TOXICOLOGICAL PROFILE FOR 

ACRYLONITRILE 

Agency for Toxic Substances and Disease Registry

U.S. Public Health Service 

December 1990 
ii 

DISCLAIMER 

The use of company or product name(s) is for identification only and

does not imply endorsement by the Agency for Toxic Substances and Disease

Registry. 










1 

1. PUBLIC HEALTH STATEMENT 

This Statement was prepared to give you information about

acrylonitrile and to emphasize the human health effects that may result

from exposure to it. The Environmental Protection Agency (EPA) has

identified 1,177 sites on its National Priorities List (NPL).

Acrylonitrile has been found at 3 of these sites. However, we do not

know how many of the 1,177 NPL sites have been evaluated for

acrylonitrile. As EPA evaluates more sites, the number of sites at

which acrylonitrile is found may change. The information is important

for you to know because acrylonitrile may cause harmful health effects

and because these sites are potential or actual sources of human

exposure to acrylonitrile. 

When a chemical is released from a large area, such as an

industrial plant, or from a container, such as a drum or bottle, it

enters the environment as a chemical emission. This emission, which is

also called a release, does not always lead to exposure. You can be

exposed to a chemical only when you come into contact with the chemical.

You may be exposed to it in the environment by breathing, eating, or

drinking substances containing the chemical or from skin contact with

it. 

If you are exposed to a hazardous substance such as acrylonitrile,

several factors will determine whether harmful health effects will occur 

and what the type and severity of those health effects will be. These

factors include the dose (how much), the duration (how long), the route

or pathway by which you are exposed (breathing, eating, drinking, or

skin contact), the other chemicals to which you are exposed, and your

individual characteristics such as age, sex, nutritional status, family

traits, life style, and state of health. 

1.1 WHAT IS ACRYLONITRILE? 

Acrylonitrile is a colorless, liquid, man-made chemical with a

sharp, onion- or garlic-like odor. Acrylonitrile is used mostly to make

plastics, acrylic fibers, and synthetic rubber. Because acrylonitrile

evaporates quickly, it is most likely to be found in the air around

chemical plants where it is made. Acrylonitrile breaks down quickly in

the air. It has been found in small amounts in the water and soil near 

manufacturing plants and hazardous waste sites. In water, acrylonitrile

usually breaks down in about 1 to 2 weeks, although this can vary

depending on conditions. For example, high concentrations of

acrylonitrile (such as might occur after a spill) tend to be broken down

more slowly. In one case, measurable amounts of acrylonitrile were

found in nearby wells 1 year after a spill. Further information on the

properties and uses of acrylonitrile and how it behaves in the

environment may be found in Chapters 3, 4, and 5. 
2 

1. PUBLIC HEALTH STATEMENT 

1.2 HOW MIGHT I BE EXPOSED TO ACRYLONITRILE? 

Unless you live near a factory where acrylonitrile is made or near

a hazardous waste site that contains acrylonitrile, you are unlikely to

be exposed to acrylonitrile in the air you breathe or the water you

drink. Concentrations of acrylonitrile in average air samples are too

low to be measured, and most water samples also have no measurable

acrylonitrile. Measurable amounts of acrylonitrile are found primarily

near factories and hazardous waste sites. Concentrations in the air 

near a factory producing or using acrylonitrile average less than 1 part

per billion (ppb). Extremely small amounts of acrylonitrile may be

found in water near some factories that make or use it, but

acrylonitrile rapidly breaks down and disappears from water. Plastic

food containers that are made from acrylonitrile are regulated by the

Food and Drug Administration such that only 0.17 ppb can enter food;

therefore, acrylonitrile intake from food packaging would be extremely

low. Because acrylonitrile has been found in water and soil in some

hazardous waste sites that contain this chemical, residents living very

close to waste sites might possibly be exposed to acrylonitrile by

breathing the air or drinking contaminated groundwater. 

Further information on how you might be exposed to acrylonitrile is

given in Chapter 5. 

1.3 HOW CAN ACRYLONITRILE ENTER AND LEAVE MY BODY? 

Acrylonitrile can enter your body if you breathe its vapors or eat

or drink acrylonitrile-contaminated food or water. Acrylonitrile can

pass through your skin, but how much gets through is not known. Inside

the body, acrylonitrile is broken down into other chemicals, including

cyanide. Most of these breakdown products are removed from the body in

the urine. Overall, most acrylonitrile is removed from the body within

24 hours, but approximately 25% of what is taken in becomes attached to

materials inside cells of the body. More information on how

acrylonitrile enters and leaves the body is given in CLaapter 2. 

1.4 HOW CAN ACRYLONITRILE AFFECT MY HEALTH? 

The effects of acrylonitrile on your health depend on how much you

take into your body and whether you are exposed for a short or long

period of time. If the levels of acrylonitrile are high enough, or if

the exposure is for a long enough period of time, acrylonitrile can

cause death. Small children are more likely to be affected than adults.

In several cases, children died following exposures that adults found

only mildly irritating. It should be noted that specific levels of

acrylonitrile causing death were not reported. Exposure to large

amounts of acrylonitrile for a short period of time, as might occur in

the case of an industrial accident, results mainly in effects on the 
3 

1. PUBLIC HEALTH STATEMENT 

nervous system. Symptoms can include headache and nausea. At higher

concentrations of acrylonitrile there may be temporary damage to red

blood cells and the liver. These symptoms disappear when the exposure

is stopped. 

Direct contact of your skin with acrylonitrile will damage the skin

so that it may blister and peel. Exposure of the skin to high

concentrations of acrylonitrile in the air may irritate the skin and

cause it to turn red. The redness may last for several days. 

Long-term exposure to acrylonitrile in air or water may increase

your chances of getting cancer. Humans who are repeatedly exposed to

acrylonitrile in the workplace for many years may have a higher-than-average

chance of developing lung cancer, although this is not clearly

established. In animals, exposure to acrylonitrile in the air or in

drinking water has been found to increase the number of tumors occurring

in the brain, salivary glands, and intestines. 

Birth defects have been seen in animals exposed to high

concentrations of acrylonitrile in the air or drinking water.

Reproductive effects have been seen in animals given acrylonitrile in

drinking water for three generations. However, no birth defects or

effects on reproduction have been reported in humans. 

Further information on the health effects of acrylonitrile in

humans and animals can be found in Chapter 2. 

1.5 WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS? 

In humans, breathing acrylonitrile at a concentration of 16 parts

of acrylonitrile per million parts of air (ppm) causes headaches,

nausea, and disorientation (Table l-l). This concentration is close to

that at which acrylonitrile can be smelled in air (about 21 ppm).

Breathing acrylonitrile in air for long periods of time and at high

concentrations can cause death. The actual concentrations of 

acrylonitrile and breathing times which cause death have not been

measured. There is no information on human health effects from eating

or drinking acrylonitrile. Acrylonitrile can be smelled at a

concentration of 19 ppm when dissolved in water. 

In animals, drinking water that contains 142 ppm of acrylonitrile

has caused nervous system disorders leading to death (Table l-4). Birth

defects and effects on reproduction have occurred in animals that

breathed acrylonitrile in air at levels of 80 ppm or drank it in water

at 180 ppm. 
4 

1. PUBLIC HEALTH STATEMENT 

Tables l-1 through 1-4 show the relationship between exposure to

acrylonitrile and known health effects. Short-term and longer-term

Minimal Risk Levels (MRLs) are also included in Tables l-l and l-3.

These MRLs were derived from animal and human data for both short-term 

and long-term exposure, as described in Chapter 2 and in Tables 2-l and

2-2. The MRLs provide a basis for comparison with levels that people

might encounter either in the air or in food or drinking water. If a

person is exposed to acrylonitrile at an amount below the MRL, it is not

expected that harmful (noncancer) health effects will occur. Because

these levels are based only on information currently available, some

uncertainty is always associated with them. Also, because the method

for deriving MRLs does not use any information about cancer, an MRL does

not imply anything about the presence, absence, or level of risk for

cancer. 

Additional information on the levels of exposure associated with

harmful effects can be found in Chapter 2. 

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 

ACRYLONITRILE? 

There is a test that can detect acrylonitrile in blood. In

addition, the major breakdown products of acrylonitrile by the body

(termed metabolites) can be measured in urine. Some breakdown products

that can be measured are specific to acrylonitrile. However, one

breakdown product of the body (cyanide) that is commonly measured is not

specific to acrylonitrile exposure, and the results can be affected by

cigarette smoking. Because special equipment is needed, these tests

cannot be performed routinely in your doctor's office. There is not

enough information at present to use the results of such tests to

predict the nature or severity of any health effects that may result

from exposure to acrylonitrile. Further information on how

acrylonitrile can be measured in exposed humans is presented in

Chapters 2 and 6. 

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT 

HUMAN HEALTH? 

The federal government has developed regulations and advisories to

protect individuals from the potential health effects of acrylonitrile

in the environment. The U.S. Environmental Protection Agency (EPA)

recommends that acrylonitrile levels in water not exceed 0.058 ppb. Any

release to the environment of more than 100 lb must be reported to the

federal government. The Occupational Safety and Health Administration

(OSHA) has established a legally enforceable maximum limit of 2 ppm in

workplace air for an 8-hour exposure over a 40-hour work week. 




9 

1. PUBLIC HEALTH STATEMENT 

Additional information on governmental regulations can be found Chapter

7. 

1.8 WHERE CAN I GET MORE INFORMATION? 

If you have any more questions or concerns not covered here, please

contact your State Health or Environmental Depart or: 

Agency for Toxic Substances and Disease Registry

Division of Toxicology

1600 Clifton Road, E-29

Atlanta, Georgia 30333 

This agency can also give you information on the location of the nearest

occupational and environmental health clinics. Such clinics specialize in

recognizing, evaluating, and treating illnesses that

result from exposure to hazardous substances. 

11 

2. HEALTH EFFECTS 

2.1 INTRODUCTION 

This chapter contains descriptions and evaluations of studies and

interpretation of data on the health effects associated with exposure to

acrylonitrile. Its purpose is to present levels of significant exposure

for acrylonitrile based on toxicological studies, epidemiological

investigations, and environmental exposure data. This information is

presented to provide public health officials, physicians, toxicologists,

and other interested individuals and groups with (1) an overall

perspective of the toxicology of acrylonitrile and (2) a depiction of

significant exposure levels associated with various adverse health

effects. 

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 

To help public health professionals address the needs of persons

living or working near hazardous waste sites, the data in this section

are organized first by route of exposure -- inhalation, oral, and dermal

-- and then by health effect -- death, systemic, immunological,

neurological, developmental, reproductive, genotoxic, and carcinogenic

effects. These data are discussed in terms of three exposure periods --

acute, intermediate, and chronic. 

Levels of significant exposure for each exposure route and duration

(for which data exist) are presented in tables and illustrated in

figures. The points in the figures showing no-observed-adverse-effect

levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs)

reflect the actual doses (levels of exposure) used in the studies.

LOAELs have been classified into "less serious" or "serious" effects. These 

distinctions are intended to help the users of the document

identify the levels of exposure at which adverse health effects start to

appear, determine whether or not the intensity of the effects varies

with dose and/or duration, and place into perspective the possible

significance of these effects to human health. 

The significance of the exposure levels shown on the tables and

figures may differ depending on the user's perspective. For example,

physicians concerned with the interpretation of clinical findings in

exposed persons or with the identification of persons with the potential

to develop such disease may be interested in levels of exposure

associated with "serious" effects. Public health officials and project

managers concerned with response actions at Superfund sites may want

information on levels of exposure associated with more subtle effects in

humans or animals (LOAELS) or exposure levels below which no adverse

effects (NOAELs) have been observed. Estimates of levels posing minimal

risk to humans (Minimal Risk Levels, MRLs) are of interest to health

professionals and citizens alike. 
12 

2. HEALTH EFFECTS 

For certain chemicals, levels of exposure associated with

carcinogenic effects may be indicated in the figures. These levels

reflect the actual doses associated with the tumor incidences reported

in the studies cited. Because cancer effects could occur at lower 

exposure levels, the figures also show estimated excess risks, ranging

from a risk of one in 10,000 to one in 10,000,000 (10-4 to 10-7), as

developed by EPA. 

Estimates of exposure levels posing minimal risk to humans (MRLs)

have been made, where data were believed reliable, for the most

sensitive noncancer end point for each exposure duration. MRLs include

adjustments to reflect human variability and, where appropriate, the

uncertainty of extrapolating from laboratory animal data to humans.

Although methods have been established to derive these levels (Barnes

et al. 1987; EPA 1989a), uncertainties are associated with the

techniques. Furthermore, ATSDR acknowledges additional uncertainties

inherent in the application of these procedures to derive less than

lifetime MRLs. As an example, acute inhalation MRLs may not be

protective for health effects that are delayed in development or are

acquired following repeated acute insults, such as hypersensitivity

reactions, asthma, or chronic bronchitis. As these kinds of health

effects data become available and methods to assess levels of 

significant human exposure improve, these MRLs will be revised. 

2.2.1 Inhalation Exposure 

Table 2-l and Figure 2-l summarize quantitative data on the health

effects observed in humans and laboratory animals exposed to

acrylonitrile by inhalation. 

2.2.1.1 Death 

In humans, the death of a child (age 3) who was exposed by sleeping

in a room that had been fumigated with acrylonitrile has been described

by Grunske (1949). Respiratory malfunction, lip cyanosis and

tachycardia were among the symptoms described prior to death. Five

adults who spent the night in the same room complained only of eye

irritation or showed no signs of acrylonitrile poisoning. The

concentrations of acrylonitrile in the air were not reported. Several

other instances of death in children with only mild irritation in adults

were reported by Grunske (1949), but not described in detail. 

Data on the NOAELS and LOAELS for death are presented in Table 2-l

for several animal species. The data presented indicate that species

differences exist with respect to acute lethal effects. Dogs appear to

be the most susceptible species, but this is based on studies involving

only a few animals. The cause of death varied among test species. In

guinea pigs, death resulted from pulmonary irritation (see 





18 

2. HEALTH EFFECTS 

Section 2.2.1.2) while in the other species convulsions and coma

occurred (see Section 2.2.1.4) (Dudley and Neal 1942). It should be

noted that this study is based on nominal concentrations without

analytical verification. 

Chronic exposure to acrylonitrile has been reported to result in

early deaths in male and female rats (Quast et al. 1980a). A

statistically significant increase in mortality was observed within the

first year of a study in which animals were exposed to 80 ppm of

acrylonitrile. At 20 ppm, increased deaths were noted in females during

the last 10 weeks of the study. The cause of death was not specifically

identified. 

The highest NOAEL values and all reliable LOAEL values for death in

each species and duration category are recorded in Table 2-l and plotted

in Figure 2-l. 

2.2.1.2 Systemic Effects 

Respiratory Effects. In workers exposed to acrylonitrile at

concentrations of 16 to 100 ppm for periods of 20 to 45 minutes,

irritation of the nose and throat and a feeling of fullness in the chest

was reported by Wilson et al. (1948). 

Acute effects on the respiratory tract of animals demonstrate

species differences. In guinea pigs exposed to 575 ppm for 4 hours,

marked irritation of the respiratory tract was evidenced by coughing and

nasal exudate, with delayed death from lung edema (Dudley and Neal

1942). In other species (rats, rabbits, dogs and monkeys), death

occurred at lower doses than in guinea pigs, but was not related to

respiratory effects. In these animals, mild irritation of the

respiratory tract and effects resembling cyanide poisoning were noted.

