INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 154
ACETONITRILE
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
First draft prepared by Dr K. Hashimoto (Kanazawa University, Japan),
Dr. K. Morimoto (National Institute of Hygienic Sciences, Japan) and
Dr. S. Dobson (Institute of Terrestrial Ecology, Monks Wood
Experimental Station, United Kingdom)
World Health Orgnization
Geneva, 1993
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chemicals.
WHO Library Cataloguing in Publication Data
Acetonitrile.
(Environmental health criteria ; 154)
1.Acetonitriles - adverse effects 2.Acetonitriles - toxicity
3.Environmental exposure I.Series
ISBN 92 4 157154 3 (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR ACETONITRILE
1. SUMMARY
1.1. Properties, uses and analytical methods
1.2. Environmental levels and sources of human exposure
1.3. Environmental distribution and transformation
1.4. Environmental effects
1.5. Absorption, distribution, biotransformation and
elimination
1.6. Effects on laboratory mammals
1.7. Effects on humans
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1. Identity
2.2. Physical and chemical properties
2.2.1. Physical properties
2.2.2. Chemical properties
2.3. Conversion factors
2.4. Analytical methods
2.4.1. Determination of acetonitrile in ambient air
2.4.1.1 Sampling methods
2.4.1.2 Measurement of acetonitrile in
collected air samples
2.4.2. Monitoring methods for the determination of
acetonitrile and its metabolites in
biological materials
2.4.2.1 Acetonitrile in urine
2.4.2.2 Acetonitrile in serum
2.4.2.3 Acetonitrile metabolites in tissues
and biological fluids
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Anthropogenic sources
3.2.1. Production levels and processes
3.2.2. Uses
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport and distribution between media
4.1.1. Water
4.2. Transformation
4.2.1. Biodegradation
4.2.1.1 Water and sewage sludge
4.2.1.2 Soil
4.2.2. Abiotic degradation
4.2.2.1 Water
4.2.2.2 Air
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water and bottom sediment
5.1.3. Food
5.1.4. Tobacco smoke
5.1.5. Other sources of exposure
5.2. Occupational exposure
5.3. Acetonitrile in various solvent products
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1. Absorption
6.1.1. Human studies
6.1.2. Experimental animal studies
6.1.2.1 Intake through inhalation
6.1.2.2 Dermal absorption
6.1.2.3 Intake via the gastrointestinal tract
6.2. Distribution
6.2.1. Human studies
6.2.2. Experimental animal studies
6.3. Biotransformation and elimination
6.3.1. Human studies
6.3.2. Experimental animal studies and
in vitro studies
6.3.2.1 Cyanide liberation from acetonitrile
6.3.2.2 The oxidative pathway of acetonitrile
metabolism
6.4. Biological monitoring of acetonitrile uptake
7. EFFECTS ON LABORATORY MAMMALS; IN VITRO TEST SYSTEMS
7.1. Acute toxicity
7.1.1. Single exposure
7.1.2. Clinical observations
7.1.2.1 Effect on skin
7.1.2.2 Effect on the eyes
7.1.2.3 Effect on respiration
7.1.2.4 Effect on adrenals
7.1.2.5 Effect on the gastrointestinal tract
7.1.3. Biochemical changes and mechanisms of
acetonitrile toxicity
7.1.3.1 Effect on cytochrome oxidase
7.1.3.2 Effect on glutathione
7.1.4. Antidotes to acetonitrile
7.2. Subchronic toxicity
7.2.1. Inhalation exposure
7.2.2. Subcutaneous administration
7.3. Teratogenicity and embryotoxicity
7.4. Mutagenicity
7.4.1. Bacterial systems
7.4.2. Yeast assays
7.4.3. Drosophila melanogaster
7.4.4. Mammalian in vivo assays
7.4.5. Chromosome aberrations and sister chromatid
exchange
7.5. Carcinogenicity
7.6. Cytotoxicity testing
8. EFFECTS ON HUMANS
8.1. Acute toxicity
8.1.1. Inhalation exposure
8.1.2. Dermal exposure
8.1.3. Oral exposure
8.2. Chronic toxicity
8.3. Mutagenicity and carcinogenicity
8.4. Occupational exposure to cyanide
8.5. Chronic poisoning by cyanides
8.5.1. Ingestion
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.2. Aquatic organisms
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1. Evaluation of human health risks
10.2. Evaluation of effects on the environment
11. RECOMMENDATIONS FOR THE PROTECTION OF HUMAN HEALTH
12. FURTHER RESEARCH
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
REFERENCES
RESUME
RESUMEN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA FOR ACETONITRILE
Members
Dr R. Bruce, System Toxicants Assessment Branch, Office of Research
and Development, Environmental Criteria and Assessment Office,
US Environmental Protection Agency, Cincinnati, Ohio, USA
(Joint Rapporteur)
Dr R.J. Bull, College of Pharmacy, Washington State University,
Pullman, Washington, USA
Dr S. Dobson, Institute of Terrestrial Ecology, Monks Wood
Experimental Station, Huntingdon, United Kingdom
(Vice-Chairman)
Dr K. Hashimoto, Department of Hygiene, School of Medicine,
Kanazawa University, Kanazawa, Japan
Dr P. Lauriola, Local Hygiene Unit, Office of Public Hygiene,
Modena, Italy
Dr M. Lotti, Institute of Occupational Medicine, University of
Padua, Padua, Italy (Chairman)
Dr K. Morimoto, Division of Biological Chemistry and Biologicals,
National Institute of Hygienic Sciences, Tokyo, Japan (Joint
Rapporteur)
Dr Y.F. Panga, Department of Standard Setting, Chinese Academy of
Preventive Medicine, Beijing, China
Dr S.A. Soliman, Department of Pesticide Chemistry, College of
Agriculture and Veterinary Medicine, King Saud University,
Al-Qasseem, Bureidah, Saudi Arabia
Secretariat
Dr B.H. Chen, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland (Secretary)
Dr E. Smith, International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
a Invited but unable to attend.
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the
criteria monographs as accurately as possible without unduly
delaying their publication. In the interest of all users of the
Environmental Health Criteria monographs, readers are kindly
requested to communicate any errors that may have occurred to the
Director of the International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland, in order that they may be
included in corrigenda.
* * *
A detailed data profile and a legal file can be obtained from
the International Register of Potentially Toxic Chemicals, Case
postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone
No. 9799111).
* * *
This publication was made possible by grant number
5 U01 ES02617-14 from the National Institute of Environmental Health
Sciences, National Institutes of Health, USA.
WHO TASK GROUP ON ENVIRONMENTAL HEALTH
CRITERIA FOR ACETONITRILE
A WHO Task Group on Environmental Health Criteria for
Acetonitrile met in Modena, Italy, from 24 to 28 November 1992.
Mr Giorgio Baldini, the President of the Province of Modena, opened
the meeting and greeted the participants on behalf of the Province
of Modena. Dr B.H. Chen of the International Programme on Chemical
Safety (IPCS) welcomed the participants on behalf of the Director,
IPCS, and the three IPCS cooperating organizations (UNEP/ILO/WHO).
The Task Group reviewed and revised the draft criteria monograph and
made an evaluation of the risks for human health and the environment
from exposure to acetonitrile.
The first draft of this monograph was prepared by Dr K.
Hashimoto, Kanazawa University, Japan, Dr K. Morimoto, National
Institute of Hygienic Sciences, Japan, and Dr S. Dobson, Institute
of Terrestrial Ecology, Monks Wood Experimental Station, United
Kingdom. The second draft was prepared by Dr K. Morimoto
incorporating comments received following the circulation of the
first draft to the IPCS Contact Points for Environmental Health
Criteria monographs. Dr M. Lotti (Institute of Occupational
Medicine, University of Padua, Italy) made a considerable
contribution to the preparation of the final text.
Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS
Central Unit, were responsible for the overall scientific content
and technical editing, respectively. The efforts of all who helped
in the preparation and finalization of the document are gratefully
acknowledged.
* * *
Financial support for this Task Group meeting was provided by
the Province of Modena, Communes of Mirandola and Medolla, Local
Hygiene Units N. 16 of Modena and N. 15 of Mirandola, Association of
Business and Industries of the Province of Modena and ENICHEM
(National Organization of Industrialization for Chemistry) in Italy.
ABBREVIATIONS
CLD chemiluminescence nitrogen detector
GC gas chromatography
HPLC high performance liquid chromatography
NPD nitrogen-phosphorus selective detector
TCD thermal conductivity detection
TEA thermal energy analyser
1. SUMMARY
1.1 Properties, uses and analytical methods
Acetonitrile (CH3CN) is a by-product of acrylonitrile
manufacture. It may also be formed by the combustion of wood and
vegetation. It is a liquid with an ether-like odour. Acetonitrile
is a volatile, highly polar solvent used to extract fatty acids and
animal and vegetable oils. It is used in the petrochemical industry
in extractive distillation based on its selective miscibility with
organic compounds. It is used as a solvent for spinning synthetic
fibres and in casting and moulding plastics. In laboratories, it is
widely used in high-performance liquid chromatographic (HPLC)
analysis and as a solvent for DNA synthesis and peptide sequencing.
The most widely used analytical technique for acetonitrile is
gas chromatography.
1.2 Environmental levels and sources of human exposure
Very few data on acetonitrile levels in the environment are
available. Worldwide, acetonitrile concentrations in air of 200 to
42 000 ng/m3 have been reported. Slightly higher values were
obtained for urban than rural air in one study. Single measurements
before and after burning of bush and straw showed a 10-fold increase
in acetonitrile air concentration.
Acetonitrile was not detected in 72 water samples from Japan but
was found in 11 out of 60 aquatic sediment samples at
concentrations between 0.02 and 0.54 mg/kg. Acetonitrile has not
been detected in food.
Tobacco smoke contains acetonitrile and burning polyurethane
foam releases acetonitrile and hydrogen cyanide.
Whilst production of acrylonitrile offers the greatest potential
for exposure, this is carried out in a closed system. Practical
uses of acetonitrile lead to greater exposure.
1.3 Environmental distribution and transformation
Acetonitrile volatilizes from water and would also volatilize
from soil surfaces. It is readily biodegraded by several strains of
bacteria common in sewage sludge, natural waters and soil.
Acclimatization of bacteria to acetonitrile or petroleum wastes
increases the rate of degradation. Anaerobic degradation appears to
be limited or absent.
Hydrolysis of acrylonitrile in water is extremely slow. There
is no significant photodegradation in either water or the
atmosphere. Reaction with ozone is slow as is reaction with singlet
oxygen. The major mechanism for removal of acetonitrile from the
troposphere is reaction with hydroxyl radicals; residence times
have been estimated at between 20 and 200 days.
Acetonitrile does reach the stratosphere where it is
characteristically associated in positive ion clusters in the upper
regions.
1.4 Environmental effects
Acetonitrile has low toxicity to microorganisms (bacteria,
cyanobacteria, green algae and protozoans) with thresholds at
500 mg/litre or more. Freshwater invertebrates and fish acute
LC50s are 700 mg/litre or more. Acute tests have been conducted
under static conditions without analytical confirmation of
concentrations. Similar results obtained from 24- and 96-h tests
suggest volatilization of acetonitrile.
1.5 Absorption, distribution, biotransformation and elimination
Acetonitrile is readily absorbed from the gastrointestinal
tract, through the skin and the lungs. All three routes of exposure
have been reported to lead to systemic effects.
Postmortem examination of tissues from poisoned humans has
revealed that acetonitrile distributes throughout the body. This is
supported by animal studies in which acetonitrile distribution has
been found to be fairly uniform throughout the body. There are no
indications of accumulation in animal tissues following
repeated administrations of acetonitrile.
There are substantial data to suggest that most of the systemic
toxic effects of acetonitrile are mediated through its metabolism to
cyanide, which is catalysed by the cytochrome P-450 monooxygenase
system. Cyanide is subsequently conjugated with thiosulfate to form
thiocyanate which is eliminated in the urine. Peak concentrations
of cyanide in the blood of rats following administration of near
lethal doses of acetonitrile approximate to the concentrations
observed following the administration of an LD50 dose of potassium
cyanide. However, the peak concentration of cyanide after
administration of acetonitrile is delayed by up to several hours as
compared to other nitriles. Moreover, the more rapid rate at which
cyanide is produced in the mouse appears to account for the much
greater sensitivity of this species to the toxic effects of
acetonitrile. Cyanide and thiocyanate have been identified in human
tissues after exposure to acetonitrile. A portion of the
acetonitrile dose is also eliminated unchanged in expired air and in
urine.
1.6 Effects on laboratory mammals
Acetonitrile induces toxic effects similar to those observed in
acute cyanide poisoning, although the onset of symptoms is some-what
delayed compared to inorganic cyanides or other saturated nitriles.
The 8-h inhalation LC50 in male rats is 13 740 mg/m3 (7500 ppm).
The oral LD50 in the rat varies from 1.7 to 8.5 g/kg depending on
the conditions of the experiment. Mice and guinea-pigs appear to be
more sensitive, with an oral LD50 in the range of 0.2-0.4 g/kg.
The main symptoms in animals appear to be prostration followed by
seizures.
Dermal application of acetonitrile causes systemic toxicity in
animals and has been implicated in the death of one child. The
percutaneous LD50 in rabbits is 1.25 ml/kg.
Subchronic exposure of animals to acetonitrile produces effects
similar to those seen after acute exposures.
Acetonitrile is not mutagenic in assays using Salmonella
typhimurium, both with and without metabolic activation. It
induces aneuploidy in a diploid yeast strain at very high
concentrations. No animal studies on chronic or carcinogenic effects
of acetonitrile have been reported.
1.7 Effects on humans
The levels causing toxicity in man are unknown but are
probably in excess of 840 mg/m3 (500 ppm) in air. Symptoms and
signs of acute acetonitrile intoxication include chest pain,
tightness in the chest, nausea, emesis, tachycardia, hypotension,
short and shallow respiration, headache, restlessness,
semiconsciousness, and seizures. Other non-specific symptoms may be
due to the irritant effects of the compound. The systemic effects
appear to be largely attributable to the conversion of acetonitrile
to cyanide. Blood cyanide and thiocyanate levels are elevated
during acute intoxication. Two fatalities after exposure to
acetonitrile vapour in the workplace and one fatal case of a child
ingesting an acetonitrile-containing cosmetic have been reported.
Elevated tissue cyanide concentrations were found in postmortem
examin-ation of these cases.
No epidemiological study of cancer incidence relating to
acetonitrile exposure has been reported.
Acetonitrile can cause severe eye burns. Skin contact with
liquid acetonitrile should be avoided. An employee's exposure to
acetonitrile in any 8-h shift has been recommended in many
countries not to exceed a time-weighted average of 70 mg/m3 air
(40 ppm).
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, AND
ANALYTICAL METHODS
2.1 Identity
Chemical formula: CH3CN
Chemical structure:
Relative molecular mass: 41.05
CAS chemical name: acetonitrile
CAS registry number: 75-05-8
Synonyms: cyanomethane, ethanenitrile, nitrile of
acetic acid, methyl cyanide, ethyl
nitrile, methanecarbonitrile
Specifications for commercial acetonitrile are given in
Table 1. The principal organic impurity in commercial acetonitrile
is propionitrile, although small amounts of allyl alcohol may also
be present (Grayson, 1985).
2.2 Physical and chemical properties
2.2.1 Physical properties
Acetonitrile is a volatile, colourless liquid with a sweet,
ether-like odour (Grayson, 1985). It is infinitely soluble in water
and readily miscible with ethanol, ether, acetone, chloroform,
carbon tetrachloride and ethylene chloride (Clayton & Clayton,
1982). It is immiscible with many saturated hydrocarbons (petroleum
fractions) (Budavari, 1989).
Important physical constants and properties of acetonitrile are
summarized in Table 2.
Table 1. Commercial acetonitrile specificationsa
Specific gravity (at 20 °C) 0.783-0.787
Distillation range (°C)
initial point, minimum 80.5
end point, maximum 82.5
Purity (minimum), % by weight 99.0
Acidity (as acetic acid, maximum % by weight) 0.05
Copper (maximum), ppm 0.5
Iron (maximum), ppm 0.5
Water (maximum), % by weight 0.3
Colour (maximum), Pt-Co 15
a From: Grayson (1985)
2.2.2 Chemical properties
Although acetonitrile is one of the most stable nitriles, it
undergoes typical nitrile reactions and is used to produce many
types of nitrogen-containing compounds. It can be trimerized to
S-trimethyltriazine and has been telomerized with ethylene and
copolymerized with alpha-epoxides (Grayson, 1985).
Acetonitrile produces hydrogen cyanide when heated to
decomposition or when reacted with acids or oxidizing agents
(Reynolds, 1982).
2.3 Conversion factors
1 ppm = 1.68 mg/m3 (25 °C, 760 mmHg)
1 mg/m3 = 0.595 ppm (25 °C, 760 mmHg) (Clayton & Clayton, 1982)
Table 2. Physical properties of acetonitrile
Properties Value Reference
Appearance colourless liquid Budavari (1989)
Odour ether-like Budavari (1989)
Boiling point 81.6 °C (760 mmHg) Budavari (1989)
Freezing point -45.7 °C Grayson (1985)
-44 to -41 °C Verschueren (1983)
Specific gravity 0.78745 (15/4 °C) Grayson (1985)
0.7138 (30/4 °C) Grayson (1985)
Vapour density 1.42 (air = 1) Clayton & Clayton (1982)
Refractive index (ND) 1.34604 (15 °C) Clayton & Clayton (1982)
1.33934 (30 °C) Clayton & Clayton (1982)
Solubility in water infinitely soluble Clayton & Clayton (1982)
Vapour pressure
at (15.5 °C) 7.32 kPa (54.9 mmHg) US EPA (1984)
at (20.0 °C) (74.0 mmHg) Verschueren (1983)
at (30.0 °C) (115.0 mmHg) Verschueren (1983)
Water azeotrope boiling point 76 °C
water content 16% US EPA (1984)
Log P (octanol/water -0.38 Leo et al. (1971)
partition coefficient -0.34 Verschueren (1983)
Table 2 (contd)
Properties Value Reference
Flash point 5.6 °C (open cup) Reynolds (1982)
12.8 °C (closed cup) Reynolds (1982)
Ignition temperature 524 °C Sax & Lewis (1989)
Explosive limits lower 4.4 Grayson (1985)
in air (% by volume) 3.05 Prager (1985)
upper 16.0 Grayson (1985)
17.0 Prager (1985)
2.4 Analytical methods
2.4.1 Determination of acetonitrile in ambient air
2.4.1.1 Sampling methods
The use of absorption tubes to trap acetonitrile from ambient
air with subsequent thermal or liquid desorption prior to gas
chromatographic (GC) analysis has been reported in many references.
