Monochloroacetic acid
MONOCHLOROACETIC ACID
International Programme on Chemical Safety
Poisons Information Monograph 352
Chemical
1. NAME
1.1 Substance
Monochloroacetic acid
1.2 Group
Chlorinated organic acid.
1.3 Synonyms
Acetic acid, chloro-; chloracetic acid;
chloroacetic acid; alpha-chloroacetic acid;
chloroethanoic acid; monochloroacetic acid; MCA; MCAA;
monochloracetic acid; monochloroethanoic acid;
Acide chloracetique (Fr), Acide monochloroacetique (Fr);
Monochloressigsäure (Ger); Acidomonochloroacetico (Ita);
Monochloorazijnzuur (Dutch);
1.4 Identification numbers
1.4.1 CAS number
79-11-8
1.4.2 Other numbers
EINECS 2011784
1.5 Main brand names, main trade names
MCA, Na-MCA (sodium salt).
1.6 Main manufactures, main importers
Akzo (The Netherlands), Atochem (France), Eka Nobel
Skoghall AB (Sweden), Hoechst (Germany).
2. SUMMARY
2.1 Main risks and target organs
CNS, intracellular respiration, cardiac, respiratory,
renal and skeletal muscles toxicity. Corrosive.
2.2 Summary of clinical effects
Solution, solid flakes and molten MCA are corrosive. MCA
is extensively absorbed via mucous membranes and skin causing
systemic poisoning. Symptoms may be delayed for some (1 to 4)
hours. Vomiting, diarrhoea and CNS-excitability are early
signs of poisoning followed by CNS-depression, coma and
cerebral oedema. Severe myocardial depression and shock
supervene due to nonspecific myocardial damage. Severe
metabolic acidosis (lactic acidosis) and hypokalemia appears
within a couple of hours. Progressive renal failure is seen
within 12 hours probably due to extensive myoglobinuria
secondary to severe rhabdomyolysis.
2.3 Diagnosis
Monochloracetic acid concentration in serum.
Acid base balance. Serum potassium.
Development of metabolic acidosis indicates severe systemic
poisoning. Hypokalaemia is a typical early sign.
Serum calcium. Hypocalcaemia is secondary either to binding
to oxalates or secondary to rhabdomyolysis.
ECG-monitoring.
Myoglobin in serum (and urine). Low urine pH increases the
risk of kidney damage from myoglobin in urine.
2.4 First-aid measures and management principles
After ingestion gastric decontamination.
After skin exposure 1) immediate and prolonged flushing with
copious amounts of water even under the clothes, 2) remove
contaminated clothing, 3) continue flushing for at least 15
minutes.
After eye exposure immediate flushing with water for 15
minutes.
After inhalation fresh air, oxygen and other treatment as for
irritant gases.
Symptomatic therapy in systemic poisoning (fluid replacement,
correction of metabolic acidosis and hypokalaemia, adequate
urine production and alkalinization of urine to avoid
myoglobin precipitation in renal tubulus, inotropic therapy
in cardiac failure, cerebral oedema treatment). If available,
Dichloroacetic acid (DCA), buffered to 7.2, should be given,
50 mg/kg as slow intravenous injection or infusion,
preferably prior to the onset of lactic acidosis, in all
cases with more than 5% body surface contamination. Repeat
after two hours.
If no DCA is available, phenobarbitone in high dosages,
sufficient to cause deep pre-coma, might be attempted if
respiratory support can be given, and/or hemodialysis should
be performed.
N-Acetylcysteine and/or ethanol, as recommended in some
previous publications, is probably useless. Plasmapheresis
may be considered in severe rhabdomyolysis.
3. PHYSICO-CHEMICAL PROPERTIES
3.1 Origin of the substance
MCA is produced by a reaction under pressure between
chlorine and acetic acid (Budavari, 1996).
3.2 Chemical structure:
Molecular Formula: ClCH2-COOH
Molecular weight: 94.5
3.3 Physical properties:
3.3.1 Colour
At temperature <19°C: colourless or white
deliquescent crystals
3.3.2 State/Form
solid-crystals
solid-flakes
solid-powder
liquid-other
3.3.3 Description
At temperature <19°C: colourless or white
deliquescent crystals
At temperature >19°C: liquid
In industry different physical forms of MCA are
used:
Molten at approximately 60°C (transportation in
heating tanks)
Aqueous solution (often 80% concentration, heated to
35°C)
Flakes
MCA sodium salt, a white powder (Hommel 1980,
Budavari 1996).
Odour - penetrating, burning
Odour threshold 0.045 ppm
Calculation factors: 1 ppm = 3.86 mg/m3
1 mg/m3 = 0.20 ppm
pH<1 for 80% aqueous solution
pKa: 2.82 (is a stronger acid than acetic acid - pKa
4.75)
Dissociation constant: Ka 1.5 M at 25°C
Viscosity (100°C): 1.9 mPa (the 80% solution
solidifies at 19°C)
Specific gravity: 1.27 at 25°C for 80% aqueous
solution, 1.40 at 20°C for flakes
Solubility: very soluble in water (at 25°C 84
weight%), soluble in alcohol, methanol, acetone,
carbon, disulphide, benzene, chloroform, ether.
Slightly soluble in hydrocarbons and chlorinated
hydrocarbons
Melting point: 61 to 63°C
Boiling point: 143°C for 80% aqueous solution, 189°C
for flakes
Flammable point (flash point): 118°C for 80% aqueous
solution, 126°C for flakes
Vapour density (air=1): 0.03
Vapour pressure: 17.8 mm Hg at 25°C for 80% aqueous
solution, 0.20 mm Hg at 25°C for flakes
Relative vapour density (air=1): 3.3
(Hommel 1980, Huismanss et al 1980, Budavari
1996, RTECS 1986, Weast 1978-9).