Respiration was initially stimulated, but then followed by rapid shallow

breathing (Dudley and Neal 1942). 

Reported exposure at lower doses shows no acrylonitrile-related

effects on the respiratory system. For example, rats repeatedly exposed

for 5 days to 129 ppm of acrylonitrile showed no gross or histological

changes in lung tissue (Gut et al. 1984). However, chronic exposure of

rats to acrylonitrile appears to cause irritation of the nasal passages.

In a 2-year study, histopathological evaluation of tissues of the

respiratory system revealed degenerative and inflammatory changes of the

nasal turbinates at 80 ppm (Quast et al. 1980a). These effects were not

noted at 20 ppm. 
19 

2. HEALTH EFFECTS 

The highest NOAEL values and all reliable LOAEL values for

respiratory effects in each species and duration category are recorded

in Table 2-l and plotted in Figure 2-l. 

Cardiovascular Effects. In humans, tachycardia was among the

symptoms described in a child (age 3) who was exposed by sleeping in a

room that had been fumigated with acrylonitrile. The child died as a

result of the exposure (see Section 2.2.1.1) (Grunske 1949).

No studies were located regarding cardiovascular effects in animals

following inhalation exposure to acrylonitrile. 

Gastrointestinal Effects. Though tumors of the small intestine

were noted in a comprehensive and well-conducted study by Quast et al.

(1980a) (see Section 2.2.1.8), there were no nonneoplastic

histopathologic changes observed in any portion of the gastrointestinal

tract of rats at doses up to 80 ppm for 2 years. 

Hematological Effects. Humans exposed to acrylonitrile at

concentrations where nausea, vomiting and weakness occurred (16 to

100 ppm for 20 to 45 minutes), were also reported to have low grade

anemia. However, complete recovery after cessation of exposure was

reported (Wilson 1944; Wilson et al. 1948). No adverse hematological

effects were detected in Japanese workers exposed to acrylonitrile for

10 to 13 years at exposure levels averaging 2.1 to 14.1 ppm (Sakurai

et al. 1978). 

In a chronic study in rats (Quast et al. 1980a), some changes in

the blood parameters measured were observed at various intervals during

the study, but the findings did not occur consistently and were not

dose-related. Therefore, the authors concluded that these findings were

not direct effects of exposure to acrylonitrile, but rather were a

secondary response to other effects such as weight loss, tumor

formation, or inflammatory reactions. 

The highest NOAEL values and all reliable LOAEL values for

hematological effects in each species and duration category are recorded

in Table 2-l and plotted in Figure 2-l. 

Musculoskeletal Effects. No studies were located regarding

musculoskeletal effects in humans or animals following inhalation

exposure to acrylonitrile. 

Hepatic Effects. Acrylonitrile is metabolized in the liver to

potentially toxic metabolites (see Section 2.3). There are limited

indications that the liver is a target organ for acrylonitrile toxicity. 
20 

2. HEALTH EFFECTS 

In humans, mild jaundice lasting several days to 4 weeks has been

observed after acute occupational exposure to acrylonitrile vapors at

high concentrations (Wilson 1944); however, the concentrations of

acrylonitrile to which workers were exposed were not reported. The

effects were fully reversible. In factory workers exposed to

acrylonitrile for 10 years or more, Sakurai et al. (1978) reported an

increase in palpable livers of workers. However, the authors considered

these results to be inconclusive because the increase was not 

statistically significant and subjective judgments were involved. Also,

blood chemistry evaluations did not indicate liver damage. 

In animals, acrylonitrile does not appear to cause damage to the

liver following acute or chronic inhalation exposure, though some

biochemical changes are noted. Exposure of rats for 5 days to 129 ppm

of acrylonitrile resulted in slightly lower liver weight, but no

histopathological changes were found (Gut et al. 1984). Depletion of

glutathione and effects on carbohydrate and lipid metabolism were

observed (Gut et al. 1984, 1985). These effects would be expected

considering the affinity of acrylonitrile for sulfhydryl groups on

proteins and the involvement of glutathione in the metabolism of

acrylonitrile (see Section 2.6). A 2-year chronic study in rats showed

no liver injury as evaluated by serum enzyme activity and

histopathological evaluation of the tissue (Quast et al. 1980a). 

The highest NOAEL values and all reliable LOAEL values for hepatic

effects in each species and duration category are recorded in Table 2-l

and plotted in Figure 2-l. 

Renal Effects. Most studies indicate that inhalation exposure to

acrylonitrile does not result in significant kidney injury. For

example, physical examination of workers exposed to acrylonitrile vapors

in the workplace for 10 or more years provided no indication of renal

effects (Sakurai et al. 1978). In animals, no histological or

biochemical signs of renal injury were seen following exposure of rats

to 129 ppm of acrylonitrile for 5 days (Gut et al. 1984), or to 80 ppm 

for 2 years (Quast et al. 1980a). Small increases in urinary levels of

glucose, gamma-glutamyl transpeptidase, and N-acetyl-glucosaminidase

were observed in rats exposed to 200 ppm of acrylonitrile for 4 hours

(Rouisse et al. 1986), but this was not accompanied by any significant

effect on urinary creatinine or blood urea nitrogen. No significant

effects were noted at 100 ppm for this duration of exposure. 

The highest NOAEL values and all reliable LOAEL values for renal

effects in each species and duration category are recorded in Table 2-1

and plotted in Figure 2-l. 
21 

2. HEALTH EFFECTS 

Dermal/Ocular Effects. In humans, direct skin irritation resulting

from exposure to acrylonitrile vapors has been observed (see Section

2.2.3). 

A skin redness reported in experimental animals (rats, rabbits,

cats and monkeys) after inhalation exposure to acrylonitrile may be due

to a vasodilatory effect, rather than a direct irritant action (Ahmed

and Pate1 1981). Guinea pigs, which do not exhibit the cyanide-type

effects of acrylonitrile poisoning (see Section 2.2.1.4), were observed

to have nose and eye irritation from the acrylonitrile vapors (Dudley

and Neal 1942). 

The highest NOAEL values and all reliable LOAEL values for

dermal/ocular effects in each species and duration category are recorded

in Table 2-l and plotted in Figure 2-l. 

2.2.1.3 Immunological Effects 

No studies were located regarding immunologic effects in humans or

animals following inhalation exposure to acrylonitrile. 

2.2.1.4 Neurological Effects 

In humans, acute exposure to acrylonitrile results in

characteristics of cyanide-type toxicity. Symptoms in humans associated

with acrylonitrile poisoning include limb weakness, labored and

irregular breathing, dizziness and impaired judgment, cyanosis, nausea,

collapse, and convulsions (Baxter 1979). However, the doses that

produce these effects were not clearly defined. Workers exposed to 16

to 100 ppm for 20 to 45 minutes complained of headaches and nausea,

apprehension and nervous irritation (Wilson et al. 1948). The workers

exposed to acrylonitrile vapors fully recovered. In a study with human

volunteers exposed to acrylonitrile at doses of 2.3 and 4.6 ppm, no

symptoms attributable to effects on the nervous system were observed

(Jakubowski et al. 1987). The dose of 4.6 ppm was used to calculate the

acute inhalation MRL of 0.1 ppm, as described in the footnote in

Table 2-l. 

Animals exposed to acrylonitrile usually display acute neurological

symptoms. Dogs appear to be particularly sensitive. Excessive

salivation in dogs occurred at concentrations of 30 ppm of

acrylonitrile, and paralysis of the hind limbs occurred at 100 ppm. In

cats, excessive salivation occurred at 100 ppm; at 275 ppm animals were

observed to paw their heads and stomachs and howl as if in pain. In

monkeys, "weakness" was reported at 90 ppm, but higher doses were not

tested. Guinea pigs showed no measurable signs of neurological effects

from acute exposure to acrylonitrile at a dose that caused death 
22 

2. HEALTH EFFECTS 

(575 ppm) (Dudley and Neal 1942). It should be noted that this study is

based on nominal concentrations with no analytical verification.

Therefore, the overall usefulness of the study is limited. 

Chronic exposure of rats to 80 ppm acrylonitrile resulted in focal

gliosis and perivascular cuffing in the brain (Quast et al. 1980a). The

gliosis appeared to be a pre-malignant lesion related to the formation 

of brain tumors, and is discussed in more detail in Section 2.2.1.8

(below). 

The highest NOAEL values and all reliable LOAEL values for

neurological effects are recorded in Table 2-l and plotted Figure 2-l. 

2.2.1.5 Developmental Effects 

Inhalation exposure to acrylonitrile results in teratogenic effects

in rats. Inhalation of 80 ppm acrylonitrile during days 6 to 15 of

gestation (the critical period of organogenesis) resulted in a

significant increase in fetal malformations. These malformations

included short tail, missing vertebrae, short trunk, omphalocele and

hemivertebra. In this well-conducted study, mean number of

implantations, live fetus and resorptions were not significantly altered

by exposure to 40 or 80 ppm of acrylonitrile. No effects on fetal body

size were evident. Maternal toxicity was observed at both dose levels

tested (40 and 80 ppm), as evidenced by decreased weight gain (Murray

et al. 1978). 

2.2.1.6 Reproductive Effects 

No studies were located regarding reproductive effects in humans or

animals following inhalation exposure to acrylonitrile. 

2.2.1.7 Genotoxic Effects 

Factory workers exposed for an average of 15 years to acrylonitrile

vapors showed no increase in chromosomal aberrations in the peripheral

lymphocytes (Thiess and Fleig 1978). As in most human studies, the

actual concentration of acrylonitrile to which these workers were

exposed was not reported. However, monitoring data indicated that the

average exposure concentration for the workers was 5 ppm for the

majority of the exposure period (approximately 10 years); at the time

the study was conducted, acrylonitrile levels in the workplace had been

reduced to 1.5 ppm. 

No studies were located regarding genotoxic effects in animals

following inhalation exposure to acrylonitrile. 
23 

2. HEALTH EFFECTS 

2.2.1.8 Cancer 

A number of epidemiological studies have been conducted to evaluate

the association between lung cancer and occupational exposure to

acrylonitrile (Collins et al. 1989; Delzell and Monson 1982; Kiesselbach

et al. 1979; O'Berg 1980; O'Berg et al. 1985). However, many of the

studies suffer from deficiencies such as an insufficient quantification

of exposure, short follow-up, small and relatively youthful cohorts or

lack of consideration of the effects of smoking, and the results of the

studies are often inconsistent. 

The most reliable of the epidemiology studies on acrylonitrile is

that conducted by O'Berg (1980) in which 1,345 male workers in a textile

factory were followed over a period of 25 years. Exposures to

acrylonitrile were divided into three groups (low, medium and high),

although quantitative estimates of exposure levels were not assigned.

O'Berg (1980) concluded that there may be an association between human

lung cancer and acrylonitrile inhalation exposure. The incidence of

cancer did not increase significantly in exposed workers over the

unexposed population. The data from this on-going study were updated by

O'Berg et al. (1985) to include an additional 7 years of follow-up.

Though an increased incidence of lung cancer in workers exposed to

acrylonitrile was observed, the effect was not as pronounced as it had

been in the previous report. The authors concluded that continued

follow-up was needed. 

Statistically significant cancer excesses have been observed in

other studies; however, due to limitations in the studies firm

conclusions cannot be made. In an analysis of mortality among 327

rubber workers, nine deaths from lung cancer were observed compared to

4.7 to 5.9 expected deaths among the general population and other rubber

workers (Delzell and Monson 1982). The observed and expected numbers of

death were small and the study did not evaluate cigarette smoking as a

confounding factor contributing to excess death. 

Another well-designed epidemiology study (Collins et al. 1989) did

not find an increased risk of lung cancer from acrylonitrile exposure.

In this study, 2,671 males (1,774 with known acrylonitrile exposure)

were followed for 32 years. Workers in acrylic fiber manufacturing

plants were categorized into four dose ranges (expressed in ppm/year).

Smoking histories were taken into consideration. No significant

relationship between lung cancer and acrylonitrile exposure was

established, although the authors found some evidence in this study of

confounding association between smoking status and cumulative exposure

to acrylonitrile. In this study, as in the previously discussed studies

(O'Berg 1980; O'Berg et al. 1985), the subjects were relatively young, 
24 

2. HEALTH EFFECTS 

and only 9% of the cohort had died. Additional follow-up will be

necessary to determine whether death can be associated with cancers

resulting from acrylonitrile exposure. 

Epidemiology studies have also suggested a possible association

between acrylonitrile exposure and prostate cancer (Chen et al. 1987;

O'Berg et al. 1985), but the data are too limited to warrant any firm

conclusion. Collins et al. (1989) found no increase in prostate cancer

in acrylonitrile-exposed workers, but again the data are too limited to

be meaningful. 

Deaths from cancer of the stomach were statistically elevated in

one study of six manufacturing plants in the United Kingdom involved in

the polymerization of acrylonitrile and the spinning of acrylic fibers

(Werner and Carter 1981). No quantitative data on the exposure levels

to acrylonitrile were given and the numbers of expected deaths was too

small to provide confidence in the results. 

In animals, chronic studies provide convincing evidence that

acrylonitrile is carcinogenic when administered by the inhalation route

of exposure. Tumors in the brain, Zymbal gland and mammary glands in

rats exposed to acrylonitrile for 2 years were reported by both Quast

et al. (1980a) and Maltoni et al. (1988). Quast et al. (1980a) reported

two types of lesions in the central nervous system: astrocytomas and

focal or multifocal glial cell proliferation. The glial cell

proliferation was considered to be a microscopic change suggestive of

early tumorigenesis. Brain tumors were observed in males exposed to

80 ppm of acrylonitrile, and in females at 20 and 80 ppm. In addition,

Quast et al. (1980a) reported tumors of the tongue and small intestine

in males (80 ppm). Maltoni et al. (1988) noted tumors in the liver

(60 ppm). 

2.2.2 Oral Exposure 

No studies were located regarding health effects in humans

associated with the oral ingestion of acrylonitrile. Table 2-2 and

Figure 2-2 summarize the health effects observed in experimental animals

following oral exposure to acrylonitrile. These effects are discussed

below. 

2.2.2.1 Death 

The acute oral LD50 has been estimated to be 93 mg acrylonitrile/kg

body weight (mg/kg) in rats (Back et al. 1972) and 27 mg/kg for mice

(Ahmed and Pate1 1981). Longer term intake (6 months) in dogs at

16 mg/kg/day resulted in early deaths. Animals lost weight and were

described as depressed, lethargic, weak and emaciated prior to death. 








33 

2. HEALTH EFFECTS 

Chronic studies in rats indicate that lifetime exposure to doses of

4.4 mg acrylonitrile/kg body weight/day (mg/kg/day) or higher may result

in premature death (Bio/dynamics 1980a, 1980b, 1980c; Gallagher et al.

1988; Quast et al. 1980b). The cause of death was not specifically

identified. 

The highest NOAEL values and all reliable LOAEL values for death in

each species and duration category are recorded in Table 2-2 and plotted

in Figure 2-2. 

2.2.2.2 Systemic Effects 

Respiratory Effects. Chronic oral exposure of animals to low

levels of acrylonitrile has not been found to result in damage to the

lungs. Histopathological evaluation of lung tissues from rats showed no

lung injury at doses up to 25 mg/kg/day for 2 years (Bio/dynamics 1980a,

1980b, 1980c; Quast et al. 1980b). 

Cardiovascular Effects. No injury to the cardiovascular system has

been detected in studies in animals. No effects were seen in dogs

exposed to 18 mg/kg/day in drinking water for 6 months (Quast et al.