The National Institute of Occupational Safety and Health (NIOSH,
1977, 1984) recommended the use of a glass tube (9 cm long and 6 mm
internal diameter) containing two sections of 20-40 mesh activated
(600 °C) coconut charcoal (front = 400 mg and back = 200 mg)
separated by 3 mm section urethane foam and held in place with plugs
of silanized glass wool. The tube is then flame-sealed at both ends
until it is used for air sampling. Other sampling tubes containing
different sorbents (i.e. porous polymer beads) have also been
recommended (Campbell & Moore, 1979; Berg et al., 1980; Rigby,
1981; Kashihira, 1983; Kashihira et al., 1984; Wood, 1985; Cobb
et al., 1986).
2.4.1.2 Measurement of acetonitrile in collected air samples
Several methods have been used to measure acetonitrile in
environmental samples. Most of the reported methods are based on
the use of GC.
a) Gas chromatography
GC is frequently used for determining acetonitrile using
different kinds of detectors in conjunction with the charcoal or
porous polymer beads sampling technique. A number of detectors have
been recommended. Until recently, almost all of the
published work involved the use of flame ionization detection (FID).
However, it was found that FID did not respond to acetonitrile in a
repeatable way even with the use of internal standards (Joshipura
et al., 1983).
Attention has therefore turned to the use of thermal
conductivity detection (TCD) (Joshipura et al., 1983) and to
nitrogen-phosphorus selective detector, NPD (Cooper et al., 1986).
Rounbehler et al. (1982) described a modification for the thermal
energy analyser (TEA), a highly sensitive nitrosyl-specific GC
chemiluminescence detector, which allows it to be used as a highly
selective one in detecting nitrogen-containing compounds. They
concluded that the modified TEA was as sensitive as the alkali-bead
flame ionization detection (AFID) but had a much higher selectivity
toward nitrogen-containing compounds. Using the TEA, these
investigators were not able to detect any acetonitrile in bacon or
beer. Kashihira et al. (1984) used a chemiluminescence nitrogen
detector GC (CLD-GC) method to measure acetonitrile and
acrylonitrile in air. The method was able to detect as little as
20 ng of acetonitrile per injection.
Cooper et al. (1986) developed a very sensitive method of
measuring nitrogen-containing hazardous pollutants in complex
matrices by GC with NPD and were able to detect 1.5 pg acetonitrile.
Table 3 summarizes the different types of detectors used in GC
analysis of acetonitrile along with the conditions employed and
their corresponding detectability.
b) High-performance liquid chromatography (HPLC)
The use of HPLC to determine trace amount of acetonitrile in
environmental samples has not been reported.
c) Microwave spectrometry
Kadaba et al. (1978) analysed toxic constituents including
acetonitrile in tobacco smoke by microwave spectroscopy and were
able to measure acetonitrile down to 2 ppm.
2.4.2 Monitoring methods for the determination of acetonitrile and
its metabolites in biological materials
2.4.2.1 Acetonitrile in urine
Mckee et al. (1962) determined acetonitrile in urine samples
obtained from 20 male nonsmokers and 40 male smokers by a
modification of the method reported by Rhoades (1958, 1960) for the
analysis of coffee volatiles. The modification permitted the
stripping of urinary volatiles at 37 °C and at reduced pressure.
The stripped volatiles were collected in a liquid nitrogen trap,
vapourized, and analysed by GC with a thermal conductivity detector.
The column, which was packed with 15% Carbowax 1500 and silicone oil
200 (ratio 2:1) on 40-60 mesh Chromosorb P, was operated at 40 °C.
The carrier gas was helium at a pressure of 4 pounds per square
inch. Acetonitrile concentrations as low as 2.9 µg/litre could be
measured in urine using this method.
Table 3. Gas chromatographic conditions for acetonitrile determination
Packing Conditions Detection Reported level of References
detectability
Porapak 250 x 0.25 cm, 160 °C injector FID 10 ppm in Thomson (1969)
150 °C helium, 70 ml/min acrylonitrile
Porapak Q 122 x 0.63 cm, 180 °C injector FID 10 mg/m3 in air NIOSH (1977)
270 °C nitrogen, 50 ml/min (6 ppm)
Porapak Q 305 x 0.32 cm, 200 °C injector FID 0.01 ppm in air Campbell & Moore (1979)
200 °C nitrogen, 20 ml/min
0.1% SP 1000 200 x 0.19 cm, 35-235 °C injector FID 0.07 ppm in air Berg et al. (1980)
on Carbopack C 125 °C nitrogen, 21 ml/min
20% Carbowax 180 x 0.2 cm, 90-145 °C injector TEA 0.041 ppm Rounbehler et al. (1982)
20 M 120 °C
Chromosorb 103 90 x 0.3 cm, 85 °C injector CLD 1 ppb in air Kashihira et al. (1984)
150 °C helium, 60 ml/min
Porapak Q 508 x 0.32 cm, 170 °C injector FID 0.2 ppm in air Wood (1985)
200 °C nitrogen, 30 ml/min
20% SP-1200W/0.1% 305 x 0.32 cm, 180 °C injector NPD 1.5 ppb Cooper et al. (1986)
Carbowax 1500 190 °C nitrogen, 30 ml/min or
helium, 35 ml/min
FID = Flame ionization detection; CLD = Chemiluminescent nitrogen detection; NPD =
Nitrogen-phosphorous detection; TEA = Thermal energy analyser
2.4.2.2 Acetonitrile in serum
Freeman & Hayes (1985a) determined serum acetonitrile
concentrations in rats dosed orally with acetone, acetonitrile, and
a mixture of acetone and acetonitrile by GC equipped with FID. The
analysis was performed isothermally (150 °C) at a helium flow rate
of 30 ml/min using a 2 mm x 1.22 m Chromosob 104 column (100/120
mesh) with a 15-cm precolumn. Propionitrile was added to the serum
samples as an internal standard prior to injection, and the samples
were injected directly into the column. Under the conditions of
this study, the retention times of acetone, acetonitrile and
propionitrile were 2.05, 3.65 and 6.20 min, respectively. The limit
of detection was not reported. However, it was reported that the
serum acetonitrile concentrations of animals in the control group
were all below 1 mg/litre.
2.4.2.3 Acetonitrile metabolites in tissues and biological fluids
a) Cyanide
Since hydrogen cyanide is a reactive and volatile nucleophile,
a variety of problems are encountered in its assay in biological
materials due to tissue binding or diffusibility (Troup &
Ballantyne, 1987). To reduce artefacts due to simple evaporative
losses, cyanide should be extracted under alkaline conditions.
Amdur (1959) determined the cyanide level in the blood of 16
workers, who were accidentally exposed to acetonitrile, by the
method of Feldstein & Klendshoj (1954), which uses a Conway
microdiffusion approach (Conway, 1950). The sensitivity of this
method is as low as 0.1 µg cyanide in a 1 ml sample. Willhite &
Smith (1981) measured cyanide concentrations in the liver and brain
of mice challenged by acetonitrile using the method of Bruce et al.
(1955), which is capable of determining 0.05 µg cyanide in a 1 ml
sample. Haguenoer et al. (1975a,b) determined free cyanide in the
tissues and urine of rats using the pyridine-benzidine method
described by Aldridge (1944); the sensitivity of this method was
0.7 µg hydrogen cyanide in a 1 ml sample. Ahmed & Farooqui (1982)
determined the tissue and blood cyanide levels in rats by the Conway
diffusion method described by Pettigrew & Fell (1973). Willhite
(1983) determined tissue cyanide level in hamsters by the procedure
of Bruce et al. (1955). A combination of the aeration procedure
of Bruce et al. (1955) with the colorimetric method of Epstein
(1947), which can determine 0.2 µg of cyanide in a 1 ml sample, has
been used to determine the cyanide level in brain (Tanii &
Hashimoto, 1984a) and in liver microsomes of mice (Tanii &
Hashimoto, 1984b). The aeration apparatus consists of three serial
tubes containing 25 ml 20% NaOH, 5 ml 20% trichloroacetic acid and
0.5 ml 0.1 N NaOH. An aliquot of samples is added to the tube
containing trichloroacetic acid, which is then aerated at a flow
rate of 600 ml/min, passing from the tube containing 20% NaOH for
10 min toward the tube containing 0.1 N NaOH. An aliquot from the
tube containing 0.1N NaOH is then removed, neutralized with acetic
acid and subjected to analysis for cyanide. Under these conditions,
the recovery of known amounts of cyanide is 97-100%. Freeman &
Hayes (1985a) determined cyanide in the blood of rats by a
microdiffusion method modified from Feldstein & Klendshoj (1954).
Samples were analysed colorimetrically at 586 nm using
pyridine-barbituric acid reagent as described by Blanke (1976).
Cyanide concentrations as low as 0.1 mg/litre could be reproducibly
detected by these methods. Zamecnik & Tam (1987) reported an
improved GC method for cyanide analysis in blood with acetonitrile
as an internal standard. GC with NPD was used with a 180 x 0.2 cm
column packed with 100/120 mesh Porapak Q. Other conditions were:
temperature, column 120 °C, detector 250 °C, and a helium gas flow
rate of 20 ml/min. The blood samples containing cyanide were
pipetted into disposable vials. Samples were then sealed and
glacial acetic acid was injected into the vials. These were then
vortexed and allowed to equilibrate for 30 min at room temperature.
The head space was injected into the gas chromatograph. The typical
retention times for the cyanide and acetonitrile peaks were 0.6 min
and 2.5 min, respectively. The sensitivity for cyanide was
0.05 ppm. Three procedures for the determination of cyanide in
biological fluids have been reported with full detail (Rieders &
Valentour, 1975). The first procedure is qualitative, the second
colorimetric (chloramine-T and barbituric acid and pyridine), and
the third depends on GC using electron capture detection.
Table 4 summarizes the methods which have been used for cyanide
analysis in biological samples.
b) Thiocyanate
Pozzani et al. (1959a) determined urinary thiocyanate levels
in various animals by means of the colorimetric method of Chesley
(1941). Using this method, 25-180 mg thiocyanate/litre urine could
be measured with a ± 4% error. Silver et al. (1982) determined
thiocyanate in the urine of rats dosed with acetonitrile.
Thiocyanate was first isolated from urine by separation on an ion
exchange column (10 x 1 cm) of Amberlite CG-400 as described by
Kanai & Hashimoto (1965) and then measured colorimetrically
according to the method of Epstein (1947). Willhite (1983)
determined the tissue thiocyanate levels in hamsters using the
method described by Bruce et al. (1955).
Table 4. Analysis of cyanide in biological materials
Analytical methods Application
Principle Detectability References Biological materials References
(µg/ml)
Conway diffusion method 0.1 Feldstein & Klendshoj (1954) human blood Amdur (1959)
0.1 Pettigrew & Fell (1973) rat tissues and blood Ahmed & Farooqui (1982)
0.1 Feldstein & Klendshoj (1954); rat blood Freeman & Hayes (1985a)
Blanke (1976)
Benzidine and pyridine 0.1 Aldridge (1944) rat tissues and Haguenoer et al.
methods, colorimetry urine (1975a,b)
Aeration procedure and 0.2 Bruce et al. (1955); mouse brain Tanii & Hashimoto
colorimetry Epstein (1947) (1984a,b)
0.05 Bruce et al. (1955) mouse liver and brain Willhite & Smith (1981)
0.05 Bruce et al. (1955) hamster tissues Willhite (1983)
GC, nitrogen-phosphorus 0.05 - blood Zamecnik & Tam (1987)
detector
Pereira et al. (1984) used the method of Contessa & Santi
(1973) to determine thiocyanate levels in urine samples collected
from rats treated with different nitriles. The method was able to
detect thiocyanate concentrations as low as 100 µg in a 0.2 ml urine
sample.
Table 5 summarizes the methods reported for analysis of
thiocyanate in biological samples.
Table 5. Analysis of thiocyanate in biological materials
Analytical methods Application
Principle Detectability References Biological materials References
(µg/ml)
Colorimetry 25 Chesley (1941) animal urine Pozzani (1959a)
0.6 Bruce et al. (1955) hamster tissues Willhite (1983)
Ion exchange separation 0.5 Kanai & Hashimoto (1965); rat urine Silver et al. (1982)
and colorimetry Epstein (1947)
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
Acetonitrile may be formed by combustion of wood, straw and
other vegetation. However, the rate of formation and the
contribution to atmospheric acetonitrile has not been quantified
(Becker & Ionescu, 1982).
3.2 Anthropogenic sources
3.2.1 Production levels and processes
Acetonitrile is a by-product of acrylonitrile synthesis. This
process is known as the SOHIO (Standard Oil Company of Ohio) process
and involves a high temperature catalytic reaction between propylene
and ammonia. The SOHIO process is the principal route to both
acrylonitrile and acetonitrile, produced in the ratio of 0.035 kg
acetonitrile/kg acrylonitrile (Lowenheim & Moran, 1975).
Acetonitrile can be synthesized by several other routes. Good
yields are obtained by dehydration of an acetic acid and ammonia
mixture, acetamide or ammonium acetate.
CH3COOH + NH3 -> CH3CN + 2H2O
CH3CONH2 -> CH3CN + H2O
CH3CO2NH4 -> CH3CN + 2H20
A 90% yield of acetonitrile is obtained by the reaction of
ethanol and ammonia in the presence of catalyst such as Ag, Cu,
MoO3, and ZnS at moderate temperatures. Acetonitrile is also
produced by the reaction of cyanogen chloride with methane, ketones,
ethanol, alkylene epoxides, and paraffins or olefins.
The principal organic impurity in commercial acetonitrile is
propionitrile, together with a small amount of allyl alcohol (US
EPA, 1992).
Reported production of acetonitrile in the USA during the
period 1980-83 (US EPA, 1985) was:
Year Production (millions of kg)
1980 10.1
1981 9.5
1982 9.4
1983 11.4
3.2.2 Uses
Being a volatile highly polar solvent, acetonitrile finds its
greatest use as an extracting fluid for fatty acids and animal and
vegetable oils.
Acetonitrile has been widely used as an extractive distillation
solvent in the petrochemical industry for separating olefin-diolefin
mixtures and for C4-hydrocarbons. When acetonitrile is used in this
way, recycling is effected by water dilution of the extract and
condensate with subsequent phase separation, after which the
acetonitrile is azeotroped from the aqueous phase.
Acetonitrile has been used as a solvent for polymer spinning
and casting because of the combination of high solubility and
desirable intermediate volatility. It is also used as a solvent for
isolating components from crude products such as crude wool resin.
Acetonitrile is used as a common laboratory solvent for
recrystallizing various chemicals and is widely used as a solvent in
HPLC analysis. Acetonitrile is also used in biotechnology research
as a solvent in the synthesis of DNA and peptide sequencing (Borman,
1990).
Acetonitrile can be used to remove tars, phenols and colouring
matter from petroleum hydrocarbons that are not soluble in
acetonitrile.
Acetonitrile is also used as a starting material for the
synthesis of many chemicals such as acetophenone, alpha-naphthyl
acetic acid, thiamine and acetomidine (Hawley, 1971).
The use patterns of acetonitrile are summarized in Table 6.
Table 6. Main use patterns of acetonitrilea
Extraction of fatty acids and animal and vegetable oils
Extraction of unsaturated petroleum hydrocarbons
Solvent for polymer spinning and casting
Moulding of plastics
Removal of tars, phenols and colouring matter from petroleum
hydrocarbons
Purification of wool resin
Recrystallization of steroids
Starting material for synthesis of chemicals
Solvent in DNA synthesis and peptide sequencing
Medium for promoting reactions
Solvent in non-aqueous titrations
Non-aqueous solvent for inorganic salts
High-pressure liquid chromatographic analysis
Catalyst and component of transition-metal complex catalysts
Extraction and refining of copper
Stabilizer for chlorinated solvents
Perfume manufacture
Pharmaceutical solvents
a From: Veatch et al. (1964); NIOSH (1978); Toxic Substances
Control Act (1979); Smiley (1983); Borman (1990)
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport and distribution between media
4.1.1 Water
Hine & Mookerjee (1975) reported that the ratio of
concentration in the water phase to the gas phase of a dilute
aqueous solution of acetonitrile at equilibrium at 25 °C is 891:1.
The inverse of this ratio (1.1 x 10-3) is the unit-less Henry's
Law constant. Conversion to units, using an RT value of 2.4 x
10-2-m3 atm/mol (where R is the gas constant and T is the
temperature in K), yields a Henry's Law constant of
2.6 x 10-5-m3 atm/mol. This value of Henry's Law constant
indicates that the volatilization of acetonitrile is probably
significant for most environmental bodies of water (Lymann et al.,
1982). The concentration of acetonitrile in river water decreased
to 5% of the original level after 72 h in a study carried out under
stable conditions (Chen et al., 1981).
4.2 Transformation
4.2.1 Biodegradation
4.2.1.1 Water and sewage sludge
Ludzack et al. (1958, 1959) measured the biodegradation of
acetonitrile in Ohio River water and in aged sewage by measuring
CO2 production. Degradation in the river water occurred at a
faster rate than in the sewage; the 12-day biological oxygen demand
(BOD) was 40% in river water but only 20% in the sewage.
Acclimatization of microorganisms was examined by reculturing, and
the degradation was found to occur 5 times more rapidly using
acclimatized microorganisms. The effect of temperature on
biodegradation was also studied; degradation at 5 °C took 2.5-5
times longer than at 20 °C. Ludzack et al. (1961) examined the
degradation of acetonitrile by activated sludge in a continuous feed
test at 22-25 °C; 82-94% BOD was removed during 4 weeks of test
operation. Anaerobic digestion does not appear to be an effective
means of removing the compound from waste water (Ludzack et al.,
1961).
