This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization, or the World Health Organization.

First draft prepared by R. Gomes and M.E. Meek, Existing Substances Division, Bureau of Chemical Hazards, Health Canada, Ottawa, Canada, and M. Eggleton, Environment Canada, Hull, Quebec

Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization, and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

World Health Organization

Geneva, 2002

The International Programme on Chemical Safety (IPCS), established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO), and the World Health Organization (WHO). The overall objectives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals.

The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research, and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen cooperation and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment.

WHO Library Cataloguing-in-Publication Data

Acrolein.

(Concise international chemical assessment document ; 43)

1.Acrolein - adverse effects 2.Acrolein - toxicity 3.Risk assessment

4.Environmental exposure I.International Programme on Chemical Safety II.Series

ISBN 92 4 153043 X       (NLM Classification: QV 627)

ISSN 1020-6167

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Concise International Chemical Assessment Documents (CICADs) are the latest in a family of publications from the International Programme on Chemical Safety (IPCS) — a cooperative programme of the World Health Organization (WHO), the International Labour Organization (ILO), and the United Nations Environment Programme (UNEP). CICADs join the Environmental Health Criteria documents (EHCs) as authoritative documents on the risk assessment of chemicals.

International Chemical Safety Cards on the relevant chemical(s) are attached at the end of the CICAD, to provide the reader with concise information on the protection of human health and on emergency action. They are produced in a separate peer-reviewed procedure at IPCS.

CICADs are concise documents that provide summaries of the relevant scientific information concerning the potential effects of chemicals upon human health and/or the environment. They are based on selected national or regional evaluation documents or on existing EHCs. Before acceptance for publication as CICADs by IPCS, these documents undergo extensive peer review by internationally selected experts to ensure their completeness, accuracy in the way in which the original data are represented, and the validity of the conclusions drawn.

The primary objective of CICADs is characterization of hazard and dose–response from exposure to a chemical. CICADs are not a summary of all available data on a particular chemical; rather, they include only that information considered critical for characterization of the risk posed by the chemical. The critical studies are, however, presented in sufficient detail to support the conclusions drawn. For additional information, the reader should consult the identified source documents upon which the CICAD has been based.

Risks to human health and the environment will vary considerably depending upon the type and extent of exposure. Responsible authorities are strongly encouraged to characterize risk on the basis of locally measured or predicted exposure scenarios. To assist the reader, examples of exposure estimation and risk characterization are provided in CICADs, whenever possible. These examples cannot be considered as representing all possible exposure situations, but are provided as guidance only. The reader is referred to EHC 170.¹

While every effort is made to ensure that CICADs represent the current status of knowledge, new information is being developed constantly. Unless otherwise stated, CICADs are based on a search of the scientific literature to the date shown in the executive summary. In the event that a reader becomes aware of new information that would change the conclusions drawn in a CICAD, the reader is requested to contact IPCS to inform it of the new information.

The flow chart shows the procedures followed to produce a CICAD. These procedures are designed to take advantage of the expertise that exists around the world — expertise that is required to produce the high-quality evaluations of toxicological, exposure, and other data that are necessary for assessing risks to human health and/or the environment. The IPCS Risk Assessment Steering Group advises the Coordinator, IPCS, on the selection of chemicals for an IPCS risk assessment based on the following criteria:

• there is the probability of exposure; and/or
• there is significant toxicity/ecotoxicity.

Thus, a priority chemical typically

• is of transboundary concern;
• is of concern to a range of countries (developed, developing, and those with economies in transition) for possible risk management;
• is significantly traded internationally;
• has high production volume;
• has dispersive use.

The Steering Group will also advise IPCS on the appropriate form of the document (i.e., EHC or CICAD) and which institution bears the responsibility of the document production, as well as on the type and extent of the international peer review.

The first draft is based on an existing national, regional, or international review. Authors of the first draft are usually, but not necessarily, from the institution that developed the original review. A standard outline has been developed to encourage consistency in form. The first draft undergoes primary review by IPCS to ensure that it meets the specified criteria for CICADs.

The second stage involves international peer review by scientists known for their particular expertise and by scientists selected from an international roster compiled by IPCS through recommendations from IPCS national Contact Points and from IPCS Participating Institutions. Adequate time is allowed for the selected experts to undertake a thorough review. Authors are required to take reviewers’ comments into account and revise their draft, if necessary. The resulting second draft is submitted to a Final Review Board together with the reviewers’ comments. At any stage in the international review process, a consultative group may be necessary to address specific areas of the science.

The CICAD Final Review Board has several important functions:

• to ensure that each CICAD has been subjected to an appropriate and thorough peer review;
• to verify that the peer reviewers’ comments have been addressed appropriately;
• to provide guidance to those responsible for the preparation of CICADs on how to resolve any remaining issues if, in the opinion of the Board, the author has not adequately addressed all comments of the reviewers; and
• to approve CICADs as international assessments.

Board members serve in their personal capacity, not as representatives of any organization, government, or industry. They are selected because of their expertise in human and environmental toxicology or because of their experience in the regulation of chemicals. Boards are chosen according to the range of expertise required for a meeting and the need for balanced geographic representation.

Board members, authors, reviewers, consultants, and advisers who participate in the preparation of a CICAD are required to declare any real or potential conflict of interest in relation to the subjects under discussion at any stage of the process. Representatives of nongovernmental organizations may be invited to observe the proceedings of the Final Review Board. Observers may participate in Board discussions only at the invitation of the Chairperson, and they may not participate in the final decision-making process.

This CICAD on acrolein was prepared jointly by the Environmental Health Directorate of Health Canada and the Commercial Chemicals Evaluation Branch of Environment Canada based on documentation prepared concurrently as part of the Priority Substances Program under the Canadian Environmental Protection Act (CEPA). The objective of assessments on priority substances under CEPA is to assess potential effects of indirect exposure in the general environment on human health as well as environmental effects. Data identified as of the end of May 1998 (environmental effects) and October 1998 (human health effects) were considered in this review.² Information on the nature of the peer review and availability of the source document is presented in Appendix 1. Other reviews that were also consulted include IARC (1979, 1985, 1987, 1995), ATSDR (1990), IPCS (1992, 1996), BUA (1994), US EPA (1996), and EU (1999). Information on the peer review of this CICAD is presented in Appendix 2. This CICAD was approved as an international assessment at a meeting of the Final Review Board, held in Ottawa, Canada, on 29 October – 1 November 2001. Participants at the Final Review Board meeting are listed in Appendix 3. The International Chemical Safety Card for acrolein (ICSC 0090), produced by the International Programme on Chemical Safety (IPCS, 1993), has also been reproduced in this document.

Acrolein (CAS No. 107-02-8) is a clear, colourless liquid with an intensively acrid odour. It is released to the atmosphere as a product of fermentation and ripening processes. It is also emitted by forest fires as a product of incomplete combustion.

In the source country (i.e., Canada), acrolein is used mainly as an aquatic herbicide in irrigation canals and as a microbiocide in produced water during oil exploration. An estimated minimum of 218 tonnes of acrolein is released yearly to the atmosphere from anthropogenic sources involving the combustion of organic matter (i.e., predominantly as a component of vehicle exhaust) or the forest industry. Unquantified amounts are also released from the photo-oxidation of organic pollutants in air. No releases of "non-pesticidal" acrolein to water, sediments, or soils in Canada have been identified.

Acrolein is unlikely to be transported over long distances because of its high reactivity and estimated short half-lives in air and water. It is also unlikely to partition from these compartments to soil or sediments. Acrolein is rapidly metabolized by organisms and does not bioaccumulate. The highest environmental concentrations of acrolein not directly released during its application as a pesticide in the source country (Canada) have been measured in air from urban areas. With the exception of samples taken in the vicinity of pesticidal application, acrolein has not been detected in water, sediment, or soil in the source country (Canada).

Based upon studies conducted primarily in laboratory animals, adverse health effects associated with exposure to acrolein are mostly confined to the tissue of first contact (i.e., the respiratory and gastrointestinal tracts after inhalation and ingestion, respectively) and are concentration related. Studies of the systemic effects of acrolein in humans have not been identified, with available data relevant to the assessment of the potential adverse effects in humans limited primarily to irritation. In humans and experimental species, acrolein is an upper respiratory tract and eye irritant.

Informative epidemiological studies on the long-term effects of acrolein have not been identified. Available data are inadequate to serve as a basis for assessment of the carcinogenicity of acrolein following inhalation. In the more extensive of limited studies concerning the chronic toxicity/carcinogenicity of acrolein following oral exposure in rats and dogs, there have been no increases in the incidence of tumours of any type, although mortality, the cause of which is unclear, was increased in rats and mice. Acrolein is mutagenic in vitro, but limited available data do not indicate genotoxic effects in the nasal mucosa (i.e., the site of contact) in rats exposed by inhalation, although in vitro studies indicate that acrolein can interact directly with DNA and induce DNA damage. In extensive studies, acrolein did not induce reproductive toxicity in experimental animals following oral administration.

The effects of acrolein have been most extensively investigated following exposure by inhalation. Acrolein is cytotoxic; histopathological effects in the bronchi and/or trachea (including exfoliation, oedema, inflammation, vascular congestion, and haemorrhagic necrosis) have been observed in hamsters, guinea-pigs, and rabbits following single inhalation exposure to acrolein. In short- and long-term inhalation studies conducted in several species (rats, mice, guinea-pigs, hamsters, monkeys, and dogs), at lowest concentrations, effects (degenerative histopathological lesions) have occurred consistently at the site of entry (i.e., the respiratory tract). Effects in other organs have also sometimes been observed, although inconsistently. This is consistent with the results of toxicokinetic studies in rodents and dogs, in which there has been a high degree of retention of inhaled acrolein at the site of contact.