1975). In chronic studies in rats exposed to 14 mg/kg/day in drinking

water (Bio/dynamics 1980b) or by gavage (Bio/dynamics 198Oc), an

increased heart-to-body-weight ratio was observed. However, the effects

were not seen in other studies where acrylonitrile was given to rats in

drinking water (Bio/dynamics 1980a; Quast et al. 1980b). No

histopathological changes were reported in heart tissues in any of the

chronic studies (Bio/dynamics 1980a, 1980b, 1980c; Quast et al. 1980b). 

The highest NOAEL values and all reliable LOAEL values for

cardiovascular effects in each species and duration category are

recorded in Table 2-2 and plotted in Figure 2-2. 

Gastrointestinal Effects. Studies in animals suggest that oral

exposure to acrylonitrile is irritating to the esophagus and stomach.

An acute oral dose of acrylonitrile resulted in hemorrhagic necrosis of

the forestomach of rats (Szabo et al. 1984). In dogs given

acrylonitrile in drinking water for 6 months at 16 mg/kg/day, gross and

microscopic evaluation showed focal erosions and ulcerations in the

esophagus (Quast et al. 1975). The authors considered these lesions to

be due to irritation to the mucous membranes, No esophageal lesions

were present at 10 mg/kg/day. Rats given acrylonitrile in drinking

water for 50 weeks at doses up to 70 mg/kg/day showed no effects on the

gastrointestinal tract (Beliles et al. 1980), indicating that rats are

less sensitive to this effect than dogs. Rats exposed to acrylonitrile

in drinking water for 2 years developed papillomatous proliferations of

the epithelium of the forestomach at a dose of 28 mg/kg/day, but not at 
34
 

2. HEALTH EFFECTS
 

7.1 mg/kg/day (Gallagher et al. 1988). This effect is discussed under

Section 2.2.2.8 below. Nonproliferative effects on the stomach were not

reported. 

The method by which an oral dose is administered may also determine

whether gastrointestinal effects occur. While no effects were observed

in rats given acrylonitrile in drinking water at doses up to

70 mg/kg/day for 50 weeks (Beliles et al. 1980), administration by

gavage of 25 mg/kg/day acrylonitrile to rats for 10 days resulted in

thickening of the nonglandular portion of the stomach (Murray et al.

1978). A single gavage dose of 50 mg/kg to rats was reported to cause

gastrointestinal bleeding, as measured by increased heme content in the

gastrointestinal tract (Ghanayem and Ahmed 1983). 

The highest NOAEL values and all reliable LOAEL values for gastrontestinal effects in each species and duration category are recorded in Table

2-2 and plotted in Figure 2-2. 

Hematological Effects. Decreased red blood cell counts, hematocrit,

and hemoglobin content have been reported following acute, intermediate

and chronic oral studies in animals (Bio/dynamics 1980a, 1980b,

198Oc; Farooqui and Ahmed 1983a; Quast et al. 1975). Although the

mechanism of these hemotoxic effects is not clear, Farooqui and Ahmed

(1983) found that acrylonitrile bound covalently both to red blood cell

membranes and to hemoglobin. In dogs administered acrylonitrile at

doses up to 18 mg/kg/day for 6 months, decreased red cell counts,

hematocrit, and hemoglobin content were seen only in animals that died

(Quast et al. 1975). In chronic studies in rats, lower red cell

parameters were seen at 14 mg/kg/day, but these effects were not

specifically identified with animals that died during the study

(Bio/dynamics 1980a, 1980b, 1980c). In another chronic study in rats at

doses up to 25 mg/kg/day for 2 years, no effects on red cell parameters

were observed, though early deaths were observed in the study (Quast

et al. 1980b). Based on lower red cell parameters (Bio/dynamics 1982a),

a chronic oral MRL of 0.04 mg/kg/day was calculated as described in the

footnote in Table 2-2. 

The highest NOAEL values and all reliable LOAEL values for

hematological effects in each species and duration category are recorded

in Table 2-2 and plotted in Figure 2-2. 

Musculoskeletal Effects. No studies were located regarding

musculoskeletal effects in humans or animals following oral exposure to

acrylonitrile. 
35 

2. HEALTH EFFECTS 

Hepatic Effects. Although acrylonitrile is metabolized by the

liver to potentially toxic metabolites (see Section 2.3.3), the liver

does not appear to be an important target organ for acrylonitrile

toxicity (Silver et al. 1982). In chronic studies in rats, microscopic

examination of liver tissue showed no damage after 2 years of exposure

to acrylonitrile at doses up to 25 mg/kg/day (Bio/dynamics 1980a, 1980b,

198Oc; Quast et al. 1980b). 

Some effects in the liver have been reported, but they may be

adaptive changes related to increased metabolic activity. Increased

glutathione levels were reported at doses of 70 mg/kg/day for 21 days

(Szabo et al. 1977). Because the metabolism of acrylonitrile includes

pathways that utilize glutathione (see Section 2.3.3), the higher

glutathione levels in the liver may be due to increased demand for

glutathione for the metabolism of acrylonitrile. 

A consistent observation in rats exposed to acrylonitrile was

increased liver weight, both in acute studies at 65 mg/kg/day (Murray

et al. 1978) and chronic studies at 10 mg/kg/day (Bio/dynamics 1980a,

1980b, 1980c). Again, this may be an adaptive change related to

increased metabolic activity by the liver due to the presence of

acrylonitrile in the body. 

The highest NOAEL values and all reliable LOAEL values for hepatic

effects in each species and duration category are recorded in Table 2-2

and plotted in Figure 2-2. 

Renal Effects. No adverse effects on the renal system have been

reported in animals administered acrylonitrile via the oral route. In

chronic studies in rats, increased kidney weights relative to body

weight were observed (Bio/dynamics 1980a, 1980b, 1980c). However, the

significance of this observation, if any, is not known, because no

histopathological, blood chemistry, or urinalysis findings suggestive of

kidney injury were observed in intermediate and chronic studies in rats

or dogs (Bio/dynamics 1980a, 1980b, 1980c; Quast et al. 1975, 1980b). 

The highest NOAEL values and all reliable LOAEL values for renal

effects in each species and duration category are recorded in Table 2-2

and plotted in Figure 2-2. 

Dermal/Ocular Effects. No studies were located regarding dermal or

ocular effects in humans or animals following oral exposure to

acrylonitrile. 
36 

2. HEALTH EFFECTS 

Other Systemic Effects. Decreased adrenal weight, adrenal atrophy,

and decreased aldosterone and corticosterone levels in plasma were

observed in rats administered acrylonitrile in drinking water for

3 weeks at 70 mg/kg/day (Szabo et al. 1984). Similar effects were

observed when the dosing period was extended to 60 days (Szabo et al.

1984). However, no effects on adrenal weight or histopathology of the

adrenals were observed in several chronic studies in which doses were 

similar to the 21- and 60-day studies by Szabo et al. (1984)

(Bio/dynamics 1980a, 1980b, 198Oc; Quast et al. 1980b). 

The highest NOAEL values and all reliable LOAEL values for other

systemic effects in each species and duration category are recorded in

Table 2-2 and plotted in Figure 2-2. 

2.2.2.3 Immunological Effects 

No studies were located regarding immunologic effects in humans or

animals following oral exposure to acrylonitrile. 

2.2.2.4 Neurological Effects 

Exposure to acrylonitrile caused effects similar to those of

cyanide poisoning. Intermediate and chronic exposure of animals to

acrylonitrile resulted in decreased activity and depression (Beliles et

al. 1980; Bigner et al. 1986; Quast et al. 1975). Species differences

are apparent, dogs being more susceptible than rats. In dogs

administered acrylonitrile for 6 months at 16 mg/kg/day, depression and

lethargy were reported, with the majority of the experimental groups

animals dying before the end of the study period (Quast et al. 1975).

In rats, acute exposure results in a transient cholinomimetic

stimulatory phase (salivation, diarrhea, lachrymation, vasodilation),

followed by a central nervous system depression (Ahmed and Farooqui

1982; Ahmed and Pate1 1981). In rats exposed for 1 to 2 years at

70 mg/kg/day, decreased activity, abnormal gait, and prostration were

noted but no deaths were reported (Beliles et al. 1980; Bigner et al.

1986). No histopathological changes in the nervous system were reported

except those related to tumor formation (see Section 2.2.2.8) (Beliles

et al. 1980). 

The highest NOAEL values and all reliable LOAEL values for

neurological effects in each species and duration category are recorded

in Table 2-2 and plotted in Figure 2-2. 
37 

2. HEALTH EFFECTS 

2.2.2.5 Developmental Effects 

Oral exposure to acrylonitrile has been shown to result in

teratogenic effects in rats (Murray et al. 1978). Oral administration

of 25 mg/kg/day of acrylonitrile during days 6 to 15 of gestation

resulted in an increased incidence of malformations. Although the

incidence of malformations at 25 mg/kg/day was not statistically

significant, the authors considered them related to the administration

of acrylonitrile. At a higher dose (65 mg/kg/day), the increase in

malformations was statistically significant, and the same malformations

were seen at both doses. Statistically significant lowered fetal body

weight and shorter crown-rump length also were observed at 65 mg/kg/day.

The number of live pups and resorption per litter were not affected by

the administration of acrylonitrile. In this study a NOAEL of

10 mg/kg/day was established. Based on this value an acute oral MRL of

0.1 mg/kg/day was calculated as described in the footnote in Table 2-2.

The highest NOAEL values and all reliable LOAEL values for

developmental effects in each species and duration category are recorded

in Table 2-2 and plotted in Figure 2-2. 

2.2.2.6 Reproductive Effects 

In a three-generation reproduction study in rats, Beliles et al. 

(1980) found that exposure of animals to acrylonitrile in drinking water

at 70 mg/kg/day resulted in reduced viability and lactation indices in

all generations. The authors considered the reduced pup indices to be

the result of maternal toxicity, possibly related to reduced milk

production due to decreased water intake by the dams. Fostering of pups

on untreated dams lessened pup mortality. Measurement of acrylonitrile

in the pups was not performed. 

Animal studies suggest possible effects of acrylonitrile on the

male reproductive system. Tandon et al. (1988) observed histological

and biochemical evidence of degenerative changes in testicular tubules

of mice exposed to 10 mg/kg/day of acrylonitrile for 60 days. These

changes were accompanied by a 45% decrease in sperm count. Whether the

tubular changes or the decreased sperm count have an effect on fertility

is not known because no studies have been conducted to evaluate the 

effects of acrylonitrile on the reproductive capability of treated mice.

Based on the reduced sperm count and the degenerative changes in

testicular tubules, an intermediate oral MRL of 0.01 mg/kg/day was

calculated as described in the footnote in Table 2-2. 

There appear to be significant inter-species differences with

respect to histopathological effects of acrylonitrile on the male

reproductive system. Histological examination did not reveal testicular

degeneration in rats or dogs given acrylonitrile for 2 years

(Bio/dynamics 1980a, 1980b, 198Oc; Quast et al. 1975, 1980b), although 
38 

2. HEALTH EFFECTS 

an increase in testicular weight was observed in rats given

acrylonitrile in drinking water at doses of 14 mg/kg/day for 2 years

(Bio/dynamics 1980a). The biological significance of this effect is not

clear, because this was observed in only one chronic drinking water

study in rats, and was not observed in a gavage study in the same strain

of rat (Spartan) or at comparable doses in Fisher 344 rats (Bio/dynamics

1980b, 1980c). 

The highest NOAEL values and all reliable LOAEL values for

reproductive effects in each species and duration category are recorded

in Table 2-2 and plotted in Figure 2-2. 

2.2.2.7 Genotoxic Effects 

In vivo studies in animals suggest that oral exposure to acrylonitrile

has limited genotoxic potential. Acrylonitrile produced no

significant increase in chromosomal aberrations in bone marrow cells

from rats administered up to 21 mg/kg/day (Rabello-Gay and Ahmed 1980),

and no significant effect in a dominant lethal assay in rats at doses up

to 60 mg/kg/day (Working et al. 1987). Studies on unscheduled DNA

synthesis in liver and brain of rats exposed to doses of 50 mg/kg showed

increased DNA synthesis in the liver but not in the brain, suggesting

limited potential for acrylonitrile to be genotoxic (Hogy and Guengerich

1986). However, unscheduled DNA synthesis was not observed in an

in vivo spermatocyte assay in rats exposed to 60 mg/kg/day (Hurtt et al.

1987). 

2.2.2.8 Cancer 

No studies were located regarding cancer in humans following oral

exposure to acrylonitrile. 

Chronic studies in rats provide convincing evidence that

acrylonitrile is carcinogenic to animals when administered orally

(Beliles et al. 1980; Bigner et al. 1986; Bio/dynamics 1980a, 1980b,

198Oc; Gallagher et al. 1988; Quast et al. 1980a). Tumors of the

central nervous system and Zymbal gland were identified in most studies

at doses of 1.4 mg/kg/day and higher. Tumors of the gastrointestinal

tract (forestomach, intestines) and mammary gland (in females) were also

common at doses of 3.4 mg/kg/day or higher (Bigner et al. 1986;

Bio/dynamics 1980a, 198Oc; Maltoni et al. 1977; Quast et al. 1980b).

Gallagher et al. (1988) noted a dose-dependent decrease in the number of

rats with pituitary tumors (mainly prolactinomas) following chronic oral

exposure to acrylonitrile in drinking water. 
39 

2. HEALTH EFFECTS 

2.2.3 Dermal Exposure 

2.2.3.1 Death 

The death of a 10-year-old girl following dermal exposure to

acrylonitrile was reported by Lorz (1950). An acrylonitrile preparation

had been applied to the scalp of the child as a treatment for head lice.

The child experienced nausea, headache and dizziness. Death occurred

4 hours after application. The concentration was not specified in this

case report. 

In guinea pigs, the dermal LD50 was reported to be 370 mg/kg

(Roudabush et al. 1965). Values of 226 to 250 mg/kg have been noted in

rabbits (Back et al. 1972; Roudabush et al. 1965). 

The highest NOAEL values and all reliable LOAEL values for death in

each species and duration category are recorded in Table 2-3. 

2.2.3.2 Systemic Effects 

No studies were located regarding systemic effects in animals

following dermal exposure to acrylonitrile. 

In humans, one study of a worker accidentally sprayed with

acrylonitrile indicated that transient injury to liver and muscle may

have occurred, but the data are too limited to draw any firm conclusions

(Vogel and Kirkendall 1984). 

Workers exposed to acrylonitrile vapors at 16 to 100 ppm for 20 to

45 minutes complained of intolerable itching of the skin, but no

dermatitis was observed (Wilson et al. 1948). This is presumably a

direct irritant effect of acrylonitrile on the skin. 

In a study of Japanese workers exposed to acrylonitrile, irritation

of the conjunctiva and upper respiratory tract was reported. Workers

who may have been exposed to particularly high concentrations (inside

polymerization tanks) experienced transient irritation of the scrotal

skin. No concentrations of acrylonitrile were specified (Sakurai et al.

1978). 

2.2.3.3 Immunological Effects 

No studies were located regarding immunological effects in humans

or animals following dermal exposure to acrylonitrile. 

41 

2. HEALTH EFFECTS 

2.2.3.4 Neurological Effects 

Signs of cyanide poisoning were exhibited by a man accidentally

sprayed with acrylonitrile. Dizziness, redness, nausea, vomiting and

hallucinations were reported (Vogel and Kirkendall 1984). The symptoms

persisted for 3 days. 

No studies were located regarding the following health effects in

humans or animals after dermal exposure to acrylonitrile. 

