volume
and to the duration of exposure (Davidson et al.,1978).
5.3 Dermal
Dermal exposure may cause irritation (especially of the
most sensitive areas such as the anogenital region and,
although absorption via this route is usually not
significant, systemic effects changes may occur which
resembling those produced by inhalation (Royal Society of
Chemistry, 1986).
5.4 Eye
Liquid chloroform irritates the eye but systemic
absorption is not significant.
5.5 Parenteral
Parenteral administration may be an act of deliberate
self poisoning, criminal poisoning or medical error.
5.6 Others
No data available.
6. KINETICS
6.1 Absorption by route of exposure
The gastrointestinal absorption of chloroform has not
been satisfactorily studied but is said to occur readily; the
peak blood concentration occurs one hour after ingestion
(Davidson et al., 1978).
Inhalation is the principal route of entry of chloroform into
the body. The total quantity absorbed through the lungs is
directly proportional to:
the concentration in the inspired air;
the exposure time;
the blood/air Ostwald solubility coefficient;
the solubility in the various body tissuesphysical
activity.
The basic kinetic parameters of chloroform absorption by
inhalation and its equilibration in the body apply equally to
both low and high concentrations. At concentrations inducing
anaesthesia (8000 - 10,000 ppm), a high blood level (about
100 mg/l) is obtained within a couple of minutes.
Skin exposure: rarely causes absorption of significant
amounts of chloroform.
Ocular exposure: small amounts may be absorbed.
6.2 Distribution by route of exposure
The distribution of chloroform in the body does not
differ qualitatively between the various routes of exposure.
Chloroform is rapidly absorbed and distributed to all body
tissues (IARC, 1979). Chloroform is lipophilic and therefore
it concentrates mainly in lipid-containing organs such as
adipose tissue, the central nervous system, kidney and liver.
Chloroform remains in these tissues at least for several
hours after exposure and accumulation of chloroform in the
body will occur during repeated exposures.
Chloroform passes the placental barrier and it has been found
in fresh cow's milk; it probably occurs in human colostrum
and mature milk (Davidson et al., 1978).
6.3 Biological half-life by route of exposure
No data available.
6.4 Metabolism
Chloroform is extensively metabolized by the liver.
Phosgene, carbene and chlorine are some of the metabolites
which may account for its cytotoxic activity.
6.5 Elimination by route of exposure
The elimination of chloroform is not qualitatively
affected by the route of exposure. About 60 - 70% is
eliminated unchanged in expired air; 30 - 40% is metabolized
and excreted in urine and faeces. Its metabolism is
dose-dependent and may be proportionally higher at lower
exposures (Davidson et al., 1979).
7. TOXICOLOGY
7.1 Mode of Action
Chloroform causes progressive depression of the central
nervous system, ultimately producing deep coma and
respiratory centre depression. It is also hepatotoxic and
nephrotoxic, although liver and kidney damage can be
influenced by various treatments which affect hepatic
drug-metabolizing enzymes (IARC, 1979): induction of hepatic
enzymes with barbiturates, DDT or ethanol potentiates hepatic
cell necrosis and kidney damage (NIOSH, 1979b). The reactive
intermediates of chloroform metabolism (phosgene, carbene and
Cl) which bind covalently and irreversibly to cellular
macromolecules are believed to account for cellular damage
within the liver and kidney (Davidson et al., 1978).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Chloroform has been widely used as
an anaesthetic but it has now been abandoned
due to its toxicity. Prolonged administration
as an anaesthetic may lead to profound
toxaemia and damage to the liver, heart and
kidneys. Inhalation of concentrated
chloroform vapour causes irritation of
exposed mucous surfaces. Narcosis is
ordinarily preceded by a stage of excitation
which is followed by loss of
reflexes,sensation and
consciousness.
7.2.1.2 Children
No specific data available.
7.2.2 Relevant animal data
Concentrations of 68,000 - 28,000 ppm kill most
animals in a few minutes; 14,000ppm is dangerous to
life after an exposure of 30 to 60 minutes; 5,000 to
6,000 ppm can be tolerated by animals for one hour
without serious disturbances. The maximum
concentration tolerated for several hours or for
prolonged exposure with slight symptoms is 2,000 to
2,500 ppm. The harmful effects are narcosis, and
damage to the liver and heart. Experimentally
prolonged but light anaesthesia in dogs produces a
typical hepatitis.
