Methylene chloride
| 1. NAME |
| 1.1 Substance |
| 1.2 Group |
| 1.3 Synonyms |
| 1.4 Identification numbers |
| 1.4.1 CAS |
| 1.4.2 Other numbers |
| 1.5 Main brand names/Trade names |
| 1.6 Main manufacturers, 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 Other characteristics |
| 4. USES/HIGH RISK CIRCUMSTANCES OF POISONING |
| 4.1 Uses |
| 4.1.1 Uses |
| 4.1.2 Description |
| 4.2 High risk circumstances of poisoning |
| 4.3 Occupationally exposed population |
| 5. ROUTES OF ENTRY |
| 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 AND BIOMEDICAL INVESTIGATIONS |
| 8.1 Material |
| 8.1.1 Sampling |
| 8.1.1.1 Toxicological analyses |
| 8.1.1.2 Biomedical analyses |
| 8.1.1.3 Arterial blood gases |
| 8.1.1.4 Haematological investigations |
| 8.1.2 Storage |
| 8.1.3 Transport |
| 8.2 Toxicological analyses and their interpretation |
| 8.2.1 Tests for toxic ingredient |
| 8.2.1.1 Simple qualitative test |
| 8.2.1.2 Advanced qualitative test |
| 8.2.1.3 Simple quantitative method |
| 8.2.1.4 Advanced quantitative method |
| 8.2.2 Tests for biological samples |
| 8.2.2.1 Simple qualitative test |
| 8.2.2.2 Advanced qualitative test |
| 8.2.2.3 Simple quantitative method |
| 8.2.2.4 Advanced quantitative method |
| 8.2.2.5 Other dedicated methods |
| 8.2.3 Interpretation |
| 8.3 Biomedical investigations and their interpretation |
| 8.3.1 Biochemical analysis |
| 8.3.1.1 Blood |
| 8.3.1.2 Urine |
| 8.3.1.3 Other |
| 8.3.2 Arterial blood gas analyses |
| 8.3.3 Haematological analyses |
| 8.4 Other relevant biomedical investigations and their interpretation |
| 8.5 Overall interpretation |
| 9. CLINICAL EFFECTS |
| 9.1 Acute poisoning by: |
| 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 by: |
| 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 Neurologic |
| 9.4.3.1 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 Dermatologic |
| 9.4.9 Eye, ears, nose, throat; local effects |
| 9.4.10 Hematologic |
| 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 risk |
| 9.5 Others |
| 10. MANAGEMENT |
| 10.1 General principles |
| 10.2 Relevant laboratory analyses and other investigations |
| 10.2.1 Sample collection |
| 10.2.2 Biomedical analysis |
| 10.2.3 Toxicological analysis |
| 10.2.4 Other investigations |
| 10.3 Life supportive procedures and symptomatic treatment |
| 10.4 Decontamination |
| 10.5 Elimination |
| 10.6 Antidote treatment |
| 10.6.1 Adults |
| 10.6.2 Children |
| 10.7 Management discussion: alternatives, controversies and research needs |
| 11. ILLUSTRATIVE CASES |
| 11.1 Case reports from literature |
| 11.2 Internally extracted data on cases |
| 11.3 Internal cases (added by the PC using monograph) |
| 12. ADDITIONAL INFORMATION |
| 12.1 Availability of antidotes and antisera |
| 12.2 Specific preventive measures |
| 12.3 Other |
| 13. REFERENCES |
| 14. AUTHOR(S), REVIEWER(S) DATE (INCLUDING EACH UP-DATE), COMPLETE AUTHOR(S), ADDRESSES |
1. NAME
1.1 Substance
Methylene chloride
1.2 Group
Halo-alkane
alkyl halide
alkyl chloride
1.3 Synonyms
dichloromethane
methane dichloride
methylene bichloride
methylene chloride
methylene dichloride
dichlorethane (German)
chlorure de methane (French)
dichloromethane (French)
dichlorometano (Italian)
methyleenchloride (Dutch)
metylenu chlorek (Polish)
1.4 Identification numbers
1.4.1 CAS
75-09-2
1.4.2 Other numbers
UN 1593
RTECS PA8050000
NCI c50102
NIOSH PA8050000
1.5 Main brand names/Trade names
Aerothene MM
Freon 30
Narkotill
Solaesthin
Solmethine
1.6 Main manufacturers, importers
To be added by the PCC using the monograph.
2. SUMMARY
2.1 Main risks and target organs
Methylene chloride is a highly volatile liquid.
Toxicity levels are time- and concentration-dependent. Most
poisonings are due to accidental inhalations causing headache
and nausea; high concentrations depress the central nervous
system, and fatalities have occurred.
Methylene chloride is also an hepatotoxic agent. Blood
carboxyhaemoglobin levels become clinically significant at
exposures around 500 ppm and may cause ischaemia and induce
dysrhythmias in heart patients. An additive effect occurs
with other forms of carbon monoxide exposure (e.g., from
tobacco smoking, and exhaust systems in industry).
Serious poisonings form methylene chloride exposure may occur
without significant elevation of carboxyhaemoglobin
levels.
Absorption also occurs through the skin, but probably not in
quantities sufficient to cause systemic toxicity.
High vapour concentrations cause ocular pain. Direct
application to the eye can cause burning and temporary ocular
damage.
Ingestion is unusual. A case study has indicated that rapid
gut absorption occurs. A corrosive action has been observed
on mucous membranes.
Chronic inhalation exposure may result in neurological
symptoms, including paraesthesiae, respiratory irritation and
gastrointestinal disturbances.