2.2.3.5 Developmental Effects 

2.2.3.6 Reproductive Effects 

2.2.3.7 Genotoxic Effects 

2.2.3.8 Cancer 

2.3 TOXICOKINETICS 

2.3.1 Absorption 

2.3.1.1 Inhalation Exposure 

In a well-controlled and conducted study with human volunteers,

Jakubowski et al. (1987) reported that an average of 52% of the inhaled

dose of acrylonitrile (5 or 10 mg/m3

) is absorbed by the lungs. Similar

results were reported by Rogaczewska and Piotrowski (1968), who found

that 46% of inhaled acrylonitrile is retained by the lungs of humans. 

Pilon et al. (1988b) demonstrated in rats exposed to 4 mg/kg

acrylonitrile (2,3-14C) in a closed-circuit inhalation chamber that the

absorption of acrylonitrile was biphasic, characterized by a rapid dosedependent phase that was followed by a slower dose-independent phase. 

2.3.1.2 Oral Exposure 

No studies were located regarding absorption in humans following

oral exposure to acrylonitrile. 

Results of studies in laboratory animals with 14C-acrylonitrile

indicate acrylonitrile is rapidly and extensively absorbed by the oral

route. Radiolabeled acrylonitrile is detected in blood within

30 minutes after administration of an oral dose and peak plasma

concentrations are reached 6 hours after administration (Farooqui and

Ahmed 1982). Extensive absorption is indicated by the fact that only 2

to 10% of administered radioactivity is recovered in the feces (Ahmed

et al. 1982, 1983; Farooqui and Ahmed 1982; Young et al. 1977). 
42 

2. HEALTH EFFECTS 

2.3.1.3 Dermal Exposure 

In studies in human volunteers conducted by Rogaczewska and

Piotrowski (1968), absorption by skin was estimated to be 0.6 mg/cm2

/hr.

Though no quantitative estimates of dermal absorption could be made,

absorption of acrylonitrile via the dermal route by humans was

demonstrated in a case study by Vogel and Kirkendall (1984). Accidental

spraying of a man with acrylonitrile resulted in marked symptoms of

acrylonitrile toxicity, indicating that significant amounts of

acrylonitrile had been absorbed, primarily through the skin. 

No studies were located regarding absorption in animals following

dermal exposure to acrylonitrile. 

2.3.2 Distribution 

2.3.2.1 Inhalation Exposure 

No studies were located regarding distribution of acrylonitrile in

humans following inhalation exposure to acrylonitrile. 

Acrylonitrile is rapidly distributed throughout the body after

inhalation exposure. Measurable amounts of acrylonitrile derived

radiolabel were present in the brain, stomach, liver, kidney, lung and

blood within 1 hour of initiation of exposure (Pilon et al. 1988b). 

2.3.2.2 Oral Exposure 

Tissue distribution of radioactivity in rats after a single oral

dose of 14C-acrylonitrile indicates that acrylonitrile and its

metabolites are rapidly distributed to all tissues (Ahmed et al. 1982,

1983; Silver et al. 1987; Young et al. 1977). Species differences are

apparent. In mice, cyanide levels in the blood peaked at 1 hour, while

in rats peak levels were not reached until 3 hours after administration

(Ahmed and Pate1 1981). The highest levels of radioactivity were

recovered in the gastrointestinal tract, in particular in the stomach.

The retention of acrylonitrile and its metabolites in the stomach

appears to be due, at least in part, to covalent binding (Ahmed et al.

1982; Silver et al. 1987). Young et al. (1977) noted that label

accumulated in the stomach following intravenous as well as oral

exposure to 14C-acrylonitrile, suggesting that enterogastric circulation

may be important in the preferential retention in the stomach. 

Distribution studies by whole-body autoradiography in rats and

monkeys revealed accumulation of radiolabel in the liver, kidney, lung,

adrenal cortex and stomach. In fetuses exposed in utero, only the eye

lens accumulated radiolabel at a higher concentration than that observed

in maternal blood (Sandberg and Slanina 1980). 
43 

2. HEALTH EFFECTS 

2.3.2.3 Dermal Exposure 

No studies were located regarding distribution in humans or animals

following dermal exposure to acrylonitrile. 

2.3.3 Metabolism 

Proposed pathways for the metabolism of acrylonitrile are presented

in Figure 2-3 (Ahmed et al. 1983; EPA 1980a; Langvardt et al. 1980;

Linhart et al. 1988; Muller et al. 1987; Pilon et al. 1988a; Roberts

et al. 1989). Studies indicate that the metabolism of acrylonitrile in

animals proceeds by the same pathways whether exposure is by the oral

(Ahmed et al. 1983; Langvardt et al. 1980; Pilon et al. 1988a) or the

inhalation route (Gut et al. 1985; Muller et al. 1987; Tardif et al.

1987). No data were located regarding the metabolism of acrylonitrile

following dermal exposure. 

Both enzymatic and nonenzymatic biotransformation of acrylonitrile

occurs. Acrylonitrile is capable of covalently binding to proteins and

other macromolecules such as lipids or nucleic acids, or acrylonitrile

can also be directly conjugated to glutathione and excreted in urine as

cyanoethylmercapturic acid. 

Alternatively, acrylonitrile is metabolized to 2-cyanoethylene

oxide by the microsomal enzyme system. 2-Cyanoethylene oxide can react

directly with tissue macromolecules or it can be further metabolized to

oxidation products that release cyanide. Cyanide is converted to

thiocyanate and excreted in the urine. 2-Cyanoethylene oxide is also

conjugated with glutathione and metabolized to 2-hydroxyethylmercapturic

acid which is excreted in the urine. 

Acrylonitrile is also metabolized to CO2 which is eliminated 

through the lungs. Carbon dioxide is produced when acrylonitrile is

metabolized to ethylene oxide and degraded to oxidation products and

cyanide via the epoxide hydratase pathways (Farooqui and Ahmed 1982;

Young et al. 1977). 

Studies indicate that acrylonitrile conjugation with glutathione is

the preferred pathway for metabolism (Ghanayem and Ahmed 1982; Miller

and Villaume 1978; Pilon et al. 1988a). However, if glutathione is

depleted or the pathway is overloaded (as may be the case at high

doses), metabolism to the thiocyanate via 2-cyanoethylene oxide is

increased. Increased thiocyanate excretion with glutathione depletion

or increased dose was demonstrated by Pilon et al. (1988a). Glutathione 

45 

2. HEALTH EFFECTS 

depleted rats excreted 58% of an orally administered dose as

thiocyanate, while normal rats given the same dose (4 mg/kg) of

acrylonitrile excreted only 23% as thiocyanate. Normal rats given

acrylonitrile at 4 or 10 mg/kg excreted 16% and 23% of the dose as

thiocyanate, respectively. 

The increased metabolism of acrylonitrile to 2-cyanoethylene oxide

has significant implications in acrylonitrile toxicity. 2-Cyanoethylene

oxide has been shown to react with cell macromolecules (including

nucleic acids) both in vivo and in vitro (Guengerich et al. 1981; Hogy

and Guengerich 1986). This metabolite may be responsible for the

carcinogenic effects of acrylonitrile. 

Urinary excretion patterns of thiocyanate suggest that there are

quantitative species differences in acrylonitrile metabolism (Ahmed and

Pate1 1981). Thiocyanate was identified as a metabolite in rats, mice,

rabbits and Chinese hamsters. About 20 to 23% of the administered dose 

was excreted as thiocyanate in rats, rabbits and Chinese hamsters, while

35% was excreted as thiocyanate in mice (Gut et al. 1975). It has also

been observed that mice metabolize acrylonitrile more rapidly than rats

(Ahmed and Pate1 1981; Gut et al. 1975). Maximum blood cyanide

concentrations were observed 1 hour after dosing in mice, but 3 hours

after dosing in rats (Ahmed and Pate1 1981). In mice, thiocyanate was

present in the urine within 4 hours of dosing, while in rats,

thiocyanate was present in urine only at time intervals longer than

4 hours (Gut et al, 1975). 

In humans, metabolites of acrylonitrile have been identified in

urine following occupational exposure (assumed to be by the inhalation

route), and also in controlled exposure studies. Metabolites identified

in humans were the same as those in animals (Jakubowski et al. 1987;

Sakurai et al. 1978). Acrylonitrile and thiocyanate were quantified in

urine of workers exposed to acrylonitrile. Dose-related increases in

thiocyanate were observed, indicating that cyanide is liberated with the

metabolism of acrylonitrile. In a study with human volunteers under

controlled conditions, 2-cyanoethylmercapturic acid (CMA) was monitored

in urine as an indication of exposure. On average, 22% of the absorbed

acrylonitrile was metabolized to CMA; however, considerable individual

variability was observed. The CMA excretion ranged from 13% to 39% of

the absorbed dose (Jakubowski et al. 1987). 

In a case study of a human male accidentally sprayed with

acrylonitrile, recurring signs of cyanide poisoning were seen over a

3 day period (Vogel and Kirkendall 1984). This indicates that

acrylonitrile is also metabolized to cyanide following predominantly

dermal exposure. 
46 

2. HEALTH EFFECTS 

2.3.4 Excretion 

2.3.4.1 Inhalation Exposure 

Studies on workers in an occupational setting showed a doseresponse relationship between the concentration of acrylonitrile of

inspired air and the recovery of metabolites in the urine (Houthuijs

et al. 1982; Sakurai et al. 1978). In a controlled study using human

volunteers, urinary metabolite data suggested that the elimination of

acrylonitrile followed first-order kinetics, with a half-life of seven

to eight hours (Jakubowski et al. 1987). 

The predominant route of excretion in rats is via urine (Gut et al.

1985; Tardif et al. 1987; Young et al. 1977). In rats exposed to 5 ppm

of l-14C-acrylonitrile for 6 hours, 68% of the absorbed radioactivity

was excreted in the urine within 220 hours, with 3.9% in the feces, 6.1%

in expired air as 14C02, and 18% of the radioactivity being retained in

the body tissues. Following exposure to a higher concentration

(100 mm), a larger fraction of the dose was recovered in urine (82%)

and a smaller fraction (2.6%) was retained in the body (Young et al.

1977), indicating that urinary excretion is dose-dependent. Percent

fecal excretion was similar at both doses. 

2.3.4.2 Oral Exposure 

Following oral exposure, the major route of excretion of

acrylonitrile in rats is via the urine, either as thiocyanate or as

other products of conjugation. Within the first 24 hours of a single

oral dose, 40% to 60% was recovered in the urine (Ahmed et al. 1983).

Farooqui and Ahmed (1982) reported that 10 days after the administration

of a single dose, 61% of the dose had been accounted for in the urine,

3% in feces and 13% in the expired air. Approximately 25% was retained

in the body covalently bound to tissues (see Section 2.3.3). 

A study by Young et al. (1977) showed that retention and excretion

of acrylonitrile are not directly proportional to dose. The data

suggest a saturation process, perhaps due to covalent binding to tissue

macromolecules. Seventy-two hours after administration of single oral

doses of either 0.1 or 10 mg/kg, the proportion of the dose retained in

the carcass was 37% at the low dose (0.1 mg/kg) and 27% at the high dose

(10 mg/kg). 

2.3.4.3 Dermal Exposure 

No studies were located regarding excretion in humans or animals

following dermal exposure to acrylonitrile. 
47 

2. HEALTH EFFECTS 

2.4 RELEVANCE TO PUBLIC HEALTH 

Acrylonitrile is a common industrial chemical, and humans may be

exposed to acrylonitrile around factories where it is made or used, or

near chemical waste sites where it has been improperly stored or

disposed of. The two most likely exposure pathways are breathing

acrylonitrile that has evaporated into air (it is readily volatile), or

drinking water that has been contaminated (acrylonitrile is highly

soluble and stable in water). However, data describing acrylonitrile

levels in drinking water are currently lacking. The low odor threshold

of acrylonitrile in water (19 ppm) could limit exposure to this

substance through contaminated drinking water. 

Short exposures at high concentrations show cyanide-type toxicity.

In humans, symptoms include headaches, feelings of nausea, irritability,

and apprehension. These symptoms are reversible. However, prolonged

exposure can result in death. Limited data suggest that children may be

more susceptible to acrylonitrile toxicity than adults. However,

current data are not significant to draw firm conclusions. In animals,

acrylonitrile has been shown to result in teratogenic effects when

administered by either the inhalation or oral routes of exposure.

Impaired reproductive capability has also been demonstrated in mice.

Exposures high enough to cause neurological, developmental, or

reproductive effects in humans are rather unlikely to occur except in

cases of spills or accidents. 

Epidemiologic studies have associated acrylonitrile exposure in the

workplace with increased incidence of lung cancer and possibly prostate

cancer. Because only six cases of prostate cancer were observed and all

were found in workers at ages when the incidence rate increases, firm

conclusions cannot be made about the potential for acrylonitrile to

cause prostate cancer. In animals, acrylonitrile has been demonstrated

to cause tumors at multiple sites, including the nervous system,

gastrointestinal tract, Zymbal gland and mammary gland. Because of this

clear carcinogenic potential, chronic low-level exposure to

acrylonitrile is of special concern. 

Death. Several cases of death in children following inhalation or

dermal exposure to acrylonitrile has been reported (Grunske 1949; Lorz

1950). Children seem to be more susceptible to the lethal effect of

acrylonitrile than adults. However, current data are not sufficient to

draw firm conclusions regarding risk. In the case studies where

children had died after sleeping in rooms fumigated with acrylonitrile,

the adults that shared the quarters reported few, if any, effects. 
48 

2. HEALTH EFFECTS 

In animals, deaths from acrylonitrile have been reported in several

species following inhalation, oral or dermal exposure. In most species,

death appears to be related to cyanide poisoning. That the cyanide

moiety is involved in human toxicity of acrylonitrile has been reported

in a case study in which a human male was sprayed with acrylonitrile

when a valve burst (Vogel and Kirkendall 1984). This individual

suffered symptoms characteristic of cyanide poisoning, and treatments

designed to reduce cyanide levels in the blood were required in order to

save his life. 

Systemic Effects. Humans exposed to high levels of acrylonitrile

in the workplace have complained of nasal irritation and an oppressive

feeling in the upper respiratory passages (Wilson 1944; Wilson et al.

1948). Acute exposure of guinea pigs to acrylonitrile has resulted in

severe pulmonary irritation and lung edema. In other species, only mild

pulmonary irritation has been reported (Dudley and Neal 1942). Chronic

exposure to acrylonitrile via inhalation has resulted in degenerative

and inflammatory changes in the nasal passages in rats (Quast et al.

1980a). The concentrations at which these effects have been seen in

animals are irritating to the respiratory tract of humans. 

The gastrointestinal tract does not appear to be a target organ of

acrylonitrile toxicity in humans. In animals, noncarcinogenic lesions

in the esophagus and stomach suggest an irritational effect on the 

gastrointestinal tract (Murray et al. 1978; Quast et al. 1975).

However, several investigators (Cote et al. 1984; Ghanayem and Ahmed

1983; Ghanayem et al. 1985; Szabo et al. 1983) have demonstrated that

gastrointestinal bleeding and duodenal ulcers may occur even when rats

were given acrylonitrile by routes other than oral, suggesting that the

effects on the gastrointestinal tract may not be due exclusively to

irritation. More study is needed in this area before any conclusions

about the relevance to human health can be drawn. 

