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Acrolein
CASRN 107-02-8
Contents
0364
Acrolein; CASRN 107-02-8
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Acrolein
File On-Line 09/07/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 07/01/1993
Carcinogenicity Assessment (II.) on-line 02/01/1994
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Acrolein
CASRN -- 107-02-8
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Acrolein
CASRN -- 107-02-8
Last Revised -- 07/01/1993
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ---------
Squamous metaplasia NOAEL: None 1000 1 2E-5
and neutrophilic mg/cu.m
infiltration of LOAEL: 0.917 mg/cu.m (0.4 ppm)
nasal epithelium LOAEL(ADJ): 0.164 mg/cu.m
LOAEL(HEC): 0.02 mg/cu.m
Subchronic Rat
Inhalation Studies
Kutzman, 1981;
Feron et al., 1978
*Conversion Factors: MW = 56.06.
Kutzman, 1981: Assuming 25C and 760 mmHg, LOAEL(mg/cu.m) = 0.4 ppm x
56.06/24.45 = 0.917. LOAEL(ADJ) = 0.917 mg/cu.m x 6 hours/24 hours x 5 days/7
days = 0.164 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory
effect in the ExtraThoracic region. MVa = 0.18 cu.m/day, MVh = 20 cu.m/day,
Sa(ET) = 11.6 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) =
0.14. LOAEL(HEC) = LOAEL(ADJ) x RGDR = 0.02 mg/cu.m.
Feron et al., 1978: Assuming 25C and 760 mmHg, LOAEL(mg/cu.m) = 0.4 ppm x
56.06/24.45 = 0.917. LOAEL(ADJ) = 0.917 x 6 hours/24 hours x 5 days/7 days =
0.164 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in
the ExtraThoracic region. MVa = 0.23 cu.m/day, MVh = 20 cu.m/day, Sa(ET) =
11.6 sq. cm., Sh(ET) = 177 sq. cm. RGDR(ET) = (MVa/Sa) / (MVh/Sh) = 0.18.
LOAEL(HEC) = LOAEL(ADJ) x RGDR = 0.03 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Kutzman, R.S. 1981. A subchronic inhalation study of Fischer 344 rats
exposed to 0, 0.4, 1.4, or 4.0 ppm acrolein. Brookhaven National Laboratory,
Upton, NY. National Toxicology Program: Interagency Agreement No. 222-Y01-
ES-9-0043.
Feron, V.J., A. Kruysse, H.P. Til and H.R. Immel. 1978. Repeated exposure to
acrolein vapour: Subacute studies in hamsters, rats and rabbits. Toxicology.
9: 47-57.
Kutzman (1981) exposed male F344 rats to concentrations of 0, 0.4, 1.4 and
4.0 ppm (0, 0.917, 3.21 and 11.23 mg/cu.m, respectively) 6 hours/day, 5
days/week for 62 days. Duration-adjusted concentrations are 0, 0.164, 0.573
and 2.0 mg/cu.m. respectively. Twenty-four animals exposed at each level were
used to assess both pulmonary function and the compositional analysis and
pathology of the lungs. After pulmonary function testing, the animals were
sacrificed and the right lung was submitted for compositional analysis while
the left lung was processed for pathological examination. An additional eight
rats were designated for pathology only and another eight for reproductive
testing described in the additional comments section (Kutzman, 1981). A
series of pulmonary function tests (PFT) were performed using a constant
volume plethysmograph. Lung volumes, including FRC; expiratory volumes;
pulmonary resistance; dynamic compliance; diffusion capacity of CO (single
breath and rebreathing); and multibreath N2 washout were determined. After
pulmonary physiology determinations the animals were exsanguinated and the
right lungs were homogenized for compositional analysis. Collagen, elastin,
DNA, and total protein contents were determined. The left lung of each animal
was submitted for histopathological examination including morphometric
analyses. Details of the compositional analysis are also described in Kutzman
et al. (1985). Alveolar mean linear intercepts (Lm); specific densities for
the parenchymal tissues, alveolar, and alveolar ductal spaces; and the
internal surface areas (SAT) were determined on 10 fields of each midsagittal
lung section of each animal. Costa et al. (1986) provides additional details
on the PFT and morphometric analyses. Heart rate and EKG were monitored to
assess cardiotoxicity. Cytological endpoints assessed included sister
chromatid exchanges and cell proliferation kinetics in bone marrow cells and
peripheral blood lymphocytes. Additional histopathology performed on the
eight animals designated per group included: lung, peribronchial lymph nodes,
nasal turbinate, brain, kidney, liver, spleen, testes, and heart. All
analyses were held post-exposure for 6 days to minimize the "acute" effects of
acrolein before the above endpoints were assessed.
Mortality was high among male rats exposed to 4 ppm (32/57) while none of
the eight females exposed at this level died. Most of the mortality occurred
within the first 10 exposure days. Histologic examination indicated that the
animals died of acute bronchopneumonia. Surviving males and females exposed
to 4 ppm had reduced weight gain. The growth of both sexes in the 1.4- and
0.4-ppm exposure groups was similar to that of their respective controls.
