Chloroform

General information


Key Points

Fire
Non-flammable
Reacts with strong bases in the presence of organic solvents and alkali metals which
explode on impact
Emits toxic fumes of phosgene, hydrogen chloride and chlorine on decomposition
In the event of a fire involving chloroform, use fine water spray and normal fire kit with
breathing apparatus

Health
Toxic by inhalation or ingestion
Harmful, irritant and possibly carcinogenic after prolonged exposure
Immediate symptoms following ingestion or inhalation include excitement and nausea
followed by dizziness, drowsiness, coma and convulsions
Delayed effects may include kidney and liver damage
Inhalation causes shortness of breath and dryness of the mouth and throat
Ingestion causes a burning sensation of the mouth and throat and stomach upset
Skin or eye contact may cause irritation and inflammation
Chloroform is classified by the International Agency for Research on Cancer as
possibly carcinogenic in humans

Environment
Avoid release into the environment
Inform Environment Agency of substantial incident








Prepared by K Foxall
CHAPD HQ, HPA
2007
Version 1

General Information: Page 2 of 5


CHLOROFORM GENERAL INFORMATION
Background

Chloroform is a clear, colourless, volatile
liquid with a characteristic sweet odour.

Chloroform is indirectly produced when
chlorine reacts with organic compounds.
Therefore, a number of water disinfection
processes including the chlorination of
drinking water, waste water and swimming
pools contribute to the formation and
release of chloroform into the
environment. Disinfection processes at
pulp and paper plants are also potential
sources of chloroform.



Chloroform is mainly used in the
production of refrigerant gases, but is also
used in pesticide formulations, as a
solvent and as a chemical intermediate.

Chloroform is present at low levels in air
and may also occur in drinking water, sea
and ground water.

Potential sources of chloroform exposure
for the general population include
contaminated air and food. Drinking water
may also be a source of exposure to trace
amounts.



Occupational exposure may occur during
the production and use of chloroform. It
may also occur at drinking-water plants
and waste-water treatment sites.


Inhalation of chloroform vapours may lead
to symptoms such as shortness of breath
and dryness of the mouth and throat.
Ingestion of chloroform can cause a
burning sensation in the mouth and throat,
nausea and vomiting. Skin contact with
chloroform may lead to irritation and
inflammation of the exposed area.
Exposure of the eyes to chloroform vapour
may cause a stinging sensation, and eye
contact with liquid chloroform can cause
immediate pain and inflammation.

Chloroform can be absorbed into the body
via ingestion or inhalation. Symptoms
include excitement and nausea followed
by dizziness and drowsiness. More severe
exposures to chloroform may cause heart
problems, convulsions, unconsciousness
and in some cases death. Delayed effects
(up to 48 hours after the exposure) of
chloroform exposure are liver and kidney
damage.

Long-term exposure to chloroform can
cause liver damage.

There is no evidence to suggest that
chloroform, at concentrations that do not
affect the mother, can affect the health of
the unborn child.

The International Agency for Research on
Cancer (IARC) has classified chloroform
as possibly having the ability to cause
cancer in humans. Prolonged exposure to
high enough levels of chloroform to cause
liver damage is thought to be necessary to
cause cancer. Chloroform does not have
any significant mutagenic properties.






General Information: Page 3 of 5


CHLOROFORM GENERAL INFORMATION
Production and Uses


Key Points

Chloroform is produced industrially by hydrochlorination of methanol or chlorination of
methane
The main use of chloroform is in the production of the refrigerant HCFC-22
It is also used in pesticide formulation, as a solvent and chemical intermediate
Chloroform was used as a general anaesthetic in the past.



Chloroform is produced by hydrochlorination of methanol or by chlorination of methane. It is
used primarily in the production of refrigerant HCFC-22 (chlorodifluoromethane or
hydrochlorofluorocarbon 22). HCFC-22 is used for home air conditioners or large
supermarket freezers and in the production of fluoropolymers.

Chloroform is used in pesticide formulations, as a solvent and chemical intermediate in
laboratories and industrial situations, as a cleansing agent, in fire extinguishers and in the
rubber industry. It is also used in the manufacture of fluorocarbon plastics, resins and
propellants.

In the past, chloroform was extensively used to induce and maintain medical anaesthesia. Its
use as an anaesthetic was discontinued due to the severe adverse health effects associated
with its use.

General Information: Page 4 of 5


CHLOROFORM GENERAL INFORMATION
Frequently Asked Questions

What is chloroform?

Chloroform is a clear, colourless non-flammable liquid with a characteristic sweet odour. The
main use of chloroform is the production of the refrigerant gas (HCFC-22). Chloroform is also
used in pesticide formulations, as a solvent and as a chemical intermediate.

How does chloroform get into the environment?

Chloroform can exist naturally in the environment and is also released from workplaces
where it is manufactured and used. Water treatment processes involving chlorination can
also lead to the production and release of small quantities of chloroform.

How will I be exposed to chloroform?

People may be exposed to chloroform by inhaling contaminated air, drinking contaminated
water or by eating food containing chloroform. Workers involved in the production and use of
chloroform and those working at sites where chloroform is indirectly produced (e.g. water-
treatment plants), may be exposed to higher levels of chloroform than the general population.

If there is chloroform in the environment will I have any adverse health effects?

The presence of chloroform in the environment does not always lead to exposure. Clearly, in
order for it to cause any adverse health effects you must come into contact with it. You may
be exposed by breathing, eating, or drinking the substance or by skin contact. Following
exposure to any chemical, the adverse health effects you may encounter depend on several
factors, including the amount to which you are exposed (dose), the way you are exposed, the
duration of exposure, the form of the chemical and if you were exposed to any other
chemicals.