2.2 Summary of clinical effects
Inhalation of the vapour may give rise to dizziness,
nausea, tingling or numbness of the extremities; a sense of
fullness in the head; a sense of heat; stupor or dullness;
lethargy and drunkenness. Very high concentrations may lead
rapidly to unconsciousness, coma and death.
High concentrations of vapour are irritant to the eyes.
Splash contacts cause an immediate burning sensation.
The liquid is irritant to the skin and pain is associated
with direct dermal application. Second and third degree
burns were experienced by a victim who lay comatose in
methylene chloride for 30 minutes.
2.3 Diagnosis
Following serious methylene chloride exposures the
following analyses are recommended:
complete blood count
hepatic aminotransferase levels
creatinine levels
urinanalysis including urine myoglobin
blood carboxyhaemoglobin levels
Serious poisonings from methylene chloride exposure may occur
without significant elevation of carboxyhaemoglobin
levels.
Follow-up measurements of hepatic aminotransferase levels
should be undertaken within one week of exposure.
2.4 First-aid measures and management principles
Inhalation: Take proper precautions to ensure personal
safety before attempting rescue (see Section 12.2).
Immediately remove the victim to fresh air. If the victim is
conscious, inquire immediately upon the circumstances of the
poisoning, noting that the patient may become unconscious at
any time. Keep the victim at rest. Physical activity will
enhance total body distribution from increased blood flow.
Place in the recovery position and keep war. Monitor
respiration. Obtain medical attention immediately.
Ingestion: Dilute with water. (Milk is not indicated for
dilution and may increase gut absorption of methylene
chloride). Induce emesis using syrup of ipecac but consider
the risk of unconsciousness. Obtain medical advice
immediately.
Eye contact: Remove any contact lenses then flush the
contaminated eyes gently with water for 10 to 15 minutes
holding the eyelids open. Obtain medical advice
immediately.
Skin contact: Avoid direct contact with the chemical; wear
impervious gloves if necessary. Remove any contaminated
clothing and other tight articles against the body. Flush
the contaminated area gently with water for 10 to 15 minutes.
Obtain medical attention immediately.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
Methylene chloride is a synthetic halogenated
hydrocarbon, commercially produced mainly by two methods:
1. Direct chlorination of methane (where the major product
methyl chloride is further chlorinated).
2. Catalytical hydrochlorination of methanol, in vapour or
liquid phase.
(CEFIC, 1983)
3.2 Chemical structure
Structural formula CH2Cl2
Molecular weight 84.93 daltons.
3.3 Physical properties
3.3.1 Colour
Clear, colourless.
3.3.2 State/form
Volatile liquid.
3.3.3 Description
boiling point 39.5 to 40.5 °C
melting point -96.7 °C
autoignition temperature 624 °C
specific gravity 1.318 to 1.322
vapour density 2.93 (air = 1.02)
vapour pressure 46.5 kPa
refractive index 1.4327 (20 °C)
percentage in "saturated" air 55% (25 °C)
water solubility 2 g/100 mL
Soluble in ethanol, ether and dimethylformamide.
It has a sweetish chloroform-like odour above 300 ppm
which becomes unpleasant to most people at about 1000
ppm. At 2300 ppm it is strong and intensely irritating
(Clayton & Clayton 1981).
Flammable regions may exist above -9 °C. Methylene
chloride is flammable at concentrations of 12 to 15%
in ambient air, but only with elevated temperature and
pressure, or in oxygen-enriched air
(Bretherick, 1981).
conversion factors: 1 ppm in air (3.5 mg/1000 L)
[1 mg/1000 L = 0.29 ppm in air]
3.4 Other characteristics
Commercial grades of methylene chloride may contain
0.0001 to 1% of added stabilisers, such as phenol,
hydroquinone, p-cresol, resorcinol, thymol, 1-naphthol or
amines (RSC/CEC, 1986).
Although non-flammable, methylene chloride may, in the
presence of heat and moisture, form hydrochloric acid, carbon
dioxide, carbon monoxide, and phosgene. Phosgene formed by
thermal decomposition caused death when paint remover was
used in a poorly ventilated area heated by a kerosene strove
(CEFIC, 1983).
Fire management: Wear full protection clothing including
self-contained breathing apparatus. Use water spray to keep
fire-exposed containers cool.
Spill management: For large spills, evacuate area. Wear
full protective clothing and self contained breathing
apparatus. Absorb spilled material onto sand and remove to
lined drums for disposal.
To dispose, send to licensed reclaimers or permitted
incinerators. Do not dump into sewers. Compliance with
local regulations must be ensured.
4. USES/HIGH RISK CIRCUMSTANCES OF POISONING
4.1 Uses
4.1.1 Uses
4.1.2 Description
Methylene chloride has a variety of
applications based mainly on its high solvency power
and low boiling point. Uses include:
- paint and varnish stripper formulations (retail
and trade)
- extraction in food and pharmaceutical industries
- as a solvent in aerosol formulations
- process solvent in cellulose ester production, and
fibre and film forming
- adhesive formulations
- process solvent in polycarbonate production
- plastic processing
- extraction of fats and paraffins
- metal and textile treatment
- secondary blowing agent in flexible polyurethane
foams
- registered insecticide (USA) for commodity
fumigation of various grains
- fruit-ripening agent
- refrigerant
4.2 High risk circumstances of poisoning
Small or enclosed areas which are poorly ventilated
enable a build up of vapour concentration.
In industry, impairment of "senses" in workers following
inhalation of methylene chloride may cause "careless"
accidents and injury.
4.3 Occupationally exposed population
Paint and varnish stripping operations (greater than 30%
of total methylene chloride production is used in paint
stripper formulations).