Based on irritant effects at the site of contact in experimental animals, a tolerable concentration for acrolein of 0.4 µg/m³ in air has been derived. For ingestion, the provisional tolerable concentration is 1.5 µg/litre.

Sample probabilistic estimates of the distribution of time-weighted 24-h concentrations of acrolein in air in the source country (Canada) indicate that between 5% and 10% of the general population is exposed to at least 5 µg/m³. This is greater than the tolerable concentration.

Indoor air is an important source of exposure, although the relative contribution of various sources therein is unknown. Considerably higher concentrations of acrolein have been reported in tobacco smoke. For the general population, the relative contribution of ambient air to overall exposure to inhaled acrolein is expected to be small, compared with exposure from indoor air. However, for populations residing in the vicinity of locations heavily impacted by vehicular exhaust, ambient air may be an important source of exposure via inhalation.

Although available data are limited, the range of concentrations measured in food in various countries (although highly dependent upon such factors as method of cooking) is within the range of the provisional tolerable concentration for ingestion.

Acute and chronic toxicity data are available for aquatic organisms. Only acute data were identified for terrestrial crop plants. Terrestrial organisms appear less sensitive to acrolein than aquatic organisms. Concentrations of acrolein in the atmosphere of the source country (Canada) are less than the threshold for adverse effects estimated for terrestrial organisms. Exposure of other organisms to non-pesticidal acrolein is considered unlikely, since no sources or detectable concentrations of acrolein have been identified in other compartments.

Acrolein (CAS No. 107-02-8) is also known as acrylaldehyde, allyl aldehyde, acrylic aldehyde, propenal, prop-2-enal, and prop-2-en-1-al. Its molecular formula is CHOCHCH₂, and its molecular mass is 56.06. Acrolein’s chemical structure is shown in Figure 1.

At room temperature, acrolein is a clear, colourless liquid with an intensively acrid odour. The ranges of values reported for selected physical/chemical properties are presented in Table 1. Additional properties are given in the International Chemical Safety Card (ICSC 0900) reproduced in this document.

The conversion factor for acrolein in air at 25 °C and 101.3 kPa, used throughout this report, is 1 ppm = 2.29 mg/m³.³

Methods for the determination of acrolein in air, exhaust gas, aqueous solution, rainwater, biological samples, and liquid and solid wastes have been reviewed (IARC, 1995) and are presented in Table 2.

Aldehydes, including acrolein, in environmental samples and in ozonated drinking-water are derivatized with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride, then identified using gas chromatography and/or mass spectrometry (Le Lacheur et al., 1993). The detection limits of methods involving gas chromatography/electron capture detection and gas chromatography/mass spectrometry with ion-selective monitoring are 3.5 and 16.4 µg/litre, respectively (Glaze et al., 1989).

Personal exposure to acrolein and other airborne aldehydes in emissions is monitored by both passive and active sampling methods. These methods are based on derivatization of the aldehydes with 2,4-dinitrophenylhydrazine (DNPH) during collection. The adsorbent materials are extracted with toluene and analysed by gas chromatography with flame ionization detection (limit of detection 0.05 mg/m³) (Otson et al., 1993). A limit of detection of acrolein in air of 0.05 µg/m³ has been determined following sample collection with DNPH-coated silica gel sorbent tubes, elution of acrolein with acetonitrile, and analysis by high-performance liquid chromatography (Dann et al., 1994; T. Dann, personal communication, 1998).

Technical difficulties in the measurement of acrolein in air include possible interference of propionaldehyde-DNPH and acetone-DNPH derivatives with the acrolein-DNPH derivative during gas chromatography or high-performance liquid chromatography and potentially low recovery of acrolein from DNPH-coated silica gel (Risner, 1995).

Data on sources and emissions from the source country of the national assessment on which this CICAD is based (i.e., Canada) are presented here as an example. Sources and patterns of emissions in other countries are expected to be similar, although quantitative values may vary.

Acrolein is released into the environment as a product of fermentation and ripening processes. It has been identified as a volatile component of essential oils extracted from the wood of oak trees (Slooff et al., 1994). It is also emitted by forest fires as a product of the incomplete combustion of organic matter (Lipari et al., 1984) and produced by photochemical oxidation of hydrocarbons in the atmosphere (Ghilarducci & Tjeerdema, 1995). Quantitative data on the total production of acrolein from natural sources have not been identified.

Although uncertain owing to limitations of relevant identified information, estimates of releases of acrolein to the atmosphere in the source country (i.e., Canada) are presented in Table 3. The principal anthropogenic source of emissions into the Canadian environment is estimated to be activities involving the combustion of organic matter. As a product of the incomplete combustion of organic matter, acrolein is released by waste incinerators, furnaces, fireplaces, power plants, burning vegetation (e.g., forest fires), combustion of polyethylene plastics, and the cooking of food. The main combustion source is considered to be gas and diesel motor vehicle emissions. Few data are available for aircraft, railway engines, ships, and other off-road vehicles, but releases from these sources could exceed those of road vehicles (see Table 3).

Acrolein is formed by the reaction and photodecomposition of other airborne pollutants, such as 1,3-butadiene and allyl chloride (Maldotti et al., 1980; Edney et al., 1986a,b). Forest product manufacturing processes that release volatile organic compounds emit appreciable amounts of acrolein to air (Environment Canada, 1997). The formation of acrolein as a contaminant at 0.4% in the production of vinyl acetate has also been reported. In this case, acrolein and other impurities are separated and processed for recovery or disposal (Environment Canada, 1997).

Although reported in the mid-1980s in liquid effluents from a limited number of organic chemical manufacturing plants in the source country (i.e., Canada) (King & Sherbin, 1986), releases of acrolein to the aqueous environment were not identified in a survey conducted in the mid-1990s (Environment Canada, 1997). Sources of releases to Canadian waters, sediments, or soils for other than the application of acrolein-based pesticides have, therefore, not been identified. During use as the hydrogen sulfide scavenger, acrolein is assumed to be fully consumed. During its application in petroleum operations (i.e., crude oil exploration and extraction operations at oil wells), the acrolein reacts with sulfides in oil/water mixtures to form a non-hazardous, water-soluble product, which is then re-injected into deep wells (BPCI, 1991). The acrolein used is considered to be completely reacted (I. Viti, personal communication, 1998). Releases are therefore expected to be negligible.

Isolated acrolein is produced in a closed system by heterogeneously catalysed gas-phase oxidation of propene. Acrolein is also produced as a non-isolated intermediate during the manufacture of acrylic acid. Reported values for the annual production (between 1980 and the early 1990s) of isolated acrolein are as follows: USA, 27 000–35 000 tonnes/year; Japan (several sites), 20 000 tonnes/year; European Union (France and Germany, two production sites), 60 000 tonnes/year; Russia, 10 500 tonnes/year (BUA, 1994).

In the European Union, acrolein is produced and used by the chemical industry only, as an intermediate in the production of substances used as animal feed additives, biocides, and leather tanning agents (EU, 1999). In other countries (e.g., Canada, Egypt, Argentina, Australia, and the USA), acrolein is used principally as a broad-band biocide in process water circuits, irrigation canals, cooling water towers, and water treatment basins (BUA, 1994).

The main "non-pesticidal" use of acrolein in the source country (Canada) is as the active ingredient (92%) in a product used by oil companies to scavenge hydrogen sulfide from produced fluids in petroleum operations. This product can also solubilize ferrous sulfide deposits that obstruct wells, tanks, and barrels (BPCI, 1991). Small quantities of acrolein have also been used for research purposes (Environment Canada, 1996a).

Small amounts (2 kg) of acrolein were present in hazardous wastes imported into Canada for treatment or disposal between 1994 and 1997 (Environment Canada, 1994; J. Wittwer, personal communication, 1998). Acrolein has also been identified as an impurity (1%) in imports of acetaldehyde (Environment Canada, 1997).

Due to its high reactivity, acrolein does not tend to persist in the environment, and its intercompartmental movement is small.

Acrolein emitted to air reacts primarily with photochemically generated hydroxyl radicals in the troposphere (Ghilarducci & Tjeerdema, 1995). Minor processes include direct photolysis, reaction with nitrate radicals, and reaction with ozone (Atkinson et al., 1987; Haag et al., 1988a; Howard, 1989; BUA, 1994). Acrolein has been detected in rainwater, indicating that it may be removed by wet deposition (Grosjean & Wright, 1983). The calculated atmospheric half-life of acrolein, based on rate constants for hydroxyl radical reaction, is between 3.4 and 33.7 h (Atkinson, 1985; Edney et al., 1986b; Haag et al., 1988a; Howard, 1989; Howard et al., 1991; BUA, 1994). The overall reactivity-based half-life of acrolein in air, as estimated by Mackay et al. (1995), is less than 10 h. Based on these short estimated half-lives, acrolein is not a candidate for long-range atmospheric transport.

