EPA-560/11-80-016
June 1980
SUPPORT DOCUMENT
DECISION NOT TO REQUIRE
TESTING FOR HEALTH EFFECTS:
ACRYLAMIDE
ASSESSMENT DIVISION
OFFICE OF TOXIC SUBSTANCES
Washington, D.C. 20460
U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF PESTICIDES AND TOXIC SUBSTANCES
WASHINGTON, D.C. 20460
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I, INTRODUCTION
Section 4(e) of the Toxic Substances Control Act (TSCA: 90
Stat. 2003, 15 USC 2601 et seq.) established an Interagency
Testing Committee (ITC) to recommend to the Administrator of the
Environmental Protection Agency (EPA) a list of chemical
substances and mixtures to be considered for the promulgation of
testing rules under Section 4(a) of the Act. The ITC may have up
to 50 of its recommendations designated at any one time for
priority consideration by EPA. TSCA requires EPA to respond to
such recommendations within 12 months of the date on which they
are made either by initiating rulemaking proceedings under
Section 4(a) or by publishing in the Federal Register reasons for
not. having taken such action.
The ITC recommended that acrylamide be tested for carcino-
*
genie, mutagenic, teratogenic, and environmental effects and that
an epidemiologic study be performed. The recommendations were
based on (1) the possible entry of this highly water-soluble
compound into surface water and groundwater as a result of its
wide use as a chemical grout and that of its polymers in
municipal and industrial wastewater treatment, paper strengthen-
ing and retention, and various other applications; (2) the severe
neurotoxicity of acrylamide, which raises the possibility that
other serious effects might result from long-term, low-level
exposure; and (3) the potential exposure of about 20,000 workers
to acrylamide during its manufacture, processing, use, and
disposal and the potential widespread exposure of the general
population via release of the compound to the environment.
SPA has completed its review of the health effects of
acrylamide basing its evaluation on the following publicly
available information: the ITC dossier (TSCA ITC 1978) and its
references; studies and reports identified by an EPA supplemen-
tary literature search; public comments submitted in response to
publication of the April 10, 1978, revision of ITC's original
list which included the ITC's recommendations concerning
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acrylamide; data supplied by acrylamide manufacturers; and a con-
tract report prepared for the Agency by the Midwest Research
Institute (Conway et al. 1979). The health effects of concern to
the ITC plus the neurotoxicity of acrylamide were considered.
The contract report (Conway et al. 1979) evaluated studies
related to mutagenicity, teratogenicity, carcinogenicity, as well
as neurotoxicity and other health effects. EPA, having reviewed
this work and a report by Shiraishi (1978) discussing chromosomal
aberrations from acrylamide exposure, has focused its more
detailed evaluation upon the very potent and relatively well-
characterized neurotoxic properties of this compound to reach the
tentative conclusions set forth in this Support Document and *
discussed in the notice in the FEDERAL REGISTER ( FR )
on
Two recent reviews (NIOSH 1976, US EPA 1976) and several
primary sources formed the basis of the review by Conway et al.
(1979), which is summarized here. EPA staff have consulted the
primary sources to validate the secondary review findings.
II. PHYSICAL AND CHEMICAL PROPERTIES
Acrylamide (CH2=CHCONH2) occurs as white, odorless crystals
that are stable at room temperature but polymerize on being
heated to the melting point, resulting in a highly cross-linked,
insoluble gel. It is also available as a 30-50 wt% aqueous
solution. The important chemical and physical properties of the
crystalline form of acrylamide are shown in Table 1. Synonyms
for acrylamide include propenamide and propenoic acid amide.
Acrylamide reacts through its amide group or its conjugated
ethylenic bond (Conway et al. 1979). Reactions of the amide
group include hydrolysis, dehydration, and alcoholysis. Diels-
Alder additions, polymerization, and the addition (with/without
catalyst) of nucleophilic reactants across the double bond are
characteristic reactions of the conjugated ethylenic group.
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table 1. Chemical and Physical Properties of Acrylamide
CAS No.
NIOSH No.
Molecular formula
Molecular weight
Melting point
Vapor pressure
Appearance
Boiling point
Heat of polymerization
Density
Solubility in g/100 ml
of solvent at 30° C
acetone
benzene
chloroform
dimethyl sulfoxide
ethanol
ethyl acetate
n-heptane
methanol
water
79-06-1
A533250
71.08
84.5 +_ 0.3° C
0.007 mmHg at 25° C
0.033 mmHg at 40° C
0.07 mmHg at 50" C
White crystalline solid
87° C at 2 mmHg
103* C _at 5 mmHg
125° C at 25 mmHg
19.8 Tccal/mole
1.122 g/cm3 at 30" C
63.1
0.346
2.66
124
86.2
12.6
0.0068
155
215.5
NIOSH (1976) and Conway et al (1979); portions were adapted from
the Condensed Chemical Dictionary (1977) and the Handbook of
Chemistry and Physics (1976).
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Ammonia, aliphatic amines, bisulfite, chlorine, and dithiocarba-
mates represent some of the nucleophilic reactants that can be
added across the double bond.
Acrylamide also combines with anions and undergoes homo-
polymerization or copolymerization. In most commercially useful
methods for either reaction, free-radical initiators of redox
catalytic systems are used.
III. EXPOSURE ASPECTS
A. Manufacture
Acrylamide monomer has been manufactured by two processes:
sulfuric acid hydration and catalytic hydration. Acrylonitrile
is the starting material for both. Sulfuric acid hydration is no
longer used and is only of historical interest. Since 1971, all
domestically produced acrylamide has been made by the catalytic
hydration of acrylonitrile (Figure 1). The conversion efficiency
is high, and the resulting aqueous solution of acrylamide, after
undergoing filtration and purging, has a purity of 99.5%-99.9%
(Chem. Eng. 1973, Conway et al. 1979, Otsuka et al. 1975).
Residual acrylonitrile, the primary contaminant, has been
reported to be present at levels of about 50-100 ppm (American
Cyanamid 1977) and 1-5 ppm (Dow Chemical 1980). Levels of
contaminants in imported acrylamide aire not known by EPA;
however, the imported compound also is manufactured by catalytic
hydration.
The manufacture of acrylamide essentially is a continuous
process in which unreacted acrylonitrile is recycled into a
reaction vessel, presumably in a closed system (US EPA 1976).
Although monomer manufacture does not generate large volumes of
by-products, acrylamide-containing waste streams are generated
during polyacrylamide manufacture (Conway et al. 1979).
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FIGURE 1
CATALYTIC HYDRATION METHOD
(ACRYLONITRILS) (COPPER CATALYST]
CONDENSATION
f
""3 MYTH? AT i ON -
i
FILTRATION
!
— • CVAPuRA i ION
1
CONCENTRATION
ADJUSTMENT
( ACRYLAMIDE ^v
UQUEOUS SOLUTION)
CH » CHCN >
COPPER
„
CATALYST
CHo - CHCONH,
Taken from Conway et al. 1979,
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B. Production Volume and Trends
Currently acrylamide is produced in the U.S. by three
manufacturers at four sites. A fourth manufacturer is scheduled
to enter the market in 1980. At the beginning of 1978, Dow
Chemical estimated that the domestic production of acrylamide was
40-50 million Ib/yr (about 50% of capacity), with growth expected
to continue at about 9%/yr, the historical growth rate (Coriway et
al. 1979). In the past, imports of acrylamide have been small,
but this source may become more important as suppliers of
acrylamide-based grout turn to foreign markets to replace
material deleted from one domestic company's product line (Nitto
Chemical 1979, Avanti International 1979).
