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Acetaldehyde
CASRN 75-07-0
Contents
0290
Acetaldehyde; CASRN 75-07-0
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 Acetaldehyde
File On-Line 06/30/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 10/01/1991
Carcinogenicity Assessment (II.) on-line 01/01/1991
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Acetaldehyde
CASRN -- 75-07-0
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Acetaldehyde
CASRN -- 75-07-0
Last Revised -- 10/01/1991
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
-------------------- --------------------------- ----- --- ---------
Degeneration of NOAEL: 273 mg/cu.m (150 ppm) 1000 1 9E-3
olfactory epithelium NOAEL(ADJ): 48.75 mg/cu.m mg/cu.m
NOAEL(HEC): 8.7 mg/cu.m
Short-term Rat
Inhalation Studies LOAEL: 728 mg/cu.m (400 ppm)
LOAEL(ADJ): 130 mg/cu.m
Appleman et al., 1986; LOAEL(HEC): 16.9 mg/cu.m
1982
*Conversion Factors: MW = 44.5.
Appleman et al., 1986: Assuming 25C and 760 mmHg, NOAEL(mg/cu.m) = 150 ppm
x 44.5/24.45 = 273. NOAEL(ADJ) = 273 mg/cu.m x 6 hours/day x 5 days/7 days =
48.75 mg/cu.m. The NOAEL(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.
NOAEL(HEC) = NOAEL(ADJ) x RGDR = 8.7 mg/cu.m.
Appleman et al., 1982: Assuming 25C and 760 mmHg, LOAEL(mg/cu.m) = 400 ppm x
44.5/24.45 = 130. LOAEL(ADJ) = 728 mg/cu. m x 6 hours/day x 5 days/7days =
130 mg/cu.m. The LOAEL(HEC) was calculated for a gas:respiratory effect in
the ExtraThoracic region. MVa = 0.17 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) = 0.13.
LOAEL(HEC) = LOAEL(ADJ) x RGDR = 16.9 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Appleman, L.M., R.A. Woutersen, V.J. Feron, R.N. Hooftman and W.R.F. Notten.
1986. Effect of variable versus fixed exposure levels on the toxicity of
acetaldehyde in rats. J. Appl. Toxicol. 6(5): 331-336.
Appleman, L.M., R.A. Woutersen, and V.J. Feron. 1982. Inhalation toxicity of
acetaldehyde in rats. I. Acute and subacute studies. Toxicology. 23:
293-297.
Two short-term studies conducted by the same reSEARCH group are the
principal studies used. While these studies are short-term in duration,
together they establish a concentration-response for lesions after only 4
weeks of exposure. These same types of lesions appear at longer exposure
times and higher exposure levels in chronic studies (Wouterson et al., 1986;
Wouterson and Feron, 1987; Kruysse et al., 1975). Under other circumstances,
studies of short duration may not be considered appropriate, but for this
chemical the observed effects are consistent with pathology seen in long-term
studies. The 150-ppm exposure level was therefore established as the NOAEL
from the Appleman et al. (1986) study and the LOAEL from the Appleman et al.
(1982) study.
Appleman et al. (1986) conducted two inhalation studies on male Wistar
rats (10/group) exposing them 6 hours/day, 5 days/week for 4 weeks to 0, 150,
and 500 ppm (0, 273 and 910 mg/cu.m, respectively). Duration-adjusted
concentrations are 0, 48.75, and 162.5 mg/cu.m, respectively. One group was
exposed without interruption, a second group was interrupted for 1.5 hours
between the first and second 3-hour period, and a third group was interrupted
as described with a superimposed peak exposure profile of 4 peaks at 6-fold
the basic concentration per 3-hour period. The purpose was to test
intermittent and peak exposure effects. Urine samples were collected from all
rats and lung lavage performed on 4-5 per group at the end of the experiment.
Cell density, viability, number of phagocytosing cells, and phagocytic index
were determined on the lavage fluid. Microscopic examination was performed on
the nasal cavity, larynx, trachea with bifurcation and pulmonary lobes of all
rats of all groups.
Continuous and interrupted exposure to 500 ppm did not induce any visible
effect on general condition or behavior, but peak exposures at this level
caused irritation. No behavioral differences were noted in the other groups.
Mean body weights of the group exposed to 500 ppm with interruption and with
peak exposures were statistically significantly lower than those of the
controls. Body weights were similar to controls in the other exposure groups.
Mean cell density and cell viability were significantly decreased in the group
exposed to 500 ppm with or without peak exposures. The mean percentage of
phagocytosing cells and the phagocytic index were significantly lower than
controls in all groups exposed to 500 ppm, especially the group exposed to
superimposed peaks. Histopathological changes attributable to exposure were
found only in the nasal cavity. Degeneration of the olfactory epithelium was
observed in rats exposed to 500 ppm. Interruption of the exposure or
interruption combined with peak exposure did not visibly influence this
adverse effect. No compound-related effects were observed in rats
interruptedly or uninterruptedly exposed to 150 ppm during the 4-week exposure
period; therefore, the NOAEL is 150 ppm. The NOAEL(HEC) based on effects on
the olfactory epithelium in the extrathoracic region is 8.7 mg/cu.m.