Acrolein is removed from surface water primarily by reversible hydration, biodegradation by acclimatized microorganisms, and volatilization (Bowmer & Higgins, 1976; Tabak et al., 1981; Irwin, 1987; Haag et al., 1988b; Howard, 1989; ATSDR, 1990; Springborn Laboratories, 1993). In groundwater, acrolein is removed by anaerobic biodegradation and hydrolysis (Chou & Spanggord, 1990a). The overall reactivity-based half-life of acrolein in surface water is estimated to be between 30 and 100 h (Mackay et al., 1995). In groundwater, half-lives of 11 days and 336–1344 h (14–56 days) are estimated based on aerobic and anaerobic degradation, respectively (Howard et al., 1991). Observed dissipation half-lives of acrolein applied as a herbicide in irrigation canals range from 7.3 to 10.2 h (Jacobson & Gresham, 1991a,b,c; Nordone et al., 1996a). The relatively short observed half-lives of acrolein in surface waters make long-range aquatic transport unlikely.

In sediment/water systems, acrolein undergoes hydrolysis, self-oxidation, and biodegradation. Experimental half-lives of 7.6 h and 10 days were determined for aerobic and anaerobic conditions, respectively (Smith et al., 1995). An overall reactivity-based half-life is estimated by Mackay et al. (1995) to be between 100 and 300 h. Because of its low organic carbon/water partition coefficient (K_oc) and high water solubility, acrolein is not expected to significantly adsorb to suspended solids or sediments, nor are these suspended solids or sediments expected to significantly absorb acrolein from water (Irwin, 1988; Howard, 1989).

In the terrestrial environment, acrolein undergoes biodegradation, hydrolysis, volatilization, and irreversible sorption to soil (Irwin, 1988; Howard, 1989; Chou & Spanggord, 1990b). These processes are expected to significantly decrease the high infiltration rate of acrolein estimated from its low experimental K_oc (Irwin, 1988). The overall reactivity-based half-life of acrolein in soil is estimated to be between 30 and 100 h (Mackay et al., 1995).

Based on the high water solubility, low octanol/water partition coefficient (K_ow), and high reactivity of acrolein, uptake by organisms is predicted to be low. A bioconcentration factor (BCF) of 344 and a half-life of greater than 7 days were reported for acrolein in bluegill (Lepomis macrochirus) following exposure to acrolein at a mean concentration of 13 µg/litre for a 28-day period (Barrows et al., 1980). However, these values may be overestimates, as the total ¹⁴C measured in the fish may have included metabolites. A lower BCF of 0.6 was estimated using the linear regression equation of Veith et al. (1980) and a log K_ow of -0.01 for acrolein. Acrolein was not detected in the tissues of fish and shellfish sampled 1 day after a second exposure to [¹⁴C]acrolein in water (0.02 and 0.1 mg/litre for the first and second exposures, respectively) over a 1-week period. The presence of metabolites indicates that these species were able to rapidly metabolize acrolein and its residues (Nordone et al., 1998). Based on these results and the low reported BCFs, acrolein is unlikely to bioaccumulate or bioconcentrate significantly in aquatic organisms (Howard, 1989; ATSDR, 1990; DFO, 1995; Nordone et al., 1996b). Absorption of acrolein by terrestrial plants is poor (WSSA, 1983).

Fugacity modelling was conducted to characterize key reaction, intercompartment, and advection (movement out of a system) pathways for acrolein and its overall distribution in the environment. A steady-state, non-equilibrium model (Level III fugacity model) was run using the methods developed by Mackay (1991) and Mackay & Paterson (1991). Assumptions, input parameters, and results are presented in Mackay et al. (1995) and summarized here. Values for input parameters were as follows: molecular mass, 56.06; melting point, -86.95 °C; water solubility, 208 g/litre; vapour pressure, 36.5 kPa at 20 °C; log K_ow, -0.01; Henry’s law constant, 9.8 Pa·m³/mol; half-life in air, 5 h; half-life in water, 55 h; half-life in soil, 55 h; half-life in sediments, 170 h. Modelling was based on an assumed default emission rate of 1000 kg/h into a region of 100 000 km², which includes a surface water area (20 m deep) of 10 000 km². The height of the atmosphere was set at 1000 m. Sediments and soils were assumed to have an organic carbon content of 4% and 2% and a depth of 1 cm and 10 cm, respectively. The estimated percent distribution predicted by this model is not affected by the assumed emission rate.

Results of the modelling indicate that acrolein behaves differently depending on the medium to which it is released. Generally, when acrolein is continuously discharged into a specific medium, most of it can be expected to remain in that medium. For example, if discharged into air, almost all of it will exist in the atmosphere, with very small amounts in soil and water. The same applies for discharge to water and soil (Mackay et al., 1995). These predicted distributions suggest that acrolein does not tend to partition from one compartment to another. It could also be possible that when acrolein does partition to another compartment, its persistence in that second compartment is so short that little remains there.

While data on concentrations in the environment for the source country (i.e., Canada) are emphasized here, levels of acrolein in other countries have been summarized (IPCS, 1992; IARC, 1995; US EPA, 1996). Based on this information, patterns of exposure appear to be similar.

6.1.1 Ambient air

Available sampling and analytical methodologies are sufficiently sensitive to detect the presence of acrolein in many samples of ambient (outdoor) air. In urban areas in Canada, mean concentrations of acrolein in 4- or 24-h samples are generally less than 0.2 µg/m³. Acrolein was detected (detection limit 0.05 µg/m³) in 1597 (or 57%) of 2816 24-h samples collected between 1989 and 1996 under the National Air Pollution Surveillance (NAPS) programme from rural, suburban, and urban locations (n = 15) in five provinces (Environment Canada, 1996b; T. Dann, personal communication, 1998). The mean concentration in all samples was 0.18 µg/m³. Levels ranged from below the detection limit of 0.05 µg/m³ up to 2.47 µg/m³ for seven urban sites. Concentrations ranged up to 1.85 µg/m³ for two suburban sites and up to 0.33 µg/m³ for two rural sites considered to be affected by urban areas. The highest mean concentration of acrolein in air measured weekly over any three consecutive months during the NAPS monitoring between 1989 and 1996 was 1.58 µg/m³. This value was obtained for an urban site during the period of June–August 1994 (Environment Canada, 1996b).

Concentrations of acrolein in ambient air corresponding to the 90th, 95th, and 99th percentiles of the NAPS data set are 0.4 µg/m³, 0.6 µg/m³, and 1.1 µg/m³, respectively. Based on these data, there is some evidence that concentrations of acrolein in ambient air in Canada are increasing at urban and suburban sites.

Acrolein was less frequently detected in ambient air collected at rural sites. Mean concentrations at four rural sites considered to be regionally representative generally did not exceed 0.1 µg/m³; maximum concentrations were less than 0.5 µg/m³ in 24-h samples (Environment Canada, 1996b; T. Dann, personal communication, 1998). Concentrations of acrolein in urban and rural areas of Canada are similar to, but generally less than, those in other countries.

6.1.2 Indoor air

In general, concentrations of acrolein in indoor air in Canada are about 2- to 20-fold higher than outdoor levels, although few potential sources of this compound in indoor locations have been identified. Acrolein was detected (detection limit 0.05 µg/m³) in all 29 indoor air samples collected from homes in Windsor, Ontario, between 1991 and 1992 (Bell et al., 1994a; R.W. Bell, personal communication, 1995). The mean concentration of acrolein in these samples (3.0 µg/m³) was considerably higher than the mean ambient concentration (0.16 µg/m³; n = 29), with individual values in indoor air ranging from 0.4 to 8.1 µg/m³. Acrolein was detected (detection limit 0.05 µg/m³) in 3 of 11 samples of indoor air collected in 1993 from homes in residential and commercial areas of Hamilton, Ontario (R.W. Bell, personal communications, 1996, 1997). The mean concentration was 1.1 µg/m³, with individual values ranging from <0.05 to 5.4 µg/m³; acrolein was not detected (detection limit 0.05 µg/m³) in any of the 11 corresponding samples of ambient air.

There was a general trend of increasing concentrations of acrolein in the indoor air of these homes with increasing concentrations of acetaldehyde and/or formaldehyde. The average concentrations of acrolein in the indoor air of Windsor and Hamilton homes with and without environmental tobacco smoke — i.e., 3.0 µg/m³ and 2.2 µg/m³, respectively — provide some support for the hypothesis that cigarette smoking is a source of acrolein in indoor air. Deliveries of acrolein in mainstream smoke from commercial cigarettes purchased in the USA and the United Kingdom ranged from 3 to 260 µg/cigarette (Magin, 1980; Manning et al., 1983; Guerin et al., 1987; Hoffmann et al., 1991; Phillips & Waller, 1991).

Acrolein was detected (detection limit 0.43 µg/m³) in 3 of 35 samples of indoor air collected in 1997 from randomly selected homes in the Greater Toronto Area at concentrations of 16, 22, and 23 µg/m³ (Conor Pacific Environmental, 1998). It was not detected (detection limit 0.4 µg/m³) in any of the 35 samples of outdoor air from these locations. Acrolein was not detected (detection limit 0.43 µg/m³) in an additional 15 samples of indoor air collected from randomly selected homes in Nova Scotia (n = 6) or Alberta (n = 15), nor was it detected in the outdoor air at these locations (Conor Pacific Environmental, 1998).

