4

Allyl Alcohol1

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 Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established 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 levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined 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

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1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Chemical Manager George Rodgers (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 reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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4 Allyl Alcohol1 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 levels—AEGL-1, AEGL-2, and AEGL-3—are 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 defined 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 1 This document was prepared by the AEGL Development Team composed of Claudia Troxel (Oak Ridge National Laboratory), Heather Carlson-Lynch (SRC, Inc.), Lisa Ingerman (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager Robert Benson (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazard- ous 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 reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 180

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Allyl Alcohol 181 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 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 Allyl alcohol is a colorless liquid that is a potent sensory irritant. Signs of intoxication following inhalation exposure to allyl alcohol vapor include lacri- mation, pulmonary edema and congestion, and inflammation, hemorrhage, and degeneration of the liver and kidneys. Human data include studies of voluntary exposures to allyl alcohol for short durations and general descriptions of symp- toms after accidental occupational exposures at unknown concentrations and durations. Animal data include a relatively recent detailed inhalation study in rats, studies in which only lethality was evaluated, studies of subchronic expo- sures, and single-exposure experiments in which only the RD50 (concentration that reduces the respiratory rate of test organisms by 50%) was measured. Data from the study by Nielsen et al. (1984) were used as the basis of the AEGL-1 values for allyl alcohol. An RD10 of 0.27 ppm (30 min) in mice was used an estimate of the threshold for irritation. A total uncertainty factor of 3 was applied, as irritant effects are not expected to vary greatly between species or individuals. Time scaling was not applied because of the short duration of exposure. The Kirkpatrick (2008) study in rats was selected as the basis for deriving AEGL-2 values. No-effect levels for disabling effects (reduced response to stimulus and gasping) from allyl alcohol were 51 ppm for 1 h, 22 ppm for 4 h, and 10 ppm for 8 h; these values were used as the points-of-departure for the 1-,

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182 Acute Exposure Guideline Levels 4- and 8-h AEGL-2 values, respectively. A total uncertainty factor of 30 was applied. An interspecies uncertainty factor of 3 was used because similar 1-h no- effect levels for lethality have been reported for rats (200-423 ppm) (Union Car- bide and Carbon Corporation 1951; Kirkpatrick 2008), mice (200 ppm) (Union Carbide and Carbon Corporation 1951), and rabbits (200 ppm) (Union Carbide and Carbon Corporation 1951). An intraspecies factor of 10 was applied because of the uncertainty about whether effects are due to allyl alcohol, one of its me- tabolites, or both. Furthermore, humans have genetic polymorphisms for alde- hyde dehydrogenase. Time scaling was performed for the 10- and 30-min values using the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). An empirical value for n of 0.95 was derived from rat lethali- ty data (see Appendix A). AEGL-3 values for allyl alcohol are based on the calculated LC01 (lethal concentration, 1% lethality) values in rats of 2,600 ppm for 10 min, 820 ppm for 30 min, 400 ppm for 1 h, 93 ppm for 4 h, and 45 ppm for 8 h. LC01 values were calculated using the ten Berge software program and rat mortality data from four studies (McCord 1932; Smyth and Carpenter 1948; Union Carbide and Carbon Corporation 1951; Kirkpatrick 2008) (see Appendix A). As noted for AEGL-2, the ten Berge program estimated a value for n of 0.95 for time scaling. A total uncertainty factor of 30 was applied for the same reasons described for the AEGL-2 values. A level of distinct odor awareness, which is the concentration above which more than half of the exposed population is predicted to experience at least a distinct odor intensity and about 10% will experience a strong odor intensity, could not be determined due to inadequate data. Although odor thresholds of 1.4 and 2.1 ppm have been reported for allyl alcohol, concurrent odor-threshold data for the reference chemical n-butanol (odor detection threshold 0.04 ppm) were not available. AEGL values for allyl alcohol are presented in Table 4-1. TABLE 4-1 AEGL Values for Allyl Alcohol Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 0.09 ppm 0.09 ppm 0.09 ppm 0.09 ppm 0.09 ppm Irritation threshold in (nondisabling) (0.22 (0.22 (0.22 (0.22 (0.22 mice (Nielsen et al. 1984) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-2 11 ppm 3.5 ppm 1.7 ppm 0.73 ppm 0.33 ppm Gasping and reduced (disabling) (27 (8.5 (4.1 (1.8 (0.80 response to stimulus in mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) rats (Kirkpatrick 2008) AEGL-3 87 ppm 27 ppm 13 ppm 3.1 ppm 1.5 ppm Estimated LC01 value (lethal) (210 (65 mg/m3) (31 (7.5 (3.6 in rats (McCord 1932; mg/m3) mg/m3) mg/m3) mg/m3) Smyth and Carpenter 1948;Union Carbide and Carbon Corporation 1951; Kirkpatrick 2008)