3.4 Hazardous characteristics
Hazardous decompostion products include oxides of carbon
as well as ionic or oxidised chlorine.
Incompatablities: strong bases, oxidising agents and most
common metals.
4. USES
4.1 Uses
4.1.1 Uses
4.1.2 Description
MCA is widely used in chemical industries as
intermediates in the synthesis of
carboxymethylcellulose, phenoxyacetic acid,
thioglycolic acid, glycine, indigoid dyes and others.
MCA is stored and transported as flakes or as an 80%
aqueous solution in transport tanks at 35°C (it
solidifies at 19°C). It may also be desolved in
ethanol or methanol. The sodium salt, Na-MCA, is
usually transported as white granule in paper bags
with polyethylene coating. (Hommel 1980, Budavari
1996).
4.2 High risk circumstances of poisoning
When handling and transporting MCA, especially molten
and solutions; skin contamination is the most common cause of
systemic poisoning.
4.3 Occupationally exposed population
Workers at plants producing and using MCA. Transport
workers when filling and emptying MCA in tankers.
5. ROUTES OF EXPOSURE
5.1 Oral
Ingestion of MCA produces corrosive damage and systemic
poisoning
The sodium salt (Na-MCA) is also absorbed and causes
poisoning.
(Huismans et al., 1986; Gosselin et al., 1984; RTECS 1986;
Woodard 1941; Feldham et al 1993; Rogers 1995).
5.2 Inhalation
Inhalation of MCA fumes or aerosols will cause damage
similar to other irritant gases. Systemic poisoning may also
occur (Zeldenrust,1951).
5.3 Dermal
MCA is corrosive to skin and will penetrate damaged and
even apparently undamaged skin producing systemic poisoning
(Contassot et al., 1987; Kulling et al., 1992; Kusch et al.,
1990; Vincenti, 1987).
The sodium salt, Na-MCA, is not corrosive as such and does
not penetrate skin (Nyström,1986; Andersson, 1992).
5.4 Eye
MCA is corrosive to eyes (Grant, 1986).
5.5 Parenteral
Parenteral administration of MCA in experimental animals
is quickly lethal at dosages comparable to oral and dermal
lethal dosages. No human data are available.(Huismanss et
al., 1986).
5.6 Others
No data available
6. KINETICS
6.1 Absorption by route of exposure
MCA and Na-MCA are readily absorbed after ingestion
(Huismans et al., 1986; Maksimov & Dubinina, 1974; RTECS,
1986; Woodard et al., 1941). MCA is also absorbed very
quickly through the skin (Contassot et al., 1987; Kulling et
al., 1992; Kusch et al., 1990; Vernont et al., 1977;
Vincenti, 1987).
6.2 Distribution by route of exposure
Animal studies indicate accumulation in liver and
kidneys, followed by accumulation in the brain several hours
later (Hayes et al., 1973; Bhat et al., 1983).
6.3 Biological half-life by route of exposure
Elimination is of first order kinetics (biphasic)
t´ blood approx 2 hours (Kulling et al., 1992).
t´ (elimination) 15 hours (Dancer et al., 1965).
6.4 Metabolism
It has been suggested that MCA binds to
gluthathione-S-transferase (GST) rather than to glutathione
(Dierckz, 1984), while others suggest that MCA binds to
glutathione or other sulfhydryl containing substances
(Dalgaard-Mikkelsen et al., 1955; Fuhrman et al., 1955;
Gosselin et al., 1984; Hayes et al., 1973; Hirade et al.,
1950; Huismanss et al., 1986; Yllner, 1971). Another author
suggests that the main metabolites (in mice) were
non-conjugated S-carboxymethyl cysteine, thio-diacetic acid,
and some glycolic acid and suggests the following metabolic
pathway for chloroacetate in mice:
CH2Cl-COOH --> (CH2OHCOOH --> (CO2
MCA glycolic acid
' '
COOH-COOH "CH2NH2COOH"
oxalic acid
"G-S-CH2COOH S-carboxymethyl glutathione"
'
HOOC-CH(NH2)CH2SCH2COOH S-carboxymethyl cysteine
'
HOOC-CH2-S-CH2-COOH thio-diacetic acid
Compounds in " " were not isolated (Huismanss et al., 1986,
Yllner, 1971)
Glycolic acid is metabolised in man to glyoxylic acid, which
is metabolised to formic acid, glycine and oxalic acid
(Jacobsen et al 1984).
6.5 Elimination and excretion
In one human case the majority of MCA was excreted as
nonmetabolized MCA. A minor part reacted with glutathione and
was excreted in urine as the conjugate. A small amount was
metabolized and excreted as carbon dioxide in exhaled air
(Dancer et al., 1965).
In mice 80-90% of administered MCA was excreted in urine
within 24 hours, probably as metabolites, 8% was excreted via
exhaled air as CO2 (Yllner, 1971).
7. TOXICOLOGY
7.1 Mode of action
MCA is corrosive to skin, mucous membranes and eyes.
(Contassot et al., 1987; Gosselin et al., 1984; Kulling et
al., 1992; Maksimov & Dubinina, 1974; Millischer and Ruty,
1986; Sax, 1984; Grant, 1986). MCA also penetrates the skin,
especially damaged skin (Contassot et al., 1987; Kulling et
al., 1992; Kusch et al., 1990).
The ethylester of MCA may cause skin sensitisation (Braun &
van der Walle, 1987; Huismanss et al., 1986).