Similar concentrations of acrolein have been measured in indoor air in residential and non-residential locations in other countries (Badré et al., 1978; Weber et al., 1979; Highsmith et al., 1988; Löfroth et al., 1989; CARB, 1991; Sheldon et al., 1992; Lindstrom et al., 1995; Williams et al., 1996). Data from other countries are almost exclusively restricted to environments where there is an active combustion source (e.g., cigarettes, woodstoves and fireplaces, cooking). For example, levels of acrolein in the air in four restaurants were between 11 and 23 µg/m³ (IPCS, 1992).

6.1.3 Drinking-water

Available quantitative data concerning the levels of acrolein in drinking-water in Canada were limited to two investigations in which acrolein was not detected in raw or treated water supplies.

In monitoring studies conducted between July 1982 and May 1983, acrolein was below the limit of detection (i.e., <0.1 µg/litre) in samples (n = 42) of treated drinking-water collected at 10 municipalities in Ontario (Otson, 1987). In an extensive survey of municipal drinking-water supplies at 150 locations in the four Atlantic provinces conducted between May 1985 and October 1988, acrolein was not detected (detection limit 1.0–2.5 µg/litre) in an unspecified number of samples of raw or treated drinking-water (Environment Canada, 1989a,b,c,d).

In studies conducted in the USA, acrolein was not detected (detection limit 3.5 µg/litre) in an unspecified number of samples of raw and finished drinking-water from three treatment plants surveyed between May and July 1988 (Glaze et al., 1989). In other studies, acrolein was detected (detection limit not reported) in only 2 of 798 samples of well or surface water collected from unspecified locations throughout the USA between 1980 and 1982; the median concentration of acrolein in these samples was <14 µg/litre (Staples et al., 1985).

6.1.4 Surface water

Acrolein was not detected (detection limit 0.1 µg/litre) in 42 raw water samples collected from potable water treatment plants in the Great Lakes region during 1982 and 1983 (Otson, 1987). In 1985, acrolein was detected at concentrations of 6.9 and 7.8 µg/litre (detection limit 5 µg/litre) in liquid effluents from two organic chemical manufacturing plants that discharged into the St. Clair River at Sarnia, Ontario (King & Sherbin, 1986). During 1989 and 1990, however, acrolein was not detected (detection limit 4 µg/litre) in the intake water or effluent of these or 24 other organic chemical manufacturing plants in Ontario (OMEE, 1993).

6.1.5 Sediment and soil

Adequate data on concentrations of acrolein in sediments and soils were not identified.

6.1.6 Food

Acrolein is produced during the cooking or processing of fat-containing foods (Beauchamp et al., 1985; Hirayama et al., 1989; Lane & Smathers, 1991). Concentrations of acrolein ranged from 11.9 to 38.1 µg/g (mean 28.5 µg/g) in samples of five varieties of cooking oil heated to 80 °C and aerated for 20 h (Hirayama et al., 1991). Acrolein was detected in the emissions from four varieties of heated cooking oils in China (Shields et al., 1995) at concentrations ranging from 49 µg/litre (peanut oil) to 392 µg/litre (rapeseed oil). Lane & Smathers (1991) indicated that in addition to the production of acrolein from the frying medium, some ingredients common to commercial batter and breading systems may indirectly lead to the production of acrolein in fried foods.

Acrolein may be generated during the ripening of fruit (Kallio & Linko, 1973; Hayase et al., 1984) and some types of cheese (e.g., Egyptian Domiati, 290–1024 µg/g; Collin et al., 1993). Feron et al. (1991) reported concentrations of acrolein ranging from <0.01 to 0.05 µg/g in fruit and a maximum concentration of 0.59 µg/g in vegetables; however, information concerning the location(s) and date(s) of sample acquisition and the number(s) of samples analysed was not presented. Acrolein has been detected (but not quantified) in cheese, caviar, and lamb (Feron et al., 1991), souring salted pork (Cantoni et al., 1969), raw and cooked poultry (Hrdlicka & Kuca, 1965; Grey & Shrimpton, 1967), cocoa beans and chocolate liquor (Boyd et al., 1965), and molasses (Hrdlicka & Janicek, 1968).

Acrolein may be produced as an unwanted by-product during alcoholic fermentation or during the storage and maturation of alcoholic products (Feron et al., 1991), although available quantitative data are extremely limited. A maximum concentration of 3.8 µg/g was reported for red wine (Feron et al., 1991). Mean concentrations of acrolein in samples of fresh (n = 3) and aged (n = 3) lager from the United Kingdom were 1.6 µg/litre and 5.0 µg/litre, respectively (Greenhoff & Wheeler, 1981), while acrolein was detected in only trace amounts (<10 µg/litre) in an unspecified number of samples of Canadian apple wine purchased at a retail outlet in Ontario (Subden et al., 1986). Acrolein was also detected in non-alcoholic beverages (i.e., coffee and tea), although quantitative data were not presented (Feron et al., 1991).

Acrolein is also produced as a thermal degradation product of cellophane and polystyrene thermoplastics used to package foods (Robles, 1968; Zitting & Heinonen, 1980), although data on the extent of migration to packaged food items have not been identified.

Therefore, with the exception of data on heated vegetable oil (Hirayama et al., 1991), the ripening of Egyptian Domiati cheese (Collin et al., 1993), and the reported concentration of 3.8 µg/g for red wine (Feron et al., 1991), there are no reports of concentrations of acrolein greater than 1 µg/g in any food items.

Since adverse health effects of acrolein are primarily confined to the tissue of first contact (i.e., the respiratory and gastrointestinal tracts after inhalation and ingestion, respectively) and are concentration related (see section 8), exposures via inhalation and ingestion have been assessed separately.

Data on levels in food are limited to a small number of foodstuffs from various countries. While concentrations of acrolein as high as 0.1% by weight have been determined on rare occasions in some items, the remainder contained less than 40 µg acrolein/g and, in most cases, less than 1 µg/g. Acrolein has not been detected in two surveys of drinking-water supplies in Ontario and the Atlantic provinces (detection limits <0.1 and 1.0–2.5 µg/litre, respectively).

Available data are sufficient to serve as a basis for development of probabilistic estimates of 24-h time-weighted average concentrations of acrolein in the air to which the general population in Canada is exposed. The assumptions on which these estimates are based and output for two simulations are presented in Table 4. Based on the assumptions underlying these scenarios, between 5% and 10% of the population would be expected to be exposed to a 24-h time-weighted average concentration of acrolein of at least 5 µg/m³ (Table 4).

Based on limited available data on concentrations of acrolein in mainstream smoke of Canadian cigarettes (Rickert et al., 1980), smokers would be directly exposed to considerably higher concentrations of acrolein.

Workers are exposed to acrolein in a wide variety of industrial settings. Data on airborne levels in various occupational environments are summarized in Table 5 (IARC, 1995).

Small amounts of acrolein are produced endogenously during the normal intermediary catabolism of various amino acids and polyamines (Alarcon, 1970, 1972, 1976) and during the peroxidation of membrane lipids (Nath et al., 1997). Consistent with the highly reactive nature of acrolein and observed effects being restricted primarily to the initial site of contact following inhalation (i.e., the respiratory tract) (see section 8), available data indicate that the greatest proportion of exogenous inhaled acrolein is retained at the site of exposure, becoming rapidly and irreversibly bound to free protein and non-protein sulfhydryl groups (most notably glutathione; quantitative data were not identified). Based upon kinetic studies in dogs, rats, and ferrets (Egle, 1972; Ben-Jebria et al., 1995; Morris, 1996), the absorption of inhaled acrolein into the systemic circulation is not extensive. No quantitative or qualitative data were identified concerning the absorption of acrolein following oral or dermal exposure. Based on the metabolites most frequently identified in the urine of exposed animals, the predominant pathway for the metabolism of acrolein appears to involve conjugation with glutathione and subsequent conversion to N-acetylcysteine compounds (Figure 2).

Acrolein is highly acutely toxic, with LC₅₀s for 4- or 6-h inhalation exposures of rats, mice, and hamsters ranging from 18 to 151 mg/m³ (8 to 66 ppm) and LD₅₀s for oral administration to rats, mice, and hamsters ranging from 7 to 46 mg/kg body weight. Signs of acute toxicity include irritation of the respiratory and gastrointestinal tracts and central nervous system depression.⁴

Increased respiratory flow resistance and tidal volume and decreased respiratory rate have been observed in guinea-pigs exposed by inhalation to 39 mg acrolein/m³ (17 ppm) for 1 h (Davis et al., 1967) or to 0.7 or 0.9 mg acrolein/m³ (0.3 or 0.4 ppm) for 2 h (Murphy et al., 1963; Leikauf, 1992). Reductions in pulmonary resistance, pulmonary compliance, tidal volume, and respiratory rate have been observed among male Swiss mice exposed via tracheal cannula to acrolein vapour at 300 or 600 mg/m³ for 5 min (Watanabe & Aviado, 1974).

In rats, exposure (nose only) to 0.57 or 1.53 mg acrolein/m³ (0.25 or 0.67 ppm) for 6 h produced a significant (P < 0.01) reduction in glutathione reductase activity in the nasal respiratory epithelium; no histopathological effects or decreases in glutathione content within the nasal passages were observed (Cassee et al., 1996). There have been histopathological effects in the bronchi and/or trachea (including exfoliation, oedema, inflammation, vascular congestion, and haemorrhagic necrosis) in Syrian golden hamsters (Kilburn & McKenzie, 1978), guinea-pigs (Dahlgren et al., 1972; Leikauf, 1992), and New Zealand white rabbits (Beeley et al., 1986) following single exposures to acrolein vapour at concentrations ranging from 2.08 to 1120 mg/m³ (0.91 to 489 ppm).