Solvent workers and degreasers.
5. ROUTES OF ENTRY
5.1 Oral
Unlikely unless intentional harm or accidental splashing.
5.2 Inhalation
Most significant and frequent route of exposure and the
primary concern with respect to toxicity.
5.3 Dermal
Limited absorption through intact skin occurs, but
probably not in quantities sufficient to cause systemic
toxicity.
5.4 Eye
Significant absorption unlikely - data unavailable.
5.5 Parenteral
No data available at time of preparation of monograph.
5.6 Others
No data available at time of preparation of monograph.
6. KINETICS
6.1 Absorption by route of exposure
Inhalation: Most occupational exposures occur via the
respiratory tract. Of the inhaled amount, 55% is absorbed at
rest, 40% with light work, and 25% with heavy physical work.
However, total net absorption is greater with work, due to an
increased respiratory ventilation rate.
Blood: air partition coefficient at 37 °C approx. 8 to 10
Fat: air partition coefficient at 37 °C approx. 150 to 160
Studies in man show that steady state is achieved rapidly
after inhalation. This usually occurs in less than one hour,
with no substantial increase after 7.5 hours. In the 50 to
500 ppm range, net values of 52 to 75% are absorbed at steady
state (lower values at higher concentrations) (Illing &
Shillaker, 1985).
No differences have been noted between the sexes but net
absorption is greater in obese individuals (Illing &
Shillaker, 1985).
An 8-hour exposure to 250 ppm increases the
carboxyhaemoglobin level to greater than 8% (Ellenhorn &
Barceloux, 1988).
Dermal: The degree of absorption is dependent on the type of
skin, (thickness, vascularity, age), surface area, and
duration of exposure.
Immersion of only one thumb in methylene chloride for 30
minutes produced a mean peak breath concentration of 3.1 ppm;
by 2 hours post-exposure the mean value was 0.699 (Stewart &
Dodd, 1964).
Topical application of 99% pure methylene chloride on the
mouse skin gave a rapid absorption rate compared to other
halogenated hydrocarbons (Tsurata, 1975). However, it is
unlikely that toxic levels are attainable through dermal
absorption of the hands and forearms in industry. Dermal
confinement may accentuate toxicity, e.g. by occlusion under
"skin" formed by paint remover applications, or splashed
articles of clothing.
6.2 Distribution by route of exposure
Although initial studies in humans suggested that
methylene chloride may be stored in fat tissue, recent
investigations have failed to detect significant retention in
fat or other tissue stores (Ellenhorn & Barceloux,
1988).
6.3 Biological half-life by route of exposure
The half-life of methylene chloride is dependent on the
length of exposure and the time of sampling and so is
variable. However, the concentration in the expired breath
approximately follows the blood concentration (Hearne et al.,
1987).
6.4 Metabolism
The liver is the primary site of metabolism.
Metabolic conversion to carbon monoxide occurs. The half-
life of carboxyhaemoglobin is almost twice that following an
equivalent inhalation of carbon monoxide. This is because
hepatic biotransformation to carbon monoxide is dependent on
the enzymatic metabolic rate (see Section 6.4), and the rate
at which methylene chloride is released from tissue stores.
Consequently, carboxyhaemoglobin production may continue for
several hours following cessation of exposure to methylene
chloride (Hayes & Laws, 1991). In one specific case, a 5-
hour treatment with 100% oxygen was required to reduce blood
carboxyhaemoglobin levels from 13% to 7.5%.
Hepatic conversion occurs via two pathways (Hayes & Laws,
1991):
1. Mixed functions oxidase system of cytochrome P450. A
high affinity low capacity pathway, forming carbon
monoxide, carbon dioxide and chloride, via a
formylchloride intermediate. This pathway is associated
with detoxification and is saturable at a few hundred
ppm.
2. Cytosolic transformation (glutathione transferase
dependent) where formaldehyde and formic acid
intermediates are produced. This is a low affinity high
capacity system associated with intoxication which shows
no indication of saturation up to vapour concentrations
of 10,000 ppm.
The extent to which each pathway contributes to total hepatic
metabolism varies in humans, especially with exposure levels.
Thus, toxicity extrapolation between high and low doses is
complex.
6.5 Elimination by route of exposure
Inhalation: Methylene chloride and its metabolites are
chiefly excreted via the lungs with small amounts appearing
in the urine and bile (Illing & Shillaker, 1985). Low doses
of 14C-labelled methylene chloride were excreted mainly as
14C-carbon monoxide (with 14C-carbon dioxide) whereas high
concentrations were excreted in the expirate largely
unchanged as 14C-methylene chloride.
Dermal: A thumb immersion experiment into 80 mL of methylene
chloride for 30 minutes resulted in an expiratory
concentration peaking at 2 to 3 ppm in less than 30 minutes.
This value decreased to 0.7 ppm after 2 hours (Stewart &
Dodd, 1964).
7. TOXICOLOGY
7.1 Mode of action
Methylene chloride acts primarily as a CNS depressant,
as do other halogenated hydrocarbons. Its metabolites,
chloride ion and carbon monoxide, respectively cause acidity
and reduces the oxygen-carrying capacity in the blood
(Dreisbach & Robertson, 1987).
However, methylene chloride is the least toxic of the
chloromethanes (Clayton & Clayton, 1981) and complete
recovery has been attained in a significant number of cases.
Methylene chloride had been used as a general anaesthetic
until fatalities occurred (Hayes & Laws, 1991).
The metabolite, carbon monoxide, may increase the risk of
death in people with compromised myocardial function (e.g.,
angina), enhancing ischaemia and increasing the risk of
arrhythmias.
