Acrolein (CASRN 107-02-8) 

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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 First On-Line 09/07/1988

Category (section)	Status	Last Revised

Oral RfD Assessment (I.A.)	on-line	06/03/2003

Inhalation RfC Assessment (I.B.)	on-line	06/03/2003

Carcinogenicity Assessment (II.)	on-line	06/03/2003

_I.  Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Acrolein

CASRN — 107-28-8

Last Revised — 06/03/2003 

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is
expressed in units of mg/kg-day. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily
exposure to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects during a
lifetime. Please refer to the Background Document for an elaboration of
these concepts. RfDs can also be derived for the noncarcinogenic health
effects of substances that are also 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. 

An RfD for acrolein was not previously available on IRIS.

__I.A.1. Oral RfD Summary

Critical Effect	Experimental Doses*	UF	MF	RfD

Decreased survival

Chronic gavage rat study

Parent et al., 1992a	NOAEL: 0.05 mg/kg-day

FEL*: 0.5 mg/kg-day	100	1	5 x 10-4

mg/kg-day

* FEL — frank effect level (an objective, clinically evident effect)

__I.A.2. Principal and Supporting Studies (Oral RfD)

Parent et al. (1992a) administered acrolein in water daily via gavage to
Sprague-Dawley rats, 70/sex/group, at dose levels of 0, 0.05, 0.5, and
2.5 mg/kg BW. Dosing volume was 10 ml/kg. Ten animals from each group
were sacrificed after one year and the remainder after two years. An
extensive array of tissues was examined microscopically, including
stomach tissue. Although it was not explicitly stated that both the
glandular stomach and forestomach were examined, it is unlikely that
both parts of the stomach were not examined. Daily observations were
made and various clinical, hematological and urinary parameters were
measured after 3, 6, 12, and 18 months of treatment and immediately
prior to sacrifice. There were no statistically significant increased
incidences of microscopic lesions in the treated rats, whether
neoplastic or non-neoplastic. Food consumption and body weights were
unaffected by treatment. With the exception of a statistically
significant depression of creatinine phosphokinase (creatine kinase) at
all dose levels and at most time intervals (except 12 months), clinical
chemistry parameters, hematology and urinalysis measurements were
unaffected by treatment. 

The most definitive responses reported were treatment-related increases
in early cumulative mortality. Data were provided in the form of
survival curves. Among high-dose males, survival was significantly
reduced after one year (p<0.05), and marginally reduced among mid-dose
males (p value not reported). Among high-dose males, a trend test for
survival during the first year indicated a highly statistically
significant (p=0.003) decrease; however, the statistical differences are
nullified when the survival data for two years are included in the
analysis. Survival among females during the first year corresponded
closely to those obtained for males. A statistically significant
decrease in survival (p<0.05) was reported in the high-dose group, while
a decrease in survival in the mid-dose group was marginally significant
(p value not reported). Unlike responses in males, the significant
associations between dosing and survival persisted in females through
the end of the study. After two years, a statistically significant
reduction in survival was noted based on four different statistical
tests for the mid-dose group and in three of four statistical tests in
the high-dose group (p values not reported). Although the differences in
survival were statistically significant in females after two years, it
should be noted that the differences were relatively small. No
differences in survival compared to controls were seen in either the
male or female low-dose groups (0.05 mg/kg/day). Thus, 0.5 mg/kg/day is
considered a frank effect level (FEL) for the rat, and 0.05 mg/kg/day
the no-observed-adverse-effect level (NOAEL). The FEL is defined as "a
level of exposure or dose which produces irreversible, adverse effects
at a statistically or biologically significant increase in frequency or
severity between those exposed and those not exposed" (IRIS, 2003). 

Other studies support the findings of reduced survival in laboratory
animals exposed to acrolein as reported by Parent et al. (1992a). In a
study designed to evaluate the potential carcinogenicity of acrolein
(Parent et al., 1991), Swiss albino CD-1 mice (70-75/sex/group) were
dosed via gavage (acrolein in distilled water and stabilized with
hydroquinone) with 0, 0.5, 2.0 or 4.5 mg/kg/day for 18 months. The
primary effect was increased mortality only in high-dose males of the
4.5 mg/kg/day group; mortality in the mid- and low-dose groups was less
than control. There were no dose-related adverse histopathological or
clinical findings. 

In a 13-week daily gavage study of acrolein (in 0.5% methyl cellulose)
in F344 rats and B6C3F1 mice conducted for the National Toxicology
Program (NTP, 1995), 10 rats/sex/dose were administered 0, 0.75, 1.25,
2.5, 5.0, and 10 mg acrolein/kg; 10 mice/sex/dose received 0, 1.25, 2.5,
5.0, 10 and 20 mg/kg. Dose volume was 5 ml/kg for rats and 10 ml/kg for
mice. Treatment resulted in similar dose-related effects in both sexes
of both species: hemorrhage and necrosis and other lesions of the
forestomach and glandular stomach and secondary changes associated with
acrolein-induced mortality in high-dose animals (NTP, 1995; Pathology
Working Group Review, 1997). Abnormal breathing and nasal/eye discharge
were among the clinical findings in high-dose rats. Nearly all high-dose
animals died or were removed from study because of gastrointestinal
toxicity. The NOAEL was 0.75 mg/kg for female rats and 1.25 mg/kg for
males, based on forestomach squamous epithelial hyperplasia in the 1.25
mg/kg group and 2.5 mg/kg group, respectively. There were no clinical
signs of toxicity in mice. The forestomach lesions in mice were similar
to those in the rat. Glandular stomach lesions were only seen in the 10
and 20 mg/kg males and in the 20 mg/kg females. Statistically
significant increases in absolute and relative liver weights were seen
in male mice at 10 mg/kg without attendant hepatic histopathology. There
was no NOAEL for the male mouse (i.e., one male had squamous epithelial
hyperplasia at the lowest dose of 1.25 mg/kg). The NOAEL for female mice
was 1.25 mg/kg. Reasons for no reported observations of stomach lesions
in Sprague-Dawley female rats at the highest dose (2.5 mg/kg) of the
Parent et al. (1992a) study compared with forestomach squamous
epithelial hyperplasia observed in female F344 rats in the NTP study at
1.25 mg/kg/day are not readily apparent, but may relate to differences
in strain sensitivity or vehicle. The vehicle dose volume was 5 ml/kg in
the NTP (1995) study and 10 ml/kg in the Parent et al. (1992a) study for
rats, and there may have been a reduced local gastric mucosal irritation
and pathology by virtue of dilution. There were also differences in the
vehicle solution and, possibly, the stability of the dosing solutions.
Parent et al. (1992a) conducted stability studies on acrolein in water,
and monitored the stability of their dosing solutions (reporting losses
of less than 10% for 3 hours at room temperature). They used a
stabilizing agent, 0.25% hydroquinone, in the stock solution, and
prepared dosing solutions daily. The NTP study used a dose vehicle of
0.5% methylcellulose in deionized water, and no information was
available on stability or stabilizing agents. 

