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3 Methacrylaldehyde1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levelsâAEGL-1, AEGL-2, and AEGL-3âare developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are de- fined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Tom Marshall (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager Susan Ripple (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then re- viewed by the National Research Council (NRC) Committee on Acute Exposure Guide- line Levels. The NRC committee has concluded that the AEGLs developed in this docu- ment are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 62
Methacrylaldehyde 63 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Methacrylaldehyde is a colorless liquid at ambient temperature and pres- sure. It is an intermediate in the production of methacrylonitrile and methacrylic acid, and has been found in the emissions from automobile exhaust, liquid floor wax, steel-protective paints, and trees. Production of methacrylaldehyde in the United States (other than as a chemical intermediate) was discontinued in the late 1970s because better catalysts in propylene oxidation became available for the production of copolymers and resins. Methacrylaldehyde is highly irritating to mucous membranes, especially the upper respiratory tract and eyes (HSDB 2002). Data on the acute lethality of methacrylaldehyde in animals are sparse. Inhalation studies indicate that it is an irritant and that the upper respiratory tract is the target for toxicity in laboratory animals. Irritant effects were evident in studies of durations ranging from a single 6-h exposure to repeated exposures for 2-13 weeks. The AEGL-1 values for methacrylaldehyde are based on ocular irritation in healthy human subjects (Nojgaard et al. 2005). The nondominant eyes of 10 men were exposed for 20 min to methacrylaldehyde at concentrations of 0, 0.089, 0.189, and 0.286 ppm in eight sessions. Blinking frequency was recorded as a measure of irritation and the subjects described the intensity of any ocular discomfort or irritation during the exposures. The number of complaints about irritation and its intensity were not different at any concentration relative to that described by the control group. The relative change in blinking frequency was statistically higher (18%; p = 0.001) during exposure at 0.286 ppm. The no-
64 Acute Exposure Guideline Levels observed-adverse-effect level (NOAEL) for blinking frequency was 0.189 ppm, which served as the point-of-departure for all of the AEGL-1 values for methac- rylaldehyde. No uncertainty factors were applied because the blinking frequency is not a perceived effect but an objective measurement that precedes perceived irritation. The same AEGL-1 value was used for all durations because mild irri- tation is not expected to vary over time. The AEGL-2 values are based on sensory irritation observed in a study by Coombs et al. (1994), in which Sprague-Dawley rats were exposed to methac- rylaldehyde at 1, 4.9, and 15.3 ppm for 6 h/day, 5 days/week for 13 weeks. An- imals exposed at the two highest concentrations were observed keeping their eyes half-closed or closed during exposure and animals exposed at 15.3 ppm occasionally exhibited salivation. No signs of ocular irritation were observed at 1 ppm. Lesions of the upper airways were evidence that the upper respiratory tract is also a target for toxicity. No relevant single exposure or short-term expo- sure studies were available. Because half-closed or closed eyes may be impair- ments for escape, 1 ppm was used as the point-of-departure. Typically, two un- certainty factors of 3 would be used for direct-acting irritants; one to account for interspecies differences and one to account for intraspecies variability. However, adjusting the 1-ppm point-of-departure by a total uncertainty factor of 10 would result in values lower than 0.189 ppm, the concentration which did not result in perceived irritation or change in blinking frequency in the Nojgaard et al. (2005) study used as the basis of the AEGL-1 values. Thus, a total uncertainty factor of 3 was used. Time scaling was not performed because half-closed or closed eyes are signs of contact irritation. The AEGL-3 values are based on a study of a single 6-h exposure to methacrylaldehyde at 77 ppm, which resulted in 90% mortality in rats (Coombs et al. 1992). No deaths were observed in rats exposed at 19 ppm for 6 h/day, 5 days/week for 2 weeks (Coombs et al. 1992) or in rats exposed at 15.3 ppm for 6 h/day, 5 days/week for 13 weeks (Coombs et al. 1994). The concentration of 19 ppm was selected as the point-of-departure for AEGL-3 values. Selecting a no-effect level as the basis of the AEGL-3 values is supported by the steep con- centration-response relationship; a 4-fold increase in concentration resulted in a 90% increase in mortality. AEGL-3 values were time-scaled using the equation Cn à t = k (ten Berge et al. 1986). Default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations were used. The 30-min AEGL-3 value was adopted as the 10-min value because extrapolation from a 6-h point-of-departure to a 10-min guideline is not recommended (NRC 2001). A total uncertainty factor of 10 was applied; a factor of 3 was used to account for interspecies differences and a factor of 3 was used to account for intraspecies variability. Factors of 10 were considered unnecessary because the toxic effects of methacrylaldehyde appear to be related to contact irritation, so effects are not expected to differ substantially between species or among indi- viduals. The AEGL values for methacrylaldehyde are presented in Table 3-1.