In fatal exposure in dogs, it was concluded that the fall in
arterial blood pressure, rise in venous pressure, and the
slowing of the heart were probably due to depression of the
medullary centres and later depression of the cardiac muscle.
Respiratory depression involved the medullary centres at
first, but later there was a temporary hypoxic stimulation
when circulatory failure was well advanced. The heart
usually stopped before respiration (Hayes & Laws,
1991).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Exposure to approximately 1000 ppm
for several hours resulted in blood
carboxyhaemoglobin levels as high as 15%
(Hayes & Laws, 1991).
In one case, exposure to 20,000 ppm for more
than 30 minutes resulted in coma (Ellenhorn &
Barceloux, 1988).
The adult fatal dose by ingestion or
inhalation has been estimated to be 25 mL
(Dreisbach & Robertson, 1987).
Vapour Conc. Effect Exposure time
300 ppm odour threshold no acute effects up
100 to 280 ppm to 7.5 hours
300 to 800 ppm psychomotor/sensory
impaired 40 min
500 to 1000 ppm light-headedness 1 to 2 hrs
2300 ppm irritation, dizziness 5 min
2300 ppm nausea 30 min
up to 5000 ppm headache, fatigue,
irritation
7200 ppm paraesthesia, irritation 8 min
8000 to
20000 ppm narcosis 0.5 to 4 hrs
50,000 ppm
plus immediate danger to
life or health
7.2.1.2 Children
No data available.
7.2.2 Relevant animal data
Inhaled
Rat LCLO = 88000/m3/30 minutes
Dog LCLO = 14108 ppm/7 hours
Rabbit LCLO = 10000 ppm/7 hours
Mouse LCLO = 14400 ppm/7 hours
Subcutaneous
Dog LDLO = 2700 mg/kg
Rabbit LD50 = 2700 mg/kg
Mouse LDLO = 6460 mg/kg
Oral
Rat LD50 = 2136 mg/kg
Dog LDLO = 3000 mg/kg
Rabbit LDLO = 1900 mg/kg
(RTECS, 1987)
7.2.3 Relevant in vitro data
No data available.
7.2.4 Workplace standards
Currently, the limit in Britain is 100 ppm for
long term exposures and 250 ppm for short term
exposure (Reynolds, 1989).
The Occupational Safety and Health Administration
(OSHA) established an 8-hour TWA of 500 ppm to prevent
acute narcosis and liver injury. In 1976 the National
Institute for Occupational Safety and Health (NIOSH)
recommended a TLV of 75 ppm due to the unacceptable
carboxyhaemoglobin level of 5% following exposure
during an 8 hour work shift.
Exposure at the ACGIH level (100 ppm) would permit
occupational exposure at the rate of 50 mg/kg/day.
The ACGIH has proposed lowering the current threshold
limit to 50 ppm because of possible tumorigenicity in
animals (Hayes & Laws, 1991).
7.2.5 Acceptable daily intake (ADI) and other guideline
levels
No value has been established.
The Food and Drug Administration (USA) has permitted:
10 ppm residual in decaffeinated coffee;
no greater than 2.2% in hops extract;
no greater than 30 mg/kg spice oleoresins as a residue
after spice extraction; but it has banned its use as
an ingredient in cosmetics (RSC/CEC, 1986).
7.3 Carcinogenicity
Methylene chloride has been reported to produce benign
mammary tumours and malignant liver and lung neoplasms in
several animal species. From this evidence the US
Environmental Protection Agency considers methylene chloride
a possible human carcinogen, although significant variation
in metabolic pathways may exist between the species.
Methylene chloride does not appear to be directly genotoxic
in vivo, but it does produce altered homeoestasis in the
lung and liver of mice (tissues susceptible to tumour
development) and it is therefore probable that methylene
chloride does affect a later stage of the tumorigenic
process. However, a review of the mechanistic and
pharmacokinetics data for methylene chloride indicate a very
low likelihood that this material is a carcinogen in humans
(Hayes & Laws, 1991).
A long term epidemiologic study (1964 to 1984) of chronic
methylene chloride exposure to workers in a Kodak
photographic plant, reported no statistically significant
increase in deaths from lung and liver cancer. An increase
in pancreatic deaths was noted (8 compared to an expected
value of 3.1). However, this has been disputed by the
National Toxicological Program (USA) (Hearne et al.,,
1990).
Excess liver and biliary tract cancer deaths were reported in
an epidemiological study of workers exposed to methylene
chloride in a fibre production plant. However, the data were
inadequate to draw firm conclusions (RSC/CEC, 1986).
7.4 Teratogenicity
No teratogenic effects were found in pregnant rats
exposed to 4500 ppm vapour during gestation (Hayes & Laws,
1991).
Schwetz et al., (1975) exposed to pregnant mice and rats to
methylene chloride vapour in concentrations which were twice
the maximum allowable limit for human industrial exposure
(1225 ppm). Both species were exposed for 7 hour periods
daily, on days 6 through 15 of gestation. No foetal toxicity
or teratogenicity was found.
Poisoning from a metabolite of methylene chloride, carbon
monoxide, in pregnancy can result in foetal and infant death
or severe neurological impairment in the off-spring (Koren,
1990).
7.5 Mutagenicity
There is no significant evidence that methylene chloride
is a mutagen. No unscheduled DNA synthesis occurred in V79
cells or primary human fibroblasts. A higher percentage of
mutations in the Drosophila did not occur (CEFIC, 1983). No
increase in cytogenic aberrations of rat bone marrow cells
were noted following 6 months repeated exposure to 500, 1500
or 3500 ppm (Clayton & Clayton, 1981).