Appelman et al. (1982) exposed Wistar rats (10/sex/group) for 6 hours/day,
5 days/week for 4 weeks to 0, 400, 1000, 2200, or 5000 ppm acetaldehyde (0,
728, 1820, 4004 and 9100 mg/cu.m, respectively). Duration-adjusted
concentrations are 0, 130, 325, 715 and 1625 mg/cu.m, respectively. The
general condition and behavior of the rats were checked daily. Blood picture
(Hb, Hct, RBC, total and differential WBC, and plasma protein) and chemistry
were examined at the end of the treatment period. Activities of plasma
glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, and alkaline
phosphatase were also determined. Urine was analyzed for density, volume, pH,
protein, glucose, occult blood, ketones, and appearance. The kidneys, lungs,
liver, and spleen were weighed. Microscopic examination was performed on the
lungs, trachea, larynx, and nasal cavity (3 transverse sections) of all
animals and on the kidneys, liver, and spleen of all control and high-
concentration groups.
During the first 30 minutes of each exposure at the 5000-ppm level, rats
exhibited severe dyspnea that gradually became less severe during the
subsequent exposure period. Two animals died at this level (1 female, 1 male)
and one male died at the 2200-ppm level, but the cause of death could not be
determined due to autolysis or cannibalism. Growth was retarded in males at
the three highest exposure concentrations and in females at the 5000-ppm
level. The percentage of lymphocytes in the blood was lower and the percentage
of neutrophilic leukocytes higher in males and females of the 5000-ppm group
than in controls. There were a few statistically significant differences in
several blood chemistry parameters between the exposure groups and the control
group but none of them were concentration-related. Statistically significant
changes in organ-to-body weight ratios included decreased liver weights in
both sexes and increased lung weights in males at the 5000-ppm level. Males
in the 5000-ppm level produced less urine, but it was of higher density.
Compound-related histopathological changes were observed only in the
respiratory system. The nasal cavity was most severely affected and exhibited
a concentration-response relationship. At the 400-ppm level, compound-related
changes included: slight to severe degeneration of the nasal olfactory
epithelium, without hyper- and metaplasia, and disarrangement of epithelial
cells. At the 1000- and 2200-ppm levels, more severe degenerative changes
occurred, with hyperplastic and metaplastic changes in the olfactory and
respiratory epithelium of the nasal cavity. Degeneration with
hyperplasia/metaplasia also occurred in the laryngeal and tracheal epithelium
at these levels. At 5000 ppm changes included severe degenerative
hyperplastic and metaplastic changes of the nasal, laryngeal, and tracheal
epithelium. Based on the degenerative changes observed in the olfactory
epithelium, the 400-ppm level is designated as a LOAEL. The LOAEL(HEC), based
on the ventilation rates for female rats, is 16.9 mg/cu.m. No NOAEL was
identified.
Woutersen et al.(1986) exposed Wistar rats (105/sex/group) for 6
hours/day, 5 days/week for up to 28 months to 0, 750, 1500 and 3000/1000 ppm
(0, 1365, 2730, 5460/1820 mg/cu.m, respectively). The highest concentration
was gradually decreased because of severe growth retardation, occasional loss
of body weight, and early mortality in this group. The duration-adjusted
concentrations are 0, 244, 488, and 975/325 mg/cu.m, respectively. The
general condition and behavior of the rats were checked daily. Samples of a
wide range (otherwise not specified) of tissues, including the nasal cavity,
trachea with main bronchi, and lungs were examined by light microscopy. The
rats in the high-exposure concentration showed excessive salivation, labored
respiration, and mouth breathing. The respiratory distress was still observed
when the concentration was reduced to 1000 ppm, although fewer were dyspneic.
Only a few rats died during the first 6 months of the study but thereafter a
sharp increase in the numbers of deaths occurred in the high-concentration
group. All top concentration rats had died by 25 months. When the study was
terminated, only a few animals remained alive in the mid-concentration group.