Methacrylaldehyde 65 1. INTRODUCTION Methacrylaldehyde is a colorless liquid at ambient temperature and pres- sure. It is highly irritating to mucous membranes, especially the upper respirato- ry tract and eyes (HSDB 2002). Production of methacrylaldehyde in the United States other than as a chemical intermediate was discontinued in the late 1970s because better catalysts in propylene oxidation became available in the produc- tion of copolymers and resins. It is an intermediate in the production of methac- rylonitrile and methacrylic acid. It has been found in the emissions from auto- mobile exhaust, liquid floor wax, steel protective paints, and trees. The chemical and physical properties of methacrylaldehyde are presented in Table 3-2. TABLE 3-1 AEGL Values for Methacrylaldehyde Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm Eye blinking frequency (nondisabling) (0.58 (0.58 (0.58 (0.58 (0.58 in human subjects mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Nojgaard et al. 2005) AEGL-2 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm No-effect level for (disabling) (0.96 (0.96 (0.96 (0.96 (0.96 ocular irritation in rats mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Coombs et al. 1994) AEGL-3 4.3 ppm 4.3 ppm 3.5 ppm 2.2 ppm 1.4 ppm No deaths in rats (lethal) (12 (12 (10 (6.4 (4.1 (Coombs et al. 1992) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) TABLE 3-2 Chemical and Physical Properties of Methacrylaldehyde Parameter Value References Synonyms Methacrolein; 2-methylpropenal; Borchers 2012 methacraldehyde; 2-methyl-2-propenal; 2-methylacrolein; isobutenal; methacrolein CAS registry no. 78-85-3 Borchers 2012 Chemical formula C4H6O HSDB 2002 Molecular weight 70.09 Borchers 2012 Physical state Colorless liquid HSDB 2002 Melting point -81°C HSDB 2002 Boiling point 68.4°C HSDB 2002 Density/specific gravity (water = 1) 0.849 at 25°C HSDB 2002 Vapor density (air = 1) 2.4 HSDB 2002 Solubility in water 5.9% (59,000 mg/L) at 20°C; miscible HSDB 2002 with water, ethanol, and ether Vapor pressure 155 mm Hg at 25 °C HSDB 2002 Lower explosive limit (volume % 2.6 IPCS 1995 in air) Conversion factors 1 ppm = 2.9 mg/m3 HSDB 2002 1 mg/m3 = 0.35 ppm
66 Acute Exposure Guideline Levels 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No studies of the acute lethality of methacrylaldehyde in humans were found. 2.2. Nonlethal Toxicity 2.2.1. Clinical Studies The nondominant eye of 10 healthy men was exposed for 20 min to meth- acrylaldehyde at concentrations of 0, 0.089, 0.189, and 0.286 ppm (Nojgaard et al. 2005). Methacrylaldehyde vapors were mixed with clean air that was adjust- ed to a flow rate that generated the desired concentration. Exposures were con- ducted using a clear plastic eyepiece though which the vapors passed after mix- ing with clean air at 20% relative humidity. Concentrations delivered to the eyepiece were measured at a point in the delivery system before reaching the eyepiece. Blinking frequency was recorded as a measure of irritation and the subjects reported the perceived intensity of any eye discomfort or irritation dur- ing the exposure sessions. The subjects were recorded by a digital video camera and the same researcher viewed all of the videos and counted the number of blinks per session. The subjects were asked to rate perceived irritation of the eye, eyelid, or skin as none, weak, moderate, or strong. A baseline for blinking frequency was established by having four successive stages in each exposure session: an acclimatization stage, which included 3 min of clean air; an initial baseline recording with 8 min of clean air; a 20 min stage of chemical or clean air; and a final 8 min of clean air. The latter stage was divided into 4 min of re- covery and 4 min of a final baseline recording. The number of complaints about irritation and its perceived intensity were not different at any concentration rela- tive to the control exposure (see Table 3-3). The relative change in blinking fre- quency was statistically higher (18%; p = 0.001) during exposure at the highest concentration of 0.286 ppm. The NOAELs were 0.286 ppm for perceived irrita- tion and 0.189 ppm for blinking frequency. A mixture of limolene oxidation products and ozone was tested separately in this study. The results showed that those materials increased blinking frequency by as much as 34%, and also showed that lower relative humidity (20% vs. 50%) exacerbated the response. 2.3. Neurotoxicity No studies of the neurotoxicity of methacrylaldehyde in humans were found.
Methacrylaldehyde 67 TABLE 3-3 Results of Blinking Frequency Tests in Humans Exposed to Methacrylaldehyde Test Parameter Control 0.089 ppm 0.189 ppm 0.286 ppm Subjects perceiving irritation 3/10 4/10 5/10 4/10 Perceived intensity <weak <weak, weak <weak, weak <weak, weak Relative change in blinking -9 10 8 18b frequency (%) a 95% Confidence interval (%) -19 to 3 -2 to 23 -2 to 20 7 to 30 p-valuec 0.14 0.09 0.13 0.001 a Change relative to baseline of each subject calculated using log-transformed data. b p = 0.001. c Calculated by repeated-analysis using ANOVA software program. Source: Adapted from Nojgaard et al. 2005. 2.4. Developmental and Reproductive Toxicity No studies of the developmental or reproductive toxicity of methacrylal- dehyde in humans were found. 2.5. Genotoxicity No studies of the genotoxicity of methacrylaldehyde in humans were found. 2.6. Carcinogenicity No studies of the carcinogenicity of methacrylaldehyde in humans were found. 2.7. Summary The single human study on methacrylaldehyde indicates that it is a direct- acting irritant, confirming that effects in people are similar to those observed in animal studies. 3. ANIMAL TOXICITY DATA The results of toxicity studies of laboratory animals exposed to methac- rylaldehyde by inhalation are summarized in Table 3-4.
68 TABLE 3-4 Result of Toxicity Studies of Methacrylaldehyde Species Exposure Duration Concentration (ppm) End Point Reference Mouse 30 min 2.0 NOAEL (10% decrease in respiratory rate) Larsen and Nielsen 2000 4.4 LOAEL (30% decrease in respiratory rate) 6.6 40% decrease in respiratory rate 10.2 50% decrease in respiratory rate 13.1 55% decrease in respiratory rate 26.3 70% decrease in respiratory rate 1.3 (95% CI: 0.8-2.1) RD0 Rat 4h 125 Lethal to 2/6, 3/6, or 4/6 rats Carpenter et al. 1949 Rat 4h 195 LC50; severe irritation of respiratory tract BG Chemie 1995 Rat 6h 77 Lethal to 9/10 in 48 h; acute irritation, pulmonary lesions Coombs et al. 1992 5 NOAEL; eyes half-closed during exposure 6 h/d, 5 d/wk for 2 wk 19 LOAEL; multiple clinical signs related to respiratory irritation, respiratory tract lesions Rat 6 h/d, 5 d/wk for 13 wk 1.0 NOEL Coombs et al. 1994 4.9 NOAEL; eyes half-closed during exposure 15.3 LOAEL; multiple clinical signs related to respiratory irritation, respiratory tract lesions, evidence of reversal 4 wk after exposure Rat Unknown 10 Maternal toxicity BG Chemie 1995 20 Maternal and fetal toxicity (reduced birth weight) Abbreviations: CI, confidence interval; LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; NOEL, no- observed-effect level; RD0, extrapolated threshold concentration for reduction in respiratory rate.