Using the Japanese MITI (Ministry of International Trade and
Industry) test, Sasaki (1978) reported that acetonitrile is "readily
biodegradable", meaning that oxygen consumption is > 30% in 2
weeks. Thom & Agg (1975) reported that acetonitrile should be
degradable by biological sewage treatment with appropriate
acclimatization. Mimura et al. (1969) isolated the bacterium
Corynebacterium nitrilophius from activated sludge and found that
this microorganism was capable of assimilating acetonitrile. Kelly
et al. (1967) found virtually no degradation of acetonitrile using
a nitrogenase from Azotobacter chroococcum.
Goud et al. (1985) isolated bacteria of several genera from
various points in an effluent treatment plant at a petrochemical
installation. Azobacter spp and, more particularly, Pseudomonas
spp were able to degrade acetonitrile, added to the culture medium
at 1% as sole carbon source. Aeromonas spp and Bacillus spp,
however, were unable to degrade acetonitrile. The authors pointed
out that many of the bacterial species tested are common in the
environment, and that regular exposure to petrochemicals selects
strains that are able to degrade such compounds.
Chapatwala et al. (1992) investigated mixed cultures of
bacteria isolated from an area contaminated with organic cyanide and
polychlorinated biphenyls and found that they readily utilized
acetonitrile as sole carbon and nitrogen source. Nearly 70% of
14C-labelled acetonitrile was recovered as CO2, the remainder
being incorporated into bacterial growth. The mixed culture lost
its capacity to degrade biphenyl when repeatedly recultured with
acetonitrile, indicating more ready degradation of the nitrile.
Ludzack et al. (1961) observed high levels of nitrates in
effluents from activated sludge degrading acetonitrile. Firmin &
Gray (1976) used a species of Pseudomonas capable of utilizing
acetonitrile as sole carbon source to show that acetonitrile
undergoes direct enzymatic hydrolysis. These authors postulated the
following metabolic pathway based on their results with [2-14C]
acetonitrile: acetonitrile -> acetamide -> acetate -> tricarboxylic
acid cycle intermediates (citrate, succinate, fumarate, malate,
glutamate, etc.).
4.2.1.2 Soil
DiGeronimo & Antoine (1976) isolated Nocardia rhodochrus
Ll100-21 from barnyard soil and demonstrated that the
microorganism was capable of using acetonitrile as a source of
carbon and nitrogen. A decrease in acetonitrile content within the
culture medium was correlated with an increase in acetamide and
acetic acid levels; ammonia was also detected. Under the test
conditions, the initial concentration of acetonitrile was reduced by
14% in 3 h and by 52% in 8 h. Crude cell-free extracts were also
found to degrade acetonitrile by an enzymatic hydrolysis
mechanism that was reported to be inducible. Kuwahara et al.
(1980) found that Aeromonas species BN 7013 could be grown
using acetonitrile as a nitrogen source; the microorganism was
isolated from soil. Harper (1977) isolated a strain of the fungus
Fusarium solani from soil and found that cell-free extracts,
containing the nitrilase enzyme, were capable of hydrolysing
acetonitrile enzymatically.
4.2.2 Abiotic degradation
4.2.2.1 Water
Brown et al. (1975) reported that the hydrolysis rate
constant for acetonitrile in an aqueous solution of pH 10 is 1.195 x
10-8 M-1 sec-1. Assuming a constant pH of 10, the half-life
for this process would be > 18 000 years.
Anbar & Neta (1967) reported that the rate constant for the
reaction of acetonitrile with hydroxyl radicals in aqueous solution
at pH 9 and room temperature is 2.1 x 106 M-1 sec-1; assuming
an environmental hydroxyl radical concentration at 10-17 M, a
half-life of 1042 years can be calculated. Dorfman & Adams (1973)
reported a similar hydroxyl radical rate constant of 3.5 x 106
M-1 sec-1.
The absorption maximum for acetonitrile in the UV range is
< 160 nm (Silverstein & Bassler, 1967); therefore, the direct
photolysis of acetonitrile in the aquatic environment is not
expected to occur.
4.2.2.2 Air
Harris et al. (1981) found in laboratory studies that the
rate of reaction of acetonitrile with ozone was relatively slow, the
rate constant being < 1.5 x 10-19 cm3 molecule-1 sec-1.
Assuming a typical atmosphere concentration of 1012 ozone
molecules/cm3, a half-life of > 54 days can be calculated from
this rate constant.
The reaction rate constant between singlet oxygen and
acetonitrile is reported to be 2.4 x 10-16 cm3 molecule-1
sec-1 (Graedel, 1978); this predicts an atmospheric half-life of >
5000 years for acetonitrile.
Dimitriades & Joshi (1977) reported on the reactivity of
acetonitrile as measured in an US EPA smog chamber with 22
blacklights, 7 sunlamps, 4 ppm acetonitrile and 0.2 ppm NOx.
Acetonitrile was found to be unreactive with respect to ozone yield.
The average rate of disappearance of acetonitrile was found to be
0.02% per hour, i.e. 100 times slower than that measured for
propane. Kagiya et al. (1975) measured the photochemical
decomposition rate of acetonitrile (300-2000 ppm) in air saturated
with water in a reaction cell irradiated with a mercury lamp. No
degradation was observed, however, when chlorine gas (2000 ppm) was
added to the cell, the decomposition rate being 1.32% per second.
Reaction between chlorine radicals and acetonitrile in the
atmosphere is not thought to be significant in relation to hydroxyl
radical reaction (Arijs et al., 1983).
The absorption maximum for acetonitrile in the UV range is
< 160 nm (Silverstein & Bassler, 1967). Therefore, the direct
photolysis of acetonitrile in the ambient atmosphere is not expected
to occur.
The major mechanism for removal of acetonitrile from the
troposphere is reaction with hydroxyl radicals. The rate constant
for the gas-phase reaction of acetonitrile with hydroxyl radicals
has been experimentally determined by Harris et al. (1981) to be
0.494 x 10-13 cm3 molecule-1 sec-1 at 24.2 °C; in the
temperature range 298-424 °K (25-151 °C), the rate constant was
described by the equation k = 5.86 x 10-13 exp (-1500 cal
mole-1/RT). From this rate constant data, Harris et al. (1981)
calculated the tropospheric destruction rate of acetonitrile at
25 °C to be approximately 5 x 10-7 sec-1 for a mean
concentration of 107 hydroxyl radicals/cm3 in a moderately
polluted troposphere; this rate yielded a tropospheric lifetime of
approximately 20 days. In a more average atmosphere of 106
hydroxyl radicals/cm3, the lifetime will be 10 times longer.
Guesten et al. (1981) reported the rate constant for the reaction
between hydroxyl radicals and acetonitrile in the gas phase to be
approximately 0.2 x 10-13 cm3 molecule-1 sec-1 at room
temperature, which agrees reasonably well with the findings of
Harris et al. (1981). The Arrhenius activation energy of
approximately 1500 cal mole-1, as determined by Harris et al.
(1981), indicates that the reaction proceeds largely or entirely by
abstraction of a hydrogen atom.
Acetonitrile does reach the upper atmosphere. It is
characteristically associated in positive ion clusters of the form
H+(CH3CN)m (H2O)n. These ions do not occur in the
ionosphere but become important at 35 km altitude. At lower
altitudes still (about 12 km), acetone ions become evident (Arijs
et al., 1983; Huertas & Marenco, 1986).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
Becker & Ionescu (1982) monitored air near to the ground in
both urban and rural areas and detected acetonitrile at
concentrations of 3360 to 11 960 µg/m3 (2-7 ppb by volume) using
GC/MS. There was some indication that results from city centre
samples were higher than general rural samples; acetonitrile at
concentrations of 7.4 ± 2.4 ppb was reported for the city centre in
Wuppertal, Germany. Given the small number of samples, however, a
comparison of the sites is difficult. A rural site was sampled in
the air before and after burning of bush and grass by farm workers
and results showed an increase in acetonitrile concentration from
4.0 to 34.9 ppb. This seems to be the only reported demonstration
of non-anthropogenic sources of atmospheric acetonitrile.
Acetonitrile has also been reported to be present in the upper
stratosphere (Arijs et al., 1983). It was detected at
concentrations of 210 to 42 000 ng/m3 in the Environmental Survey
of Chemicals in Japan (Office of Health Studies, Environment Agency,
1990).
In the USA, two samplings of air over a period of 24 h in a
rural area gave daily mean levels of 0.048 ppb by volume. A single
sampling of urban air was below the detection limit of the
analytical method (US EPA, 1988).
5.1.2 Water and bottom sediment
Acetonitrile was not detected in water but was detected in
bottom sediment in the Environmental Survey of Chemicals in Japan
(Office of Health Studies, Environment Agency, 1990). The sampling
was conducted in all 47 prefectures of Japan, but no information is
available concerning the nature of the sampling sites. It is not
known, therefore, whether the high ends of the ranges in air and
aquatic sediment were associated with industrial production and
release (Table 7).
5.1.3 Food
No report has been published showing contamination of food by
acetonitrile.
Table 7. Environmental levels in Japan of acetonitrile in 1987a
Concentration Frequency of Detection limit
detectionb
Water not detected 0/72 3 µg/litre
Sediment 0.021 to 0.54 mg/kg 11/60 0.021 mg/kg
Air 210 to 42 000 ng/m3 44/70 200 ng/m3
a From: Office of Health Studies (1990)
b Number of detections/number of samples
5.1.4 Tobacco smoke
The absorption of acetonitrile from smoke has been confirmed by
GC/MS analysis of a composite sample of the urine of 40 smokers
(Mckee et al., 1962). The average acetonitrile level was
117.6 µg/litre urine, while the average level for 20 nonsmokers was
2.9 µg/litre urine.
5.1.5 Other sources of exposure
Nitrogen-containing products such as hydrogen cyanide,
acetonitrile and acrylonitrile, and some other toxic gases have been
detected from the thermal decomposition of flexible polyurethane
foams (Woolley, 1972). The yield of hydrogen cyanide and
acetonitrile, respectively, from 10 mg foam was 26.4 and 21.4 µg at
800 °C, where a volatile yellow smoke was produced, and 522 and
30.5 µg at 1000 °C, where the yellow smoke was decomposed.
5.2 Occupational exposure
Synthesis of acetonitrile is usually carried out in a closed
system. Therefore, occupational exposure would only be accidental.
NIOSH estimated that 23 000 workers may be exposed to acetonitrile
in the USA. Since much of the acetonitrile produced has noncaptive
uses, the general population may also be exposed (NIOSH, 1979).
The occupational exposure limit for acetonitrile in various
countries is shown in Table 8.
Table 8. Occupational exposure limits for various countriesa
Country TWA STEL
(ppm) (mg/m3) (ppm) (mg/m3)
Australia 40 70 60 105
Belgium 40 67 60 101
Denmark 40 70 - -
Finland 40 70 60 105
France 40 70 - -
Germany 40 70 - -
Hungary - 50 - 100
Switzerland 40 70 80 140
United Kingdom 40 70 60 105
USA
(ACGIH) 40 67 60 101
(NIOSH/OSHA) 40 70 60 101
USSR - - - 10
a From: ILO (1991)
5.3 Acetonitrile in various solvent products
After a nationwide survey in Japan of organic solvent
components in various solvent products, acetonitrile was not
detected in either thinners (321 samples) or miscellaneous solvents
(56 samples), but was detected in 1% of the degreasers (145 samples)
(Inoue et al., 1983).
6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
6.1 Absorption
6.1.1 Human studies
Acetonitrile is well absorbed by inhalation. There is little
information on absorption of inhaled acetonitrile in humans.
Studies on smokers showed that 91 ± 4% of the acetonitrile
inhaled in cigarette smoke was retained (Dalhamn et al., 1968a).
A significant portion of this could have been retained in the mouth,
as 74% of the acetonitrile was retained as a result of holding smoke
in the mouth for 2 sec (Dalhamn et al., 1968b).
There are no absorption studies concerning dermal or oral
exposure. However, human poisoning cases indicate that acetonitrile
is well absorbed by both routes.
6.1.2 Experimental animal studies
6.1.2.1 Intake through inhalation
Although there is information that acetonitrile is easily
absorbed from the lungs of animals exposed to acetonitrile vapour,
no quantitative analytical data is available on the pulmonary
absorption of acetonitrile.
6.1.2.2 Dermal absorption
Pozzani et al. (1959a) studied the skin penetration of
undiluted or diluted acetonitrile under polyethylene sheeting in
rabbits (the site of application was not reported). The dermal
LD50 value was decreased when application was made as a 75% (by
volume) aqueous solution, i.e. from 1.25 (0.84 to 1.85) ml/kg in the
case of the undiluted compound to 0.5 (0.37 to 0.67) ml/kg in the
case of the diluted aqueous solution. These LD50 values are
similar or even lower than those obtained after oral administration
in other animal species, indicating effective skin absorption of
acetonitrile.
6.1.2.3 Intake via the gastrointestinal tract
Although there is information that acetonitrile is easily
absorbed from the gastrointestinal tract, no quantitative analytical
data are available.
6.2 Distribution
6.2.1 Human studies
A postmortem investigation on a man accidentally exposed to
acetonitrile suggested that acetonitrile absorbed through inhalation
or skin contact is distributed in the body as shown in Table 21
(section 8.1.1).
6.2.2 Experimental animal studies
Ahmed et al. (1992) studied by means of whole body
auto-radiography the distribution of radioactivity derived from
2-14C-acetonitrile in the body of ICR mice at time points between
5 min and 48 h after administration of a single intravenous dose.
Irreversible association of label was determined in co-precipitated
protein and nucleic acids and extracted lipid. No attempt was made
to distinguish between metabolically incorporated or adducted label.
The highest concentrations of non-volatile radioactive compounds
were generally found in the liver, kidney and the contents of the
upper gastrointestinal tract. A significant fraction (40-50%) of
the radioactivity found in liver at 24 and 48 h was bound to the
macromolecular fractions of the tissues. The radioactivity contents
of other organs were, in large part (40-50% of total), present in
the lipid fraction of the tissue.
6.3 Biotransformation and elimination
6.3.1 Human studies
There is no specific human study describing acetonitrile
biotransformation and elimination. However, accidental poisoning
cases indicate that acetonitrile is biotransformed to cyanide and
thiocyanate, which are then excreted from urine (see section 9).
6.3.2 Experimental animal studies and in vitro studies
6.3.2.1 Cyanide liberation from acetonitrile
The release of cyanide from acetonitrile and its subsequent
metabolism to thiocyanate have been studied under a number of
experimental conditions and in several animal species.
Biotransformation of acetonitrile to cyanide and thiocyanate
has been demonstrated in a variety of in vitro preparations.
Liver slices obtained from male golden hamsters show an increasing
generation of cyanide and thiocyanate as the concentration of
acetonitrile increases (Willhite, 1983). Release of cyanide from
acetonitrile is also catalysed by liver microsomes of hamster in a
concentration-dependent manner (Willhite, 1983). Production of
cyanide from acetonitrile has been demonstrated in isolated
hepatocytes from female SD rats; the Km and Vmax values (mean ±
SD) were 3.4 ± 0.8 mM and 1.1 ± 0.1 nmol cyanide/106 cells per
10 min, respectively (Freeman & Hayes, 1987). The release of
hydrogen cyanide from acetonitrile has also been demonstrated in
mouse liver microsomes, both with and without NADPH (Ohkawa et al.,
1972). The Km and Vmax values obtained from male ddY mouse
microsomes were 4.19 mM and 14.3 ng cyanide formed in 15 min per mg
protein, respectively (Tanii & Hashimoto, 1984a).
Dahl & Waruszewski (1989) studied the metabolism of
aceto-nitrile to cyanide in rat nasal and liver tissues and found
that the maximum rates of cyanide production from acetonitrile by
nasal maxilloturbinate and ethmoturbinate microsomes and liver
microsomes were 0, 0.9 ± 0.2 and 0.098 ± 0.008 nmol cyanide/mg
protein per min, respectively.
In vivo metabolism of acetonitrile to cyanide and thiocyanate
was first demonstrated by Pozzani et al. (1959a). Studies were
conducted in rats, monkeys and dogs under a number of experimental
conditions. Fifteen male and fifteen female rats were exposed to
acetonitrile vapour (166, 330, and 655 ppm) 7 h/day, 5 days/week for
90 days. During the 5-day sampling period (inhalation days 59 to
63), thiocyanate concentrations in urine ranged from 27 to 79 and 29
to 60 mg/100 ml for the 166 and 330 ppm exposure groups,
respectively. Thiocyanate was not completely eliminated between
daily exposures, but was almost completely excreted during the
2.5-day rest period over weekends. The excretion of thiocyanate in
the higher exposure group was not reported.
The concentrations of thiocyanate in the urine of three dogs
exposed to 350 ppm acetonitrile in air increased from 69 to
252 mg/litre over the same 5-day inhalation period as described
above for rats. Unlike the rats, dogs continued to eliminate
thiocyanate beyond the 2.5-day rest period over the weekend. When
three monkeys were exposed to 350 ppm acetonitrile in the same
manner as the dogs, the urinary thiocyanate concentration ranged
from 60 to 114 mg/litre. Thiocyanate was also excreted after the
2.5-day rest period.
Rhesus monkeys were injected intravenously either with
acetonitrile (0.1 ml/kg) or with thiocyanate (1.55 ml/kg of a 10%
solution in saline). The percentages of the dose excreted as
thiocyanate were 12% and 55%, respectively. It seems therefore that
more than 12% of the injected acetonitrile was converted into
thiocyanate (Pozzani et al., 1959a).
After a single intraperitoneal administration of acetonitrile
(780 mg/kg) in rats, all animals died in 3 to 12 h, and acetonitrile
was found to be distributed in various organs (Dequidt & Haguenoer,
1972). The free cyanide varied from 170 µg/kg in the liver to
3.5 mg/kg in the spleen. Concentrations of combined cyanide in the
liver, spleen, stomach and skin were 3.6, 13.5, 17.6 and 10.5 mg/kg
tissue, respectively.