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Allyl Alcohol 183 1. INTRODUCTION Allyl alcohol is a colorless liquid that is a potent sensory irritant. The chem- ical has a pungent, mustard-like odor, with a reported odor-recognition concentra- tion of 0.78 ppm (Dunlap et al. 1958; HSDB 2013) and odor-detection threshold of 1.4-2.1 ppm (AIHA 1989). Primarily used in the production of allyl esters for use in resins and plasticizers, allyl alcohol is also used as an intermediate in the production of pharmaceuticals and other organic chemicals, as a fungicide and herbicide, in the production of glycerol and acrolein, and as a flavoring agent (Ta- bershaw et al. 1977; ACGIH 2001; O’Neil et al. 2006). Allyl alcohol is not cur- rently registered for pesticide use in the United States, but approved pesticide uses may change periodically (HSDB 2013). Allyl alcohol is produced from the isom- erization of propylene oxide at a high temperature using a lithium phosphate cata- lyst (Lyondell 2006; HSDB 2013). Acrolein is an intermediate in manufacturing processes and, therefore, may be a contaminant of allyl alcohol (Nagato 2004). Information on the production volume and sales quantities of ally alcohol was not available from the US Environmental Protection Agency’s nonconfidential Chem- ical Data Reporting (EPA 2013a). The 2006 Inventory Update Rule estimated nonconfidential production volumes of allyl alcohol of 100-500 million pounds (EPA 2010). EPA’s Toxic Release Inventory (EPA 2013b) reported a total envi- ronmental release and off-site waste transfer value of 484,955 pounds. Allyl alco- hol is transported by rail, truck, ship, and aircraft (Lyondell 2006). In the atmos- phere, allyl alcohol is degraded by reaction with photochemically-produced hydroxyl radicals. On the basis of a rate constant of 3.0 × 10-11 cu cm/molecule- sec at 25 ºC, the half-life for that reaction in the atmosphere is approximately 4.32 h (EPA 2013c). The physical and chemical properties of allyl alcohol are present- ed in Table 4-2. Vaporized and liquid allyl alcohol is intensely irritating to intact skin, eyes, and mucous membranes. Contact of ally alcohol with the eye can produce corneal burns. Direct skin contact can produce first- and second-degree burns and can in- duce epidermal necrosis. At sufficiently high concentrations, inhaled allyl alcohol can induce pulmonary edema (Shell Chemical Corporation 1957). Human data included controlled studies with human volunteers; no lethality or epidemiologic data on allyl alcohol inhalation exposure were available. Studies addressing lethal and nonlethal toxicity of allyl alcohol in laboratory animals were available. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No reports of death following inhalation exposure to allyl alcohol were found in the published literature. Toennes et al. (2002) reported a case of an individual dying within 100 min of ingesting a weed killer containing 85% (w/v)

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184 Acute Exposure Guideline Levels allyl alcohol. Kononenko (1970) briefly described a case in which a man died within 90 min of ingesting allylic alcohol at approximately 150 mL; loss of con- sciousness was reported to occur 20 min after ingestion. 2.2. Nonlethal Toxicity 2.2.1. Acute Studies Groups of five to seven volunteers, ranging in age from 19 to 39 years, were exposed to allyl alcohol for 5 min in an exposure room from one to three times per week over a total of 50 days (Dunlap et al. 1958). The 18,000-L expo- sure room had a revolving fan for mixing the vapor in the room. Vapor was gen- erated by flash vaporization of allyl alcohol using a heat source. Five minutes of TABLE 4-2 Chemical and Physical Properties of Allyl Alcohol Parameter Data Reference Synonyms 2-propen-1-ol; 1-propenol-3-ol; O’Neil et al. 2006 vinyl carbinol CAS registry no. 107-18-6 ACGIH 2001 Chemical formula C3H6O O’Neil et al. 2006 Molecular weight 58.08 O’Neil et al. 2006 Physical state Liquid O’Neil et al. 2006 Color Colorless O’Neil et al. 2006 Melting point -50°C O’Neil et al. 2006 Boiling point 96-97°C O’Neil et al. 2006 Freezing point -129°C HSDB 2013 Flash point 20.9°C NIOSH 2011 Specific gravity (water = 1) 0.8540 at 20/4°C NIOSH 2011; O’Neil et al. 2006 Solubility Miscible with water, alcohol, O’Neil et al. 2006 chloroform, ether, petroleum ether Vapor density (air = 1) 2.0 HSDB 2013 Vapor pressure 25.4 mmHg at 25°C;17 mmHg at 20°C ACGIH 2001; HSDB 2013 Conversion factors in air 1 ppm = 2.42 mg/m3 ACGIH 2001; 1 mg/m3 = 0.413 ppm NIOSH 2011

