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6 Propargyl 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 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 Robert Young (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager George Cushmac (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 neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee 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). 176

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Propargyl Alcohol 177 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 Propargyl alcohol is a moderately volatile, three-carbon acetylenic alcohol with a geranium-like odor. It is used as a chemical intermediate, solvent stabi- lizer, soil fumigant, and corrosion inhibitor. Annual production in the United States has been estimated at 0.5 to 2.8 million pounds. No information on human exposure to propargyl alcohol is available. On the basis of animal data, the chemical is likely to be irritating to the eyes and respiratory tract. Toxicity data on propargyl alcohol are available from studies of rats, mice, guinea pigs, rabbits, and cats. The studies involved acute (1-2 h) and longer- term exposures (9 days to 13 weeks). Lethality data included estimated or tested concentrations associated with 50% lethality of approximately 1,000-1,200 ppm for rats and 1,300 ppm for cats after 1-h exposures, and 850 ppm for rats and 875 ppm in mice after 2-h exposures. In longer-term studies, repeated exposure to propargyl alcohol at concentrations up to 88 ppm for 14 days or 64 ppm for 13 weeks were not lethal but resulted in notable histopathologic changes in the olfactory and respiratory epithelium of rats and mice. No reproductive toxicity, developmental toxicity, or carcinogenicity data on inhalation exposure to pro- pargyl alcohol are available. Genotoxicity findings are equivocal. Propargyl alcohol is rapidly metabolized to propargyl aldehyde and various conjugation products; excretion is primarily via the urine. AEGL-1 values were based on a concentration of 25.3 ppm, which was a no-effect level for histopathologic changes in the respiratory tract of mice ex-

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178 Acute Exposure Guideline Levels posed to propargyl alcohol for 6 h (Zissu 1995). That concentration was consid- ered an appropriate point of departure because a 7-h exposure of rats to propar- gyl alcohol at 80 ppm (the first of 59 exposures) produced signs of ocular irrita- tion and lethargy to which the test animals subsequently adapted (Dow Chemical Co. 1964). Toxicologic response to propargyl alcohol appeared to be similar qualitatively among species tested, and individual responses are not ex- pected to vary more than three-fold for simple direct-contact irritants. Therefore, an interspecies uncertainty factor of 3 and an intraspecies uncertainty factor of 3 were applied (total uncertainty factor of 10). Because slight direct-contact irrita- tion is not expected to vary markedly with exposure duration, the same value was used for all AEGL-1 exposure durations. AEGL-2 values were based on a point of departure of 88 ppm, a concen- tration that produced severe histologic alterations in the olfactory and respiratory epithelium of mice exposed to propargyl alcohol for 6 h/day for 4, 9, or 14 days. The point of departure is supported by observations of ocular irritation and leth- argy in rats after the first of 59 exposures to propargyl alcohol at 80 ppm for 7 h (adaptation occurred during subsequent exposures) (Dow Chemical Co. 1964). An uncertainty factor of 3 was applied to account for interspecies differences because the toxic effects of propargyl alcohol do not appear to vary greatly be- tween species. Because histopathologic lesions from propargyl alcohol are likely the result of direct-contact irritation, an uncertainty factor of 3 was applied to account for intraindividual variability. Time scaling from the 6-h experimental exposure duration to AEGL-specific exposure durations was performed using the equation Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Data on propargyl alcohol were inadequate for deriving an empiri- cal value for n, so default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used. However, because of uncertainties associated with extrapolating a 6-h exposure to a 10-min value, the 30-min AEGL-2 value was adopted for the 10-min value (NRC 2001). AEGL-3 values were based on mouse lethality data reported by Stasenko- va and Kochetkova (1966). A BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) of 573 ppm (2-h exposure) was the point of departure. That BMCL05 is consistent with the range of 1-h lethal concentrations of 1,040-1,200 ppm reported for rats (Vernot et al. 1977). Further, BASF (1965) reported no lethality in two rabbits or six guinea pigs exposed to propargyl alco- hol at 1,300 ppm for 1 h, but one of two cats died from the same exposure. The available data support an interspecies uncertainty factor of 3. Animal data sug- gest that olfactory and respiratory-tract epithelium are the primary targets of propargyl alcohol and that damage to these tissues is likely instrumental in deaths after a single acute exposure. Studies of repeated exposures to propargyl alcohol (about 90 days) provided evidence of renal and hepatic toxicity, but the data do not support the contention that such systemic toxicity would follow a single acute exposure. Therefore, an intraspecies uncertainty factor of 3 was used. Time scaling was performed using the same method described for the AEGL-2 values.