In humans, severe cases of acrylonitrile poisoning have resulted in

low grade anemia (Wilson 1944; Wilson et al. 1948), but complete

recovery was reported. Chronic occupational exposure to low levels of

acrylonitrile has not resulted in detectable effects on the

hematological system (Sakurai et al. 1978). In intermediate and chronic

studies in animals, decreased red cell count, hemoglobin concentration

and hematocyte were observed (Bio/dynamics 1980a, 1980b, 198Oc; Quast

et al. 1975; 198Oa). However, it is not certain if these effects are

due to acrylonitrile binding to red blood cell membranes and proteins

(Farooqui and Ahmed 1982), or are secondary effects related to the poor

physical condition which develops in the exposed animals. 
49 

2. HEALTH EFFECTS 

Some liver damage has been reported in humans after acute exposure

to high doses. In workers exposed to high levels of acrylonitrile

vapors, mild jaundice was diagnosed (Wilson 1944). In a case of an

accidental dermal exposure of a man, enzyme levels in the blood

suggestive of liver injury were reported for several days (Vogel and

Kirkendall 1984). These effects appeared to be fully reversible. 

The liver has been reported to be the primary site of acrylonitrile

metabolism. Metabolism studies indicate that a toxic metabolite 

(2-cyanoethylene oxide) is formed that covalently binds to liver tissue.

However, the liver has not been indicated as a target organ for

intermediate or chronic exposure in humans or animals. In factory

workers exposed to acrylonitrile for 10 or more years, no liver damage

has been observed (Sakurai et al. 1978). In animal studies, microscopic

examination of liver tissue has revealed no hepatic damage after 90 days

to 2 years of exposure by the inhalation or oral routes (Bio/dynamics

1980a, 1980b, 198Oc; Humiston et al. 1975; Quast 1975, 1980a, 1980b). 

Some effects seen in the livers of animals may suggest that

adaptive changes occur as a response to increased metabolic activity.

These include increased glutathione levels, possibly due to an increased

demand for glutathione for the metabolism of acrylonitrile. Increased

liver weights have also been observed in both acute and chronic oral

studies (Bio/dynamics 1980a, 1980b, 198Oc; Murray et al. 1978). 

Skin irritation results from direct contact with liquid or gaseous

acrylonitrile. Workers exposed to high levels of acrylonitrile in air

have complained of itching, but no dermatitis was observed (Wilson

et al. 1948). Also, transient irritation of scrotal skin has been noted

by workers after entering areas with high ambient acrylonitrile

concentrations. Direct contact of acrylonitrile with the skin has

resulted in erythema, desquamation and slow healing (Dudley and Neal

1942). In both humans and animals, skin redness has been reported

subsequent to acute exposures (Dudley and Neal 1942; Vogel and

Kirkendall 1984). 

Immunological Effects. Immunological effects of acrylonitrile have

not been studied in humans or animals. 

Neurological Effects. Acute effects have been described as being a

cyanide-type poisoning (Dudley and Neal 1942; Vogel and Kirkendall

1984). These observations are consistent with results from studies in

animals where it has been shown that the major metabolic pathways

include cyanide and thiocyanate as products of acrylonitrile metabolism

(Ahmed et al. 1983; EPA 1980a; Langvardt et al. 1980; Pilon et al.

1988a). The formation of cyanide following oral exposure is greater

than inhalation or subcutaneous exposure (Gut et al. 1975), indicating 
50 

2. HEALTH EFFECTS 

that the amount of acrylonitrile reaching the liver in free form (i.e.,

not covalently bound) may determine the amount of cyanide formed.

Symptoms which have been associated with acrylonitrile poisoning in

humans include limb weakness, labored and irregular breathing, dizziness

and impaired judgment, cyanosis and nausea, collapse, and convulsions

(Baxter 1979). Case studies of occupational exposure to acrylonitrile

suggest that the acute nonlethal effects in humans may be fully

reversible (Vogel and Kirkendall 1984; Wilson 1944; Wilson et al. 1948). 

Acute exposure of several species of animals has been reported to

lead to convulsions and coma (Dudley and Neal 1942). Exposure of

animals for 6 months or more at 16 mg of acrylonitrile per kilogram body

weight per day (mg/kg/day) results in neurological effects characterized

by decreased activity and depression (Bigner et al. 1986; Beliles et al.

1980; Quast et al. 1975). However, the only histopathological changes

seen in the nervous system have been those associated with the formation

of tumors (Bio/dynamics 1980a, 1980b, 1980c; Quast et al. 1975, 1980a,

1980b). 

Developmental Effects. There are no data available on 

developmental effects of acrylonitrile in humans; however, two well-conducted

studies in rats have shown that acrylonitrile is teratogenic

in animals by both inhalation and oral exposure (Murray et al. 1978).

Fetal malformations occurred in a dose-related manner. When 

administered orally, malformations were present even at doses in which

no maternal or fetal toxicity was apparent. 

Reproductive Effects. There are no data available on the 

reproductive effects in humans. However, a three-generation

reproduction study in rats showed that acrylonitrile has an effect on

reproduction. In all three generations, viability and lactation indices

were affected by 'the presence of acrylonitrile in the drinking water

(Beliles et al. 1980). Species differences were observed with respect

to the effects of acrylonitrile on male reproductive organs. In mice,

adverse effects on male reproductive organs were demonstrated at

10 mg/kg/day in a 60-day study (Tandon et al. 1988). In rats, no

effects on male reproductive organs were seen even when exposure was at

14 mg/kg/day for 2 years (Bio/dynamics 1980a, 1980b, 198Oc; Quast et al.

1980a, 1980b). 

Genotoxic Effects. The genotoxicity of acrylonitrile in vitro has 

been extensively studied (Table 2-4). Although the results are not

entirely consistent, positive results have been observed for all end

points evaluated: gene mutations, chromosomal aberrations, DNA damage,

and cell transformation. However, in vivo genotoxicity studies have

generally been negative in mammalian systems, including humans

(Table 2-5). Tests in Drosonhila melanozaster suggest that 



54 

2. HEALTH EFFECTS 

acrylonitrile may have potential for genotoxicity in vivo. 

Acrylonitrile and its metabolites have been shown to bind to nucleic

acids both in vivo and in vitro suggesting that acrylonitrile does have

potential for genetic damage. 

Cancer. Studies in rats by inhalation and oral exposure have all

demonstrated that acrylonitrile is carcinogenic. Multiple tumor sites

have been identified (Bio/dynamics 1980a, 1980b, 1980c; Quast et al.

1980a, 1980b). There is limited evidence that acrylonitrile is a human

carcinogen. Some epidemiology studies indicate that occupational

exposure to acrylonitrile results in an increased incidence of lung

cancer (O'Berg 1980; O'Berg et al. 1985). However, other studies have

not reached this conclusion (Collins et al. 1989; Kiesselbach et al.

1979). There is also a suggestion that acrylonitrile exposure may

result in an increased incidence of prostate cancer (Chen et al. 1987;

O'Berg et al. 1985). Limitations of these studies do not allow firm

conclusions about the potential for acrylonitrile to cause prostate

cancer. EPA has classified acrylonitrile as a probable human carcinogen

(IRIS 1988). There is sufficient evidence in animals that acrylonitrile

is carcinogenic, but the human evidence is limited. 

2.5 BIOMARKERS OF EXPOSURE AND EFFECT 

Biomarkers are broadly defined as indicators signaling events in

biologic systems or samples. They have been classified as biomarkers of

exposure, biomarkers of effect, and biomarkers of susceptibility

(NAS/NRC 1989). 

A biomarker of exposure is a xenobiotic substance or its

metabolite(s) or the product of an interaction between a xenobiotic

agent and some target molecule or cell that is measured within a

compartment of an organism (NAS/NRC 1989). The preferred biomarkers of

exposure are generally the substance itself or substance-specific

metabolites in readily obtainable body fluid or excreta. However,

several factors can confound the use and interpretation of biomarkers of

exposure. The body burden of a substance may be the result of exposures

from more than one source. The substance being measured may be a

metabolite of another xenobiotic (e.g., high urinary levels of phenol

can result from exposure to several different aromatic compounds).

Depending on the properties of the substance (e.g., biologic half-life)

and environmental conditions (e.g., duration and route of exposure), the

substance and all of its metabolites may have left the body by the time

biologic samples can be taken. It may be difficult to identify

individuals exposed to hazardous substances that are commonly found in

body tissues and fluids (e.g., essential mineral nutrients such as

copper, zinc and selenium). Biomarkers of exposure to acrylonitrile are

discussed in Section 2.5.1. 
55 

2. HEALTH EFFECTS 

Biomarkers of effect are defined as any measurable biochemical,

physiologic, or other alteration within an organism that, depending on

magnitude, can be recognized as an established or potential health

impairment or disease (NAS/NRC 1989). This definition encompasses

biochemical or cellular signals of tissue dysfunction (e.g., increased

liver enzyme activity or pathologic changes in female genital epithelium

cells), as well as physiologic signs of dysfunction such as increased

blood pressure or decreased lung capacity. Note that these markers are

often not substance specific. They also may not be directly adverse,

but can indicate potential health impairment (e.g., DNA adducts).

Biomarkers of effects caused by acrylonitrile are discussed in

Section 2.5.2. 

A biomarker of susceptibility is an indicator of an inherent or

acquired limitation of an organism's ability to respond to the challenge

of exposure to a specific xenobiotic. It can be an intrinsic genetic or

other characteristic or a preexisting disease that results in an

increase in absorbed dose, biologically effective dose, or target tissue

response. If biomarkers of susceptibility exist, they are discussed in

Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." 

2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to

Acrylonitrile 

Parent acrylonitrile molecule and its metabolites have been

measured in blood and urine, but, except for measurement of thiocyanate,

methods have not been developed for routine monitoring of exposed

humans. 

Factory workers exposed to an average of 0.1, 0.5 and 4.2 ppm of

acrylonitrile in the air during an 8-hour work day averaged 3.9, 19.7,

and 360 μg/L acrylonitrile in the urine, respectively, and 4.5, 5.78,

and 11.4 mg/L thiocyanate in the urine, respectively (Sakurai et al.

1978). No acrylonitrile was detected in the urine of a control group,

but an average of 4.00 mg/L of thiocyanate was found in the urine. The

presence of thiocyanate in the urine of workers not exposed to

acrylonitrile has been related to cigarette smoking (Houthuijs et al.

1882; Sakuria et al. 1978). Houthuijs et al. (1982) reported post-shift

acrylonitrile values of 39 μg/L when the mean acrylonitrile

concentration in the air was 0.13 ppm. 

2.5.2 Biomarkers Used to Characterize Effects Caused by Acrylonitrile 

A variety of effects have been demonstrated following acrylonitrile

exposure in humans and animals. These effects show a close similarity

to an underlying cyanide effect, particularly for acute exposures.

Effects can be detected in groups of exposed individuals by monitoring 
56 

2. HEALTH EFFECTS 

signs and symptoms such as increased salivation, dizziness, and labored

and irregular breathing. In some cases convulsions and coma may occur.

Because the release of cyanide for producing toxic effects is common for

other compounds, measuring these effects is not specific for

acrylonitrile exposure. These effects do identify potential health

impairment. It should be noted that the toxicity of acrylonitrile

resides not only in the cyanide radical but in the entire molecule. The

latter structure explains various chronic effects such as cancer that

result from acrylonitrile, as opposed to cyanide whose effects are more

relevant for acute toxicity. Studies that identify subtle physiological

changes that can be used to detect or predict risk of disease following

long-term exposure to acrylonitrile are not available. 

2.6 INTERACTIONS WITH OTHER CHEMICALS 

The interaction between acrylonitrile and other chemicals has not

been thoroughly studied. O'Berg (1980) noted that out of 8 workers

exposed to acrylonitrile who developed lung cancer, 7 were smokers

(smoking history was not available for the eighth individual). This

suggests that smoking might increase lung cancer risk from

acrylonitrile, but the data are too limited to draw any firm conclusions

on this point. 

Radimer et al. (1974) described four cases of severe epidermal

necrolysis in individuals who had been exposed to the residual fumes of

a mixture of acrylonitrile and carbon tetrachloride used to fumigate

their homes. Three of the people died. The authors thought this was

most likely due to the effects of acrylonitrile, but noted that an

interaction between carbon tetrachloride and acrylonitrile was possible. 

In animals, the hemorrhagic effects of acrylonitrile exposure on

the adrenals may be reduced by prior exposure of the animals to

adrenergic blockers or chemicals that deplete the adrenal cortex of

catecholamines (Silver et al. 1987; Szabo et al. 1980). It is difficult

to judge whether adrenergic antagonists would have a similar protective

effect in humans, because effects of acrylonitrile on the adrenal have

not been described in humans. 

Acrylonitrile alone has little tendency to produce duodenal ulcers

in animals, but pretreatment with phenobarbital or Aroclor results in a

marked increase in the incidence of such ulcers (Szabo et al. 1983,

1984). Although the mechanism of the ulcerogenic effect is not obvious,

these data indicate that agents which enhanced mixed-function oxidase

activity may also increase the toxicity of acrylonitrile. 
57 

2. HEALTH EFFECTS 

2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE 

Case studies of acrylonitrile poisoning in humans following

fumigation of living quarters in post-World War II Germany suggest that

children are more susceptible to acrylonitrile than adults (Grunske

1949). Children died after sleeping in rooms recently fumigated with

acrylonitrile for lice and bed bugs, while adults sharing the same

quarters reported few, if any, effects (skin or eye irritation). 

Studies in animals indicate that acrylonitrile can produce

teratogenic effects at doses that have little maternal toxicity,

suggesting that pregnant women may also be susceptible. It also seems

likely that individuals in poor health or with respiratory problems

might be particularly susceptible to acrylonitrile, but there are no

data on this point. 

2.8 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of

the Public Health Service) to assess whether adequate information on the

health effects of acrylonitrile is available. Where adequate

information is not available, ATSDR, in conjunction with the National

Toxicology Program (NTP), is required to assure the initiation of a

program of research designed to determine the health effects (and

techniques for developing methods to determine such health effects) of

acrylonitrile. 

The following categories of possible data needs have been

identified by a joint team of scientists from ATSDR, NTP, and EPA. They

are defined as substance-specific informational needs that, if met would

reduce or eliminate the uncertainties of human health assessment. In 

the future, the identified data needs will be evaluated and prioritized,

and a substance-specific research agenda will be proposed. 

2.8.1 Existing Information on the Health Effects of Acrylonitrile 

Figure 2-4 summarizes areas concerning the health effects of

acrylonitrile where studies have and have not been performed. There are

some data available on the effects in humans following acute or chronic

exposure to acrylonitrile via the inhalation route of exposure. The

target organ for acute toxicity is the nervous system. Chronic exposure

to acrylonitrile has been associated with cancer. However, many of the

available reports lack quantitative information on exposure levels. In

humans, there are no data on oral exposure to acrylonitrile and a very

limited amount of acute data on dermal exposure. In animals, there are

data available on inhalation and oral exposure and limited dermal

exposure data. 

59 

2. HEALTH EFFECTS 

2.8.2 Identification of Data Needs 

Acute-Duration Exposure. Information is available regarding the

effects of acute-duration inhalation exposure of humans to acrylonitrile

and the effects are characteristic of cyanide-type toxicity.

Quantitative data are limited but are sufficient to derive an acute

inhalation MRL. Further studies of humans exposed to low levels of

acrylonitrile in the workplace would increase the confidence of the

acute MRL. Studies in animals support and confirm these findings. No

studies are available on the effects of acute-duration oral exposure in

humans; however, exposure to acrylonitrile reveals neurological

disturbances characteristic of cyanide-type toxicity and lethal effects

in rats and mice. Rats also develop birth defects. Animal data are

sufficient to derive an acute oral MRL. Additional studies employing

other species and various dose levels would be useful in confirming

target tissues and determining thresholds for these effects. In humans,

acrylonitrile causes irritation of the skin and eyes. No data are

available on acute dermal exposures in animals. 