7.6 Interactions
Methylene chloride is often formulated with other
contaminants. These other substances may enhance or reduce
its toxic effects (see Section 3.4).
Since methylene chloride elevates carboxyhaemoglobin levels,
symptoms of carbon monoxide poisoning may occur, especially
in patients with cardiopulmonary disease or workers who are
exposed to other sources of carbon monoxide (Ellenhorn &
Barceloux, 1988).
8. TOXICOLOGICAL AND BIOMEDICAL INVESTIGATIONS
Exposure measurements include blood methylene chloride and
carboxyhaemoglobin levels in addition to air sampling. For
average sedentary, non-smoking workers, maximum allowable
exposures (200 ppm) produce methylene chloride levels of 80 ppm in
expired air and 0.18 mg/100 ml in blood, and carboxyhaemoglobin
levels of 6.8% (Ellenhorn & Barceloux, 1988).
8.1 Material
8.1.1 Sampling
No data available.
8.1.1.1 Toxicological analyses
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gases
8.1.1.4 Haematological investigations
8.1.2 Storage
No data available.
8.1.3 Transport
No data available.
8.2 Toxicological analyses and their interpretation
8.2.1 Tests for toxic ingredient
No data available.
8.2.1.1 Simple qualitative test
8.2.1.2 Advanced qualitative test
8.2.1.3 Simple quantitative method
8.2.1.4 Advanced quantitative method
8.2.2 Tests for biological samples
8.2.2.1 Simple qualitative test
8.2.2.2 Advanced qualitative test
8.2.2.3 Simple quantitative method
8.2.2.4 Advanced quantitative method
8.2.2.5 Other dedicated methods
No data available.
8.2.3 Interpretation
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood
After serious methylene chloride
exposures the following analyses are
recommended:
1. complete blood count
2. hepatic amino transferase levels
3. creatinine levels
4. blood carboxyhaemoglobin levels
Serious poisonings from methylene chloride
exposure may occur without significant
elevation of carboxyhaemoglobin levels.
Follow-up measurements of hepatic amino-
transferase levels should be undertaken
within one week of exposure.
(Ellenhorn & Barceloux, 1988)
8.3.1.2 Urine
After serious methylene chloride
exposures urinanalysis including urine
myoglobin should be undertaken (Ellenhorn &
Barceloux, 1988). Haemoglobin products in
urine indicate intravascular haemolysis
(Dreisbach & Robertson, 1987).
8.3.1.3 Other
Blood in the stools will indicate
gastrointestinal injury (Dreisbach &
Robertson, 1987).
Radiographic examination will reveal the
extent of ulceration of the duodenum and
jejunum after ingestion (Dreisbach &
Robertson, 1987).
8.3.2 Arterial blood gas analyses
No data available.
8.3.3 Haematological analyses
No data available.
8.4 Other relevant biomedical investigations and their
interpretation
No data available.
8.5 Overall interpretation
No data available.
9. CLINICAL EFFECTS
9.1 Acute poisoning by:
9.1.1 Ingestion
Methylene chloride is a potent irritant of
mucous membranes. Rapid gut absorption has been
indicated, with resulting anaesthetic deaths in
laboratory animals (Clayton & Clayton, 1981).
An ingestion of 0.5 to 1 L of paint remover, mostly
consisting of methylene chloride, resulted in coma,
intravascular haemolysis and, later jejunal ulceration
and diverticular formation (Reynolds, 1989).
Narrowing of the intestinal lumen may occur as a
result of erosions. Pharyngeal erosions may disturb
the swallowing mechanism, resulting in aspiration
pneumonia (Dreisbach & Robertson, 1987).
9.1.2 Inhalation
Concentrations of 1,000 ppm produce
lightheadedness and alterations in visual reflexes.
Exposures greater than 2,000 ppm have resulted in
nausea and lassitude after 30 min. At levels between
7,000 and 10,000 ppm, paraesthesiae and eye irritation
occur. In one case, a concentration greater than
20,000 ppm led to coma. Methylene chloride may
produce pulmonary oedema by a direct toxic effect
(Ellenhorn & Barceloux, 1988).
Paraesthesia occurred in the extremities within 8
minutes at 7,200 ppm; pulse acceleration to 100/min
occurred after 16 minutes. Within the first 20
minutes, congestion of the head, slight eye
irritation, and a sense of heat was experienced. At
2,300 ppm, nausea occurred within 30 minutes, however
there was no feeling of dizziness after one hour of
exposure. Experiments have shown that exposure to
25,000 ppm for two hours is not lethal (Sax,
1984).
CEFIC (1983) notes that narcotic effects occur at
1,000 ppm and higher, and pre-narcotic actions,
anaesthetic-like effects, headache and irritation to
the eyes occur at vapour concentrations greater than
500 ppm. Significant CNS effects occur at exposures
of 300, 500 and 800 ppm (Illing & Shillaker,
1985).
Most symptoms subside with discontinued exposure,
although respiration and circulation should still be
monitored in severe poisonings (Von Oettingen,
1955).
CEFIC (1983) records that phosgene formed by thermal
decomposition caused death when paint remover was used
in a poorly ventilated area heated by a kerosene
stove.
9.1.3 Skin exposure
CEFIC (1983) reports skin absorption, but not
in amounts sufficient to cause adverse systemic
effects. Methylene chloride also has a defatting
action on the skin.
NBOSH (1981), however, state that under certain
conditions skin uptake may significantly contribute to
toxicity.