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Propargyl Alcohol 179 AEGL values for propargyl alcohol are summarized in the Table 6-1. 1. INTRODUCTION Propargyl alcohol is a moderately volatile three-carbon acetylenic alcohol with a geranium-like odor. It is used as a chemical intermediate, solvent stabi- lizer, soil fumigant, and corrosion inhibitor (Bevan 2001). Annual production in the United States has been estimated at 0.5 to 2.8 million pounds (J. Walker, EPA, Washington, DC, personal commun., April 26, and June 8, 1995). Selected chemical and physical properties for propargyl alcohol isomers are presented in Table 6-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No data regarding lethality in humans following inhalation exposure to propargyl alcohol were available. 2.2. Nonlethal Toxicity Propargyl alcohol is reportedly irritating to the eyes, skin, and respiratory tract (Bevan 2001). However, definitive concentration-response data in humans are unavailable. TABLE 6-1 AEGL Values for Propargyl Alcohol End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 2.5 ppm 2.5 ppm 2.5 ppm 2.5 ppm 2.5 ppm No-observed- (nondisabling) (5.7 (5.7 (5.7 (5.7 (5.7 adverse-effect level mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) for histopathologic changes in respiratory tract of mice (Zissu 1995) AEGL-2 20 ppm 20 ppm 16 ppm 10 ppm 6.6 ppm Lesions in olfactory (disabling) (46 (46 37 23 15 and respiratory mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) epithelium (Zissu 1995) AEGL-3 130 ppm 91 ppm 72 ppm 29 ppm 14 ppm Estimated lethality (lethal) (300 (210 (160 (66 (32 threshold in mice mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Stasenkova and Kochetkova 1966)

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180 Acute Exposure Guideline Levels TABLE 6-2 Chemical and Physical Data for Propargyl Alcohol Parameter Value Reference Synonyms 2-Propyn-l-ol; acetylene carbinol; O’Neil et al. 2006; propiolic alcohol; 2-propynol; 2- ACGIH 2007 propynyl alcohol; 1-propyn-3-ol CAS registry no. 107-19-7 O’Neil et al. 2006 Chemical formula C3H4O O’Neil et al. 2006 Molecular weight 56.06 O’Neil et al. 2006 Physical state Colorless to straw-colored liquid NIOSH 2011 Freezing point -52 to -48°C O’Neil et al. 2006 Boiling point 114-115°C O’Neil et al. 2006; ACGIH 2007 Density/specific gravity 0.97 at 20°C NIOSH 2011 Solubility in water Miscible O’Neil et al. 2006 Vapor pressure 12 mm Hg at 20°C NIOSH 2011 Saturated vapor pressure 15,800 ppm at 20°C Calculated 3 Conversion factors in air 1 ppm = 2.29 mg/m NIOSH 2011 1 mg/m3 = 0.437 ppm 2.3. Developmental and Reproductive Effects No human developmental or reproductive toxicity data on propargyl alco- hol were available. 2.4. Genotoxicity No human genotoxicity data on propargyl alcohol were available. 2.5. Carcinogenicity No human data on the carcinogenic potential of propargyl alcohol were available. 2.6. Summary No definitive information on the effects of propargyl alcohol in humans is available.