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Allyl Alcohol 185 vaporization and equilibration were allowed before the volunteers entered the room for the static exposure. Volunteers were exposed to allyl alcohol at 0.78, 6.25, 12.5, or 25.0 ppm; whether these concentrations were calculated or meas- ured was not specified. Volunteers were prepared to describe their reactions by reviewing with them the different subjective sensations associated with a partic- ular level of response, but the subject was not aware of the nature of the materi- al. During the static exposure at 1-min intervals, they graded their ocular and nasal irritation, olfactory recognition, central-nervous-system effects, and pul- monary effects as absent, slight, moderate, severe, or extreme. A summary of the findings is presented in Table 4-3. After each exposure, the eyes of each sub- ject were visually inspected, and physical examination of the chest was made at the end of the day’s run or when the subject noted subjective symptoms. Olfac- tory recognition was noted as at least slight by five of six subjects at the lowest concentration of 0.78 ppm, and became at least moderate at 6.25 ppm in two of six subjects. At 12.5 ppm, nasal irritation of moderate or greater severity was experienced by four of seven volunteers, and all subjects described nasal irrita- tion as moderate or greater at 25.0 ppm. Ocular irritation was slight in one of six and one of seven individuals at 6.25 and 12.5 ppm, respectively, and was mod- erate or greater at 25.0 ppm in all five exposed volunteers. The investigators described the ocular irritation at 25.0 ppm as severe, but it was not clear whether responses varied with repeated exposure. Separate from these tests with volun- teers, Dunlap et al. (1958) described symptoms in workers who were exposed to “moderate” concentrations of allyl alcohol (concentrations not specified). Symp- toms included lacrimation, retrobulbar pain, and blurred vision, which persisted for 24-48 h after exposure ended. No permanent damage to the cornea was re- ported. Ten volunteers were exposed to allyl alcohol at 2 ppm for 1-3 min (Tor- kelson et al. 1959a). Groups of two or three volunteers entered a large exposure chamber once the desired concentration of allyl alcohol was achieved (methods described in Torkelson et al. 1959b). Half of the volunteers reported a distinct odor but no irritation. McCord (1932) commented that workers exposed to allyl alcohol (concentration, duration, and exposure situation not reported) had signs and symptoms of severe irritation of the mucous membranes, including edema, excessive secretions, conjunctivitis, and lacrimation, and that exposure at 5 ppm would produce some irritation. One worker was temporarily blinded by delayed corneal necrosis after exposure to the vapor, although the nature of the exposure was not described (Smyth 1956). The investigators reported that the primary toxic effect following exposure to allyl alcohol vapor is irritation manifested by pulmonary edema and disabling corneal injury. Odor-detection threshold values for allyl alcohol reported by the American Industrial Hygiene Association (AIHA 1989) were 1.4 ppm (3.3 mg/m3) and 2.1 ppm (5 mg/m3). Those values are based on two studies (Katz and Talbert 1930; Dravnieks 1974) judged by AIHA to be acceptable.

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186 Acute Exposure Guideline Levels TABLE 4-3 Summary of Sensory Responses to Ally Alcohol During 5-Minute Exposure Olfactory Recognition Ocular Irritation Nasal Irritation Concentration No. Any Any Any ≥ (ppm) Subjects Responsea ≥ Moderateb Responsea ≥ Moderateb Responsea Moderateb 0.78 6 5 1 0 0 2 0 6.25 6 5 2 1 0 3 1 12.5 7 6 1 1 0 7 4 c 25.0 5 3 1 5 5 5 5 Source: Adapted from Dunlap et al. 1958. a Number of people showing any response. b Number of people with responses greater than “slight.” c Response was graded as severe. 2.2.2. Epidemiologic Studies Epidemiologic studies of human exposure to allyl alcohol were not availa- ble. 2.3. Developmental and Reproductive Toxicity No human data on the developmental and reproductive toxicity of allyl al- cohol were available. 2.4. Genotoxicity No information on the genotoxicity of allyl alcohol in humans was availa- ble. 2.5. Carcinogenicity No information on the potential carcinogenicity of allyl alcohol in humans was available. 2.6. Summary There were no reported cases of human deaths following inhalation expo- sure to allyl alcohol, and no case reports of accidental occupational exposures. Volunteers exposed to allyl alcohol for 5 min reported nasal irritation at 12.5 ppm and severe ocular irritation at 25 ppm. Workers exposed to moderate con- centrations (not specified) were reported to experience lacrimation, retrobulbar pain, and blurred vision. Odor-detection thresholds of 1.4 ppm and 2.1 ppm and an odor-recognition threshold of 0.78 ppm were reported for allyl alcohol.