Chloroform vapours can cause shortness of breath and mouth and throat dryness. Ingestion
of chloroform may cause burning of the mouth and throat and vomiting. Skin or eye contact
will lead to irritation and inflammation. More severe exposures to chloroform by inhalation or
ingestion will cause dizziness, drowsiness, liver and kidney damage, convulsions, heart
problems, unconsciousness and in some cases death.

Long-term exposure to chloroform can cause liver damage.

Can chloroform cause cancer?

Chloroform has been classified by the International Agency for Research on Cancer as
possibly causing cancer in humans. Prolonged exposure to high levels sufficient to cause
liver damage is believed to be necessary to cause cancer.


Does chloroform affect children or damage the unborn child?

Children will be affected by chloroform in the same way as adults. There is no evidence to
suggest that chloroform, at concentrations that do not affect the mother, can affect the health
of the unborn child.



General Information: Page 5 of 5


CHLOROFORM GENERAL INFORMATION

What should I do if I am exposed to chloroform?

It is very unlikely that the general population will be exposed to a level of chloroform high
enough to cause adverse health effects.

























This document from the HPA Centre for Radiation, Chemical and Environmental Hazards reflects
understanding and evaluation of the current scientific evidence as presented and referenced in this
document.






Chloroform

Incident management


Key Points

Fire
Not combustible
Reacts with strong bases in the presence of organic solvents and alkali metals which
explode on impact
Emits toxic fumes of phosgene, hydrogen chloride and chlorine on decomposition
In the event of a fire involving chloroform, use fine water spray and normal fire kit with
breathing apparatus

Health
Toxic by inhalation and ingestion
Immediate signs and symptoms of exposure include initial excitement and nausea
followed by CNS depression, ataxia, fatigue and dizziness
Delayed effects (up to 48 hours post exposure) may include liver and kidney damage
Inhalation causes nose and throat irritation, dry mouth and throat and shortness of
breath
Ingestion causes a burning sensation of mouth and throat, nausea and vomiting.
Dermal exposure causes irritation, defatting of skin and dermatitis.
Ocular exposure to vapours may be irritating. Direct contact with liquid causes
immediate pain and conjunctivitis

Environment
Avoid release into the environment
Inform Environment Agency of substantial incidents










CRCE HQ, HPA
03/2012
Version 2

Incident management: Page 2 of 11

CHLOROFORM INCIDENT MANAGEMENT
Hazard Identification

Standard (UK) Dangerous Goods Emergency Action Codes
(a)


UN 1888
Chloroform
EAC 2Z
Use fine water spray. Wear normal fire kit in combination with
breathing apparatus *. Spillages and decontamination run-off
should be prevented from entering drains and watercourses.
APP -
Hazards
Class 6.1 Toxic substance
Sub
risks
-
HIN 60 Toxic or slightly toxic substance
UN United Nations number; EAC Emergency Action Code; APP Additional Personal
Protection; HIN - Hazard Identification Number























*Normal fire fighting clothing i.e. fire kit (BS EN 469), gloves (BS EN 659) and boots (HO
specification A29 and A30) in combination with self-contained open circuit positive pressure
compressed air breathing apparatus (BS EN 137).


a
Dangerous Goods Emergency Action Code List 2011. National Chemical Emergency Centre
(NCEC). The Stationary Office, London.


Incident management: Page 3 of 11

CHLOROFORM INCIDENT MANAGEMENT

Chemical Hazard Information and Packaging for Supply Classification
(a)


Classification
Xn Harmful
Xi Irritant
Carc. Cat 3 Category 3 carcinogen
Risk phrases
R22 Harmful if swallowed
R38 Irritating to skin
R40 Limited evidence of a carcinogenic effect
R48/20/22
Harmful: danger of serious damage to health by prolonged
exposure through inhalation and if swallowed
Safety phrases
S2 Keep out of the reach of children
S36/37 Wear suitable protective clothing and gloves


Specific concentration limits

Concentration Classification
C 5 % Xn; R22
C 5 % Xn; R48/20/22


a
Annex VI to Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging of
Substances and Mixtures- Table 3.2.
http://esis.jrc.ec.europa.eu/index.php?PGM=cla (accessed 03/2012)


Incident management: Page 4 of 11

CHLOROFORM INCIDENT MANAGEMENT
Globally Harmonised System of Classification and Labelling of Chemicals
(GHS)
(a)


Hazard Class
and Category
Carc. 2 Carcinogenicity, category 2
Acute Tox. 4 Acute toxicity, category 4
STOT RE 2
Specific target organ systemic toxicity
following repeated exposure, category 2
Skin Irrit. 2 Skin irritation, category 2
Hazard
Statement
H351 Suspected of causing cancer
H302 Harmful if swallowed
H373
May cause damage to organs through prolonged or repeated
exposure
H315 Causes skin irritation
Signal Words WARNING


Specific concentration limits

Concentration
Hazard Class
and Category
Hazard Statement
C 5 % STOT RE 2 H373
May cause damage to organs through
prolonged or repeated exposure


a
Annex VI to Regulation (EC) No 1272/2008 on Classification, Labelling and Packaging of
Substances and Mixtures- Table 3.1.
http://esis.jrc.ec.europa.eu/index.php?PGM=cla (accessed 01/2012)