Mortality was increased in male F344 rats administered a single intragastric dose of 25 mg acrolein/kg body weight (in saline) (Sakata et al., 1989). Other effects included degenerative changes in the liver (eosinophilic degeneration with microvesicular steatosis), forestomach, and glandular stomach (severe inflammation, haemorrhagic gastritis, multifocal ulceration, fibrin deposition, focal haemorrhage, oedema, and polymorphonuclear leukocyte infiltration); however, no histopathological changes were observed in the urinary bladder, lungs, kidneys, or spleen.

Acrolein causes sensory irritation in the upper respiratory tract following inhalation; RD₅₀ (the concentration resulting in a 50% reduction in respiratory rate) values of >2.4 mg acrolein/m³ have been reported in rodents (EU, 1999). Based on in vitro studies conducted in several animal species (sheep, chickens, cows), acrolein induces a significant reduction (30–100%) in ciliary movement in the upper respiratory tract (BUA, 1994). Acrolein is irritating to the skin of rabbits and the eyes of laboratory animals; 1% solutions of acrolein produced serious eye and skin damage (Albin, 1964; BSC, 1980a,b; BUA, 1994). Although results of the only relevant study identified (i.e., a guinea-pig maximization test reported by Susten & Breitenstein, 1990) were suggestive, due to limitations in the protocol and reporting of results, available data are considered inadequate to allow an assessment of the potential of acrolein to induce sensitization.

8.3.1 Inhalation

Exposure (nose only) of male Wistar rats (n = 5–6) to 0.57 or 1.53 mg/m³ (0.25 or 0.67 ppm) acrolein vapour for 6 h/day for 3 days produced concentration-related histopathological changes (including disarrangement, necrosis, thickening, desquamation, and basal cell hyperplasia) in the nasal respiratory/transitional epithelium, but not in the olfactory epithelium (Cassee et al., 1996). [Lowest-observed-adverse-effect level (LOAEL) = 0.57 mg/m³ (0.25 ppm)]

In studies with female rats from Dahl selected lines (one susceptible and one resistant to salt-induced hypertension) exposed via inhalation (whole body) to 0.9, 3.2, or 9.2 mg/m³ (0.4, 1.4, or 4.0 ppm) acrolein vapour for 6 h/day, 5 days/week, for up to 62 days, slight proliferative histopathological changes were observed in the lungs (including epithelial hyperplasia, squamous metaplasia, and peripheral lymphoid aggregates) of both strains at 0.9 and 3.2 mg/m³ (0.4 and 1.4 ppm). There were severe histopathological lesions in the lungs (necrosis, oedema, haemorrhage) and trachea (squamous metaplasia) at 9.2 mg acrolein/m³ (4.0 ppm). No microscopic changes were observed in the nasal turbinates, brain, heart, liver, kidneys, or spleen in either strain 7 days following the last exposure to acrolein (Kutzman et al., 1984). [LOAEL = 0.9 mg/m³ (0.4 ppm)] However, histopathological changes in the nasal passages but not the lungs of rats were reported in a more recent study (Leach et al., 1987) in which male Sprague-Dawley rats were exposed (whole body) to 0.39, 2.45, or 6.82 mg/m³ (0.17, 1.07, or 2.98 ppm) acrolein vapour for 6 h/day, 5 days/week, for 3 weeks. [Systemic and site-of-contact effects at 6.82 mg/m³ (2.98 ppm)]

Following repeated exposure (whole body) of F344 rats (n = 24 per sex) to 0.9, 3.2, or 9.2 mg/m³ (0.4, 1.4, or 4.0 ppm) acrolein vapour for 6 h/day, 5 days/week, for up to 62 days, there were no adverse effects at 0.9 mg/m³ (0.4 ppm). In animals exposed to 3.2 mg/m³ (1.4 ppm), there were biochemical (i.e., increased collagen) and histopathological changes in the lungs compared with unexposed controls. Effects observed following exposure to 9.2 mg acrolein/m³ (4.0 ppm) included increased mortality in males and histopathological changes in the trachea and lungs. Data on other systemic effects and histopathology in the nasal passages were not presented in these reports (Kutzman et al., 1985; Costa et al., 1986); however, in an original report of this study (Kutzman, 1981), fluctuations in the incidence of submucosal lymphoid aggregates within the nasal turbinate were noted. In animals exposed to 0, 0.9, 3.2, or 9.2 mg acrolein/m³ (0, 0.4, 1.4, or 4.0 ppm), the incidence (statistical evaluation not presented) of submucosal lymphoid aggregates within the nasal turbinate was 1/8, 3/8, 2/7, and 3/5, respectively. [Lowest-observed-effect level (LOEL) = 0.9 mg/m³ (0.4 ppm)]

Repeated inhalation exposure (whole body) of Sprague-Dawley rats, Princeton or Hartley guinea-pigs, male squirrel monkeys, and very small groups of male beagle dogs to 1.6 or 8.5 mg/m³ (0.7 or 3.7 ppm) acrolein vapour for 8 h/day, 5 days/week, for 6 weeks produced histopathological inflammatory changes and mild emphysema in the lungs of all species (most notably in dogs and monkeys) at 1.6 mg/m³ (0.7 ppm) (Lyon et al., 1970). Exposure to 8.5 mg acrolein/m³ (3.7 ppm) produced mortality in monkeys, clinical signs of toxicity in dogs and monkeys, significantly (P < 0.005) reduced body weights in rats, and exposure-related histopathological effects in the trachea (squamous metaplasia and basal cell hyperplasia) of dogs and monkeys and in the lungs (necrotizing bronchitis, bronchiolitis with squamous metaplasia) of monkeys.

Subchronic studies of the toxicity of inhaled acrolein are limited to two investigations in which survival, growth, urinary and haematological parameters, serum biochemistry, and histopathology were examined in several species (Lyon et al., 1970; Feron et al., 1978). In one study, Wistar rats, Dutch rabbits, and Syrian golden hamsters were exposed to 0.9, 3.2, or 11.2 mg/m³ (0.4, 1.4, or 4.9 ppm) acrolein vapour for 6 h/day, 5 days/week, for 13 weeks (Feron et al., 1978). In rats, the frequency and severity of histopathological effects within the nasal passages were concentration dependent; exposure to 0.9 mg acrolein/m³ (0.4 ppm) produced only a slight reduction in relative heart weight and histopathological lesions in the nasal passages of one animal, while exposure to 11.2 mg acrolein/m³ (4.9 ppm) increased mortality, as well as producing moderate to severe histopathological changes in the nasal passages, larynx, trachea, bronchi, and lungs. In hamsters, exposure to 3.2 mg acrolein/m³ (1.4 ppm) produced slight inflammatory changes in the nasal passages, while exposure to 11.2 mg acrolein/m³ (4.9 ppm) produced slight to severe histopathological changes in the nasal passages, larynx, and trachea. In rabbits, slight to moderate histopathological changes in the nasal passages, trachea, bronchi, and lungs were observed only in animals exposed to 11.2 mg acrolein/m³ (4.9 ppm) (Feron et al., 1978).

The continuous inhalation of 0.50, 2.3, or 4.1 mg acrolein/m³ (0.22, 1.0, or 1.8 ppm) by groups of Sprague-Dawley rats (n = 15 per sex), Princeton or Hartley guinea-pigs (n = 15 per sex), male beagle dogs (n = 2–4), and male squirrel monkeys (n = 9–17) for 90 days produced exposure-related histopathological lesions in dogs (lungs, spleen, and thyroid) at the lowest concentration tested, 0.50 mg/m³ (0.22 ppm). Histopathological changes in the lung, trachea, liver, and/or kidney (in all species) were observed at higher concentrations; however, effects in the nasal passages were not assessed (Lyon et al., 1970). Systemic effects (which are not well characterized) have not been consistently observed at lowest concentrations and thus are not considered critical. [LOAEL (dogs) = 0.50 mg/m³ (0.22 ppm)]

8.3.2 Ingestion

Uncertainty concerning the doses administered and lack of clear exposure-related effects on survival, behaviour, body weight, organ weights, haematological parameters, or stomach histopathology limit the usefulness, in the characterization of effects, of early short- and medium-term toxicological studies in which rats were administered drinking-water containing acrolein (Newell, 1958). In a study in which only a limited number of end-points was assessed, the oral administration (by gavage) of 4.6–9.0 mg acrolein/kg body weight per day (at concentrations ranging from 0.46 to 0.90 mg/ml) for 14 consecutive days to male and female CD-1 mice had no dose-related effect upon mortality or weight gain, although there was a clear increase in the occurrence of white thickening of the gastric mucosa in the high-dose groups (BSC, 1983).