Haguenoer et al. (1975a,b) studied the pharmacokinetics of
acetonitrile in male Wistar rats after a single intraperitoneal
acetonitrile injection or inhalation exposure. Rats given 2340 or
1500 mg/kg died within 3 to 28 h after the intraperitoneal
injection, but rats given 600 mg/kg survived with no apparent
symptoms. After administration of 2340 mg/kg, concentrations of
acetonitrile and free and combined cyanide in various organs ranged
from 900 to 1700 mg/kg, 200 to 3500 µg/kg, and 3.5 to 17 mg/kg
tissue, respectively. Mean total urinary acetonitrile and free and
combined cyanide (essentially all thiocyanate) excreted during the
11 days following an intraperitoneal injection of 600 mg/kg were 28,
0.2 and 12 mg, respectively. These values were equivalent to 3,
0.035 and 2.3% of the acetonitrile dose, respectively. Urinary
acetonitrile was detectable for 4 days after dosing, whereas free
and combined cyanide were detectable until 11 days, at which time
the animals were sacrificed. Rats inhaling 25 000 ppm died within
30 min from the beginning of exposure. The concentration of
acetonitrile in muscle and kidney ranged from about 1.4 to 24 mg/kg,
and that of free cyanide in liver and spleen from 0.3 to 4 mg/kg
tissue. When three rats were exposed to 2800 ppm (2 h/day for
3-5 days) the concentrations of acetonitrile and free cyanide in
various tissues at the time of death were 1000-2900 mg/kg and
0.5-10 mg/kg tissue, respectively.
The liver and brain cyanide levels of male CD-1 mice (n = 9-10)
that died 2.5 h after intraperitoneal administration of 175 mg
acetonitrile/kg were found to be 47.8 ± 36.1 and 13.4 ± 4.8 µmol/kg,
respectively (Willhite & Smith, 1981). Sprague-Dawley rats
administered an oral LD50 of acetonitrile (2460 mg/kg) were found
to have cyanide levels of 16 ± 6 mg/kg in liver, 102 ± 39 mg/kg in
kidney and 28 ± 5 mg/kg in brain (Ahmed & Farrooqui, 1982).
Freeman & Hayes (1985a) found that the peak blood cyanide
concentration (5.2 ± 0.5 mg/litre) was achieved 35 h after oral
administration of 1470 mg/kg to female SD rats. Silver et al.
(1982) reported that urinary thiocyanate excretion for a 24-h period
following oral or intraperitoneal adminstration of acetonitrile
(30.8 mg/kg) in SD rats was 11.8 ± 2.5 and 4.4 ± 0.5% of the dose,
respectively. Inhalation studies on male and female Wistar rats
exposed to 166 and 330 ppm (660 ppm was fatal) indicated that the
amount of thiocyanate in urine was not proportional to the
concentration of acetonitrile inhaled (Pozzani et al., 1959a).
Table 9 shows that acetonitrile is converted to cyanide at a
slower rate than other nitriles. In fact, one hour after
acetonitrile administration the blood level of cyanide was much
lower than those after acute toxic doses of other nitriles. Peak
concentrations of blood cyanide were found 7.5 h after acetonitrile
dosing and were comparable to those of other nitriles measured one
hour after dosing.
Brain cyanide concentration one hour after acetonitrile dosing
was also lower than those after exposure to potassium cyanide (KCN)
or other nitriles. Urinary excretion of thiocyanate after exposure
to various nitriles indicated that for acetonitrile the percentage
of the dose excreted was lower than for other nitriles, even though
the absolute given amount of acetonitrile, based on its oral LD50
value, was much higher. These data, taken together, indicate that
the toxicity of acetonitrile is lower than those of cyanide and
other nitriles, as shown by oral LD50 values in Table 9. The
reason for this is most probably the slower transformation of
acetonitrile to cyanide and consequently the more efficient
detoxification via thiocyanate excretion.
The relevance of acetonitrile pharmacokinetics is further
illustrated by examining the relationship between symptoms produced
by acetonitrile one hour after exposure and the amounts of cyanide,
as well as the effect on cytochrome c oxidase in the brain
(Table 10). Animals treated with acetonitrile were asymptomatic at
this time, but animals treated with other nitriles or KCN at LD50
doses were symptomatic. In fact, the inhibition of brain cytochrome
c oxidase paralleled brain cyanide concentrations. In the case of
acetonitrile, the brain cyanide concentration was too low to affect
cytochrome c oxidase activity and therefore to cause symptoms.
In conclusion, the data reported in Tables 9 and 10 indicate
that the apparent lack of relationship, assessed shortly after
dosing, between acetonitrile toxicity and cyanide production is due
to the slow transformation of acetonitrile to cyanide.
There is sufficient evidence from all animal species studied
that the toxicity of acetonitrile is due to cyanide. Interspecies
variations, as shown in Tables 11 and 12, are probably related to
the relative speed of cyanide formation from acetonitrile (data of
Willhite & Smith, 1981 in mice versus the data of Ahmed & Farooqui,
1982 in rats).
Table 9. Metabolism of nitriles to cyanide in relation to their lethal effects
Compound Cyanide concentration Urinary thiocyanate Oral LD50
(1 h after an oral LD50) excretion (mg/kg body weight)c
Blood (mg/litre)a Brain (mg/kg)c (% dose/24 h)d
Potassium cyanide 6.3 748 ± 200 not measured 10
Acetonitrile 0.3b 28 ± 5 11.8 ± 2.5 2460
Propionitrile 4.0 508 ± 84 65.1 ± 2.9 40
Butyronitrile 3.8 437 ± 106 64.9 ± 3.5 50
Malononitrile 6.5 649 ± 209 not measured 60
Isobutyronitrile not measured not measured 74.0 ± 2.6 160
Acrylonitrile 4.1 395-106 37.3 ± 1.9 90
a Estimated from: Ahmed & Farooqui (1982)
b 7.5 h after oral administration (1470 mg/kg body weight), the blood cyanide level was found to
be 7.3 mg/litre (Estimated from: Freeman & Hayes, 1985a)
c Ahmed & Farooqui (1982) 1 h after oral LD50
d Silver et al. (1982)
6.3.2.2 The oxidative pathway of acetonitrile metabolism
Following the observation of acetonitrile metabolism to cyanide
and thiocyanate by Pozzani et al. (1959a), many authors reported
the same results in humans as well as in experimental animals both
in vitro and in vivo (Amdur, 1959; Ohkawa et al., 1972;
Willhite & Smith, 1981; Ahmed & Farooqui, 1982; Silver et al.,
1982; Willhite, 1983; Pereira et al., 1984; Tanii & Hashimoto,
1984a,b, 1986; Freeman & Hayes, 1985a,b; Ahmed et al., 1992).
They all suggested a metabolic pathway in which acetonitrile is
bio-transformed by cytochrome P-450 monooxygenase system initially
to cyanohydrin, which then spontaneously decomposes to hydrogen
cyanide and formaldehyde as shown in Fig. 1. Formaldehyde has not
been identified in all of these studies, but this could be due to
its high reactivity and rapid conversion into a simple metabolite
(CO2).
Acetone, an inducer of cytochrome P-450 isozyme LM3a (Koop &
Casazza, 1985; Johannsen et al., 1986), has been demonstrated to
stimulate the metabolism of acetonitrile to cyanide in vivo in
rabbits (Freeman & Hayes, 1985a). In an in vitro study, liver
microsomes were isolated and pooled 24 h after pretreatment of
female Sprague-Dawley rats with acetone. Microsomal metabolism of
acetonitrile to cyanide was found to be NADPH-dependent and
heat-inactivated tissue was unable to catalyse this reaction
(Freeman & Hayes, 1985b). The metabolism of some nitriles,
including acetonitrile to cyanide by mouse hepatic microsome system,
has been shown to be NADPH-dependent and enhanced by pretreatment
with ethanol (Tanni & Hashimoto, 1986). Ohkawa et al. (1972)
found that the amount of hydrogen cyanide released in mouse liver
microsomal preparations was increased greatly by the addition of
NADPH. It is known that treatment of rats with cobalt-heme
effectively depletes liver cytochrome P-450 concentrations (Drummond
& Kappas, 1982). Freeman & Hayes (1987) demonstrated a marked
decrease in acetonitrile metabolism in isolated hepatocytes prepared
from rats pretreated subcutaneously with cobalt-heme (90 µmol/kg)
48 h before killing. However, the rate of acetonitrile
biotransformation into cyanide by liver microsomal preparation
obtained from cobalt-heme-treated rats was 13% of controls, while
the total cytochrome P-450 content was reduced by only 41% compared
to the controls.
Table 10. Biochemical and clinical effects in Sprague-Dawley male rats dosed with cyanide and nitrilesa
Compound Brain cyanide Brain cytochrome c CNS Convulsionb Respiratory
concentration oxidase activity depressionb failureb
(mg/kg) (% of control)
Control 0 100 no no no
Potassium cyanide 748 ± 200 29 4 4 4
Acetonitrile 28 ± 5 92 no no no
Propionitrile 508 ± 54 47 3 1 1
Butyronitrile 437 ± 106 41 2 1 1
Malononitrile 649 ± 209 73 3 3 2
a Measured 1 h after an LD50; data from: Ahmed & Farooqui (1982)
b Physiological changes were graded on a scale of 1 (lowest) to 4 (highest)
NADPH, O2 spontaneous
CH3CN -------> HOCH2CN -------> [HCHO] + CN- (1)
mixed-function
oxidases
rhodanese
CN- -------> SCN- (2)
S2O3
[HCHO] has not been identified
CN- and SCN- have been identified both
in vitro and in vivo
Fig. 1. Oxidation (1) and conjugation (2) reactions in acetonitrile
metabolism
Treatment of rats with inducers of P-450 IIE1, such as
pyrazole, 4-methylpyrazole and ethanol, resulted in a 4- to 5-fold
increase in cyanide production from acetonitrile by isolated
microsomes (Feierman & Cederbaum, 1989). Phenobarbital treatment
had a small stimulatory effect, whereas 3-methylcholan-threne
treatment decreased microsomal oxidation of acetonitrile. Cyanide
production was inhibited by carbon monoxide, ethanol, 2-butanol,
dimethyl sulfoxide (DMSO) and 4-methylpyrazole in vitro.
Oxidation of acetonitrile to cyanide by microsomes from rats treated
with pyrazole or 4-methylpyrazole was nearly completely inhibited by
an antibody (IgG) against P-450 3a.
These results imply a role for P-450 in the oxidation of
acetonitrile to cyanide and suggest that P-450 IIE1 may be the
specific catalyst for this oxidation. Acetonitrile oxidation was
not affected by hydroxyl radical scavengers or by desferrioxamine.
The results of human and animal studies indicate that cyanide
formed in vivo is subsequently conjugated with thiosulfate to form
thiocyanate, which is then eliminated in urine. This conjugation is
catalysed by the enzyme rhodanese (thiosulfate cyanide sulfur
transferase: EC 2.8.1.1) (Pozzani et al., 1959a; Takizaw &
Nakayama, 1979; Silver et al., 1982; Willhite, 1983; Pereira
et al., 1984).
Acetone inhibits acetonitrile metabolism when the two compounds
are administered simultaneously. Blood cyanide concentrations were
maximally elevated 9 to 15 h after female SD rats were dosed with
acetonitrile alone at 1470 mg/kg. In rats dosed concomitantly with
acetonitrile (1470 mg/kg) and acetone (1960 mg/kg), blood cyanide
concentrations measured 0 to 24 h after dosing were much lower than
those in rats given the same dose of acetonitrile alone. Blood
cyanide levels, however, reached peak concentration 39 to 48 h after
dosing with the two compounds and were 50% higher than those
measured in rats treated with acetonitrile only (Freeman & Hayes,
1985a).
From these time courses of blood cyanide it was postulated that
acetone has a biphasic effect on acetonitrile metabolism, causing an
initial inhibition and a subsequent stimulation of cyanide
generation from acetonitrile. Freeman & Hayes (1985b) also found
that the in vitro metabolism of acetonitrile to cyanide by either
hepatic microsomal preparations or by isolated liver cells
(hepatocytes) from rats pretreated with acetone (2.5 ml/kg) was
significantly increased (2 fold). However, when acetone was
incubated with hepatocytes, it inhibited acetonitrile metabolism
without affecting cell viability.
Ethanol has also been shown to affect the in vitro metabolism
of some nitriles, including acetonitrile (Tanii & Hashimoto, 1986).
A 1.8-fold increase in cyanide liberation from acetonitrile was
observed in hepatic microsomes from male ddY mice pretreated with
ethanol (4.0 g/kg) 13 h prior to the study.
Freeman & Hayes (1988) further investigated the metabolism of
acetonitrile in vitro and the effects of acetone and other
compounds. They suggested that the conversion of acetonitrile to
cyanide is mediated by specific acetone-inducible isoforms of
cytochrome P-450 and cytochrome P-450j (LM3, LMeb). Acetone,
dimethylsulfoxide and ethanol competitively inhibited this
conversion. Aniline HCl has been shown to reduce acetonitrile
metabolism.
6.4 Biological monitoring of acetonitrile uptake
Workers accidentally exposed to acetonitrile vapour showed
increased serum cyanide and thiocyanate levels but the exposure
concentrations were unknown (Amdur, 1959). In three human
volunteers exposed at different times to concentrations of up to
160 ppm for 4 h (Pozzani, 1959a), no significant changes in urinary
blood cyanide and thiocyanate levels were observed compared to those
measured prior to exposure. In experimental animal studies using
various routes of exposure, blood cyanide and thiocyanate levels
showed increases but they were not proportional to the exposures
(Pozzani, 1959a). It should be noted that there is a delay of
several hours in the formation of cyanide following exposure to
acetonitrile, and the timing of blood sampling is therefore
critical.
From these data it is not possible to derive biological indices
for exposure monitoring.
7. EFFECTS ON LABORATORY MAMMALS; IN VITRO TEST SYSTEMS
7.1 Acute toxicity
7.1.1 Single exposure
The LD50 values for acetonitrile in mammals are summarized in
Table 11; they range between 175 and 5620 mg/kg body weight. The
mouse and the guinea-pig seem to be the most sensitive species. No
consistent effects of sex, administration route or vehicle were
observed. An experiment using four different age groups of rats
showed that new-born rats (24 to 48 h old, 5-8 g) are the most
sensitive. Significant differences in LD50 values were found
between 14-day-old and adult rats, but not between young adults
(80-160 g body weight) and older adults (300-470 g body weight)
(Kimura et al., 1971).
The acute inhalation toxicity of acetonitrile in various animal
species is shown in Table 12. The LC50 values range between about
2700 ppm for a 1-h inhalation or 2300 ppm for a 2-h inhalation in
mice and 16 000 ppm for a 4-h inhalation or 12 000 ppm for an 8-h
inhalation in rats. Mice appear to be the most sensitive species to
acetonitrile inhalation. In Nelson rats, the LC50 value for an
8-h inhalation was significantly lower in males (7551 ppm with 5975
to 9542 confidence interval) than in females (12 435 ppm with 11 036
to 14 011 confidence interval), while that for a 4-h inhalation was
the same in both sexes (16 000 ppm with 13 070 to 19 636 confidence
interval) (Pozzani et al., 1959a).
Pozzani et al. (1959b) studied the relationship between the
observed and predicted LD50 of acetonitrile given in combination
with other chemicals to rats exposed orally or by inhalation.
Predictions were made using the method of Finney (1952). The
mixture of acetonitrile and acetone seemed to show effects that were
greater than additive. Results are summarized in Table 13.
7.1.2 Clinical observations
Signs and symptoms of acute acetonitrile intoxication are
similar in different animal species. Verbrugge (1899) described
signs of acute acetonitrile toxicity in rabbits. One to three hours
after a subcutaneous acetonitrile injection of 90 to 150 mg/kg,
rabbits showed rapid and irregular respiration, immobilization and
convulsions, and two out of seven animals died. Monkeys exposed to
2510 ppm acetonitrile vapour appeared normal after the first day of
inhalation but showed poor coordination followed by prostration and
laboured breathing during the second day. Death occurred a few
hours later (Pozzani et al., 1959a). Mice exposed to
concentrations of acetonitrile ranging from 500 to 5000 ppm (the
LC50 for a 60-min exposure was 2693 ppm) displayed dyspnoea,
tachypnoea, gasping, tremors, convulsions and corneal opacity
30-300 min after the beginning of the exposure. Exposure of mice to
5000 ppm acetonitrile for 60 min killed all the animals within 2 h.
The syndrome of acute acetonitrile toxicity was indistinguishable
from that observed after exposure to cyanide or other nitriles
(Willhite, 1981; Willhite & Smith, 1981).
In a study by Willhite (1983), pregnant hamsters were exposed
to acetonitrile concentrations from 3800 to 8000 ppm for one hour.
The number of hamsters showing tremors, hypersalivation, ataxia,
hypothermia, lethargy and coma increased with increasing dose.
Hamsters died about 3 h after exposure to 5000 ppm acetonitrile and
within 90 min after exposure to 8000 ppm acetonitrile.
In a study by Johansen et al. (1986), all of five pregnant
rats treated with acetonitrile at doses of 750 mg/kg or more per day
by gavage on gestation days 6-15 died, whereas only three out of
five animals treated with 375 mg/kg per day died. Four out of six
rats treated with 275 mg/kg had reduced body weight at parturition,
while two others died.
Ahmed & Farooqui (1982) measured cyanide levels one hour after
administration of LD50 doses of several saturated and unsaturated
nitriles to male SD rats. Few symptoms were noted with acetonitrile
in this study because little cyanide was released within the first
hour following treatment. The tissue concentrations of cyanide
after lethal doses of propionitrile, butyronitrile and malononitrile
were very similar and approximately those observed with a lethal
dose of KCN.
In female SD rats given an oral dose of acetonitrile
(1770 mg/kg), acute toxic effects appeared after 30 h (Freeman &
Hayes, 1985a).
7.1.2.1 Effect on skin
The skin irritation of acetonitrile in Sherman rats was
reported by Smyth & Carpenter (1948) to be comparable to that of
acetone, although no precise description of the technique used for
testing skin irritation was provided.