After absorption MCA blocks the cell energy supply probably
by decreasing the activity of pyruvate dehydrogenase and to
some extent of ketoglutarate dehydrogenase leading to lactic
acidosis (van Hinsbergh 1994). Lactic acid is accumulated in
the cerebrospinal fluid (Mitroka 1989). MCA damages the blood
brain barrier (Berardi et al., 1987; Mitroka, 1989). The
underlying gross mechanism of MCA toxicity is probably
microvascular damage, due to endothelial cellular damage.
Some of the metabolites are toxic like glycolic acid
(metabolic acidosis) and oxalates which may induce kidney and
CNS toxicity
In vitro, MCA blocks the cell energy supply in an as yet
incompletely resolved manner, leading to a gradual decrease
in ATP generation and in protein synthesis. Supplementation
of intermediates of the Krebs-cycle or of acetyl-donors does
not reduce this effect whereas incubation with the sodium
salt of MCA causes a slow but marked decrease in the activity
of pyruvate dehydrogenase and to a lesser degree of
keto-glutarate dehydrogenase (van Hinsbergh, 1994).
Former hypotheses of MCA toxicity:
MCA and/or its metabolites were thought to act like
fluoroacetic acid by blocking the tricarboxylic acid cycle
(Krebs cycle) (Gosselin et al., 1984; Fuhrman et al., 1955;
Gosselin et al., 1984; Hayes et al., 1973; Huismanss et al.,
1986; Zenz, 1975).
It was also thought that MCA probably reacts with sulfhydryl
(-SH) groups in enzymes and other substances. MCA reduces
sulfhydryl content in rat liver and kidney
(Dalgaard-Mikkelsen et al., 1955; Fuhrman et al., 1955;
Gosselin et al., 1984; Hayes et al., 1973; Hirade et al.,
1950; Huismanss et al., 1986).
7.2 Toxicity
7.2.1 Human data
7.2.1.1 Adults
Skin exposure
It can be difficult to determine at an early stage the
percentage of body burns, due to irregular or rather
blotchy vasoconstriction that seems to be typical of
MCA burns. 2 or 3 days later skin burns may be up to
50% larger than at first glance (Vincenti, 1987).
up to 5% body surface possibly moderate
(80% solution) systemic poisoning
6-10% body surface (molten 80°C) severe, up to lethal
systemic poisoning
approx 10% body surface moderate
(90% solution) systemic
(Kusch et al 1990) poisoning
15% body surface (80% solution) lethal
(Millischer and Ruty, 1986; systemic
Contassot et al., 1987; poisoning
Vincenti, 1987)
25-30% body surface (80% solution) lethal
(Kulling et al., 1992) systemic
poisoning
unknown % body surface lethal
+ inhalation systemic
(von Oettingen, 1958; poisoning
Zeldenrust, 1951)
7.2.1.2 Children
No data available
7.2.2 Relevant animal data
Prolonged inhalation of MCA vapours in rats
induced breathing difficulties, decreased oxygen
consumption, haemoconcentration and inflammatory
reaction of the bronchial tree (Maksimov & Dubinina,
1974).
LD50 MCA (oral) (rat, mouse) 55 to165 mg/kg (Hayes et
al., 1973; Huismanss et al., 1986; Maksimov &
Dubinina, 1974; RTECS 1986; Woodard et al., 1941).
LD50 MCA (oral) (mouse) 260 mg/kg (Berardi et al.,
1987).
LD50 Na-MCA (oral) (rat, mouse, guinea pig) 76.2 to
255 mg/kg (Huismanss et al., 1986; Maksimov &
Dubinina, 1974; Woodard et al., 1941).
LD50 MCA (skin, rabbit) 230 mg/kg (Vernot et al.,
1977).
In one study degeneration of Purkinje cell nuclei was
noted probably indicating blood-brain barrier damage
(Berardi et al., 1987).
7.2.3 Relevant in vitro data
In vitro studies have shown that MCA toxicity
still occurs in spite of incubation of the cells with
acetate or acetate donors (van Hinsbergh,
1994).
7.2.4 Workplace standards
1 mg/m3 (OEL-Russia STEL 1993);
8-hr TWA: 0.3 ppm, skin (AIHA 1996)
Ceiling or short-term TWA: 1 ppm, 15 min (ACGHI
1986)
7.2.5 Acceptable daily intake (ADI)
Unknown.
7.3 Carcinogenicity
One study indicated no carcinogenicity (van Duuren et al
1974).
National Toxicology Program (USA): not carcinogenic to mice
and rats (NTP, 1992; de Angelo et al., 1997).
7.4 Teratogenicity
Unknown.
7.5 Mutagenicity
According to National Toxicology Program (USA) MCA is
not genotoxic (Tennant et al., 1990).
7.6 Interactions
Unknown.
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATION
8.1 Material sampling plan
8.1.1 Sampling and specimen collection
8.1.1.1 Toxicological analyses
For analysis of MCA in the blood
take 10ml blood (heparinised tube), take away
plasma, freeze for later analysis. Take
series of samples.