Methacrylaldehyde 69 3.1. Acute Lethality 3.1.1. Rats Carpenter et al. (1949) exposed six Sherman rats (sex not specified) to methacrylaldehyde at a nominal concentration of 125 ppm for 4 h in a glass inha- lation chamber, and observed the survivors for 14 days. The report indicates that two, three, or four of the rats died. No other information was provided. The con- centration of 125 ppm is assumed to be an approximate LC50 in Sherman rats. An unconfirmed 4-h LC50 of 195 ppm is reported in a secondary source (BG Chemie 1995). BG Chemie is the German Employment Accident Insurance Fund of the Chemical Industry. The organization, which includes a scientific advisory committee, assesses the hazard of chemicals in the workplace, plans toxicity studies, and contracts the conduct of those studies to laboratories. 3.2. Nonlethal Toxicity 3.2.1. Rats In a 2-week inhalation exposure study in Sprague-Dawley rats, a single 6-h exposure to methacrylaldehyde at 77 ppm, the highest concentration tested, result- ed in death or a moribund condition in nine of 10 rats (five male, four female) within 2 days of exposure (Coombs et al. 1992). The cause of death was lesions in the respiratory tract, which were comprised of necrosis of the olfactory and respir- atory epithelium in the nasal turbinates, extensive epithelial ulceration of the lar- ynx and trachea, and necrosis of the bronchiolar epithelium of the lungs. The other two concentrations tested were 5 and 19 ppm, and groups of five male and five female rats were exposed at those concentrations for 6 h/day, 5 days/week for the full 2 weeks. Closed eyes or half-closed eyes were noted in the rats during each exposure period; rats in the 19-ppm group also adopted a hunched position during the exposure. Minimal hyperplasia of the respiratory epithelium of the nasal turbi- nates and laryngeal epithelia were observed at 19 ppm; no respiratory lesions were observed at 5 ppm. Coombs et al. (1994) exposed groups of 10 male and 10 female Sprague- Dawley rats by inhalation to methacrylaldehyde at 0, 1, 4.9, and 15.3 ppm for 6 h/day, 5 days/week for 13 weeks. Additional groups of control rats and rats exposed at 15.3 ppm were maintained and observed for 4 weeks after exposure ended. Animals exposed at 4.9 or 15.3 ppm were observed keeping their eyes half-closed during exposure days 1-6 or for most of the study, respectively; sali- vation was observed occasionally in the 15.3-ppm group. Weight gain and food consumption were decreased in both males and females at the highest concentra- tion. Lesions in the respiratory tract comprised of inflammation of the olfactory epithelium and metaplastic changes in the dorsal meatus and dorsal central nasal septum were observed in male and female rats exposed at 15.3 ppm. Similar changes were found in the larynx of some animals at that concentration. Clear
70 Acute Exposure Guideline Levels signs of repair and recovery from the lesions were found during the 4-week ob- servation period. The NOAEL was 4.9 ppm and the LOAEL was 15.3 ppm for olfactory lesions. For ocular irritation, the NOAEL was 1 ppm. 3.2.2. Mice Larsen and Nielsen (2000) studied the effects of inhaled methacrylalde- hyde on the respiratory tract of male mice (strain not specified; four per group) exposed at 0, 2.0, 4.4, 6.6, 10.2, 13.1, or 26.3 ppm for 30 min. Sensory irritation as indicated by a decreased respiratory rate, airflow limitation as indicated by the expiration flow rate at half of the tidal volume, and pulmonary irritation as indicated by the time-of-pause between the end of expiration and the beginning of inspiration were evaluated. Methacrylaldehyde caused a concentration- dependent decrease in respiratory rate of about 30, 40, 50, 55, and 70% at 4.4, 6.6, 10.2, 13.1, and 26.3 ppm, respectively. An RD50 (concentration that reduces the respiratory rate by 50%) of 10.4 ppm and an RD0 (extrapolated threshold concentration for reduction in respiratory rate) of 1.3 ppm were calculated for that indicator of sensory irritation. No response was seen in the indicators for pulmonary irritation. The investigators concluded that methacrylaldehyde is a potent sensory irritant and that desensitization does not occur in mice because the level of sensory irritation was constant during exposure. 3.3. Developmental and Reproductive Toxicity No studies of the developmental or reproductive toxicity of methacrylal- dehyde were found. 3.4. Genotoxicity Only in vitro mutagenicity data are available on methacrylaldehyde and the results are equivocal. Methacylaldehyde produced positive results in Salmo- nella typhimurium strains TA100 (Eder et al. 1990, 1993, 1994) and TA104 (Mersch-Sunderman et al. 1992) without S-9 activation, but had negative results in strain TA 98 (Kato et al. 1989). Neudecker et al. (1991) showed that the addi- tion of S-9 activation reduced methacrylaldehyde mutagenicity even when the liver preparation was boiled or when epoxide hydrolase was inhibited. That in- dicates that the positive results seen in this bacterial assay are of a direct-acting nature. Methacrylaldehyde was weakly positive in an Escherichia coli WP2 uvrA assay without activation (Kato et al. 1989). Several studies have shown methacrylaldehyde to be inactive in the SOS chromotest (Benamira and Marnett 1992; Mersch-Sunderman 1992; Eder et al. 1990, 1993, 1994). Weak activity for DNA damage was indicated in the comet assay using rat hepatocytes (Kuchen- meister et al. 1998), and a marginally positive result was obtained in studies of DNA adduct formation (Eder et al. 1993).