There were no significant differences in heart rate, EKG, or cytological
parameters. No remarkable pathology was observed in extrarespiratory tissues.
The pattern of histopathological change in the respiratory tract was similar
to that of Feron et al. (1978). (Histopathology will be reported as results
from both the 8 animals designated per group and the additional 24 animals
used for pulmonary function and subsequent left lung examination.) The nasal
turbinate exhibited a concentration-dependent increase in submucosal lymphoid
aggregates and rhinitis. Morphologic changes in lung tissues were also
greater at the higher exposure levels. Severe peribronchiolar and bronchiolar
damage was observed in surviving rats of the 4-ppm group. Similar exposure-
related lesions such as alveolitis, hemorrhage, airway epithelial sloughing,
edema and Type II cell hyperplasia was observe in 10% of the 1.4-ppm rats. No
lung lesions were observed in the 0.4-ppm rats. This study thus supports a
LOAEL for respiratory effects in the nasal cavity at 0.4 ppm. The LOAEL(HEC)
for F344 male rats is 0.02 mg/cu.m and is used as the operational basis for
the RfC since it more conservative than the HEC based on Wistar rats (Feron et
al., 1978).
Pulmonary function testing and the morphometric and compositional analyses
indicated the dynamic nature of compensation to injury in the lung. At 0.4
ppm, parenchymal tissue density was significantly increased. The MEFV was
also significantly increased, i.e., exhibited "supernormal" maximum air flows
suggesting greater patency of interdependent flow-limiting airways. This
enhanced air flow is consistent with the increase in tissue density which
infers some degree of parenchymal restriction. This restriction may be the
result of acrolein "fixing" the supporting infrastructure of the flaccid
airway tissues without causing changes noticeable on light microscopy. No
changes in composition different than control values were noted at this level.
At 4 ppm, decreases in MEFV, increases in RV, increases in quasi-static
compliance, and increases in N2 washout suggested obstructive lesions in both
small and large airways sufficient to cause impaired ventilation. Elastin and
collagen were increased significantly (p<.01) relative to control at this
level. Other than the slight but significant elevation in DLCO/TLC evident at
all exposure levels, the animals in the 1.4-ppm group did not differ
functionally from the controls. Only collagen concentrations were
significantly increased (p<0.05). Without the data from the 0.4- and 4-ppm
groups, this response would have at best been uninterpretable and at worst,
misleading. Since pulmonary function tests describe the overall function of a
complex system with possesses tremendous compensatory capacity, they represent
a composite functional picture summed over lesions which differ in character,
quality or location that may each independently or interdependently alter that
function. Under the exposure regimen studied, acrolein may have produced
lesions which expressed themselves in a contradictory or compensatory manner.
The extremes of the functional effects were observed at 0.4 and 4 ppm, while
these effects essentially cancelled in the 1.4-ppm group and resulted in an
apparently normal intermediate response (Kutzman, 1981; Costa et al., 1986).
Thus, based on the restrictive changes discussed above, 0.4 is a LOAEL for
lower respiratory effects. The LOAEL(HEC) based on thoracic surface area is
0.29 mg/cu.m.
Feron et al. (1978) exposed Syrian Golden hamsters (10/sex/concentration),
Wistar rats (6/sex/concentration) and Dutch rabbits (2/sex/concentration) at
0, 0.4, 1.4, and 4.9 ppm (0, 0.917, 3.21, and 11.23 mg/cu.m, respectively) to
acrolein 6 hours/day, 5 days/week for 13 weeks. Duration-adjusted
concentrations are 0, 0.164, 0.573, and 2.0 mg/cu.m., respectively. Animals
were weighed once each week. Food consumption was recorded every week for the
first 4 weeks. Hematological data were collected in week 12 and included Hb
and Hct in rats; and Hb, Hct, RBC, and WBC (total and differential) in
hamsters and rabbits. Urinalysis included: pH, glucose, protein, ketones, and
occult blood. Activities of SGOT, SGPT, and SAP were determined in hamsters
and rabbits only. Weights and tissue samples of the major organs were taken.
Histopathology of extrarespiratory tissue was restricted to the control and
highest concentration group. Histopathology of the nasal cavity (3 transverse
sections), larynx, trachea with main bronchi and each of the pulmonary lobes
was performed on all exposure and control groups.
Rats appeared to be the most sensitive of the three species tested. Three
male and three female rats of the highest exposure group died in the first 4
weeks. Statistically decreased body weight gain occurred at both the 4.9- and
1.4-ppm exposure levels although it is reported (data not shown) that food
intake was diminished in these exposure groups. Hematological values and
serum enzyme activities were not affected. Slight increases in amorphous
material in the urine sediment was reported for the high exposure group.
Relative lung, heart and kidney weights were increased significantly in the
highest exposure group. Increases in relative brain and gonad weights and
decreases in thymus weights were attributed to decreased body weight.