For the mouse results, there is a similar divergence between the absence
of reported forestomach lesions in the CD-1 mice at 4.5 mg/kg in the
Parent et al. (1991) study compared with effects observed in female
B6C3F1 at 2.5 mg/kg in the NTP study. Species differences and dose
volume again may have accounted for observed differences in response.
Dose volume in the NTP study for mice was 10 ml/kg, and was unspecified
in the Parent et al. (1991) study. 

A benchmark dose approach was unsuitable for RfD development because the
data in the Parent et al. (1992a) study were presented graphically, with
statistical evaluation at one and two-year time points, but no numerical
values. Moreover, the NOAEL derived from the Parent et al. study and
used as the basis for the RfD is from a statistically significant
increase in mortality, a frank effect. A benchmark dose analysis would
not be appropriate when the dose-response is for early cumulative
mortality.

__I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF = 100. 

A default UFA of 10 was applied to account for interspecies differences
between laboratory animals and humans. No information was available to
support a change from the default. 

A default UFH of 10 was applied for intraspecies uncertainty to account
for human variability and sensitive subpopulations, i.e., to account for
human variability in the severity or range of response from any given
acrolein exposure amongst different individuals. 

A UFD was not applied because the database for acrolein was considered
complete. The available oral database includes chronic toxicity studies
in the rat and mouse, an oral reproductive toxicity study in
Sprague-Dawley rats and an oral developmental toxicity study in New
Zealand white rabbits. The findings from the oral reproductive and
developmental toxicity studies are supported by an inhalation
reproductive toxicity study of acrolein in Fisher 344 rats that revealed
no reproductive or developmental effects. Acrolein's high reactivity at
the point of contact and the evidence for minimal systemic distribution
of acrolein obviates the need for additional repeat dose studies. 

The RfD is based on a NOAEL from a chronic study, which obviates the
need for an uncertainty factor for LOAEL to NOAEL extrapolation or for
subchronic to chronic extrapolation. 

MF = 1.

__I.A.4. Additional Studies/Comments (Oral RfD)

Administration of acrolein in water by oral gavage at 0.05, 0.5, and 5.0
mg/kg to male and female Sprague-Dawley rats (30/sex/group) daily, 5
days per week for 13 weeks did not produce any significant adverse
effects on mortality, on clinical, hematological, or urinalysis
parameters, or on histopathology (Bioassay Systems Corp., 1981). This
study was a precursor to Parent et al. (1992a), identified as the
principal study. 

In a range-finding gavage study in artificially inseminated New Zealand
white rabbits (3-4/group), acrolein (0, 0.5, 1.0, 2.0, 4.0, and 6.0
mg/kg/day) produced high incidences of maternal mortality, spontaneous
abortion, resorption, clinical signs, gastric ulceration, and/or
sloughing of the gastric mucosa. The dose-response curve for mortality
was steep. A factor of 2 in dose (from 2 to 4 mg/kg) resulted in 25%
mortality in the high-dose animals compared to 0% in lower-dose animals
(Parent et al., 1993). Mortality was 100% at 6 mg/kg. 

In a two-generation reproductive toxicity study, four groups of 30 male
and 30 female Sprague-Dawley rats were gavaged with 70 daily doses of
acrolein at levels of 0, 1, 3, or 6 mg/kg in a dosing volume of 5 ml/kg
(Parent, 1992b). Rats within each dosing group (F0 generation) were then
assigned to a 21-day period of cohabitation. Dosing continued for
females through cohabitation, gestation, and lactation. A similar regime
was carried out for F1 generation offspring, resulting in F2 generation
pups. Mortality was significant (at 6 mg/kg) in both males and female of
the F0 and F1 generations with the pattern continuing with F1 mid-dose
animals, the latter showing signs of respiratory distress and
histopathological lesions in the lungs and stomach. Reproductive
parameters (i.e., mating performance and fertility indices) were
unaffected. No treatment-related gross or microscopic effects were
observed in the reproductive tissues of the F0 or F1 animals, and no
gross abnormalities were observed in F2 generation pups. The data
provide evidence that acrolein is not a selective reproductive toxicant
but does produce toxicological effects at doses as low as 3 mg/kg/day. 

Arumugam et al. (1999) exposed male Wistar rats, 5 animals/group, daily
to acrolein via intubation (2.5 mg/kg BW) for 45 days. The incidence of
mortality, if any, was not reported in this study. This study clearly
showed damage to mitochondria (through the loss of mitochondrial
lamellae of the cristae), a decrease in the availability of reduced
glutathione (a substrate for glutathione peroxidase), and a 30-56%
decrease in activities of citric acid cycle enzymes, resulting in
decreased energy production in liver cells. These results indicate that
at least some uptake occurs from the oral route; however, the stomach
was not examined by light microscopy. 

Because of the highly reactive nature of acrolein, the concentration of
a dose administered by gavage can affect the time course and degree of
severity of toxicity at the point of entry and the relevance of the
gavage bolus dose to human exposure. Rats have both a forestomach and a
glandular stomach, while humans have only a glandular stomach. The
glandular stomach is more resistant than the forestomach to pH changes
and irritation. The residence time in the forestomach (of approximately
2 hours) is sufficiently long compared to the reaction time for toxicity
with airway tissue observed in inhalation studies (i.e., microseconds)
so that the dose to the glandular stomach may be much lower than that to
the forestomach (TERA, 1998). The dog is a better model for glandular
stomach toxicity than the rat, however, Parent et al. (1992c)
administered acrolein (0.1% aqueous) in gelatin capsules to beagle dogs,
so the dose concentration to the glandular tissue is not known. In lieu
of studies that provide data on glandular stomach toxicity, the Parent
et al. (1992a) study in the rat remains the most suitable choice for the
principal study.