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Allyl Alcohol 187 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Monkeys One monkey (sex not specified) exposed to allyl alcohol at 1,000 ppm died 4 h into the exposure (McCord 1932). Prior to death, the monkey vomited, had diarrhea, and appeared to be in severe pain. Necropsy revealed subcutane- ous hemorrhage of the abdomen, petechial hemorrhage and inflammation of the intestine, a distended gastrointestinal tract, and hemorrhage of the spleen and kidneys. Inflammation was found in the brain, meninges, and blood vessels, and the lungs had edema with hemorrhagic exudate. 3.1.2. Rats Groups of five male and five female Crl:CD(SD) rats were exposed by whole body inhalation to allyl alcohol vapor at measured concentrations of 0, 51, 220, or 403 ppm (nominal concentrations were 0, 50, 200, or 400 ppm) for 1 h; at 0, 22, 52, or 102 ppm (nominal concentrations were 0, 20, 50, or 100 ppm) for 4 h; or at 0, 10, 21, or 52 ppm (nominal concentrations were 0, 10, 20, or 50 ppm) for 8 h (Kirkpatrick 2008). All animals survived to the end of the study, except for one male rat exposed at 52 ppm for 8 h that died the day after expo- sure. The dead rat had severe ulceration and degeneration of the olfactory epi- thelium, mild hemorrhage and edema in the lungs, moderate to severe erosion of the epithelium in the larynx and trachea, and severe epithelial ulceration in the larynx. Further details are provided in Section 3.2.1. Groups of six male Long-Evans rats were exposed to allyl alcohol at 40- 2,300 ppm (individual concentrations not specified) for 1, 4, or 8 h to determine LC50 values (lethal concentration, 50% lethality) for allyl alcohol, (Dunlap et al. 1958). No mention was made of a concurrent control group. Exposures were conducted in a 19.5-L cylindrical glass chamber, and airflow was set at 8.6-12.9 L/min. Vapor concentrations of allyl alcohol were analyzed by drawing a sample of air through distilled water, adding bromine in acetic acid in the presence of mercapturic acetate as a catalyst, reducing the excess bromine with iodide, and then titrating the iodine with thiosulfate. The analyses showed that concentra- tions of allyl alcohol were 15-25% less than nominal concentrations. Animals were observed for at least 10 days after exposure. The uncorrected 1-, 4-, and 8- h LC50 values were 1,060, 165, and 76 ppm, respectively. Dunlap et al. (1958) conducted studies of different exposure routes with several species (inhalation [rats], intragastric administration [rabbit, mouse, and rat], intraperitoneal injec- tion [mouse and rat], and percutaneous [rabbits]), but did not describe signs of toxicity and pathologic effects separately for the different exposure routes. Therefore, it was unclear whether some signs of toxicity were specifically relat- ed to inhalation exposure or were independent of the route of exposure. General

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188 Acute Exposure Guideline Levels signs of toxicity in rats were lacrimation and tremors, with coma preceding death. Gross necropsy findings in both rats and rabbits (findings not presented separately) included pulmonary edema and congestion, visceral congestion, and discolored liver. Microscopic examination of rats and rabbits showed hepatic damage, including congestion of the periportal sinusoids, periportal necrosis, central pallor, and central necrosis. The kidneys of rats were swollen and discol- ored. A published abstract by Dunlap and Hine (1955) indicates that toxic signs and pathologic changes are not dependent on the route of exposure to allyl alco- hol. The abstract states that allyl alcohol-induced lesions, such as necrosis, hem- orrhage, and discoloration of the liver, discoloration of the kidneys, and conges- tion and hemorrhage of the intestines, did not vary with the route of administration. However, ocular and nasal irritation and profuse lacrimation were specifically noted for test of single 1-h inhalation exposures in rats (con- centrations not specified), from which the 1-h LC50 value of 1,060 ppm was de- rived (also reported in Dunlap et al. 1958). Six Sherman rats (sex not specified) were exposed to allyl alcohol vapor at 1,000 ppm for 1 h, and were observed for 14 days (Smyth and Carpenter 1948). No details about the exposure conditions were provided, exposure concentration was not confirmed by analytic methods, and no controls were used. Four of rats died. In another study by this group (Carpenter et al. 1949), a 4-h exposure to allyl alcohol at 250 ppm killed two of six, three of six, or four of six Sherman rats; no additional information was provided. McCord (1932) exposed rats (strain and sex not specified) to several con- centrations of allyl alcohol vapor for various durations. Six rats exposed at 1,000 ppm died 3 h into an intended 7-h exposure. Necropsy results were not de- scribed, but were reported to be similar to the findings in the monkey (see Sec- tion 3.1.1) and rabbits (see Section 3.1.4). (The primary findings in the monkey and rabbits were hemorrhage in the lungs, intestinal tract, bladder, and kidneys.) Four rats exposed at 200 ppm for 7 h/day died on the first or second day of ex- posure, and necropsy revealed similar findings. Four of five rats exposed at 50 ppm for 7 h/day died after approximately 30 days of exposure (it was inferred from the study description that exposures were conducted 7 days/week until termination). Necropsy information was not provided. No changes were ob- served in any of the control animals (number and treatment of controls not de- scribed). Union Carbide and Carbon Corporation (1951) tabulated the mortality re- sults of inhalation toxicity studies of allyl alcohol in rats. No information about controls, method of exposure, strain or sex of rats, analytic verification of con- centrations, or period of observation was provided. The mortality results of the studies are presented in Table 4-4. In a series of three experiments, groups of 10 Long-Evans male rats were exposed to allyl alcohol at 0, 1, 2, 5, 20, 40, 60, 100, or 150 ppm for 7 h/day, 5 days/week for a total of 60 exposures (Dunlap et al. 1958). Analyses of the va- por concentrations at 40 ppm and greater were within 10% of nominal concen- trations (information on the measured concentrations at the lower concentrations