Exposure-related histopathological changes were observed only in the
respiratory tract. Histopathology/incidence data were reported as severity
scores. At the highest exposure level (4.9 ppm) "marked" changes in the
epithelial lining of the nasal cavity included necrotizing rhinitis with
partial replacement of normal epithelium by stratified squamous epithelium
with occasional keratinization. Neutrophilic infiltration was also
consistently observed. At the intermediate level, squamous metaplasia and
neutrophilic infiltration was "moderately affected". At the lowest level, 0.4
ppm, one male rat was reported as showing metaplastic and inflammatory changes
and this was scored as "slightly affected". Effects in the larynx, trachea,
and bronchi/lungs were observed only in the high exposure level and reported
as "moderate," "marked" and "marked," respectively. The LOAEL for effects in
the nasal cavity is 0.4 ppm based on the slightly affected metaplastic and
inflammatory changes. The LOAEL(HEC), using the ventilation rate for male
Wistar rats, is 0.03 mg/cu.m. The NOAEL and LOAEL for respiratory effects in
the tracheobronchial region are 1.4 and 4.9 ppm, respectively. The NOAEL(HEC)
is 0.88 mg/cu.m and the LOAEL(HEC) is 3.08 mg/cu.m.
Hamster body weights were depressed significantly at the highest
concentration, and the authors made no note of decreased food consumption.
Female hamsters in the high exposure group showed statistical increases in
RBC, Hct, Hb and the number of lymphocytes accompanied by a decrease in the
number of neutrophilic leucocytes. All serum enzyme activities were within
normal ranges. Slight increases in amorphous material in the urine sediment
was reported for the high exposure group. Relative increases in lung, heart
and kidneys were also noted at the highest concentration and the increase in
relative brain and gonad weight again attributed to decrease body weight gain.
As in the rats, the only remarkable histopathology occurred in the respiratory
system. "Markedly increased" histopathological changes in the nasal cavity,
as described for the rats, occurred in the 4.9-ppm exposure group but only
"slightly increased" changes occurred in the 1.4 ppm group. The larynx and
trachea were affected "slightly" and "moderately", respectively, in the high
exposure group only. No changes in the bronchi and lungs were observed in
hamsters at any exposure level. These data suggest a NOAEL for effects in the
nasal cavity at 0.4 ppm but the lack of surface area data for that respiratory
region in hamsters precludes calculation of a NOAEL(HEC). The NOAEL for
tracheobronchial effects is 1.4 ppm; again, the lack of surface area data
precludes HEC calculation.
Body weights of rabbits were also depressed significantly in the highest
exposure group although decreased food consumption was noted (no data shown).
Hematological parameters and serum enzyme activities in rabbits were not
affected. Slight increases in amorphous material in the urine sediment was
reported for the high exposure group. No statistical changes in relative
organ weights occurred although a trend for increase in lung weights was
noted. As in the other two species, the only remarkable histopathology
occurred in the respiratory system. "Moderately increased" effects in the
nasal cavity, as described for the rats, occurred at the highest exposure
concentration. No effects occurred in the nasal cavity at the low- or mid-
exposure levels. "Slightly increased" and "moderately increased" effects in
the trachea and bronchi/lungs, respectively, were reported. The NOAEL for
nasal cavity effects in rabbits thus appears to be 1.4 ppm and the LOAEL is
4.9 ppm. The NOAEL and LOAEL for tracheobronchial effects are at the same
levels. Calculation of HEC estimates for these effects is precluded due to
lack of respiratory surface area data for these regions in rabbits.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- An uncertainty factor of 10 was used to account for sensitive human
populations. An uncertainty factor of 10 was used for both interspecies
extrapolation, due to use of the dosimetric adjustment based on respiratory
surface areas, and to account for the mild nature of the LOAEL. Another
factor of 10 was used to account for the lack of chronic studies. This is
also sufficient for the lack of reproductive and developmental studies in the
data base.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
Kane et al. (1979) determined an RD50 value (exposure concentration to
evoke a 50% decrease in respiratory rate) for sensory irritation in Swiss-
Webster mice for acrolein of 1.68 ppm (95% C.I. 1.26-2.24 ppm) by plotting the
percentage decrease in respiratory rate versus the logarithm of the exposure
concentration. A minimal irritation level for humans was predicted at
0.01RD50 = 0.02 ppm (0.05 mg/cu.m) and a highest concentration for an air
quality standard at 0.001RD50 = 0.002 ppm (0.005 mg/cu.m).
Buckley et al. (1984) reported upper respiratory tract lesions in Swiss-
Webster mice exposed to the RD50 concentration for acrolein (1.7 ppm) 6
hours/day for 5 days. Histopathology was performed by light microscopy on the
nasal passages, trachea and lungs. Lesions were graded with respect to
incidence and severity. "Moderate" changes included exfoliation, erosion,
ulceration, inflammation and necrosis in the respiratory epithelium. "Severe"
squamous metaplasia was also noted in the respiratory epithelium. "Moderate"
ulceration and necrosis of the olfactory epithelium was reported, as well as
"minimal" squamous metaplasia and serous exudate. No lesions were observed in
the trachea and lower respiratory tract.