Incident management: Page 5 of 11

CHLOROFORM INCIDENT MANAGEMENT
Physicochemical Properties

References
(a,b,c)



a
Chloroform (HAZARDTEXT

Hazard Management). In: Klasco RK (Ed): TOMES

System, Thomson
Micromedex, Greenwood Village, Colorado, USA. (electronic version). RightAnswer.com, Inc.,
Midland, MI, USA, Available at: http://www.rightanswerknowledge.com/data/dt/dt651.htm (accessed
01/2012).
b
The Merck Index (14
th
Edition). Entry 2141: Chloroform, 2006.
c
The Dictionary of Substances and their Effects. Ed. S Gangolli. Second Edition, Volume 2, 1999.
CAS number 67-66-3
Molecular weight 119
Empirical formula CHCl
3

Common synonyms Trichloromethane; Methyl trichloride.
State at room temperature Liquid
Volatility Vapour pressure 197mm Hg at 25C.
Specific gravity

1.5 at 20C
Flammability

Not combustible
Lower explosive limit

Not applicable
Upper explosive limit

Not applicable
Water solubility

Solubility in water, 7.7 g L
-1
at 25C. Soluble in alcohol,
benzene, ether and other organic solvents
Reactivity

Reactive. Chloroform reacts violently with strong bases in the
presence of an organic solvent, causing risk of fire or explosion.
Reacts with alkali metals which are explosive when subjected to
an impact
Reaction or degradation
products
Emits toxic and corrosive fumes of phosgene, hydrogen chloride
and chlorine when heated to decomposition
Odour Sweet
Structure


Incident management: Page 6 of 11

CHLOROFORM INCIDENT MANAGEMENT
Threshold Toxicity Values

EXPOSURE VIA INHALATION

ppm mg m
-3
SIGNS AND SYMPTOMS REFERENCES
< 50 < 249 Discomfort a
500 2490 Symptoms of illness a
2000 9960
Severe toxic effects (60 minutes
exposure)
a
4896 14892 24000 73000 Induction of anaesthesia a

EXPOSURE VIA INGESTION

g SIGNS AND SYMPTOMS REFERENCES
7.5 Serious illness b
45 Estimated mean lethal oral dose for an adult b

a
International Programme on Chemical Safety, Environmental Health Criteria 163: Chloroform, 1994.
b
International Programme on Chemical Safety. Concise Chemical International Chemical Assessment
Document 58. Chloroform, 2004.

Incident management: Page 7 of 11

CHLOROFORM INCIDENT MANAGEMENT
Published Emergency Response Guidelines

Emergency Response Planning Guideline (ERPG) Values
(a)



Listed value
(ppm)
Calculated value
(mg m
-3
)
ERPG-1* NA NA
ERPG-2** 50 244
ERPG-3*** 5000 24413

NA = Not appropriate
* Maximum airborne concentration below which it is believed that nearly all individuals could be
exposed for up to 1 hr without experiencing other than mild transient adverse health effects or
perceiving a clearly defined, objectionable odour.
** Maximum airborne concentration below which it is believed that nearly all individuals could be
exposed for up to 1 hr without experiencing or developing irreversible or other serious health effects or
symptoms which could impair an individual's ability to take protective action.
*** Maximum airborne concentration below which it is believed that nearly all individuals could be
exposed for up to 1 hr without experiencing or developing life-threatening health effects.



Interim Acute Exposure Guideline Levels (AEGLs)
(b)


ppm
10 min 30 min 60 min 4 hr 8 hr
AEGL-1

NR NR NR NR NR
AEGL-2

120 80 64 40 29
AEGL-3

4000 4000 3200 2000 1600

NR = Not recommended due to insufficient data.

The level of the chemical in air at or above which the general population could experience notable
discomfort.

The level of the chemical in air at or above which there may be irreversible or other serious long-
lasting effects or impaired ability to escape.

The level of the chemical in air at or above which the general population could experience life-
threatening health effects or death.

a
American Industrial Hygiene Association (AIHA). 2011 Emergency Response Planning Guideline
Values.
http://www.aiha.org/insideaiha/GuidelineDevelopment/ERPG/Documents/2011erpgweelhandbook_tabl
e-only.pdf (accessed 03/2011).
b
U.S. Environmental Protection Agency. Acute Exposure Guideline Levels,
http://www.epa.gov/oppt/aegl/pubs/chemlist.htm (accessed 03/2011).

Incident management: Page 8 of 11

CHLOROFORM INCIDENT MANAGEMENT
Exposure Standards, Guidelines or Regulations

Occupational standards

WEL
(a)
http://www.hse.gov.uk/

LTEL (8 hour reference period): 2 ppm
(9.9 mg m
-3
)
STEL(15 min reference period): No guideline value
specified

Public health guidelines


DRINKING
WATER QUALITY GUIDELINE
(b)
http://www.who.int/en/

0.3 mg L
-1

AIR QUALITY GUIDELINE No guideline value specified
SOIL GUIDELINE VALUE AND
HEALTH CRITERIA VALUES


No guideline value specified
WEL Workplace exposure limit; LTEL - Long-term exposure limit; STEL Short-term
exposure limit

a
EH40/2005 Workplace Exposure Limits (second edition, published 2011).
http://www.hse.gov.uk/pubns/priced/eh40.pdf (accessed 03/2012)
b
Guidelines for Drinking-Water Quality, Fourth Edition. WHO, Geneva. 2011.


Incident management: Page 9 of 11

CHLOROFORM INCIDENT MANAGEMENT
Health Effects

Major route of exposure
(a)


Toxic by inhalation and ingestion and to a lesser extent by eye and skin exposure.