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Propargyl Alcohol 181 3. ANIMAL TOXICITY DATA 3.1. Lethality 3.1.1. Rats All rats (groups of three) exposed to saturated atmospheres (about16,000 ppm) of propargyl alcohol for 0.2-2.0 h died (Dow Chemical Co. 1953). Time to death was inversely proportional to exposure duration; death occurred within 2 days from a 0.2-h exposure, within 2 h for a 0.5-h exposure, and within 2 h for a 2.0-h exposure. Two of three rats died after a 0.1-h exposure to a saturated at- mosphere; deaths occurred within 4 days and the surviving rat recovered over 2 weeks. No further details of the experiment were provided. BASF (1963) exposed rats (strain and gender not specified) to “vapor- enriched atmospheres” (likely a saturated propargyl alcohol vapor at about 16,000 ppm). Six of 12 rats died after a 3-min exposure, six of six rats died after a 10-min exposure, and six of six died after either a 1-h or 3-h exposure. Re- sponses included mucous membrane irritation, pallor of paws and ears, and dyspnea. BASF (1965) conducted an acute toxicity study of propargyl alcohol in multiple species. Ten rats were exposed for 1 h to propargyl alcohol at approxi- mately 1,300 ppm (3 mg/L, purity not specified) in a closed 400-L chamber. No signs of toxicity were observed during exposure. One rat died after 3 days. Gross pathologic examination of the rat revealed evidence of liver toxicity. A 5-day study was also conducted using one cat, one rabbits, four guinea pigs, 10 rats, and 10 mice exposed to propargyl alcohol at about 1,300 ppm for 1 h/day (BASF 1965). Similar to the single-exposure study, none of the rabbits or guinea pigs died but the cat died after 2 days, four rats after 3-4 days, and seven mice after 23 days. Gross pathologic findings in these animals revealed liver damage. BASF (1965) also provided a brief description of a longer-term study, in which 30 rats (12 males, 18 females) were exposed to propargyl alcohol at 100 ppm (analytic concentration 90 ppm) for 6 h/day, 5 days/week, for up to a total of 75 exposures, depending on the specific treatment group. Seventeen rats died during the later stages of the study. Results of clinical chemistry test and gross pathologic examinations showed hepatic and renal damage in most of the test animals. Vernot et al. (1977) reported 1-h LC50 values for propargyl alcohol of 1,200 ppm (1,180-1,220 ppm) and 1,040 ppm (970-1,120 ppm) for male and female Sprague Dawley rats, respectively. Groups of five rats were exposed to the test article in bell jars or large desiccators. LC50 values were determined by probit analysis (method of Finney 1971). No additional details were provided in the study report. Hazelton Laboratories America, Inc. (1989) conducted limit tests under Good Laboratory Practices with 10 male and 10 female Sprague-Dawley rats

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182 Acute Exposure Guideline Levels exposed to propargyl alcohol at 1,490 ± 159.8 ppm (time-weighted-average ex- posure) for 1 h. Rats were exposed in a 100-L plexiglass dynamic-flow chamber (19.2 L/min). Vapor was generated by passing filtered air through bubblers con- taining the propargyl alcohol, and its concentration was determined by infrared analysis (MIRAN assay). Rats were observed every 15 min during exposure. Physical examinations were performed before, immediately after, and 1 h after exposure, and daily thereafter. Treated animals exhibited hunched posture, rough hair coat, listlessness, low body temperature, prostration, and death. All rats were dead 3 days after exposure. Necropsy findings were reported to be indicative of post-mortem changes and did not reveal changes directly attributed to the test article. Kennedy and Graepel (1991) reported a 2-h LC50 of 850 ppm for propar- gyl alcohol in a study that compared oral and inhalation acute toxicity data for rats. In their overall assessment of the acute toxicity of 108 chemicals, propargyl alcohol was classified as moderately toxic (LC50 range of 100-1,000 ppm). No details of experimental methods were provided in the report. 3.1.2. Mice Three of 10 mice died 1 day after being exposed to propargyl alcohol at 3,000 ppm for 1 h (BASF 1965). Necropsy of the mice revealed signs of mu- cous-membrane and colon irritation. Surviving mice examined 7 days after ex- posure had no remarkable signs of toxicity. A longer-term exposure study was also conducted, in which 30 male and 30 female mice were exposed to propargy alcohol at 100 ppm (analytic concen- tration 90 ppm) for 6 h/day, 5 days/week, for up to a total of 75 exposures, de- pending on the specific treatment group (BASF 1965). Results of clinical chem- istry tests and gross pathologic examinations suggested both hepatic and renal damage, although the hepatic damage appeared to be reversible. In a multiple species study by BASF (1965), 10 mice were exposed for 1 h to propargyl alcohol at approximately 1,300 ppm (3 mg/L, purity not specified) in a closed 400-L chamber. No signs of toxicity during the exposure were ob- served. Three of 10 mice died after 1 day. Gross pathologic examination of ani- mals that died revealed evidence of hepatic toxicity. Lethal effects of propargyl alcohol in mice were also reported by Stasen- kova and Kochetkova (1966). Exposure of rats to propargyl alcohol for 2 h at 500, 1,500, 2,000, or 3,500 mg/m3 (220, 655, 875, and 1,500 ppm) resulted in mortality incidences of 1/20, 1/20, 10/20, and 20/20, respectively. 3.1.3. Cats In an experiment reported by BASF (1965), one of two cats died after a 1- h exposure to propargyl alcohol at 3,000 mg/m3 (1,300 ppm). The time of death was not specified, but a 14-day observation period was reported. The cat was