A review of the production/import volume statistics for
acrylamide shows that between 10 million and 51 million pounds of
this chemical, which is listed in the initial TSCA Inventory
(1977), were produced/imported in 1977. This production/import
range information does not include any data claimed to be
confidential by the person(s) reporting for the TSCA Inventory or
any data that would compromise Confidential Business
Information. The data submitted to the TSCA Inventory, including
production range information, are subject to the limitations
contained in the Inventory Reporting Regulations (40 CFR 710).
C. Use
Approximately 80%-85% of domestic acrylamide production is
consumed in the manufacture of polyacrylamide polymers and
copolymers (US EPA 1976). The level of residual acrylamide
monomer in polyacrylamides ranges between 0.05% and 0.75%,
depending on the intended use of the product (Conway et al.
1979). The level of residual acrylonitrile monomer in
polyacrylamide products has been estimated to be about 1 ppm (AT
Kearney, Inc. 1978).
Acrylamide is also used to manufacture a number of N-sub-
stituted acrylamide and methacrylamide derivatives; the
production volume of the N-methylolacrylamide derivative is the
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largest: (US EPA 1976). These derivatives generally are used to
produce polyacrylamides. Residual levels of acrylamide in these
products are unknown.
The only example of a large-scale use of acrylamide monomer
other than in the manufacture of polymers or monomeric deriva-
tives is its use as a chemical grout, an application that will
consume about 2.2 million Ib of domestically produced monomer in
1980. Approximately another 2.2 million Ib of acrylamide grout
will be imported from Japan. The chemical grouts are used to
repair sewer lines; waterproof mines, tunnels, and foundations;
and consolidate soil around roadbeds and dams. In these specific
applications, an aqueous solution of acrylamide monomer and
suitable catalysts and initiators are injected into the site to
be grouted, and polymerization is allowed to occur in situ.
Although acrylamide grout represents only a small fraction of all
the acrylamide used in the U.S., it also represents a situation
in which toxic monomer Is released directly to the environment.
If the polymerization is incomplete, acrylamide grout can pose a
potential environmental hazard (Conway et al. 1979).
In a recent communication, however, Dow Chemical (1980)
informed EPA that there is technology for the in situ cross-
linking of the polymer, rather than the monomer, in grouting
operations. If adopted, this method would decrease the amount of
acrylamide used for grouting purposes and, thus, the degree of
exposure of grouting workers to this compound.
According to estimates, more than 43% of the acrylamide
manufactured in 1973 was used to produce polyacrylamides for use
in municipal and industrial wastewater treatment and municipal
drinking water treatment (NIOSH 1976, Conway et al. 1979). These
products included polyacrylamide flocculants and sewage
dewatering aids. Approximately 20% was used to produce poly-
acrylamides for the pulp and paper industry, in which the
polymers were used principally as dry strength agents and as
retention and draining aids. In lesser quantities, acrylamide
monomer was employed to produce polyacrylamides for use in
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8
drilling muds; polyester-laminating resins; textile resins,
flocculation of ores, mine tailings, and coal; friction
reduction; thickening agents; soil stabilizers; oil-in-water de-
eraulsifiers; gel chromatography and electrophoresis; photographyr
dyeing; and ceramics (Bikales 1973, Flock and Rausch 1973,
MacWilliams et al. 1973, NIOSH 1976, US EPA 1976, Conway et al.
1979. A more extensive list of uses can be found in these
references)..
D. Occupational Exposure
Although EPA does not hav& quantitative information on the
extent of human exposure to acrylamide resulting from its
manufacture, processing, distribution in commerce, use, or
disposal, the principal opportunities for direct human exposure
appear to be in occupational settings, including the use of
acrylamide solutions for the in situ formation of polyacrylamide
grouts. In 1976, NIOSH estimated that approximately 20,000
workers may be exposed to acrylamide in the U.S. (NIOSH 1976).
There was no indication, however, that this estimate included
grouting workers ~
According to industry estimates, the acrylamide grout market.
could reach 4-5 million Ib/yr by 1980. Based on this estimate
and the number of existing grouting rigs, the number of grouting
workers that could be exposed to acrylamide was conservatively
estimated to be 2,000 (Conway et al. 1979). Although EPA is not,
aware of any monitoring data for grouting applications, there is
reason to believe that grouting workers can be exposed to levels
high enough to cause signs and symptoms of neurotoxicity. Of the
53 cases of acrylamide toxicity reported in the literature, 14
were associated with acrylamide grouts (see the Health Effects
section).
The only monitoring study of an industrial environment was
conducted in an acrylamide-manufacturing plant (NIOSH 1976). The
compound was manufactured by sulfuric acid hydration, a process
that was phased-out during the 1970's. Five months after the
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plant began using this process in 1953, numbness and tingling of
the hands together with general hand and leg weakness were noted
in a small group (number undefined) of potentially exposed
workers. Air sampling indicated only trace quantities of
acrylamide. It was calculated that 1.8 mg/kg of acrylamide was
the maximum amount that could have been inhaled over the 5-mo
period. There are no monitoring data on worker exposures that
may result during catalytic hydration.
Because of government activity in the areas of pollution and
energy, the use of acrylamide in sewer repair and soil con-
solidation and polyacrylamides in wastewater treatment, mining,
and drilling operations is likely to increase. This will
increase the potential for the exposure of workers to acrylamide.
The American Conference of Governmental Industrial
Hygienists has recommended that no more than 0.05 mg/kg/day of
acrylamide be absorbed by workers. Assuming that the respiratory
T "3
exchange is 10 m /day, an airborne limit of 0.3 mg/m (0.1 ppm)
may be calculated as a time-weighted average (TWA) concentration
for a normal 8-hr workday or a 40-hr week (AGGIH 1971). This
limit was based on the work of McCollister et al. (1964), which
is discussed in the Health Effects section.
In 1976, after a critical evaluation of the data, NIOSH
indicated that available animal and human studies did not provide
an adequate basis for altering the existing Federal standard of
0.3 mg/m of air as a TWA value.
E. General Population Exposure
Conway et al. (1979) estimated that 10%-12% of the U.S.
population is exposed to acrylamide monomer in drinking water as
a result of treatment with polyacrylamides. Most of the exposure
was concentrated in Chicago, Kansas City, Las Vegas, Los Angeles,
New Orleans, and St. Louis. These cities used 93% of the total
amount of polyacrylamides designated for water clarification.
City water supply officials who confirmed that they treat potable
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10
water with polyacrylamides stated that they use them at a
concentration of less than 1 mg/liter.
By obtaining data from municipal officials and extrapolating
from the monomer concentration expected in the grade of polymer
used to treat potable water, Conway et al. (1979) estimated the
level of acrylamide monomer reaching the population via treated
drinking water to be less than 0.5 ppb. Note, however, that this
estimate does not take into account the presence of other
residues of polyacrylamides in the finished drinking water that
may also be soluble. The use of polyacrylamides for potable
water treatment has been increasing at the rate of 2%/yr.* It is
therefore possible that some drinking waters will contain
increasing amounts of residual polyacrylamides or oligomeric or
monomeric acrylamide.
Case reports of occupational and nonoccupational exposure
are discussed in the Health Effects section.
F. Environmental Release
Acrylamide can enter the environment from a number of
sources: from monomer- or polymer-manufacturing sites, from
polymer-application sites as residual monomer, and from spills or
leaks that may occur during transportation and handling (Conway
et al . 1979, US EPA 1978). Few data are available on the release
of acrylamide to the environment from these sources. The results
of monitoring studies (US EPA 1978) performed near six plants
that produce acrylamide and/or polyacrylamides showed, within
analytical limits, no acrylamide monomer in air (i.e., less than
0.2 ug/m ), in either the vapor or particulate form, or in soil
or sediment samples (i.e., less than 0.02 ppm). Acrylamide,
however, was detected at a level of 1,500 ppb in the discharge
stream of one plant producing polyacrylamides (US EPA 1978).