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Allyl Alcohol 189 was not provided). Animals were observed daily and weighed weekly. After 90 days, the survivors were killed and necropsies were performed. Liver, kidneys, and lungs from all animals were weighed and examined microscopically. The thyroid, heart, thymus, pancreas, spleen, adrenal glands, testes, bladder, and brain were removed from every other animal and examined microscopically. Exposure to allyl alcohol at 1, 2, 5, and 20 ppm failed to produce any clinical signs of toxicity or abnormal gross or microscopic effects, although the animals in the 20-ppm group experienced a significant reduction in body weight gain. Rats exposed at 150 ppm exhibited gasping, severe depression, nasal discharge, and ocular irritation. All of the rats in the 150-ppm group died; four died during the first exposure, two after the first exposure, two during the second exposure, and two by the tenth exposure. The two rats surviving until the tenth exposure were lethargic, had red-rimmed eyes, and lost a third of their original body weight. Necropsy findings included hemorrhagic livers, pale and spotted lungs, and bloated gastrointestinal tracts. Slight congestion of the liver and lungs were found during microscopic evaluation. Rats exposed to allyl alcohol at 100, 60, or 40 ppm had similar but less intense signs, lesions, and microscopic findings. Six of the 10 rats exposed at 100 ppm died by the forty-sixth exposure, and the re- maining rats were accidentally killed on exposure day 56. Gasping and muzzle rubbing occurred during the first few exposures at 60 ppm but disappeared thereafter, and persistent ocular discharge was observed throughout the experi- ment. The 60-ppm group also had statistically increased hepatic and renal weights, and one death occurred (day not specified). All signs of irritation in animals exposed at 40 ppm resolved after the first few exposures, but pulmonary weight was statistically increased at necropsy. A toxicity data sheet by the Shell Chemical Corporation (1957) appears to include some of the same data that was published by Dunlap et al. (1958). Rats were exposed to allyl alcohol for 8 h at 1, 5, 10, 20, 40, 60, 100, or 150 ppm for a total of 60 exposures over 90 days (Shell Chemical Corporation 1957). Infor- mation on the strain, sex, and number of rats was not specified. No adverse ef- fects were found in animals exposed at 20 ppm or less. Decreased growth and mild to moderate pulmonary congestion were found in the 40-ppm group. Ani- mals in the 60-ppm group developed pulmonary congestion and increased renal and pulmonary weights, and one of 10 rats died. All animals exposed at 100 ppm died after 32 exposures and rats exposed at 150 ppm died after two expo- sures. TABLE 4-4 Summary of Mortality Data in Rats Exposed to Allyl Alcohol Concentration (ppm) Time (h) Deaths 200 1 0/10 1,000 0.5 1/6 1,000 1 4/6 1,000 2 6/6 Source: Union Carbide and Carbon Corporation 1951.

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190 Acute Exposure Guideline Levels 3.1.3. Mice Union Carbide and Carbon Corporation (1951) tabulated the mortality re- sults of inhalation toxicity studies of allyl alcohol in mice. No information about controls, method of exposure, strain or sex of mice, analytic verification of con- centration, or the period of observation was provided. The mortality results of the studies are presented in Table 4-5. Groups of 10 mice (strain and sex not specified) exposed to allyl alcohol between 2,450 and 26,000 ppm died within 165 and 24 min, respectively (Shell Chemical Corporation 1957). All animals developed spastic paralysis of the ex- tremities, particularly of the hindlimbs, before dying convulsively. Necropsy results included irritation and inflammation of the respiratory tract and irritation and congestion of the liver, kidneys, and spleen. All mice exposed at 22,000 ppm for 10 min died (no other details provided). No deaths resulted when mice were exposed at 12,200 ppm for 10 min, but all died when exposed for another 10 min period (period of observation and time between exposures not specified). When mice were exposed daily to allyl alcohol at 2,450 ppm for 10 min, 10% of the animals died within three exposures and 30% were dead after nine expo- sures. Necropsy revealed irritation and inflammation of the respiratory tract and congestion of the gastrointestinal tract. Mice repeatedly exposed to allyl alcohol at 2,450 ppm developed severe ocular and nasal irritation. 3.1.4. Rabbits When two rabbits (strain and sex not specified) were exposed to allyl al- cohol at 1,000 ppm, one died 3.5 h into the exposure and the other died 4.25 h into the exposure (McCord 1932). The rabbits had rales, and fluid dripped from their noses and mouths. Pulmonary hemorrhage, hemorrhage and inflammation of the intestinal tract, bladder, and kidneys, and gaseous distention of the gastro- intestinal tract were found in both rabbits at necropsy. One rabbit also had hem- orrhaging of the eyes, opaque sclerae, and inflamed genitalia. In a second exper- iment, three rabbits were exposed to allyl alcohol at 200 ppm for 7 h/day. TABLE 4-5 Summary of Mortality Data in Mice Exposed to Allyl Alcohol Concentration (ppm) Time (h) Deaths 200 1 0/10 500 0.5 0/10 500 1 4/10 1,000 1 6/10 1,000 2 8/10 1,000 4 10/10 Source: Union Carbide and Carbon Corporation 1951.