The cause of early death or moribund condition was nearly always partial or
complete occlusion of the nose by excessive amounts of keratin and
inflammatory exudate. Several showed acute bronchopneumonia occasionally
accompanied by tracheitis. Growth retardation occurred in males of each test
group and in females of the two highest concentrations. The only exposure-
related histopathology occurred in the respiratory system and showed a
concentration-response relationship. The most severe abnormalities were found
in the nasal cavity. Basal cell hyperplasia of the olfactory epithelium was
seen in the low- and mid-concentration rats. The decrease in these changes in
the olfactory epithelium was attributed to the incidence of adenocarcinomas at
the higher levels. The respiratory epithelium of the nasal cavity was
involved (hyperplasia and squamous metaplasia with keratinization) at the mid
and high concentrations. Hyperplasia and squamous metaplasia, occasionally
accompanied by keratinization, occurred in the larynx of rats exposed at the
mid and high concentrations. The tracheal epithelium was not visibly affected
at any exposure level. Adenocarcinomas occurred at all exposure
concentrations and squamous cell carcinoma at the mid and high concentrations
only. It thus appeared that the nasal tumors could be distinguished into two
major types: adenocarcinomas from olfactory epithelium, and squamous cell
carcinoma from the respiratory epithelium. The lowest exposure concentration,
750 ppm, is clearly a LOAEL based on the above changes in the olfactory
epithelium. The LOAEL(HEC) is 56 mg/cu.m. No NOAEL was identified.
Woutersen and Feron (1987) conducted an inhalation study in which Wistar
rats (30 rats/sex/group) were exposed to 0, 750, 1500, or 3000/1500 ppm
acetaldehyde (0, 1365, 2730, 5460/2730 mg/cu.m, respectively) for 6 hours/day,
5 days/week for 52 weeks with a 26- or 52-week recovery period. The highest
concentration was gradually decreased because of severe growth retardation,
occasional loss of body weight, and early mortality. Duration-adjusted
concentrations are 0, 244, 488, and 975/488 mg/cu.m, respectively. The
general condition and behavior of the rats were checked daily. Histopathology
was performed as described for Wouterson et al. (1986).
At the end of the 52-week exposure period, most of the animals in the
high-concentration group exhibited labored respiration and mouth breathing.
The respiratory distress diminished during the recovery period but did not
disappear completely. Adenocarcinoma and squamous cell carcinoma occurred at
the mid and high concentrations. Degeneration of the olfactory epithelium was
similar in rats terminated after 26 weeks of recovery and rats killed
immediately after exposure termination. Histopathological changes found in
the respiratory epithelium were comparable with, but less severe than, those
observed immediately after exposure termination. After 52 weeks of recovery,
the degeneration of the olfactory epithelium was still visible to a slight
degree in animals from all exposure groups. Animals in the high-concentration
group did not show restoration of the olfactory epithelium. At the low
concentration, normal olfactory epithelium was present in some animals but
replacement of olfactory epithelium by respiratory epithelium was frequently
seen. Histopathological changes in the respiratory epithelium of the two
females of the high-concentration group examined were essentially comparable
with those found in rats terminated after 26 weeks of recovery. These data
suggest that there is incomplete recovery of olfactory and respiratory
epithelium changes induced at all exposure concentrations for periods as long
as 52 weeks after exposure termination.
Kruysse et al. (1975) conducted a 90-day inhalation study in hamsters
(10/sex/concentration). The hamsters were exposed to acetaldehyde vapor at
concentrations of 0, 390, 1340, or 4560 ppm (0, 127, 435.5 or 1482 mg/cu.m,
adjusted for duration, respectively), for 6 hours/day, 5 days/week for 90
days. Histopathological changes attributable to exposure were observed only
in the respiratory tract. At 4560 ppm, body weights were significantly
reduced and the relative weights of heart, kidney, brain, testicle, and lung
were significantly increased. Histopathological changes of the nasal cavity,
larynx, trachea, and bronchi included necrosis, inflammatory changes, and
hyperplasia and metaplasia of the epithelium. Mild effects observed at 1340
ppm consisted of statistically significant increased kidney weight in males,
and small areas of stratified epithelium in the trachea in both sexes (30% of
the animals). At 390 ppm, with the exception of a tiny focus of metaplastic
epithelium in the trachea of 1 out of the 20 animals examined, no adverse
effects were observed. The 390-ppm concentration was identified by the
authors as a NOAEL. The study by Appelman et al. (1982) identified a similar
level (400 ppm) as a LOAEL [LOAEL(HEC) = 16.9 mg/cu.m] for Wistar rats, but
surface area values in hamsters are not available so that a comparison on HEC
values could not be made to determine the relative sensitivities of the
species to acetaldehyde. The LOAEL for the extrarespiratory effects (effect
on kidney weight) is 1340 ppm and the NOAEL also at 390 ppm. The NOAEL(HEC)
for extrarespiratory effects is 127 mg/cu.m.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- An uncertainty factor of 10 was applied to account for sensitive human
populations. A factor of 10 was applied for both uncertainty in the
interspecies extrapolation using dosimetric adjustments and to account for the
incompleteness of the data base. A factor of 10 was applied to account for
subchronic to chronic extrapolation.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
Saldiva et al. (1985) exposed male Wistar rats (12/group) to 0 or 243 ppm
(442 mg/cu.m) of acetaldehyde 8 hours/day, 5 days/week for 5 weeks. Duration-
adjusted values are 0 and 105 mg/cu.m., respectively. The animals were
evaluated for pulmonary mechanics before and after the exposure period, and
gross and paraffin-embedded sample observations were made after exposure,
especially of the respiratory system. Increases in RF, FRC, RV, and TLC were
significantly different from control values. Damage to distal airways was
suggested since functional tests for damage to elasticity or for severe
obstruction were not demonstrated. Histopathological investigation showed an
intense inflammatory reaction with olfactory epithelium hyperplasia and
polymorphonuclear and mononuclear infiltration of the submucosa. Cannulation
precluded evaluation of tracheal effects and no differences between the
control and exposed animals were observed for the lower respiratory tract.