Intermediate-Duration Exposure. No information is available on the 

effects of intermediate-duration inhalation, oral, or dermal exposure in

humans or inhalation and dermal exposures in animals. There is

information on intermediate-duration oral exposure in animals. Studies

revealed decreased reproductive indices, decreased sperm count and

tubular degeneration in rats and mice. Blood cell counts were low in

rats and there was evidence of ulcerogenic effects in dogs.

Acrylonitrile was also lethal in dogs. Data in animals were sufficient

to derive an intermediate-duration oral MRL. Further studies in animals 

would be useful in defining threshold for these effects. 

Chronic-Duration Exposure and Cancer. No studies were located 

evaluating chronic effects associated with acrylonitrile exposure in

humans by any route of exposure. There is evidence of hematological

effects and alterations in organ weights (kidney, liver) in rats

following oral exposure. Additional chronic-duration studies in other

species by inhalation and oral exposures would be useful in determining

other target organs and thresholds for these effects. There are studies

of humans chronically exposed to acrylonitrile in workplace air. These

studies link acrylonitrile exposure to lung cancer and it has been

suggested that the chemical may have the potential to cause prostate

cancer. Due to limitations of these studies, firm conclusions cannot be

made. Additional studies providing quantitative exposure data and

evaluating confounding associations would be useful in clarifying

potential risk. 
60 

2. HEALTH EFFECTS 

Genotoxicity. Microbiol and mammalian assays are available on the

genotoxic effects of acrylonitrile. Results of in vitro tests 

evaluating gene mutation in prokaryotic and eukaryotic cell types are

variable. Similarly, results were mixed for in vitro mammalian assays

evaluating gene mutation, chromosomal aberration and DNA repair and

damage. In vivo tests evaluating chromosomal aberrations were negative.

Additional investigations evaluating structural and numerical

chromosomal aberrations in humans exposed in the workplace would be

useful in determining the significance of effects found in animal

assays. 

Reproductive Toxicity. No studies have been conducted in humans 

regarding reproductive toxicity of acrylonitrile after inhalation, oral,

or dermal exposure or inhalation and dermal exposures in animals.

Studies in male mice have shown that exposure to acrylonitrile in

drinking water affects sperm count and results in tubular degeneration.

No effects on male reproductive organs have been reported in rats.

Studies to further evaluate the significance of the testicular effects

on reproductive capability in mice and other species would be very

valuable. Studies on reproduction via the inhalation route would be

valuable in determining whether the effects seen in oral studies are

unique to that route of exposure. 

Developmental Toxicity. No information is available on 

developmental effects of acrylonitrile in humans by any route of

exposure. Acrylonitrile is teratogenic and embryotoxic in rats both by

the oral and inhalation routes of exposure. Developmental studies on

other animal species have not been conducted. Because species

differences for acute acrylonitrile toxicity and metabolism have been

demonstrated, additional developmental studies in other species using

various dose leve.ls would be valuable in evaluating the potential for

acrylonitrile to cause developmental effects in humans. Because the

available oral study was conducted by gavage, additional studies are

needed to determine if these effects will occur following ingestion of

drinking water or food. 

Immunotoxicity. No information was found on the immunological

effects of acrylonitrile in humans or animals by any route of exposure.

Because no immunopathological effects have been reported in subchronic

and chronic studies involving multiple species, additional studies

employing a more specific testing battery are not warranted at this

time. 

Neurotoxicity. Clinical signs indicative of disturbances of the

nervous system in exposed humans have been well documented in short-term

studies at high doses and appear to be reversible. These effects are

characteristic of cyanide toxicity. Animal studies confirm findings in 
61 

2. HEALTH EFFECTS 

humans. In longer-term studies, effects on the nervous system have also

been reported, but it is not certain if these effects are permanent or

reversible following termination of acrylonitrile exposure. 

Epidemiological and Human Dosimetry Studies. There are studies on 

the adverse effects of acrylonitrile in humans. These studies link

acrylonitrile exposure and lung cancer. It has also been suggested that

acrylonitrile may have the potential to cause prostate cancer. Many of

the studies have major limitations including insufficient quantification

of exposure, short follow-up, small study population, and inadequate

evaluation of confounding associations. Additional studies would be

useful in clarifying the cancer risk and estimating the exposure levels

that lead to these effects. 

Biomarkers of Exposure and Effect. The presence of thiocyanate and

2-cyanoethyl mercapturic acid have been monitored in urine as indicators

of acrylonitrile exposure. 

Effects produced by exposure to acrylonitrile, particularly after

acute exposures, are characteristic of cyanide toxicity. These effects

can be detected in people exposed by evaluating signs and symptoms such

as limb weakness, labored and irregular breathing, dizziness and

impaired judgement, cyanosis and convulsions. While tests are not

specific for acrylonitrile-induced toxicity, they do identify potential

health impairment. Studies to develop more specific biomarkers of

acrylonitrile-induced effects would be useful in assessing the potential

health risk of acrylonitrile near hazardous waste sites. 

Absorption, Distribution, Metabolism, and Excretion. Metabolism 

and excretion in animals exposed to acrylonitrile by the inhalation and

oral routes have been studied extensively. However, only limited data

on absorption and distribution are available. Some data on humans

exposed by inhalation are available. No data are available on the

toxicokinetics of acrylonitrile when the exposure route is dermal. More

extensive information on absorption and distribution of acrylonitrile

would be valuable to fully understand the toxicokinetics of

acrylonitrile. Some data on the toxicokinetics of acrylonitrile by the

dermal route would be valuable in order to determine if metabolism of 

acrylonitrile differs by route of exposure. Development of

physiologically-based toxicokinetic models would also be valuable in

extrapolation of animal data to humans. 

Comparative Toxicokinetics. The absorption, distribution,

metabolism, and excretion of acrylonitrile in rats has been studied.

Limited work in other species suggests that important species 
62 

2. HEALTH EFFECTS 

differences do exist. Further evaluation of these differences, and

comparison of metabolic patterns in humans with those of animals would

assist in determining the most appropriate animal species for evaluating

the hazard and risk of human exposure to acrylonitrile. 

2.8.3 On-going Studies 

A number of research projects in progress are investigating the

mechanism of toxicity and tumor formation of acrylonitrile. The

projects are summarized in Table 2-6. 

A number of on-going epidemiology studies are evaluating the

effects of occupational exposure to acrylonitrile. Independent

investigations are being conducted by Dr. R. D. Jones of the Employment

Medical Advisory Service of the United Kingdom; Dr. L.J. Lucas of

American Cyanamid Company; and Dr. L. I. Glass of SRA Technologies, Inc. 








________________________ 

71 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

4.1 PRODUCTION 

Acrylonitrile is produced commercially by the process of propylene

ammoxidation, in which propylene, ammonia and air are reacted in a

fluidized bed in the presence of a catalyst (EPA 1984, 1985a).

Production in the United States has increased gradually over the past

20 years from 304,300 kkga

 in 1967 (Cogswell 1984) to 1,112,754 kkg in

1987 (USITC 1988). 

Acrylonitrile is currently produced by five manufacturers at six

locations in the United States: American Cyanamid Company, Avondale,

Louisiana; BP America, Inc., Green Lake, Texas and Lima, Ohio; E.I.

duPont de Nemours and Company, Inc., Beaumont, Texas; Monsanto Company,

Chocolate Bayou, Texas; and Sterling Chemicals, Inc., Texas City, Texas

(SRI 1988). 

4.2 IMPORT 

Imports of acrylonitrile have been relatively small. In recent

years, imports of acrylonitrile have decreased from a high of 7,000 kkg

in 1974 to negligible level in 1981 and thereafter. 

A substantial fraction of the acrylonitrile produced in the United

States is exported. Exports rose from 23,500 kkg in 1972 to 364,000 kkg

(39% of United States production) in 1982 (Cogswell 1984). 

4.3 USE 

The primary use of acrylonitrile is as the raw material for the

manufacture of acrylic and modacrylic fibers. Other major uses include

the production of plastics (acrylonitrile-butadiene-styrene (ABS) and

styrene-acrylonitrile (SAN)), nitrile rubbers, nitrile barrier resins,

adiponitrile and acrylamide (EPA 1984). 

Acrylonitrile has been used, in a mixture with carbon

tetrachloride, as a fumigant for flour milling and bakery food

processing equipment and for stored tobacco. However, most pesticide

products containing acrylonitrile have been voluntarily withdrawn by

the manufacturers (IARC 1979). Currently, acrylonitrile in combination

with carbon tetrachloride is registered as a restricted-use pesticide. 

a

l kkg = 1,000 kg (1 metric ton, equivalent to 2,200 pounds) 
72 

4. PRODUCTION, IMPORT, USE, AND DISPOSAL 

In 1982, 51% of the United States consumption of acrylonitrile was

used for acrylic fibers, 18% for ABS and SAN resins, 14% for

adiponitrile, 5% for acrylamide and 3% for nitrile elastomers. The

remaining 9% was for miscellaneous uses (Cogswell 1984). 

4.4 DISPOSAL 

Because acrylonitrile is listed as a hazardous substance, disposal

of waste acrylonitrile is controlled by a number of federal regulations

(see Chapter 7). Rotary kiln, fluidized bed and liquid injection

incineration are acceptable methods of acrylonitrile disposal (HSDB

1988). Underground injection is another disposal method. The most

recent quantitative information on amount of acrylonitrile disposed in

waste sites is for 1987. Emissions were 0.9 metric tons in surface 

water, 152 metric tons disposed through Publically Owned Treatment Works

(POTW), 92 metric tons disposed of on land and 1,912 metric tons by

underground injection (TRI 1988). Because acrylonitrile is relatively

volatile and is also readily soluble in water, release to the

environment from waste sites is of concern. 
73 

5. POTENTIAL FOR HUMAN EXPOSURE 

5.1 OVERVIEW 

Humans may be exposed to acrylonitrile through air, water and food.

Acrylonitrile has been identified in 3 of 1,177 NPL sites. The

frequency of these sites within the United States can be seen in

Figure 5-l. 

Acrylonitrile is readily volatile, and significant quantities

escape into air during manufacture and use. Volatilization may also

occur from hazardous waste sites. In air, acrylonitrile is degraded

primarily by reaction with hydroxyl radicals, with an estimated halflife of 5 to 50 hours. Acrylonitrile has been detected in air in the

vicinity of various industrial sources at concentrations from 0.1 to

325 ppb, but has not been detected in typical ambient air. 

Acrylonitrile is also readily soluble in water, and current total

discharges to water via industrial effluents are low. Water

contamination may also occur following a spill or near a chemical site.

In water, acrylonitrile has little tendency to adsorb to sediment, but

is subject to biodegradation by microorganisms. The rate and extent of

degradation depend upon conditions and upon the time for Microbiol

acclimation. Degradation may approach 100% under favorable circumstances,

but may be inhibited by high concentrations of acrylonitrile. 

For members of the general public who do not live near an

industrial source or a chemical waste site, exposure to very low levels

of acrylonitrile may occur though contact with consumer products such as

acrylic carpeting or by ingestion of food stored in acrylic plastic

containers. Acrylonitrile may enter human food materials by leaching

from plastic food containers. For people who do live near such a

source, inhalation of acrylonitrile in air is likely to be the main

route of exposure, although intake through water could also be of

concern. Inhalation of acrylonitrile in air may be much higher for

workers in industries that produce or use acrylonitrile. Acrylonitrile

has been detected in surface water and groundwater near some industrial

sources and hazardous waste sites, usually at concentrations between 20

and 4,700 ppb. 

5.2 RELEASES TO THE ENVIRONMENT 

5.2.1 Air 

Because acrylonitrile is readily volatile, significant releases to

air may occur during acrylonitrile production and use (Hughes and Horn

1977; Miller and Villaume 1978). Kayser et al. (1982) estimated that

11,790 kkg/yr (metric tons per year) of acrylonitrile was released from

these sources, accounting for 87% of all acrylonitrile released to the 

75 

5. POTENTIAL FOR HUMAN EXPOSURE 

environment. Quantitative data on air releases from other sources were

not located, but volatilization might be significant following a spill

or in the vicinity of a chemical waste site containing acrylonitrile. 

5.2.2 Water 

Acrylonitrile may also be released to water during production and

use. According to data collected under SARA 313, total reported

releases to water during 1987 were 0.9 metric tons (TRI 1988). No data

were located on acrylonitrile releases to water from other sources, but

because acrylonitrile is readily soluble and is not strongly adsorbed to

soil or sediment (see Section 5.3.1 below), large accidental spills or

leaks from chemical waste sites could lead to significant water

contamination. While acrylonitrile is rapidly biodegraded in water,

high concentrations may inhibit degradation. Several examples of

groundwater contamination following spills have been reported (Miller

and Villaume 1978). Acrylonitrile may also be released to water by

leaks or emissions from hazardous waste sites. Acrylonitrile has been

detected in surface water at 2 sites and in groundwater at 5 sites of

862 hazardous waste sites (including NPL and other sites) being

investigated under Superfund (CLPSD 1988). 

5.2.3 Soil 

Direct release of acrylonitrile to soil during acrylonitrile

production and use is believed to be minimal (less than 1 kkg/yr)

(Kayser et al. 1982). Accidental spills or leaks from hazardous waste

sites could lead to local areas of soil contamination, and acrylonitrile

has been detected in soil at 3 chemical waste sites (NPL and other

sites) being investigated under Superfund (CLPSD 1988). 

5.3 ENVIRONMENTAL FATE 

5.3.1 Transport and Partitioning 

Acrylonitrile is both readily volatile in air (0.13 atm at 23°C)

(Mabey et al. 1982) and highly soluble in water (79,000 mg/L) (Klein

et al. 1957). These characteristics dominate the behavior of

acrylonitrile in the environment. While present in air, acrylonitrile

has little tendency to adsorb to particulate matter (Cupitt 1980), so

air transport of volatilized material is determined mainly by wind speed

and direction. Similarly, acrylonitrile dissolved in water has only a

low tendency to adsorb to suspended soils or sediments (Roy and Griffin

1985), so surface transport is determined by water flow parameters.

Based on its relatively high water solubility, acrylonitrile is expected

to be highly mobile in moist soils. In addition, acrylonitrile may 
76
 

5. POTENTIAL FOR HUMAN EXPOSURE 

penetrate into groundwater from surface spills or from contaminated

surface water. The high vapor pressure indicates that evaporation from

dry soil samples is expected to occur rapidly (EPA 1987). 

The tendency of acrylonitrile to partition between air and water is

described by Henry's law constant (H). The value of H for acrylonitrile

has not been determined experimentally, but has been calculated to be

8.8 x 10-5 atm-m3

/mole (Mabey et al. 1982). This value indicates that

acrylonitrile will occur in both air and water, tending to transfer

between air and water phases only slowly. Cupitt (1980) estimated the

half-time of acrylonitrile clearance from air in wet precipitation to be

greater than 10 months. 

Based on the relatively low value of the octanol/water partition

coefficient (Kow) for acrylonitrile (log Kow = -0.92) (Verschueren 1983),

it would not be expected that acrylonitrile will strongly bioaccumulate

in the tissues of aquatic organisms (Kenaga 1980; Neely et al. 1974).

