Acetaldehyde (CASRN 75-07-0) 

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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 First 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. 

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_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

Degenration of 

olfactory epithelium

Short-term Rat

Inhalation Studies

Appleman et al.,

1986;1982	NOAEL: 273 mg/cu.m (150 ppm)

NOAEL:(ADJ): 48.75 mg/cu.m

NOAEL(HEC): 8.7 mg/cu.m

LOAEL: 728 mg/cu.m (400 ppm)

LOAEL(ADJ): 130 mg/cu.m

LOAEL(HEC): 16.9 mg/cu.m	1000	1	9E-3

mg/cu.m

*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 database. 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 weeks.
Duration- adjusted values are and 105/cu.m., respectively. The animals
were evaluated pulmonary mechanics before after exposure period, gross
paraffin-embedded sample observations made exposure, especially
respiratory system. Increases in RF, FRC, RV, TLC significantly
different from control values. Damage distal airways was suggested since
functional tests elasticity severe obstruction not demonstrated.
Histopathological investigation showed an intense inflammatory reaction
with olfactory epithelium hyperplasia polymorphonuclear mononuclear
infiltration submucosa. Cannulation precluded evaluation tracheal
effects no differences between observed lower tract. Although this study
presents pathology data only a descriptive fashion, it identifies LOAEL
nasal/cu.m (HEC = 13.7 that is consistent principal studies. LOAEL(HEC)
thoracic on function 220.5/cu.m. 

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

Database — 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 database 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 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).

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_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 Human Carcinogenicity

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

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. 

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

Not available.

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_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 Appleman, 1984

Dose 	Tumor

Incidence

Lifetime Average Exposure

	Administered (ppm)	Human 

Equivalent (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. 

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_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. EPA Review (Carcinogenicity Assessment)

Agency Work Group Review — 01/13/1988

Verification Date — 01/13/1988

__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
 (internet address).

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_III.  [reserved]

_IV.  [reserved] 

_V.  [reserved]

_VI.  Bibliography 

Substance Name — Acetaldehyde

CASRN — 75-07-0

Last Revised — 10/01/1991

_VI.A. Oral RfD References

None

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_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. 

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_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.

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_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

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.

12/10/1998	I., II.	This chemical is being reassessed under the IRIS
Program.



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_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