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=67"  the
toxicological review, Section 4.8  (PDF). 

__I.A.5. Confidence in the Oral RfD

Study — Medium

Database — High

RfD — Medium to High

The overall confidence in this RfD assessment is medium to high.
Confidence in the principal study is medium. Several supporting studies
involving other species also indicated that mortality increases sharply
with elevated dose. The research demonstrating acrolein's high
reactivity, low systemic distribution, toxicity at the point of entry,
pronounced decreases in serum creatinine phosphokinase (creatine
kinase), citric acid cycle enzymes and liver GSH, and increased
mitochondrial damage in the Wistar rat suggest interference with normal
metabolic processes or possibly the absorption of essential nutrients
sufficient to lead to early mortality. Further research is needed,
however, to support a definitive mode of action. In the NTP (1995)
study, glandular stomach and forestomach lesions were reported at higher
doses and likely played a role in the observed mortality. Confidence in
the database is judged high with chronic exposure studies in 2 species.
Moreover, two studies (Parent et al., 1992b; Parent et al., 1993)
provide evidence that reproductive and developmental effects are not
critical endpoints although only one species was tested for reproductive
effects (rat) and for developmental effects (rabbit). While the
possibility of some transport of acrolein or a metabolite of acrolein to
systemic sites remains, the critical target sites (discussed further in
the Toxicological Review of Acrolein) are at the point of contact, e.g.,
the respiratory system, the gastrointestinal tract, mucous membranes,
and skin. The high reactivity of acrolein and the lack of significant
systemic distribution obviates the need to examine
reproductive/developmental effects in a second species. The overall
confidence in this RfD assessment is medium-to-high; a variety of
studies across different durations of exposure and in several different
laboratory animal species has been consistent in demonstrating that in
the absence of mortality there are no clear indications of adverse
effects.

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l
"page=76"  the toxicological review, Section 6  (PDF). 

__I.A.6. EPA Documentation and Review of the Oral RfD

Source Document - U.S. EPA (2003) 

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of the
IRIS Summary. A record of these comments is included as an appendix to
the Toxicological Review of Acrolein (U.S. EPA, 2003).   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=101"  To
review this appendix, exit to the toxicological review, Appendix A,
Summary of External Peer Review Comments and Disposition (PDF) .

Agency Consensus Date - 05/16/2003

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(FAX), or   HYPERLINK "mailto:hotline.iris@epa.gov" 
hotline.iris@epa.gov  (email address).

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Substance Name — Acrolein

CASRN — 107-02-8

Last Revised — 06/03/2003

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 generally 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. 

The revised RfC is the same value as the previous RfC of 2 x 10-5 mg/m3
entered on IRIS 10/01/1991; however, this new RfC is based on an updated
interpretation of the database.

__I.B.1. Inhalation RfC Summary

Critical Effect	Experimental Doses*	UF	MF	RfC

Nasal lesions

Subchronic rat inhalation study

Feron et al., 1978	NOAEL: none

LOAEL: 0.4 ppm (0.9 mg/m3)

LOAEL (ADJ): 0.16 mg/m3

LOAEL (HEC): 0.02 mg/m3	1,000	1	2 x 10-5 mg/m3

*Conversion Factors and Assumptions: MW = 56.06 (HSDB, 2003). Assuming
25ºC and 760 mm Hg, the LOAEL of 0.4 ppm (0.9 mg/m3) was adjusted to a
continuous exposure as follows: LOAEL (ADJ) = 0.9 mg/m3 x 6/24 x 5/7 =
0.16 mg/m3. The LOAEL(HEC) was calculated for a Category 1
gas:respiratory effect in the extra-thoracic region by multiplying the
LOAEL (ADJ) by the Regional Gas Dosimetry Ratio (RGDR(ET)), to derive a
comparable human exposure (U.S. EPA, 1994). The calculation for the
RGDR(ET) = (MVa/SAa) / (MVh/SAh) where MVa = 0.20 m3/day, MVh = 20
m3/day, SAa(ET) = 15.0 cm2, SAh(ET) = 200 cm2 RGDR(ET) =
(0.20/15)/(20/200) = 0.14. The LOAEL(HEC) = LOAEL(ADJ) x RGDR(ET) = 0.16
mg/m3 x 0.14 = 0.02 mg/m3. Derivation of the RGDR is further described
in the Toxicological Review for Acrolein.

__I.B.2. Principal and Supporting Studies (Inhalation RfC)

Feron et al. (1978) exposed 6 Wistar rats/sex/concentration, 10 Syrian
golden hamsters/sex/concentration, and 2 Dutch rabbits/sex/concentration
for 6 hr/day, 5 days/week for 13 weeks to 0, 0.4, 1.4, or 4.9 ppm (0,
0.9, 3.2, or 11 mg/m3) acrolein in a whole-body exposure chamber.
Incidence data were not reported, but histopathological changes in the
nasal cavity, lung, larynx, and trachea were graded as slightly,
moderately, or severely affected. In rats, hematological parameters were
unaffected by acrolein. Body weight gain was significantly inhibited at
the high dose in rats, and less so at the intermediate concentration,
but food consumption appeared to be decreased in these groups as well.
At the intermediate concentration, both male and female rats showed
significantly retarded weight gain (p<0.05). Three male and 3 female
rats died during exposure at the highest dose. No other deaths
considered to be treatment-related were reported in any of the species
or exposure groups. 

Histopathologic changes described as "slightly affected" were found in
the nasal cavity of 1 of 12 rats exposed to 0.4 ppm (0.9 mg/m3).
Severity increased at the higher levels of exposure. No nasal lesions
were reported in other species at 0.4 ppm (0.9 mg/m3). The severity of
nasal lesions was concentration-related in all 3 species, most clearly
so in the rat. In the 4.9 ppm (11 mg/m3) groups of all 3 species,
slightly to markedly increased lesions were reported in the nasal cavity
and trachea; moderate to marked effects were seen in the bronchi and
lungs of rats and rabbits (but not hamsters). Based upon the
concentration-related severity of lesions, the rat is clearly the most
sensitive species, with hamsters and rabbits intermediate in
sensitivity. 

Although the Feron et al. (1978) study was adequately designed, the
incidence of nasal lesions for treated groups was not reported. However,
histopathological grading allowed the determination of NOAELs, LOAELs
and FELs for the 3 species, identification of the critical target site,
and a comparison of sensitivities among the 3 species tested. Other
limitations of this study include an exposure duration of 3 months
rather than lifetime, histopathological examination of only 3 sections
of the nasal cavity, lack of characterization of the type of nasal
lesions by sex, and only 6 rats/sex exposed. 

