EPA 749-F-94-004a http://www.epa.gov/chemfact/s_acenit.txt
CHEMICAL SUMMARY FOR ACETONITRILE (CAS NO. 75-05-8)
prepared by
OFFICE OF POLLUTION PREVENTION AND TOXICS
U.S. ENVIRONMENTAL PROTECTION AGENCY
August 1994
This summary is based on information retrieved from a systematic
search limited to secondary sources (see Appendix A). These sources
include online databases, unpublished EPA information, government
publications, review documents, and standard reference materials. No
attempt has been made to verify information in these databases and
secondary sources.
Acetonitrile is metabolized in the body to hydrogen cyanide and thiocyanate; these chemicals are thought to be
responsible for the adverse effects of acetonitrile.
II. PRODUCTION, USE, AND TRENDS
A. Production
There are four producers of acetonitrile in the United States:
BP Chemicals; Dupont; J.T. Baker Chemical; and Sterling Chemicals.
In 1992, 14.7 million kilograms (32.3 million pounds) were
produced in the United States. (U.S. International Trade
Commission 1994).
B. Use
Acetonitrile has a number of uses, primarily as an extraction
solvent for butadiene; as a chemical intermediate in pesticide
manufacturing; and as a solvent for both inorganic and organic
compounds. Uses also include use as a starting material for the
production of acetophenone, alpha-naphthalenacetic acid, thiamine,
and acetamidine; to remove tars, phenols, and coloring matter
from petroleum hydrocarbons not soluble in acetonitrile; in the
production of acrylic fibers; and in pharmaceuticals, perfumes,
nitrile rubber, and ABS (acrylonitrile-butadiene-styrene) resins
(HSDB 1994).
C. Trends
Because it is a byproduct of acrylonitrile production, production
trends for acetonitrile should follow trends in acrylonitrile
production, which are expected to generally mirror trends in
United States economic growth (Mannsville, "Acrylonitrile," 1992.)
III. ENVIRONMENTAL FATE
A. Environmental Release
Of the total acetonitrile released to the environment in 1992,
11.3 million pounds were into the atmosphere, 20 million pounds
were into underground sites, 50 thousand pounds were into surface
water, and only 29 pounds were onto the land (TRI92 1994).
Acetonitrile has been detected in air near ground levels, ranging
from 2 to 7 ppb in both urban and rural areas (HSDB 1994). The
chemical occurs naturally in coal tar and cigarette smoke (HSDB
1994).
B. Transport
Acetonitrile is expected to adsorb weakly to soils as predicted
by its KOC value; removal occurs primarily by volatilization and
leaching into groundwater (HSDB 1994). Volatilization from
surface waters is slow due to the high water solubility, moderate
vapor pressure (91.1 mm Hg), and low Henry's law constant (3.46 x
10-5 atmùm3/mole) of the chemical (HSDB 1994). The water
solubility of acetonitrile suggests that dissolution into clouds
and raindrops may occur leading to possible removal in rainfall
(U.S. EPA 1985).
IV. HUMAN HEALTH EFFECTS
Acetonitrile is metabolized in the body to hydrogen cyanide and
thiocyanate; these chemicals are thought to be responsible for the
adverse effects of acetonitrile.
A. Pharmacokinetics
1. Absorption - Absorption of acetonitrile occurs after oral,
dermal, or inhalation exposure. Although no quantitative
absorption data were found for oral exposure, signs of acute
toxicity, observed after oral exposure, indicate that absorption
occurs (U.S. EPA 1987). In humans, 74% of acetonitrile was
absorbed from cigarette smoke held in the mouth for 2 seconds;
when inhaled into the lungs, absorption increased to 91% (U.S.
EPA 1985; 1987). Dogs exposed by inhalation to 16,000 ppm for
4 hours appeared to reach steady-state blood concentrations
within 3-4 hours (U.S. EPA 1985; 1987).
2. Distribution - Acetonitrile and its metabolites are transported
throughout the body in the blood (U.S. EPA 1985). After oral or
inhalation exposures to experimental animals, parent compound or
metabolites were found in the brain, heart, liver, kidney,
spleen, blood, stomach, and muscle (U.S. EPA 1985). After a fatal
human inhalation exposure, metabolites were also found in those
organs as well as skin, lungs, intestine, testes, and urine (U.S.
EPA 1985).
3. Metabolism - Acetonitrile is metabolized to hydrogen cyanide
and thiocyanate which are responsible for the toxic effects
of the chemical (HSDB 1994; U.S. EPA 1985). Metabolism is
mediated by the cytochrome P-450 system (U.S. EPA 1985).
4. Excretion - Acetonitrile is excreted as the parent chemical in
expired air and as parent or metabolite in urine (U.S. EPA 1985).
Urinary excretion of thiocyanate following oral exposure in rats
ranged from 11.8% (U.S. EPA 1985) to 37% (HSDB 1994) of
administered dose. Concentrations of acetonitrile of 2.2-20
microgram/100 mL of urine have been found for heavy smokers
(U.S. EPA 1985).
B. Acute Toxicity
Acetonitrile liquid or vapor is irritating to the skin, eyes, and
respiratory tract. At high enough doses, death can occur quickly
from respiratory failure. Lower doses cause typical symptoms of
cyanide poisoning such as salivation, nausea, vomiting, anxiety,
confusion, hyperpnea, dyspnea, rapid pulse, unconsciousness, and
convulsions.