However, data in aquatic organisms exposed to water containing

acrylonitrile show that it does accumulate in fat tissue. Barrows

et al. (1978) measured a steady-state bioconcentration factor (BCF) of

48 in bluegill sunfish. Based on the relative proportion of fat in

sunfish and other aquatic organisms, EPA (1980a) estimated an average

BCF of about 30 for the edible portions of freshwater and marine

species. 

5.3.2 Transformation and Degradation 

5.3.2.1 Air 

The principal pathway leading to degradation of acrylonitrile in

air is believed to be photooxidation, mainly by reaction with hydroxyl

radicals (OH). The rate constant for acrylonitrile reaction with OH

has been measured as 4.1 x 10-l2 cm3

/molecule/second (Harris et al.

1981). This would correspond to an atmospheric half-life of about 5 to

50 hours. This is consistent with a value of 9 to 10 hours measured in 

a smog chamber (Suta 1979). 

The photooxidation of acrylonitrile by hydroxyl radicals in the

presence of nitric oxide has been observed to yield formaldehyde (HCHO)

and formyl cyanide (HCOCN) (Hashimoto et al. 1984). From these results,

the following reaction was proposed: 

OH + CH2CHCN + 2N0 + 202 --> HCHO + HCOCN + 2N02 + OH. 

Data given by Hashimoto et al. (1984) suggest that the half-life of

acrylonitrile in the atmosphere may be on the order of 12 hours. 
 

77 

5. POTENTIAL FOR HUMAN EXPOSURE 

Acrylonitrile may also be oxidized by other atmospheric components

such as ozone and oxygen, but the rates of these reactions are much

lower than for OH. and are not considered to be an important degradative

pathway (Harris et al. 1981). 

5.3.2.2 Water 

Very little is known about nonbiologically mediated transformations

of acrylonitrile in water. There are no data to suggest that

acrylonitrile hydrolyzes under ambient conditions. While it is known

that acrylonitrile photooxidizes in air, no reliable information was

found on photochemical reactions in water. There were also no data on

the oxidation of acrylonitrile in water. Acrylonitrile is susceptible

to oxidation by strong oxidants such as chlorine used to disinfect

drinking water. 

Acrylonitrile is readily degraded by aerobic microorganisms in

water, especially if there is time for acclimation (Cherry et al. 1956;

Mills and Stack 1953, 1955; Stover and Kincannon 1983). After 27 days

of acclimation, about 70% of the acrylonitrile initially present in

river water was degraded under laboratory conditions, yielding acrylic

acid and ammonia. Complete degradation occurred under ideal conditions

where nutrients were added to promote Microbiol growth (Cherry et al.

1956). 

A bacterium classified as Nocardia rhodochrous LL 100-2 has been 

reported to be able to degrade acrylonitrile (DiGeronimo and Antoine

1976). An aerobic bacterium classified as Arthrobacter in an acclimated

sludge decompletely degraded acrylonitrile after 48 hours yielding

acrylic acid (Yamada et al. 1979). It was proposed that acrylonitrile

was biodegraded by the following reaction: 

CH2CHCN + H20 --> CH2CHCONH2 + H20 --> CH2CHCOOH + NH3 

It has been shown that low concentrations of acrylonitrile in

solution (10 mg/L or less) can be completely degraded in a laboratory,

static-culture batch experiment where domestic sewage water was the

source of the Microbiol inoculum (Tabak et al. 1981). A solution of

acrylonitrile (152 mg/L) was degraded to less than 0.05 mg/L in a

continuous flow activated sludge system under laboratory conditions

(Kincannon et al. 1983). 

Studies performed using sewage sludge indicate that acrylonitrile

may also be degraded by methanogenic bacteria under anaerobic

conditions, although concentrations of 50 to 1,000 mg/L lead to moderate

inhibition of bacterial fermentation (Miller and Villaume 1978). This 
78 

5. POTENTIAL FOR HUMAN EXPOSURE 

suggests that Microbiol degradation of acrylonitrile in anaerobic

groundwater may not proceed efficiently if acrylonitrile levels were

high, as might occur after a spill. 

5.3.2.3 Soil 

No studies were located regarding the biodegradation of

acrylonitrile in soil. However, it seems likely that acrylonitrile in

moist soil would be subject to biodegradation similar to that observed

in aerobic water, although degradation rates might differ. 

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 

5.4.1 Air 

Acrylonitrile has not been found to occur at measurable

concentrations in ambient air (Brodzinsky and Singh 1983). Measurable

levels of atmospheric acrylonitrile are associated with industrial

sources. 

Air samples collected in one acrylonitrile-fiber plant ranged from

3 to 20 mg/m3

 (EPA 1980a). Mean 24-hour acrylonitrile concentrations in

atmospheric samples collected within 5 km of 11 factories producing or

using acrylonitrile ranged from less than 0.1 to 325 μg/m3

 (Suta 1979).

The occurrence of acrylonitrile was correlated to wind patterns; the

highest concentrations were downwind of and in close proximity to the

plant. The median concentration of acrylonitrile for 43 measurements in

"source-dominated areas" (i.e., near chemical plants) was 2.1 μg/m3 

(Brodzinsky and Singh 1983). There were no data available on the

concentration of acrylonitrile in air near chemical waste sites, but

because acrylonitrile is easily volatilized, this is an exposure pathway

of concern. 

5.4.2 Water 

Acrylonitrile is not a common contaminant of typical surface water

or groundwater. In a state-wide survey of over 1,700 wells in

Wisconsin, acrylonitrile was not detected in any sample (Krill and

Sonzogni 1986). Acrylonitrile was detected in 46 of 914 samples of

surface water and groundwater taken across the United States (Staples

et al. 1985), generally at levels less than 10 ppb. 

The most likely source of acrylonitrile in water is industrial

discharges. Levels of acrylonitrile measured in the effluents from a

variety of industrial sites (iron and steel factories, textile mills,

chemical plants) have ranged from 20 to 4,700 ppb, resulting in 
79 

5. POTENTIAL FOR HUMAN EXPOSURE 

concentrations in nearby rivers ranging from below detection limits to

4,300 ppb (EPA 1983c). Data collected under SARA indicated total

discharges to water during 1987 were 0.9 metric tons (TRI 1988). 

Another source of acrylonitrile in water is leachate from chemical

waste sites. Preliminary data from the Contact Laboratory Program (CLP)

Statistical Database indicates that acrylonitrile has been detected in

surface water samples collected at two of 862 hazardous-waste sites

(including NPL and other sites) being investigated under Superfund. The

median concentration of the positive samples was 100 μg/L (CLPSD 1988).

Acrylonitrile was detected in 12 groundwater samples collected at

5 sites, also at a median concentration of 100 μg/L. 

5.4.3 Soil 

Staples et al. (1985) reported that acrylonitrile was not present

at detectable concentrations in 351 sediment samples collected from lake

and river bottoms across the United States. Preliminary data from the

Contract Laboratory Program (CLP) Statistical Database (CLPSD 1988)

indicated that acrylonitrile was detected in soils at 3 of 862 hazardous

waste sites (including NPL and other sites) being investigated under

Superfund. The median concentration of five samples was 120 μg/kg. 

5.4.4 Other Media 

Foods may become contaminated with acrylonitrile as a result of the

migration of the monomer from chemical containers made of acrylonitrile

polymers. Acrylonitrile has been found to desorb from polyacrylonitrile

resins and partition into cooking oil (Gilbert et al. 1980). Other

foods which may be contaminated by acrylonitrile from their containers

include luncheon meat, peanut butter, margarine, fruit juice, and

vegetable oil (EPA 1980a, 1983c; FDA 1984). There are few data on the

extent of food-related acrylonitrile exposure. The FDA reported typical

acrylonitrile concentrations in margarine of 25 μg/kg (FDA 1984), and

the Commission of European Communities (1983) reported that the levels

of acrylonitrile in contaminated foods are generally about 1 μg/kg.

While past data suggest potential exposure, there is little current

migration of the monomer from current packaging materials because food

is packaged in vastly different resins that have been drastically

improved (AN Group 1990). 

Acrylonitrile was detected in the smoke of cigarettes made in the

United States in the 1960s and 197Os, usually at levels of 1 to 2 mg per

cigarette (IARC 1979). At that time, acrylonitrile was used as a

fumigant for stored tobacco. Most pesticide registrations for

acrylonitrile were cancelled in 1978, and the use of acrylonitrile as a 
80
 

5. POTENTIAL FOR HUMAN EXPOSURE 

fumigant has been discontinued. Although no data were located,

cigarette smoking is probably no longer a major source of human exposure

to acrylonitrile. 

Residual acrylonitrile monomer may also occur in commercially-made

polymeric materials used in rugs and other products. Estimated levels

include acrylic and modacrylic fibers (less than 1 mg acrylonitrile/kg

polymeric material), acrylonitrile-based resins (15 to 50 mg/kg), and

nitrile rubber and latex (0 to 750 mg/kg) (IARC 1979; Miller and

Villaume 1978). It is possible that acrylonitrile may evaporate into

air or leach into water from these products, but no data on this topic

were located. 

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE 

As shown in Table 5-1, only people living near chemical factories

or work sites are likely to be exposed to measurable amounts of

acrylonitrile in air and water. Dispersion modeling studies have

indicated that approximately 2.6 million people living within 30 km of

emission sources may be exposed to atmospheric acrylonitrile (Suta

1979). Members of the general population may also be potentially

exposed to acrylonitrile through the consumption of acrylonitrile-contaminated

food. However, it should be recalled that only foods in

direct contact with acrylonitrile-based plastics are subject to

contamination, and then only at very low levels. 

Occupational exposures via inhalation of acrylonitrile vapor at the

work place are likely to be considerably greater than exposures outside

the workplace (Table 5-l). Exposure levels may be highest for workers

in plants where the chemical is synthesized (EPA 1984). 

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 

It has been estimated that over 100,000 workers are potentially

exposed to acrylonitrile during production and use (NIOSH 1977, 1988).

Occupational exposures include plastic and polymer manufacturers,

polymer molders, polymer combustion workers, furniture makers, and

manufacturers of fibers and synthetic rubber (EPA 1980a). Other

populations who could have elevated exposure to acrylonitrile are

residents in the vicinity of industrial sources or chemical waste sites. 

5.7 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of

the Public Health Service) to assess whether adequate information on the

health effects of acrylonitrile is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is 

82 

5. POTENTIAL FOR HUMAN EXPOSURE 

required to assure the initiation of a program of research designed to

determine the health effects (and techniques for developing methods to

determine such health effects) of acrylonitrile. 

The following categories of possible data needs have been

identified by a joint team of scientists from ATSDR, NTP, and EPA. They

are defined as substance-specific informational needs that, if met would

reduce or eliminate the uncertainties of human health assessment. In 

the future, the identified data needs will be evaluated and prioritized,

and a substance-specific research agenda will be proposed. 

5.7.1 Identification of Data Needs 

Physical and Chemical Properties. Most of the important physical-chemical

properties of acrylonitrile have been determined (see

Chapter 3). However, the partitioning of acrylonitrile between the air

and water has been evaluated by using an estimated value for a Henry's

law constant. This general approach assumes that the concentration of

the chemical in water is low. Because acrylonitrile is relatively

soluble in water, this approach may not be accurate. Experimental

measurement of the partition coefficient for acrylonitrile at water-air

interfaces would be useful in refining models on the behavior of

acrylonitrile in the environment. 

Production, Use, Release and Disposal. Substantial data exist on 

past production, use and emissions of acrylonitrile in the United

States. Data on current releases to the environment and disposal

practices are collected under SARA 313. Additional studies are not

needed at this time because these data are readily available. 

According to. the Emergency Planning and Community Right to Know Act

of 1986 (EPCRTKA), (§313), (Pub. L. 99-499, Title III, (§313), industries

are required to submit release information to the EPA. The Toxic

Release Inventory (TRI), which contains release information for 1987 and

1988, became available in May of 1989. This database will be updated

yearly and should provide a more reliable estimate of industrial

production and emission. 

Environmental Fate. Laboratory studies indicate that acrylonitrile

is biodegraded in aqueous systems promoting microbial growth, but

typical degradation rates in lakes or rivers have not been studied in

detail. Similarly, it is not known if acrylonitrile will biodegrade

significantly in soil. Data on the chemical oxidation,

photodegradation, and biodegradation of acrylonitrile in surface and

groundwater would be helpful. 
83 

5. POTENTIAL FOR HUMAN EXPOSURE 

Bioavailability from Environmental Media. There are limited data 

on the bioavailability of acrylonitrile in different environmental

media. Data on the bioavailability of acrylonitrile would be valuable. 

Food Chain Bioaccumulation. There are no data on the 

bioaccumulation of acrylonitrile in the food chain. The lack of data

may not be a major limitation, because limited data suggest that

acrylonitrile has a relatively low tendency to be bioconcentrated by

lower trophic levels. 

Exposure Levels in Environmental Media. Existing studies have not

provided data on acrylonitrile levels in typical ambient air. Studies

using analytical methods with lower detection limits would be helpful in

determining if ambient air is an exposure medium of concern. Because

higher levels of exposure are most likely near industrial sources or

chemical waste sites, additional data on the occurrence of acrylonitrile

in the atmosphere, surface water, and groundwater near such sites would

be useful. 

Exposure Levels in Humans. Human exposure levels to acrylonitrile

can only be estimated based on average concentrations in air, food and

water. Direct studies of personal exposure levels for individuals with

exposures judged to be average and above average (e.g., people living

near industrial sources or hazardous waste sites) would be helpful in

improving total dose estimates, and in identifying exposure pathways of

concern. 

Exposure Registries. No exposure registries for acrylonitrile were

located. This compound is not currently one of the compounds for which

a subregistry has been established in the National Exposure Registry.

The compound will be considered in the future when chemical selection is

made for subregistries to be established. The information that is

amassed in the National Exposure Registry facilitates the

epidemiological research needed to assess adverse health outcomes that

may be related to the exposure to this compound. 

5.7.2 On-going Studies 

The Acrylonitrile Group, Inc. is currently performing an

acrylonitrile degradation study in groundwater and surrounding soil to

obtain kinetic data for hydrolysis, biodegradation, primary metabolites

and rates of mineralization. Radiolabeled material at three 

concentrations over three orders of magnitude will be used. The data

will also establish the effect of accumulation on biodegradation

kinetics. 

85 

6. ANALYTICAL METHODS 

The purpose of this chapter is to describe the analytical methods

that are available for detecting and/or measuring and monitoring

acrylonitrile in environmental media and in biological samples. The

intent is not to provide an exhaustive list of analytical methods that

could be used to detect and quantify acrylonitrile. Rather, the

intention is to identify well-established methods that are used as the

standard methods of analysis. Many of the analytical methods used to

detect acrylonitrile in environmental samples are the methods approved

by federal agencies such as EPA and the National Institute for

Occupational Safety and Health (NIOSH). Other methods presented in this

chapter are those that are approved by a trade association such as the

Association of Official Analytical Chemists (AOAC) and the American

Public Health Association (APHA). Additionally, analytical methods are

included that refine previously used methods to obtain lower detection

limits, and/or to improve accuracy and precision. 

6.1 BIOLOGICAL MATERIALS 

Acrylonitrile in both biological and environmental samples is most

commonly determined by gas chromatography with a nitrogen-phosphorus

detector (GC/NPD) (Page 1985), gas chromatography/flame ionization

detection (GC/FID) (EPA 1982a), or gas chromatography/mass spectroscopy

(GC/MS) (Anderson and Harland 1980). Infrared spectroscopy (Jacobs and

Syrjala 1978) may also be used. In the handling of samples and

standards, acrylonitrile should be treated with precautions appropriate

for a probable human carcinogen. 