Methacrylaldehyde 71 3.5. Chronic Toxicity and Carcinogenicity No studies of the chronic toxicity or carcinogenicity of methacrylaldehyde were found. 3.6. Summary Acute lethality data from animal studies are sparse. Nonlethal inhalation studies indicate that methacrylaldehyde is an irritant and that the upper respira- tory tract is the target for toxicity. Signs of respiratory irritation in rats were gasping and closed or half-closed eyes during inhalation exposure. At higher concentrations, lesions of the upper airways were evident. Data in mice show that methacrylaldehyde suppresses respiration in a manner that indicates signifi- cant irritation. Genotoxicity data are equivocal. No data on the reproductive tox- icity, developmental toxicity, or carcinogenicity of methacrylaldehyde were available. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition No studies on the metabolism and disposition of methacrylaldehyde were available. According to HSDB (2002), the fate of methacrylaldehyde is probably similar to other short chain aldehydes that are readily oxidized by aldehyde de- hydrogenase to organic acids, which can then serve as substrates for fatty oxida- tion and the Krebs cycle. A second pathway is for aldehydes to be inactivated by reaction with sulfhydryl groups, particularly glutathione. 4.2. Mechanism of Toxicity The short chain alkenes related to acrolein are known to react with sulfhy- dryl groups (Beauchamp et al. 1985). Acrolein is the most toxic of the 2-alkenals (including methacrylaldehyde, crotonaldehyde, pentenal, and hexenal) and is also the most reactive toward sulfhydryl groups. The respiratory irritancy of acrolein and related aldehydes may be due to reactivity toward sulfhydryl groups in recep- tor proteins in the nasal mucosa. 4.3. Structure-Activity Relationships Neudecker et al. (1991) showed that relative to acrolein the size of the alkyl- ating substituent influences the direct mutagenicity of the aldehyde, with activity decreasing in the order of 2-methylacrolein, 2-ethylacolein, and 2-propylacrolein.
72 Acute Exposure Guideline Levels 4.4. Other Relevant Information 4.4.1. Species Variability Studies in rats and mice (Table 3-4) do not indicate much variability in the toxic effects of methacrylaldehyde. That is likely due to the direct irritating ef- fect of methacrylaldehyde on the airways. 4.4.2. Concentration-Exposure Duration Relationship The concentration-exposure duration relationship for many irritant and systemically-acting vapors and gases may be described by the equation Cn à t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain health-protective AEGL values in the absence of an empirically derived scaling exponent, temporal scaling may be performed using default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations (NRC 2001). 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 The only human toxicity study of methacrylaldehyde shows that the chemi- cal has the potential for ocular irritation (Nojgaard et al. 2005). The nondominant eyes of 10 men were exposed for 20 min to methacrylaldehyde at concentrations of 0, 0.089, 0.189, and 0.286 ppm in eight sessions. Blinking frequency was rec- orded as a measure of irritation and the subjects described the intensity of any ocu- lar discomfort or irritation during the exposures. The number of complaints about irritation and its intensity were not different at any concentration relative to that described by the control group. The relative change in blinking frequency was statistically higher (18%; p = 0.001) during exposure at 0.286 ppm. The NOAEL for blinking frequency was 0.189 ppm. 5.2. Animal Data Relevant to AEGL-1 Data in rats show that inhaled methacrylaldehyde is a contact irritant. For a 2-week exposure, the NOAEL was 4.9 ppm and the LOAEL was 19 ppm for respiratory-tract lesions (Coombs et al. 1992). A 13-week study in rats demon- strated a NOAEL of 5 ppm and a LOAEL of 15.3 ppm for olfactory lesions and a NOAEL of 1 ppm for ocular irritation (Coombs et al. 1994).
Methacrylaldehyde 73 5.3. Derivation of AEGL-1 Values The point-of-departure for the AEGL-1 values for methacrylaldehyde is the NOAEL of 0.189 ppm for blinking frequency in human subjects (Nojgaard et al. 2005). No uncertainty factors were applied because blinking frequency is not a perceived effect, but is rather an objective measurement that precedes per- ceived irritation. The same concentration was used for all durations because mild irritation is not expected to vary over time. The AEGL-1 values for meth- acrylaldehyde are presented in Table 3-5. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data relevant to deriving AEGL-2 values for methacrylalde- hyde were found. 6.2. Animal Data Relevant to AEGL-2 Data in rats show that inhaled methacrylaldehyde is a contact irritant. For a 2-week exposure to methacrylaldehyde, the NOAEL and LOAEL for respira- tory-tract lesions in rats was 5 and 19 ppm, respectively (Coombs et al. 1992). In another study, Sprague-Dawley rats were exposed to methacrylaldehyde at 1, 4.9, and 15.3 ppm for 6 h/day, 5 days/week for 13 weeks. At the two highest concentrations, the animals kept their eyes half-closed or closed during expo- sure. Salivation (indicative of substantial sensory irritation) was observed occa- sionally in animals exposed at 15.3 ppm. No signs of ocular irritation were ob- served at 1 ppm. The upper respiratory tract is also a target of toxicity for methacrylaldehyde, as evidenced by olfactory lesions found in rats exposed at 15.3 ppm. Data in mice show that methacrylaldehyde suppresses respiration in a manner that indicates significant irritation (Larsen and Nielsen 2000). 6.3. Derivation of AEGL-2 Values The AEGL-2 values for methacrylaldehyde are based on a NOAEL of 1 ppm for ocular irritation in rats (Coombs et al. 1994). Typically, two uncertainty factors of 3 would be applied to determine AEGL values for direct-acting irritants; one to account for interspecies differences and one to account for intraspecies var- iability. However, adjusting the 1-ppm point-of-departure by a total uncertainty factor of 10 would result in values lower than 0.189 ppm, which is a NOAEL for ocular irritation in humans (Nojgaard et al. 2005) and the basis of the AEGL-1 values for methacrylaldehyde. Thus, a total uncertainty factor of 3 was applied instead. Time scaling was not performed because mild ocular irritation is not ex- pected to vary over time. The AEGL-2 values for methacrylaldehyde are presented in Table 3-6, and the calculations are presented in Appendix A.