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Allyl Alcohol 225 APPENDIX B DERIVATION OF AEGL VALUES FOR ALLYL ALCOHOL Derivation of AEGL-1 Values Key study: Nielsen, G.D., J.C. Bakbo, and E. Holst. 1984. Sensory irritation and pulmonary irritation by airborne allyl acetate, allyl alcohol, and allyl ether compared to acrolein. Acta Pharmacol. Toxicol. 54(4):292-298. Toxicity end point: RD10 = 27 ppm (estimated threshold for irritation) Time scaling: Not applied Uncertainty factors: 3, because irritant effects are not expected to vary greatly between species or individuals Calculation: 0.27 ppm ÷ 3 = 0.090 ppm (applied to all AEGL-1 durations) Derivation of AEGL-2 Values Key study: Kirkpatrick, D.T. 2008. Acute Inhalation Toxicity Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-hour Exposure Durations). Study Number WIL-14068; WIL Research Laboratories, LLC., Ashland, OH. Toxicity end point: No effect level for disabling effects: 51 ppm for 1 h, 22 ppm for 4 h, and 10 ppm for 8 h Time scaling: Performed for the 10- and 30-min values. Cn × t = k, where n = 0.95 (derived from rat lethality data; see Appendix B) C0.95 × t = k (51 ppm)0.95 × 1 h = 42 ppm-h Uncertainty Factors: 3 for interspecies differences 10 for intraspecies variability Calculations: 10-min AEGL-2: C0.95 × 0.0167 h = 42 ppm-h C0.95 = 251 ppm C = 336 ppm 336 ÷ 30 = 11 ppm

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226 Acute Exposure Guideline Levels 30-min AEGL-2: C0.95 × 0.5 h = 42 ppm-h C0.95 = 84 ppm C = 106 ppm 106 ÷ 30 = 3.5 ppm 1-h AEGL-2: 51 ppm ÷ 30 = 1.7 ppm 4-h AEGL-2: 22 ppm ÷ 30 = 0.73 8-h AEGL-2: 10 ppm ÷ 30 = 0.33 Derivation of AEGL-3 Values Key studies: Kirkpatrick, D.T. 2008. Acute Inhalation Toxicity Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-hour Exposure Durations). Study Number WIL-14068; WIL Research Laboratories, LLC., Ashland, OH. McCord, C.P. 1932. The toxicity of allyl alcohol. J. Am. Med. Assoc. 98(26):2269-2270. Smyth, H.F., and C.P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30(1):63-68. Union Carbide and Carbon Corporation. 1951. Initial submission: Letter from DuPont Chem Regarding a Letter About Toxicity Studies with Allyl Alcohol, Union Carbide and Carbon Corporation, New York, January 29, 1951. Subbmited by DuPont, Wilmington, DE to EPA with cover letter dated October 27, 1992. EPA Document No. 88-920009857. Microfische No. OTS0571508. Toxicity end point: Calculated LC01 values: 2,600 ppm for 10 min, 820 ppm for 30 min, 400 ppm for 1 h, 93 ppm for 4 h, and 45 ppm for 8 h. Time scaling: A point of departure for each AEGL exposure duration was calculated using ten Berge program; the program calculated an n value 0.95 (see Appendix B). Uncertainty factors: 3 for interspecies differences 10 for intraspecies variability

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Allyl Alcohol 227 Calculations: 10-min AEGL-3: 2,600 ppm ÷ 30 = 87 ppm 30-min AEGL-3: 820 ppm ÷ 30 = 27 ppm 1-h AEGL-3: 400 ppm ÷ 30 = 13 ppm 4-h AEGL-3: 93 ppm ÷ 30 = 3.1 ppm 8-h AEGL-3: 45 ppm ÷ 30 = 1.5 ppm

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228 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR ALLY ALCOHOL Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.090 ppm 0.090 ppm 0.090 ppm 0.090 ppm 0.090 ppm (0.22 mg/m3) (0.22 mg/m3) (0.22 mg/m3) (0.22 mg/m3) (0.22 mg/m3) Key reference: Nielsen, G.D., J.C. Bakbo, and E. Holst. 1984. Sensory irritation and pulmonary irritation by airborne allyl acetate, allyl alcohol, and allyl ether compared to acrolein. Acta Pharmacol. Toxicol. 54(4):292-298. Test species/Strain/Sex/Number: Mice, Ssc:CF-1; 4 males per group Exposure route/Concentrations/Durations: Inhalation (head only), 0.42, 2.00, 4.55, or 18.10 ppm for 30 min Effects: Reduction in respiratory rate, RD50 = 3.9 ppm; RD10 = 0.27 ppm End point/Concentration/Rationale: Estimate of irritation threshold, RD10 = 0.27 ppm Uncertainty factors/Rationale: Total uncertainty factor: 3, irritant effects are not expected to vary greatly between species or individuals. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: None Data adequacy: Data are adequate to derive AEGL-1 values. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 11 ppm 3.5 ppm 1.7 ppm 0.73 ppm 0.33 ppm (27 mg/m3) (8.5 mg/m3) (4.1 mg/m3) (1.8 mg/m3) (0.80 mg/m3) Key reference: Kirkpatrick, D.T. 2008. Acute Inhalation Toxicity Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-Hour Exposure Durations). Study Number WIL-14068; WIL Research Laboratories, LLC., Ashland, OH. Test species/Strain/Sex/Number: Rats, Crl:CD(DS), 5 males and 5 females per group Exposure route/Concentrations/Durations: Inhalation; 51, 220, or 403 ppm for 1 h, 22, 52, or 102 ppm for 4 h, and 10, 21, or 52 ppm for 8 h. Effects: Duration Concentration Effects 1h 51 ppm Alcohol flush and nasal irritation. 220 ppm Same as at 51 ppm, plus decreased response to stimulus.