Immediate signs or symptoms of acute exposure
(a)


Systemic toxicity: progressive CNS depression with initial excitement and nausea
followed by ataxia, dysarthria, fatigue and dizziness. These effects will be markedly
increased by co-ingestion of alcohol. In severe cases there is coma and respiratory
depression. Cardiac arrhythmias and arrest are caused by sensitisation of the
myocardium to circulating catecholamines.
After acute exposures, hepatotoxicity can occur up to 48 hours later. Effects can
include enlarged liver, jaundice and elevated liver enzyme activities. Renal damage
has also been reported.
Inhalation causes nose and throat irritation, dry mouth and throat. Shortness of breath
may also occur.
Ingestion causes a burning sensation of mouth and throat, nausea and vomiting.
Systemic toxicity may follow.
Dermal exposure may cause irritation, defatting of skin and dermatitis. Prolonged skin
contact may produce burns.
Ocular exposure with chloroform vapours may causes irritation. Direct contact with
liquid causes immediate pain and conjunctivitis, loss of the corneal epithelium may
occur, but with prompt regeneration.

TOXBASE - http://www.toxbase.org (accessed 01/2012)
a
TOXBASE: Chloroform, 2004.

Incident management: Page 10 of 11

CHLOROFORM INCIDENT MANAGEMENT
Decontamination and First Aid

Important Notes

Ambulance staff, paramedics and emergency department staff treating chemically-
contaminated casualties should be equipped with Department of Health approved,
gas-tight (Respirex) decontamination suits based on EN466:1995, EN12941:1998
and prEN943-1:2001, where appropriate.
Decontamination should be performed using local protocols in designated areas such
as a decontamination cubicle with adequate ventilation.

Dermal exposure
(a)


Remove patient from exposure.
The patient should remove all clothing and personal effects.
Double-bag soiled clothing and place in a sealed container clearly labelled as a
chemical hazard.
Gently blot away any adherent liquid from the patient.
Wash hair and all contaminated skin with copious amounts of water (preferably warm)
and soap for at least 10-15 minutes. Decontaminate open wounds first and avoid
contamination of unexposed skin.
Pay special attention to skin folds, axillae, ears, fingernails, genital areas and feet.

Ocular exposure
(b)


Remove patient from exposure.
Remove contact lenses if present and immediately irrigate the affected eye
thoroughly with water or 0.9% saline for at least 10-15 minutes.
Patients with corneal damage or those whose symptoms do not resolve rapidly
should be referred for urgent ophthalmological assessment.

Inhalation
(c)

Remove patient from exposure.
Ensure a clear airway and adequate ventilation.
Give oxygen if required.
Manage as below if systemic features are present.

Ingestion
(c)

Remove patient from exposure.
Consider gastric aspiration if a life threatening amount has been ingested by an adult
within 1 hour.
Manage as below if systemic features are present.


TOXBASE - http://www.toxbase.org (accessed 01/2012)
a
TOXBASE: Skin decontamination solvents, 1996.
b
TOXBASE: Eye irritants, 2002.
c
TOXBASE: Chloroform, 2004.

Incident management: Page 11 of 11

CHLOROFORM INCIDENT MANAGEMENT
Systemic
(a)


Remove patient from exposure.
Ensure a clear airway and adequate ventilation.
Monitor pulse and blood pressure and perform 12 lead ECG in symptomatic patients.
Apply other supportive measures as indicated by the patient's clinical condition.
















































This document from the HPA Centre for Radiation, Chemical and Environmental Hazards reflects
understanding and evaluation of the current scientific evidence as presented and referenced in this
document.


TOXBASE - http://www.toxbase.org (accessed 01/2012)
a
TOXBASE: Chloroform, 2004.






Chloroform

Toxicological overview


Key Points

Kinetics and metabolism

Chloroform is readily absorbed from the lungs, gastrointestinal tract and skin
Chloroform undergoes metabolism via an oxidative or a reductive pathway
Chloroform is mainly excreted via the lungs unchanged or as the main metabolite
carbon dioxide

Health effects of acute exposure

Harmful, irritant and possibly carcinogenic after prolonged exposure
Acute inhalation of chloroform can cause systemic effects such as excitement,
nausea, vomiting followed by dizziness, ataxia and drowsiness. Convulsions, coma
and death may occur following substantial exposures
Delayed effects of chloroform exposure include renal and hepatic damage (up to 48
hours post exposure)
Local effects are observed following inhalation (irritation of the nose and throat),
ingestion (burning sensation of the mouth and throat), ocular (stinging) and dermal
exposure (irritation and redness)


Health effects of chronic exposure

Chronic inhalation or ingestion of chloroform may cause hepatic damage
The International Agency for Research on Cancer (IARC) classified chloroform as a
category 2B carcinogen i.e. possibly carcinogenic to humans







Prepared by K Foxall
CHAPD HQ, HPA
2007
Version 1

Toxicological Overview: Page 2 of 12

CHLOROFORM TOXICOLOGICAL OVERVIEW
Toxicological Overview

Summary of Health Effects

Local effects following inhalation of chloroform include shortness of breath and irritation of
the nose and throat. Acute inhalation can cause systemic effects such as, excitement,
nausea and vomiting followed by ataxia, dizziness, drowsiness. Exposure to high
concentrations may cause convulsions, coma and death due to respiratory failure or cardiac
arrhythmias. Individuals who survive an acute exposure to chloroform may develop hepatic
dysfunction and renal damage several days later. Chronic inhalation of chloroform may
cause hepatic damage.