8.1.1.2 Biomedical analyses
8.1.1.3 Arterial blood gas analysis
8.1.1.4 Haematological analyses
8.1.1.5 Other (unspecified) analyses
8.1.2 Storage of laboratory samples and specimens
8.1.2.1 Toxicological analyses
8.1.2.2 Biomedical analyses
8.1.2.3 Arterial blood gas analysis
8.1.2.4 Haematological analyses
8.1.2.5 Other (unspecified) analyses
8.1.3 Transport of laboratory samples and specimens
8.1.3.1 Toxicological analyses
8.1.3.2 Biomedical analyses
8.1.3.3 Arterial blood gas analysis
8.1.3.4 Haematological analyses
8.1.3.5 Other (unspecified) analyses
8.2 Toxicological Analyses and Their Interpretation
8.2.1 Tests on toxic ingredient(s) of material
8.2.1.1 Simple Qualitative Test(s)
8.2.1.2 Advanced Qualitative Confirmation Test(s)
8.2.1.3 Simple Quantitative Method(s)
8.2.1.4 Advanced Quantitative Method(s)
8.2.2 Tests for biological specimens
8.2.2.1 Simple Qualitative Test(s)
8.2.2.2 Advanced Qualitative Confirmation Test(s)
8.2.2.3 Simple Quantitative Method(s)
8.2.2.4 Advanced Quantitative Method(s)
8.2.2.5 Other Dedicated Method(s)
8.2.3 Interpretation of toxicological analyses
8.3 Biomedical investigations and their interpretation
8.3.1 Biochemical analysis
8.3.1.1 Blood, plasma or serum
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.2 Urine
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.1.3 Other fluids
8.3.2 Arterial blood gas analyses
8.3.3 Haematological analyses
"Basic analyses"
"Dedicated analyses"
"Optional analyses"
8.3.4 Interpretation of biomedical investigations
8.4 Other biomedical (diagnostic) investigations and their
interpretation
8.5 Overall interpretation of all toxicological analyses and
toxicological investigations
9. CLINICAL EFFECTS
9.1 Acute poisoning
9.1.1 Ingestion
MCA and Na-MCA produce systemic poisoning.
Symptoms of systemic poisoning may be delayed for some
(1 to 4) hours.
Vomiting and diarrhoea are early signs of systemic
poisoning.
CNS-excitability with disorientation (an early sign of
systemic poisoning), delirium and convulsions followed
by CNS-depression and coma. Cerebral oedema. Typical
initial sign is alteration of CNS-excitation and
CNS-depression.
Severe myocardial depression, shock, arrhythmias
(atrial tachycardia, ventricular
tachycardia-fibrillation), ECG changes indicative of
nonspecific myocardial damage.
Progressive renal failure starting within 12 hours
leading to anuria.
Hypokalaemia during the first 24 hours. Severe
metabolic acidosis starting within a couple of hours.
Hypocalcaemia (may be delayed for 1 to 2 days), high
creatine kinase (CK) values as well as AST and ALT as
signs of extensive tissue damage affecting skeletal
muscles, heart, and brain. Myoglobinaemia and
leucocytosis may occur
The proposed inhibition of pyruvate dehydrogenase
activity will cause impaired energy production in
cells leading to severe cell damage of especially
energy rich organs such as brain, skeletal muscle and
heart, and causing metabolic acidosis.
Blood brain barrier damage increases intracerebral
lactic acidosis.
The acidosis is mainly due to accumulation of lactic
acid but may also be due to the formation of glycolic
acid. Renal impairment might be due to the toxic
action of MCA (as to other organs) but may also be
secondary to myoglobin and oxalate precipitation in
the tubuli. Binding of calcium to oxalates probably
causes the hypocalcaemia, but hypocalcaemia can also
be secondary to rhabdomyolysis.
(Kulling et al., 1992)
9.1.2 Inhalation
Irritant - risk of toxic pulmonary oedema.
Probably risk of systemic poisoning as for
ingestion.
(Kulling et al., 1992)
9.1.3 Skin exposure
Liquid: Irritant and corrosive (1st - 2nd
degree burns) and high risk of systemic poisoning if
>6% of body surface exposed is affected. MCA is
rapidly absorbed even through intact skin. Typical
skin lesion: hyperaemia with a central white zone
(perhaps due to vasoconstriction). Systemic poisoning
as for ingestion.
Solid MCA: flakes of MCA are very corrosive when they
come in contact with water i.e. moist skin or mucous
membranes; molten MCA (>60°C) is also corrosive. Both
give 3rd degree burns, risk of systemic poisoning as
for liquid (if >1% of body surface is affected),
which however is less likely to occur.
(Kulling et al., 1992)
9.1.4 Eye contact
Liquid and solid MCA will cause corrosive damage.
(Kulling et al., 1992)
9.1.5 Parenteral exposure
Not known.
9.2.1 Other
Not known
9.2 Chronic poisoning
9.2.1 Ingestion
No data available.
9.2.1 Inhalation
No data available.
9.2.1 Skin contact
No data available.
9.2.1 Eye contact
No data available.
9.2.1 Parenteral exposure
No data available.
9.2.6 Other
No data available.
9.3 Course, prognosis, cause of death
Systemic poisoning is usually severe and carries a poor
prognosis. Hypokalaemia may occur during the first 24 hours.
Severe metabolic acidosis starts within a couple of hours.
Hypocalcaemia (may be delayed for 1-2 days), high creatine
kinase (CK) values as well as AST and ALT are signs of
extensive tissue damage (skeletal muscles, heart, brain).
Myoglobinaemia and leucocytosis may also occur. The cause of
death is cardiac insufficiency/arrhythmias, renal failure,
and cerebral oedema
(Kulling et al., 1992).
9.4 Systematic description of clinical effects
9.4.1 Cardiovascular
Severe myocardial depression, shock,
arrhythmias (atrial tachycardia, ventricular
tachycardia-fibrillation), ECG changes indicative of
nonspecific myocardial damage. (Contassot et al.,
1987; Feldhaus et al., 1993; Kulling et al., 1992;
Kusch et al., 1990; Millischer & Ruty, 1986; Rogers,
1995; Vincenti, 1987).
9.4.2 Respiratory
Local mucous membrane damage, pulmonary oedema
probably after MCA inhalation/aspiration (Zeldenrust,
1951).
9.4.3 Neurologic
9.4.3.1 CNS
Anxiousness, excitability,
CNS-depression, coma, seizures, cerebral
oedema after a few hours delay (Contassot et
al., 1987; Kulling et al., 1992; Millischer
and Ruty; 1986).