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Propargyl Alcohol 183 described as lethargic, without appetite, and vomiting before death. Mucous membrane irritation, presence of urobilinogen and protein in the urine, and in- creased serum aminotransferase activity were reported (but it was unclear whether the effects were found in one or both animals). In a longer-term exposure study, three cats were exposed to propargyl al- cohol at 100 ppm (analytic concentration 90 ppm) for 6 h/day, 5 days/week (BASF 1965). The cats died after 29, 32, and 43 exposures. 3.1.4. Rabbits BASF (1965) briefly described a longer-term exposure study, in which three rabbits were exposed to propargyl alcohol at 100 ppm (analytic concentra- tion 90 ppm) for 6 h/day, 5 days/week, for up to a total of 75 exposures. One rabbit died after 45 exposures. Results of clinical chemistry tests and gross path- ologic examinations showed both hepatic and renal damage in most of the test animals. 3.1.5. Summary of Animal Lethality Data Lethality data for propargyl alcohol in various laboratory species are summarized in Table 6-3. TABLE 6-3 Lethality of Inhaled Propargyl Alcohol in Laboratory Species Exposure Exposure Species Duration (min) Concentration (ppm) Lethality Reference Rat (males) 60 1,200 LC50a Vernot et al. 1977 Rat (females) 60 1,040 LC50a Rat 60 1,490 10/10 Hazelton Laboratories America Inc. 1989 Rat 120 850 LC50b Kennedy and Graepel 1991 Mouse 60 3,000 3/10 BASF 1965 Mouse 120 220 1/20 Stasenkova and 655 1/20 Kochetkova 1996 875 10/20 1,500 20/20 Cat 60 1,300 1/2 BASF 1965 a Five male and five females per exposure group. b No experimental details.