7.1.2.2 Effect on the eyes
Eye injury caused by acetonitrile, reported by Smyth &
Carpenter (1948), is of intermediate intensity and similar to that
produced by acetone (Carpenter & Smyth, 1946). Corneal opacity has
been observed after either inhalation or intraperitoneal
administration of acetonitrile in male mice (Willhite, 1981;
Willhite & Smith 1981). Pregnant hamsters exposed to 8000 ppm
acetonitrile via inhalation for 60 min showed eye irritation
(Willhite, 1983).
Table 11. LD50 values of acetonitrile for various species and different routes of administration
Species (strain) Sex Observation Route LD50 (mg/kg or Vehicle References
period (days) ml/kg body weightb
Mouse (Kunming) male -a gavage 453 mg/kg water Chen et al. (1981)
Mouse 1 intraperitoneal 520.79 mg/kg Yoshikawa (1968)
Mouse - intraperitoneal 0.25 ml/kg saline Pozzani et al. (1959a)
Mouse (NMRI) 7 intraperitoneal 400 mg/kg water Zeller et al. (1969)
Mouse (CD-1) male 7 intraperitoneal 175 mg/kg water Willhite & Smith (1981)
Mouse (ddY) male 7 oral 269 mg/kg water Tanii & Hashimoto (1984a)
Rat (Sherman) - oral 3800 mg/kg -a Smyth & Carpenter (1948)
Rat (Wistar) or albino male - gavage 1.68 ml/kg undiluted Pozzani et al. (1959a)
Rat (Wistar) or albino male - gavage 2460 mg/kg water Pozzani et al. (1959a)
Rat (Wistar) or albino male - intravenous 1.68 ml/kg undiluted Pozzani et al. (1959a)
Rat (Wistar) or albino female - gavage 2230 mg/kg 1% Tgc Pozzani et al. (1959a)
Rat (Wistar) or albino female - gavage 1730 mg/kg corn oil Pozzani et al. (1959a)
Rat (Wistar) or albino female - gavage 8.56 ml/kg undiluted Pozzani et al. (1959a)
Rat (Wistar) or albino female - intraperitoneal 7.96 ml/kg undiluted Pozzani et al. (1959a)
Rat (Wistar) or albino female - intraperitoneal 5620 mg/kg saline Pozzani et al. (1959a)
Rat (Wistar) or albino female - intraperitoneal 0.85 ml/kg undiluted Pozzani et al. (1959a)
Rat (Wistar) or albino female - intravenous 1.68 ml/kg undiluted Pozzani et al. (1959a)
Rat (SD) - oral 3200 mg/kg water Zeller et al. (1969)
Rat (SD) 14-day old male - oral 0.2 ml/kg undiluted Kimura et al. (1971)
Rat (SD) young adult male - oral 3.9 ml/kg undiluted Kimura et al. (1971)
Rat (SD) older adult male - oral 4.4 ml/kg undiluted Kimura et al. (1971)
Rat (SD) female 3 oral 4050 mg/kg undiluted Freeman & Hayes (1985a)
Table 11 (contd).
Species (strain) Sex Observation Route LD50 (mg/kg or Vehicle References
period (days) ml/kg body weightb
Guinea-pig male - gavage 0.177 ml/kg undiluted Pozzani et al. (1959a)
Rabbit - skin 5.0 ml/kg undiluted Smyth & Carpenter (1948)
Rabbit male - skin 1.25 ml/kg undiluted Pozzani et al. (1959a)
Rabbit male - skin 0.50 ml/kg water Pozzani et al. (1959a)
a - = not reported
b 1 ml acetonitrile = 783-787 mg at 20 °C
c Tg = Tergitol 7 in water
Table 12. Acute inhalation toxicity of acetonitrilea
Species (strain) Sex Concentration Exposure Mortality
(ppm) time (h) measuresb
Mouse (Kunming) 2300 2 LC50
Mouse (Kunming) 5700 2 LC50
Mouse (CD-1) male 2700 1 LC50
male 5000 1 10/10
Rat (Nelson) male 7551 8 LC50
female 12 435 8 LC50
male 16 000 4 LC50
female 16 000 4 LC50
Rat (Wistar) 12 000 2 MLC
Guinea-pig male + 5655 4 LC50
female
Guinea-pig 7400 2 MLC
Rabbit male 2800 4 LC50
Rabbit 4500 2 MLC
Dog male 32 000 4 1/1
male 16 000 4 3/3
male 8000 4 0/1
male 2000 4 0/2
a From: Willhite (1981), Pozzani et al. (1959a,b), Wang et al. (1964)
b MLC = minimum lethal concentration
Table 13. Predicted and observed LC50 and LD50 values of acetonitrile in
combination with other solvents in rata
4-h inhalation (g/m3) Oral (ml/kg)
PLC50 OLC50 PLD50 OLD50
Acetonitrile - 26.9 - 8.27
Acetonitrile + n-hexane 45.6 74.1 - -
Acetonitrile + acetone 39.7 14.6 9.99 2.75
Acetonitrile + ethyl 32.4 51.4 9.40 14.1
acetate
Acetonitrile + carbon 31.5 45.5 4.35 6.77
tetrachloride
Acetonitrile + toluene 22.3 44.4 8.68 3.73
a From: Pozzani et al. (1959b)
PLC50 or PLD50 = predicted LC50 or LD50
OLC50 or OLD50 = observed LC50 or LD50
7.1.2.3 Effect on respiration
Animals exposed to acetonitrile via different routes of dosing
always showed respiratory symptoms: rapid and irregular respiration
after subcutaneous administration in rabbits (Verbrugge, 1899),
laboured or difficult breathing after inhalation exposure in monkeys
(Pozzani et al., 1959a) or rats (Haguenoer et al., 1975b), and
intense dyspnoea after either inhalation or intraperitoneal
administration in mice (Willhite, 1981; Willhite & Smith, 1981).
Histopathological investigations of rat lungs after acetonitrile
inhalation showed haemorrhage and congestion (Haguenoer et al.,
1975b). After inhaling 660 ppm acetonitrile for 2 h, two monkeys
showed focal areas of emphysema and atelectasis, with occasional
proliferation of alveolar septa (Pozzani et al., 1959a).
7.1.2.4 Effect on adrenals
Szabo et al. (1982) studied structure-activity relationships
of 56 chemicals, including acetonitrile, with respect to their
potential for causing adrenocortical necrosis in rats. The dose was
selected on the basis of preliminary experiments and was aimed to
lead to 70 to 100% mortality in 4 to 5 days. The compounds were
given 3 times per day for 4 days, and surviving animals were
sacrificed on the 5th day. Acetonitrile, along with 13 other
compounds out of 56 test chemicals, did not show any
adrenocorticolytic effect in rats.
7.1.2.5 Effect on the gastrointestinal tract
Rats that inhaled acetonitrile at a concentration of 2800 ppm
(2 h/day for 2 days) showed temporary diarrhoea (Haguenoer et al.,
1975b).
Acetonitrile did not produce duodenal ulcers in female SD rats
after oral or subcutaneous administration 3 times per day for 4
days, the total dose being 432 mmol/kg (Szabo et al., 1982).
7.1.3 Biochemical changes and mechanisms of acetonitrile toxicity
7.1.3.1 Effect on cytochrome oxidase
An in vitro study carried out by Willhite & Smith (1981)
showed that high concentrations of acetonitrile (up to 0.47 M) did
not inhibit cytochrome c oxidase activity. Ahmed & Farooqui
(1982) investigated the ability of acetonitrile and other nitriles
to inhibit cytochrome c oxidase one hour after they were
administered at the LD50 to male SD rats. There was no direct
evidence for the inhibition of cytochrome oxidase after the
administration of acetonitrile. However, very little increase in
tissue or blood cyanide concentrations was observed one hour after
dosing with acetonitrile. Symptoms had not occurred within this
time period, and the evidence from other studies indicates that peak
cyanide levels are achieved much later than one hour (in 9-15 h)
(Freeman & Hayes, 1985a). The need to consider the different
pharmacokinetic and metabolic factors involved in making such
comparisons was emphasized by Willhite & Smith (1981).
7.1.3.2 Effect on glutathione
Levels of glutathione (GSH) in liver, kidney and brain were
unaffected one hour after oral administration of acetonitrile (at
the LD50 level) in male SD rats (Ahmed & Farooqui, 1982). Aitio &
Bend (1979) studied the in vitro effect of 12 organic solvents,
including acetonitrile, on the activity of rat liver soluble
glutathione S-transferase. They demonstrated that in the presence
of 630 mM acetonitrile, the conjugation of styrene oxide,
benzo[ a]pyrene-4,5-oxide and 1,2-dichloro-4-nitrobenzene by GSH
was reduced to 79.0 ± 5.2, 92.6 ± 3.0 and 59.2 ± 1.4%,
respectively, of the control values.
7.1.4 Antidotes to acetonitrile
Multiple intraperitoneal administrations of 1 g sodium
thiosulfate per kg at the rate of one injection every 100 min over a
10-h period or two intraperitoneal injections of 75 mg sodium
nitrite per kg significantly reduced mortality in CD-1 mice exposed
to 3800 or 5000 ppm acetonitrile by inhalation for 60 min (Willhite,
1981). Treatment of animals with thiosulfate at a dose rate of
1 g/kg every 100 min for an 8-h period was effective in providing
significant protection against the lethal effect of an
intraperitoneal injection of acetonitrile (575 mg/kg) in male CD-1
mice (Willhite & Smith, 1981). An intraperitoneal injection of
sodium thiosulfate (300 mg/kg) 20 min prior to inhalation of
8000 ppm acetonitrile in pregnant hamsters abolished the overt signs
of acetonitrile poisoning and reduced mortality from 3 out of 12
hamsters to zero (Willhite, 1983). Repeated intraperitoneal
administrations (6 injections in 10 h) of sodium thiosulfate
(1 g/kg), which started at the onset of acute toxicity about 30 h
after oral administration of acetone (1960 mg/kg) and acetonitrile
(1770 mg/kg) given simultaneously, provided significant protection
against mortality in female SD rats (Freeman & Hayes, 1985a).
Two intraperitoneal injections of 75 mg sodium nitrite did not
provide CD-1 mice with any significant protection against the lethal
effect of acetonitrile (575 mg/kg) (Willhite & Smith, 1981).
7.2 Subchronic toxicity
7.2.1 Inhalation exposure
In a rat study, the body weight gain and organ weights of male
and female rats which inhaled 166, 330 or 655 ppm acetonitrile
(7 h/day, 5 days/week, for a total of 90 days) did not differ
significantly from those of the controls (Pozzani et al., 1959a).
Histopathological examination showed that of the 28 rats that
inhaled 166 ppm, one had histiocyte clumps in the alveoli and
another had atelectasis. Of 26 rats that inhaled 330 ppm, three
showed bronchitis, pneumonia, atelectasis and histiocyte clumps in
the alveoli. After the inhalation of 655 ppm acetonitrile vapour,
10 out of 27 animals showed alveolar capillary congestion and/or
focal oedema in the lung, often accompanied by bronchial
inflammation, desquamation and hypersecretion. Tubular cloudy
swelling of the kidneys in eight rats and swelling of the livers of
seven rats were observed. These effects were statistically
significant (lungs, P < 0.001; kidney, P < 0.005; liver,
P < 0.04) compared with control animals. No lesions were found in
the adrenals, pancreas, spleen, testes or trachea. Focal cerebral
haemorrhage was observed in one of the five brains examined.
Wang et al. (1964) reported that there was no change of
iodine levels in the thyroid of Wistar rats exposed to 80 or 400 mg
acetonitrile/m3 (4 h/day, 6 days/week) for 10 weeks. Degenerative
changes in the epithelial cells of thyroid follicles were observed
in rabbits exposed to 400 mg/m3 (4 h/day, 6 days/week) for 16
weeks.
In an inhalation study (7 h/day) on four Rhesus monkeys, one
female monkey was exposed to 2510 ppm, two females to 660 ppm and
one male to 330 ppm (Pozzani et al., 1959a). The monkey exposed
to 2510 ppm appeared normal during the first inhalation day but on
the second day showed incoordination and laboured breathing and died
a few hours later. In the two monkeys exposed to 600 ppm there was
also incoordination from the second week. One monkey died on day 23
and the other on day 51. The monkey exposed to 330 ppm showed
overextension reflexes and hyperexcitability towards the end of the
99-day inhalation period and was sacrificed then. At autopsy, the
monkey exposed to 2510 ppm had engorgement of the dural capillaries,
and the animals exposed to 660 and 330 ppm showed focal dural or
subdural haemorrhage in the parietal and/or occipital tissues
adjacent to the superior sagittal sinus. The monkey exposed to
2510 ppm had pleural effusion, and those exposed to 660 ppm had
focal areas of emphysema and atelectasis with occasional
proliferation of alveolar septa, and cloudy swelling of the proximal
and convoluted tubules of the kidneys. The monkey exposed to
330 ppm had pneumonitis as shown by diffuse proliferation of
alveolar septa, monocytic infiltration and pleural adhesions.
In another inhalation study (Pozzani et al., 1959a), three
male Rhesus monkeys were exposed to 350 ppm acetonitrile (7 h/day,
5 days/week) for 91 days, and at the end of the study the animals
were sacrificed. At autopsy, haemorrhages of the superior and
inferior sagittal sinuses were found in the brains of all three
monkeys. Small discrete caseous nodules were seen in the lungs of
two monkeys and one monkey had a pale liver. Histological
investigations of the lung showed focal emphysema, diffuse
proliferation of alveolar septa, and focal accumulations of
pigment-bearing macrophages. In two of the monkeys there was cloudy
swelling of the proximal tubules of the kidney.
One female and two male dogs inhaled 350 ppm acetonitrile
(7 h/day, 5 days/week) for 91 days. The haematocrit and haemoglobin
values of the three dogs were depressed by the fifth week of
inhalation, but with the exception of one dog, there was a return to
pre-inhalation values toward the end of the 91-day inhalation
period. No significant deviation of the erythrocyte counts was seen
in any dogs. Histopathological examination of these dogs showed
some focal emphysema and proliferation of alveolar septa.
Roloff et al. (1985) exposed groups of male and female rats
(strain unspecified) to acetonitrile vapour (0, 1038, 3104 and
10 485 mg/m3) for one month (6 h/day, 5 days/week). Death and
reduced body weight gains were observed at the highest exposure
level. Respiratory and/or ocular irritation were noted in animals
exposed to 3104 and 10 485 mg/m3.
In a 13-week inhalation study of acetonitrile (100, 200 and
400 ppm) in 25 male mice and male rats, there were no effects on
body weight or on testicular weight and sperm motility (Morrissey
et al., 1988).
In a 13-week inhalation study on acetonitrile in mice and rats,
ten mice (B6C3F1) and ten rats (F-344/N) of each sex were exposed
to acetonitrile vapour at 0, 100, 200, 400, 800 and 1600 ppm
(6 h/day, excluding weekends and holidays) for 13 weeks (Battelle,
Pacific Northwest Laboratories, 1986a,b). At 400 ppm one female
mouse, at 800 ppm one male and four female mice, and at 1600 ppm ten
female and ten male mice were found dead during the study. The
majority of the mortality occurred after two weeks of exposure.
Clinical signs observed were hypoactivity and a hunched rigid
posture. Body weight gains were comparable to control values for
all surviving mice. An increase in absolute and relative liver
weight was attributed to acetonitrile exposure. The maximum
tolerated concentration determined by this 13-week subchronic study
was 200 ppm. Significant changes were observed in the liver and
stomach of male mice exposed to 400 ppm of acetonitrile and female
mice exposed to 200 ppm or more. At 800 ppm one male rat and at
1600 ppm six male and three female rats were either moribund (and so
sacrificed) or found dead during the study. The clinical signs
observed were hypoactive, abnormal posture, ataxia, bloody crusts on
nose and/or mouth and a rough haircoat. The moribund, sacrificed
rats exhibited tonic/clonic convulsions. Reductions in body weight
gain were observed in rats exposed to 1600 ppm. Minimum to mild
lesions were found in the lungs and brain of some rats exposed to
800 ppm (Table 14).
In a 92-day study, reported as an abstract, acetonitrile was
administered by inhalation to B6C3F1 mice and Fischer-344 rats at
concentrations of (25, 50, 100, 200 and 400 ppm) for a total of 65
days (Hazleton, 1990b). In mice, one male in each of the 50, 200
and 400 ppm groups died. There was an increase in body weight gain
in all males exposed to 50, 100, 200 and 400 ppm acetonitrile and in
the females of the 200 and 400 ppm groups. Body weight gain was
decreased by comparison with controls in the 25, 50 and 100 ppm
female groups. Liver/body weight ratio was increased in males at
400 ppm group and in females at 100, 200 and 400 ppm groups.
Liver/brain weight ratio was increased in males at the 400 ppm and
in female at 100 and 400 ppm groups. There was slight cytoplasmic
vacuolization of hepatocytes in both males and females in the 200
and 400 ppm groups. Mean haemato-crit and erythrocyte counts were
marginally reduced in females at 200 and 400 ppm group. In females
of the 200 and 400 ppm groups haematocrit, haemoglobin, red and
white blood cell counts, and serum IgG were all depressed. In rats,
one male in the 400 ppm group died during the study. There was
slight cytoplasmic vacuolization of hepatocytes in females at
400 ppm. Marginal decreases in mean leucocyte counts were reported
in males at 100 and 200 ppm and in both males and females at
400 ppm.
7.2.2 Subcutaneous administration
Marine et al. (1932a) gave daily subcutaneous injections of
0.1 ml acetonitrile to 4-month-old rabbits for 21 days. Two groups
of four male rabbits developed pronounced (more than twice normal
size) thyroid hyperplasia whereas one group of four females showed
no effect. Allyl-benzyl and phenyl nitriles produced less
pronounced hyperplasia or no effect on thyroids at up to 4 times the
dose of acetonitrile. A further study (Marine et al., 1932b)
suggested that young rabbits were more susceptible than adults and
that the effect varied with the strain.
7.3 Teratogenicity and embryotoxicity
In a study by Berteau et al. (1982), mated rats were
administered daily aqueous solutions of acetonitrile by gavage
(125, 190 and 275 mg/kg) on gestation days 6-19. Although maternal
body weights were reduced and death occurred in the high-dose group,
no other maternal effects were noted in any treated group.