9.4.3.2 Peripheral nervous system
No symptoms reported.
9.4.3.3 Autonomic nervous system
No symptoms reported.
9.4.3.4 Skeletal and smooth muscle
Rhabdomyolysis (Kulling et al.,
1992; Millischer and Ruty, 1986).
9.4.4 Gastrointestinal
Nausea, vomiting, diarrhoea (Kulling et al.,
1992; Kusch et al., 1990; Millischer and Ruty, 1986;
Vincenti, 1987).
9.4.5 Hepatic
Elevation of transaminases after 1 to 2 days
(Kulling et al., 1992; Millischer and Ruty,
1986).
9.4.6 Urinary
9.4.6.1 Renal
Tubular necrosis, progressive renal
insufficiency (Kulling et al., 1992;
Millischer and Ruty, 1986).
9.4.6.2 Others
9.4.7 Endocrine and reproductive system
No symptoms reported.
9.4.8 Dermatologic
Corrosive damage (1st-3rd degree burns)
(Contassot et al., 1987; Kulling et al., 1992; Kusch
et al., 1990; Millischer and Ruty, 1986). Typical skin
lesion: hyperaemia with a central white zone (Kulling
et al., 1992; Millischer and Ruty, 1986).
9.4.9 Eye, ear, noise, throat: local effects
Probably corrosive damage.
9.4.10 Haematological
Leucocytosis (Kulling et al., 1992).
9.4.11 Immunologic
No symptoms reported.
9.4.12 Metabolic
9.4.12.1 Acid-base disturbances
Severe metabolic acidosis
(Contassot et al., 1987; Feldhaus et al.,
1993; Kulling et al., 1992; Millischer and
Ruty, 1986; Rogers, 1995) mainly due to
lactic acid accumulation.
9.4.12.2 Fluid and electrolyte disturbances
Skin damage may cause fluid loss.
In the initial phase hypokalaemia occurs,
(Kulling et al., 1992; Kusch et al., 1990;
Millischer and Ruty, 1986). Hypocalcaemia is
seen after some hours delay (Kulling et al.,
1992).
9.4.12.3 Others
Multi organ effects have been seen
(increased creatine kinase activity,
increased transaminases) (Kulling et al.,
1992; Millischer and Ruty, 1987).
9.4.13 Allergic reactions
Allergy has been induced by the ethylester of
MCA but not by MCA alone (Braun & van der Walle, 1987;
Huismanss et al., 1986).
9.4.14 Other clinical effects
9.4.15 Special risks
Unknown
9.5 Others
10. MANAGEMENT
10.1 General principles
Institute life supportive measures.
After skin contact and ingestion immediate decontamination is
of crucial importance and must be started as soon as
possible. Skin decontamination with water should be continued
for at least 15 minutes. Early signs indicating systemic
poisoning should be looked for (i.e. agitation, malaise,
vomiting, diarrhoea, CNS-depression, metabolic acidosis).
Symptomatic therapy is vital (support ventilation and
circulation, treat cerebral oedema). If signs of systemic
poisoning appear immediate haemodialysis should be performed.
Antidote therapy (dichloroacetate - DCA) should also be
started. Ensure urine flow to prevent kidney damage and
institute alkalinization of urine if signs of rhabdomyolysis
occur.
10.2 Life supportive procedures and symptomatic treatment
Maintain free airway and assist ventilation when
needed
Adequate fluid therapy - note the risk of cerebral
oedema.
Correction of metabolic acidosis (large doses of buffer
solution may be needed) and electrolyte disturbances
(hypokalaemia, hypocalcaemia).
Alkalinization of urine to prevent myoglobin precipitation in
the renal tubule.
Inotropic support (dopamine, dobutamine) in case of
myocardial insufficiency.
Prevention and treatment of cerebral oedema.
Further symptomatic therapy as needed.
10.3 Decontamination
Ingestion
Give water for dilution. Gastric emptying by a thin
nasogastric tube as soon as possible followed by cautious
gastric lavage with cold water. After ingestion, gastric
emptying is recommended in spite of the risk of corrosive
damage as systemic poisoning of MCA is so severe. Treatment
of local damage to the gastrointestinal tract as for acids in
general.
Inhalation
Move the patient to fresh air. If initial symptoms of
irritant damage such as cough occur, place the patient in
absolute rest, - if possible in a semi-recumbent position.
Give supplemental oxygen. Optimal symptomatic treatment
including broncho-dilators (beta-2-receptor stimulants),
assisted ventilation etc. Corticosteroid therapy may be
beneficial for pulmonary manifestations.
Skin exposure
Immediately flush with plenty of water - even under the
clothes. Remove contaminated clothing, wrist watch etc.
Flushing with water should be continued for at least 15
minutes. (At some plants where MCA is produced special
arrangements have been carried out e.g. bath tubs filled with
saturated 3-5% sodium bicarbonate solution into which the
exposed person jumps, or after the initial flushing with
water exposed areas are covered with dressings soaked with
sodium bicarbonate solution.)
Decontamination must be started without any delay to prevent
skin absorption.
If exposed area is >1% of body surface (the palm of the
hand) immediate transport to hospital (after adequate
decontamination). It would be prudent to keep victims under
observation for at least six hours.
Eye exposure
Immediate gentle flushing with water for at least 15 minutes.
Examination by an ophthalmologist should be carried
out.
10.4 Enhanced elimination
At the slightest sign of systemic poisoning or if large
areas are exposed (>5 to 10% of body surface) haemodialysis
should be started. If signs of myoglobinaemia haemodialysis
should be combined with plasmapheresis.