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184 Acute Exposure Guideline Levels 3.2. Nonlethal Toxicity 3.2.1. Rats Groups of six male and six female rats (strain not specified) were exposed to propargyl alcohol at a nominal concentration of 100 ppm (80 ppm by infrared analysis) in 160-L glass chambers (Dow Chemical Co. 1964). An additional six male and six female rats were maintained as unexposed controls. Exposure was for 7 h/day, 5 days/week, for 89 days (59 exposures). Although signs of ocular irritation and lethargy were observed during the first exposure, rats reportedly adapted and exhibited no additional responses throughout the remainder of the experiment. Gross necropsy findings consisted of enlarged livers in both sexes (females more so) with microscopic correlates indicative of degenerative chang- es (focal centrilobular necrosis, hydropic degeneration with cellular infiltration, and midzonal fatty metamorphosis). Severity of hepatic lesions ranged from mild to severe. Slight pneumonitis and mild degenerative changes in the kidneys were also noted. Serum enzyme activity (serum glutamic pyruvic transaminase and alkaline phosphatase) was slightly elevated. Hematologic changes (hemato- crit, erythrocytes, serum urea nitrogen, hemoglobin concentration, and differen- tial counts) were normal or only slightly altered. Bone marrow smears were normal. BASF (1992a) conducted a 2-week study (OECD guideline 421) in which male and female Wistar rats (five per group) were exposed to propargyl alcohol (99.4% purity) at nominal concentrations of 0, 10, 50, or 200 ppm (analytic con- centrations 0, 9.8, 50.4, and 199 ppm) for 6 h/day, 5 days/week. No clinical signs were observed in the control, 10-ppm, or 50-ppm groups. At the highest concentration, rats exhibited irregular breathing, lethargy, and nasal discharge during exposure (also in between exposures later in the study period). One fe- male rat in the 200-ppm group died and the surviving rats exhibited decreased body weight gain and elevated serum alanine aminotransferase and serum alka- line phosphatase. Histopathologic findings included metaplasia of the olfactory mucosa (50 and 200 ppm) and hepatocellular hypertrophy, parenchymal single- cell necrosis, and cytoplasmic granulation (200 ppm). These findings were char- acterized as minimal in the 10-ppm and 50-ppm groups. Significantly increased relative liver weight was detected in males of the 200-ppm group, and signifi- cantly increased relative kidney weight was found in males and females of the 50- and 200-ppm groups. BASF (1992b) conducted a 90-day study under Good Laboratory Practic- es, in which groups of 10 male and 10 female Wistar rats were exposed to pro- pargyl alcohol vapor (99% pure) at nominal concentrations of 1, 5, or 25 ppm (analytic concentrations 1.1, 5.1, and 24.6 ppm) for 6 h/day, 5 days/week, for a total of 65 exposures; controls were exposed to clean air. No mortality or clini- cal signs of toxicity occurred. Clinical chemistry and hematologic assessments were negative. Results of gross pathologic and histopathologic examinations were unremarkable. Although a statistically significant reduction in body weight gain was noted for male rats during the first 2 weeks of exposure, no significant

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Propargyl Alcohol 185 effect on body weight gain was detected at the end of the study. Absolute renal weight and kidney-to-body weight ratio were increased in female rats exposed at 24.6 ppm. These rats also exhibited a slight decrease in serum cholinesterase activity, but no gross or histopathologic effects were found. No post-exposure period was indicated. The no-observed-adverse-effect level was 5.1 ppm and the lowest-observed-adverse-effect level was 24.6 ppm. Exposure of groups of 10 male and 10 female Fischer 344 rats to propar- gyl alcohol at 0, 4, 8, 16, 32, or 64 ppm for 13 weeks did not result in any gross lesions or other significant toxic responses (NTP 2008). Chamber concentra- tions, monitored daily, were within the range specified in the experimental pro- tocol and propargyl alcohol was stable throughout the experiment. Hyperplasia of the nasal epithelium was observed in male rats at all concentrations, squa- mous metaplasia of nasal epithelium was detected in males and females at the highest concentration, and necrosis of the olfactory epithelium occurred in males and females at the two highest concentrations (see Table 6-4). A decrease in serum cholinesterase activity (p < 0.05) was detected in female rats 3 days after exposure at 32 and 64 ppm; no effect was observed in males until day 23. An increase in blood urea nitrogen (p < 0.01) was observed in males and females 3 days after exposure to propargyl alcohol at 32 and 64 ppm. These minor altera- tions in clinical chemistry parameters continued through the exposure period. Hematologic parameters were unaffected. 3.2.2. Mice Zissu (1995) exposed groups of 10 Swiss mice to propargyl alcohol at concentrations of 88 or 25.3 ppm (analytic concentrations 81.0-104.0 ppm and 22.0-31.0 ppm, respectively) for 6 h/day for 4, 9, or 14 days. Analytic concen- trations were determined from chamber air samples collected with a solid adsor- bent (silica gel). Breathing rates were monitored during exposure. No significant toxic effects were observed at the lower concentration. Histopathologic exami- nations of animals exposed at 88 ppm revealed changes in the olfactory epitheli- um (dorsal meatus) and respiratory epithelium (adjacent to the vestibule and characterized by rhinitis and necrosis extending into the underlying connective tissue and bone). Neither the trachea nor the lungs were affected. Lesions were most severe after 4 days of treatment and did not increase in severity after 14 days; however, there was no evidence of repair as was observed with other test chemicals (allyl alcohol, dichlorobenzene, and formaldehyde). In a subchronic study conducted under Good Laboratory Practices, groups of 10 male and 10 female B6C3F1 mice were exposed (whole-body) for 13 weeks to propargyl alcohol at nominal concentrations of 0, 4, 8, 16, 32, or 64 ppm (NTP 2008). No treatment-related deaths occurred. Mean body weight was decreased in all exposure groups, and was significantly lower in the three high- est exposure groups (-8.5, -11.3, and -15.6%, respectively; p < 0.05) relative to the control group. Exposures resulted in significantly increased kidney-to-body