A more recent study, Cassee et al. (1996) examined the nasal effects of
inhalation exposure of formaldehyde, acetaldehyde, and acrolein on male
Wistar rats (5-6/group) exposed 6 hr/day, for 3 consecutive days, in a
nose-only exposure chamber to acrolein at concentrations of 0, 0.25,
0.67, or 1.4 ppm (0, 0.6, 1.5, or 3.2 mg/m3). The Cassee et al. (1996)
study was designed to evaluate the severity of effects from mixtures
versus single chemical exposure, and analyzed six levels of the nasal
tract for histopathological and biochemical changes immediately after
the last exposure. After one 6-hour exposure, no treatment-related
histopathological lesions were found in any of the treatment groups.
Only the histopathology of the 0.25 and 0.67 ppm (0.6 or 1.5 mg/m3)
groups were reported following 3 days of exposure; effects at 1.4 ppm
(3.2 mg/m3) were not reported. After 3 days, slight to moderate effects
were observed from acrolein exposure in two of the four histopathology
categories evaluated. In the category for disarrangement, necrosis,
thickening and desquamation in the respiratory/transitional epithelium,
4/5 animals exposed to 0.25 ppm (0.6 mg/m3) were observed to have slight
effects (characterized as mainly disarrangement) and 1/5 developed a
moderate level of effect. In the 0.67 ppm (1.5 mg/m3) group, 3/6 were
classified as slightly affected and 3/6 rats developed a moderate degree
of response. For rhinitis, 1/5 of the 0.25 ppm (0.6 mg/m3) rats
developed a moderate response, and only 1/6 of the 0.67 ppm (1.5 mg/m3)
rats had a response and it was scored as a slight response. For the
other two categories, single cell necrosis or atrophy of the olfactory
epithelium, no effects were observed in either the 0.25 ppm (0.6 mg/m3)
or 0.67 ppm (1.5 mg/m3) group. After one 6-hr exposure, no
treatment-related proliferative response (defined as basal cell
proliferation and/or an increased number of mitotic figures in
respiratory/transitional epithelium) was found in any of the treatment
groups. After 3 days, 3/5 rats at 0.25 ppm (0.6 mg/m3) developed a
slight focal proliferative response, and all rats in the 0.67 ppm (1.5
mg/m3) group developed a slight or moderate response. Proliferative
effects were not reported for the 1.4 ppm (3.2 mg/m3) exposure group.
Among biotransformation enzymes measured in homogenates of nasal tissue,
glutathione S-transferase activity was significantly depressed in the
1.4 ppm (3.2 mg/m3) exposure group (p<0.01) while formaldehyde
dehydrogenase and aldehyde dehydrogenase activities was significantly
increased (p<0.05). No changes were reported in the lower dose groups,
or for glutathione peroxidase activity in any of the dose groups.
Non-protein sulfhydryl (NPSH) depletion was not observed in this study.
No biochemical effects were observed in olfactory tissue. The LOAEL in
this study was 0.25 ppm (0.6 mg/m3). 

The occurrence of lesions at lower doses in the Cassee et al. (1996)
study than used in the Feron et al. (1978) study may be: (1) a
consequence of nose-only exposure where, unlike whole-body exposure, the
animals cannot minimize exposure by burying their noses in their fur, so
that animals receive a full and uninterrupted dose; or (2) due to a
higher resolution evaluation from the use of extended sectioning (6
sections) of the nasal tract compared to only 3 in the Feron et al.
(1978) study. 

Cassee et al. (1996) do not discuss the persistence or reversibility of
the observed histopathological changes in the low-dose group with
exposures greater than 3 days (e.g., adaptive response). An adaptive
response in nonprotein sulfhydryl levels after 3 days of exposure was
observed and is discussed. Because the Feron et al. (1978) study was
much longer in duration, it is possible that some adaptation to the
irritant effects of acrolein occurred with increasing duration, or that
cessation of exposure for 2 days each week provided a period during
which partial recovery from nasal effects might have occurred. 

The rationale for choosing the Feron et al. (1978) study over the Cassee
et al. (1996) study includes: (1) the higher number of test animals [12
(6/sex) vs. 6 male only]; (2) the longer duration [5 days/week for 13
weeks vs. 3 days]; (3) the testing of multiple species and both sexes in
the Feron et al. study; and 4) the better characterization of multiple
endpoints and the dose-response. Feron et al. evaluated many different
end points and demonstrated dose response for all 3 dose groups in all 3
species tested. The Feron et al. study also evaluated a dose response
over a 12-fold increase in dose from low to high dose. The Cassee et al.
study used about a 6-fold increase in dose level from low to high. 

A benchmark dose approach for derivation of the RfC was not possible
because nasal pathology incidence data were not provided. Therefore, the
approach used to derive the RfC was the determination of a LOAEL as the
point of departure and application of uncertainty factors.

__I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)

UF = 1,000. 

A UFA of 3 (101/2) was used for interspecies extrapolation, since this
factor embodies two areas of uncertainty: pharmacokinetics and
pharmacodynamics. In this assessment, the pharmacokinetic component was
addressed by the calculation of the human equivalent concentration (HEC)
according to the procedures in the RfC methodology (U.S. EPA, 1994b).
Accordingly, only the pharmacodynamic area of uncertainty remains as a
partial factor for interspecies uncertainty (101/2 or approximately 3). 

A default UFH of 10 was applied for intraspecies uncertainty to account
for human variability and sensitive subpopulations, i.e., to account for
human variability in the severity or range of response from any given
acrolein exposure amongst different individuals. 

A UFS of 10 was applied for adjustment from subchronic to chronic
duration because the principal study involved a 13-week dosing period
and because there are insufficient inhalation data to preclude an
increase in severity (or incidence) with an increase in exposure
duration from subchronic to chronic. 

A UFL of 3 (101/2) was applied for use of a minimal LOAEL of 0.4 ppm
(0.9 mg/m3) in lieu of a NOAEL. Although the severity of the nasal
effect at the 0.4 ppm level was minimal and in only 1 of 12 animals in
the Feron et al. (1978) study, a 3-day study in the male Wistar rat by
Cassee et al. (1996) also reported slight nasal effects in the
respiratory/transitional epithelium from nose-only inhalation exposure
at 0.25 ppm (0.6 mg/m3). An exposure concentration of 0.4 ppm (0.9
mg/m3) was designated a minimal LOAEL instead of a NOAEL, considering
the Cassee et al. (1996) results and the observed increase in the
severity of the effects with increasing dose in the Feron et al. (1978)
study. 