74 Acute Exposure Guideline Levels TABLE 3-6 AEGL-2 Values for Methacrylaldehyde 10 min 30 min 1h 4h 8h 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data relevant to deriving AEGL-3 values for methacrylalde- hyde were found. 7.2. Animal Data Relevant to AEGL-3 Values Data in rats show that inhaled methacrylaldehyde is a sufficiently severe contact irritant that it causes serious effects, including lethality (Table 3-4). A single exposure of rats to methacrylaldehyde at 77 ppm for 6 h resulted in 90% mortality (Coombs et al. 1992). No deaths were observed in rats exposed at 19 ppm for 6 h/day, 5 days/week for 2 weeks or in rats exposed at 15.3 ppm 6 h/day, 5 days/week for 13 weeks (Coombs et al. 1994). Other supporting stud- ies include an assumed 4-h LC50 in Sherman rats of about 125 ppm (nominal) reported by Carpenter et al. (1949), and an unconfirmed 4-h LC50 of 195 ppm reported in a secondary source (BG Chemie 1995). 7.3. Derivation of AEGL-3 Values On the basis of the study by Coombs et al. (1992), the 2-week NOAEL for lethality of 19 ppm was selected as the point-of-departure for AEGL-3 values for methacrylaldehyde. Time scaling was performed using the equation Cn à t = k (ten Berge et al. 1986). Data on methacrylaldehyde were inadequate for deriv- ing an empirical value for the exponent n, so default values of n = 3 to extrapo- late to shorter durations and n = 1 to extrapolate to longer durations were used. A total uncertainty factor of 10 was applied; a factor of 3 to account for inter- species differences and a factor of 3 to account for intraspecies variability. Fac- tors of 10 were considered unnecessary because the toxic effects of methacrylal- dehyde appear to be related to contact irritation, so effects are not expected to differ substantially between species or among individuals. Furthermore, use of a factor of 10 for either the interspecies or intraspecies uncertainty factor would result in AEGL-3 values that are less consistent with the available data. (A total uncertainty factor of 30 yields AEGL-3 values of 1.4 ppm for the 10- and 30- min durations, 1.1 ppm for the 1-h duration, 0.7 ppm for the 4-h duration, and 0.47 ppm for the 8-h duration. No effects were observed in rats exposed at 1.0 ppm for 6 h/day, 5 days/week for 13 weeks, and half-closed eyes and respiratory irritation were observed in rats similarly exposed at 4.9 ppm).
Methacrylaldehyde 75 The AEGL-3 values for methacrylaldehyde are presented in Table 3-7, and the calculations are provided in Appendix A. 8. SUMMARY OF AEGLS 8.1. AEGL Values and Toxicity End Points The AEGL values for methacrylaldehyde are presented in Table 3-8. The AEGL-1 values are based on a study of ocular irritation in healthy human subjects, which identified a NOAEL and a LOAEL for blinking frequency (Nojgaard et al. 2005). The AEGL-2 values are based on a study by Coombs et al. (1994), in which Sprague-Dawley rats exposed to methacrylaldehyde had clinical signs of ocular irritation. The AEGL-3 values are based on a concentration of methacrylal- dehyde not resulting in deaths in rats exposed for 6 h/day, 5 days/week for 13 weeks (Coombs et al. 1992). 8.2. Other Standards and Guidelines No other standards or guidelines for methacrylaldehyde were found. 8.3. Data Adequacy and Research Human data appropriate for derivation of AEGL-1 values for methacrylal- dehyde were available from a well-conducted study. However, no information was available concerning effects in young, elderly, or asthmatic individuals. Minimal animal data were available for derivation of AEGL-2 or AEGL-3 values. TABLE 3-7 AEGL-3 Values for Methacrylaldehyde 10 min 30 min 1h 4h 8h 4.3 ppm 4.3 ppm 3.5 ppm 2.2 ppm 1.4 ppm (12 mg/m3) (12 mg/m3) (10 mg/m3) (6.4 mg/m3) (4.1 mg/m3) TABLE 3-8 AEGL Values for Methacrylaldehyde Classification 10 min 30min 1h 4h 8h AEGL-1 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm (nondisabling) (0.58 mg/m3) (0.5860 mg/m3) (0.58 mg/m3) (0.58 mg/m3) (0.58 mg/m3) AEGL-2 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm (disabling) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) AEGL-3 4.3 ppm 4.3 ppm 3.5 ppm 2.2 ppm 1.4 ppm (lethal) (12 mg/m3) (12 mg/m3) (10 mg/m3) (6.4 mg/m3) (4.1 mg/m3)