Following acute ingestion of chloroform, systemic effects as seen following inhalation may
occur as well as a burning sensation in the mouth and throat, nausea and vomiting. Hepatic
toxicity has been reported following chronic ingestion of chloroform.

Following acute dermal exposure to chloroform, local effects may include irritation and
redness. Prolonged contact may result in systemic toxicty, dermatitis and burns.

Acute ocular exposure to chloroform may cause a stinging sensation and exposure to
chloroform liquid can cause irritation of the conjunctival tissue, corneal necrosis and ulcers.

Chloroform does not have any significant mutagenic properties.

The IARC has concluded that there is inadequate evidence in humans for the carcinogenicity
of chloroform but sufficient evidence in experimental animals for the carcinogenicity of
chloroform, and it is therefore classified as possibly carcinogenic to humans (Group 2B). The
tumours seen in animal bioassays were only at dose levels producing chronic cytotoxicity in
the target organs (liver and kidney) and were believed to be secondary to the sustained cell
proliferation that this induced.
Data from experimental studies in animals indicates that adverse effects on development
would not be expected at exposures below those producing overt toxicity in the maternal
animals. Similarly no adverse effects on fertility were seen at dose levels below those
producing maternal systemic toxicity (reduction in weight gain and hepatotoxicity).

Toxicological Overview: Page 3 of 12

CHLOROFORM TOXICOLOGICAL OVERVIEW
Kinetics and Metabolism

Chloroform is readily absorbed from the lungs, gastrointestinal tract and skin [1, 2].
Approximately 60 80% of inhaled chloroform is absorbed [1].

Following absorption, chloroform is distributed throughout the body. Human and animal
inhalation and oral exposure studies have recorded high chloroform concentrations in
adipose tissue, brain, liver, kidneys, adrenals and blood [1, 2].

Chloroform is metabolised in humans and animals by oxidative or reductive cytochrome
P450 dependent pathways. It has been suggested that chloroform metabolism mainly occurs
via the oxidative pathway [3, 4].

In the presence of oxygen (oxidative pathway) chloroform undergoes oxidative dechlorination
to form trichloromethanol, which spontaneously dehydrochlorinates to form phosgene.
Subsequent hydrolysis of phosgene forms hydrochloric acid and the main metabolite carbon
dioxide [3, 4], Phosgene may also react with cellular macromolecules (such as enzymes,
proteins or the polar heads of phospholipids), leading to the formation of covalent adducts.
The adducts can interfere with molecular function which may result in loss of cellular function
and cell death [3].

In the absence of oxygen (reductive pathway), the main metabolite is dichloromethyl free
radical, which is extremely reactive and forms covalent adducts with microsomal enzymes
and fatty acid tails of phospholipids. This may result in the loss of microsomal enzyme
activity and can also lead to lipid peroxidation [3].

Almost all tissues are capable of metabolising chloroform, the highest levels of metabolism
occur in the liver, kidney and nasal mucosa.[3]. Chloroform is excreted via the lungs
unchanged or in the form of the metabolite carbon dioxide, with small amounts of either
detectable in the urine and faeces. [2].

Sources and Route of Exposure

Exposure to chloroform may occur via inhalation (contaminated air), ingestion (contaminated
food, beverages and water) and possibly through dermal contact (showering, cleaning and
swimming) [1, 2, 4].

Chloroform may be released into the environment from its use, production and transport. It is
also indirectly formed as a result of the reaction of chlorine with organic compounds [1].
Processes known to contribute to the indirect formation and emission of chloroform include
paper bleaching with chlorine and chlorination of municipal water, swimming pools and waste
water [1, 2]. Under certain conditions some bacteria can dehalogenate carbon tetrachloride
to release chloroform [2].

The majority of chloroform that enters the environment will eventually enter the atmosphere,
due to its volatility [1, 2]. The degradation of chloroform involves a reaction with hydroxyl
radicals; the half-life for degradation is reported to be approximately 100 180 days [1].

Chloroform is a by-product of water chlorination and is therefore present in drinking water.
The drinking water quality guideline for chloroform is 0.2 mg L
-1
[5]. It has also been detected
in sea, waste and ground waters [1].


Toxicological Overview: Page 4 of 12

CHLOROFORM TOXICOLOGICAL OVERVIEW
Atmospheric chloroform levels in remote, urban and source-dominated areas have been
reported to range from 0.1 0.25, 0.9 9.9 and 4.1 110 g m
-3
, respectively. The indoor air
concentration of chloroform can be up to ten-fold higher than outdoor air concentrations. The
use of chlorinated water in homes is thought to significantly contribute to levels of chloroform
in indoor air [1]. Concentrations of chloroform may exceed 1000 g m
-3
in a shower cubical,
as a result of volatilisation from hot water [2].

Exposure to chloroform may also occur in the workplace. Individuals that work at or near
facilities that manufacture or use chloroform (e.g. drinking water-plants, waste water-
treatment plants and pulp and paper plants) may be exposed to considerably higher levels of
chloroform than the general population [2].




















Toxicological Overview: Page 5 of 12

CHLOROFORM TOXICOLOGICAL OVERVIEW

Health Effects of Acute / Single Exposure

Human Data

General toxicity

The main target organs of chloroform-induced toxicity are the central nervous system and the
liver. The main symptoms of acute chloroform poisoning depend upon the concentration of
chloroform absorbed, rather than the route of exposure [6]. Older clinical reports involving
patients exposed to chloroform as a method of anaesthesia, have reported that exposure to
40,000 ppm chloroform (195,600 mg m
-3
) for several minutes may be lethal [2, 7]. Dizziness
and vertigo were observed in humans exposed to 920 ppm chloroform (4498 mg m
-3
) for 3
minutes [2]. Chloroform can cause symptoms of illness at 2490 mg m
-3
and discomfort at
levels below 249 mg m
-3
[1].