Embryotoxic effects, as shown by increases in early resorptions and
postimplantation losses, were also noted in the high-dose group.
However, no teratogenic responses were observed at any dose level.
Table 14. Subchronic inhalation toxicity of acetonitrile in mice and rats
Species (strain) Sex Number of Concentration Duration Effects References
animals (ppm)
Mice (B6C3F1) M, F 10, 10 100, 200, 400 6 h/day, changes in liver and stomach at Battelle, Pacific
800, 1600 5 days/week, > 400 ppm, hypoactivity, rigid Northwest Laboratories
13 weeks posture; NOEL for males 200 ppm, (1986a)
for females 100 ppm
Mice (B6C3F1) M, F 10, 10 25, 50, 100, 6 h/day, increased body weight gain in male Hazleton Laboratories
200, 400 65/92 days groups 50, 100, 200 and 400 ppm (1990a)
and female groups 200 and 400 ppm;
liver/body weight ratio increased
in 400 ppm males and 100, 200 and
400 ppm females; liver/brain weight
ratio increased in 400 ppm males and
100 and 400 ppm females; minimal
cytoplasmic vacuolization of
hepatocytes in male and female 200
and 400 ppm groups; no effects on
male reproductive system
Mice M 25 100, 200, 400 no effect on reproductive system Morrissey et al.
(1988)
Rat (Carworth) M, F 15, 15 166 7 h/day, bronchitis, pneumonia, atelectasis, Pozzani et al.
15, 15 330 5 days/week, alveolar congestion, kidney and (1959a)
15, 15 655 90 days liver changes
Table 14 (contd).
Species (strain) Sex Number of Concentration Duration Effects References
animals (ppm)
Rat (F-344) M, F 10, 10 25, 50, 100, 6 h/day, minimal cytoplasmic vacuolization Hazleton
200, 400 65/92 days of hepatocytes in 400 ppm females, (1990b)
slightly decreased mean leucocyte
counts in 100 and 200 ppm males
and 400 ppm males and females
Rat M, F not 1038, 3104, 6 h/day, eye/nose irritation, body weight Roloff et al.
specified 10 485 5 days/week, loss, nervous system effects, mild (1985)
1 month anaemia at mid- and high-exposure
levels
Rat (F-344/N) M, F 10, 10 100, 200, 400, 6 h/day, hypoactive, ataxia at > 800 ppm, Battelle, Pacific
800, 1600 5 days/week, body weight loss at > 1600 ppm Northwest Laboratories
13 weeks (1986b)
Dog (Basenji) M, F 2, 1 350 7 h/day, body weight drop on day 3 and 5 Pozzani et al.
5 days/week, decreased Hb (1959a)
91 days
Monkey (Rhesus) F 2 660 7 h/day, 1 died on day 23 and 1 on day Pozzani et al.
23 days and 51; brain haemorrhages, emphysema, (1959a)
51 days atelectasis, cloudy swelling
of renal convoluted tubes
Table 14 (contd).
Species (strain) Sex Number of Concentration Duration Effects References
animals (ppm)
Monkey (Rhesus) M 3 350 7 h/day, brain haemorrhages, focal emphysema, Pozzani et al.
5 days/week, cloudy swelling of renal convoluted (1959a)
91 days tubes
Monkey (Rhesus) M 1 330 7 h/day, chronic pneumonitis, "excitability" Pozzani et al.
5 days/week, (1959a)
99 days
When pregnant rabbits were given acetonitrile orally on
gestation days 6-18 at dose levels of 0, 2, 15 and 30 mg/kg per day,
animals given the highest dose showed anorexia and decreased body
weight gain, and death occurred in 5 out of 25 rabbits at this
level. Body weight gain was also reduced in animals receiving
15 mg/kg per day, but not at the lowest dose level. With respect to
the fetuses of the treated animals, evidence of toxicity was only
observed at the highest dose level. Therefore, acetonitrile is not
considered to be toxic to fetuses at doses below those causing
maternal toxicity (Argus Res Labs., 1984).
In a study by Willhite (1983), pregnant golden hamsters were
exposed by inhalation for one hour to 0, 1800, 3800, 5000 or
8000 ppm acetonitrile on the 8th day of gestation. There was a
significant and dose-dependent increase in the number of abnormal
fetuses from animals exposed to the two highest dose levels.
Pregnant golden hamsters were exposed to a single gavage or a
single intraperitoneal injection of 0, 100, 200, 300 or 400 mg/kg on
the 8th day of gestation. Animals exposed intraperitoneally were
killed on day 14 while those exposed orally were killed on day 15.
An intraperitoneal injection of 200 to 400 mg/kg produced a
significant increase in the average fetal body weight compared to
controls. A single gavage dose of 300 to 400 mg/kg produced a
significant increase in the number of malformed fetuses
(particularly rib malformations) or resorptions. There was a
significant decrease in the average fetal body weight, but not in
maternal weight, at all dose levels. The same dose given by gavage
seemed to show greater toxic and teratogenic effects than when given
intraperitoneally (Willhite, 1983). The results of the teratologic
studies are summarized in Table 15.
When rats were orally administered acetonitrile, no changes in
pregnancy rate, resorption of litters or perinatal toxicity in the
offspring were found, even at doses of 300 and 500 mg/kg, which are
toxic to the majority of females (Smith et al., 1987).
7.4 Mutagenicity
Table 16 summarizes the short-term genotoxicity testing of
acetonitrile. Most of these tests have been performed using
extremely high concentrations and therefore the interpretation of
results is difficult.
Table 15. Teratogenic effects of acetonitrile on Syrian golden hamstera
Route of Dosage Maternal effects Fetal effects
administration
Inhalation 1800 ppm, 60 min none none
Inhalation 3800 ppm, 60 min dyspnoea, tremors, etc., death none
in one out of six hamsters
after 3 h
Inhalation 5000 ppm, 60 min irritation, dyspnoea, tremor, 6 out of 53 abnormal fetuses, exencephaly, encephalocoele,
etc., death in one out of rib fusions
six hamsters after 5 h
Inhalation 8000 ppm, 60 min respiratory difficulty and ataxia 29 out of 115 abnormal fetuses, exencephaly, encephalocoele,
in 4 out of 12 hamsters; death extrathoracie ectopia cordis, severe axial skeletal dysraphic
in 3 out of 4 hamsters after 1.5 h disorders, reduced body weight
Intraperitoneal 100-400 mg/kg none encephalocoele, retrocession of maxilla, increase in
average fetal body weight
Oral 100-400 mg/kg none increase in malformed fetuses (12 out of 65 at 300 mg/kg;
14 out of 76 at 400 mg/kg) and resorptions, decrease
in body weight gain
a From: Willhite (1983)
7.4.1 Bacterial systems
Within a dose range up to 10 mg/plate, acetonitrile was not
mutagenic toward Salmonella strains TA1535, TA1537, TA97, TA98 and
TA100 either in the presence or the absence of the metabolic
activation systems prepared from SD rats pretreated with Aroclor
1254. The test was performed in two different laboratories and
showed good reproducibility (Mortelmans et al., 1986).
Schlegelmilch et al. (1988) reported that acetonitrile does not
show any mutagenicity activity in the Ames test
(Salmonella/microsome assay) performed with strains TA98 and TA100.
7.4.2 Yeast assays
Acetonitrile has been found to induce aneuploidy, but not
recombination or point mutations, in a diploid yeast strain D61.M
(Zimmermann et al., 1985).
7.4.3 Drosophila melanogaster
FIX and ZESTE genetic test systems employing female Drosophila
melanogaster were performed by Osgood et al. (1991a,b). Positive
responses were obtained in these assays at acetonitrile
concentrations of 0.2, 0.5, 2 and 5% (Osgood et al., 1991a). The
Drosophila ZESTE system was used to monitor the induction of sex
chromosome aneuploidy following inhalation exposure of adult females
to acetonitrile. Acetonitrile was a highly effective aneuploidogen,
inducing both chromosome loss and gain following short exposure to a
concentration of 131 ppm (Osgood et al., 1991b).
7.4.4 Mammalian in vivo assays
Schlegelmilch et al. (1988) showed that a weak positive
effect occurs with acetonitrile in the micronucleus assay 24 h after
intraperitoneal injection of a dose equivalent to 60% of the LD50
value to four male and four female NMRI mice (13 weeks old).
7.4.5 Chromosome aberrations and sister chromatid exchange
Galloway et al. (1987) tested the ability of 108 chemicals,
including acetonitrile, to induce chromosome aberration and sister
chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells both
with and without a rat liver metabolic activation system. At
5000 mg acetonitrile/litre, there was a slight increase in SCE both
with and without S9 activation, but chromosomal abberation tests
yielded negative results.
Table 16. Short-term genotoxicity tests of acetonitrile
Assay Concentration Experimental Results Reference
conditions
Salmonella TA100 3.8 µmol/plate +S9 - Maron et al. (1981)
Salmonella TA100, TA1535 2.4-24.4 µmol/plate +S9 - Mortelmans et al. (1986)
Salmonella TA98, TA100 0.27 approx 1350 mM -S9 - Schlegelmilch et al. (1988)
+S9 -
Sister chromatid exchange 3.9-121.8 mM +S9 - Galloway et al. (1987)
in CHO cells 121.8 mM -S9 ±
Induction of aneuploidy in 553-904 mM + Zimmermann et al. (1985)
Saccharomyces cerevisiae (D61.M)
Induction of aneuploidy in 38-950 mM FIX and ZESTE + Osgood et al. (1991a)
Drosophila
Aneuploidy in Drosophila 131 ppm ZESTE system + Osgood et al. (1991b)
inhalation
exposure
(30, 50, 70 min)
Micronucleus test in male 60% of LD50 24 h after ± Schlegelmilch et al. (1988)
NMRI-mice intraperitoneal
injection
7.5 Carcinogenicity
No data is available on the carcinogenicity of acetonitrile in
experimental animals. It is noteworthy, however, that the US
National Toxicology Program has long-term oncogenicity studies
underway in mice and rats.
7.6 Cytotoxicity testing
Table 17 summarizes the cytotoxicity of acetonitrile. The
cytotoxicity to 3T3-L1, BCL-D1 and human hepatoma Hep G 2 was very
weak. The IC50 values in mouse neuroblastoma cells and in rat
glioma cells, were 17.8 and > 20 mM, respectively.
Table 17. Cytotoxicity of acetonitrile
Cell type Method Harvest time Results Reference
Mouse 3T3-L1 FRAME Kenacid blue after 72 h IC50 = 562 mM Clothier & Hulme (1987)
BCL-D1 dye binding after 72 h IC20 > 24 mM Knox et al. (1986)
IC50 > 24 mM
IC80 > 24 mM
Human hepatoma cellular protection after 24 h IC50 = 494 mM Dierickx (1989)
Hep G2 content
8. EFFECTS ON HUMANS
8.1 Acute toxicity
8.1.1 Inhalation exposure
Grabois (1955) reported on 16 workers at a chemical plant
accidentally poisoned with acetonitrile vapour during the brush
painting of the inside walls of a storage tank with
corrosion-resistant paint. One died after two days exposure, two
were seriously ill and the remaining 13 workers were also affected.
Amdur (1959) studied this incident further. The tank was of
22 730 litre capacity, approximately 6 m high, and 2.75 m at its
greatest diameter. The paint contained 30-40% acetonitrile and the
thinner contained 90-95% acetonitrile. Because of the viscosity of
the paint, the tank was heated to 25 °C and thinned on the second
day before application. Ventilation of the tank was stopped.
Details of the fatal case (Case 1), and the two seriously ill cases
(Cases 2 and 3) are as follows:
Case 1. A 23-year-old man was painting within the tank during
day 2. He returned home without any symptoms but awoke shortly
after midnight with malaise and chest pain. Nausea, vomiting and
blood-spitting were followed by convulsions, and he was admitted to
hospital in a coma at about 9:15 a.m. Respiration was shallow,
irregular and infrequent and he died within one hour of admission.
Post-mortem examination revealed cerebral, thyroid, liver, splenic
and renal congestion, and a "peach pit" odour of all tissues. The
blood and urine cyanide concentrations were 7960 and 2150 mg/litre,
respectively. There was a trace of cyanide in the gastric fluid.
Spleen, kidney and lung concentrations of cyanide were 3180, 2050
and 1280 mg/kg tissue, respectively. No cyanide was detected in the
liver.
Case 2. A 35-year-old man painted for 3 h inside the tank.
During the next day he began to feel ill and severe nausea and
vomiting followed. He was admitted to hospital with a slow pulse
rate (55 per min), severe hypotension and slow shallow respiration.
He was treated with oxygen, intravenous fluids and whole blood,
ascorbic acid, and sodium thiosulfate. Twelve hours after admission
he recovered and he returned to work after ten days. The laboratory
data are shown in Table 18.
Table 18. Laboratory data for case 2a
Approximate Blood cyanide Serum thiocyanate
time after
exposure (µg/litre) (mg/litre)
14 h 3060 ND
23 h 1930 ND
1 day ND 160
2 days 2120 150
3 days 2180 ND
4 days ND 120
5 days 1020 ND
27 days ND 30
36 days not detected ND
a From: Amdur (1959); ND = not done
Case 3. A 28-year-old man painted outside and inside the tank.
In the night he felt unwell and had diarrhoea, and by morning he
felt nauseated and weak and he was sent to hospital at 12:30 in a
semiconscious state with a pulse rate of 45 per min and a blood
pressure of 100/50 mmHg. Respiration was shallow and intermittent,
motor power was severely impaired, and deep tendon reflexes were not
elicited. He was treated with oxygen, intravenous fluids and whole
blood, ascorbic acid and sodium thiosulfate, and improved rapidly.
He was in hospital for 10 days and returned to work after 20 days.
The laboratory data are shown in Table 19.
The laboratory data for twelve other workmen are summarized in
Table 20, together with those for three severe cases described
above.
Dequidt et al. (1974) reported a fatal case of acute
acetonitrile poisoning in a 19-year-old male laboratory worker.
After handling acetonitrile for 2 days without problems, he poured
an unknown amount of acetonitrile and boiling water on the floor to
clean it. Four hours after work he complained of epigastric pain
and nausea and vomited repeatedly. Next day he became comatose and
had convulsions. On admission to hospital large amounts of cyanide,
thiocyanate and acetonitrile were found in the blood and urine.
Treatment with dicobalt ethylenediaminetetraacetic acid (EDTA) and
hydroxycobalamine was ineffective and he died 6 days after the
poisoning. Table 21 shows the results of clinical and postmortem
examinations of cyanides in blood and tissues.
Table 19. Laboratory data for case 3a
Approximate Blood cyanide Serum thiocyanate
time after
exposure (µg/litre) (mg/litre)
24 h 9700 150
2 days 10 880 230
3 days 8800 ND
4 days ND 200
5 days 2960 ND
8 days 1400 ND
10 days ND 100
20 days 35 ND
36 days not detected ND
a From: Amdur (1959); ND = not done
In a human volunteer study, Pozzani et al. (1959a) studied
the acute inhalation toxicity of acetonitrile in three men between
the age of 31 and 47. They first inhaled 40 ppm acetonitrile vapour
for 4 h in a 7900-litre chamber. The two older subjects had no
subjective response during or after the 4-h inhalation period.
There was no appreciable increase in urinary thiocyanate and no
detectable blood cyanide. The youngest subject experienced a slight
tightness in the chest during the evening after inhalation. The
following morning he also reported a cooling sensation, which
persisted for about 24 h and was similar to that experienced when
menthol was inhaled. There was only a slight increase in the
urinary thiocyanate levels in this subject. All three subjects
detected the odour of acetonitrile for the first 2 or 3 h, after
which they experienced some olfactory fatigue.
The two older subjects then inhaled 80 ppm acetonitrile vapour
for 4 h one week after the 40 ppm trial, with no symptoms. No blood
cyanide was detected in any of the samples taken after the
inhalation period. The urinary thiocyanate value in one subject was
higher immediately before inhalation than it was after. The values
for the other subject were relatively constant.
The same two subjects inhaled 160 ppm acetonitrile vapour for
4 h, 9 days after the 80-ppm run. One subject reported a slight
transitory flushing of the face 2 h after inhalation, and a slight
feeling of bronchial tightness about 5 h later, which disappeared
overnight. The blood cyanide and urinary thiocyanate levels of both
subjects did not change significantly from pre-inhalation values.
Table 20. Summary of clinical findings of acute acetonitrile intoxication in mana
Case No. Age Working condition Symptoms and signs Outcome Blood cyanide Serum thiocyanate
highest value highest value
(µg/litre) (mg/litre)
1 23 hand-brushing inside chest pain, nausea, emesis, blood death 14 h after 7960 -
of tank for 12 h spitting, convulsions, shallow, work
irregular and infrequent
respiration
2 35 hand-brushing inside lightheaded, weakness, nausea, returned to work 3060 160
of tank for 3 h emesis, tachycardia, pallor, after 11 days
shallow respiration, abdominal
pain
3 28 hand-brushing outside semiconsciousness, slate gray returned to work 10 880 230
of tank for 12 h colour, BP 100/50, shallow and after 18 days
intermittent respiration, impaired
motor power, deep tendon reflexes
absent, headache
4 28 hand-brushing inside - returned to work 720 145
of tank for 2.5 h after 10 days
Table 20 (contd).
Case No. Age Working condition Symptoms and signs Outcome Blood cyanide Serum thiocyanate
highest value highest value
(µg/litre) (mg/litre)
5 20 not clear nausea, headache, lassitude, - 580 180
hyper-ventilation
6 18 sand-blasted and headache, weakness, tightness recovered after 330 100
mixed paint for 7 h of chest and abdomen 5 days
7 42 mixed paint nausea, tiredness returned to work ND 135
within one week
8 25 present in the work severe pain of chest and returned to work ND 60
area for entire day abdomen after 3 days, after two weeks
hepatomegaly
9 24 mixed paint for 3 h nausea, listlessness - ND 100
10-16 - various no complaint - ND under 30
a From: Amdur (1959); ND = not detected
Table 21. Cyanides in blood, urine and tissues after acetonitrile intoxicationa
Sample Days after Free HCNb Combined HCNb Acetonitrileb
acetonitrile
exposure
Blood 2 1120 3760 -
Blood 3 870 10 380 11760
Urine 4 4600 1050 311 000
Heart 6 trace 2420 6130
Lung 6 340 11 120 2870
Liver 6 123 2670 11 840
Spleen 6 440 3860 9340
Kidney 6 270 2620 13 550
Brain 6 220 2370 -
Pancreas 6 200 1090 trace
Bladder 6 trace 910 trace
a From: Dequidt et al. (1974)
b µg/litre for blood and urine, µg/kg for tissues
8.1.2 Dermal exposure
Caravati & Litovitz (1988) reported two cases of paediatric
accidental exposure to an acetonitrile-containing cosmetic. The
exposure occurred both via the skin and by inhalation.