In a 13-week study, acrolein was administered by oral gavage in a 5% aqueous solution of methylcellulose to Fischer 344 rats at concentrations of 0.15, 0.25, 0.5, 1.0, or 2.0 mg/ml (0.75, 1.25, 2.5, 5.0, or 10.0 mg/kg body weight per day) and to B6C3F₁ mice at concentrations of 0.125, 0.25, 0.5, 1.0, or 2.0 mg/ml (1.25, 2.5, 5.0, 10.0, or 20.0 mg/kg body weight per day) (NTP, 1998). In a preliminary report of the results, histopathological lesions in the stomach (including haemorrhage, necrosis, and inflammation of the glandular stomach and forestomach and squamous epithelial hyperplasia of the forestomach) were observed in rats receiving >0.25 mg acrolein/ml and in mice receiving >0.125 mg acrolein/ml (i.e., in 1/10 males at the lowest concentration); however, the incidence and statistical significance of these lesions were either poorly reported or not presented. Systemic effects in rats (increased liver weights) and mice (increased liver and kidney weights) were observed at doses >2.5 mg acrolein/kg body weight per day (NTP, 1998). [No-observed-effect level (NOEL) (rats) = 0.75 mg/kg body weight per day (0.15 mg/ml); LOEL (mice) = 1.25 mg/kg body weight per day (0.125 mg/ml)]

8.3.3 Dermal exposure

Erythema, oedema, and histopathological changes in the skin (hyperkeratosis, acanthosis, parakeratosis) have been observed in male and female New Zealand white rabbits exposed dermally to acrolein (7, 21, or 63 mg/kg body weight; concentrations of 3.5, 10.5, and 31.5 mg/ml) for 6 h/day, 5 days/week, for 3 weeks (BSC, 1982a).

Identified data concerning the chronic toxicity/carcinogenicity of acrolein following the inhalation exposure of laboratory species are restricted to the results of two limited studies. In one study in which groups of Syrian golden hamsters (18 animals per sex) were exposed (whole body) to 0 or 9.2 mg/m³ (0 or 4.0 ppm) acrolein vapour for 7 h/day, 5 days/week, for 52 weeks (Feron & Kruysse, 1977), followed by a 29-week recovery period, exposure to acrolein produced variable (statistically significant) reductions in body weight among males (P < 0.01 to P < 0.05) and females (P < 0.001 to P < 0.05), an increase (P < 0.05) in relative lung weights and a reduction (P < 0.05) in relative liver weights in females, as well as slight to moderate histopathological effects in the anterior portion of the nasal passages. No exposure-related tumours were observed among animals exposed to acrolein; however, this study is limited by the relatively short exposure period, small group sizes, and single exposure concentration.

Limited exposure (1 h/day) of small numbers (n = 20) of female Sprague-Dawley rats to a single concentration (18 mg/m³; 8 ppm) of acrolein for up to 18 months had no apparent adverse effects on body weight, lung weight, or histopathology in major tissues and organs (including nasal fossae, larynx, trachea, and lungs) (LeBouffant et al., 1980).

Available data concerning the chronic toxicity/carcinogenicity of acrolein following oral exposure include three bioassays in which a wide range of end-points was examined in Sprague-Dawley rats (Parent et al., 1992a), CD-1 mice (Parent et al., 1991), and beagle dogs (Parent et al., 1992b) and an earlier study in male F344 rats, in which only mortality and histopathology in selected tissues were examined (Lijinsky & Reuber, 1987).

In a study in which Sprague-Dawley rats were administered (by oral gavage) 0.05, 0.5, or 2.5 mg acrolein/kg body weight per day (solutions were prepared fresh daily in deionized water at concentrations of 0.005, 0.05, and 0.25 mg/ml) for up to 102 weeks, there was an unspecified reduction (P < 0.05) in serum creatinine phosphokinase levels among both sexes at all levels of exposure. There was also a (dose-related) increase in mortality among males (P = 0.003) at 0.5 and 2.5 mg acrolein/kg body weight per day during the first year only and in females (P < 0.001) at 0.5 and 2.5 mg/kg body weight per day throughout the entire exposure period (Parent et al., 1992a). The cause of the increased mortality was not specified, and adverse effects other than those noted here were not observed. Exposure-related histopathological effects were not observed; examinations were conducted on all major tissues and organs (including oesophagus, stomach, and intestines) from animals in the control and high-dose groups and in animals found dead or sacrificed moribund, although only the stomachs of some animals sacrificed after 13 weeks were examined histopathologically. After the first year of the study, survival in the mid- and high-dose male rats was reduced compared with the controls; however, survival appeared to be higher among males exposed to acrolein (at all dose levels) during the second year of exposure than in controls. No statistical evaluation of this apparent increase in survival in the acrolein-exposed male rats was presented. Although histopathological effects in the stomach were not observed in rats exposed to acrolein in this investigation, such changes have been noted in other adequate subchronic oral studies conducted with Fischer 344 rats (NTP, 1998), in which the time-point of histopathological analysis was similar to one of those included in this study by Parent et al. (1992a).

Similarly, no apparent dose-related effects on clinical or haematological parameters, organ weight, gross pathology, or histopathology were observed when CD-1 mice were administered (by oral gavage) 0.5, 2.0, or 4.5 mg acrolein/kg body weight per day (solutions were prepared fresh daily in deionized water at concentrations of 0.05, 0.20, and 0.45 mg/ml) for 18 months (Parent et al., 1991). Administration of 4.5 mg acrolein/kg body weight per day produced effects in male mice only, which included a significant (P < 0.05) reduction in growth (approximately 5%) and a significant (P < 0.05) increase in mortality throughout the entire study period, the cause of which was not specified. Notably, survival was higher in the low- and mid-dose males throughout the entire exposure period than in unexposed controls; no statistical evaluation of this apparent increase in survival in treated male mice was presented. Once again, although there was an absence of histopathological effects in the stomachs of mice exposed to acrolein in this study, such changes have been observed in other adequate subchronic oral studies (NTP, 1998) conducted with B6C3F₁ mice.

In studies of small groups (n = 20) of male F344 rats receiving drinking-water containing 0, 100, 250, or 625 mg acrolein/litre (0, 14, 36, or 89 mg/kg body weight per day)⁵ for 5 days/week for up to 124 weeks or male and female rats receiving drinking-water containing 0 or 625 mg acrolein/litre (0 or 89 mg/kg body weight per day) for up to 104 weeks, exposure to acrolein had no significant effect on mortality in either sex or on histopathology (including the forestomach, peritoneum, and colon) in male rats (Lijinsky & Reuber, 1987). Female rats receiving drinking-water containing 625 mg acrolein/litre (89 mg/kg body weight per day) had a marginal increase in the incidence of adrenal cortical adenomas (5/20, P = 0.091) and in the combined incidence of adrenal cortical adenomas and "hyperplastic nodules" (7/20, P = 0.022) compared with unexposed controls (Lijinsky & Reuber, 1987). However, no additional details were provided. Re-examination of slides prepared from tissue blocks derived from the Lijinsky & Reuber (1987) study revealed no evidence of acrolein-induced carcinogenesis in the adrenal glands of female rats (Parent et al., 1992a). It should be noted that there was no indication in the Lijinsky & Reuber (1987) study that precautions had been taken to control the instability of acrolein in water or prevent the likely volatilization of acrolein; therefore, the doses that the animals received were likely considerably less than the nominal doses indicated above. Indeed, the highest dose at which non-neoplastic effects were not observed is considerably greater than reported LD₅₀s.

Non-neoplastic effects in dogs administered up to 2.0 mg acrolein/kg body weight per day, 7 days a week for up to 53 weeks, were limited to transient (dose-dependent) vomiting at all levels of exposure, which decreased over time (suggesting that animals developed tolerance to acrolein), and (persistent) significant (P < 0.05) alterations in serum biochemical parameters (including reduced total protein [up to 17%], albumin [up to 19%], and calcium [up to 7%]) in animals at the highest dose (Parent et al., 1992b).

There were no increases in diethylnitrosamine-induced respiratory tract tumours in hamsters exposed simultaneously to acrolein, and there was only limited evidence of an enhancing effect on carcinogenesis induced by benzo[a]pyrene (Feron & Kruysse, 1977). Cohen et al. (1992) reported an increased incidence of urinary bladder papillomas in rats administered acrolein by intraperitoneal injection (in water) followed by uracil in the diet, compared with controls administered water by intraperitoneal injection followed by uracil.

In the absence of cytotoxicity, acrolein induces gene mutations in both bacteria (with or without metabolic activation) (Hemminki et al., 1980; Lijinsky & Andrews, 1980; Hales, 1982; Lutz et al., 1982; Haworth et al., 1983; Marnett et al., 1985; Foiles et al., 1989; Parent et al., 1996) and mammalian cells in culture (Smith et al., 1990), as well as structural chromosomal aberrations in Chinese hamster ovary (CHO) cells (Au et al., 1980) and sister chromatid exchanges in CHO cells (Au et al., 1980; Galloway et al., 1987) and cultured human lymphocytes (Wilmer et al., 1986). The mode of induction of the genotoxicity of acrolein appears to involve the induction of DNA damage. Acrolein binds to DNA, forms DNA–protein cross-links (Grafstrom et al., 1988), and induces DNA single strand breaks in human fibroblasts (Dypbukt et al., 1993) and bronchial epithelial cells (Grafstrom et al., 1988). In human fibroblasts, acrolein induces mutations at the HPRT locus in DNA repair-deficient cells from xeroderma pigmentosum patients but not in normal cells (Curren et al., 1988), supporting DNA damage as the primary mechanism for acrolein-induced mutagenesis. The results of in vitro studies suggest that intracellular glutathione (or other free sulfhydryl groups) may protect against the DNA-damaging effects of acrolein (Eisenbrand et al., 1995).

Although the results of in vitro studies indicate that acrolein can react directly with DNA and proteins to form stable adducts, an increased formation of DNA–protein cross-links was not observed in the nasal mucosa of male F344 rats exposed in vivo (by inhalation) to 5 mg acrolein/m³ (2 ppm) for 6 h (Lam et al., 1985).