76 Acute Exposure Guideline Levels 9. REFERENCES Beauchamp, R. O., D.A. Andjelkovich, A.O. Klingerman, K.T. Morgan, and H.D. Heck. 1985. A critical review of the literature on acrolein toxicity. Crit. Rev. Toxicol. 14(4):309-380. Benamira, M., and L.J. Marnett. 1992. The lipid peroxidation product 4-hydroxynonenal is a potent inducer of the SOS Response. Mutat. Res. 293(1):1-10. BG Chemie. 1995. Toxicological Evaluation: No. 108. Methacrolein [in German]. Berufsgenossenschaft der chemischen Industrie, Heidelberg [online]. Available: http://www.bgrci.de/fileadmin/BGRCI/Downloads/DL_Praevention/Fachwissen/Gef ahrstoffe/TOXIKOLOGISCHE_BEWERTUNGEN/Bewertungen/ToxBew108-K.pdf [accessed Dec. 3, 2014]. Borchers, M.T. 2012. Aldehydes and acetals. Pp. 655-733 in Patty's Toxicology, 6th Ed. New York: John Wiley and Sons. Carpenter, C.S., H.F. Smyth, and U.C. Pozzani. 1949. The assay of acute vapor toxicity and the grading and interpretation of results on 96 compounds. J. Ind. Hyg. Toxi- col. 31(6):343-346. Coombs, D.W., T.J. Kenny, and C.J. Hardy. 1992. Methacrolein (BG No. 108) 2-week Repeat Dose Preliminary Inhalation Toxicity Study in Rats. BGH 50/932334. BGH 40/920648. Study performed on behalf of the BG Chemie, Heidelberg, Ger- many, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, Eng- land. http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/C0DE274286C070E28 5257A2C0054C6E1/$File/84990000009.pdf [accessed Dec. 1, 2014]. Coombs, D.W., T.J. Kenny, D. Crook, and W.A. Gibson. 1994. Methacrolein (BG No. 108) 13-week Inhalation Toxicity Study in Rats. BGH 50/932334. Study performed on behalf of the BG Chemie, Heidelberg, Germany, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. November 1994 [online]. Available: http://yosemite.epa.gov/oppts/epatscat8.nsf/by+Service/C0DE274286C070E285257A2 C0054C6E1/$File/84990000009.pdf [accessed Dec. 1, 2014]. Eder, E., C. Hoffman, H. Bastian, C. Deininger, and S. Scheckenbach. 1990. Molecular mechanisms of DNA damage initiated by α,β-unsaturated carbonyl compounds as criteria for genotoxicity and mutagenicity. Environ. Health Perspect. 88:99-106. Eder, E., S. Scheckenbach, C. Deininger, and C. Hoffman. 1993. The possible role of α,β- unsaturated carbonyl compounds in mutagenesis and carcinogenesis. Toxicol. Lett. 67(1-3):87-103. Eder, E., C. Hoffman, C. Deininger, and S. Scheckenbach. 1994. Risk assessment for mutagenic and carcinogenic activities of α,β-unsaturated carbonyl compounds by a screening strategy based on structure activity relationships. Toxicol. In Vitro 8(4):707-110. HSDB (Hazardous Substances Data Bank). 2002. Methacrolein (CAS Reg. No. 78-85-3). TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen? HSDB [accessed August 20, 2013]. IPCS (International Programme on Chemical Safety). 1995. Methacrylaldehyde (CAS Reg. No. 78-85-3). International Chemical Safety Card No. 1259. International Programme on Chemical Safety and European Commission [online]. Available: http://www.inchem.org/documents/icsc/icsc/eics1259.htm [accessed August 20, 2013].
Methacrylaldehyde 77 Kato, F.A., K. Araki, K. Nozaki, and T. Matsushima. 1989. Mutagenicity of aldehydes and diketones. Mutat. Res. 216:366 [abstract 23]. Kuchenmeister, F., P. Schmezer, and G. Engelhardt. 1998. Genotoxic bifunctional alde- hydes produce specific images in the comet assay. Mutat. Res. 419(1-3):69-78. Larsen, S.T., and G.D. Nielsen. 2000. Effects of methacrolein on the respiratory tract of mice. Toxicol. Lett. 114(1-3):197-202. Mersch-Sunderman, V., U. Schneider, G. Klopman, and H.S. Rosenkranz. 1992. SOS induction in Escherichia coli and Salmonella mutagenicity: A comparison using 330 compounds. Mutagenesis 9(3):205-224. Neudecker, T., E. Eder, C. Deininger, and D. Henschler. 1991. Mutagenicity of 2- metylacrolein, 2-ethylacrolein and 2-propylacrolein in Salmonella typhimurium TA100. A comparative study. Mutat. Res. 264(4):193-196. Nojgaard, J.K., K.B. Christensen, and P. Wolkoff. 2005. The effect on human blink fre- quency of exposure to limonene oxidation products and methacrolein. Toxicol Lett. 156(2):241-251. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309.