A UFD was not applied because the database for acrolein was considered
complete. The available inhalation database includes subchronic toxicity
studies in multiple species, and an inhalation reproductive toxicity
study of acrolein in Fisher 344 rats that revealed no reproductive or
developmental effects. Acrolein's high reactivity at the point of
contact and the evidence for minimal systemic distribution of acrolein
obviates the need for additional studies of repeat-dose toxicity or
reproductive/developmental toxicity. 

MF = 1. 

__I.B.4. Additional Studies/Comments (Inhalation RfC)

Studies by Kutzman (1981), Kutzman et al. (1985) and Costa et al. (1986)
support the Feron et al. (1978) results with additional evidence of lung
deficits from exposure to acrolein. The Kutzman studies were cited as
co-principal studies in the assessment previously on IRIS. Male F344
rats exposed to 0, 0.4, 1.4, or 4.0 ppm (0, 0.9, 3.2, or 9.2 mg/m3) 6
hr/day, for a total of 62 exposure days over a duration of 12.4 weeks
were examined on the sixth day post-exposure (to minimize acute effects)
(Kutzman, 1981; Kutzman et al., 1985). Mortality (32/57) was observed
only in males at the highest concentration, with many displaying severe
acute bronchopneumonia. The changes in the nasal region consisted of
only minimal evidence of submucosal lymphoid aggregates at 0.4 ppm (0.9
mg/m3); although degree of involvement increased to moderate at higher
concentrations, more extensive damage to the nasal epithelium was not
observed. Lungs from the 0.4 or 1.4 ppm (0.9 or 3.2 mg/m3) groups did
not display treatment-related histopathological changes. At 4.0 ppm (9.2
mg/m3) the surviving animals demonstrated bronchiolar epithelial
necrosis and sloughing, bronchiolar edema with macrophages, and focal
pulmonary edema. 

Support for acrolein's respiratory effects and association with
increased mortality is provided by Kutzman et al. (1984). Dahl rats
(derived from the Sprague-Dawley rat) that were either susceptible (DS)
or resistant (DR) to salt-induced hypertension were exposed in whole
body inhalation chambers to 0.4, 1.4, and 4.0 ppm (0.9, 3.2, and 9.2
mg/m3) acrolein; increased mortality (100% and 40% in DS and DR rats,
respectively) was reported at 4.0 ppm (9.2 mg/m3). Dose-response
increases in the severity of epithelial lesions occurred in both species
with the DS rats being more sensitive, and demonstrating a different
pathological response at the high dose. 

A continuous 90-day inhalation study involving exposure of dogs, guinea
pigs, rats and monkeys to acrolein did not include an examination of the
nasal tract by light microscopy (Lyon et al., 1970). Exposure
concentrations were 0.22, 1.0 and 1.8 ppm (0.5, 2.3, and 4.1 mg/m3).
There was no mention of the use of control animals in the report
although Lyon (2001) indicated that controls (not concurrent) were used.
Two of the four dogs exposed to 0.22 ppm (0.5 mg/m3) acrolein in this
study showed moderate emphysema, acute congestion and occasionally some
degree of constriction of the bronchioles. Monkeys also showed some
apparent inflammatory effects at this concentration. It is uncertain if
the effects seen at this concentration were directly related to exposure
given the absence of control results. No histopathologic effects were
reported for rats or guinea pigs at 0.22 ppm (0.5 mg/m3). 

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=67"  the
toxicological review, Section 4.8  (PDF).

__I.B.5. Confidence in the Inhalation RfC

Study — Medium

Database — Low to Medium

RfC — Medium 

The overall confidence in this RfC assessment is medium. The confidence
in the principal study is medium. Although the principal study (3
species) was adequately designed and examined a wide range of endpoints,
it had several shortcomings: (1) only 3 sections of the nasal cavity
were examined, (2) there was low sample size, and (3) a lack of
incidence data. Support for the minimal LOAEL is provided by subchronic
studies in 2 other species (rabbit and hamster) and a 3-day study
(Cassee et al., 1996) in the rat in which nasal lesions of similar type
and severity were observed. The primary limitation in the database is
the lack of a chronic inhalation study and the attendant uncertainty
relating to the incidence/severity of nasal lesions at
subchronic/chronic exposure levels lower than 0.4 ppm (0.9 mg/m3). The
high reactivity of acrolein at the point of contact, the lack of
significant systemic distribution demonstrated in studies with the dog
and rat, and the lack of effects in oral studies lessens the priority
for an evaluation of reproductive/developmental endpoints in a
two-generation inhalation study. Additional evaluation of immunological
endpoints is warranted especially focusing on potential contribution to
asthma or compromise in respiratory response. Thus, confidence in the
database is judged low to medium. The confidence in the RfC is judged
medium.

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l
"page=76"  the toxicological review, Section 6  (PDF). 

__I.B.6. EPA Documentation and Review of the Inhalation RfC

Source Document — U.S. EPA (2003) 

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included as an appendix to
the Toxicological Review of Acrolein (U.S. EPA, 2003).   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=101"  To
review this appendix, exit to the toxicological review, Appendix A,
Summary of External Peer Review Comments and Disposition (PDF) .

Agency Consensus Date — 05/16/2003

__I.B.7. EPA Contacts (Inhalation RfC)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(FAX) or   HYPERLINK "mailto:hotline.iris@epa.gov"  hotline.iris@epa.gov
 (internet address). 

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_II.  Carcinogenicity Assessment for Lifetime Exposure

Substance Name — Acrolein

CASRN — 107-02-8

Last Revised — 06/03/2003 

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 inhalation
exposure. Users are referred to Section I of this IRIS file for
information on long-term toxic effects other than carcinogenicity. 

