Acetaldehyde (CASRN 75-07-0) 

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Reference Dose for Chronic Oral Exposure (RfD)

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-ofentry) 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 concentrationresponse 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 highconcentration 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 durationadjusted 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. Durationadjusted 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 highconcentration 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 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 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 sisterchromatid 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. CIVOInstitutes 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.
Top of page

_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