78 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR METHACRYLALDEHYDE Derivation of AEGL-1 Values Key study: Nojgaard, J.K., K.B. Christensen, and P. Wolkoff. 2005. The effect on human blink frequency of exposure to limonene oxidation products and methacrolein. Toxicol Lett. 156(2):241-251. Toxicity end point: Blinking frequency, NOAEL = 0.189 ppm Time scaling: None Uncertainty factors: None Modifying factor: None Calculations: 10-min AEGL-1: 0.189 ppm (rounded to 0.20 ppm) 30-min AEGL-1: 0.189 ppm (rounded to 0.20 ppm) 1-h AEGL-1: 0.189 ppm (rounded to 0.20 ppm) 4-h AEGL-1: 0.189 ppm (rounded to 0.20 ppm) 8-h AEGL-1: 0.189 ppm (rounded to 0.20 ppm) Derivation of AEGL-2 Values Key study: Coombs, D.W., T.J. Kenny, D. Crook, and W.A. Gibson. 1994. Methacrolein (BG No. 108) 13-week Inhalation Toxicity Study in Rats. BGH 50/932334. Study performed on behalf of the BG Chemie, Heidelberg, Germany, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Toxicity end point: No signs of ocular irritation in rats at 1 ppm Time scaling: None Uncertainty factors: 3 for interspecies differences and intraspecies variability
Methacrylaldehyde 79 Modifying factor: None 10-min AEGL-2: 1 ppm ÷ 3 = 0.33 ppm 30-min AEGL-2: 1 ppm ÷ 3 = 0.33 ppm 1-h AEGL-2: 1 ppm ÷ 3 = 0.33 ppm 4-h AEGL-2: 1 ppm ÷ 3 = 0.33 ppm 8-h AEGL-2: 1 ppm ÷ 3 = 0.33 ppm Derivation of AEGL-3 Values Key study: Coombs, D.W., T.J. Kenny, and C.J. Hardy. 1992. Methacrolein (BG No. 108) 2-week Repeat Dose Preliminary Inhalation Toxicity Study in Rats. BGH 50/932334. BGH 40/920648. Study performed on behalf of the BG Chemie, Heidelberg, Germany, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Toxicity end point: No deaths in rats exposed at 19 ppm for 6 h/day, 5 days/week for 2 weeks Time scaling: Cn à t = k (ten Berge et al.1986); default values of n = 3 for extrapolation to shorter durations and n = 1 for longer durations. The 30-min value was adopted as the 10-min value because of the uncertainty associated with extrapolating a 6-h point-of-departure to a 10-min value (NRC 2001). (19 ppm)3 à 6 h = 41,154 ppm-h (19 ppm)1 à 6 h = 114 ppm-h Uncertainty factors: 3 for interspecies differences 3 for intraspecies variability Modifying factor: None 10-min AEGL-3: 4.3 ppm (same as the 30-min AEGL-3 value) 30-min AEGL-3: C3 à 0.5 h = 41,154 ppm-h C3 = 82,308 ppm C = 43.5 ppm 43.5 ppm ÷ 10 = 4.3 ppm
80 Acute Exposure Guideline Levels 1-h AEGL-3: C3 à 1 h = 41,154 ppm-h C3 = 41,154 ppm C = 34.5 ppm 34.5 ppm ÷ 10 = 3.5 ppm 4-h AEGL-3: C3 à 4 h = 41.154 ppm-h C3 = 10,288 ppm C = 21.7 ppm 21.7 ppm ÷ 10 = 2.2 ppm 8-h AEGL-3: C1 à 8 h = 114 ppm-h C = 14.25 ppm 14.25 ppm ÷ 10 = 1.4 ppm
Methacrylaldehyde 81 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR METHACRYLALDEHYDE Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm 0.20 ppm (0.58 mg/m3) (0.58 mg/m3) (0.58 mg/m3) (0.58 mg/m3) (0.58 mg/m3) Key reference: Nojgaard, J.K., K.B. Christensen, and P. Wolkoff. 2005. The effect on human blink frequency of exposure to limonene oxidation products and methacrolein. Toxicol Lett. 156(2):241-251. Test species/Strain/Number: 10 healthy men Exposure route/Concentration/Duration: Ocular exposure via eyepiece; 0, 0.089, 0.189, and 0.286 ppm for 20 min. Effects: 0.089 ppm = NOAEL 0.189 ppm = NOAEL for increased blinking frequency 0.286 ppm = LOAEL for increased blinking frequency 0.286 ppm = NOAEL for perceived ocular irritation End point/Concentration/Rationale: Blinking frequency as a measure of ocular irritation; NOAEL = 0.189 ppm Uncertainty factors/Rationale: No uncertainty factors were necessary because blinking frequency is not a perceived effect, but an objective measurement that precedes perceived irritation. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: None; the same value was applied to all durations because mild irritation is not expected to vary over time. Data adequacy: Well-conducted human study. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm 0.33 ppm (0.96 mg/m3) 0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) (0.96 mg/m3) Key reference: Coombs, D.W., T.J. Kenny, D. Crook, and W.A. Gibson. 1994. Methacrolein (BG No. 108) 13-week Inhalation Toxicity Study in Rats. BGH 50/932334. Study performed on behalf of the BG Chemie, Heidelberg, Germany, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Test species/Strain/Number: Rat; Sprague-Dawley; 10 males and 10 females/group (Continued)
82 Acute Exposure Guideline Levels AEGL-2 VALUES Continued Exposure route/Concentrations/Durations: Inhalation; 1, 4.9, and 15.3 ppm for 6 h/day, 5 days/week for 13 weeks Effects: Half-closed or closed eyes were observed during exposure days 1-6 in rats exposed at 4.9 ppm and for most of the study in rats exposed at 15.3 ppm. Histopathologic evidence of respiratory-tract irritation was found at the end of the 13-week exposure period in rats exposed at 15.3 ppm. End point/Concentration/Rationale: NOAEL for ocular irritation of 1 ppm, because ocular irritation could impair ability to escape. Uncertainty factors/Rationale: Total uncertainty factor: 3 Studies of human volunteers and rodents indicate that methacrylaldehyde is a direct-acting irritant. Repeated exposure studies in rats show that the eyes and upper respiratory tract are targets for acute and subchronic toxicity. Data in mice show that methacrylaldehyde suppresses respiration in a manner consistent with significant irritation. Typically, two factors of 3 would be used for direct-acting irritants; one to account for interspecies differences and one to account for intraspecies variability. However, adjusting the 1-ppm point-of-departure by a total uncertainty factor of 10 would result in values lower than 0.189 ppm, the NOAEL for ocular irritation in humans (Nojgaard et al. 2005) and the basis for the AEGL-1 values for methacrylaldehyde. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Not performed because mild ocular irritation is unlikely to vary with exposure duration. Data adequacy: Well-conducted subchronic study. No single or short-term exposure studies were available. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 4.3 ppm 4.3 ppm 3.5 ppm 2.2 ppm 1.4 ppm (12 mg/m3) (12 mg/m3) (10 mg/m3) (6.4 mg/m3) (4.1 mg/m3) Key reference: Coombs, D.W., T.J. Kenny, and C.J. Hardy. 1992. Methacrolein (BG. No. 108) 2-week repeat dose preliminary inhalation toxicity study in rats BGH 50/932334. BGH 40/920648. Study performed on behalf of the BG Chemie, Heidelberg, Germany, by Huntingdon Research Centre Ltd., Huntingdon, Cambridgeshire, England. Test species/Strain/Number: Rat; Sprague-Dawley; 5 males and 5 females/group Exposure route/Concentrations/Durations: Inhalation; 5, 19, and 77 ppm for 6 h/day, 5 days/week for 2 weeks. Effects: No deaths observed at 19 ppm. After a single exposure to methacrylaldehyde at 77 ppm for 6 h, nine of 10 rats died or were moribund within 48 h. End point/Concentration/Rationale: No deaths at 19 ppm. Uncertainty factors/Rationale: Total uncertainty factor: 10 (Continued)
Methacrylaldehyde 83 AEGL-3 VALUES Continued Interspecies: 3, because methacrylaldehyde is a direct-acting irritant and its effects are unlikely to differ substantial between species. Intraspecies: 3, because methacrylaldehyde is a direct-acting irritant and its effects are unlikely to differ among individuals. Studies of human volunteers and rodents indicate that methacrylaldehyde is a direct-acting irritant. Repeated exposure studies in rats show that the eyes and upper respiratory tract are targets for acute and subchronic toxicity. Data in mice show that methacrylaldehyde suppresses respiration in a manner consistent with significant irritation. Furthermore, use of a default value of 10 for either the interspecies or intraspecies uncertainty factor would result in AEGL-3 values that are less consistent with the available data. (Use of a total uncertainty factor of 30 would yield AEGL-3 values of 1.4 ppm for the 10- and 30-min durations, 1.1 ppm for the 1-h duration, 0.7 ppm for the 4-h duration, and 0.47 ppm for the 8-h duration. No effects were found in rats exposed at 1.0 ppm for 6 h/day, 5 days/week for 13 weeks. Half-closed eyes were observed during exposure and reversible respiratory lesions were found in rats similarly exposed at 4.9 ppm). Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn à t = k (ten Berge et al.1986); data on methacrylaldehyde were in adequate to derive an empirical value for the exponent n, so default values of n = 3 for extrapolation to shorter durations and n = 1 for extrapolation to longer durations were used (NRC 2001). The 30-min value was adopted as the 10-min value because of the uncertainty associated with extrapolating a 6-h point-of-departure to a 10-min value (NRC 2001). Data adequacy: The inhalation study that demonstrated lethality after a single 6-h exposure to methacrylaldehyde was well conducted. The cause of death was lesions in the respiratory tract, comprised of necrosis of the olfactory and respiratory epithelium in the nasal turbinates, extensive epithelial ulceration of the larynx and trachea, and necrosis of the bronchiolar epithelium in the lung. No deaths were observed at the other two concentrations tested (5 and 19 ppm for 6 h/day, 5 days/week) for the full 2 weeks.
84 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR METHACRYLALDEHYDE FIGURE C-1 Category plot of toxicity data and AEGL values for methacrylaldehyde. TABLE C-1 Date Used in Category Plot for Methacrylaldehyde Source Species ppm Minutes Category Comments AEGL-1 0.2 10 AEGL AEGL-1 0.2 30 AEGL AEGL-1 0.2 60 AEGL AEGL-1 0.2 240 AEGL AEGL-1 0.2 480 AEGL AEGL-2 0.33 10 AEGL AEGL-2 0.33 30 AEGL AEGL-2 0.33 60 AEGL AEGL-2 0.33 240 AEGL AEGL-2 0.33 480 AEGL AEGL-3 4.2 10 AEGL AEGL-3 4.2 30 AEGL AEGL-3 3.5 60 AEGL (Continued)
Methacrylaldehyde 85 TABLE C-1 Continued AEGL-3 2.2 240 AEGL AEGL-3 1.4 480 AEGL Nojgaard et al. 2005 Human 0.089 20 0 Nojgaard et al. 2005 Human 0.189 20 0 Nojgaard et al. 2005 Human 0.286 20 1 Increased blinking frequency Coombs et al. 1992 Rat 1.0 360 0 Coombs et al. 1992, 1994 Rat 5 360 1 Half-closed or closed eyes Coombs et al. 1992 Rat 15.3 360 1 Ocular and respiratory irritation Coombs et al. 1994 Rat 19 360 1 Ocular and respiratory irritation Coombs et al. 1992 Rat 77 360 SL 90% lethality Carpenter et al. 1949 Rat 125 240 SL 2/6, 3/6, or 4/6 deaths Larsen and Nielsen 2000 Mouse 2.0 30 0 Larsen and Nielsen 2000 Mouse 4.4 30 1 30% decrease in respiratory rate Larsen and Nielsen 2000 Mouse 6.6 30 1 40% decrease in respiratory rate Larsen and Nielsen 2000 Mouse 10.2 30 1 50% decrease in respiratory rate Larsen and Nielsen 2000 Mouse 13.1 30 2 55% decrease in respiratory rate Larsen and Nielsen 2000 Mouse 26.3 30 2 70% decrease in respiratory rate For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal- ity.