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Allyl Alcohol 229 Duration Concentration Effects 403 ppm Same as at 220 ppm, plus gasping. 4h 22 ppm Clear red material around mouth. 52 ppm Same as at 22 ppm, plus nasal irritation, gasping, and reduce response to stimulus. 102 ppm Same as at 52 ppm. 8h 10 ppm Alcohol flush and nasal irritation. 21 ppm Same as at 10 ppm, plus gasping and reduced response to stimulus. 52 ppm Same as at 21 ppm. End point/Concentration/Rationale: No-effect level for AEGL-2 effects; 51 ppm for 1 h, 22 ppm for 4 h, and 10 ppm for 8 h. Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 3, similar 1-h no-effect levels for lethality reported for rats (200-423 ppm), mice (200 ppm), and rabbits (200 ppm). Intraspecies: 10, unknown if effects of allyl alcohol are due to parent compound, metabolites, or both. Also, accounts for genetic polymorphisms for aldehyde dehydrogenase in humans. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Performed for the 10- and 30-min values. Cn × t = k, where n = 0.95 (derived from rat lethality data; see Appendix B). Data adequacy: Data sufficient to derive AELG-2 values. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 87 ppm 27 ppm 13 ppm 3.1 ppm 1.5 ppm (210 mg/m3) (65 mg/m3) (31 mg/m3) (7.5 mg/m3) (3.6 mg/m3) Key references: Kirkpatrick, D.T. 2008. Acute Inhalation Toxicity Study of Allyl Alcohol in Albino Rats (with 1-, 4-, and 8-Hour Exposure Durations). Study Number WIL-14068; WIL Research Laboratories, LLC, Ashland, OH. McCord, C.P. 1932. The toxicity of allyl alcohol. J. Am. Med. Assoc. 98(26):2269-2270. Smyth, H.F., and C.P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30(1):63-68. Union Carbide and Carbon Corporation. 1951. Initial submission: Letter from DuPont Chem Regarding a Letter About Toxicity Studies with Allyl Alcohol, Union Carbide and Carbon Corporation, New York, January 29, 1951. Subbmited by DuPont, Wilmington, DE to EPA with cover letter dated October 27, 1992. EPA Document No. 88-920009857. Microfische No. OTS0571508. Test species/Strain/Sex/Number: Rat (see table below for number of animals for each study) (Continued)

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230 Acute Exposure Guideline Levels AEGL-3 VALUES Continued Exposure route/Concentrations/Durations: Inhalation, 10-1,000 ppm for 1-8 h Effects: Concentration (ppm) Minutes Exposed Responded Reference 51 60 10 0 Kirkpatrick 2008 220 60 10 0 Kirkpatrick 2008 403 60 10 0 Kirkpatrick 2008 22 240 10 0 Kirkpatrick 2008 52 240 10 0 Kirkpatrick 2008 102 240 10 0 Kirkpatrick 2008 10 480 10 0 Kirkpatrick 2008 21 480 10 0 Kirkpatrick 2008 52 480 10 1 Kirkpatrick 2008 200 60 10 0 Union Carbide and Carbon Corporation 1951 1,000 30 6 1 Union Carbide and Carbon Corporation 1951 1,000 60 6 4 Union Carbide and Carbon Corporation 1951 1,000 120 6 6 Union Carbide and Carbon Corporation 1951 1,000 60 6 4 Smyth and Carpenter 1948 1,000 180 6 6 McCord 1932 638 60 6 0 Kirkpatrick 2008 423 60 6 0 Kirkpatrick 2008 114 240 6 0 Kirkpatrick 2008 52 480 6 0 Kirkpatrick 2008 End point/Concentration/Rationale: Estimated lethality thresholds, LC01s of 2,600 ppm for 10 min, 820 ppm for 30 min, 400 ppm for 1 h, 93 ppm for 4 h, and 45 ppm for 8 h. LC01 values calculated using log-probit model of ten Berge (see Appendix B). Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 3, similar 1-h no-effect levels for lethality reported for rats (200-423 ppm), mice (200 ppm), and rabbits (200 ppm). Intraspecies: 10, unknown if effects of allyl alcohol are due to parent compound, metabolites, or both. Also, accounts for genetic polymorphisms for aldehyde dehydrogenase in humans. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: A point of departure for each AEGL exposure duration was calculated using ten Berge program; program calculated an n value 0.95 (see Appendix B). Data adequacy: Data were adequate to derive AEGL-3 values. The most recent study with measured concentrations of allyl alcohol reported minimal mortality; therefore, mortality data from earlier studies with less than adequate analytic techniques were included.

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Allyl Alcohol 231 APPENDIX D CATEGORY PLOT FOR ALLYL ALCOHOL A useful way to evaluate AEGL values in the context of empirical data is presented in Figure D-1. For this plot, toxic responses were placed into severity categories. The severity categories fit into definitions of the AEGL health effects of no effects, discomfort, disabling, some lethality (an experimental concentra- tion at which some of the animals died and some did not), and lethal. The effects that place an experimental result into a particular category vary according to the spectrum of data available on a specific chemical and the effects from exposure to that chemical. The doses often span a several orders of magnitude, especially when human data are available. Therefore, the concentration in the plot is placed on a log scale. The graph in Figure D-1 plots the AEGL values for allyl alcohol and acute human and animal toxicity data for the chemical. FIGURE D-1 Category plot of toxicity data and AEGL values for allyl alcohol.