Although less relevant to the assessment of genotoxicity at the site of initial contact (i.e., where critical effects occur), in vivo studies of the genotoxicity of acrolein at systemic sites are not extensive. In a dominant lethal study in male ICR/Ha Swiss mice, acrolein (administered by intraperitoneal injection) at doses up to 2.2 mg/kg body weight had no effect upon the numbers of pregnancies, implants, or fetal deaths (Epstein et al., 1972). Increases in the frequency of chromosomal aberrations in peripheral blood lymphocytes or bone marrow cells were not observed in studies in which F344 rats were exposed (by inhalation) to concentrations up to 9.2 mg acrolein/m³ (4.0 ppm) for 6 h/day, 5 days/week, for 62 days (Kutzman, 1981) or in which Sprague-Dawley rats were administered (by intraperitoneal injection) single doses of up to 4.1 mg acrolein/kg body weight (BSC, 1982b), respectively.

Identified in vivo studies (using physiologically relevant routes of exposure) on the developmental/reproductive toxicity of acrolein conducted by oral gavage include a two-generation reproduction study in rats (Parent et al., 1992c) and developmental toxicity studies in rabbits (Parent et al., 1993), rats (BSC, 1982c,d), and mice (BSC, 1982c,d), while studies in which animals were exposed via inhalation are limited to the results of a single-generation reproductive study in rats (Bouley et al., 1976). On the basis of these investigations, effects generally at the site of contact (e.g., gastric lesions) in the parental generation have been limiting (i.e., adverse effects have been confined primarily to the parental generation, although in studies involving non-physiological routes of administration, feto/embryotoxic and teratogenic effects have been observed).

In the most extensive reproductive bioassay identified, reproductive function (including mating performance, fertility indices, duration of gestation, pup viability and body weight, lactation indices, and maternal and pup behaviour) was assessed in two generations of rats administered acrolein by gastric intubation (Parent et al., 1992c). Sprague-Dawley rats (F₀) were administered (by gavage) 1.0, 3.0, or 6.0 mg acrolein/kg body weight per day (solutions prepared daily in deionized water at concentrations of 0.2, 0.6, and 1.2 mg/ml) for 70 days and throughout a 21-day mating period (females only). A statistically significant (P < 0.01) reduction in body weight in F₀ males and females and gastric lesions (i.e., erosion of the glandular mucosa and hyperplasia/hyperkeratosis of the forestomach) in F₀ and F₁ females were also observed in animals receiving 3.0 mg acrolein/kg body weight per day (0.6 mg/ml).

Limited data on neurotoxicity indicate a lack of morphological changes in the tracheal or pulmonary nerves of rats exposed by inhalation to up to 570 mg acrolein/m³ (249 ppm) for 10 min (Springall et al., 1990), no histopathological changes in the nerve cells of the nasal olfactory epithelium of mice exposed by inhalation to 3.9 mg acrolein/m³ (1.7 ppm) for 6 h/day for 5 days (Buckley et al., 1984), and no behavioural effects in rats exposed by inhalation to up to 9.2 mg acrolein/m³ (4.0 ppm) for 6 h/day, 5 days/week, for up to 62 days (Kutzman et al., 1984).

The direct effects of acrolein on the immune system (including host resistance, pulmonary bacterial clearance, antibody responsiveness, lymphocyte blastogenesis, and respiratory damage) have been investigated in in vivo studies conducted with rats (Bouley et al., 1976; Sherwood et al., 1986; Leach et al., 1987) and mice (Jakab, 1977; Astry & Jakab, 1983; Aranyi et al., 1986) exposed via inhalation. Immunological effects (i.e., reduced pulmonary bacterial clearance) have been observed in mice exposed to concentrations of acrolein as low as 0.23 mg/m³ (i.e., 0.10 ppm for 3 h/day for 5 days; single administered concentration) (Aranyi et al., 1986), although effects have been transient in long-term studies. Transient effects on immunological parameters and decreased splenic weight have been observed in rats exposed to higher concentrations of acrolein.

Due to its highly reactive nature, acrolein can bind rapidly (both enzymatically and non-enzymatically) with cellular components. Many of the toxicological effects of acrolein may be due to the saturation of protective cellular mechanisms (most notably glutathione) and subsequent reaction with critical sulfhydryl groups in proteins and peptides (Gurtoo et al., 1981; Marinello et al., 1984). In rats, inhalation of acrolein at levels ranging from 0.2 to 39 mg/m³ (0.1 to 17 ppm) produces a concentration-dependent reduction in non-protein sulfhydryl groups in the respiratory tract, but not in the liver (McNulty et al., 1984; Lam et al., 1985; Heck et al., 1986; Walk & Haussmann, 1989). Some studies have revealed that pretreatment with compounds containing free sulfhydryl groups (e.g., cysteine) is protective against the acute lethality of acrolein (Sprince et al., 1979; Gurtoo et al., 1981). Similarly, the studies of Eisenbrand et al. (1995) suggest that intracellular glutathione (or other free sulfhydryl groups) may protect against the DNA-damaging effects of acrolein. Although there have been some suggestions that the toxic effects of acrolein may be mediated, at least in part, through mechanisms involving acrolein–glutathione conjugates (Mitchell & Petersen, 1989; Horvath et al., 1992; Ramu et al., 1996), available data remain inconclusive. In one study, acrolein and its glutathione adduct, glutathionylpropionaldehyde, induced oxygen radical formation (Adams & Klaidman, 1993).

The nature of responses associated with exposure to acrolein is qualitatively similar to that of other aldehydes. Acrolein is, however, the most irritating of these compounds. The pattern of observed irritancy of acrolein at the site of contact and the results of in vitro studies indicating that it can react directly with DNA and proteins to form stable adducts are findings similar to those for other aldehydes (such as formaldehyde) that have been carcinogenic to the respiratory system in sensitive inhalation bioassays. Although the exact mechanism is unknown, induction of tumours by these aldehydes (notably formaldehyde) is considered to be a function of both regenerative proliferative response and DNA–protein cross-linking at the site of contact.

The limited available data indicate, however, that the pattern of DNA–protein cross-linking and proliferative response induced by acrolein differs from that of acetaldehyde and formaldehyde. For acetaldehyde, at the concentrations at which tumours are observed (1350 mg/m³ [750 ppm]), there are increases in DNA–protein cross-links in the respiratory and olfactory mucosa of rats but no increase in proliferation (Cassee et al., 1996). For formaldehyde, at the lower concentrations at which tumours are observed (7 mg/m³ [6 ppm]), there are increases in DNA–protein cross-links and proliferation in the nasal respiratory (but not olfactory) epithelium (Casanova et al., 1994).

Moreover, available data are inadequate to assess whether acrolein is carcinogenic or interacts directly with DNA at the site of contact following inhalation, although in vitro studies have demonstrated that acrolein can react directly with DNA to form adducts and induce DNA damage. While there was no increase in DNA–protein cross-links in the nasal mucosa of Wistar rats exposed (by inhalation) to a single concentration of 5 mg acrolein/m³ (2 ppm) alone, acrolein enhanced the formation of formaldehyde-induced DNA–protein cross-links (Lam et al., 1986). It is possible that the lack of observation of DNA–protein cross-links at the site of exposure at the single dose administered in studies conducted to date (Lam et al., 1985) might be attributable to preferential binding to sulfhydryl-containing nucleophiles (such as glutathione). Moreover, it appears that the cytotoxicity of acrolein at low concentrations associated with the saturation of protective mechanisms (namely glutathione) may be the crucial determinant in the toxicity of this compound at the site of exposure.

Increases in cell proliferation have been observed in the nasal respiratory epithelium (but not olfactory epithelium) of Wistar rats following single (Roemer et al., 1993) or repeated exposure (Cassee et al., 1996) (by inhalation) to relatively low concentrations (0.5 mg/m³ [0.2 ppm] or greater) of acrolein, although data in this regard are also not completely consistent.

Acrolein is an upper respiratory tract and eye irritant in humans. The threshold concentration for the perception of acrolein vapour may be as low as 0.07 mg/m³ (Sinkuvene, 1970), while the odour recognition threshold may be as low as 0.48 mg/m³ (Leonardos et al., 1969). Sensory ocular irritation has been observed at concentrations that were reported to be as low as 0.13 mg acrolein/m³ (calculated value) (Darley et al., 1960), while nasal (sensory) irritation has been reported following exposure to concentrations as low as 0.34 mg/m³ (Weber-Tschopp et al., 1977). Respiratory rate was reduced in male volunteers exposed to concentrations as low as 0.69 mg/m³ for 40 min (Weber-Tschopp et al., 1977). Inhalation of concentrations as low as 0.6 mg acrolein/m³ may cause respiratory effects, including coughing, nasal irritation, chest pain, and difficulty breathing (Kirk et al., 1991). Most individuals cannot tolerate exposure to concentrations of acrolein in air of 5 mg/m³ or higher for more than 2 min, while exposure to concentrations above 20 mg/m³ may be lethal (Einhorn, 1975; Kirk et al., 1991).