7.2.3 Relevant in vitro data
No recent references available providing
reliable relevant information.
7.2.4 Workplace standards
NIOSH recommends a time-averaged limit of 10
ppm (NIOSH 1979b).
7.2.5 Acceptable daily intake (ADI) and other guideline
levels
Data not available.
7.3 Carcinogenicity
There is sufficient evidence that chloroform is
carcinogenic in mice and rats. In the absence of adequate
data in humans, it is reasonable for practical purposes to
regard chloroform as potentially carcinogenic in man (IARC,
1979). Animal data should be extrapolated to man only with
caution. Nonetheless, when theoretical risk assessment models
are applied to the available data, the estimated virtual
human dose for a cancer risk of 1 per million is 0.26 mg/day
or less. In animals, very low levels of chloroform (0.75 and
75 ppm) in the drinking water (equivalent to about 0.15 and
15 mg/kg/day in mice) appears to be sufficient to promote the
growth and spread of tumours (Davidson et al., 1978).
7.4 Teratogenicity
Chloroform is teratogenic in the rat, mouse and rabbit
(IARC, 1979) but human data are not available.
7.5 Mutagenicity
Chloroform is not mutagenic in animals; no human data
are available (IARC, 1979).
7.6 Interactions
Chloroform is more hepatotoxic and nephrotoxic when
administered after alcohols, barbiturates or DDT (NIOSH,
1979b).
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
8.3.1.2 Urine
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and
their interpretation
8.5 Overall Interpretation of all toxicological analyses and
toxicological investigations
Collect samples of blood and urine for biomedical
analyses mentioned below.
Estimation of chloroform or its metabolites in the body
fluids plays no practical role in the management of acute or
chronic poisoning.
Arterial O2, CO2 and pH should be monitored in cases of
severe poisoning with respiratory failure.
Monitor serum bilirubin, transaminases, plasma prothrombin
alkaline phosphatase and gamma-glutamyl transpeptidase to
detect the degree of liver damage. In case of liver damage
increased urinary concentrations of bilirubin may occur.
Daily urine collection, plasma creatinine and urea
measurement are needed to detect renal failure.
Chloroform is toxic to the bone marrow and may also cause a
deficiency of plasma prothrombin and fibrinogen. A full blood
count should be performed; monitor plamsa prothrombin and
fibrinogen (Winslow & Gerstner, 1978).
In severe cases, serum electrolytes, urea and creatinine
should be monitored. Glucose may be elevated and ketoacidosis
found due to the incomplete oxidation of fats (Winslow &
Gerstner, 1978).
Estimation of chloroform or its metabolites in the body
fluids plays no practical role in the management of acute or
chronic poisoning.
Chloroform may be measured in the air of the workshop
atmospheres using portable or static sampling devices
(NIOSH, 1979a), in water and food (Kaiser & Oliver, 1976;
Piet et al., 1978; Simmonds & Kerns, 1979; Gruber, 1984;
Ploder, 1974; Pereira & Hughes, 1980) and in the biological
fluids (blood, urine) or tissues of the poisoned person
(Peoples et al., 1979).
The following spectroscopic data are available (Grasselli &
Ritchley, 1975): infra-red, Raman, ultraviolet, nuclear
magnetic resonance and mass spectrometry. The concentration
of chloroform in air is measured, as recommended by NIOSH
(1977), by an activated charcoal trapping method for
collection and concentration, followed by solvent extraction
of the charcoal and a gas chromatographic (GC) analysis of
the extract.
The collection tube is 7 cm long with a 4 mm internal
diameter. It contains a total of 150 g of activated charcoal
(20-40 mesh), divided into a front section of 100mg and a
rear section of 50mg separated by a plug of urethane foam.
Air is sampled at a flow rate of 200 ml per minute by means
of a small pump. The entire apparatus is portable and it may
be carried in a pocket with the sampling tube in the
breathing zone (normally a coat lapel). The apparatus can
also be static.
Carbon disulphide is used to extract the chloroform, which is
separated on a 6.10 m by 3.18 mm stainless steel packed with
10% FFAP on Chromosorb using flame ionization detection.
Water samples are purged with helium and the volatile
substances including chloroform are trapped on Tenax-GC prior
to GC analysis. A Tracor conductivity detector, operated in
the catalytic pyrolysis mode, was used successfully in place
of the usual electron capture detection (Pape, 1977).