The rationale and methods used to develop the carcinogenicity
information in IRIS is described in the Draft Revised Guidelines for
Carcinogen Risk Assessment (U.S. EPA, 1999. Guidelines for carcinogen
risk assessment. Review Draft, NCEA-F-0644, July. Risk Assessment Forum.
  HYPERLINK "http://www.epa.gov/ncea/raf/cancer.htm" 
http://www.epa.gov/ncea/raf/cancer.htm ). The quantitative risk
estimates result from application of a low-dose extrapolation procedure,
and both the central estimate and upper bound estimate of risk per unit
of exposure are presented. The quantitative risk estimates are presented
in three ways to facilitate their use. The oral slope factor is the 95%
upper bound on the estimate of risk per (mg/kg)/day of oral exposure.
The unit risk is the 95% upper bound on the estimate of risk, either per
µg/L drinking water or per µg/cu.m air breathed. The third form in
which risk is presented is the 95% lower bound on the estimated
concentration of the chemical in drinking water or air associated with
cancer risks of 1 in 10,000, 1 in 100,000, or 1 in 1,000,000.

_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Under the Draft Revised Guidelines for Carcinogen Risk Assessment (U.S.
EPA, 1999), the potential carcinogenicity of acrolein cannot be
determined because the existing "data are inadequate for an assessment
of human carcinogenic potential for either the oral or inhalation route
of exposure." 

There are no adequate human studies of the carcinogenic potential of
acrolein. Collectively, experimental studies provide inadequate evidence
that acrolein causes cancer in laboratory animals. Specifically, two
inhalation bioassays in laboratory animals are inadequate to make a
determination because of protocol limitations. Two gavage bioassays
failed to show an acrolein-induced tumor response in 2 species of
laboratory animals. Suggestive evidence of an extra-thoracic tumorigenic
response in a drinking water study in female rats was not supported in
the reanalysis of data by an independently-convened pathology working
group. Questions were also raised about the accuracy of the reported
levels of acrolein in the drinking water from this study. A skin tumor
initiation-promotion study was negative, and the findings from an
intraperitoneal injection study were of uncertain significance. Although
acrolein has been shown to be capable of inducing sister chromatid
exchange, DNA cross-linking and mutations under certain conditions, its
highly reactive nature and the lack of tumor induction at portals of
entry make it unlikely that acrolein reaches systemic sites at
biologically-significant exposure levels. The observations of positive
mutagenic results in bacterial systems occurred at high concentrations
near the lethal dose. 

This evaluation replaces the cancer assessment for acrolein added to the
IRIS database in 1988. Under the Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) applied at that time, acrolein was classified as a
possible human carcinogen (Category C). The 1988 classification for
acrolein was based on the increased incidence of adrenal cortical
adenomas in female rats and carcinogenic potential of an acrolein
metabolite, its mutagenicity in bacteria, and its structural
relationship to probable or known human carcinogens. The updated cancer
characterization considered new study results and reevaluated previous
studies. 

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l
"page=76"  the toxicological review, Section 6  (PDF).

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=67"  the
toxicological review, Section 4.8  (PDF). 

__II.A.2. Human Carcinogenicity Data

No data are available on carcinogenicity in humans exposed solely to
acrolein. The only study relating to cancer was a nested case control
study by Ott et al. (1989), in which individuals were classified as
having been exposed to one of a large number of chemicals in the work
environment. The study investigators reported non-Hodgkin's lymphoma (52
cases), multiple myeloma (20 cases), nonlymphocytic leukemia (39 cases),
and lymphocytic leukemia (18 cases) within a cohort of employed men from
two chemical manufacturing facilities and a research and development
center. Exposure odds ratios were examined in relation to 111 work
areas, 21 specific chemicals, and 52 chemical activity groups. Odds
ratios of 2.6 (2 cases) for non-Hodgkin's lymphoma, 1.7 (1 case) for
multiple myeloma, and 2.6 (3 cases) for nonlymphocytic leukemia were
reported for workers exposed to acrolein. None of the lower 95%
confidence limits exceeded 1.0. Because of a lack of a statistically
significant increase in the cancer endpoints and the likelihood of
confounding by concomitant exposure to other chemicals in the workplace,
the results must be considered equivocal.

__II.A.3. Animal Carcinogenicity Data

Feron and Kryusse (1977) reported negative findings for lung cancer
induction in Syrian golden hamsters exposed 35 hours/week for 52 weeks
to 4.0 ppm (9.2 mg/m3) acrolein via inhalation, followed by sacrifice at
81 weeks. Le Bouffant et al. (1980) exposed 20 female Sprague-Dawley
rats to 8 ppm (18 mg/m3) acrolein, 5 hours/week for 10 or 18 months,
with negative results. These findings, while negative, nevertheless fail
to provide conclusive evidence that acrolein is not carcinogenic by the
inhalation route. Both the rat and hamster studies were (1) less than
lifetime, (2) the maximum tolerated dose may not have been achieved, and
(3) only one concentration was used. 

Negative results for carcinogenicity were reported for Sprague-Dawley
rats, 70/sex/group, exposed via gavage to acrolein at doses of 0.0,
0.05, 0.5 and 2.5 mg/kg BW for 24 months (Parent et al., 1992a). Parent
et al. (1991) also reported negative results in Swiss albino mice,
70-75/sex/group, administered acrolein via gavage at doses of 0.2, 2.0
and 4.5 mg/kg/day for 18 months. 

The only suggestive evidence for carcinogenicity of acrolein was
marginally significant increases in adrenal cortical tumors in a
drinking water study reported by Lijinsky and Reuber (1987), and weak
evidence for tumor initiating ability of acrolein reported by Cohen et
al. (1992). Because no increase in adrenal cortical tumors was noted for
either species in the Parent et al. (1991, 1992a) studies, an
independent pathology working group (PWG) was convened to reevaluate the
adrenocortical tumors reported by Lijinsky and Reuber (1987). According
to the PWG (cited in Parent et al., 1992a), the "slightly elevated
incidence of pheochromocytomas (3/20; 15%) in the treated females were
well within limits for historical controls (3/34; 9%) and were of no
biological significance (sic)." Parent et al. (1992a) further suggested
that acrolein at a high dose may not have been as stable as assumed in
the Lijinsky and Reuber study. Based on some assumptions about water
intake and rat weight, Parent et al. estimated that the daily dose at
the highest concentration administered by Lijinsky and Reuber would have
exceeded the LD50 for rats. These questions concerning the stability of
acrolein in high dose solutions and the rate of intake render the
results of the Lijinsky and Reuber study less certain. Moreover,
concurrent controls were not used in the Lijinsky and Reuber study. 