There is no information on the environmental
* EPA's office of Drinking Water is initiating assessments of
direct and indirect additives in drinking water (including
acrylamide monomer, polyacrylamides, and their by-products) to
establish if there are human health risks associated with the
presence of these substances.
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11
*-
release of acrylamide that may result from its transportation,
handling, and disposal.
Significant, localized, environmental concentrations of
acrylamide may result from its use in soil grouting. In in situ
soil grouting, unreacted acrylamide monomer may come into direct
contact with surface water or groundwater and travel great
distances in groundwater or deep rock aquifers, where biodegrada-
tion reportedly is absent (Conway et al. 1979). Other potential
sources of environmental release are the monomer residues in
polyacrylamide flocculants, products that are widely used to
condition sludge and ore-tailing deposits and to clarify and
purify municipal drinking water and industrial and municipal
wastewaters (Conway et al. 1979, US EPA 1976).
No data or reliable estimates of acrylamide levels in
wastewater treated with various types of poiyacrylamide
flocculants were found in the available literature. The release
from this source is likely to increase as a result of the
additional emphasis being placed on the cleanup of industrial and
municipal wastewaters nationwide. The potential for acrylamide
contamination of waters by treatment processes also is suggested
by the results of one laboratory experiment. Croll et al. (1974)
demonstrated that under conditions employed in many processes,
such as chlorination at pH 8.5, acrylamide is not removed from
the treated water.
G. Environmental Degradation
Studies of the biodegradation of acrylamide in river water
and soils under various conditions suggest that acrylamide
degrades to low to nondetectable levels over a period of 2-12
days (Conway et al. 1979). In most of these studies, however,
acrylamide was measured indirectly and recoveries were low. In
addition, factors such as the photopolymerization, chemical
* According to Conway et al. (1979), acrylamide manufacturers
are not aware of any spills occurring during transportation;
however, they practice and recommend special handling procedures.
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12
degradation, or adsorption of acrylamide on container walls were
not adequately characterized, precluding a quantitative inter-
pretation of the results.
Lande et al. (1977) studied the leaching and mobility of
acrylamide in topsoil according to procedures outlined in the
Guidelines for Registering Pesticides in the United States (US
EPA 1975). The results suggest that:
(1) The pathways of acrylamide degradation differ under
aerobic and anaerobic conditions. Acrylamide may
have a longer lifetime under anaerobic conditions.
(2) Acrylamide is degraded fairly rapidly by an apparent
metabolic process in aerobic soils. The half-life is
on the order of 20-45 hr for 25 ppm acrylamide at
ambient temperature (22°C). Increasing the acryla-
mide concentration or decreasing the temperature
increases the half-life.
(3) Acrylamide is mobile in various types of soil. When
thin-layer chromatography was applied to Hilton loam
(pH 4.8, organic matter 2.82%), Crogham loamy fine
sand (pH 5.8, organic matter 3.85%), Williamston silt
loam (pH 5.8, organic matter 8.25%), and silt clay
(pH 6.7, organic matter 15.72%), the R^ values for
acrylamide were 0.715, 0.805, 0.880, and 0.657,
respectively. These experiments were run with Lake
water as a solvent; when seawater was used, the Rf
values were slightly, but not significantly, lower.
Unfortunately, no studies have been made of the behavior of
acrylamide in subsurface soil (the site of acrylamide polymeriza-
tion in most grouting operations).
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13
H. Biological Uptake
In a review document prepared for EPA (US EPA 1976), it was
revealed that the available literature contains little or no data
on the bioconcentration potential of acrylamide. However,
calculation of log P (octanol/water partition coefficient) based
on the methods of Hansch and Leo (1979) yields an approximate
value of -1.65 (EPA estimate). The relationship of log P to
bioconcentration potential, as calculated by Neely et al. (1974),
indicates that only compounds with positive log P values near 3
or above are likely to be significantly concentrated in the fatty
tissues of organisms. The negative log P value for acrylamide
shows that the solubility of this compound in water is very high,
compared with that in lipid, and it suggests that the bioconcen-
tration of acrylamide would be minimal.
IV. HEALTH EFFECTS
The major effects of acrylamide toxicity are central-
peripheral distal axonopathies and skin changes associated with
the dermal route of exposure. With the exception of a few high-
dose animal studies, there are no reports of adverse effects on
other organ systems.
A. Case Reports
Acrylamide toxicity has been primarily an occupational
problem. Of the 53 cases of acrylamide toxicity in the published
literature (summarized in Tables 2 and 3), only 5 resulted from
nonoccupational exposures (Igisu et al. 1975). The latter cases
represent a Japanese family who ingested and briefly bathed in
well water contaminated by acrylamide grout. Only one case of
acrylamide poisoning has been reported in the U.S., although some
authors allude to other probable cases (Kuperman 1958, NIOSH
1976, Spencer and Schaumburg 1974a).
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Table 2. Case Reports of Human Acrylamide Toxicity
Number
of cases
Source of exposure
(location)
Reference
15
10
6
6
5
4
3
2
1
1
Polyacrylamide mfg. (Japan)
Monomer mfg. (Japan)
Polyacrylamide mfg. (England)
Chemical grout (England)
Contaminated well water
(Japan)
Monomer mfg. (Prance)
(Japan)
Chemical grout (France)
Chemical grout (Canada)
Polyacrylamide mfg. (U.S.)
Takahashi et al. 1971
Fujita et al. 1960
Garland and Patterson
1967
Kesson et al. 1977
Igisu et al. 1975
Morviller 1969
Satoyoshi et al. 1971
Graveleau et al. 1970
Cavigneaux and Cabas-
son 1972
Auld and Bedwell 1967
Davenport et al. 1976
Based on a comparison of these case reports, a general
pattern of acrylamide toxicity can be described, although each
individual did not manifest all the signs and symptoms. The
earliest sign of acrylamide toxicity appears to occur in the
skin. Desquamation (skin peeling) of the hands and, less often,
of the feet normally occurs within 2 weeks of the initial dermal
contact with acrylamide. Erythema, dermatitis, and skin
ulcerations often persist throughout the duration of exposure.
Other early symptoms in the extremities include numbness and
tingling, coldness of skin and tenderness to the touch, excessive
sweating, bluish—red skin color, and muscle weakness, sometimes
reflected as an inability to write or to climb stairs.
Concomitant with or shortly after the onset of these
symptoms, fatigue and drowsiness may appear along with increasing
muscle weakness. Other reported symptoms include mental con-
fusion and other psychological changes,, gastrointestinal
problems, and weight loss. Weight loss appears to occur
primarily in patients with longer term exposure to acrylamide.
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15
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The above symptoms precede signs of overt peripheral neuro-
logical involvement. Neurological signs that may become evident
in as little as 4 wk after the first exposure to acrylamide
include ataxia and weak or absent tendon reflexes. As the axono-
pathy progresses/ occasional inability to stand, body tremors,
slurred speech, and mild difficulty in swallowing may occur. In
some instances, these signs worsen progressively for up to 2 wk
after the exposure period.
Peripheral and central nervous system involvement has been
confirmed by clinical neurological examinations. Electrophysio-
logic examinations of the peripheral nervous system have revealed
moderate disturbances of sensory nerve function, in terms of
reduced action potential, and reduced sensory and, to a lesser
extent, motor nerve conduction velocities (Davenport et al. 1976,
Kesson et al. 1977, Takahashi et al. 1971). An examination of
sural nerve biopsies suggested that simultaneous axonal
degeneration and regeneration of nerve fibers had occurred
(Davenport et al. 1976).
