Compendia of Chemical Hazards CHLOROFORM v2

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.



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.



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.



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.



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)



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)



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 (14th 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 CHCl3

Common synonyms Trichloromethane; Methyl trichloride.

State at room temperature Liquid

Volatility Vapour pressure 197mm Hg at 25°C.

Specific gravity 1.5 at 20°C

Flammability Not combustible

Lower explosive limit Not applicable

Upper explosive limit Not applicable

Water solubility Solubility in water, 7.7 g L-1 at 25°C. 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



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.



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_table-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).



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.



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.



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.



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).



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].



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 µg 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 µg 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].



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



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 ED50 in mice for acute neurological effects (ataxia, incoordination and anaesthesia) was 484 mg kg-1 bw. Hepatic



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 LD50 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].



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.



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, BDF1 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



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 B6C3F1 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].



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 F1 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].



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.

Date post:	21-Jul-2016
Category:	Documents
Upload:	aaryanrajesh
View:	13 times
Download:	0 times