Methylene chloride, both as a liquid and a vapour, is
a potent cutaneous and mucous membrane irritant
(Ellenhorn & Barceloux, 1988). Significant pain, then
pain and numbness followed by burns were experienced
after immersion. Second and third degree burns were
experienced by a victim who lay comatose in methylene
chloride for 30 minutes (Ellenhorn & Barceloux,
1988).
9.1.4 Eye contact
High vapour concentrations can cause ocular
pain (CEFIC, 1983), and psychological tests of visual-
motor performance and critical flicker frequency
showed some impairment of performance (Grant,
1986).
Splash contacts cause an immediate burning sensation
which subsides in 15 to 20 minutes after flushing the
eye with water Generally there is not persistent
damage (Grant, 1986).
9.1.5 Parenteral exposure
No data available.
9.1.6 Other
No data available.
9.2 Chronic poisoning by:
Long-term exposure to methylene chloride causes damage
to the CNS and the liver (IARC, 1979).
9.2.1 Ingestion
Not applicable.
9.2.2 Inhalation
IARC (1979) state that long term occupational
exposure damages the CNS and liver. However, there is
no evidence that this increases mortality.
ACGIH (1980) reports that a 1 year exposure to
methylene chloride caused the development of
encephalosis, acoustic and optical delusions, and
hallucinations in a chemist. Concentrations
frequently exceeded 500 ppm, and were measured at 660,
800 and 3,600 ppm near the floor. Liver disease has
been noted in workers exposed to methylene
chloride.
A case of dementia was attributed to 20-year
occupational exposure to 500 to 1,000 ppm methylene
chloride (Ellenhorn & Barceloux, 1988).
9.2.3 Skin exposure
Skin may become rough and dry with prolonged
and repeated contact, and therefore susceptible to
infection and irritation. Erythema and scaling may
occur.
Methylene chloride can be absorbed by intact skin, but
probably not in quantities sufficient to cause
systemic toxicity (Stewart & Dodd, 1964).
9.2.4 Eye contact
Chronic exposure is unlikely due to its acute
irritant properties (see Section 9.1.4).
9.2.5 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
The predominant effects of methylene chloride are due to
its narcotic properties. Depending on exposure and
concentration, symptoms vary from light headedness to stupor,
irritability, drunkenness and gait disturbances. Eventually,
unconsciousness and lack of response to painful stimuli
result, then coma and death.
Respiration initially increases, but is then slowed.
Pulmonary oedema may occur.
9.4 Systematic description of clinical effects:
9.4.1 Cardiovascular
Cardiac function of 24 healthy workers
chronically exposed to methylene chloride at
concentrations of 60 to 475 ppm was monitored by ECG.
No increase in ventricular and supraventricular
ectopic activity, or episodic depression of the ST
segment occurred. Furthermore, no evidence of ECG
abnormalities or cardiac sensitization to adrenaline
have been noted in healthy subjects rendered
unconscious by acute exposure.
Increased carboxyhaemoglobin levels from methylene
chloride metabolism will reduce the oxygen content of
blood perfusing the myocardium. Arrhythmias may occur
in patients already suffering from cardiovascular
stress (angina/coronary artery disease) where
carboxyhaemoglobin levels of 2 to 3% saturation can
adversely affect such individuals.
Carboxyhaemoglobin levels reach up to 5% in normal
smokers and 12% in heavy smokers. Following 500 ppm
exposures of methylene chloride, smokers can reach
carboxyhaemoglobin levels of 15% and more. These
levels, however, are non-hazardous in healthy
individuals (Rosenberg & Hathaway, 1990).
9.4.2 Respiratory
Pulmonary oedema may occur from acute
exposures. Phosgene produced from the combustion of
methylene chloride may cause a delayed toxicity to the
lung (Ellenhorn & Barceloux, 1988).
9.4.3 Neurologic
The predominant effects are due to CNS
depression. Depending on exposure and concentration,
symptoms vary from light headedness, nausea, headache,
concentration and co-ordination impairment to stupor,
irritability, drunkenness and gait disturbances.
Eventually, unconsciousness and lack of response to
painful stimuli result, then coma and death (Ellenhorn
& Barceloux, 1988).
No evidence of long-term damage could be attributed to
methylene chloride inhaled at levels of < 100 ppm and
evaluation of motor conduction velocities of ulnar and
median nerves, ECG, or psychological tests designed to
detect minimal brain damage (Hayes & Laws,
1991).
9.4.3.1 CNS
Encephalopathy has occurred after
repeated exposure to 500 ppm levels
(Dreisbach & Robertson, 1987).
9.4.3.2 Peripheral nervous system
Generalized neural depression occurs.
9.4.3.3 Autonomic nervous system
Generalized neural depression occurs.
9.4.3.4 Skeletal and smooth muscle
No data available.
9.4.4 Gastrointestinal
Ingestion has resulted in jejunal ulceration
and diverticular formation from which strictures may
develop. Methylene chloride is a potent irritant of
mucous membranes (Roberts & Marshall, 1976).
9.4.5 Hepatic
Although methylene chloride is a weak
hepatotoxin in animals there is no firm link to
chronic liver disease in industrial workers. Raised
serum concentrations of alanine aminotransferase
levels (not aspartate) developed 1 week after exposure
and resolved the following week (Ellenhorn &
Barceloux, 1988).
9.4.6 Urinary
9.4.6.1 Renal
A previously healthy man exposed to
methylene chloride vapour developed
myoglobinuria and acute tubular necrosis
leading to renal failure (Ellenhorn &
Barceloux, 1988).
Intravascular haemolysis has lead to gross
haematuria. Haemoglobinuria and increase in
carboxyhaemoglobin levels in rats have been
noted (Illing & Shillaker, 1985).