10.5 Antidote treatment
10.5.1 Adults
Dichloroacetate (DCA) (as aqueous solution of
the sodium salt) should be given if >6% of body
surface is exposed to MCA (or ingested): 50 mg/kg body
weight intravenously during 10 minutes. This dose is
repeated after 2 hours. The dose of DCA should
probably be doubled if hemodialysis is performed.
10.5.2 Children
See 10.5.1
10.6 Management discussion
Decontamination: After skin exposure immediate
decontamination is of crucial importance to prevent skin
absorption. At some plants bicarbonate is used as a
decontaminating fluid. Bicarbonate is used for neutralization
of MCA and perhaps also to extract MCA absorbed through the
skin (Huismanss, Akzo Zout Chemie, Hengelo, Holland).
Probably instant decontamination (by flushing with water or
jumping into bicarbonate solution) is the most important
measure after skin exposure.
After ingestion, gastric emptying is recommended in spite of
the risk of corrosive damage as systemic poisoning of MCA is
so severe.
Haemodialysis should be performed as soon as possible at any
sign of systemic poisoning to eliminate the toxic products
(MCA and its metabolites) as well as to treat renal failure
(Kulling et al., 1992).
Plasmapheresis could be added to haemodialysis for
elimination of myoglobin molecules that are poorly dialysable
(Kulling et al., 1992).
Antidote treatment: Dichloroacetate can compensate loss of
activity of pyruvate dehydrogenase and ketoglutarate
dehydrogenase, but only if not all molecules are inhibited.
Dichloroacetate acts by inhibiting PHD-kinase, a protein
which is attached to the pyruvate dehydrogenase complex and
inactivates PHD by phosphorylation; thus, inhibition of the
kinase would lead to a greater availability of PHD. Since DCA
completely abolishes mortality in rodents (see below) if
administered 15 minutes after MCA intoxication, it seems
likely that this mechanism is of prime importance.
In rodents DCA was given 15 minutes after MCA intoxication
(80 mg/kg iv) and survival rate increased from 8% (untreated)
to 83% (50 mg/kg DCA) and to 100% (100 mg DCA) (Régnier et
al., 1996).
DCA has been used in clinical studies in the treatment of
lactic acidosis from several origins (Stacpoole, 1989;
Stacpoole et al., 1992) and has been quite extensively
studied (Curry et al., 1985; Curry et al., 1991; Krishna et
al., 1994; Stacpoole, 1989; Stacpoole et al., 1988; Wells et
al., 1980). No side effects from this treatment has been
reported in these studies.
Mortality in severe MCA poisoning is high. DCA seems to be an
effective antidote in the treatment of MCA poisoning in
animal models and from clinical trials DCA seems to be safe.
This treatment should be tried in severe MCA poisoning.
However, as there are no clinical experience in treating MCA
poisoning with DCA each case should be carefully monitored
for the evaluation of this proposed treatment. A protocol for
this purpose is given below.
[Earlier recommended therapy (not longer recommended as this
therapy was based on a hypothesis proven to be wrong).
Ethanol as an acetate donor (oxidation of ethanol to acetate)
to prevent systemic poisoning (Gosselin et al., 1984).
Ethanol protects rats and monkeys against monochloro-ethanol
(Pieterson et al., 1968) and is given as an acetate donor in
fluoroacetate poisoning (Chenoweth, 1949; Hutchens et al.,
1949; Pieterson et al., 1968). Ethanol may also block some
metabolic step(s) preventing formation of toxic metabolites.
Monoacetin (glycerol monoacetate) as an acetate donor for
fluoroacetate poisoning (Chenoweth et al., 1951; Gosselin et
al., 1984). However, there is no clinical evidence of its
efficacy. It might even induce sedation, respiratory
stimulation, vasodilatation, haemolysis, capillary damage
(Spoerke et al., 1986). While glycerol acetate protects
animals against the toxicity of MFA (monofluoro acetate)
similar doses of glycerol monoacetate potentiated the
toxicity of MCA (Gibson, 1971).
N-acetylcysteine as a sulfhydryl donor and as a glutathione
precursor. In animal studies cysteine has proven effective in
reducing MCA toxicity (Bakhisek, 1978; Kurchatov & Vasileva,
1976).
The following protocol has been recommended for studies of
DCA treatment in MCA poisonings.
1. Adequate documentation of skin damage - drawing on the
skin, photo etc.
2. Monitor haemodynamics at regular intervals (hourly)
for 24 hours (or longer)- blood pressure, heart rate,
and if possible central venous pressure, pulmonary
artery pressure, pulmonary capillary wedge pressure,
cardiac output etc.
3. Blood analyses
Time Acid/base, Electrolytes B-Glucose S-Creatinine,
lactate (K+, Na+, Cl-) S-Urea
Entry × × × ×
1 h ×
2 h × × × ×
3 h ×
4 h × × × ×
5 h ×
6 h × × × ×
7 h ×
8 h × × × ×
12 h × × × ×
16 h × × × ×
20 h × × × ×
24 h × × × ×
36 h × × × ×
48 h × × × ×
Time S-Creatine S-AST, S-Myoglobin Coagualtion
kinase S-ALT, parameters
S-Bilirubin
Entry × × × ×
1 h
2 h
3 h
4 h
5 h
6 h
7 h
8 h × × × ×
12 h
16 h × × × ×
20 h
24 h × × × ×
36 h × × × ×
48 h × × × ×
4. Analyses of MCA and DCA concentrations in plasma
(EDTA/heparin tubes) minimum 2 mL blood. Separate and
freeze the plasma.