Although peripheral nerve damage appears to predominate* in
acrylamide toxicity, central nervous system involvement also has
been found. Igisu et al. (1975), for example, have reported the
occurrence of hallucinations and mental confusion in affected
subjects. Many authors have reported instances of drowsiness
that presumably are due to midbrain involvement (Garland and
Patterson 1967). This presumption was confirmed by the EEG
measurements of Takahashi et al. (1971). Other signs postulated
to reflect central nervous system damage are slurred speech;
coarse, generalized tremor; truncal ataxia; and ataxia dis-
proportionate with the observed degree of muscle weakness arid
peripheral nerve deficiency (Garland and Patterson 1967). Pujita
et al. (1960) further suggested the possibility of cerebellar
involvement on the basis of the ataxia, positive Romberg sign,
and positive finger-nose test (for coordinated movements of the
extremities) observed in several patients.
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17
No pertinent abnormalities were found in individuals in whom
clinical tests of blood, urine, cerebrospinal fluid, and liver
and kidney function were performed (Auld and Bedwell 1967,
Davenport et al. 1976, Fujita et al. 1960, Garland and Patterson
1967, Takahashi et al. 1971). Tests usually were given on
admission to the medical facility. Similarly, examination of the
cardiovascular system, bones, and joints showed no pertinent
deviations from normal (Auld and Bedwell 1967, Fujita et al.
1960, Garland and Patterson 1967), although marked wasting of the
digital muscles of the hands, probably secondary to nerve loss,
was noted in some cases (Davenport et al. 1976, Garland and
Patterson 1967). Blood electrolyte levels were not explicitly
reported in any of the cited studies.
A correlation between the level of acrylamide exposure and
the neurotoxic effects manifested in humans is not possible
because conditions surrounding the exposure incidents differed
widely, and, in most cases, individuals were exposed to unknown
concentrations of acrylamide that varied over time. The' dermal
route of exposure, with some respiratory exposure, predominated
in all of the occupational incidents. It is possible that slight
oral ingestion also occurred as a result of hand contamination.
The exact time of the appearance of symptoms after dermal
exposure was not reproducible. The onset times varied from 2 wk
(Kesson et al. 1977) to 4 wk (Auld and Bedwell 1967, Garland and
Patterson 1967, Igisu et al. 1975) to 8 yr (Takahashi et al.
1971). Time to recovery was related to the severity of the signs
and symptoms rather than simply to length of occupational
exposure. Although recovery generally occurred, two patients
showed little sign of recovery 15 mo after diagnosis and
cessation of exposure to acrylamide (Kesson et al. 1977). This
finding plus central nervous system involvement, in which nerves
do not regenerate but reserve capacity may allow functional
recovery, indicate that permanent damage may occur.
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18
B. Animal Studies
1. Acute and Short-Term Studies
Acrylamide toxicity has been studied in a variety of
laboratory animals, including mice, rats, guinea pigs, rabbits,
cats, dogs, and monkeys. LD5Q values for rats range from
120 mg/kg via the intraperitoneal (ip) route (Druckery et al.
1953) to 203 mg/kg via oral administration (Fullerton and Barnes
1966). Keeler et al. (1975), however, reported single oral dose
LDgQ values of 240 mg/kg in female rats cind 277 mg/kg in male
rats of unspecified strain, age, and weight. McCollister et al.
(1964) estimated the single oral dose LDt;Q for rats, guinea pigs,
and rabbits to be in the range of 150-180 mg/kg. Although LDi5Q
estimates are not available for cats or monkeys, deaths have been
reported following two daily injections of 50 mg/kg ip in cats
(Kuperman 1958) and two daily injections of 100 mg/kg ip in
monkeys (McCollister et al. 1964). In most fatal exposures,
death occurred 1-3 days after dosing.
Regardless of species, nearly all acute studies of acryla-
mide toxicity involve manifestations of various degrees of neuro-
toxicity (the major reported toxic effect in humans). Examples
of these studies are- presented here.
Hamblin (1956) reported that administration of 50 or 100
mg/kg/day to albino rats by oral intubation produced prostration
and death after 15 and 3 days, respectively. Fullerton and
Barnes (1966) observed that a single oral dose of 100 mg/kg
produced only fine tremors in rats; when this dose was repeated
24 hr later, most of the animals died within 3 days. When rats
were given 12 oral doses of 50 mg/kg over a 15-day period, they
developed severe weakness and died within a few days after the
final dose. Ataxia, labored respiration, convulsions, and
behavioral changes resembling fright or excitement also have been
noted in fatally exposed rats (Druckery et al. 1953). The direct
cause of death in rats and cats has been attributed to respira-
tory failure associated with laryngeal spasm and pulmonary
obstruction (Spencer and Schaumburg 1974b; Druckery et al. 1953).
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19
Kuperraan (1958) gave single intravenous (iv) or ip doses of
75-1,000 mg/kg to cats. The most consistent effects, in order of
appearance, were ataxia, tremors, weakness, emesis, defecation,
signs of mass sympathetic discharge, behavior suggestive of
hallucinations, and periodic tonic-clonic convulsions prior to
death.
In one monkey given an ip injection of 100 mg/kg acrylamide
on 2 successive days, death occurred 1 day after the last
injection (McCollister et al. 1964). Prior to death, the monkey
had no sense of balance, but it was able to use its muscles for
crawling. No convulsions were reported. The histopathological
effects of acrylamide poisoning in this animal included con-
gestion of the lungs, congestion of the kidneys with degeneration
of the convoluted tubular epithelium and glomeruli, and necrosis
and fatty degeneration of the liver. Rats that died after acute
exposures showed only fine fatty infiltration of the liver.
2. Subacute, Subchronic, and Chronic Animal Studies
The studies described below provide information on the
minimum levels of acrylamide monomer that cause signs of
neurotoxicity, the effect of exposure route on the development of
these signs, and pathologic alterations of the nervous system
that occur after exposure.
a. Minimum Toxic Levels of Acrylamide
Table 4 (Conway et al. 1979) summarizes published data on
acrylamide doses that produce observable signs of central-
peripheral axonopathy in experimental animals. The table
includes the route of administration, dosage schedule, time to
onset of observable neurological signs, and total administered
dose at the onset of these signs.