9.4.6.2 Others
No data available.
9.4.7 Endocrine and reproductive systems
Methylene chloride has been reported to produce
benign mammary tumours in experimental animals, but
has not been reported in humans. However, methylene
chloride can enter breast milk and the foetus through
the placenta, like many other organic solvents
(Rosenberg & Hathaway, 1990).
Exposure of rats to inhaled concentrations of
methylene chloride as high as 1500 ppm for 6 hours/day
did not affect any reproductive parameters over two
generations (Hayes & Laws, 1991).
9.4.8 Dermatologic
Methylene chloride can cause burns, and elicit
a defatting action on the skin. Erythema and scaling
have been noted.
9.4.9 Eye, ears, nose, throat; local effects
High vapour concentrations can cause ocular
pain (CEFIC 1983), and psychological tests of visual-
motor performance and critical flicker frequency
showed some impairment of performance (Grant,
1986).
Splash contacts cause an immediate burning sensation
which subsides in 15-20 minutes after flushing the eye
with water. Generally there is no persistent damage
(Grant, 1986).
9.4.10 Hematologic
Victims of an industrial accident involving
excessive inhalation of methylene chloride had
moderate leukocytosis and moderate depression of red
cell count and haemoglobin level (Hayes & Laws,
1991).
9.4.11 Immunological
No data available.
9.4.12 Metabolic
9.4.12.1 Acid base disturbances
Hepatic biotransformation forms
chloride ions, which in turn induce
acidosis.
9.4.12.2 Fluid and electrolyte disturbances
Lung oedema may result from a
direct toxic effect on the lungs (Ellenhorn &
Barceloux, 1988).
9.4.12.3 Others
No data available.
9.4.13 Allergic reactions
No data available.
9.4.14 Other clinical effects
No data available.
9.4.15 Special risk
In glueing operatives, methylene chloride was
found to cross the placenta and occur in breast milk
(Barlow & Sullivan, 1982). Chlorinated hydrocarbons
were found in breast milk up to 17 hours post
exposure.
Maternal carbon monoxide levels in the blood from
methylene chloride metabolism may lead to foetal and
infant death or severe neurological impairment in the
off-spring (Koren, 1990).
Since methylene chloride elevates carboxyhaemoglobin
levels, symptoms of carbon monoxide poisoning may
occur, especially in patients with cardiopulmonary
disease or workers who are exposed to other carbon
monoxide sources (Ellenhorn & Barceloux,
1988).
9.5 Others
No data available.
10. MANAGEMENT
10.1 General principles
Initial attention should be directed toward removal
from exposure, supportive respiration and monitoring for
dysrhythmias.
Oxygen is the primary therapy for reduction of
carboxyhaemoglobin levels. Levels may continue to rise 5 to 6
hours following acute exposure, in which peak values of
approximately 25% have generally been reported. The
carboxyhaemoglobin half-life in room air is approximately 5.3
hours. This may be reduced to 60 to 90 minutes with 100%
oxygen, and in more severe cases 20 to 40 minutes following
hyperbaric oxygen treatment. Monitoring heart function for
dysrhythmias is indicated.
Hyperbaric oxygen has been used successfully to treat carbon
monoxide poisoning following inhalation of methylene chloride
(Rudge, 1990).
Baseline liver function tests with periodic monitoring will
detect possible hepatic toxicity (Ellenhorn & Barceloux,
1988).
Steroids have been recommended (Dreisbach & Robertson, 1987).
10.2 Relevant laboratory analyses and other investigations
10.2.1 Sample collection
Methylene chloride can be detected in exhaled
air several hours post exposure. Inhalation of 200
ppm in ambient air will result in expiratory
concentrations of around 80 ppm, and exhaled air will
generally reflect ambient levels up to about 500 ppm.
Methylene chloride can be directly measured in the
blood shortly after exposure. 25-90% of the absorbed
methylene chloride is eliminated within 2 hours post-
exposure. After 16 hours, none will be detected in
the blood.
Metabolic production of carbon monoxide will only be
detected in the blood about 30 minutes after exposure
in non-smokers.
10.2.2 Biomedical analysis
A variety of tests may be employed to monitor
chronically exposed individuals for methylene chloride
poisoning, e.g.
carboxyhaemoglobin level:
arterial blood gas
hepatic enzyme levels
urinalysis
serial ECGs.
10.2.3 Toxicological analysis
Exposure measurements include blood methylene
chloride and carboxyhaemoglobin levels as well as air
sampling. For average sedentary, non-smoking workers,
maximum allowable exposures (200 ppm) produce
methylene chloride levels of 80 ppm in expired air and
0.18 mg/100 mL in blood, and carboxyhaemoglobin levels
of 6.8% (Ellenhorn & Barceloux, 1988).
Methylene chloride concentrations following fatal
inhalation after home use of a paint remover were:
510 mg/L in blood
248 mg/kg in brain
144 mg/kg in liver
The blood carboxyhaemoglobin concentration was 3%
(Baselt, 1982).
10.2.4 Other investigations
No data available.
10.3 Life supportive procedures and symptomatic treatment
Immediately remove the victim to fresh air. If the
victim is conscious, inquire immediately upon the
circumstances of the poisoning, noting that the patient may
become unconscious at any time. Keep the victim at rest.
Physical activity will enhance total body distribution from
increased blood flow. Place in the recovery position and
keep warm. Monitor respiration. Positive pressure 100%
oxygen will help reduce blood carboxyhaemoglobin levels.
This may take several hours. This is an important factor if
cardiac function is already compromised (e.g., patients with
angina pectoris). Monitor for dysrhythmias.