MCA as soon as possible and thereafter after 5, 10,
20, 40, 60, 120, 240 minutes and thereafter after
another 2 hours, 6 hours, 10 hours and 22 hours
DCA 5 minutes before administration, at administration
and thereafter as for MCA after 5, 10, 20, 40, 60,
120, 240 minutes and thereafter after another 2 hours,
6 hours, 10 hours and 22 hours.
Time MCA * DCA
Entry Not appl.
5 min
10 min
20 min
40 min
1 h
2 h
4 h
6 h
12 h
22 h
44 h
*: tag timepoint immediately prior to administration of DCA:
determine DCA in this and all subsequent blood samples.
11. ILLUSTRATIVE CASES
11.1 Case reports from literature
Skin exposure
1. It is quite unclear why systemic intoxication occurs in
some cases while in many others under seemingly comparable
circumstances such as body surface, temperature and physical
state of MCA, first aid etc no systemic symptoms appear (no
biological data are available in these cases) (Vincent,
1987).
2. A 25-year-old man who was splashed with monochloroacetic
acid at 60°C suffered extensive first degree burns of the
face, neck, upper chest, groins and legs. One hour after the
accident he developed a cough with bloody sputum, and
convulsions, became unconscious and died four hours later. At
autopsy there were signs of alveolar damage and petaechial
haemorrhages in the pericardium and pleura, and dilatation of
the right heart (von Oettingen, 1958; Zeldenrust, 1951).
3. Summary of 3 lethal and 1 severe cases (Millischer and
Ruty, 1986).
a) Two people were exposed to molten MCA over approximately
10% of their body surface. Immediate showering was probably
performed. They both died after 11 hours and 18 hours
respectively. Symptoms in one of the cases were vomiting,
convulsions, cardiovascular shock, coma and hypokalaemia.
b) A male was exposed to concentrated solution over 5 to 10%
of his body surface. He immediately showered. Systemic
symptoms after 1 hour were vomiting, cardiovascular shock,
hypokalaemia and low urinary output. He recovered without
specific therapy.
c) A male was exposed to an 80% solution over 15% of his body
surface. He immediately showered. Systemic poisoning after
one hour included vomiting, cardiovascular shock,
convulsions, coma, low urinary output. He died after six
hours. Autopsy revealed lung and kidney damage.
4. A 47-year-old worker employed in a production plant was
splashed with molten MCA at 80°C from a drain valve located
near the ground. He showered immediately and undressed under
the shower.
Five minutes later in the medical department of the plant, he
had another shower for 15 minutes. At this time he had first
degree burns of the front side of both legs estimated at 6%
of the body surface. The burns were washed and coated with a
fat cream. His clinical state appeared to be fine and his
burn pain was bearable. He was taken to his home.
After 3 hours he has experienced vomiting, diarrhoea,
alteration of consciousness with alternation of catatonia and
agitation. His state deteriorates, he becomes delirious and
is sent to hospital.
After 5 hours post exposure at hospital, he is comatose and
goes into cardiovascular shock. A severe metabolic acidosis
is observed (pH=7.22 after infusion of 500 ml of sodium
bicarbonate 1.4 g/100 mL), with hypokalaemia (3.1 mmol/l),
hyperglycaemia (9 mmol/L) and leucocytosis (28,000
giga/L).
After 7 hours post exposure, second degree cutaneous burns
(some severe) are estimated at 10% of body area. (CK: at most
1,500 Ui/L). Symptomatic treatment and metabolic acidosis
control are difficult (1,250 mL THAM at 3.66 g/100 mL allows
to correct pH from 7.18 to 7.35 in 3 hours).
After 9 hours post exposure he is treated with ethanol over 2
days according to the protocol for treatment of methanol
intoxication.
The outcome is favourable with correction of clinical and
biological signs within 36 hours. Consciousness is normal at
the 40th hour. No more complication afterwards (Vincenti,
1987).
5. A 28-year-old man was splashed with MCA (80% solution). He
was not wearing any special protective clothing. His clothes
were removed within a couple of minutes and he was then
showered with water for 20 minutes. At admission to hospital
one hour after the accident he had developed 25 to 30% first
to second degree burns, except for slight disorientation he
was otherwise unaffected. One hour later his systolic blood
pressure decreased to 60 mm Hg and he became agitated. Later
on he became unconscious. ECG showed changes indicative of
unspecific myocardial damage. Hypokalaemia was prominent the
first 24 hours (min 2.3 mmol/L 12 hours after the accident).
He was put on the ventilator and intravenous fluids and high
doses of inotropic drugs (dopamine, dobutamine) were given.
His circulation stabilized, but during the first 24 hours
metabolic acidosis was pronounced (Base Deficit approximately
10 mOsm/L) in spite of continuous buffer solution
administration. Antidote therapy with ethanol and
N-acetylcysteine was given during the first 24 hours.
Progressive renal failure developed and on the second day he
became anuric. Treatment with continuous arteriovenous
haemofiltration and haemofiltration was started. On the
second day pronounced hypocalcaemia developed. Creatine
kinase values were very high (max 1800 µkat/L) indicating
extensive tissue damage and AST max 42 µkat/L, ALT max 11
µkat/L.
Due to repeated seizure activity on the fourth day
barbiturates and diazepam were given. On the fifth day he
also had signs of increased intracranial pressure.
Hyperventilation was started, but two days later (Day 7) his
cerebral status deteriorated and he showed signs of cerebral
herniation. EEG and angiogram verified cerebral death. MCA in
blood 4, 6, 8 and 12 hours after exposure were 33, 15, 7.8
and 0.22 mg/L respectively. Autopsy findings indicated that
kidney damage was to some extent secondary to myoglobin
precipitation in the renal tubular (Kulling et al.,
1992).