Astry and Jakab (1983) showed that exposure to acrolein suppressed
pulmonary antibacterial defenses in a concentration-related manner. Female
Swiss mice were exposed to 3 or 6 ppm of acrolein for 8 hours immediately
after bacterial challenge via inhalation with Staphylococcus aureus for 45
minutes. Bactericidal activity was measured by assaying the percent of
initial viable bacteria remaining at various time points after challenge
compared with controls. The control exposure was not described. Bactericidal
activity was also tested in mice preinfected with Influenza A/PR8/34 virus. A
statistically significant increase in the percentage of viable staphylococcus
remaining in the lungs at 8 hours was shown in the 3-ppm (12.3 +/- 1.7%) and
6-ppm (33.9 +/- 4.9%) exposure groups compared to controls (3.2 +/- 3%). In
mice with pre-existing viral infection, suppression of the intrapulmonary
staphylococcal inactivation was further increased. Approximately 50 +/- 6% of
the initial viable bacteria remained in the lungs of virus-infected mice after
exposure to 3 ppm of acrolein. Exposure to 6 ppm totally abrogated pulmonary
antibacterial defenses allowing proliferation of the staphylococci to 150 +/-
32% of the initial challenge.
Leach et al. (1987) investigated the immunologic effects in male Sprague-
Dawley rats (40/group) exposed to 0, 0.1, 1.0, or 3.0 ppm of acrolein 6
hours/day, 5 days/week for 3 weeks. Twelve rats per group were used to assay
for the ability of lymphocytes isolated from spleen- and lung-associated lymph
nodes to respond to either the T-cell mitogen, phytohemagglutinin-P (PHA), or
the B-cell mitogen, Salmonella typhimurium (STM). Ten rats per group were
given an intratracheal challenge of sheep RBC and lung-associated lymph node
cells were analyzed 7 days later for ability to form plagues [plaque-forming
cell (PFC) assay]. The remaining 18 rats were challenged i.v. with Listeria
monocytogenes and observed over a 10-day period in a host-resistance assay
that ascertained the mortality and the mean survival time. In addition, the
lungs and nasal turbinates of 12 rats each from the 3-ppm and the control
group were examined for histopathology. Five consecutive transverse sections
were examined microscopically in the nasal cavity.
Body weights were slightly depressed in the 3-ppm group after 1 week and
remained depressed throughout the remainder of the study. Body weights in all
other exposure groups were not different from the controls. There were no
statistically significant effects of acrolein on the immune response, as
measured by the PFC assay with lung-associated lymph node cells or as measured
by the ability to respond to mitogens. Exposure also had no effect on
resistance to Listeria, either in total number of deaths or mean survival
time. It is noted that bacteria were given i.v. rather than intratracheally,
which may have been a more relevant route to assess respiratory effects.
Also, mortality as an endpoint is less sensitive than the macrophage function
assessed in the Astry and Jakab (1983) investigation. Histopathology revealed
hyperplastic, metaplastic and dysplastic changes in the mucous, respiratory
and olfactory epithelium of the nasal cavity in the 3-ppm group. These
changes were most prominent on the septum and in the anterior and ventral
areas. Mild inflammation was also present, characterized by neutrophils and
presence of a protein-rich transudate.
Feron and Kruysse (1977) exposed Syrian Golden hamsters (18/gender) to 4.0
ppm (9.17 mg/cu.m) acrolein 7 hours/day, 5 days/week for 52 weeks. The
duration-adjusted concentration is 1.9 mg/cu.m. Three animals/sex were
randomly selected at the end of the exposure period for hematology,
urinalysis, and determination of serum enzyme activities (SGOT, SGPT, SAT).
Weights and tissue samples were also taken. Histopathology included four
transverse sections across the nasal cavity and three longitudinal sections
through larynx, trachea with main bronchi and pulmonary lobes. The remaining
animals were killed terminally at 81 weeks. Decreased body weights occurred
in both genders during exposure, with slight recovery in the post-exposure
period. Hematology and blood biochemistry parameters were not affected except
for Hb and Hct which were slightly increased in females. Relative lung
weights were increased and relative liver weights slightly decreased.
Increases in relative brain weights were attributed to the inverse
relationship between brain weight and body weight. The only treatment-related
histopathological changes occurred in the respiratory tract. Slight to
moderate inflammation and epithelial metaplasia occurred in the nasal cavity,
including neutrophilic infiltrates in the mucosa and submucosa, thickening of
the submucosa, reduction of the number of subepithelial glands, and
metaplastic stratified squamous epithelium that occasionally showed
keratinization. About 20% of the animals killed terminally still showed
treatment-related lesions in the nasal cavity. No changes in other parts of
the respiratory tract were noted. This study supports the LOAEL(HEC) for
nasal cavity effects in hamsters derived in the critical study (Feron et al.,
1978). The lack of analogous effects in the lower respiratory tract (trachea
and larynx) may be because of the slightly lower concentration in this study.