Cohen et al. (1992) administered acrolein via intraperitoneal injection,
2 mg/kg/twice weekly to male Fischer 344 rats, 30/group, for either 53
weeks or for six weeks followed by an additional 47 weeks without
treatment. Because of extreme toxicity, the animals were sacrificed
after 53 weeks, rather than two years as originally planned. No
increases in tumor incidences were reported. In an additional group
administered acrolein for six weeks followed by tumor promotion with 3%
uracil in the drinking water for 20 weeks, urinary bladder papillomas
were reported in 18 of 30 and carcinoma in 1 of 30 rats, compared with
papillomas in 8 of 30 and carcinoma in 1 of 30 rats treated with uracil
alone (p<0.05). While it appears that acrolein may have some tumor
initiating capability, when the incidence of nodular hyperplasias
(considered precursors to papillomas) and papillomas were combined,
there were no significant differences between the two groups. Acrolein
was too toxic to evaluate its tumor promoting potential, and the impact
of its cytotoxicity on conclusions about its tumor initiating potential
cannot be determined from this study alone. 

No sarcomas were reported in a group of 15 female albino mice
administered 0.2 mg acrolein by subcutaneous injection, weekly for 24
weeks, then held for a lifetime (Steiner et al., 1943). No evidence for
skin tumor initiating capability was reported in S strain mice
administered acrolein dermally in ten weekly applications for a total
dose of 12.6 mg/animal, followed by treatment with the tumor promoter
croton oil (Salaman and Roe, 1956).

__II.A.4. Supporting Data for Carcinogenicity 

In vitro, acrolein has been shown to induce DNA adducts in a variety of
cell types as well as mutagenesis in Drosophila and microorganisms under
certain conditions, but there is only limited information regarding the
ability of acrolein to induce mutations in normal mammalian cells. In
mammalian cell in vitro assays, acrolein has been shown to induce sister
chromatid exchange, DNA cross-linking, and binding to DNA polymerase.
Even in the in vitro assays, acrolein is so reactive that special
techniques must generally be employed to reduce cytotoxicity and induce
positive effects. While mutagenic activity has occasionally been shown,
positive results generally occurred only in a narrow, near lethal, dose
range. 

There have been conflicting results reported in the literature for in
vitro mutagenicity. In a series of Ames assays, Parent et al. (1996b)
proposed an explanation for the conflicting data by considering the
presence or absence of non-DNA nucleophiles from the S9 activation
mixture, in the test chemical solution, or in the plating solutions.
Parent et al. suggest that in the presence of non-DNA nucleophiles,
acrolein will rapidly and indiscriminately react with any available
species and not reach the DNA target. 

According to Beauchamp et al. (1985), acrolein administered by the
inhalation route is retained primarily in the upper respiratory tract
because of its reactivity. Some evidence for systemic uptake following
oral exposure was noted by Draminski et al. (1983); however, the large
doses used (10 mg/kg) would be expected to induce cellular damage, which
may allow for some absorption. Tissues at the site of contact are,
therefore, expected to be most highly exposed, and no evidence of tumor
induction in the respiratory tract, skin or gastrointestinal tract has
been reported. Studies by Parent et al. (1996a, 1998) indicate little
systemic distribution to tissues. 

The highly reactive nature of acrolein and studies supporting the lack
of systemic distribution of acrolein suggest that acrolein is not likely
to reach potential target sites at a sufficient concentration to
initiate a carcinogenic process in mammalian species.

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

Not applicable.

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation
Exposure

Not applicable.

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity
Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA (2003). 

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included as an appendix to
the Toxicological Review of Acrolein (U.S. EPA, 2003).   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0364-tr.pdf" \l "page=101"  To
review this appendix, exit to the toxicological review, Appendix A,
Summary of External Peer Review Comments and Disposition (PDF) .

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Consensus Date — 05/16/2003

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(FAX) or   HYPERLINK "mailto:hotline.iris@epa.gov"  hotline.iris@epa.gov
 (email address). 

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_III.  [reserved]

_IV.  [reserved] 

_V.  [reserved]

_VI.  Bibliography 

Substance Name — Acrolein

CASRN — 107-02-8

Last Revised — 06/03/2003

_VI.A. Oral RfD References

Arumugam, N; Thanislass, J; Ragunath, K; et al. (1999) Acrolein-induced
toxicity - defective mitochondrial function as a possible mechanism.
Arch Environ Contam Toxicol 36(4):373-376. 

Bioassay Systems Corp. (1981) Subchronic oral toxicity of acrolein in
rats. Project #10258. (Results section and tables). 

IRIS. (2003). Glossary of IRIS Terms. Available online at:   HYPERLINK
"http://www.epa.gov/iris/help_gloss.htm" 
http://www.epa.gov/ncea/iris/help_gloss.htm  

National Toxicology Program (NTP). (1995) 13-week gavage toxicity
studies of allyl acetate, allyl alcohol, and acrolein in Fischer 344
rats and B6C3F1 mice. Abstract with tables. 

Parent, RA; Caravello, HE; Long, JE. (1991) Oncogenicity study of
acrolein in mice. J Am Coll Toxicol 10(6):647-659. 

Parent, RA; Caravello, HE; Long, JE. (1992a) Two-year toxicity and
carcinogenicity study of acrolein in rats. J Appl Toxicol 12(2):131-139.


Parent, RA; Caravello, HE; Hoberman, AM. (1992b) Reproductive study of
acrolein on two generations of rats. Fundam Appl Toxicol 19(2):228-237. 

Parent, RA; Caravello, HE; Balmer, MF; et al. (1992c) One-year toxicity
of orally administered acrolein to the beagle dog. J Appl Toxicol
12(5):311-316. 

Parent, RA; Caravello, HE; Christian, MS; et al. (1993) Developmental
toxicity of acrolein in New Zealand white rabbits. Fundam Appl Toxicol
20(2):248-256. 

Pathology Working Group. (1997) Chairperson's report, Pathology Working
Group review of acrolein 13-week subchronic gavage study in F344 rats
and B6C3F1 mice conducted at Battelle-Columbus. 

  

U.S. EPA (U.S. Environmental Protection Agency). (2003) Toxicological
review of acrolein in support of summary information on Integrated Risk
Information System (IRIS) National Center for Environmental Assessment,
Washington, DC. EPA/635/R-03/003. Available online at:   HYPERLINK
"http://www.epa.gov/iris/index.html"  http://www.epa.gov/ncea/iris .