Chloroform also causes progressive central nervous system depression. Initial symptoms
include excitement, nausea and vomiting followed by ataxia, dizziness, drowsiness,
convulsions and coma [6, 8]. In severe cases paralysis of the medullary respiratory centre
may lead to respiratory failure and sudden death [6].

Early death following exposure to high levels of chloroform is often due to cardiac
arrhythmias. Chloroform may also cause hypotension [1, 2, 6].
In the past, chloroform was extensively used to induce and maintain medical anaesthesia. Its
use as an anaesthetic was abandoned because it caused hepatic damage and deaths due to
respiratory and cardiac arrhythmias and failure [1]. Chloroform levels of 3,000 30,000 ppm
(14,670 146,700 mg m
-3
) were used to induce anaesthesia [2].

Inhalation

Inhalation of chloroform can cause severe acute toxicity, as described in the general toxicity
section. Inhalation of concentrated chloroform vapour causes irritation of exposed mucous
membranes, including the nose and throat [7]. Shortness of breath may also occur [6].

Other effects reported following the use of chloroform as an anaesthetic include hypothermia,
depression of gastrointestinal tract motility, respiratory acidosis, hyperglycaemia,
ketoacidosis, constriction of the spleen and an increase in leukocyte count [1, 6].

Ingestion

Ingestion of chloroform can cause severe acute toxicity, as described in the general toxicity
section. Local effects following ingestion of chloroform include gastrointestinal irritation with
abdominal pain, nausea, vomiting and diarrhoea [6].

There are considerable inter-individual differences in susceptibility to chloroform following
acute ingestion. Serious illness has been reported following ingestion of 7.5 g chloroform.
Fatal doses have been reported to be as low as 14.8 g, whereas other individuals have

Toxicological Overview: Page 6 of 12

CHLOROFORM TOXICOLOGICAL OVERVIEW
survived a dose of 270 g chloroform [1, 2]. The mean lethal dose for adults is estimated to
be approximately 45 g [1].

Dermal / ocular exposure

Chloroform may be absorbed across the skin and prolonged exposure may result in systemic
toxicity, as described in the inhalation section. Skin exposure causes irritation and redness at
the site of contact, especially sensitive areas such as the eyelids and neck [6]. Prolonged
contact may result in burns and dermatitis [7].

Liquid chloroform splashed in the eye causes immediate burning pain, tearing and reddening
of the conjunctiva. The corneal epithelium is usually injured but regeneration is prompt and
as a rule the eye returns to normal within 1 - 3 days [9].


Delayed effects following an acute exposure

Individuals who survive an acute exposure to chloroform may develop hepatic dysfunction
several days later. Symptoms include prostration, nausea, vomiting, jaundice, coma and in
some cases death [1]. Necrosis of the liver may occur, resulting in increased concentrations
of serum bilirubin and transaminases [6].

Renal damage is less common than hepatic damage but it may occur following acute
exposure to chloroform. Renal tubular necrosis and renal dysfunction (anuria, proteinuria and
uraemia) have been reported in individuals who were exposed to chloroform as an
anaesthetic [4].


Animal and In-Vitro Data

General toxicity

The acute toxic effects of chloroform in animals are similar to those observed in humans. The
main target organs are the liver, kidneys and the central nervous system.

Inhalation

Exposure to chloroform at concentrations in the range of 10 100 g m
-3
resulted in
anaesthesia in mice, rabbits, guinea pigs and cats. Cardiac effects including decreased
diastolic pressure, reduction of stroke volume and decreased cardiac output were reported in
rabbits exposed to 224 mg m
-3
chloroform for one minute. Liver toxicity was observed in mice
and rats exposed to 490 and 1410 mg m
-3
chloroform, respectively. Kidney effects including
necrosis of the proximal and distal tubules were reported in male mice exposed to 3400
5400 mg m
-3
chloroform for 1 3 hours [1].

Ingestion

Oral administration of chloroform can result in anaesthesia. The ED
50
in mice for acute
neurological effects (ataxia, incoordination and anaesthesia) was 484 mg kg
-1
bw. Hepatic

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CHLOROFORM TOXICOLOGICAL OVERVIEW
effects (centrilobular fatty infiltration) have been observed in mice at doses as low as 35 mg
kg
-1
bw and chloroform administered at 250 mg kg
-1
bw by gavage has caused hepatic
necrosis in mice [1, 4]. In rats, piloerection, sedation, flaccid muscle tone, ataxia, prostration,
reduced food intake and kidney and liver effects following exposure to 546 mg kg
-1
bw [1].

The acute oral LD
50
for chloroform in mice ranges from 36 1366 mg kg
-1
bw and for rats it
ranges from 450 2000 mg kg
-1
bw.

Dermal / ocular exposure

Moderate necrosis, hyperaemia and eschar formation were observed when chloroform (1000
or 4000 mg kg
-1
bw) was applied under a patch to the skin of rabbits for 24 hours. Systemic
effects including weight loss and degenerative changes in the tubules of the kidneys were
also reported [1, 7].

Eye contact with chloroform liquid has resulted in corneal injury and conjunctivitis in rabbits
[1, 7].