Cats developed neurological signs after exposure to as
little as 1 mg/kg/day (ip or iv) five times per week over 125-180
days (Hamblin 1956, Kuperman 1958). Schaumburg et al. (1974)
found that cats given single acrylamide doses as low as 3
nig/kg/day in drinking water exhibited neurological signs at 70
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20
Table- 4-
Producing Early Sign* o£ Peripheral Neuropathy in VSriou* Mamnals
Organism
Rats
Tadult)
cats
Dogs
Primates
Route- rose, schedule
100 mg/kg, 2 dosae/v4cc
Oral 100 mg/kg, 1 dosa/vfc
100 mg/kg, 1 doae/2 wfc
Ip 75 mg/kg, 1 dose/day
Ip 50 mg/kg, 3 dosesA*
Ip 50 rag/kg, 1 dose/day
Oral 40 ing/kg/day3
Ip 40 mg/kg, 1 dose/day
Oral 30 mg/kg/day0
Ip 30 mg/kg, 1 dose/day
Oral 25 mg/kg, 5 dosea/v*
Ip 25 mg/kg, 1 dose/day
Oral 9 mg/kg/day
Ip 50 mg/kg, 1 dose/day
Oral 20 rng/kg, 1 dose/day
Ip 20 mg/kg, 1 dose/day
Ip 10 mg/kg, 1 dose/day
Sc 10 mg/kg, 1 dose/day
Oral 3 rag/kg, 5 doses/vfc
in chow
Oral 3 mg/kg, 1 dose/day
in water
Ip 1 mg/kg, 5-6 doses/wk
Iv 1 mg/kg, 5 doses/wie
Oral 15 mg/kg, 1 dose/day
Oral 10 mg/kg, 1 dose/day
Oral 5 mg/kg, 1 dose/day
Oral
in fruit 2O mg/kg, 1 dose/day
Oral
in fruit 25 mg/kg, 1 dose/day
Oral
in fruit 10 mg/kg, 1 dose/day
Oral
in water 10 mg/kg, 49 doses/69
Cays to Total
initial affect adrtiniatered
(1*5. of doses) dose (mg/kg) Refiarencw-
21(6)a
42(6)
210(15)
4.6b
18(7-8)
6.4b
14
6.713
21
10. -P
28(20)
16.813
56d
2(2)
14-21
5
13-16
17-22
68
70,163
125
180
2la
28-35*
2la
16
42
42-97
days 43
600
600
1500
345
350-400
320
560
268
630
321
500
420
504
100
280-420
100
130-160
170-220
144
210,489
100
130
315
280-350
105
320
630
420-970
340
BMllerton and
Barnes. 1966
Kaplan and Murphy
1972
Suzuki and Pfaff
1973
Kaplan and Murphy
1972
McCollistar et al.
1964
Kaplan et al. 1973
MoCoUiater at al.
1964
Kaplan et al. 1973
Fuller-ton and
Barnes 1966
Kaplan and Murphy
1972
MoOollister et al.
1964
Kfcpannan 1958
raswrir;- and Ribelin
1969
ScJiauntxirc et al.
1974
Schauifaurg^ af al.
1974
Prinaa* 1969
McOallistar at al.
1964
Schauwburg at al.
1974
KUpennan 1958
Hanblin 1956
Tftonam et al. 1974
ffentolin 1956
Thanam at al. 1974
Efcffcins 1970
EtopWLns.1970
napkins 1970
McCollister et al.
1964
Source] Cbnway et al. (1979)
*Signs of intoxication probably appeared earlier than noted.
Sions of intcnticsiticn based on electrorod measm. amenta.
c^-rylamide mixed with food. Cose estimated by McColliater and ooworkera, 1964.
Effect noted in only 1/20 exposed animals.
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21
and 163 days. In all three studies, the total administered doses
were 100-489 mg/kg at the time of onset of signs.
Dogs* and primates appear to be somewhat less sensitive to
acrylamide than cats, requiring daily doses of 5-25 mg/kg to
develop early signs of central-peripheral axonopathy in the same
time frame (Hamblin 1956, Hopkins 1970, McCollister et al. 1964,
Thomann et al. 1974). Calculated total administered doses at the
onset of signs varied from 105 to 970 mg/kg , but they were
generally around 325 mg/kg. Rats appeared to be relatively more
resistant to acrylamide than dogs and primates. Total doses
producing early neurological signs in rats typically fell in the
range of 300-600 mg/kg (Kaplan and Murphy 1972, Kaplan et al.
1973, McCollister et al. 1964).
It should be noted that species may differ in the ease with
which early signs can be identified by observers and in the
complexity of their gaits.
b. No-Effect Levels
Table 5 (Conway et al. 1979) lists acrylamide doses found to
have no apparent neurological effects on animals. The animals
reportedly tolerated much higher total doses of acrylamide when
the compound was given in low daily doses over prolonged periods
of time. For example, total doses of 1,323-2,079 mg/kg given
orally to rats over a 6 mo period caused no signs of limb impair-
ment. In contrast, 560-630 mg/kg given over 2-3 wk resulted in
obvious signs of hind limb weakness (McCollister et al. 1964). A
similar, although less marked, comparison was made in the rat
study of Fullerton and Barnes (1966). Relationships between
duration of exposure and the effects of comparable total daily
doses also are apparent with cats, primates, and dogs
(McCollister et al. 1964, Hamblin 1956).
* Data of Thomann et al. (1974), and Hamblin (1956), are
conflicting; dogs may not be less sensitive than cats based on a
consideration of total administered dose.
** The monkey given this total dose was reportedly reluctant
to consume all of its contaminated fruit; the next highest total
dose administered was 820 mg/kg (Hopkins).
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22
Table 5. Acrylamide Doses Reported To Produce No Observable Signs of Mverse Effects
(All doses given orally)
Organism
Rats
Cats
Dogs
Primates
Dose schedule
3 mg/kg/day
10 mg/kg/day
10 mg/kg/day
7 mg/kg/day3
11 mg/kg/day3
0.3 mg/kg/day
1.0 mg/kg/day
1 mg/kg/day
5 mg/kg/day
8 mg/kg/day
1 mg/kg/day
3 mg/kg/day
Days of
Exposure
(No. of doses)
90
70(55)
116a(116)
189
189
365(260)
367(257)
133
35
28
363(255)
363(255)
Ttotal
administered
dose (mg/kg)
270
550
1,160
1,323
2,079
78
257
133
175
224
255
765
Reference
McCollister et al.
1964
Fullerton and Barnes 1966
Fullerton and Barnes 1966
McCollister et al. 1964
McCollister et al.
McCollister et al.
McCollister et al.
Hamblin 1956
Hamblin 1956
Hamblin 1965
McCollister et al.
McCollister et al.
1964
1964
1964
1964
1964.
Source: Ccnway et al. (1979).
aDuration not specified; estimate of minimum duration based 131 1 dose/day.
kficrylamide mixed with food; dose estimated by McCollister et al. (1964).
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23
McColli3ter at al. (1964) concluded that a safe, no-effect
acrylamide level for cats on long-term oral administration is
probably 1.0 mg/kg/day and certainly at or above 0.3 mg/kg/day.
They also concluded, from studies of monkeys given repeated oral
doses of acrylamide over a 1-yr period, that no-effect levels for
monkeys were between 1.0 and 3.0 mg/kg/day.
Spencer (1979) reported minor pathological central nervous
system effects that consisted of scattered axonal swellings in
the medulla oblongata (gracile tract) and lumbar spinal cord
(ventromedial quadrant of gray matter) in one Rhesus monkey
exposed to 3 mg/kg/day for 49 wk. No peripheral nerve effects
were noted. Monkeys exposed to 1, 2, or 0.5 mg/kg/day for 338,
325, and 546 days, respectively, showed no effects upon being
examined by modern histopathological or electron microscopic
techniques. He concluded that 3 mg/kg/day, the dose reported by
McCollister et al. (1964) as a no-effect level in primates,
represents a level for nervous system damage and that 0.5
mg/kg/day is the lowest dose at which no effects were observed in
monkeys.
Burek et al. (1979) conducted a 90-day study of rats given
0.05-20 mg/kg/day of acrylamide in drinking water. In three rats
exposed to 1 mg/kg/day for 90 days, 25% of the fields examined by
electron microscopy showed axolemma invaginations, with cell
organelles and/or dense bodies being found in sciatic nerves.
These changes were not apparent roughly 1 mo after exposure.
Rats exposed to 0.05 or 0.2 mg/kg/day showed no effects. The
author concluded that 1 mg/kg/day for 90 days is a minimal effect
level in the rat.