Although this study presents the pathology data in only a descriptive fashion,
it identifies a LOAEL for nasal effects of 105 mg/cu.m (HEC = 13.7 mg/cu.m)
that is consistent with the principal studies. The LOAEL(HEC) for thoracic
effects on pulmonary function is 220.5 mg/cu.m.
Feron (1979) exposed Syrian golden hamsters (35 males/group) by inhalation
to 1500 ppm acetaldehyde 7 hours/day, 5 days/week for 52 weeks. The duration-
adjusted concentration is 487.5 mg/cu.m. Exposure to acetaldehyde vapor
resulted in epithelial hyperplasia and metaplasia, accompanied by inflammation
in the nasal cavity and trachea. No evidence of carcinogenicity was observed.
In an inhalation study Feron et al. (1982) exposed Syrian golden hamsters
to 2500 ppm (948 mg/cu.m adjusted for duration) for the first 9 weeks, 2250
ppm, (853 mg/cu.m adjusted for duration) for weeks 10-20, 2000 ppm (758
mg/cu.m adjusted for duration) for weeks 21-29, 1800 ppm (682.5 mg/cu.m
adjusted for duration) for weeks 30-44, and 1650 ppm (626 mg/cu.m adjusted for
duration) for weeks 42-52, for 7 hours/day, 5 days/week for a total of 52
weeks. Compound-related changes included rhinitis, hyperplasia, and
metaplasia of the nasal, laryngeal, and tracheal epithelium, and nasal and
laryngeal carcinomas. No LOAEL was identified.
No inhalation studies for reproductive or developmental effects have been
performed. No oral or inhalation developmental studies, nor any reproductive
studies, exist.
Zorzano and Herrera (1989) studied the pattern of acetaldehyde appearance
in maternal and fetal blood, maternal and fetal liver and placenta after oral
ethanol administration or intravenous acetaldehyde administration (10 mg/kg)
to pregnant Wistar rats. The study demonstrated that acetaldehyde was able to
cross the placental barrier at high concentrations (fetal blood concentrations
were only detectable when maternal blood concentrations were greater than 80
uM). The fetal oxidation capacity in liver and placenta was shown to be lower
than that of the maternal liver. A threshold above which the removal capacity
of acetaldehyde metabolism by the fetoplacental unit would be surpassed was
estimated to be 80 uM (maternal blood concentration) in the 21-day pregnant
rat and possibly lower at early pregnancy when aldehyde dehydrogenase is
absent from fetal liver.
Retention of acetaldehyde in humans under "physiologic conditions" of
breathing rate and tidal volume has been shown to be approximately 60% between
100 and 200 mg/cu.m for a few minutes (Egle, 1970), and retention was shown to
decrease slightly at higher concentrations. Breathing rate and volume and
exposure concentration were shown to influence retention. Retention has not
been determined at lower concentrations comparable with the HEC estimates
derived here, however. Retention of acetaldehyde from cigarette smoke was
shown to be 99% (Dalhamn et al., 1968). Acetaldehyde has been shown to be
absorbed via inhalation at high concentrations (9000-10,000) for 1 hour
(Watanabe et al., 1986). Binding and metabolism in blood and rat nasal mucosa
have been demonstrated (Hagihara et al., 1981; Casanova-Schmitz et al., 1984).
Casanova-Schmitz et al. (1984) observed that rats exposed to 700 ppm for 2
hours demonstrated only 0.7 mM in circulating blood 5 minutes after exposure
termination, suggesting that binding in the respiratory tract and rapid
metabolism significantly reduces systemic circulation at steady state.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Data Base -- Low
RfC -- Low
Confidence in the principal studies is medium since appropriate
histopathology was performed on an adequate number of animals and a NOAEL and
LOAEL were identified, but the duration was short and only one species was
tested. Confidence in the data base is low due to the lack of chronic data
establishing NOAELs and due to the lack of reproductive and developmental
toxicity data. Low confidence in the RfC results.