Further treatment is symptomatic. Monitor for possible
haemolytic reaction. Administer hydrocortisone
intravenously, 200 mg every hour. Treat aspiration pneumonia
with antibiotics. Blood transfusions may be necessary if
gastric bleeding is excessive. Treat acidosis and pulmonary
oedema (Dreisbach & Robertson, 1987).
10.4 Decontamination
Ingestion: Milk is not indicated for dilution and may
increase gut absorption of methylene chloride.
Eye contact: Remove any contact lenses then flush the
contaminated eyes gently with water for 10 to 15 minutes
holding the eyelids open. Corneal application of fluorescein
will display evidence of abrasion.
Skin contact: Avoid direct contact with the chemical; wear
impervious gloves if necessary. Remove any contaminated
clothing and other tight articles against the body. Flush
the contaminated area gently with water for 10 to 15
minutes.
Ingested methylene chloride may be removed by emesis
(consider whether there is a risk of impending
unconsciousness) and/or gastric lavage, and activated
charcoal. However, the efficacy of such treatment is not
known (Ellenhorn & Barceloux, 1988).
10.5 Elimination
No methods are available to enhance elimination from
inhalations.
10.6 Antidote treatment
10.6.1 Adults
No specific antidote.
10.6.2 Children
No specific antidote.
10.7 Management discussion: alternatives, controversies and
research needs
In Case 3 (see Section 11.1) where a victim ingested
0.5 to 1 L of paint remover, recovery was fast and induction
of diuresis was believed to play an important role in the
prevention of acute renal damage (Roberts & Marshall,
1976).
Ingested methylene chloride may be removed by emesis and/or
gastric lavage, and activated charcoal. However, the
efficacy of such treatment is not known and therefore should
be investigated (Ellenhorn & Barceloux, 1988).
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Case 1 Industrial inhalation, adults (Hayes & Laws, 1991)
Four night-shift workers extracting plant oleoresin using
methylene chloride in a room were found unconscious at
7:15 am. One worker died when the ambulance arrived. The
others had been unconscious for up to 3 hours, and were semi-
conscious or drowsy on arrival at the hospital at 7:30 am.
They were fully conscious by 10:00 am, and had no memory of
smelling methylene chloride. All survivors were coughing
when they reached the hospital, but rales and respiratory
irritation were detected in only two. Some had a slight
fever for a day or two, and one complained of eye irritation.
All had moderate leukocytosis, and moderate depression of red
cell counts and haemoglobin level. They were discharged
after 4 to 8 days.
Analysis of the lungs of the man found dead revealed a
concentration of 265 ppm.
Case 2 Occupational inhalation, adults (Hayes & Laws,
1991)
Two painters experienced headache, faintness, giddiness,
irritability, numbness and tingling of the extremities, loss
of appetite, and apathy when they used methylene chloride to
remove paint from the walls of a large closed room.
Case 3 Deliberate ingestion, adult (Roberts & Marshal,
1976)
A 38-year-old man drank 0.5 to 1 L of a paint remover
containing methylene chloride as the active ingredient, and
was deeply unconscious and unresponsive to painful stimuli 90
minutes later. Areas of skin where liquid had spilled from
his mouth were erythematous and blistered.
He was tachypnoeic but his pulse and blood pressure were
well-maintained. Gross haemoglobinuria and metabolic
acidosis were present. Diuresis was promoted with 80 mg
frusemide with 0.9% sodium chloride and 5% dextrose
alternately. During the first 24 hours the patient passed 18
L of urine and the haemoglobinuria ceased.
The patient regained consciousness 15 hours after the
incident, with no detectable cerebral damage. A later effect
was the development of jejunal ulceration requiring blood
transfusions and, 6 months after the incident, diverticula.
There was no hepatic damage and no evidence of cardiac
toxicity. Acute renal damage was apparently averted by the
early induction of diuresis.
Case 4 Eye contact, adult (Grant, 1986)
A man splashed his eye with a paint-remover containing
methanol and propylene dichloride in addition to methylene
chloride. He flushed his eye with water immediately, but
lost about 20% of his corneal epithelium. The eye healed
completely in two days.
Case 5 Eye contact, child (Grant, 1986)
A boy had methylene chloride splashed in his eyes from an
exploding bubbling-type christmas-tree ornament. There were
cells in the anterior chambers which, following treatment
with corticosteroid eye drops, cleared in six weeks.
11.2 Internally extracted data on cases
No case histories available.
11.3 Internal cases (added by the PC using monograph)
12. ADDITIONAL INFORMATION
12.1 Availability of antidotes and antisera
Not applicable.
12.2 Specific preventive measures
An approved air purifying respirator will provide
protection at excess atmospheric levels. Use should only be
of single short term exposures, as their effectiveness is
limited.
If TLV guidelines are greatly exceeded, approved positive
pressure self-contained breathing apparatus should be
used.
For prolonged or frequent contact, impervious protective
clothing should be used. Chemical goggles are recommended,
but full face respirators must be used if vapours cause
ocular pain.
12.3 Other
No data available.
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14. AUTHOR(S), REVIEWER(S) DATE (INCLUDING EACH UP-DATE), COMPLETE
AUTHOR(S), ADDRESSES
Author: Dr A.W Temple
National Toxicology Group
University of Otago Medical School
P.O. Box 913
Dunedin
New Zealand
Tel: 64-3-4797244
Fax: 64-3-4770509
Date: January 1992
Peer Review: Newcastle-upon-Tyne, United Kingdom, February
1992
Editor: M.Ruse
Finalised: IPCS, April 1997