3. Tissue Distribution
Edwards (1975) examined the distribution and metabolism of
acrylamide in rats given a single dose of 100 mg/kg iv. When
unbound acrylamide in the blood was analyzed as a function of
time and the data were extrapolated back to zero time, con-
centrations very close to the theoretical value for dilution in
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24
total body water (assumed to be 70% of total body weight) were
obtained. This corresponded to a Iog10 concentration in blood of
3.22 nntol/ml. There were no indications or reports of the
osraolality of urine or the osraoregulation of extracellular
fluid. The results of this experiment indicate that acrylamide
is completely distributed in the fluid compartments of the body
within less than 30 min. Edwards gave the half-life of
acrylamide in blood as 1.9 hr. However, this value may represent
only the alpha phase, as the study ended after 4 hr.
In a similar study, Hashimoto and Aldridge (1970) found that
although some acrylamide was freely distributed in vivo, the
majority was bound to tissue and circulating protein, especially
hemoglobin. Twenty-four hours after a single iv injection of [1-
l^C]-acrylamide into rats, the highest levels of free/soluble .and
protein-bound label were recorded in whole blood, with decreasing
"levels being found in kidney, liver, brain, spinal cord, and
sciatic nerve. By 14 days, the majority of free/soluble label
•had disappeared. Protein-bound label, however, remained at about
25% of the 24-hr level in all samples except for whole blood,
which remained at 100% of the 24-hr level over the full 14-day
period. The data of Hashimoto and Aldridge also suggest that the
half-life of acrylamide in blood is 13 days; this value may
represent the half-life of the beta phase.
Hashimoto and Ando (1975) studied the distribution and fate
of 14C-labeled acrylamide in rabbits. Single topical applica-
tions of 10%-30% aqueous acrylamide solutions rapidly penetrated
intact skin and appeared in the blood as free monomer and as
monomer bound to proteins, particularly hemoglobin. By 24 hr,
acrylamide concentrations were higher in tissues than in the
blood. These data suggest that acrylamide is distributed rapidly
within the body.
C. Effect of Acrylamide on Nerve Tissue.
Acrylamide is readily absorbed through intact skin and
rapidly distributed throughout the body. Although a large
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25
percentage of the absorbed acrylamide may be eliminated from the
body by metabolism and excretion (Hashimoto and Aldridge 1970,
Spencer and Schaumburg 1974a), a small amount becomes bound to
nervous system tissues, resulting in various morphologic signs of
nerve tissue deterioration. Studies have demonstrated axonal
degeneration with demyelination in mice (Bradley and Asbury
1970), rats (Fullerton and Barnes 1966, Suzuki and Pfaff 1973),
cats (Leswing and Ribelin 1969, Prineas 1969, Schaumburg et al.
1974), dogs (Thomann et al. 1974), monkeys (Leswing and Ribelin
1969), baboons (Hopkins 1970), and humans (Davenport et al. 1976,
Fullerton 1969).
Under the light microscope, the first sign of morphological
deterioration appeared to be nodal or parariodal (nodes of Ran-
vier) axonal swelling (Hopkins 1970, Prineas 1969, Schaumburg et
al. 1974, Spencer and Schaumburg 1974b). Examination by electron
microscopy characterized these swellings as masses of
neurofilaments, various dense bodies, and either enlarged or
degenerating mitochondria (Suzuki and Pfaff 1973, Schaumburg et
al. 1974, Prineas 1969). Subsequently, the myelin sheath
retracted paranodally along the axon. This was followed by
axonal degeneration and, frequently, myelin fragmentation
(Hopkins 1970, Prineas 1969, Schaumburg et al. 1974). Extensive
myelin breakdown, as opposed to retraction, occurred only after
axonal degeneration (Fullerton and Barnes 1966). In these
studies, the longer nerves were more affected than the shorter
nerves, the distal parts of the nerves were more susceptible to
damage than the proximal parts, and large-diameter asons appeared
to be more susceptible than small-diameter axons.
Prineas (1969) and Spencer and Schaumburg (1974b, 1975,
1976) also have demonstrated that distal axonal degeneration and
secondary demyelination occur in long ascending and descending
spinal cord tracts, including the dorsal and lateral columns and
the spinocerebellar tract. In more recent studies with acryla-
raide-intoxicated rats, Schaumburg and Spencer (1978) found axonal
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26
degeneration in the hypothalamus, optic tract, and anterior
cerebellum.
The distal axonal degeneration in vulnerable long tracts of
the spinal cord, brain, and peripheral nervous system (central-
peripheral distal axonopathy) seen in acrylamide toxicity
represents a common reaction of the nervous system to chronic
exposure to a variety of neurotoxic agents (Spencer and
Schaumburg 1976K Three theories have been proposed to account
for the action of acrylamide on nerve tissue (Cavanagh 1973,
Pleasure et al. 1969, Spencer and Schaumburg 1974b), but the
biochemical mechanism involved has not been demonstrated.
V. SUMMARY AND FINDINGS
EPA has reviewed the-available information on the major
health effects recommended for testing by the ITC. Except for
neurotoxicity, an extensive evaluation of other health effects
has not been performed since it has been consistently
demonstrated that acrylamide produces central-peripheral
axonopathies (Spencer and Schaumberg 1976). The animal species
in which this effect was demonstrated include rats (Edwards 1975,
Fullerton and Barnes 1966, Hashimoto and Aldridge 1970, Suzuki
and Pfaff 1973), mice (Bradley and Asbury 1970), cats
(McCollister et al. 1964, Kuperman 1958, Leswing and Ribelin
1969, Schaumburg et al^ 1974), dogs (Hamblin 1956, Thomann et al.
1974), baboons (Hopkins 1970), and monkeys (McCollister et al.
1964). In addition, there are at least 48 published cases of the
occupational toxicity and 5 cases of the nonoccupational toxicity
of acrylamide to humans (NIOSH 1976, US EPA 1976, Conway et al.
1979), many of whom manifested a measurable degree of central-
peripheral axonopathy.
In humans, the predominant signs of neurotoxicity are
related to peripheral nerve involvement and, to a lesser extent,
central nervous system involvement. A variety of other signs and
symptoms also are generally reported, the most common ones
occurring in the skin, hands, and feet. The onset of effects is
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27
delayed following initial exposure, and the effects may be
reversible, although this is not always the case.
Based on laboratory data, EPA has concluded that acrylamide
is neurotoxic at very low levels, a conclusion that is sub-
stantiated by a 1 yr study in cats indicating a no-effect level
of 0.3-1.0 mg/kg/day, given orally.
Thus, EPA does not plan to require the health effects
testing recommended by the ITC. Instead, EPA plans to evaluate
acrylamide for possible regulatory" controls.
As previously stated, acrylamide causes significant
neurological effects at very low levels. Thus, it is likely that
any control adopted on the basis of acrylamide's neurotoxicity
will provide a considerable degree of protection from other
potential health hazards. Under such circumstances, the Agency
does not believe it is in the public interest to perform a
complete assessment of nonneurological effects. Rather, EPA
believes that its rulemaking activities should be devoted to more
pressing testing needs concerning chemicals about which much less
is known. Thus, EPA has not conducted an in-depth evaluation of
other health effects and does not plan to require testing for
them.
EPA recognizes that in rejecting the alternative to require
testing for effects which are not fully characterized, it is
leaving gaps in the toxicity data base the Agency is trying to
create. As a result, EPA may in some cases fail to reduce the
risk of a health hazard to the extent it could if the effect were
fully characterized. This is particularly true where the
oncogenicity risk has not been evaluated. However, as discussed
below, Dow Chemical Company plans to conduct oncogenicity
testing. Thus, EPA believes that, as a matter of priorities and
resource allocations, the Agency should not develop a test rule
for the health effects of acrylamide to resolve remaining issues
about its toxicity but instead should seek data on chemicals for
which the need is greater.