___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, 1991
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 -- Acetaldehyde
CASRN -- 75-07-0
Last Revised -- 01/01/1991
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 -- B2; probable human carcinogen
Basis -- Based on increased incidence of nasal tumors in male and female rats
and laryngeal tumors in male and female hamsters after inhalation exposure.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. The only epidemiological study involving acetaldehyde
exposure showed an increased crude incidence rate of total cancer in
acetaldehyde production workers as compared with the general population
(Bittersohl, 1974). Because the incidence rate was not age adjusted, and
because this study has several other major methodological limitations
(including concurrent exposure to other chemicals and cigarette exposure,
short duration, small number of subjects, and lack of information on subject
selection, age and sex distribution) it is considered inadequate to evaluate
the carcinogenicity of acetaldehyde.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. Feron (1979) exposed groups of 35 male Syrian Golden hamsters
to 0 or 1500 ppm acetaldehyde by inhalation 7 hours/day, 5 days/week, for 52
weeks. These animals were also exposed weekly by intratracheal instillation
to increasing doses of benzo(a)pyrene (BaP) in 0.2 mL of 0.9% NaCl, or to NaCl
alone. Animals were killed and autopsied after exposure and 26 weeks of
recovery in air. No neoplastic effects due to acetaldehyde alone were found.
The highest BaP dose (1 mg/week for 52 weeks) combined with acetaldehyde
exposure produced twice the incidence of squamous cell carcinomas compared
with the same dose of BaP alone. In the second part of this study, no
respiratory tract tumors were found in groups of 25 male hamsters which were
intratracheally instilled once a week with 0.2 mL of 2% or 4% acetaldehyde in
0.9% NaCl for 52 weeks.
Feron et al. (1982) studied male and female hamsters exposed by inhalation
to acetaldehyde alone or in combination with intratracheally administered BaP
or diethylnitrosamine. The animals were exposed for 7 hours/day, 5 days/week,
for 52 weeks to a time weighted average concentration of 2028 ppm. They were
killed and autopsied after a 29-week recovery period; that is, at week 81. A
slight increase in nasal tumors and a significantly increased incidence of
laryngeal tumors was observed in both male and female hamsters exposed to
acetaldehyde alone. This study supported the observation of Feron (1979) that
acetaldehyde treatment enhanced tumorigenicity (production of tracheobronchial
carcinomas) of BaP.
The carcinogenicity of acetaldehyde was studied in 420 male and 420 female
albino SPF Wistar rats (Woutersen and Appelman, 1984; Woutersen et al., 1985).
After an acclimatization period of 3 weeks, these animals were randomly
assigned to four groups of 105 males and 105 females each. The animals were
then exposed by inhalation to atmospheres containing 0, 750, 1500, or 3000 ppm
acetaldehyde for 6 hours/day, 5 days/week, for 27 months. The concentration
in the highest dose group was gradually reduced from 3000 to 1000 ppm because
of severe growth retardation, occasional loss of body weight and early
mortality in this group. Interim sacrifices were carried out at 13, 26, and
52 weeks. One tumor was observed in the 52 week sacrifice group and none at
earlier times. Exposure to acetaldehyde increased the incidence of tumors in
an exposure-related manner in both male and female rats. In addition, there
were exposure-related increases in the incidences of multiple respiratory
tract tumors. Adenocarcinomas were increased significantly in both male and
female rats at all exposure levels, whereas squamous cell carcinomas were
increased significantly in male rats at middle and high doses and in female
rats only at the high dose. The squamous cell carcinoma incidences showed a
clear dose-response relationship. The incidence of adenocarcinoma was highest
in the mid-exposure group (1500 ppm) in both male and female rats, but this
was probably due to the high mortality and competing squamous cell carcinomas
at the highest exposure level. In the low-exposure group, the adenocarcinoma
incidence was higher in males than in females.
In a concurrent study, 30 animals of each sex were exposed to the same
concentrations of acetaldehyde for 52 weeks followed by a recovery period of
26 weeks (10 animals) or 52 weeks (20 animals). Significant increases in
nasal tumors were observed in male and female rats, including adenocarcinomas
and squamous cell carcinomas, in both recovery groups. These findings
indicate that after 52 weeks of exposure to acetaldehyde, proliferative
epithelial lesions of the nose may develop into tumors even without continued
exposure.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Acetaldehyde has been shown by several laboratories to induce sister
chromatid exchange (SCE) in cultured mammalian cells (Obe and Ristow, 1977;
Obe and Beer, 1979; deRaat et al., 1983; Bohlke et al., 1983; Ristow and Obe,
1978; Jansson, 1982; Norrpa et al., 1985). A recent study provided evidence
that SCE-inducing lesions may be persistent for several cell generations (He
and Lambert, 1985). The in vitro SCE response did not require metabolic
activation. The induction of SCE by acetaldehyde has also been detected in
bone marrow cells of mice and hamsters in vivo (Obe et al., 1979; Korte and
Obe, 1981). Acetaldehyde caused chromosomal aberrations in mammalian cell
culture (Bird et al., 1981; Bohlke et al., 1983) and plants (Rieger and
Michaelis, 1960), but not in Drosophila (Woodruff et al., 1985). Chromosome
gaps and breaks were found in rat embryos after a single intraamniotic
injection on day 13 of gestation (Barilyak and Kozachuk, 1983). Acetaldehyde
produced sex-linked recessive lethal gene mutations after injection in
Drosophila (Woodruff et al., 1985), but has been negative in testing in
Salmonella (Commoner, 1976, Laumbach et al., 1976; Pool and Wiesler, 1981.,
Marnett et al., 1985, Mortelmans et al., 1986). Acetaldehyde has been shown
to produce crossLINKS between protein and DNA in the nasal respiratory mucosa
(Lam et al., 1986).