Lyon et al. (1970) investigated the effects of either repeated exposures
(8 hours/day, 5 days/week) for 6 weeks to 0.7 and 3.7 ppm or continuous
exposures to 0.21, 0.23, 1.0 and 1.8 ppm acrolein for 90 days in Sprague-
Dawley rats (7 males and 8 females/group), Hartley guinea pigs (7 males and 8
females/group), Beagle dogs (2 males/group) and squirrel monkeys (7-9
males/group). Identical groups of animals were maintained in chamber
environments for control purposes. The duration-adjusted values for the
repeated exposures are 0.38 and 2.0 mg/cu.m. The results from the two lowest
continuous exposures were combined, thus, the continuous exposures are 0.50,
2.3 and 4.0 mg/cu.m, respectively. Animals were weighed and observed for
clinical signs daily. Hematology analysis included: Hb, Hct, RBC and total
WBC. BSP retention, BUN, alanine and aspartate aminotransferase activities
were determined at termination. Liver specimens were also obtained for
alkaline phosphatase and tyrosine aminotransferase activities.
Histopathologic examinations were made on some organs (heart, lung, liver,
spleen and kidney) from all dogs and monkeys, and approximately half of the
rats and guinea pigs. Trachea, brain and spinal cord were processed from
monkeys and dogs. In addition, adrenal and thyroid were retained in dogs. No
tracheas were from in the 0.22 or 0.7 exposure groups, however.
In the repeat-exposure studies, 2 monkeys died in the high exposure group
(3.7 ppm) within the first 9 days. Both dogs and monkeys salivated
excessively during the first week. Dogs showed eye irritation into the 4th
week. Rats and guinea pigs at this level (3.7 ppm) appeared to behave
normally. Weight gain was significantly reduced in rats (p<.005) compared
with controls. Nonspecific inflammatory changes were noted in sections of
lung, liver and kidney from all species at the high concentration. Focal
calcification of the renal tubular epithelium was noted in some of the rats
and monkeys. Significant treatment-related changes consisted of squamous
metaplasia and basal cell hyperplasia of the trachea from dogs and monkeys,
and necrotizing bronchitis and bronchiolitis obliterans with squamous
metaplasia of the lungs from 7 of the 9 (including the early deaths) monkeys.
Bronchopneumonia was noted in the dogs. Inflammatory changes consisting of
focal to diffuse interstitial infiltration were noted in the 0.7 ppm group and
were more prominent in dogs than monkeys. No definite alteration of the
respiratory or peribronchial smooth muscle was noted.
In the groups exposed continuously, monkeys and dogs appeared to
experience severe irritation as evidenced by excessive salivation and ocular
discharge. This irritation was observed at 1.8 and 1.0 ppm, but was not
evident at the 0.22-ppm level. The rats and guinea pigs appeared normal and
unaffected at all levels. Weight gain was reduced significantly (p<0.01%)
compared with controls only in rats in the 1.0- and 1.8-ppm groups. No
changes in the hematologic parameters were noted. Nonspecific inflammatory
changes were observed in sections of brain, heart, lung, liver and kidney from
all species exposed to 1.8 ppm. All monkeys showed squamous metaplasia and
6/9 monkeys showed basal cell hyperplasia of the trachea. The lungs from both
dogs showed confluent bronchopneumonia. At 1.0 ppm, guinea pigs showed
various degrees of pulmonary inflammation and occasional foci of liver
necrosis. Three of nine rats exhibited focal liver necrosis and occasional
pulmonary hemorrhage. Sections from dogs revealed focal inflammatory
reactions the lung, kidney and liver. Sections of lung from 2/4 dogs exposed
at 0.22 ppm showed moderate emphysema, acute congestion, focal vacuolization
of the bronchiolar epithelial cells and focal subcapsular hemorrhage in
sections of spleen. Nonspecific inflammatory changes were present in sections
of liver, lung, kidney, and heart from monkeys, guinea pigs and dogs.
Both the repeated and continuous studies seem to indicate that dogs and
monkeys are particularly sensitive to the irritation effects of acrolein.
Unfortunately, the trachea was only examined in these species and the nasal
cavity was not examined in any species, therefore interspecies comparisons of
effect levels are somewhat difficult. Further, the nature of the reporting in
this study supports only qualitative concentration-response assessment.
Minimal data addressing the reproductive and developmental effects of
acrolein have been identified. Whether or not any acrolein is absorbed for
distribution remote to the respiratory tract is a question, particularly at
lower concentrations.
Uptake in the upper respiratory tract of dogs was shown to be 80% (Egle,
1972). Lam et al. (1985) showed a concentration-dependent decrease in the
nonprotein sulfhydryl (NSPH) concentration in the nasal respiratory mucosa of
Fisher 344 rats exposed nose-only to 0.1, 0.5, 1.0 or 2.5 ppm for 3 hours.
The decrease was statistically significant at 0.5 ppm and higher. Despite the
apparent formation of DNA-protein cross-LINKS by acrolein in vitro, no
significant cross-linking was detected in rats exposed to 2 ppm for 6 hours,
suggesting a preferential reaction with sulfhydryl-containing nucleophiles
such as glutathione.