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232 TABLE D-1 Data Used in Category Plot for Allyl Alcohol Source Species Sex No. of Exposures ppm Minutes Category Comments AEGL-1 0.090 10 AEGL AEGL-1 0.090 30 AEGL AEGL-1 0.090 60 AEGL AEGL-1 0.090 240 AEGL AEGL-1 0.090 480 AEGL AEGL-2 11 10 AEGL AEGL-2 3.5 30 AEGL AEGL-2 1.7 60 AEGL AEGL-2 0.73 240 AEGL AEGL-2 0.33 480 AEGL AEGL-3 87 10 AEGL AEGL-3 27 30 AEGL AEGL-3 13 60 AEGL AEGL-3 3.1 240 AEGL AEGL-3 1.5 480 AEGL Dunlap et al. 1958 Human 0.78 5 0 Dunlap et al.1958 Human 6 5 1 Dunlap et al. 1958 Human 12.5 5 1 Dunlap et al. 1958 Human 25 5 2 Severe ocular irritation Dunlap et al. 1958 Rat Both 1 60.0 420 SL Dunlap et al. 1958 Rat Both 1 100.0 420 SL

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Dunlap et al. 1958 Rat Both 1 150.0 420 3 Dunlap et al. 1958 Rat 1 20.0 420 0 Dunlap et al. 1958 Rat 1 1.0 420 0 Dunlap et al. 1958 Rat 1 2 420 0 Dunlap et al. 1958 Rat 1 5 420 0 Kirkpatrick 2008 Rat Both 1 51 60 0 Kirkpatrick 2008 Rat Both 1 423 60 1 Kirkpatrick 2008 Rat Both 1 220 60 2 Kirkpatrick 2008 Rat Both 1 638 60 1 Kirkpatrick 2008 Rat Both 1 114.0 240 1 Kirkpatrick 2008 Rat Both 1 22 240 0 Kirkpatrick 2008 Rat Both 1 52.0 480 1 Kirkpatrick 2008 Rat Both 1 52.0 240 1 Kirkpatrick 2008 Rat Both 1 102.0 240 1 Kirkpatrick 2008 Rat Both 1 10.0 480 0 Kirkpatrick 2008 Rat Both 1 21.0 480 1 Kirkpatrick 2008 Rat Both 1 52.0 480 SL Mortality (1/10) McCord 1932 Monkey 1 1,000 240 3 Mortality (1/1) McCord 1932 Rat 1 1,000 180 3 Mortality (6/6) McCord 1932 Rat 1 420 Mortality (4/4) McCord 1932 Rat 1 50.0 420 SL Mortality (4/5) (Continued) 233

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234 TABLE D-1 Continued Source Species Sex No. of Exposures ppm Minutes Category Comments McCord 1932 Rat Both 1 420 Mortality (4/4) Shell Chemical Corp. 1957 Mouse 1 22,000 10 3 Mortality (10/10) Shell Chemical Corp. 1957 Mouse 1 12,200 20 3 Mortality (10/10) Smyth and Carpenter 1948 Rat 1 1,000 60 SL Mortality (4/6) Torkelson et al. 1959a,b Dog Both 1 2.0 420 0 Torkelson et al. 1959a,b Guinea Pig Both 1 7.0 420 0 Torkelson et al. 1959a,b Guinea Pig Both 1 2.0 420 0 Torkelson et al. 1959a,b Rabbit 1 200.0 420 2 Torkelson et al. 1959a,b Rabbit Both 1 7.0 420 0 Torkelson et al. 1959a,b Rabbit Both 1 2.0 420 0 Torkelson et al. 1959a,b Rat Both 1 7.0 420 0 Torkelson et al. 1959a,b Rat Both 1 2.0 420 0 Union Carbide and Carbon Mouse 1 200 60 0 Corporation 1951 Union Carbide and Carbon Mouse 1 500 30 2 Corporation 1951 Union Carbide and Carbon Mouse 1 500 60 SL Mortality (4/10) Corporation 1951 Union Carbide and Carbon Mouse 1 1,000 60 SL Mortality (6/10) Corporation 1951 Union Carbide and Carbon Mouse 1 1,000 120 SL Mortality (8/10) Corporation 1951

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Union Carbide and Carbon Mouse 1 1,000.0 240 3 Mortality (10/10) Corporation 1951 Union Carbide and Carbon Rabbit Both 1 500 120 2 Corporation 1951 Union Carbide and Carbon Rabbits 1 500.0 240 3 Mortality (4/4) Corporation 1951 Union Carbide and Carbon Rat 1 1,000 30 SL Mortality (1/6) Corporation 1951 Union Carbide and Carbon Rat 1 1,000 60 SL Mortality (4/6) Corporation 1951 Union Carbide and Carbon Rat 1 1,000 120 3 Mortality (6/6) Corporation 1951 For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal 235