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186 Acute Exposure Guideline Levels weight ratios at 8 ppm and liver-to-body weight ratios at 16 ppm and higher in male rats; however, female rats exhibited changes only in kidney weights at 32 and 64 ppm. No gross lesions were observed at necropsy. Hyperplasia of the nasal epithelium was considered the most sensitive treatment-related response. Other effects included necrosis and atrophy of respiratory epithelium, hepatic and renal weight changes, and decreased cholinesterase activity. The National Toxicology Program (NTP) considered 8 ppm a no-observed-adverse-effect level. Major pathologic findings are summarized in Table 6-5. 3.2.3. Guinea Pigs No lethality was observed in six guinea pigs exposed to propargyl alcohol at 3,000 mg/m3 (1,300 ppm) for 1 h (BASF 1965). Irritation of mucous mem- branes was the only effect reported. The duration of the post-exposure observa- tion period was not specified. TABLE 6-4 Effects in Fischer Rats after Exposure to Propargyl Alcohol for 13 Weeks Effect 0 ppm 4 ppm 8 ppm 16 ppm 32 ppm 64 ppm Males Olfactory epithelium 0/10 0/10 0/10 0/10 2/10 5/10 necrosis Respiratory epitheliuma Hyperplasia 2/10 6/10 2/10 4/10 8/10 10/10 Squamous metaplasia 0/10 0/10 0/10 0/10 0/10 3/10 Increased kidney/body weight - - - - - p < 0.01 Increased liver weight - - - - - p < 0.01 Increased liver/body weight - - - - p < 0.01 p < 0.01 Females Olfactory epithelium necrosis 0/10 0/10 0/10 0/10 3/10 5/10 Respiratory epitheliuma Hyperplasia 0/10 2/10 2/10 2/10 10/10 10/10 Sqauamous metaplasia 0/10 0/10 0/10 0/10 0/10 8/10 Necrosis 0/10 0/10 0/10 0/10 0/10 2/10 Increased kidney/body weight - - - - - p < 0.01 Increased liver/body weight - - - - - p < 0.01 a Nasal respiratory epithelium. Source: NTP 2008.

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Propargyl Alcohol 199 APPENDIX A DERIVATION OF AEGL VALUES FOR PROPARGYL ALCOHOL Derivation of AEGL-1 Values Key study: Zissu, D. 1995. Histological changes in the respiratory tract of mice exposed to ten families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213. Critical effect: No histologic changes in the respiratory tract of mice exposed to propargyl alcohol at 25.3 ppm for 6 h/day for 4 days (Zissu 1995). Point of departure is supported by the observation that rats exposed at 80 ppm for 7 h (the first of 59 exposures) exhibited only minor ocular irritation and lethargy (animals subsequently appeared to adapt) (Dow Chemical Co. 1964). Time scaling: Not performed Uncertainty factors: 3 for interspecies differences; data from several species indicated quantitatively and qualitatively similar responses to propargyl alcohol. 3 for intraspecies variability; responses to direct-contact irritants are not expected to vary by an order of magnitude among individuals. Calculations: All AEGL-1 values: 25.3 ppm ÷ 10 = 2.5 ppm; used for all five AEGL-1 durations, because direct-contact irritation is not expected to vary markedly with exposure duration. Derivation of AEGL-2 Values Key study: Zissu, D. 1995. Histological changes in the respiratory tract of mice exposed to ten families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213.