Kutzman (1981) also assessed reproductive potential in F344 rats exposed
to acrolein. Six days after the exposure regimen described in Section I.B.2.,
eight male rats/concentration were each housed with two unexposed females.
Eight females/concentration were mated with unexposed males (1:1) that had
been previously mated with unexposed females to assure that they were fertile.
Females from these matings were sacrificed 19 days after the first mating as
determined by the presence of sperm in the vaginal smears. The number of
viable embryos, late deaths, reabsorptions, and corpora lutea were determined.
There were no effects on these parameters at any of the exposure levels in
either group. The summary reports no significant change in sperm morphology
although this analysis is not described in the methods section nor are data
provided. This study suggests a NOAEL for reproductive effects at 4.0 ppm.
The NOAEL(HEC) = 2.0 mg/cu.m.
Bouley et al. (1976) studied reproduction and developmental toxicity in
SPF OFA rats (3 males and 21 females/concentration) exposed to 0 or 0.55 ppm
acrolein continuously for 26 days. Mating was started on the 4th day after
the beginning of exposures. The study was terminated at the 26th day (22nd
day after the beginning of mating). No differences between the groups were
observed in the number of pregnant animals or in the number and mean weight of
fetuses. No data or further experimental design detail were provided.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- High
Data Base -- Medium
RfC -- Medium
The principal studies were given high confidence because adequate numbers
of animals were used, careful attention was paid to experimental protocol and
together they demonstrated a consistent profile of histopathological changes
in the respiratory system. The data base was given low to medium confidence
due to the lack of chronic data and adequately conducted reproductive or
developmental studies. Medium confidence in the derived RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA documentation -- U.S. EPA, 1989
Agency Work Group Review -- 05/18/1989; 04/25/1991
Verification Date -- 04/25/1991
___I.B.7. EPA CONTACTS (INHALATION RFC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Acrolein
CASRN -- 107-02-8
Last Revised -- 02/01/1994
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- C; possible human carcinogen.
Basis -- Classification is based on increased incidence of adrenal cortical
adenomas to female rats and carcinogenic potential of an acrolein
metabolite. Acrolein is mutagenic in bacteria and is structurally related to
probable or known human carcinogens.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. In a study (Lijinsky and Reuber, 1987) of acrolein carcinogenic
potency by oral route, groups of 20 male Fischer 344 rats were given drinking
water with acrolein at 100, 250, 625 ppm 5 days/week for 120, 120 and 100
weeks, respectively. A group of 20 female rats was given 625 ppm acrolein in
the drinking water. Twenty male and 20 female rats served as controls. The
only significant finding was an increase in the incidence of adrenal cortical
adenomas in the female rats treated with 625 ppm acrolein (5/20 in the
treated versus 0/20 control; p=0.02). The historical incidence of this tumor
in the NCI-Frederick Cancer Research Facility is 12/263 (4.6%) in the females.
In an inhalation study (Feron and Kruysse, 1977), 36 male and 36 female
Syrian golden hamsters were exposed to 0 or 4 ppm (9.2 mg/cu.m) acrolein 7
hours/day 5 days/week for 52 weeks. Half of the animals of each sex-dose
combination were also treated with intratracheally instilled saline, making 8
total groups. At week 52, 3 animals per group were killed. Of the remainder
observed to week 81, approximately 25% of males and 40% of females died. No
increase in tumor incidence was found in acrolein-exposed animals compared
with the control. The duration of the experiment was, however, too short to
allow for latency. In addition, too few hamsters were used for each of the
dose groups.
Skin painting (Salaman and Roe, 1956) and subcutaneous injection (Steiner
et al., 1943) studies with acrolein in mice did not induce remote site
tumors, but these studies were of inadequate design to draw definitive
conclusions.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
A positive response was induced by acrolein in Salmonella typhimurium
strain TA104 (Marnett et al., 1985). Acrolein showed an equivocal response
in strain TA100 without metabolic activation and was negative with or without
metabolic activation in strains TA98, TA1535, TA1537 and TA1538 (Lutz et al.,
1982; Hales, 1982; Haworth et al., 1983). Acrolein was not mutagenic to
Escherichia coli strain K12/343/113 (Ellenberger and Mohn, 1977) but was
weakly mutagenic to strain WP2 uvrA(trp-) (Hemminki et al., 1980).
Acrolein showed an equivocal response in inducing recessive lethal
mutations in Drosophila melanogaster (Rapaport, 1948; Zimmering et al.,
1985). In the absence of hepatic homogenates, acrolein was found to increase
sister chromatid exchange in the Chinese hamster ovary cell line (Au et al.,
1980). There was no significant increase in the dominant lethal assay in the
intraperitoneal injection studies of acrolein in ICR male mice (Epstein et
al., 1972).