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CHLOROFORM TOXICOLOGICAL OVERVIEW
Health Effects of Chronic / Repeated Exposure

Human Data
General toxicity

Hepatic and central nervous system toxicity are the main effects following long term
exposure to chloroform.

Inhalation

In an occupational study, workers exposed to 14 400 ppm (68 1956 mg m
-3
) developed
toxic hepatitis and other effects, including jaundice, nausea and vomiting without fever [2, 7].

In another study, 68 workers were occupationally exposed to chloroform concentrations of 10
1000 mg m
-3
for 1 4 years. A higher frequency of hepatitis was found in the group of
workers compared with city inhabitants. Seventeen of the workers had hepatomegaly, three
of which developed hepatitis [1].

Chronic occupational exposure to 375 1330 mg m
-3
chloroform, with a peak concentration
of 5680 mg m
-3
, for periods of 3 to 10 years was reported to cause lassitude, thirst,
gastrointestinal distress, frequent and scalding urination, lack of concentration, depression
and irritability in 8 exposed workers. Nine workers who were exposed to lower concentrations
of chloroform (110 350 mg m
-3
for 10 24 months) also experienced the same effects, but
to a lesser degree [1].

A case study of an individual who abused chloroform for approximately 12 years reported
delusions, hallucinations, psychotic episodes and convulsions. Withdrawal symptoms,
including dysarthria and ataxia have been reported following the abrupt discontinuation of
chloroform use [2].

Ingestion

There is limited data available regarding the health effects of chronic exposure to chloroform
in humans.

Hepatitis and nephrosis were observed in a man who ingested cough mixture containing 1.6
2.6 g of chloroform daily for 10 years [6]. No renal or hepatic effects were observed in
humans who used ingested 0.34 0.96 mg kg
-1
bw day
-1
chloroform in mouthwash

for up to
5 years [2].

Genotoxicity

There are currently no data available regarding the genotoxic effects of chloroform in
humans.

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CHLOROFORM TOXICOLOGICAL OVERVIEW

Carcinogenicity
Chlorinated drinking water typically contains chloroform, other trihalomethanes and a wide
variety of other disinfection by-products. There has been considerable epidemiological
research into the question of associations between chlorinated drinking-water and various
diseases, and this research continues. The results have raised concern that chlorination by-
products in drinking-water may increase the risk of certain cancers. However, no
conclusions can be drawn specifically about chloroform from these studies.
The expert advisory Committee on Carcinogenicity of Chemicals in Food, Consumer
Products and the Environment (COC) considered that the evidence was inconclusive, but
advised that efforts to minimise exposure to chlorination by-products remain appropriate,
providing that they do not compromise the efficiency of disinfection of drinking-water (see the
statement at http://www.advisorybodies.doh.gov.uk/coc/drink.htm) [10]. The committee will
be reviewing these issues again shortly.

The International Agency for Research on Cancer (IARC) has concluded that there is
inadequate evidence in humans for the carcinogenicity of chloroform but sufficient evidence
in experimental animals for the carcinogenicity of chloroform. It is classified as possibly
carcinogenic to humans (Group 2B) [11].

Reproductive and developmental toxicity

There are no data available regarding the reproductive and developmental effects of
chloroform per se.
There has been considerable epidemiological research into the question of associations
between chlorinated drinking-water and various diseases, and this research continues. The
results have raised concern that chlorination by-products in drinking-water may increase the
risk of certain adverse reproductive outcomes. However, no conclusions can be drawn
specifically about chloroform from these studies.
The expert advisory Committee on Toxicity of Chemicals in Food, Consumer Products and
the Environment (COT) considered that the evidence was inconclusive, but advised that
efforts to minimise exposure to chlorination by-products remain appropriate, providing that
they do not compromise the efficiency of disinfection of drinking-water (see the statement at
http://cot.food.gov.uk/cotstatements/cotstatementsyrs/cotstatements2004/chlorwater) [12].
The committee will be reviewing these issues again shortly.


Animal and In-Vitro Data

Inhalation

The liver, kidneys and nasal cavity are primary targets for chloroform-induced toxicity
following chronic exposure [1, 2, 4]. In a medium-term study, BDF
1
mice were exposed to
chloroform 0, 59, 123, 245, 490, or 980 mg m
-3
6 hours day
-1
, 5 days week
-1
, for 13 weeks.
All the females survived but reduced growth and deaths occurred in males in all chloroform
groups. At exposure levels of 59 mg m
-3
and above, male mice showed kidney (necrosis of
the proximal tubules) and nasal cavity effects (bone thickening and degeneration of the

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CHLOROFORM TOXICOLOGICAL OVERVIEW
olfactory epithelium). Nasal cavity toxicity was observed in female mice at all exposure
levels. Liver toxicity was not observed in either sex at up to 245 mg m
-3
chloroform, abnormal
cells were seen in females at 490 mg m
-3
and swelling and necrosis at 980 mg m
-3
[4].

Ingestion

Several studies have reported nephrotoxic and heptotoxic effects in laboratory animals
chronically exposed to chloroform [1, 2, 4]. In one study it was reported that chloroform
administered by gavage in corn oil was significantly more hepatotoxic compared with
chloroform administered in aqueous emulsion. Male and female B6C3F
1
mice

were
administered 0, 130 and 270 mg kg
-1
chloroform for 90 days. Liver body weight ratios were
higher in all dose groups when chloroform was administered in corn oil. Disruption of hepatic
architecture including cirrhosis was observed in the group administered the high dose of
chloroform in corn oil. No pathological changes were observed in any of the animals
administered chloroform in aqueous emulsion [1].