Comparatively little information is available in the literature on

the determination of acrylonitrile in biological materials. Methods

have been published for the determination of acrylonitrile in blood

(Anderson and Harland 1980; Freshour and Melcher 1983) and urine

(Houthuijs et al. 1982; Sakurai et al. 1978). Acrylonitrile was widely

used in the past as a fumigant, and it is possible that methods used for

the determination of other fumigants in biological materials (Walters

1986) could be adapted to the determination of acrylonitrile in such

samples. 

Methods for detection of acrylonitrile in biological materials are

summarized in Table 6-l. 

6.2 ENVIRONMENTAL SAMPLES 

The methods of choice for the determination of acrylonitrile in

environmental samples are GC/NPD (Page 1985), GC/FID (EPA 1982a), and

GC/MS (EPA 1982b). Multiple internal reflectance infrared spectrometry

(Jacobs and Syrjala 1978) is useful for monitoring low levels of

acrylonitrile in air. 

87 

6. ANALYTICAL METHODS 

The determination of acrylonitrile in air may be accomplished by

collection on a solid sorbet, such as activated charcoal, followed by

elution and gas chromatographic measurement (NIOSH 1984). 

EPA has published a method of analysis specific for acrylonitrile

in water (EPA 1982a) and a method applicable to its determination in

water along with other purgeable organics (EPA 1982b). Other standard

EPA methods are adaptable for the determination of acrylonitrile in

wastes (EPA 1986b). 

Methods for the determination of acrylonitrile in environmental

samples are summarized in Table 6-2. 

6.3 ADEQUACY OF THE DATABASE 

Section 104(i)(5) of CERCLA, directs the Administrator of ATSDR (in

consultation with the Administrator of EPA and agencies and programs of

the Public Health Service) to assess whether adequate information on the

health effects of acrylonitrile is available. Where adequate

information is not available, ATSDR, in conjunction with the NTP, is

required to assure the initiation of a program of research designed to

determine the health effects (and techniques for developing methods to

determine such health effects) of acrylonitrile. 

The following categories of possible data needs have been

identified by a joint team of scientists from ATSDR, NTP, and EPA. They

are defined as substance-specific informational needs that, if met would

reduce or eliminate the uncertainties of human health assessment. In 

the future, the identified data needs will be evaluated and prioritized,

and a substance-specific research agenda will be proposed. 

6.3.1 Identification of Data Needs 

Method for Determining Biomarkers of Exposure and Effect. Exposure

to acrylonitrile can be determined by measuring parent acrylonitrile,

acrylonitrile metabolites and adducts. Good methods exist for detecting

and quantifying acrylonitrile in biological materials. These methods

are based on capillary gas chromatography, where a special problem is

introduction of analytes quantitatively and in a narrow band onto the

capillary GC. One of the most promising approaches to analyte transfer

is the use of cyrofocusing, in which analytes are condensed in a narrow

band on a trap or on the GC column itself. Improvements in cryofocusing

of volatile organic analytes for capillary GC determination (Washall and

Wampler 1988) should improve sensitivity for the determination of

acrylonitrile. 

89 

6. ANALYTICAL METHODS 

Acrylonitrile metabolites have been measured in blood and urine,

but, except for measurement of thiocyanate, these methods have not been

developed for routine monitoring of exposed humans. Supercritical fluid

extraction/chromatography and immunoassay analysis are two areas of

intense current activity from which substantial advances in the

determination of acrylonitrile and its metabolites in biological samples

can be anticipated. The two techniques are complementary because

supercritical fluid extraction is especially promising for the removal

of analytes from sample material and immunoassay is very analyte- selective

and sensitive (Vanderlaan et al. 1988). 

Studies using radioactivity-labeled acrylonitrile indicate that

acrylonitrile or its metabolites form covalent adducts with cellular

macromolecules in most tissues. Studies to develop chemical or

immunological methods for measuring these adducts would be especially

valuable in detecting and perhaps even quantifying human exposure to

acrylonitrile. Adverse health effects demonstrated following exposure

to acrylonitrile, particularly acute exposures, were characteristic of

cyanide toxicity. Because these effects are also indicative of exposure

to many other toxicants, additional methods are needed for more specific

biomarkers of effects of acrylonitrile exposure. 

Methods for Determining Parent Compounds and Degradation Products

in Environmental Media. Methods for determining acrylonitrile in

environmental samples are quite good. It may be assumed that the normal

incentives for both research and the development of commercial methods

of analysis will result in new analytical methods for acrylonitrile that

have improved sensitivity and selectivity. Degradation products of

acrylonitrile in environmental media are difficult to determine. This

difficulty is not as much an analytical problem as it is a problem of

knowing the fundamental environmental chemistry of these compounds in

water, soil, air and biological systems. 

6.3.2 On-going Studies 

There exists an ongoing effort to develop a "Master Analytical

Scheme" for organic compounds in water (Michael et al. 1988). The

overall goal is the development of technology capable of detecting and

quantitatively measuring organic compounds at 0.1 μg/L in effluent

waters. Analytes are to include numerous semivolatile compounds and

some compounds that are only "semisoluble" in water, as well as volatile

compounds (boiling point, less than 15O°C). 

Studies designed to improve the determination of environmental

contaminants will continue to provide refinements and improvements in

the determination of acrylonitrile. The current high level of activity

in supercritical fluid extraction of solid and semisolid samples should 
90 

6. ANALYTICAL METHODS 

yield improved recoveries and sensitivities for the determination of

acrylonitrile in solid wastes, and the compound should be amenable to

supercritical fluid chromatographic analysis. Immunoassay analysis is

another area of intense current activity from which substantial advances

in the determination of acrylonitrile in environmental samples can be

anticipated (Vanderlaan et al. 1988). 
91 

7. REGULATIONS AND ADVISORIES 

Because of its potential to cause adverse health effects in exposed

people, a number of regulations and guidelines have been established for

acrylonitrile by various national and state agencies. These values are

summarized in Table 7-l. 



_____________________ 

95 

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8. REFERENCES 

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Werner JB, Carter JT. 1981. Mortality of United Kingdom acrylonitrile

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* WHO. 1983. Environmental health criteria 28: acrylonitrile. World

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* Williams GM, Tong C, Brat SV. 1985. Tests with the rat hepatocyte

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* Wilson RH. 1944, Health hazards encountered in the manufacture of

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* Wilson RH, Hough GV, McCormick WE. 1948. Medical problems encountered

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Windholz M, ed. 1983. The Merck index: An encyclopedia of chemicals,

drugs, and biologicals. 10th ed. Rahway, NJ: Merck and Co., Inc., 20. 

* Working PK, Bentley KS, Hurtt ME, et al. 1987. Comparison of the

dominant lethal effects of acrylonitrile and acrylamide in male Fischer

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* Yamada H, Asano Y, Hino T, et al. 1979. Microbiol utilization of

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123 

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125 

9. GLOSSARY 

Acute Exposure -- Exposure to a chemical for a duration of 14 days or

less, as specified in the Toxicological Profiles. 

Adsorption Coefficient (Koc) -- The ratio of the amount of a chemical 

adsorbed per unit weight of organic carbon in the soil or sediment to

the concentration of the chemical in solution at equilibrium. 

Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment

or soil (i.e., the solid phase) divided by the amount of chemical in the

solution phase, which is in equilibrium with the solid phase, at a fixed

solid/solution ratio. It is generally expressed in micrograms of

chemical sorbed per gram of soil or sediment. 

Bioconcentration Factor (BCF) -- The quotient of the concentration of a

chemical in aquatic organisms at a specific time or during a discrete

time period of exposure divided by the concentration in the surrounding

water at the same time or during the same time period. 

Cancer Effect Level (CEL) -- The lowest dose of chemical in a study or

group of studies which produces significant increases in incidence of

cancer (or tumors) between the exposed population and its appropriate

control. 

Carcinogen -- A chemical capable of inducing cancer. 

Ceiling value (CL) -- A concentration of a substance that should not be 

exceeded, even instantaneously. 

Chronic Exposure -- Exposure to a chemical for 365 days or more, as

specified in the Toxicological Profiles. 

Developmental Toxicity -- The occurrence of adverse effects on the 

developing organism that may result from exposure to a chemical prior to

conception (either parent), during prenatal development, or postnatally

to the time of sexual maturation. Adverse developmental effects may be

detected at any point in the life span of the organism. 

Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as

a result of prenatal exposure to a chemical; the distinguishing feature

between the two terms is the stage of development during which the

insult occurred. The terms, as used here, include malformations and

variations, altered growth, and in utero death. 

EPA Health Advisory -- An estimate of acceptable drinking water levels

for a chemical substance based on health effects information. A health 

advisory is not a legally enforceable federal standard, but serves as

technical guidance to assist federal, state, and local officials. 
126 

9. GLOSSARY 

Immediately Dangerous to Life or Health (IDLH) -- The maximum 

environmental concentration of a contaminant from which one could escape

within 30 min without any escape-impairing symptoms or irreversible

health effects. 

Intermediate Exposure -- Exposure to a chemical for a duration of 15-364

days s as specified in the Toxicological Profiles. 

Immunologic Toxicity -- The occurrence of adverse effects on the immune 

system that may result from exposure to environmental agents such as

chemicals. 

In Vitro -- Isolated from the living organism and artificially

maintained, as in a test tube. 

In Vivo -- Occurring within the living organism. 

Lethal Concentration(LO) (LCLO) -- The lowest concentration of a them 

in air which has been reported to have caused death in humans or

animals. 

Lethal Concentration(50) (LC50) -- A calculated concentration of a 

chemical in air to which exposure for a specific length of time is

expected to cause death in 50% of a defined experimental animal

population. 

Lethal Dose(LO)(LDLO) -- The lowest dose of a chemical introduced by a

route other than inhalation that is expected to have caused death in

humans or animals. 

Lethal Dose(50) (LD50) -- The dose of a chemical which has been 

calculated to cause death in 50% of a defined experimental animal

population. 

Lethal Time(5O) (LT50) -- A calculated period of time within which a

specific concentration of a chemical is expected to cause death in 50%

of a defined experimental animal population. 

Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of 

chemical in a study or group of studies which produces statistically or

biologically significant increases in frequency or severity of adverse

effects between the exposed population and its appropriate control. 

Malformations -- Permanent structural changes that may adversely affect

survival, development, or function. 
127 

9. GLOSSARY 

Minimal Risk Level (MRL) -- An estimate of daily human exposure to a

chemical that is likely to be without an appreciable risk of deleterious

effects (noncancerous) over a specified duration of exposure. 

Mutagen -- A substance that causes mutations. A mutation is a change in

the genetic material in a body cell. Mutations can lead to birth

defects, miscarriages, or cancer. 

NeurotoxLcity -- The occurrence of adverse effects on the nervous system

following exposure to a chemical. 

No-Observed-Adverse-Effect Level (NOAEL) -- That dose of chemical at

which there are no statistically or biologically significant increases

in frequency or severity of adverse effects seen between the exposed

population and its appropriate control. Effects may be produced at this

dose, but they are not considered to be adverse. 

Octanol-Water Partition Coefficient (Kow) -- The equilibrium ratio of

the concentrations of a chemical in n-octanol and water, in dilute

solution. 

Permissible Exposure Limit (PEL) -- An allowable exposure level in

workplace air averaged over an 8-hour shift. 

q1* -- The upper-bound estimate of the low-dose slope of the doseResponse curve as determined by the multistage procedure. The q1* can 

be used to calculate an estimate of carcinogenic potency, the

incremental excess cancer risk per unit of exposure (usually μg/L for

water, mg/kg/day for food, and μg/m3

 for air). 

Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps

an order of magnitude) of the daily exposure of the human population to

a potential hazard that is likely to be without risk of deleterious

effects during a lifetime. The RfD is operationally derived from the

NOAEL (from animal and human studies) by a consistent application of

uncertainty factors that reflect various types of data used to estimate

RfDs and an additional modifying factor, which is based on a

professional judgment of the entire database on the chemical. The RfDs

are not applicable to nonthreshold effects such as cancer. 

Reportable Quantity (RQ) -- The quantity of a hazardous substance that

is considered reportable under CERCLA. Reportable quantities are: (1) 1

lb or greater or (2) for selected substances, an amount established by

regulation either under CERCLA or under Sect. 311 of the Clean Water

Act. Quantities are measured over a 24-hour period. 
128 

9. GLOSSARY 

Reproductive Toxicity -- The occurrence of adverse effects on the 

reproductive system that may result from exposure to a chemical. The

toxicity may be directed to the reproductive organs and/or the related

endocrine system. The manifestation of such toxicity may be noted as

alterations in sexual behavior, fertility, pregnancy outcomes, or

modifications in other functions that are dependent on the integrity of

this system. 

Short-Term Exposure Limit (STEL) -- The maximum concentration to which 

workers can be exposed for up to 15 min continually. No more than four

excursions are allowed per day, and there must be at least 60 min

between exposure periods. The daily TLV-TWA may not be exceeded. 

Target Organ Toxicity -- This term covers a broad range of adverse

effects on target organs or physiological systems (e.g., renal,

cardiovascular) extending from those arising through a single limited

exposure to those assumed over a lifetime of exposure to a chemical. 

Teratogen -- A chemical that causes structural defects that affect the 

development of an organism. 

Threshold Limit Value (TLV) -- A concentration of a substance to which 

most workers can be exposed without adverse effect. The TLV may be

expressed as a TWA, as a STEL, or as a CL. 

Time-weighted Average (TWA) -- An allowable exposure concentration

averaged over a normal 8-hour workday or 40-hour workweek. 

Toxic Dose (TD50) -- A calculated dose of a chemical, introduced by a

route other than inhalation, which is expected to cause a specific toxic

effect in 50% of a defined experimental animal population. 

Uncertainty Factor (UF) -- A factor used in operationally deriving the

RfD from experimental data. UFs are intended to account for (1) the

variation in sensitivity among the members of the human population, (2)

the uncertainty in extrapolating animal data to the case of humans, (3)

the uncertainty in extrapolating from data obtained in a study that is

of less than lifetime exposure, and (4) the uncertainty in using LOAEL

data rather than NOAEL data. Usually each of these factors is set equal

to 10. 
129 

APPENDIX 

PEER REVIEW 

A peer review panel was assembled for acrylonitrile. The panel

consisted of the following members: Dr. Ahmed Ahmed, Professor of

Environmental Pathology and Toxicology, Department of Pathology,

University of Texas Medical Branch, Galveston; Dr. Norman M. Trieff,

Professor of Environmental Toxicology, University of Texas Medical

Branch, Galveston; Dr. Sandor Szabo, Associate Professor of Pathology,

Department of Pathology, Brigham and Women's Hospital, Harvard Medical

School, Boston. These experts collectively have knowledge of

acrylonitrile's physical and chemical properties, toxicokinetics, key

health end points, mechanisms of action, human and animal exposure, and

quantification of risk to humans. All reviewers were selected in

conformity with the conditions for peer review specified in the

Superfund Amendments and Reauthorization Act of 1986, Section 110. 

A joint panel of scientists from ATSDR and EPA has reviewed the

peer reviewers' comments and determined which comments will be included

in the profile. A listing of the peer reviewers' comments not

incorporated in the profile, with a brief explanation of the rationale

for their exclusion, exists as part of the administrative record for

this compound. A list of databases reviewed and a list of unpublished

documents cited are also included in the administrative record. 

The citation of the peer review panel should not be understood to

imply their approval of the profile's final content. The responsibility

for the content of this profile lies with the Agency for Toxic

Substances and Disease Registry.