Approximately 30 ml of a nail remover (SuperNail Nail Off)
containing 98-100% acetonitrile spilled on a 2-year-old 12-kg
previously healthy boy and his bed (the actual amount of contact to
the skin was not specified). No symptoms were noted immediately
after the exposure. Eight hours later, the boy was moaning, poorly
responsive, and had vomited. On arrival at the emergency
department, he was lethargic and pale. Vital signs were as follows:
temperature, 36.9 °C; pulse rate, 140/min; respirations 56/min; and
blood pressure, 70/30 mmHg. The electrocardiogram revealed a sinus
tachycardia. Therapy included oxygen by face mask, and an
intraosseous line of 5% dextrose containing 0.2% potassium chloride
and 20 mmol of sodium hydrogen carbonate. Although the diagnosis
was known, nitrites and thiosulfate were not given due to the
patient's prompt response to supportive care. Whole-blood cyanide
levels were: 6 mg/litre 12 h after the exposure, 60-70 µmol/litre
from 24 to 48 h and 15 µmol/litre after 60 h. The patient was
discharged 3 days later in good condition.
8.1.3 Oral exposure
Caravati & Litovitz (1988) reported on a 16-month-old 11.8-kg
previously well boy who ingested 15 to 30 ml of SuperNail Nail Off
(1-2 g acetonitrile/kg body weight). The child vomited
spontaneously about 20 min after the ingestion. Telephone
assistance from the poison centre and paediatrician was sought, but
the product was mistaken for an acetone-containing nail polish
remover and toxicity was expected to be minimal. The child was put
to bed. Later the mother noted that he was breathing heavily and
noisily, but left him to sleep through the night. He was found dead
in his crib the next morning, about 12 h after the ingestion.
Postmortem examination showed moderately severe pulmonary oedema, a
blood cyanide level of 119 (3.1 mg/litre), and brain cyanide level
of 0.2 mg/kg.
Jaeger et al. (1977) reported a case of acute acetonitrile
intoxication in a 26-year-old man who ingested 40 g of acetonitrile
in a suicide attempt. After a 3-h latent period, he suffered from
vomiting, convulsions, coma, acute respiratory insufficiency, severe
metabolic acidosis, and two cardiac arrests. In addition to
supportive treatment (oxygen, mechanical ventilation, correction of
shock and acidosis), dicobalt EDTA, sodium nitrite, sodium
thiosulfate and hydroxocobalamin were also administered. His
clinical course was complicated but he fully recovered 3 months
later.
Turchen et al. (1991) reported the case of a 39-year-old
woman, who was found vomiting and confused 7 h after ingesting 59 ml
of nail polish remover containing 99% acetonitrile (4 g/kg). About
12 h after ingestion, she developed severe metabolic acidosis,
seizures and shallow respiration. Eight hours after ingestion she
had a whole blood cyanide level of 3130 µg/litre. At 65 h the serum
cyanide level was 10 mg/litre and thiocyanate was 120 mg/litre,
whereas at 77 h they were 12 mg/litre and 30 mg/litre, respectively.
She responded to the treatment with sodium nitrite and sodium
thiosulfate. Although she had several relapses, each time she
responded to sodium thiosulfate administration. On the fifth
hospital day the cyanide level was 360 µg/litre and thiocyanate
level 30 mg/litre and the patient was discharged on day six.
Geller et al. (1991) reported a case of acute acetonitrile
poisoning of a 3-year-old 17.2-kg child who presented to the
emergency department without any noticeable symptoms approximately
30 min after ingesting an estimated 15-30 ml of a nail tip and glue
remover containing acetonitrile. The amount of ingested
acetonitrile was estimated to be 0.7 to 1.4 g/kg. Gastric lavage
was performed with 1 litre of saline containing 20 g of activated
charcoal. Three hours and 45 min after ingestion, the cyanide blood
level was 1.24 mg/litre and thiocyanate 11 mg/litre. Eleven hours
after ingestion the child was alert, but 2 h later the patient
suddenly vomited, was confused and developed seizures. A dose of
35 ml of a 25% solution of sodium thiosulfate was intravenously
administered over 30 min. The patient recovered quickly and was
discharged 42 h later.
Kurt et al. (1991) reported a case of a 15.8-kg 2-year-old
girl who ingested 5-10 ml (0.25-0.5 mg/kg) of a nail glue containing
84% acetonitrile. Taken to the hospital, she was asymptomatic and
discharged. However, she later became restless and started
vomiting. Toxic clonic seizures also appeared about 14 h after
ingestion. She was admitted to the hospital comatose with
hyperpnoea and tachycardia. Gas analysis showed marked hypoxia and
acidosis. She was treated with oxygen and amyl nitrite by
inhalation. Activated charcoal was also administered. She made a
rapid recovery and was discharged after 2 days.
Michaelis et al. (1991) reported a case of suicidal oral
acetonitrile ingestion in a previously healthy 30-year-old man. He
ingested about 5 ml (64 mg/kg) of acetonitrile (98%) and, 30 min
later, about 1 ml of ammonia and vomited once. Five hours later he
was brought to the hospital because of increasing malaise. On the
way to the hospital he received 250 mg of p-dimethyl aminophenol
and 1 g of sodium thiosulfate. The patient exhibited livid skin
colour and excitation. Gastric lavage with charcoal was performed
5.5 h after ingestion, and treatment with oxygen and sodium
thiosulfate (3/g intravenous) was given over 30 min. He recovered
quickly and was transferred to a psychiatric unit 30 h after
ingestion. Peak serum acetonitrile and blood cyanide levels were
99.2 and 15.0 mg/litre. Half-lives were calculated for acetonitrile
and cyanide and found to be 32 and 15 h, respectively.
Jones et al. (1992) reported two fatal cases of a married
couple who ingested acetonitrile by mistake. They were found dead
with traces of vomit. Acetonitrile levels were 0.8 g/litre in
blood, 1.0 g/litre in urine and 1.3 g/litre in stomach contents.
Blood inorganic cyanide levels were 4.5 mg/litre (male) and
2.4 mg/litre (female).
Table 22 summarizes the reports on human acetonitrile
poisoning.
8.2 Chronic toxicity
No data are available.
8.3 Mutagenicity and carcinogenicity
No data are available concerning the mutagenicity and
carcinogenicity of acetonitrile in humans.
8.4 Occupational exposure to cyanide
El Ghawabi et al. (1975) studied the effect of chronic
cyanide exposure in the electroplating sections of three factories
employing 9, 12 and 15 male workers and compared them with a control
group. The concentrations of cyanides to which the workers were
exposed at the three factories were 10.87, 6.85 and 8.25 ppm,
respectively. The duration of exposure and the number of workers
were: 5 years, 14; more than 5 years, 14; more than 10 years, 7; and
more than 15 years, 1. The symptoms listed in order of frequency
were headache, weakness, changes in taste and smell, irritation of
the throat, vomiting, effort dyspnoea, lacrymation, abdominal colic,
and praecordial pain. Disturbances of accommodation, salivation,
and nervous instability were found in 8% of the exposed workers.
Two workers suffering from psychotic episodes worked in the part of
the factory where the concentration of cyanides was the highest.
None of the 36 workers showed any clinical signs of hypo- or
hyperthyroidism, but 20 (56%) had mild or moderate thyroid
enlargement. However, there was no correlation between duration of
exposure and the incidence of enlargement, or size of the thyroid.
131I thyroid uptakes at 4 and 24 h were significantly higher than
those in the controls (P < 0.001), while 131PBI (protein bound
iodine) was unchanged. There were increased haemoglobin and
lymphocyte counts in all exposed workers, and punctate basophilia
was reported in 28 workers. Cyanmethaemoglobin was found only in
the blood of the exposed workers, all of whom were non-smokers. The
concentration of thiocyanate in urine increased towards the middle
of the working week and then became almost stationary during the
last three days. The regression line between mean values of
urinary thiocyanate in the second half of each working week over
two successive months and the mean values of the concentration of
cyanides in air was linear, being represented by the equation
M = 0.65C (M = thiocyanate in total amount of urine in 24 h per mg,
and C = concentration of cyanide in air in ppm).
Blanc et al. (1985) studied acute and residual toxic
reactions to cyanide in 36 former male workers, aged from 19 to 62
(with mean age of 33.5 ± 11.4 (SD) years), in a silver-reclaiming
facility with exposure to high levels of cyanide. The median time
since last employment at this facility was 10.5 months and the mean
duration of employment was 11 ± 10.4 (SD) months (with a medium of
8.5 months). Mild abnormalities of vitamin B12 (P < 0.001), folate
(P < 0.001) and T3 resin uptake (P < 0.01) were detected.
8.5 Chronic poisoning by cyanides
8.5.1 Ingestion
Epidemiological studies suggested a correlation between chronic
cyanide ingestion from cassava and certain neurological disorders
(Wilson, 1983; WHO, 1992).
Table 22. Summary of reports on human acetonitrile poisoning
Route of Number Estimated Time of onset Major symptom Outcome Toxicological References
exposure of doses of symptoms findings
cases after exposure
Inhalation 16 unknown several hours nausea, vomiting, one dead, others cyanide and Admur (1959)
respiratory failure, recovered thiocyanate in
hypotension blood and urine
Inhalation 1 unknown 4 h epigastric pain, dead cyanide, thiocyanate Dequidt et.
nausea, vomiting, and acetonitrile al. (1974)
convulsions in blood and urine
Dermal/ 1 approximately 8 h moaning, poor survived cyanide in blood Carvati &
inhalation 30 ml response, vomiting, Litovitz (1988)
lethargic
Oral 1 15-30 ml several hours heavy and noisy dead 12 h later cyanide in blood Carvati &
breathing and urine Litovitz (1988)
Oral 1 40 g 3 h vomiting, convulsion, recovery after not tested Jaeger et al.
respiratory failure, 3 months (1977)
coma
Table 22 (contd).
Route of Number Estimated Time of onset Major symptom Outcome Toxicological References
exposure of doses of symptoms findings
cases after exposure
Oral 1 59 ml 12 h seizures, shallow recovery after cyanide in blood Turchen et al.
respiration 5 days (1991)
Oral 1 15 to 30 ml 12 h alert, frightened, recovery after cyanide and Geller et al.
vomit, confusion 24 h thiocyanate in (1991)
blood
Oral 1 5 to 10 ml 10 - 14 h moaning, restless, recovery after - Kurt et al.
vomiting, seizures 2 days (1991)
Oral 1 5 ml and 5 h malaise recovery after acetonitrile and Michaelis et
1 ml ammonia 30 h cyanide in blood al. (1991)
Oral 2 unknown unknown vomiting dead acetonitrile and Jones et al.
cyanide in blood (1992)
and urine
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1 Microorganisms
Collins & Knowles (1983) reported that the bacterium Nocardia
rhodochrous was able to grow at an acetonitrile concentration of
1.03 g/litre, apparently using acetonitrile as both carbon and
nitrogen sources.
Bringmann & Kuhn (1977a) calculated toxicity thresholds based
on the first detectable inhibition of cell multiplication. For the
bacterium Pseudomonas putida the threshold was 680 mg/litre
acetonitrile and for the green alga Scenedesmus quadricauda it was
7300 mg/litre. Bringmann & Kuhn (1978) calculated a toxicity
threshold for the cyanobacterium (blue-green alga) Microcystis
aeruginosa of 520 mg/litre. For the protozoan Entosiphon sulcatum
the threshold was 1810 mg/litre (Bringmann & Kuhn, 1980).
9.2 Aquatic organisms
The acute toxicity of acetonitrile to aquatic organisms is
summarized in Table 23. Due to the volatility of acetonitrile care
must be taken when interpreting the test results, especially those
based on nominal concentrations.
Acute toxicity data for various fish and other freshwater
species have been determined by a static bioassay to give an LC50.
Values range from 730 mg/litre for Cyprinus carpio after a 48-h
exposure to 6500 mg/litre for Daphnia pulex after a 3-h exposure
(Nishiuchi, 1981). According to Bringmann & Kuhn (1977b), the 24-h
LC50 for Daphnia magna is more than 10 g/litre.
Table 23. Toxicity of acetonitrile to aquatic organisms
Organism Size/age Water Temperature Hardness pH Duration LC50 References
conditionsa (°C) (mg/litre)b (h) (mg/litre)c
Invertebrates
Snail juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
(Helisoma trivolvis)
Flatworm juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
(Dugesia tigrina)
Segmented worm juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
(Lumbriculus variegatus)
Water flea juvenile stat 3 6500
(Daphnia pulex) juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
Water flea 24 h stat 20-22 7.6-7.7 24 > 10 000 n Bringmann & Kuhn
(Daphnia magna) (1977b)
Sideswimmer (scud) juvenile stat 19-21 130 6.5-8.5 96 >100 n Ewell et al. (1986)
(Gammarus fasciatus)
Pillbug juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
(Asellus intermedius)
Table 23 (contd).
Organism Size/age Water Temperature Hardness pH Duration LC50 References
conditionsa (°C) (mg/litre)b (h) (mg/litre)c
Fish
Fathead minnow 1.5 g stat 25 20 7.4 24 1050 n Henderson et al. (1961)
(Pimephales promelas) 1.5 g stat 25 20 7.4 48 1000 n Henderson et al. (1961)
1.5 g stat 25 20 7.4 96 1000 n Henderson et al. (1961)
1.5 g stat 25 380 8.2 24 1150 n Henderson et al. (1961)
1.5 g stat 25 380 8.2 48 1050 n Henderson et al. (1961)
1.5 g stat 25 380 8.2 96 1000 n Henderson et al. (1961)
juvenile stat 19-21 130 6.5-8.5 96 > 100 n Ewell et al. (1986)
Bluegill 2.0 g stat 25 20 7.4 24 & 96 1850 n Henderson et al. (1961)
(Lepomis macrohirus)
Ctenopharyngodon 5-7 g stat 10-11 7.4 24 1950 n Chen (1981)
(C. idellus) 48 880 n Chen (1981)
Guppy 0.1 g stat 25 20 7.4 24 & 96 1650 n Henderson et al. (1961)
(Poecilia reticulata)
Medaka 0.2 g stat 25 24 & 48 > 1000 n Tonogai et al. (1982)
(Oryzias latipes)
Carp juvenile 48 730 Nishiuchi (1981)
(Cyprinus carpio)
Golden orfe 48 5850-7050 Juhnke & Ludemann
(Leuciscus idus melanotus) (1978)
a stat = static conditions (water unchanged for the duration of the test)
b Hardness measured as mg CaCO3/litre
c n = nominal concentration
10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
10.1 Evaluation of human health risks
Acetonitrile is a colourless liquid with an ether-like odour.
It is found as a natural product and is manufactured for a variety
of uses. It is an excellent solvent for many inorganic and organic
compounds, including polymers. It is used for various purposes
including the separation of butadiene from other C4 hydrocarbon, a
solvent for spinning synthetic fibres, for casting and moulding
plastics, for HPLC analysis, as a starting material for organic
synthesis, and in products for removing artificial finger nails.
Acetonitrile has not been detected in water but has been in
bottom sediment in the environment in Japan. It has also been
detected in air at low concentrations in some urban and rural
environments in Germany. It has not been detected in food.
Acetonitrile is found in the stratosphere. Along with hydrogen
cyanide, acrylonitrile and other toxic products, acetonitrile is
produced from the thermal decomposition of polyurethane foams.
Acetonitrile is readily absorbed by all routes and rapidly
distributed throughout the body. It is converted enzymatically to
cyanide, which is in turn conjugated with thiosulfate, forming
thiocyanate, and eliminated via the urine. Some acetonitrile is
eliminated unchanged in the expired air and urine. Acetonitrile
does not accumulate in the body.
Acute acetonitrile toxicity is due mainly to cyanide formation
and the signs and symptoms are those of acute cyanide poisoning.
The toxic effects of acetonitrile usually appear after a latent
period (lasting several hours) following exposure.
In humans, ingestion of 1 to 2 g acetonitrile/kg causes death.
Animal experiments indicate that inhalation of acetonitrile at
concentrations of 8400 to 16 800 mg/m3 (5000 to 10 000 ppm) for
one hour is fatal. It is irritant to the eyes and respiratory
tract.
There are no available data on the chronic toxicity of
acetonitrile in experimental animals or humans.
High doses of acetonitrile are teratogenic and embryotoxic in
rats and hamsters; maternal toxicity also occurs at these dose
levels. The mechanism for these effects is related to the
production of cyanide.
Tables in sections 6 and 7 indicate the reasons for the
differences in toxicity between acetonitrile, cyanide and other
nitriles. These are based on the slow toxicokinetics of
acetonitrile due to the slower rate of formation of free cyanide
from acetonitrile compared with other nitriles. These differences
account for the different time course of blood cyanide and
thiocyanate levels and of thiocyanate excretion, as well as for the
different LD50 values. It can also be predicted that any
differences in toxicity across species are probably due to
toxicokinetics. Administration of cyanide antidotes such as sodium
nitrite and sodium thiosulfate are effective. Care needs to be
taken in the use of sodium nitrite because of its toxicity.
Occupational exposure in the production of acetonitrile is low
because of the enclosed processes. Poisoning has been associated
with use and accidental exposure. A time-weighted average (TWA)
occupational exposure limit of 67 mg/m3 (40 ppm) is used in many
countries.
10.2 Evaluation of effects on the environment
Acetonitrile has low toxicity to microorganisms and freshwater
invertebrates and fish.