Hepatic damage was observed in beagle dogs administered 15 mg kg
-1
chloroform in
toothpaste over a period of 7.5 years [1].

Genotoxicity

The genotoxic potential of chloroform has been tested in several in-vitro and in-vivo assays.
The majority of results for the Ames Salmonella assay and Escherichia coli test system were
negative, both with and without metabolic activation. Tests for unscheduled DNA synthesis
have produced negative results in human and animal cells. Chloroform did not induce
chromosome aberrations in human lymphocytes in culture. Sister chromatid exchange
assays using human lymphocytes gave mixed results. Chloroform also induced sister
chromatid exchange in mouse bone marrow cells in vivo and chromosome aberrations in rat
bone marrow in vivo [4]. Three out of four bone marrow micronuclei in-vivo studies in mice
produced negative results, the fourth study gave a weekly positive result [1, 4]. Overall, the
evidence suggests that chloroform does not have significant genotoxic potential.

Carcinogenicity

The carcinogenicity of chloroform has been investigated in rodents. Chloroform produced
renal adenomas and carcinomas in male mice exposed via inhalation or ingestion and in
male rats following oral exposure. An increase in incidence of hepatocellular adenomas and
carcinomas was observed in mice of either sex, exposed to chloroform by ingestion. Thyroid
tumours were noted in female rats orally administered chloroform. The IARC has concluded
that there is sufficient evidence in experimental animals for the carcinogenicity of chloroform
[11, 13].

There is experimental evidence to suggest that kidney and liver tumours in rodents are
secondary to the cytotoxic effects of metabolites (such as phosgene and hydrogen chloride)
and persistent associated reparative cell proliferation [1, 4]. At the high dose levels used in
the carcinogenicity bioassay in which tumours were produced, chloroform induced
cytotoxicity and regenerative cell proliferation in the target organs for cancer consistent with
the mode of action for tumourgenesis in the liver and kidney involving cytotoxicity [11].


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CHLOROFORM TOXICOLOGICAL OVERVIEW

Reproductive and developmental toxicity

Developmental studies involving oral exposure in rats have reported effects on the fetus
(reduced fetal body weight) but only at dose levels that were maternally toxic. No teratogenic
effects were observed [4].

Few data were found regarding the effects of chloroform on reproduction.

In a continuous breeding reproductive toxicity study in CD-1 mice no effects were reported
on fertility or reproduction in the F
1
generation. The mice had been exposed in utero and
during lactation (as a result of maternal treatment) and then by gavage at 41 mg kg
-1
bw day
-
1
, through to young adulthood. The dose level did not produce any effect on fertility, but did
induce hepatotoxicity in the parent animals [4].

A three generation reproductive toxicity study has been reported using ICR mice. Chloroform
was administered at 0.1, 1 or 5 mg ml
-1
in drinking water. The only statistically significant
effects noted were reduced fertility, litter size, gestation index and viability index, at the
highest dose level. Some evidence of hepatotoxicity was seen at all dose levels and mortality
was seen at the highest dose.[1].

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CHLOROFORM TOXICOLOGICAL OVERVIEW
References

1. International Programme on Chemical Safety (IPCS). Chloroform. Environmental
Health Criteria 163. 1994, WHO: Geneva.
2. Agency for Toxic Substances and Disease Registry (ATSDR). Toxicological Profile for
Chloroform. 1997, US Department of Health and Human Services: Atlanta, US.
3. U.S. Environmental Protection Agency (U.S. EPA). Toxicological Review of
Chloroform. 2001.
4. International Programme on Chemical Safety (IPCS). Chloroform. Concise
International Chemical Assessment Document 58. 2004, WHO: Geneva.
5. World Health Organisation (WHO). Guidelines for Drinking-Water Quality: Third
edition. Vol 1. Recommendations. 2004, WHO: Geneva.
6. International Programme on Chemical Safety (IPCS). Chloroform. Poisons
Information Monograph. PIM 121, WHO: Geneva.
7. Bingham B, Cohrssen B, and Powell C (eds). Patty's Toxicology. 5th Edition . Vol. 5.
2001: John Wiley & Sons, Inc.
8. National Poisons Information Service (NPIS). Chloroform. TOXBASE. 2004.
9. Grant W, M., and, and S. Schuman J. Toxicology of the Eye. 4th Edition . Vol. I.
1993, Illinois: Charles C Thomas Publisher.
10. Committee on Carcinogenicity of Chemicals in Food Consumer Products and the
Environment (COC). Chlorinated drinking water and cancer COC/99/S2. 1999.
11. International Agency for Research on Cancer (IARC). Some Chemicals that Cause
Tumours of the Kidney or Urinary Bladder in Rodents and Some Other Substances.
Vol 73, in IARC Monographs on the Evaluation of Carcinogenic Risks to Humans.
1999, IARC: Lyon.
12. Committee on Toxicity of Chemicals in Food Consumer Products and the
Environment (COT). COT Statement on chlorinated drinking water and reproductive
outcomes COT/04/8. 2004.
13. International Agency for Research on Cancer (IARC). Some Halogenated
Hydrocarbons. Vol 20., in IARC Monographs on the Evaluation of Carcinogenic Risks
to Humans. 1979, IARC: Lyon.









This document from the HPA Centre for Radiation, Chemical and Environmental Hazards reflects
understanding and evaluation of the current scientific evidence as presented and referenced in this
document.