Effects including weakness, nausea, vomiting, diarrhoea, severe respiratory and ocular irritation, shortness of breath, bronchitis, pulmonary oedema, unconsciousness, and death have been observed upon accidental exposure (by inhalation or ingestion) to acrolein. Direct dermal or ocular contact with liquid acrolein can produce severe skin or eye injury, including necrosis, oedema, erythema, dermatitis, and follicular pharyngitis (ITII, 1975; Beauchamp et al., 1985; Kirk et al., 1991; Bronstein & Sullivan, 1992; Rorison & McPherson, 1992). Effects following the ingestion or inhalation of acrolein have been consistently observed at the site of contact (i.e., stomach or respiratory tract) (Champeux et al., 1966; Gosselin et al., 1979; Schielke, 1987; Mahut et al., 1996).

In patch tests conducted with volunteers, no dermal irritation was observed following exposure to 0.01% or 0.1% acrolein; however, positive reactions (i.e., severe oedema with bullae and erythema) were observed in 6 of 48 individuals exposed to 1.0% acrolein, while more severe effects (including bullae, necrosis, inflammatory cell infiltration, and papillary oedema) were observed in 8 of 8 subjects exposed to 10% acrolein (Lacroix et al., 1976).

In a nested case–referent study among employees of chemical manufacturing companies, Ott et al. (1989) assessed the relationship between mortality from non-Hodgkin’s lymphoma (52 cases), lymphocytic leukaemia (18 cases), non-lymphocytic leukaemia (39 cases), and multiple myeloma (20 cases) and exposure to 21 different chemicals, including acrolein. The odds ratio for being a case of non-Hodgkin’s lymphoma and having exposure to acrolein was 2.6 (two exposed cases), that for non-lymphocytic leukaemia 2.6 (three exposed cases), and that for multiple myeloma 1.7 (one exposed case). None of the odds ratios was statistically significant (details of statistical analysis and confidence intervals not presented); this study was limited by the small number of cases, lack of reporting of statistical analyses, and limited characterization of exposure to acrolein (and concomitant exposure to other chemicals).

The toxicity of acrolein to aquatic organisms has been extensively studied, while the data set on the toxicity of acrolein to terrestrial organisms is more limited. A brief summary of effects is presented below, with an emphasis on the most sensitive end-points for aquatic and terrestrial organisms.

Acrolein is acutely toxic to aquatic organisms. Its toxicity in the aquatic environment has been extensively studied as a result of its use as an aquatic herbicide in irrigation canals.

The frog Xenopus laevis tadpole is the most sensitive aquatic species tested, with a 96-h LC₅₀ of 7 µg/litre (Holcombe et al., 1987). Short-term LC₅₀s for freshwater fish range from 14 to 250 µg/litre. For marine fish, LC₅₀s of 56–240 µg/litre have been reported (Holcombe et al., 1987; Eisler, 1994; EU, 1999). Invertebrates have a range of sensitivity to acrolein similar to that of fish (US EPA, 1978; Eisler, 1994). The water flea Daphnia magna is the most sensitive invertebrate, with a 48-h LC₅₀ ranging from 22 to 93 µg/litre (EU, 1999). Microbes are also sensitive to acrolein. Under closed static conditions, the 2-h growth EC₅₀ for the bacterium Proteus vulgaris was 20 µg/litre (Eisler, 1994).

According to many field trials on the efficiency of acrolein as a pesticide, most submerged aquatic weeds and algae are sensitive (BPCI, 1994). The most sensitive species identified is the alga Scenedesmus subspicatus, which has a 72-h EC₅₀ (biomass) of 26 µg/litre, a 72-h EC₅₀ (growth rate) of 61 µg/litre, and a no-observed-effect concentration (NOEC) of 10 µg/litre (EU, 1999). When acrolein is used to clear unwanted vegetation from irrigation canals, its effective dose range is 1–15 mg/litre over an exposure period of 0.25–8 h (BPCI, 1997). Most terrestrial crop plants can tolerate irrigation water containing 25 mg acrolein/litre without damage (Ferguson et al., 1961).

Few chronic toxicity studies are available for aquatic organisms. Acrolein was toxic to the fathead minnow (Pimephales promelas) following a 60-day exposure to 21.8 µg/litre (Macek et al., 1976). The survival of the F₁ fathead minnow was significantly reduced at 42 µg/litre; the NOEL for F₁ survival was estimated to be 11 µg/litre. In a 64-day exposure of the zooplankton Daphnia magna, 100% mortality occurred in the F₂ generation at 42.7 µg/litre. The NOEC for survival was estimated to be 16.9 µg/litre (Macek et al., 1976). In another study, a subchronic 14-day NOEC of 1800 µg/litre was derived for the mollusc Dreissena polymorpha (EU, 1999).

In many of the aquatic studies, the exposure solutions were periodically replenished via static renewal. In other cases, the organisms were exposed in a flow-through design to a continually renewed solution of acrolein. Dose–response relationships were frequently based on nominal concentrations of acrolein because of the ready volatilization and degradation of acrolein in aqueous solutions. The actual concentrations to which the organisms were exposed, particularly in the case of static renewal bioassays, may have been lower than reported. As a result, many of the existing data may underestimate the toxicity of acrolein to aquatic organisms.

The data on toxicity relevant for terrestrial wildlife are limited to studies on laboratory mammals and a few acute studies on crop plants. Data indicate that terrestrial organisms are less sensitive than aquatic organisms to single exposures to acrolein (Eisler, 1994).

There have been no tests on wild terrestrial animals; effects on laboratory animals are presented in section 8. In chickens (Gallus sp.), there was tracheal damage at concentrations of 113–454 mg acrolein/m³ for up to 27 days (Denine et al., 1971). With oral exposure to acrolein, the LD₅₀ for mallards (Anas platyrhynchos) is 9.1 mg/kg body weight, and treatment levels as low as 3.3 mg/kg body weight produce signs of intoxication, such as regurgitation, ataxia, imbalance, and withdrawal (Hudson et al., 1984). The 4-h LC₅₀ for the fruitfly Drosophila melanogaster, which is the only invertebrate tested, exceeded 4606 mg/litre following exposure to an aqueous solution of acrolein on a petri dish (Comendador et al., 1989).

The data on toxicity of acrolein in air to terrestrial plants are limited to three acute studies on crop plants. Smog-like leaf damage was observed for seven species exposed to concentrations of acrolein ranging from 233 to 4700 µg/m³ (Haagen-Smit et al., 1952; Darley et al., 1960; Masaru et al., 1976). The most sensitive plant tested was alfalfa (Medicago sativa), which developed speckled surface necrosis (percentage effect not given) after a 9-h exposure to 233 µg acrolein/m³, the lowest concentration tested in a study by Haagen-Smit et al. (1952). This concentration corresponded to a NOEC for the four other species of crop plants tested in that study (sugar beet, Beta sp.; endive, Cichorium endivia; spinach, Spinacia oleracea; oats, Avena sp.). The method of exposure involved the vaporization of liquid acrolein continuously injected into a fumigation chamber (Haagen-Smit et al., 1952). In a study of the Easter lily (Lilium longiflorum) seed, there was a complete inhibition of pollen tube elongation following a 5-h exposure to 910 µg acrolein/m³ (Masaru et al., 1976). Pinto beans (Phaseolus sp.) exposed to 4700 µg acrolein/m³ in air for 1.2 h exhibited 10% surface damage (Darley et al., 1960).

11.1.1 Hazard identification and exposure–response assessment

11.1.1.1 Effects in humans

Data relevant to the assessment of the potential adverse effects of exposure to acrolein in humans are limited primarily to irritation. In early clinical studies of small numbers of volunteers exposed for short periods, ocular and nasal sensory irritation were reported at acrolein concentrations as low as 0.13 mg/m³ (Darley et al., 1960) and 0.34 mg/m³ (Weber-Tschopp et al., 1977), respectively, while respiratory rate was reduced at concentrations as low as 0.69 mg/m³ (Weber-Tschopp et al., 1977). The single identified epidemiological study (Ott et al., 1989) is inadequate to serve as a basis for assessment of the carcinogenicity of acrolein.

Because of the limited nature of data in humans, hazard characterization and dose–response analysis for acrolein are based primarily on studies in animals.

Acrolein is highly acutely toxic, inducing irritation of the respiratory and gastrointestinal tracts and central nervous system depression. Acrolein is also irritating to the skin following dermal exposure. Available data suggest that acrolein may induce skin sensitization in experimental species, although these data are currently under review.

The effects of acrolein following exposure by inhalation have been most extensively investigated. Acrolein is cytotoxic; in short-, medium-, and long-term inhalation studies conducted in several species (rats, mice, guinea-pigs, hamsters, monkeys, and dogs), at lowest concentrations, effects (degenerative histopathological lesions) have occurred consistently at the site of entry (i.e., the respiratory tract). Effects in other organs have also sometimes been observed, although inconsistently. This is consistent with the results of toxicokinetic studies in rodents and dogs, in which there has been a high degree of retention of inhaled acrolein at the site of contact.

In primarily early repeated-exposure inhalation studies, in which examination of the respiratory tract was often not complete, species-related differences in sensitivity to acrolein have been observed, with adverse effects on the respiratory tract of dogs, monkeys, and rats at lowest concentrations (i.e., 0.50 mg/m³ [0.22 ppm]) (Lyon et al., 1970; Feron et al., 1978; Cassee et al., 1996). With some exceptions, and although histopathological examination was, in some cases, restricted to one area of the respiratory tract, the pattern of lesions among species is generally similar to that observed for other aldehydes. Effects in rats are primarily confined to the nasal passages at lower concentrations but are observed in the more distal airways at higher concentrations, whereas effects in hamsters and guinea-pigs are obse