Acetaldehyde is similar in stucture to formaldehyde (classified B1) which
also produces nasal tumors in animals exposed by inhalation.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
___II.C.1. SUMMARY OF RISK ESTIMATES
Inhalation Unit Risk -- 2.2E-6 per (ug/cu.m)
Extrapolation Method -- Linearized multistage-variable exposure input form
(extra risk)
Air Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 5E+1 ug/cu.m
E-5 (1 in 100,000) 5E+0 ug/cu.m
E-6 (1 in 1,000,000) 5E-1 ug/cu.m
___II.C.2. DOSE-RESPONSE DATA FOR CARCINOGENICITY, INHALATION EXPOSURE
Tumor Type -- nasal squamous cell carcinoma or adenocarcinoma
Test Animals -- rat/SPF Wistar, male
Route -- inhalation
Reference -- Woutersen and Appelman, 1984
---- Dose ----- Tumor
Lifetime Average Exposure Incidence
Admin- Human
istered Equivalent
(ppm) (ppm)
-------- ----------- ---------
0 0 1/94
750 130 20/95
1500 255 49/95
1540 279 47/92
___II.C.3. ADDITIONAL COMMENTS (CARCINOGENICITY, INHALATION EXPOSURE)
Actual measured exposures on two occasions for the low and medium dose
groups were 727/735 and 1438/1412 ppm, respectively. The highest dose
administered is given as TWA. Low-dose extrapolation was performed using two
forms of the linearized multistage model, the quantal model (Crump et al.,
1977) and a form which allows analysis for a variable dose pattern, adjusts
for intercurrent mortality, and is capable of estimating risk at any time from
any dosing pattern (Crump and Howe, 1984). The latter model is referred to as
the variable exposure form. Comparison of the results from the two models
showed very little difference in the unit risk estimates. The variable
exposure form was selected for the final unit risk estimate because it allows
the combination of the lifetime study and the recovery study for risk
estimation. The above estimates are from male rats; the unit risk calculated
from data on female rats at 18 months was 1.6E-6 per (mg/cu.m). No difference
was found in tumor incidence between animals exposed for a full lifetime and
those exposed for 12 months and allowed to recover. At the end of 24 months,
however, the tumor incidences in the recovery group were less than those in
the lifetime exposure group.
The unit risk should not be used if the air concentration exceeds 5E+3
ug/cu.m, since above this concentration the unit risk may not be appropriate.
___II.C.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, INHALATION EXPOSURE)
An adequate number of animals was observed in a lifetime study. Increases
in nasal tumors were observed in both male and female rats, and similar unit
risks were obtained using these data.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1987
The 1987 Health Assessment Document is a final draft which has received both
agency and external review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 01/13/1988
Verification Date -- 01/13/1988
___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 -- Acetaldehyde
CASRN -- 75-07-0
Last Revised -- 10/01/1991
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
Appleman, L.M., R.A. Woutersen and V.J. Feron. 1982. Inhalation toxicity of
acetaldehyde in rats. I. Acute and subacute studies. Toxicology. 23:
293-307.
Appleman, L.M., R.A. Woutersen, V.J. Feron, R.N. Hooftman and W.R.F. Notten.
1986. Effect of variable versus fixed exposure levels on the toxicity of
acetaldehyde in rats. J. Appl. Toxicol. 6(5): 331-336.
Casanova-Schmitz, M., R.M. David and H.d'A. Heck. 1984. Oxidation of
formaldehyde and acetaldehyde by NAD+ -dependent dehydrogenases in rat nasal
mucosal homogenates. Biochem. Pharmacol. 33(7): 1137-1142.
Dalhamn, T., M-L. Edfors and R. Rylander. 1968. Retention of cigarette smoke
components in Human lungs. Arch. Environ. Health. 17: 746-748.
Egle, J.L. 1970. Retention of inhaled acetaldehyde in man. J. Pharmacol.
Exp. Therap. 174(1): 14-19.
Feron, V.J. 1979. Effects of exposure to acetaldehyde in Syrian hamsters
simultaneously treated with benzo(a)pyrene or diethylnitrosamine. Prog. Exp.