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200 Acute Exposure Guideline Levels Critical effect: Estimated threshold for histologic changes in olfactory and respiratory tissues of mice exposed at 88 ppm for 6 h. Time scaling: Cn × t = k; data were inadequate for deriving an empirical value for n, so default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used. (88 ppm)1 × 6 h = 528 ppm-h (88 ppm)3 × 6 h = 4,088,832 ppm-h Because of uncertainties associated with extrapolating a 6-h experimental exposure duration to a 10-min value (NRC 2001), time scaling was not performed for the 10- min AEGL-2 value. Instead, the 30-min AEGL-2 value was adopted for the 10-min value. Uncertainty factors: 3 for interspecies differences; data from several species indicated quantitatively and qualitatively similar responses to propargyl alcohol. 3 for intraspecies variability; responses to direct-contact irritants are not expected to vary by an order of magnitude among individuals. Calculations: 10-min AEGL-2: Set equal to the 30-min AEGL-2 value of 20 ppm 30-min AEGL-2: C3 × 0.5 h = 4,088,832 ppm-h C3 = 8,177,664 ppm-h C = 201.5 ppm 201.5 ppm ÷ 10 = 20 ppm 1-h AEGL-2: C3 × 1 h = 4,088,832 ppm-h C3 = 4,088,832 ppm-h C = 159.9 ppm 159.9 ppm ÷ 10 = 16 ppm

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Propargyl Alcohol 201 4-h AEGL-2: C3 × 4 h = 4,088,832 ppm-h C3 = 1,022,208 ppm-h C = 100.7 ppm 100.7 ppm ÷ 10 = 10 ppm 8-h AEGL-2: C1 × 8 h = 528 ppm-h C = 66 ppm-h 66 ppm ÷ 10 = 6.6 ppm Derivation of AEGL-3 Values Key study: Stasenkova, K.P., and T.A. Kochetkova. 1966. Toxicological characteristics of propargyl alcohol [in Russian]. Toksikol. Novykh. Prom. Khim. Veshchestv. 8:97- 111. Critical effect: Estimated lethality threshold (BMCL05 = 573 ppm) for mice exposed for 2 h to propargyl alcohol at 500, 1,500, 2,000, or 3,500 mg/m3 (220, 655, 875, and 1,500 ppm). Mortality incidences were 1/20, 1/20, 10/20, and 20/20, respectively. No lethality reported in repeated exposure studies (90 days) of rats exposed to propargyl alcohol at concentrations as high as 80 ppm (Dow Chemical Co. 1964) or in a study of guinea pigs and rabbits exposed at 1,300 ppm for 1 h (14-day observation period) (BASF 1965). However, a 1-h exposure at 1,300 ppm was lethal to one of two cats in the same study. Time scaling: Cn × t = k; data were inadequate for deriving an empirical value for n, so default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used. (573 ppm)1 × 2 h = 1,146 ppm-h (573 ppm)3 × 2 h = 376,265,034 ppm-h Uncertainty factors: 3 for interspecies differences; data from several species indicated quantitatively and qualitatively similar responses to propargyl alcohol.

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202 Acute Exposure Guideline Levels 3 for intraspecies variability; responses to direct-contact irritants are not expected to vary by an order of magnitude among individuals. No evidence that deaths resulting from single acute exposures involved systemic toxicity or solvent narcosis. Calculations: 10-min AEGL-3: C3 × 0.1667 h = 376,265,034 ppm-h C3 = 2,257,138,776 ppm-h C = 1,311.8 ppm 1,311.8 ppm ÷ 10 = 131 ppm (rounded to 130 ppm) 30-min AEGL-3: C3 × 0.5 h = 376,265,034 ppm-h C3 = 752,530,068 ppm-h C = 910 ppm 910 ppm ÷ 10 = 91 ppm 1-h AEGL-3: C3 × 1 h = 376,265,034 ppm-h C3 = 376,265,034 ppm-h C = 722 ppm 722 ppm ÷ 10 = 72.2 ppm (rounded to72 ppm) 4-h AEGL-3: C1 × 4 h = 1,146 ppm -h C = 287 ppm 287 ppm ÷ 10 = 28.7 ppm (rounded to 29 ppm) 8-h AEGL-3: C1 × 8 h = 1,146 ppm -h C = 143 ppm 143 ppm ÷ 10 = 14.3 ppm (rounded to 14 ppm)