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28
EPA will reevaluate this decision if Dow fails to recommence
the anticipated testing. Dow had started a 2 yr chronic toxicity
oncogenicity study using CDF Fischer 344 rats in June 1979.
Doses of 0.01-1 mg/kg/day were administered orally. Because of
unexpected difficulties in maintaining the proper dose levels,
however, Dow terminated the study as of February 1980 (Rosenstein
1980). EPA understands that Dow will resume the testing
shortly. Although the proposed Dow study does not fully satisfy
EPA's test standards for these studies, i.e., only one rodent
species will be used, EPA anticipates that it will provide useful
information concerning toxic effects other than neurotoxicity.
The Agency also is aware that a functional neurologic study
in primates is under way at the University of Rochester
(Maurissen 1979) sponsored by Dow Chemical Company and other
chemical manufacturers. This study may provide information that
will allow the "no-effect level" for the general population to be
determined more precisely.
For these various reasons, EPA believes that additional
testing resources should not be expended at this time to further
characterize the health effects of acrylamide. EPA will initiate
a preregulatory assessment of acrylamide based upon existing
toxicity data.
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29
VI. REFERENCES
American Conference of Governmental Industrial Hygienists. 1971.
Committee on threshold limit values: Documentation of the
threshold values for substances in workroom air, 3rd ed.
Cincinnati: ACGIH. pp. 5-6.
American Cyanamid Co. 1977. In response to OSHA's request for
information on acrylonitrile (42 FR 33043). Letter to Docket
Officer, U.S. Department of Labor—OSHA
AT Kearney, Inc. 1978. Assessment of acrylonitrile contained in
consumer products: Draft final report. Washington, DC: U.S.
Consumer Product Safety Commission. Contract No. CPSC-C-77-0009.
Auld RB, Bedwell SF. 1967. Peripheral neuropathy with sym-
pathetic overactivity from industrial contact with acrylamide.
Can. Med. Assoc. J. 96:652-654.
Avanti International, 1275 Space Park Drive, Houston, TX 77058.
1979. Acrylamide grout data package.
Bikales NM. 1973. Preparation of acrylamide polymers. In:
Water soluble polymers, polymer science and technology series,
Vol. 2. Bikales NM, ed. New York: Plenum Press, pp. 213-225.
Bradley WG, Asbury AK. 1970. Radioautographic studies of
Schwann cell behavior. I. Acrylamide neuropathy in the mouse.
J. Neuropathol. Exp. Neurol. 29:500-506.
Burek JD, Albee RR, Beyer JE, Bell TJ, Carreon RM, Morden DC,
Wade CE, Hermann EA, and Gorzinski SJ. July 2, 1979. Results of
a 90 day toxicity study in rats of acrylamide administered in the
drinking water followed by up to 144 days of recovery. Report
from Dow Chemical Co. to U.S. EPA.
Cavanagh JB. 1973. Peripheral neuropathy caused by chemical
agents. CRC Grit. Rev. Toxicol. 2:365-377.
Cavigneaux A, Cabasson GB. 1972. Intoxication par 1'acryl-
amide. Arch. Mai. Prof. Med. Trav. Secur. Soc. 33:115-116.
Chenu Eng. 1973. New catalytic route to acrylamide. (November
26):63-69.
Condensed Chemical Dictionary, 9th ed. 1977. New York: Van
Nostrand-Reinhold Co.
Conway EJ, Petersen RJ, Colingsworth RF, Graca JG, Carter
JW. 1979. Assessment of the need for and character of limita-
tions on acrylamide and its compounds. Draft report prepared for
the Office of Pesticides and Toxic Substances. Washington, DC:
U.S. Environmental Protection Agency. Contract No. 68-01-4308.
-------
30
Croll BT, Arkell GM, Hodge RPJ. 1974. Residues of acrylamide in
water. Water Res. 8:989-993.
Davenport JG, Parrell DP, Sumi SM. 1976. Giant axonal
neuropathy caused by industrial chemicals: neurofilamentous
axonal masses in man. Neurology. 26:919-923.
Dow Chemical Co. 1980. Letter to Dr. Patricia M. Hilgard, US
Environmental Protection Agency, in response to comments on
Midwest Research Institute's draft entitled "Assessment of the
need for and character of limitations on acrylamide and its
compounds."
Druckery H, Consbnich U, Schmahl D. 1953. Effects of monomeric
acrylamide on proteins. Z. Naturforsch. 8b:145-150.
Edwards PM. 1975. Distribution and metabolism of acrylamide and
its neurotoxic analogs in rats. Biochem,. Pharmacol. 24:1277-
1282.
Flock HG, Rausch EG. 1973. Application of polyelectrolytes in
municipal waste treatment. In: Water soluble polymers, polymer
science and technology series, Vol. 2. Bikales NM, ed. New York:
Plenum Press, pp. 21—73.
Pujita A, Shibata J, Kato H, Amami Y, Itorai K, Suzuki E, Nabazawa
T, Takahashi T. 1960. Clinical observations of three cases of
acrylamide poisoning. Nippon Ijo Shimpo 1869:37-40 (summarized
in NIOSH Criteria Document 1976).
Fullerton PM. 1969. Electrophysiological and histological ob-
servations on peripheral nerves in acrylamide poisoning in man.
J. Neurol. Neurosurg. Psychiatry 32:186-192.
Fullerton PM, Barnes JM. 1966. Peripheral neuropathy in rats
produced by acrylamide. Br. J. Ind. Med. 23:210-221.
Garland TO, Patterson MWH. 1967. Six cases of acrylamide
poisoning. Br. Med. J. 4:134-138.
Graveleau J, Loirat P, Nusinovici V. 1970. Polynevrite par
1'acrylamide. Rev. Neurol. 123:62-65.
Hamblin DO. 1956. The toxicity of acrylamide — a preliminary
report. Hommage au Doyen Rene Fabre (Paris). pp. 195-199.
Handbook of Chemistry and Physics, 57th ed. 1976. Cleveland,
OH: Chemical Rubber Co.
Hansch C, Leo A. 1979. Substituent constants for correlation
analysis in chemistry and biology. New York: John Wiley and
Sons. 336 pp.
-------
.31
Hashimoto Kr Aldridge WN. 1970. Biochemical studies on acryl-
amide, a neurotoxic agent. Biochem. Pharmacol. 19:2591-2604.
Hashimoto K, Ando K. 1975. Studies on the percutaneous absorp-
tion of acrylamide. Abstracts of XVIII International Congress on
Occupational Health, Brighton, England, September 14-19. p.
453.
Hopkins A. 1970. Effect of acrylamide on the peripheral nervous
system of the baboon. J. Neurol. Neurosurg. Psychiatry 33:805-
816.
Igisu H, Goto I, Kawamura Y, Kato M, Izumi K, Kuroiwa Y. 1975.
Acrylamide encephaloneuropathy due to well water pollution. J.
Neurol. Neurosurg. Psychiatry 38:581-584.
Kaplan ML, Murphy SD. 1972. Effect of acrylamide on rotarod
performance and sciatic nerve beta-glucuronidase activity of
rats. Toxicol. Appl. Pharmacol. 22:259-268.
Kaplan ML, Murphy SD, Gilles FH. 1973. Modification of acryl-
amide neuropathy in rats by selected factors. Toxicol. Appl.
Pharmacol. 24:564-579.
Keeler PA, Betso JE, Yakel HO. 1975. Toxicological properties
of a 50.7% aqueous solution of acrylamide. Midland, MI: Dow
Chemical Co.
Kesson CM, Baird AW, Lawson DH. 1977. Acrylamide poisoning.
Postgrad. Med. J. 53:16-17.