Tumor Res. 24: 162-176.
Feron, V.J., A. Kruysse and R.A. Woutersen. 1982. Respiratory tract tumors
in hamsters exposed to acetaldehyde vapour alone or simultaneously to
benzo(a)pyrene or diethylnitrosamine. Eur. J. Cancer Clin. Oncol. 18: 13-31.
Hagihara, S., Y. Sameshima, M. Kobayashi and F. Obo. 1981. Behavior of
acetaldehyde transported in blood. Biochem. Pharmacol. 30: 657-661.
Kruysse, A., V.J. Feron and H.P. Til. 1975. Repeated exposure to acetaldehyde
vapor. Arch. Environ. Health. 30: 449-452.
Saldiva, P.H.N., M.P. do Rio Caldeira, E. Massad, et al. 1985. Effects of
formaldehyde and acetaldehyde inhalation on rat pulmonary mechanics. J.
Appl. Toxicol. 5: 288-292.
U.S. EPA. 1991. Health Assessment Document for Acetaldehyde. Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Research Triangle Park, NC. (Draft)
Watanabe, A., N. Hobara and H. Nagashima. 1986. Blood and liver acetaldehyde
concentrations in rats following acetaldehyde inhalation and intravenous and
intragastric ethanol administration. Bull. Environ. Contam. Toxicol. 37:
513-516.
Woutersen, R.A., L.M. Appelman, A.Van Garderen-Hoetmer, and V.J. Feron.
1986. Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity
study. Toxicology. 41: 213-231.
Woutersen, R.A. and V.J. Feron. 1987. Inhalation toxicity of acetaldehyde in
rats. IV. Progression and regression of nasal lesions after discontinuation
of exposure. Toxicology. 47: 295-305.
Zorzano, A. and E. Herrera. 1989. Disposition of ethanol and acetaldehyde in
late pregnant rats and their fetuses. Pediat. Res. 25: 102-106.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Barilyak, I.R. and S.Y. Kozachuk. 1983. Embryotoxic and mutagenic activity
of ethanol after intra-amniotic injection. Tsitologiya i Genetika. 17:
57-60.
Bird, R.P., H.H. Draper and P.K. Basur. 1981. Effect of malonaldehyde and
acetaldehyde on cultured mammalian cells; production of micronuclei and
chromosomal aberrations. Mutat. Res. 101: 237-246.
Bittersohl, G. 1974. Epidemiologic investigations on cancer incidence in
workers contacted by acetaldol and other aliphatic aldehydes. Arch.
Geschwulstforsch. 43: 172-176.
Bohlke, J.U., S. Singh and H.W. Goedde. 1983. Cytogenetic effects of
acetaldehyde in lymphocytes of Germans and Japanese: SCE, clastogenic activity
and cell cycle delay. Hum. Genet. 63: 285-289.
Commoner, B. 1976. Reliability of bacterial mutagenesis techniques to
distinguish carcinogenic and noncarcinogenic chemicals. U.S. EPA. EPA-600/1-
76-022.
Crump, K.S. and R.B. Howe. 1984. The multistage model with a time-dependent
dose pattern: application to carcinogenic risk assessment. Risk Analysis.
4: 163-176.
Crump, K.S., H.A. Guess and L.L. Deal. 1977. Confidence intervals and test
of hypothesis concerning dose-response relations inferred from animal
carcinogenicity data. Biometrics. 33: 437-451.
deRaat, W.K., P.B. Davis and G.L. Bakker. 1983. Induction of sister-
chromatid exchanges by alcohol and alcoholic beverages after metabolic
activation by rat-liver homogenate. Mutat. Res. 124: 85-90.
Feron, V.J., A. Kruysse, and R.A. Woutersen. 1982. Respiratory tract tumors
in hamsters exposed to acetaldehyde vapour alone or simultaneously to
benzo(a)pyrene or diethylnitrosamine. Eur. J. Cancer Clin. Oncol. 18: 13-31.
Feron, V.J. 1979. Effects of exposure to acetaldehyde in Syrian hamsters
simultaneously treated with benzo(a)pyrene or diethylnitrosamine. Prog. Exp.
Tumor Res. 24: 162-176.
He, S.M. and B. Lambert. 1985. Induction and persistence of SCE-inducing
damage in human lymphocytes exposed to vinyl acetate and acetaldehyde in
vitro. Mutat. Res. 158: 201-208.
Jansson, T. 1982. The frequency of sister chromatid exchanges in human
lymphocytes treated with ethanol and acetaldehyde. Hereditas. 97: 301-303.
Korte, A. and G. Obe. 1981. Influence of chronic ethanol uptake and acute
acetaldehyde treatment on the chromosomes of bone-marrow cells and peripheral
lymphocytes of Chinese hamsters. Mutat. Res. 88: 389-395.