Glycidaldehyde, a known metabolite of acrolein (Patel et al., 1980), has
been tested for carcinogenic response in skin painting and subcutaneous
injection studies. Shamberger et al. (1974) showed an increased incidence of
keratoacanthomas, a benign tumor with potential for progression to
malignancy, in female Swiss albino mice skin painted with glycidaldehyde. A
statistically significant incidence in papillomas was reported in female
ICR/Ha Swiss mice skin painted with 3-10% glycidaldehyde for life (Van Duuren
et al., 1967b). Mice receiving the higher dose showed subsequent development
of squamous cell carcinomas. Sprague Dawley rats and ICR/Ha Swiss mice
developed local sarcomas and sqamous cell carcinomas when injected
subcutaneously with 0.1-33 mg glycidaldehyde weekly for life (Van Duuren et
al., 1966; 1967a).
Acrolein is structurally related to two families of chemical compounds:
aldehydes and dienes. Both classes contain probable (formaldehyde,
acetaldehyde, ethylene oxide, acrylonitrile, 1,3-butadiene) or known human
carcinogens (vinyl chloride).
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986, 1987
The 1986 Health Assessment document received both Agency and External review.
The 1987 Health Effects Assessment received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 12/02/1987
Verification Date -- 12/02/1987
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Acrolein
CASRN -- 107-02-8
Last Revised -- 10/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
Astry, C.L. and G.J. Jakab. 1983. The effects of acrolein exposure on
pulmonary antibacterial defenses. Toxicol. Appl. Pharmacol. 67: 49-54.
Bouley, G., A. Dubreuil, J. Godin, M. Boisset and C. Boudene. 1976. Phenomena
of adaptation in rats continuously exposed to low concentrations of acrolein.
Ann. Occup. Hyg. 19: 27-32.
Buckley, L.A., X.Z. Jiang, R.A. James, K.T. Morgan and C.S. Barrow. 1984.
Respiratory tract lesions induced by sensory irritants at the RD50
concentration. Toxicol. Appl. Pharmacol. 74: 417-429.
Costa, D.L., R.S. Kutzman, J.R. Lehmann and R.T. Drew. 1986. Altered lung
function and structure in the rat after subchronic exposure to acrolein. Am.
Rev. Respir. Dis. 133(2): 286-291.
Egle, J.L. 1972. Retention of inhaled formaldehyde, propionaldehyde, and
acrolein in the dog. Arch. Environ. Health. 25: 119-124.
Feron, V.J. and A. Kruysse. 1977. Effects of exposure to acrolein vapor in
hamsters simultaneously treated with benzo(a)pyrene or diethylnitrosamine. J.
Toxicol. Environ. Health. 3: 379-394.
Feron, V.J., A. Kruysse, H.P. Til and H.R. Immel. 1978. Repeated exposure to
acrolein vapour: Subacute studies in hamsters, rats and rabbits. Toxicology.
9: 47-57.
Kane, L.E., C.S. Barrow and Y. Alarie. 1979. A short-term test to predict
acceptable levels of exposure to airborne sensory irritants. J. Am. Hygiene
Assoc. 40: 207-229.
Kutzman, R.S. 1981. A subchronic inhalation study of Fischer 344 rats
exposed to 0, 0.4, 1.4, or 4.0 ppm acrolein. Brookhaven National Laboratory,
Upton, NY. National Toxicology Program: Interagency Agreement No. 222-Y01-
ES-9-0043.
Kutzman, R.S., E.A. Popenoe, M. Schmaeler and R.T. Drew. 1985. Changes in
rat lung structure and composition as a result of subchronic exposure to
acrolein. Toxicology. 34: 139-151.
Lam, C-W., M. Casanova and H. d'A. Heck. 1985. Depletion of nasal mucosal
glutathione by acrolein and enhancement of formaldehyde-induced DNA-protein
cross-linking by simultaneous exposure to acrolein. Arch. Toxicol. 58:
67-71.
Leach, C.L., N.S. Hatoum, H.V. Ratajczak and J.M. Gerhart. 1987. The
pathologic and immunologic effects of inhaled acrolein in rats. Toxicol.
Lett. 39: 189-198.
Lyon, J.P., L.J. Jenkins, Jr., R.A. Jones, R.A. Coon and J. Siegel. 1970.
Repeated and continuous exposure of laboratory animals to acrolein. Toxicol.
Appl. Pharmacol. 17: 726-732.
U.S. EPA. 1989. Health Assessment Document for Acrolein. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Research Triangle Park, NC. EPA-600/8-86-014F.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Au, W., O.I. Sokova, B. Kopnin and F.E. Arrighi. 1980. Cytogenetic toxicity
of cyclophosphamide and its metabolites in vitro. Cytogenet. Cell Genet.
26: 108-116.
Ellenberger, J. and G.R. Mohn. 1977. Mutagenic activity of major mammalian
metabolites of cyclophosphamide toward several genes of Escherichia coli. J.
Toxicol. Environ. Health. 3: 637-650.
Epstein, S.S., E. Arnold, J. Andrea, W. Bass and Y. Bishop. 1972. Detection
of chemical mutagens by the dominant lethal assay in the mouse. Toxicol.
Appl. Pharmacol. 23: 288-325.