1. Humans - Liquid or vapor acetonitrile is irritating to eyes,
skin, nose, and throat (Keith and Walters 1985). Concentrations
of acetonitrile vapor up to 500 ppm cause irritation of mucous
membranes (HSDB 1994). Volunteers were exposed to 40, 80, or
160 ppm for 4 hours; several hours after exposure one person had
tightness of the chest after exposure to 40 ppm and another
experienced flushing of the face and bronchial tightness after
exposure to 160 ppm (ACGIH 1991). The concentration of 160 ppm
is roughly equivalent to a total of 19.5 mg/kg over the 4 hour
period (see end note 1). One photographic laboratory worker
died after "massive" exposure to acetonitrile vapor; gastric
distress and nausea began about 4 hours after exposure followed
by hypersalivation, conjunctivitis, low urine output, low blood
pressure, albumin in urine and cerebrospinal fluid, coma, and
death due to cardiac and respiratory failure (HSDB 1994).
Similar signs and symptoms, including death, occurred in a worker
painting the interior of a tank with a resin containing 30-40%
acetonitrile (HSDB 1994).
2. Animals - Oral LD50 values for acetonitrile in the rat range
from 2.46 to 6.5 g/kg (U.S. EPA 1985). The 4-hour inhalation
LC50 varies with species from 2828 ppm in the rabbit to 16,000
ppm in the rat; dermal LD50 values of 3.9 and 1.25 g/kg have been
reported for the rabbit (U.S. EPA 1985). Deaths occurred in dogs
exposed by inhalation to 16,000 or 32,000 ppm; necropsy indicated
pulmonary hemorrhage and vascular congestion (ACGIH 1991).
C. Subchronic/Chronic Toxicity
Limited information was found on the adverse effects of long term
human exposure to acetonitrile. Animals exposed chronically by
inhalation have liver vacuolization, cerebral hemorrhage, lung
lesions including focal emphysema and proliferation of alveolar
septa, and decreases in hematological parameters. EPA has derived an
oral reference dose (RfD) (see end note 2) of 0.006 mg/kg/day for
acetonitrile, based on adverse blood effects observed in animal
inhalation studies. Confidence in this RfD is low; it may be changed
in the near future, pending results of further review now being
conducted by EPA.
1. Humans - No information was found on the adverse effects of
long term human exposure to acetonitrile. Brief references
appear in HSDB (1994), suggesting that chronic exposure to
acetonitrile may cause headache, anorexia, dizziness, weakness,
and macular, papular, or vesicular dermatitis. No additional
information was provided in support of these statements.
2. Animals - Female mice exposed to 100, 200, or 400 ppm, 6
hours/day, 5 days/week for 90 days had thymic atrophy at the
middle and high doses and hepatic vacuolization at the high dose;
dose-related decreases were observed in hematocrit, blood
hemoglobin concentration, and erythrocyte and leucocyte counts
(U.S. EPA 1994). A no-observed-adverse effect level (NOAEL) for
this study was 100 ppm (equivalent to 19.3 mg/kg/day). Based on
these inhalation data the U.S. EPA (1994) calculated an oral
reference dose for acetonitrile of 0.006 mg/kg/day. Similar
hepatic and blood profile changes were observed in mice exposed to
200 or 400 ppm 6.5 hours/day, 5 days/week for 13 weeks (ACGIH
1991).
Rats exposed by inhalation to 166, 330, or 655 ppm acetonitrile
7 hours/day, 5 days/week for 90 days had a dose-responsive
increase in the severity of lung lesions. Animals in the low and
middle dose groups had "histiocytic clumps in alveoli,
atelectasis, bronchitis or pneumonia"; high dose animals had
alveolar congestion and focal edema, bronchial inflammation,
desquamation, and excess mucus as well as swelling of the liver
and kidneys and cerebral hemorrhage (U.S. EPA 1985; 1987). Dogs
and monkeys exposed to 350 ppm, 7 hours/day, 5 days/week for 91
days had pulmonary lesions including focal emphysema, atelectasis
and proliferation of alveolar septa; transient depression in
hematocrit and hemoglobin values also occurred in dogs, and brain
hemorrhages were observed in monkeys (U.S. EPA 1985; 1987).
Male and female mice (groups of 10/sex) were exposed to 25, 50,
100, 200, or 400 ppm, 6 hours/day for 65 days. Decreased BUN, red
blood cell counts, and hematocrit occurred in females exposed to
the two highest doses, and increased liver weights were observed
in males at 400 ppm and females at 100 and 200 ppm (U.S. EPA
1987).
G. Neurotoxicity
Exposure to high concentrations of acetonitrile causes death by
respiratory failure and has been shown to cause brain lesions in
animals.
1. Humans - The nervous system is a major target for acetonitrile
acute toxicity. Acute exposure may cause salivation, nausea,
vomiting, anxiety, confusion, hyperpnea, dyspnea, rapid pulse,
unconsciousness, and convulsions followed by death from
respiratory failure. Chronic exposure may cause headache,
anorexia, dizziness, and weakness (HSDB 1994).
2. Animals - Acetonitrile inhalation caused cerebral hemorrhages in
rats exposed to 655 ppm 7 hours/day, 5 days/week, for 90 days and
monkeys exposed to 350 ppm 7 hours/day, 5 days/week, for 91 days
(U.S. EPA 1987).