Kuperman AS. 1958. Effects of acrylamide on the central nervous
system of the cat. J. Pharmacol. Exp. Ther. 123:180-192.
Lande SS, Bosch SJ, Howard PH. 1977. Metabolism and transport of
acrylamide in soil. Draft report prepared for the U.S.
Environmental Protection Agency. Contract No. 68-01-2679.
Leswing RJ, Ribelin WE. 1969. Physiologic and pathologic changes
in acrylamide neuropathy. Arch Environ. Health 18:22-29.
MacWilliams DC, Rodgers JH, West TJ. 1973. Water-soluble
polymers in petroleum recovery. In: Water soluble polymers,
polymer science and technology series, Vol. #2. Bikales NM, ed.
New York: Plenum Press, pp. 105-126.
Maurissen J, University of Rochester, Rochester, NY. November 6,
1979. Personal communication.
McCollister DD, Oyen F, Rowe VK. 1964. Toxicology of acrylamide.
Toxicol. Appl. Pharmacol. 6:172-181.
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32
Morviller P. 1969. Propos sur un toxique Industrie! peu conriu en
France. 1' acrylamide. Arch. Mai. Prof. Med. Trav. Secur. Soc.
30(9)s527-530.
National Institute for Occupational Safety and Health (NIOSH).
1976. Criteria for a recommended standard - occupational
exposure to acrylamide. Washington, DC DHEW 77-112.
Neely WB, Branson DR, Blau GE 1974. Partition coefficient to
measure bioconcentration potential of organic chemicals in
fish. Environ. Sci. Technol. 8(13):1113-1115.
Nitto Chemical Industry Co., Ltd., Tokyo, Japan. 1979.
Specification of chemical grout main agent.
Otsuka E, Takahashi T, Hashimoto N, Matsuda P. 1975.
Development of catalytic hydration process for acrylamide
production. Chem. Econ. Eng. Rev. 7:29.
Pleasure DE, Mishler KC, Engel WK. 1969. Axonal transport of
proteins in experimental neuropathies. Science 166:524-525.
Prineas J. 1969. The pathogenesis of dying-back polyneurop-
athies. Part II. An ultrastructural study of experimental
acrylamide intoxication in the cat. J. Neuropathol. Exp.
Neurol. 28:571-597.
Rosenstein LS, Test Rules Development Branch, Assessment
Division, Office of Testing and Evaluation, Office of Pesticides
and Toxic Substances, U.S. Environmental Protection Agency.
February 5, 1980. Contact report on meeting between
representatives of Dow Chemical Co. and EPA.
Satoyoshi E, Kinoshita M, Yano H, Suzuki Y. 1971. Clin. Neurol.
(Tokyo) 11:667-671.
Schaumburq HH, Spencer PS, 1978. Environmental hydrocarbons
produce degeneration in cat hypothalamus and optic tract.
Science 199:199-200.
Schaumburg HH, Wisniewski HM, Spencer PS. 1974. Ultrastructural
studies of the dying-back process. I. Peripheral nerve terminal
and axon degeneration in systemic acrylamide intoxication. .1.
Neuropathol. Exp. Neurol. 33:260-284.
Shiraishi Y. 1978. Chromosome aberrations induced by monomeric
acrylamide in bone marrow and germ cells of mice. Mutat. Res.
57:313-321.
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33
Spencer PS. 1979. Unpublished final report. Washington, D.C:
National Institute for Occupational Safety and Health. Contract
No. OH 00535.
Spencer PS, Schaumburg HH. 1974a. A review of acrylamide
neurotoxicity. Part I. Properties, uses and human exposure.
Can. J. Neurol. Sci. 1:143-150.
Spencer PS, Schaumburg HH. 1974b. A review of acrylamide neuro-
toxicity. Part II. Experimental animal neurotoxicity and
pathologic mechanisms. Can. J. Neurol. Sci. 1:152-169.
Spencer PS, Schaumburg HH. 1975. Nervous system degeneration
produced by acrylamide monomer. Environ. Health Perspect.
11:129-133.
Spencer PS, Schaumburg HH. 1976. Central-peripheral distal
axonopathy—the pathology of dying-back polyneuropathies.
Prog. Neuropathol. 3:253-295.
Suzuki K, Pfaff LD. 1973. Acrylamide neuropathy in rats.
Electron microscopic study of degeneration and regeneration. Acta
Neuropathol. 24:197-213.
Takahashi M, Ohara T, Hashimoto K. 1971. Electrophysiological
study of nerve injuries in workers handling acrylamide. Int.
Arch. Arbietsraed. 28:1-11.
Thomann P, Koella WP, Krinke G, Petermann H, Zak F, Hess R. 1974.
Assessment of peripheral neurotoxicity in dogs. Comparative
studies with acrylamide and cliquinol. Agents Actions 4:48-54.
TSCA ITC. 1978. Toxic Substances Control Act Interagency Testing
Committee. Second Report of the TSCA Interagency Testing
Committee to the Administrator, EPA. Washington, D.C.:
Environmental Protection Agency. NTIS no. PB 285 439.
U.S. Environmental Protection Agency (US EPA). 1975. Guidelines
for registering pesticides in the United States Fed. Regist.
40:26878-26895.
U.S. Environmental Protection Agency (US EPA). 1976. Investi-
gation of selected potential environmental contaminants;
acrylamides. Washington, DC. EPA-560/2-76-008.
U.S. Environmental Protection Agency (US EPA). 1978.
Environmental monitoring near industrial sites: acrylamide.
Washington, DC. EPA-560/6-78-001.
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TECHNICAL REPORT DATA
'Please read Instructions on 'lie reiene oefore
CPT NO.
EPA-580/11-80-016
|3 RECIPIENT'S ACCESSICiVNO.
rLE AND SUBTITLE
Support Document Decision Not to Require Testing
for Health Effects: Acrylamide
!5. REPORT DATE
June 1980 (approved)
6. PERFORMING ORGANIZATION CODE
7 AUTHOR'S)
18. PERFORMING ORGANIZATION REPORT NO
9 PERFORMING ORGANIZA '' ON MAMc AND ADDRESS
Assessment Division
Office of Pesticides and Toxic Substances
401 M Street, SW
Washington, DC 20460
l 10. PROGRAM ELEMENT NO.
11 CONTRACT GRA.NT NO
U. S. Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
113. TV PE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
It has been found that acrylamide is neurotoxic, producing central-peripheral
axonopathies. The animal species in Which this effect was demonstrated include
rats, mice, cats, dogs, baboons, and monkeys. In addition, there are at least 48
published cases of the occupational toxicity and 5 cases of the nonoccupational
toxicity of acrylamide to humans, many of whom manifested a measurable degree of
neurotoxicity (central-peripheral axonopathy).
In humans, the predominant signs of neurotoxicity are ralated to peripheral
nerve involvement and, to a lesser extent, central nervous system involvement. A
variety of other signs and symptoms also are generally reported, the most common
ones occurring in the skin; hands, and feet. The onset of effects may be
reversible, although this is not always the case.
Based on laboratory data, EPA has concluded that acrylamide is a potent.
neurotoxicant at very low levels. This conclusion has been substantiated by a 1-
year (oral administration) study in cats indicating a no-effect level of 0.3-1.0
mg/kg/day.
EPA does not plan to require the health effects testing recommended by the
Interagency Testing Comrdttee. Instead, EPA plans to evaluate acrylamide for
possible regulatory controls.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS C. COSATl Field/Group
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Release unlimited.
19 SECURITY CLASS (This Report/
unclassified
21 NO. OF PAGES
i 20 SECURITY CLASS {This page I
I unclassified
22 PRICE
EPA Form 2220-1 (9-73)
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