The most sensitive species is the common carp (Cyprinus
carpio) with a 48-h LC50 of 730 mg/litre. Application of an
uncertainly factor of 100, to take into account static tests and
lack of analytical confirmation, yields a value of 7.3 mg/litre.
Acetonitrile is seldom present in the environment at measurable
levels and has not been detected in water. The highest measured
level in sediment was 0.54 mg/kg. It is, therefore, highly unlikely
that acetonitrile poses any threat to organisms in the environment
except locally after spills.
11. RECOMMENDATIONS FOR THE PROTECTION OF HUMAN HEALTH
a) Acetonitrile and mixtures containing it should be clearly
labelled with a warning of the toxicity of acetonitrile.
b) Clinicians should be aware of the delayed onset of signs and
symptoms following exposure to acetonitrile.
12. FURTHER RESEARCH
a) The measurement of acetonitrile levels in expired air and urine
should be investigated as a method for the biological
monitoring of occupationally exposed populations.
b) Comparative studies on the kinetics of cyanide formation from
acetonitrile, as well as of conjugation to thiocyanate and its
elimination, should be conducted.
c) The in vitro sensitivity of cytochrome c oxidase to cyanide
in different species, including humans, should be investigated.
13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES
No previous evaluations by international bodies are available.
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RESUME
1. Propriétés, usages et méthodes d'analyse
L'acétonitrile (CH3CN) est un sous-produit de la fabrication
de l'acrylonitrile. Il peut également se former lors de la
combustion du bois et de la végétation. C'est un liquide d'odeur
éthérée. L'acétonitrile est un solvant volatil, extrêmement
polaire, que l'on utilise pour extraire les acides gras ainsi que
les huiles animales et végétales. On l'emploie également dans
l'industrie pétrochimique pour la distillation extractive, du fait
qu'il présente une miscibilité sélective aux composés organiques.
On l'utilise également comme solvant pour le filage des fibres
synthétiques et dans le formage et le moulage des plastiques. Au
laboratoire, on l'utilise largement en chromatographie liquide à
haute performance (CLHP) ainsi que comme solvant pour la synthèse de
l'ADN et le séquençage des peptides.
La technique d'analyse la plus largement utilisée pour
l'acétonitrile est la chromatographie en phase gazeuse.
2. Concentrations dans l'environnement et sources
d'exposition humaine
On ne dispose que de très peu de données sur les concentrations
d'acétonitrile dans l'environnement. Dans l'ensemble du monde, on
fait état de concentrations atmosphériques allant de 200 à
42 000 ng/m3. Une étude donne des concentrations atmosphériques un
peu plus élevées en milieu urbain qu'en milieu rural. Une mesure
effectuée avant et après la combustion de broussailles et de paille
a montré que la concentration atmosphérique d'acétonitrile était
multipliée par dix.
On n'a pas décelé d'acétonitrile dans 72 échantillons d'eau au
Japon, mais on en a trouvé dans 11 échantillons de sédiments
aquatiques sur 60 à des concentrations allant de 0,02 à 0,54 mg/kg.
On n'a pas trouvé d'acétonitrile dans les denrées alimentaires.
La fumée de tabac contient de l'acétonitrile et la combustion
de la mousse de polyuréthanne libère de l'acétonitrile et du cyanure
d'hydrogène.
C'est la production d'acrylonitrile qui présente les plus
grands risques d'exposition mais elle s'effectue en enceinte fermée.
L'utilisation pratique de l'acétonitrile peut conduire à une
exposition plus importante.
3. Distribution et transformation dans l'environnement
L'acétonitrile s'évapore à partir de l'eau et peut également le
faire à partir de la surface du sol. Il est facilement décomposé
par plusieurs souches de bactéries communément présentes dans les
boues d'égouts, les eaux naturelles et le sol. L'acclimatation des
bactéries à l'acétonitrile ou aux déchets de pétrole augmente la
vitesse de décomposition. La décomposition anaérobie paraît
limitée, voire absente.
L'hydrolyse de l'acrylonitrile est extrêmement lente. Il n'y a
pas de photodécomposition sensible dans l'eau ou l'atmosphère. La
réaction avec l'ozone est lente, de même qu'avec l'oxygène singulet.
Le principal mécanisme d'élimination de l'acétonitrile de la
troposphère consiste dans sa réaction avec les radicaux hydroxyles;
la durée estimative de séjour est de 20 à 200 jours.
L'acétonitrile gagne la stratosphère où il se caractérise par
son association aux amas d'ions positifs situés dans les régions
élevées.
4. Effets sur l'environnement
L'acétonitrile est peu toxique pour les microorganismes
(bactéries, cyanobactéries, algues bleues et protozoaires) avec un
seuil de toxicité de l'ordre de 500 mg/litre ou davantage. Les
valeurs de la CL50 dans le cas d'une intoxication aiguë sont de
l'ordre de 700 mg/litre ou davantage pour les invertébrés et les
poissons d'eau douce. Des tests de toxicité aiguë ont été effectués
dans des conditions statiques sans confirmation analytique des
concentrations. Les résultats analogues obtenus à l'issue de tests
de 24 et 96 heures donnent à penser qu'il y a volatilisation de
l'acétonitrile.
5. Absorption, distribution, biotransformation et élimination
L'absorption de l'acétonitrile s'effectue facilement par la
voie digestive, percutanée et plumonaire. Ces trois voies
d'exposition entraînent toutes des effets généraux.
L'examen nécropsique de tissus provenant de personnes
intoxiquées montre que l'acétonitrile se répartit dans l'ensemble de
l'organisme. Cette constatation est corroborée par l'étude sur
l'animal qui montre également que la distribution de l'acétonitrile
est relativement uniforme dans l'ensemble de l'organisme. Rien
n'indique que l'administration réitérée d'acétonitrile n'entraîne
une accumulation dans les tissus chez l'animal.
On possède une quantité substantielle de données selon
lesquelles la majeure partie des effets toxiques généraux de
l'acétonitrile seraient dus à sa métabolisation en cyanure,
métabolisation qui est catalysée par le système des monooxygénases
du cytochrome P-450. La conjugaison du cyanure avec le thiosulfate
conduit à la formation de thiocyanate qui est ensuite éliminé dans
l'urine. Les concentrations maximales de cyanure dans le sang de
rats après administration de doses quasi-mortelles d'acétonitrile
correspondent sensiblement à celles que l'on observe après
l'administration d'une dose de cyanure de potassium correspondant à
la DL50. Toutefois, après administration d'acétonitrile, le pic
de concentration du cyanure apparaît avec un retard pouvant
atteindre plusieurs heures, par comparaison avec les autres
nitriles. En outre, la vitesse de formation plus élevée du cyanure
chez la souris explique la sensibilité beaucoup plus forte de cette
espèce aux effets toxiques de l'acétonitrile. On a reconnu la
présence de cyanure et de thiocyanate dans des tissus humains après
exposition à l'acétonitrile. Une partie de la dose d'acétonitrile
est également éliminée telle quelle dans l'air expiré et dans les
urines.
6. Effets sur les mammifères de laboratoire
L'acétonitrile produit des effets toxiques analogues à ceux que
l'on observe en cas d'intoxication aiguë par le cyanure, encore que
l'apparition des symptômes soit un peu plus tardive que dans le cas
des cyanures minéraux ou d'autres nitriles saturés. La CL50 par
inhalation à 8 heures pour le rat mâle est de 13 740 mg/m3
(7500 ppm). La DL50 par voie orale chez le rat va de 1,7 à 8,5 g/kg
selon les conditions de l'expérience. Les souris et les cobayes se
révèlent plus sensibles, avec une DL50 par voie orale de qui est
de l'ordre de 0,2-0,4 g/kg. Chez l'animal, les principaux symptômes
consistent en une prostration suivie de crises convulsives.
L'application cutanée d'acétonitrile entraîne une intoxication
générale chez l'animal et on lui a attribué la mort d'un enfant.
Chez le lapin, la DL50 par voie percutanée est de 1,25 mg/kg.
L'exposition subchronique d'animaux de laboratoire à
l'acétonitrile produit des effets analogues à ceux que l'on observe
après une intoxication aiguë.
D'après les épreuves effectuées sur Salmonella typhimurium,
l'acétonitrile n'est pas mutagène, qu'il y ait ou non activation
métabolique. A très forte concentration, l'acétonitrile a provoqué
une aneuploïdie chez une souche de levure diploïde. Il n'a pas été
fait état d'études sur l'animal qui concernent les effets chroniques
ou cancérogènes de l'acétonitrile.
7. Effets sur l'homme
On ne connaît pas les concentrations toxiques pour l'homme mais
il est probable qu'elles sont supérieures à 840 mg/m3
(500 ppm) d'air. Les symptômes d'une intoxication aiguë par
l'acétonitrile consistent en douleurs et sensation de constriction
au niveau du thorax, nausées, vomissements, agitation, état
semi-comateux et convulsions. D'autres symptômes non spécifiques
peuvent s'expliquer par l'effet irritant du composé. Les effets
généraux sont, semble-t-il, en grande partie attribuables à la
transformation de l'acétonitrile en cyanure. D'ailleurs, une
intoxication aiguë provoque une élévation des taux sanguins de
cyanure et de thiocyanate. On a signalé deux accidents mortels dus
à l'exposition à des vapeurs d'acétonitrile sur le lieu de travail
ainsi que la mort d'un enfant qui avait avalé un produit cosmétique
contenant de l'acétonitrile. L'examen nécropsique de ces victimes a
révélé la présence de fortes concentrations de cyanure dans les
tissus.
On ne dispose d'aucune étude épidémiologique sur l'incidence de
cancers qui seraient liés à une exposition à l'acétonitrile.
L'acétonitrile peut provoquer de graves brûlures oculaires. Il
convient d'éviter tout contact de la peau avec le composé. Dans de
nombreux pays, il est recommandé que l'exposition des travailleurs
ne dépasse pas 70 mg/m3 d'air (40 ppm) en moyenne pondérée par
rapport au temps au cours d'un poste de travail de 8 heures.
RESUMEN
1. Propiedades, usos y métodos analíticos
El acetonitrilo (CH3CN) es un subproducto de la fabricación
del acrilonitrilo. También puede formarse por combustión de madera
y de vegetación. Es un líquido de olor semejante al del éter. El
acetonitrilo es un disolvente volátil de alta polaridad utilizado
para la extracción de ácidos grasos y de aceites animales y
vegetales. Se emplea en la industria petroquímica en la destilación
extractiva debido a su miscibilidad selectiva con compuestos
orgánicos. Se utiliza como disolvente para el hilado de fibras
sintéticas y en la fusión y el moldeado de plásticos. Está muy
difundido su empleo en laboratorio en los análisis por cromatografía
líquida de alto rendimiento (HPLC) y como disolvente para la
síntesis de ADN y la secuenciación de péptidos.
La técnica analítica más ampliamente utilizada para el
acetonitrilo es la cromatografía de gases.
2. Niveles ambientales y fuentes de exposición humana
Hay muy pocos datos disponibles sobre los niveles de
acetonitrilo en el medio ambiente. A escala mundial se han
notificado concentraciones de acetonitrilo en el aire que oscilaban
entre 200 y 42 000 ng/m3. En un estudio se detectaron en el aire
de zonas urbanas valores algo más elevados que en el de zonas
rurales. Mediciones separadas efectuadas antes y después de la
quema de arbustos y paja mostraron una decuplicación de la
concentración de acetonitrilo en el aire.
No se ha detectado la presencia de acetonitrilo en 72 muestras
de agua del Japón, pero sí en 11 de 60 muestras de sedimentos
acuáticos, en concentraciones que oscilaban entre 0,02 y 0,54 mg/kg.
Tampoco se ha encontrado acetonitrilo en los alimentos.
El humo de tabaco contiene acetonitrilo y la espuma de
poliuretano al quemarse libera acetonitrilo y cianuro de hidrógeno.
Si bien la producción de acrilonitrilo conlleva el máximo
riesgo de exposición, ésta se efectúa en un sistema cerrado. Los
usos prácticos del acetonitrilo entrañan una exposición mayor.
3. Distribución y transformación en el medio ambiente
El acetonitrilo presente en el agua se volatiliza, como también
se volatilizaría el que se hallase presente en la capa superficial
del suelo. Se biodegrada fácilmente por acción de varias cepas de
bacterias comunes en el fango de alcantarillas, en las aguas
naturales y en el suelo. La aclimatación de las bacterias al
acetonitrilo o a los desechos de petróleo incrementa la tasa de
degradación. La degradación anaeróbica parece ser limitada o
inexistente.
La hidrólisis del acrilonitrilo en el agua es extremadamente
lenta. No hay fotodegradación significativa en el agua ni en la
atmósfera. La reacción con el ozono es lenta, como también lo es la
reacción con el oxígeno singlete. El principal mecanismo para
eliminar el acetonitrilo de la troposfera es la reacción con
radicales hidroxilo; los tiempos de residencia se han estimado entre
20 y 200 días.
El acetonitrilo llega hasta la estratosfera, en cuyas regiones
superiores está asociado característicamente en aglomerados de iones
positivos.
4. Efectos ambientales
El acetonitrilo es poco tóxico para los microorganismos
(bacterias, cianobacterias, algas verdes y protozoarios) con
umbrales de 500 mg/litre o más. Las CL50 agudas para
invertebrados y peces de agua dulce son de 700 mg/litre o más. Se
han hecho pruebas de toxicidad aguda en condiciones estáticas sin
confirmación analítica de las concentraciones. Algunos resultados
semejantes de otras pruebas, obtenidos después de 24 y 96 horas,
parecen indicar una volatilización del acetonitrilo.
5. Absorción, distribución, biotransformación y eliminación
El acetonitrilo se absorbe fácilmente en el tracto
gastrointestinal y a través de la piel y de los pulmones. Se ha
informado de que la exposición por estas tres vías tiene efectos
sistémicos.
El examen de tejidos en la autopsia de personas envenenadas ha
mostrado que el acetonitrilo se distribuye por todo el cuerpo. Esta
observación está corroborada por estudios realizados en animales, en
los cuales se ha encontrado que el acetonitrilo se distribuye
bastante uniformemente en todo el cuerpo. No hay indicaciones de
acumulación en los tejidos animales después de administraciones
repetidas de acetonitrilo.
Hay datos sustanciales que hacen pensar que el acetonitrilo
tiene efectos tóxicos sistémicos a través de su transformación
metabólica en cianuro, catalizada por el sistema de la
citocromo-P-450-monooxigenasa. El cianuro se conjuga posteriormente
con el tiosulfato para formar tiocianato, que se elimina por la
orina. Las concentraciones máximas de cianuro en la sangre de ratas
después de la administración de dosis casi letales de acetonitrilo
se aproximan a las concentraciones observadas después de la
administración de una DL50 de cianuro de potasio. Sin embargo, la
concentración máxima de cianuro después de la administración de
acetonitrilo se alcanza con un retraso de hasta varias horas en
comparación con otros nitrilos. Por otra parte, la mayor rapidez
con la cual se produce el cianuro en el ratón parece explicar la
sensibilidad mucho mayor de esta especie a los efectos tóxicos del
acetonitrilo. Se ha detectado la presencia de cianuro y de
tiocianato en tejidos humanos después de la exposición al
acetonitrilo. Parte de la dosis de acetonitrilo también se elimina
sin modificaciones a través del aire que se exhala y de la orina.
6. Efectos en mamíferos de laboratorio
El acetonitrilo produce efectos tóxicos similares a los
observados en el envenenamiento agudo con cianuro, aunque los
síntomas comienzan a manifestarse con algún retraso en comparación
con los producidos por cianuros inorgánicos u otros nitrilos
saturados. La CL50 en machos de rata sometidos a inhalación
durante 8 horas es de 13 740 mg/m3 (7500 ppm). La DL50 por vía
oral en la rata oscila entre 1,7 y 8,5 g/kg, según las condiciones
del experimento. Los ratones y los cobayos parecen ser más
sensibles, con una DL50 por vía oral de 0,2 a 0,4 g/kg. Los
síntomas principales en los animales parecen ser la postración
seguida de convulsiones.
La aplicación dérmica de acetonitrilo tiene efectos tóxicos
sistémicos en animales y ha sido un factor causal de defunción en un
niño. La DL50 percutánea en conejos es de 1,25 ml/kg.
La exposición subcrónica de animales al acetonitrilo produce
efectos similares a los observados después de la exposición aguda.
El acetonitrilo no ha tenido efectos mutagénicos en ensayos
realizados con Salmonella typhimurium, con y sin activación
metabólica. En concentraciones muy altas produce aneuploidía en una
estirpe diploide de levaduras. No se tiene noticia de estudios
sobre los efectos crónicos o carcinogénicos del acetonitrilo en
animales.
7. Efectos en el hombre
Se desconocen los niveles tóxicos en el hombre, pero
probablemente rebasen los 840 mg/m3 (500 ppm) en el aire. Los
síntomas y signos de la intoxicación aguda con acetonitrilo
comprenden dolor torácico, sensación de opresión en el pecho,
náuseas, vómitos, taquicardia, hipotensión, respiración corta y poco
profunda, dolor de cabeza, agitación, semiinconsciencia y
convulsiones. Otros síntomas no específicos tal vez obedezcan a los
efectos irritantes del compuesto. Los efectos sistémicos parecen
atribuibles en gran medida a la conversión del acetonitrilo en
cianuro. Los niveles de cianuro y de tiocianato en la sangre son
elevados durante la intoxicación aguda. Se han comunicado dos
defunciones posteriores a la exposición a vapores de acetonitrilo en
el lugar de trabajo y la defunción de un niño que había ingerido un
cosmético que contenía acetonitrilo. Se encontraron concentraciones
elevadas de cianuro en la autopsia de esas personas.
No se han notificado estudios epidemiológicos sobre la
incidencia de cáncer relacionada con la exposición al acetonitrilo.
El acetonitrilo puede causar quemaduras graves en los ojos.
Debe evitarse el contacto de la piel con el acetonitrilo líquido.
En muchos países se ha recomendado que la exposición de los
empleados al acetonitrilo en un turno de 8 horas no rebase un
promedio, ponderado en función del tiempo, de 70 mg/m3 de aire
(40 ppm).