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_VI.B. Inhalation RfC References

Cassee, FR; Groton, JP; Feron, VJ. (1996) Changes in the nasal
epithelium of rats exposed by inhalation to mixtures of formaldehyde,
acetaldehyde, and acrolein. Fundam Appl Toxicol 29:208-218. 

Costa, DL; Kutzman, RS; Lehmann, JR; et al. (1986) Altered lung function
and structure in the rat after subchronic exposure to acrolein. Am Rev
Resp Dis 133:286-291. 

Feron, VJ; Kryusse, A; Til, HP; et al. (1978) Repeated exposure to
acrolein vapor: subacute studies in hamsters, rats and rabbits.
Toxicology 9:47-57. 

Kutzman, RS. (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. Conducted for the National Toxicology Program:
Interagency Agreement No. 222-Y01-ES-9-0043. 

Kutzman, RS; Wehner, RW; Haber, SB. (1984) Selected responses of
hypertension-sensitive and resistant rats to inhaled acrolein.
Toxicology 31(1):53-65. 

Kutzman, RS; Popenoe, EA; Schmaeler, M; et al. (1985) Changes in rat
lung structure and composition as a result of subchronic exposure to
acrolein. Toxicology 34(2):139-151. 

Lyon, JP; Jenkins, LJ, Jr; Jones, RA; et al. (1970) Repeated and
continuous exposure of laboratory animals to acrolein. Toxicol Appl
Pharmacol 17(3):726-732. 

Lyon, JP. (2001) Personal communication with Mark Greenberg, USEPA. 

U.S. EPA (U.S. Environmental Protection Agency). (1994) Methods for
derivation of inhalation reference concentrations and application of
inhalation dosimetry. EPA/600/8-90/066F. 

U.S. EPA. (2003) Toxicological review of acrolein in support of summary
information on Integrated Risk Information System (IRIS). National
Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003.
Available online at:   HYPERLINK "http://www.epa.gov/iris/index.html" 
http://www.epa.gov/ncea/iris .

  HYPERLINK "http://www.epa.gov/iris/subst/0364.htm" \l
"content#content"  Top of page 

_VI.C. Carcinogenicity Assessment References

Beauchamp, RO, Jr; Andjelkovich, DA; Kligerman, AD; et al. (1985) A
critical review of the literature on acrolein toxicity. CRC Crit Rev
Toxicol 14:309-378. 

Cohen, SM; Garland, EM; St John, M; et al. (1992) Acrolein initiates rat
urinary bladder carcinogenesis. Cancer Res 52(13):3577-3581. 

Draminski, W; Eder, E; Henschler, D. (1983) A new pathway of acrolein
metabolism in rats (Short communication). Arch Toxicol 52(3):243-247. 

Feron, VJ; Kryusse, A. (1977) Effects of exposure to acrolein vapor in
hamsters simultaneously treated with benzo(a)pyrene or
diethylnitrosamine. J Toxicol Environ Health 3:379-394. 

Le Bouffant, L; Martin, JC; Daniel, H; et al. (1980) Actions of
intensive cigarette smoke inhalations on the rat lung. Role of
particulate and gaseous cofactors. J. Natl Cancer Inst 64(2):273-281. 

Lijinsky, W; Reuber, MD. (1987) Chronic carcinogenesis studies of
acrolein and related compounds. Toxicol Ind Health 3(3):337-345. 

Ott, MG; Teta, J; Greenberg, HL. (1989) Lymphatic and hematopoietic
tissue cancer in a chemical manufacturing environment. Am J Ind Med
16:631-643. 

Parent, RA; Caravello, HE; Long, JE. (1991) Oncogenicity study of
acrolein in mice. J Am Coll Toxicol 11:91-95. 

Parent, RA; Caravello, HE; Long, JE. (1992a) Two-year toxicity and
carcinogenicity study of acrolein in rats. J Appl Toxicol 12(2):131-139.


Parent, RA; Caravello, HE; Sharp, DE. (1996a) Metabolism and disposition
of [2,3-14C] acrolein in Sprague-Dawley rats. J Appl Toxicol
16(5):449-457. 

Parent, RA; Caravello, HE; San, RH (1996b) Mutagenic activity of
acrolein in S. typhimurium and E. coli. J Appl Toxicol 16(2):103-8. 

Parent, RA; Paust, DE; Schrimpf, MK; et al. (1998) Metabolism and
distribution of [2,3-14C]acrolein in Sprague-Dawley rats. II.
Identification of urinary and fecal metabolites. Toxicol Sci
43(2):110-120. 

Salaman, MH; Roe, FJC. (1956) Further tests for tumour initiating
activity: N,N-di(2-chloroethyl)-p-aminophenylbutyric acid (CB1348) as an
initiator of skin tumour formation in the mouse. Br J Cancer 10:363-378.


Steiner, PE; Steele, R; Koch, FC. (1943) The possible carcinogenicity of
overcooked meats, heated cholesterol, acrolein and heated sesame oil.
Cancer Res 3:100-143. 

U.S. EPA (U.S. Environmental Protection Agency). (1999) Guidelines for
carcinogen risk assessment. Review draft. NCEA-F-0644, July 1999. Risk
Assessment Forum. 

U.S. EPA. (2003) Toxicological review of acrolein in support of summary
information on Integrated Risk Information System (IRIS). National
Center for Environmental Assessment, Washington, DC. EPA/635/R-03/003.
Available online at:   HYPERLINK "http://www.epa.gov/iris/index.html" 
http://www.epa.gov/ncea/iris .

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_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

04/01/1997	III., IV., V.	Drinking Water Health Advisories, EPA
Regulatory Actions, and Supplementary Data were removed from IRIS on or
before April 1997. IRIS users were directed to the appropriate EPA
Program Offices for this information.

01/12/2000	I., II.	This chemical is being reassessed under the IRIS
Program.

06/03/2003	I., II., VI.	RfD, RfC and cancer sections updated

12/2/2004	Toxicological Review	Technical correction to Toxicological
Review describing units for ambient exposure levels (section 2) and
acute exposure regimen in Weber-Tschopp et al. (1977)



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_VIII.  Synonyms

Substance Name — Acrolein

CASRN — 107-02-8

Last Revised — 06/03/2003

107-02-8 

acralaldehyde 

acrylaldehyde 

allyl aldehyde 

ethylene aldehyde 

propenal 

prop-2-en-l-al 

2-propenal