Blood, serum and various adipose tissues were extracted with
hexane the extract was heated at 115 C and the volatiles
collected in a Tenac-silica gel trap (Peoples et al., 1979).
Chloroform, together with carbon tetrachloride,
1,2-dichloroethane and trichloroethylene were thermally
adsorbed and determined by GC on a 1.83 m by 6.35 mm column
packed with Porasil C supporting octane. Temperature
programming and a halide-specific detector were used.
8.6 References
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
Clinical effects of acute poisoning are due to
effects on both the central (headache, various degrees
of impaired consciousness, convulsions, respiratory
centre paralysis) and the autonomic nervous systems
(dizziness, nausea, vomiting). These symptoms occur
immediately after toxic exposure. Later, symptoms of
liver and kidney may develop. The main features of
acute poisoning do not depend on the route of entry
but rather on the amount of chloroform absorbed by the
body.
Direct irritation of the gastrointestinal tract causes
abdominal pain, nausea, vomiting, diarrhoea; later
involvement of the autonomic nervous system also
causes nausea and vomiting.
9.1.2 Inhalation
Inhalation is the most frequent and most
important route of poisoning with chloroform. Mild
poisoning causes slight shortness of breath and
dizziness. More severe poisoning causes nausea,
vomiting, drowsiness and various levels of impaired
consciousness, convulsions and respiratory centre
paralysis.
Later, symptoms of liver and kidney may develop. The
main features of acute poisoning do not depend on the
route of entry but rather on the amount of chloroform
absorbed by the body.
9.1.3 Skin exposure
Irritation and redness may occur at the site of
contact, especially of the more sensitive skin parts
(eyelids, neck, axillae, anogenital region) and burns
may occur. Chloroform may be absorbed through the skin
and cause systemic symptoms, although this route of
absorption is not normally significant.
9.1.4 Eye contact
Eye contact with liquid chloroform results in
painful irritation of the superficial eye structures,
burns and may cause corneal necrosis and
ulcers.
9.1.5 Parenteral exposure
Parenteral exposure is unlikely except as a
result of a voluntary poisoning or medical error. The
systemic effects appear very rapidly (see
9.1).
9.1.6 Other
No data available
9.2 Chronic poisoning
9.2.1 Ingestion
A man who ingested cough mixture containing 1.6
to 2.6 g of chloroform daily for 10 years developed
hepatitis and nephrosis. Severe cellular changes were
found on liver biopsy in another man who had ingested
21 ml of chloroform daily for an undetermined period.
No evidence of harm could be found in users of a
dentifrice containing 3.4% chloroform and a mouthwash
containing 0.43% (Pohl, 1979).
Surprisingly few clinical data are available
concerning chronic human exposure to chloroform
despite its long history of use and there are almost
no quantitative toxicological studies (Clayton and
Clayton, 1981; IARC, 1979).
9.2.2 Inhalation
Habitual inhalation of 1 oz of chloroform daily
for 7 years followed by 2 oz daily for a further 5
years was associated with delusions, restlessness,
depression, convulsions, ataxia, dysarthria, tremor of
the tongue and fingers, and insomnia (NIOSH,
1979b).
9.2.3 Skin exposure
No data available.
9.2.4 Eye contact
No data available.
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Acute poisoning with chloroform may follow a benign
course and leave no permanent damage. However, after rapid
absorption of high doses, death occurs quickly due to
respiratory paralysis or cardiac arrest, especially when
proper cardio-respiratory resuscitation is not available. If
the patient survives this early dramatic phase, or when the
exposure is less severe, moderate CNS depression is the most
prominent effect of acute poisoning. The patient may be
dizzy, stuporous or deeply unconscious and, if there is no
further absorption, recovery occurs gradually 20-60 minutes
after exposure, often with profuse vomiting.
Lower doses result in dizziness, salivation, a feeling of
pressure within the head, nausea and vomiting.
After larger or repeated exposures, liver and, less
frequently,overt kidney damage may develop after several
days. This may be followed by complete recovery within
several weeks but may also have a fatal outcome, sometimes
even within less than a week (Winslow & Gerstner,
1978).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Early death after heavy exposure to chloroform
may be due to ventricular fibrillation by a direct
effect of chloroform on the myocardium, through vagal
stimulation or by sensitizing the heart to endogenous
or exogenous catecholamines (ILO, 1983). Chloroform
also causes hypotension by decreasing the contractile
power of myocardium and peripheral vasodilatation
arising from vagal stimulation.