Feron, V.J. and Kruysse. 1977. Effects of exposure to acrolein vapor in
hamsters simultaneously treated with benzo(a)pyrene or diethylnitrosamine. J.
Toxicol. Environ. Health. 3: 379-394.
Hales, B. 1982. Comparison of the mutagenicity and teratogenicity of
cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide,
phosphoramide mustard and acrolein. Cancer Res. 42: 3016-3021.
Haworth, S. T. Lowlor, K. Mortelmans, W. Speck and E. Zeiger. 1983.
Salmonella mutagenicity test results for 250 chemicals. Environ. Mutagen.
1: 3-142.
Hemminki, K., K. Falck and H. Vainio. 1980. Comparison of alkylation rates
and mutagenicity of directly acting industrial and laboratory chemicals.
Arch. Toxicol. 46: 277-285.
Lijinsky, W. and M.D. Reuber. 1987. Chronic carcinogenesis studies of
acrolein and related compounds. Toxicol. Ind. Health. 3(3): 337-345.
Lutz, D., E. Eder, T. Neudecker and O. Henschler. 1982. Structure-
mutagenicity relationships in 2,8-unsaturated carbonylic compounds and their
corresponding allylic alcohols. Mutat. Res. 93: 303-315.
Marnett, L.J., H.K. Hurd, M.C. Hollstein, D.E. Levin, H. Esterbaure and B.N.
Ames. 1985. Naturally occurring carbonyl compounds are mutagenic in
Salmonella tester strain TA104. Mutat. Res. 148: 25-34.
Patel, J.M., J.C. Wood and K.C. Leibman. 1980. The biotransformation of
allyl alcohol and acrolein in rat liver and lung preparations. Drug Metab.
Dispos. 8: 305-308.
Rapaport, I.A. 1948. Mutations induced by unsaturated aldehydes. Dokl.
Akad. Nauk. USSR. 61: 713-715.
Salaman, M.H. and F.J.C. Roe. 1956. Further tests for tumor initiating
activity: N,N-Di(2-chloroethyl)-p-aminophenyl-butyric acid (CB 1348) as an
initiator of skin tumor formation in the mouse. Br. J. Cancer. 10: 363-378.
Shamberger, R.J., T.L. Andreone and C.E. Willis. 1974. Antioxidants and
cancer. IV. Initiating activity of malonaldehyde as a carcinogen. J. Natl.
Cancer Inst. 53: 1771-1773.
Steiner, P.E., R. Steele and F.C. Koch. 1943. The possible carcinogenicity
of overcooked meats, heated cholesterol, acrolein and heated sesame oil.
Cancer Res. 3: 100-107.
U.S. EPA. 1986. Health Assessment Document for Acrolein. Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Research Triangle Park, NC. EPA-600/8-86-014A (Review Draft).
U.S. EPA. 1987. Health Effects Assessment for Acrolein. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
Van Duuren, B.L., L. Langseth, L.L. Orris, G. Teebor, N. Nelson and M.
Kuschner. 1966. Carcinogenicity of epoxides, lactones and peroxy compounds.
IV. Tumor response in epithelial and connective tissue in mice and rats. J.
Natl. Cancer Inst. 39: 825-838.
Van Duuren, B.L., L. Langseth, L. Orris, M. Baden and M. Kuschner. 1967a.
Carcinogenicity of epoxides, lactones and peroxy compounds. V. Subcutaneous
injection in rats. J. Natl. Cancer Inst. 39: 1213-1216.
Van Duuren, B.L., L. Langseth, B. Goldschmidt and B.M. Orris. 1967a.
Carcinogenicity of epoxides, lactones and peroxy compounds. VI. Structure and
carcinogenic activity. J. Natl. Cancer Inst. 39: 1217-1228.
Zimmering, S., J.M. Mason, R. Valencia and R.C. Woodruff. 1985. Chemical
mutagenesis testing in Drosophila. II. Results of 20 coded compounds tested
for the National toxicology Program. Environ. Mutagen. 7: 87-100.
_VII. REVISION HISTORY
Substance Name -- Acrolein
CASRN -- 107-02-8
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/07/1988 II. Carcinogen summary on-line
04/01/1989 V. Supplementary data on-line
07/01/1989 I.B. Inhalation RfD now under review
03/01/1990 II.A.4. Citations clarified (3rd paragraph)
03/01/1990 VI. Bibliography on-line
05/01/1990 VI.C. Hemminki et al., 1980 citation corrected
10/01/1991 I.B. Inhalation RfC summary on-line
10/01/1991 I.B. Inhalation RfC references added
01/01/1992 IV. Regulatory Action section on-line
07/01/1993 I.B.1. LOAEL(ADJ) corrected
02/01/1994 II.D.3. Secondary contact's phone number changed
VIII. SYNONYMS
Substance Name -- Acrolein
CASRN -- 107-02-8
Last Revised -- 09/07/1988
107-02-8
acraldehyde
Acrolein
acrylaldehyde
acrylic aldehyde
2-propenal
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0364.HTM
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