Lam, C.W., M. Casanova and H.D.'A. Heck. 1986. Decreased extractability of
DNA from proteins in the rat nasal mucosa after acetaldehyde exposure. Fund.
Appl. Toxicol. 6: 541-550.
Laumbach, A.D., S. Lee, J. Wong and U.N. Streips. 1976. Studies on the
mutagenicity of vinyl chloride metabolites and related chemicals. Proceeding
of the 3rd International Symposium on the Prevention and Detection of Cancer,
Vol. 1., p. 155-169.
Marnett, L.J., H.K. Hurd, M.C. Hollestein, D.E. Levin, H. Esterbauer and B.N.
Ames. 1985. Naturally occurring carbonyl compounds are mutagenic in
Salmonella tester strain TA104. Mutat. Res. 148: 25-34.
Mortelmans, K., S. Haworth, T. Lawlor, W. Speck, B. Tainer and E. Zeiger.
1986. Salmonella mutagenicity tests. II. Results from testing of 270
chemicals. Environ. Mutagen. 8: 1-39.
Norppa, H., F. Tursi, P. Pfaffli, J. Maki-Paakkanen and H. Jarventaus. 1985.
Chromosome damage induced by vinyl acetate through in vitro formation of
acetaldehyde in human lymphocytes and Chinese hamster ovary cells. Cancer
Res. 45: 4816-4821.
Obe, G. and B. Beer. 1979. Mutagenicity of aldehydes. Drug Alcohol
Depend. 4: 91-94.
Obe, G. and H. Ristow. 1977. Acetaldehyde, but not ethanol, induces sister
chromatid exchanges in Chinese hamster cells in vitro. Mutat. Res. 56:
211-213.
Obe, G., A.T. Natarajan, M. Meyers and A. Den Hertog. 1979. Induction of
chromosomal aberrations in peripheral lymphocytes of human blood in vitro and
of SCEs in bone-marrow cells of mice in vivo by ethanol and its metabolite
acetaldehyde. Mutat. Res. 68: 291-294.
Pool, B.L. and M. Wiessler. 1981. Investigations on the mutagenicity of
primary and secondary a-acetoxynitrosamines with Salmonella typhimurium:
activation and deactivation of structrally related compounds by S-9.
Carcinogenesis. 2: 991-997.
Rieger, R. and A. Michaelis. 1960. Chromosome aberrationen nach Einwirkung
von Acetaldeyd auf Primawurzeln von Vicia faba. Biol. Zbl. 79: 1-5.
Ristow, H. and G. Obe. 1978. Acetaldehyde induces cross-LINKS in DNA and
causes sister-chromatid exchanges in human cells. Mutat. Res. 58: 115-119.
U.S. EPA. 1987. Health Assessment Document for Acetaldehyde. Prepared by
the Office of Health and Environmental Assessment, Research Triangle Park, NC
for the Office of Air Quality Planning and Standards. EPA/600/8-86/015A.
(External Review Draft).
Woodruff, R.C., J.M. Mason, R. Valencia and S. Zimmering. 1985. Chemical
mutagenesis testing in Drosophila. V. Results of 53 coded compounds tested
for the National Toxicology Program. Environ. Mutagen. 7: 677-702.
Woutersen, R.A. and L.M. Appelman. 1984. Lifespan inhalation carcinogenicity
study of acetaldehyde in rats. III. Recovery after 52 weeks of exposure.
Report No. V84.288/190172. CIVO-Institutes TNO, The Netherlands.
Wouterson, R., A. Van Garderen-Hoetmer and L.M. Appelman. 1985. Lifespan (27
months) inhalation carcinogenicity study of acetaldehyde in rats. Report No.
V85.145/190172. CIVO-Institutes TNO, The Netherlands.
_VII. REVISION HISTORY
Substance Name -- Acetaldehyde
CASRN -- 75-07-0
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
06/01/1989 II.D.3. Secondary contact changed
07/01/1989 I.B. Inhalation RfD now under review
03/01/1990 II.A.4. Citations clarified (1st paragraph)
03/01/1990 VI. Bibliography on-line
01/01/1991 II. Text edited
01/01/1991 II.C.1. Inhalation slope factor removed
10/01/1991 I.B. Inhalation RfC summary on-line
10/01/1991 VI.B. Inhalation RfC references added
01/01/1992 IV. Regulatory Action section on-line
VIII. SYNONYMS
Substance Name -- Acetaldehyde
CASRN -- 75-07-0
Last Revised -- 06/30/1988
75-07-0
ACETALDEHYD
Acetaldehyde
ACETIC ALDEHYDE
ACETYLALDEHYDE
ALDEHYDE ACETIQUE
ALDEIDE ACETICA
ETHANAL
ETHYL ALDEHYDE
NCI-C56326
OCTOWY ALDEHYD
RCRA WASTE NUMBER U001
UN 1089
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0290.HTM
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