9.4.2 Respiratory
Respiratory failure is due to paralysis of the
medullary respiratory centre, not a direct action of
chloroform on the respiratory system or to the
aspiration of vomitus.
9.4.3 Neurological
9.4.3.1 Central Nervous System (CNS)
Depression of the CNS and even coma
are the most prominent effects of acute
exposure.
Convulsions may occur. Paralysis of the
respiratory centre may cause sudden death.
Chronic exposure may cause restlessness,
depression, convulsions, ataxia, dysarthria,
tremor of the tongue and fingers and insomnia
(NIOSH, 1979b).
9.4.3.2 Peripheral nervous system
No data available
9.4.3.3 Autonomic nervous system
Vagal stimulation is associated with
dilatation of pupils, nausea, vomiting,
salivation and profuse sweating (Clayton &
Clayton, 1981). Vagal stimulation of the
heart causes various cardiac and peripheral
circulatory disturbances(see 9.1).
9.4.3.4 Skeletal and smooth muscle
Relaxation of vascular smooth muscle
leads to hypotension (ILO, 1983).
9.4.4 Gastrointestinal
Ingested chloroform irritates the
gastrointestinal mucosa and may even cause burns. It
induces vomiting mostly through vagal stimulation but
also by a direct local action. Diarrhoea may also
occur (Winslow & Gerstner, 1978).
9.4.5 Hepatic
The hepatotoxicity of chloroform is probably
due to the metabolites phosgene, carbene and chlorine
produced by the liver. Necrosis of liver cells may
occur (Winslow & Gerstner, 1978), causing increased
concentrations of serum bilirubin and transaminases.
Deficiency of prothrombin and fibrinogen may also
occur (Winslow & Gerstner, 1978). Chronic exposure
may cause liver damage although convincing evidence to
support this is lacking (Pohl, 1979).
9.4.6 Urinary
9.4.6.1 Renal
Kidney damage is less common than
injury to the liver but it may occur after
acute exposure (Clayton & Clayton, 1981).
Acute exposure may be associated with damage
to the renal tubules, mainly involving the
epithelium of Henle's loop (Winslow &
Gerstner, 1978). The renal effect may be due
to prolonged anoxia rather than to a direct
toxic effect on the kidney since proper
oxygenation seems to prevent renal damage
(Waters, 1951).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
No data available.
9.4.8 Dermatological
Local irritation and burns have been observed,
especially at the more sensitive skin areas.
9.4.9 Eye, ears, nose, throat: local effects
Conjunctivitis and corneal injury occur after
eye contact. Oral mucosa may also be irritated.
9.4.10 Haematological
Chloroform may damage the erythrocyte membrane
(NIOSH, 1979b); blood clotting may be impaired by
deficiency of prothrombin and fibrinogen (Winslow &
Gerstner, 1978).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Ketoacidosis may occur (Winslow &
Gerstner, 1978).
9.4.12.2 Fluid and electrolyte disturbances
Secondary to losses occur due to
vomiting and diarrhoea.
9.4.12.3 Others
Hyperglycaemia may occur in acute
chloroform poisoning (Winslow & Gerstner,
1978).
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risks
Pregnancy: No data available.
Breast feeding: Chloroform probably occurs in human
colostrum and milk.
Enzyme deficiencies: No data available.
9.5 Others
No data available.
9.6 Summary
10. MANAGEMENT
10.1 General principles
Paralysis of the respiratory centre or cardiac arrest
(due to ventricular fibrillation) may cause instant death if
the proper resuscitation measures are not started
immediately. The unconscious patient needs supportive
treatment (under respiratory and cardiac monitoring) and
possibly fluid replacement. Within a few days, hepatic and
renal failure may develop. Forced diuresis, peritoneal or
extracorporeal haemodialysis, haemoperfusion and
plasmapheresis are useless in the management of acute
chloroform poisoning but renal dialysis is essential if
kidney failuredevelops.
10.2 Life supportive procedures and symptomatic treatment
Monitor respiratory and cardiac function. Respiratory
assistance is often necessary and cardiac defibrillation may
be needed.
Haemodynamic status should be monitored and balanced using
intravenous administration of fluids and electrolytes.