6. A 24-year-old male worker experienced accidental exposure
to MCA in molten form (at 58°C) on the skin of both legs. The
exposure area was estimated as 10% of the victim's skin
surface. The exposed area was washed with water almost
continuously from 30 seconds after exposure to 1 hour after
exposure.
In the first hour following exposure, the victim vomited
twice and complained of numbness in the left calf, but was
alert and did not complain of pain. During the second hour,
the victim had spells of vomiting interspersed with napping
but responded when spoken to. Three hours following exposure,
the victim's respiratory rate was 30 and his pulse was 104.
Heart rate was somewhat irregular, but volume was good.
During transfer to a hospital, the victim experienced a
convulsive seizure followed by deep shock. The victim had no
palpable pulse or blood pressure, an increased respiratory
rate, and wheezing with some rales. Hemoglobin levels were
15.9 g, the white blood cell count was 25,200, and hematocrit
was 46. Blood carbon dioxide, sodium, and chloride levels
were normal, while potassium levels were low. Glucose and
saline with 80 mg solu-medrol were administered for 2 hours,
with a subsequent reduction in dose to 20 mg. Potassium
chloride was given intravenously, and antihistamines were
administered intramuscularly. Blood pressure returned to 110,
but the victim never regained consciousness and died 11 hours
following the accident.
Autopsy showed congestion, hemorrhage, and confluent petechia
of the heart, lungs and thymus, congestion of the liver, a
persistent thymus, and massive bilateral pulmonary congestion
and edema. Burns on both legs extended to just above the knee
and were first-degree in nature other than some second-degree
patches (US-EPA TSCA, 1992).
Ingestion
A 5-year-old girl was accidentally given 5-6 mL of an 80% MCA
wart remover (Verzone), from a bottle resembling Triaminicol
decongestant. Forty five minutes later, she presented to the
ED in no distress. Initial vital signs were: BP 133/91, P12,
R 20, T 95.6 and physical examination revealed pale, slightly
mottled skin, but was otherwise normal. One and one half
hours post-ingestion, she developed refractory ventricular
tachycardia, pulmonary oedema, and acidaemia. Despite
aggressive intervention, the patient died 8 hours
post-ingestion. An autopsy revealed diffuse gastric erosions,
fatty liver, and pulmonary and cerebral oedema. A post-mortem
serum MCA level of 100 mg/L confirmed the ingestion (Feldhaus
et al., 1993; Rogers, 1995).
Animal case reports
1. A group of 23 heifers (young female cows) were poisoned by
Na-MCA polluted drinking water. Nine animals died within a
few hours. Ante-mortem findings were stiffness, unsteady
gait, later lateral recumbency, exterior paralysis of the
limbs, tremor and convulsions. One heifer showed signs of
hyperexcitability and aggressiveness many hours later before
it collapsed and died within 24 hours. Post-mortems showed
extreme venous congestion of neck and thorax with petechial
haemorrhages extending into the muscle layer. Their hearts
were congested and had multiple endo- and epicardial
haemorrhages. There were no lesions to the abdominal viscera
and alimentary tract. Uptake was estimated to be about 170
mg/kg (Quick et al., 1983).
2. Two ewes and two lambs were found dead near a Na-MCA
spill. Post mortem findings were similar but also included
pulmonary congestion and oedema; uptake was estimated to be
in the range of 39 to 70 mg/kg body weight (Quick et al.,
1983).
3. Groups of two rabbits were exposed to MCA on 40%, 20%,
10%, 5%, or 3% of their skin surface area for either 15
minutes without washing, 1 minute followed by exhaustive
washing with water, or 1 minute followed by exhaustive
washing with sodium bicarbonate and application of sodium
bicarbonate paste. An additional group was exposed on 1% of
their skin surface for 15 minutes without washing.
Deaths occurred in two to five hours in all 15-minute
exposure groups except at 1%, and at 40%, 20%, and 10% and
one animal at 5% for both the water and sodium bicarbonate
wash groups. Animals showed remarkably few symptoms, but were
lethargic and comatose before death. Sodium bicarbonate
treatment did not affect mortality but did appear to lessen
the severity of skin lesions.
Gross pathological observations included distended peripheral
venous systems and lack of blood in the right ventricle of
the heart. The physiological cause of death was not clearly
determined.
Microscopic examination of the organs had not been completed
at the time of the report. (US-EPA TSCA, 1992)
12. ADDITIONAL INFORMATION
12.1 Specific preventive measures
Protective clothing including protective glasses as for
acids, should always be used when handling MCA
solutions.
12.1 Other
The antidote DCA was licensed by the Swedish Medical
Products Agency (August 1999) for use in life threatening
MCA-exposure. It is available at the Akzo-Nobel plant in
Skoghall which is the only industry in Sweden that handles
substantial amounts of MCA.
The sodium salt of DCA can be dissolved in sterile water and
subsequently filtered (not heated). The solution is stable
for at least one year when refrigerated.
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14. AUTHOR, REVIEWERS
Author
Per Kulling, Swedish Poisons Information Centre, S-171 76
Stockholm, Sweden
Phone + 46 8 33 87 65
Fax + 46 8 32 75 84
Date 10/86, Updated 8/93, Updated 2/98
Reviewers
Jacqueline Jouglard,
Centre Anti-Poisons,
Hôpital Salvator, 249,
Bd Ste-Marguerite,
13274 Marseille Cédex 9,
France
Phone +33 91 75 25 25
Chris Braun,
Akzo Nobel Nederland bv,
Postbus 9300, 6800 SB Arnhem.
The Netherlands
Phone +31 26 366 44 33
Fax +31 26 366 32 50
Date 2/98
Reviewed at INTOX 12, Erfurt, Germany November 2000
Reviewers: M. Balali-Mood, B. Groszek, W. Temple, N.
Langford.