10.3 Decontamination
Emptying the stomach after ingestion is of questionable
value because the absorption of chloroform is very rapid.
Milk, fat or fatty emulsions should not be given orally or by
gastric tube because they may enhance absorption. Clothing
soaked with chloroform should be removed. After eye contact,
wash with copious amounts of water; wash contaminated skin
with soap and water.
In case of spillage, instruct others to keep at a safe
distance. Wear breathing apparatus and gloves. Apply a
dispersing agent if available and work to an emulsion with a
brush and wash into a waste system, diluting the chloroform
greatly with copious running water. If a dispersant is not
available, absorb the spillage with sand and shovel it into a
bucket; transport this to a safe, open area so that it can
evaporate into the air. The site of the spillage should be
washed thoroughly with water and soap or detergent
(Bretherick, 1981).
10.4 Enhanced elimination
No data available
10.5 Antidote treatment
10.5.1 Adults
Not known
10.5.2 Children
Not known
10.6 Management discussion
No data available
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
A 19-year old man who was at a "chloroform party"
consumed three bottles of beer and then mistakenly drank an
unknown quantity of chloroform. He collapsed and was taken to
a local emergency room, where he was found to be stuporous.
His blood pressure was 110/60 mmHg. He was immediately
transferred to the medical intensive care unit at the
University of Wisconsin Hospital. By that time he was
comatose, cyanosis was present, and his breathing was
laboured. His blood pressure was 100/40 mmHg; pulse rate 108
beats per minute; and respiration 26/min. The only other
relevant physical finding was hypoactive deep tendon
reflexes.
Because of poor ventilatory effort, the patient was intubated
and breathing was controlled on a volume ventilator. Hypoxia
could be corrected only with continuous positive pressure
ventilation. The initial haematocrit value, white blood cell
count, urinalysis, all levels of blood urea nitrogen,
electrolytes, fibrinogen, and blood glucose were normal.
Euglobulin lysis took more than 24 hours. Liver function
abnormalities during hospitalization and on follow-up
examination are shown in the table.
Days Following Ingestion
1 2 3 4 6 90
SGOT (IU) 30 681 8080 5300 297 34
SGPT (IU) 15 - 9220 10250 3330
LDH (IU) 204 636 9280 5680 630 176
Total
bilirubin
(mg/dl) 0.2 2.3 2.4 2.7 1.3 1.0
Alkaline
phosphatase
(IU) 6.1 5.2 - 6.4 - 5.0
Prothrombin
time (sec):
Patient 14.3 19.3 - 18.4 14.3 12.3
Control 12.6 11.9 - 12.7 11.8 12.2
Ten hours after ingestion, the chloroform level in blood was
200 mg/l. Three days after admission, the patient began to
respond and was extubated. Cerebellar damage was noted,
characterized by instability of gait and a slight tremor on
finger-to-nose testing. These findings returned to normal in
two weeks. Liver function tests eight weeks after discharge
were normal (Storms 1973).
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
The work place atmosphere should not contain more than
10 ppm of chloroform.
Shipping and storage containers should carry a label warning
that chloroform is highly dangerous because of its toxic and
carcinogenic properties (ILO, 1983). Containers of
chloroform should be kept closed when not in use. Activities
in which chloroform is used should be isolated and work
should be performed with adequate ventilation. Workers
should be trained to handle the material safely. Protective
clothing, gloves, eye protection, shields and respirators
should be provided. Recommendations for work practices,
labelling, personal protective equipment, protective
clothing and sanitation are included in the references
(NIOSH, 1979a, 1979b)
12.2 Other
No data available.
13. REFERENCES
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1538
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and Toxicology. Vol.2B. Toxicology. 3rd rev. ed.
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Organohalide Compounds: An Information Overview. Oak Ridge
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ECSC-EEC-EAEC, Brussels-Luxembourg
Sax NI, (1984) Dangerous Properties of Industrial Materials. 6th
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1: 259
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
ADDRESS (ES)
Authors: Janusz Szajewski, M.D.
Szpital Praski
Dept.3 of Medicine & Warsaw Poison Control Centre
03-701 Warsaw
Poland
Tel:(4822) 19 08 97/19 66 54,
Fax:(4822) 26 38 33
Date: August 1990
Review: Newcastle-upon-Tyne, United Kingdom, January 1991
Update: Dr R. Fernando, June 1993