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Propargyl Alcohol 203 APPENDIX B ACUTE EXPOSURE GUIDELINE LEVELS FOR PROPARGYL ALCOHOL Derivation Summary AEGL-1 VALUES 10 min 30 min 1h 4h 8h 2.5 ppm 2.5 ppm 2.5 ppm 2.5 ppm 2.5 ppm Reference: Zissu, D. 1995. Histological changes in the respiratory tract of mice exposed to ten families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213. Test species/Strain/Number: Mouse, Swiss, 10 males/group Exposure route/Concentrations/Durations: Inhalation, 25.3 or 88.0 ppm, 6 h/day for 4, 9, or 14 days. Effects: No histopathologic effects at 25.3 ppm. Very severe lesions in olfactory and respiratory epithelium at 88.0 ppm; effects did not increase in severity with longer exposure. End point/Concentration/Rationale: 25.3 ppm for 6 h considered a no-observed- adverse-effect level Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, data on several species indicate quantitatively and qualitatively similar responses to propargyl alcohol Intraspecies: 3, responses to direct-contact irritants are not expected to vary by an order of magnitude among individuals. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: None. The same value (25.3 ppm ÷ 10 = 2.5 ppm) was applied to all AEGL durations because direct-contact irritation is not expected to vary markedly with exposure duration. Data adequacy: Data sufficient for deriving AEGL-1 values. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 20 ppm 20 ppm 16 ppm 10 ppm 6.6 ppm Reference: Zissu, D. 1995. Histological changes in the respiratory tract of mice exposed to ten families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213. Test species/Strain/Sex/Number: Mouse, Swiss, 10 males/group Exposure route/Concentrations/Durations: Inhalation, 25.3 or 88.0 ppm, 6 h/day for 4, 9, or 14 days (Continued)

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204 Acute Exposure Guideline Levels AEGL-2 VALUES Continued Effects: No histopathologic effects at 25.3 ppm. Very severe lesions in olfactory and respiratory epithelium at 88.0 ppm; effects did not increase in severity with longer exposure (up to 14 days). End point/Concentration/Rationale: A single 6-h exposure at 88.0 ppm was estimated to be a threshold for histologic changes in olfactory tissue. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, data on several species indicate quantitatively and qualitatively similar responses to propargyl alcohol Intraspecies: 3, histopathologic effects are likely due to direct-contact irritation, which is not expected to vary by an order of magnitude among individuals. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Cn × t = k; data were inadequate for deriving an empirical value for n, so default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used. Data adequacy: Data sufficient to derive AEGL-2 values. A more robust single acute exposure-response data set would be beneficial. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 130 ppm 91 ppm 72 ppm 29 ppm 14 ppm Reference: Stasenkova, K.P., and T.A. Kochetkova. 1966. Toxicological characteristics of propargyl alcohol [in Russian]. Toksikol. Novykh. Prom. Khim. Veshchestv. 8:97-111. Test species/Strain/Sex/Number: Mouse, strain and gender not specified, 20/group. Exposure route/Concentrations/Durations: Inhalation; 500, 1,500, 2,000, and 3,500 mg/m3 (220, 655, 875, and 1,500 ppm) for 2 h. Effects: Mortality incidences of 1/20 (220 ppm), 1/20(655 ppm), 10/20 (875 ppm), and 20/20 (1,500 ppm). End point/Concentration/Rationale: Estimated lethality threshold, 2-h BMDL05 of 573 ppm Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, data on several species indicate quantitatively and qualitatively similar responses to propargyl alcohol. Intraspecies: 3, histopathologic effects are likely due to direct-contact irritation, which is not expected to vary by an order of magnitude among individuals. Modifying factor: None Animal-to-human dosimetric adjustment: None

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Propargyl Alcohol 205 Time scaling: Cn × t = k; data were inadequate for deriving an empirical value for n, so default values of n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations were used. Data adequacy: Data sufficient to derive AEGL-3 values. Data in multiple species allowed for interspecies comparisons.

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206 Acute Exposure Guideline Levels APPENDIX C CATEGORY PLOT FOR PROPARGYL ALCOHOL Chemical Toxicity - TSD All Data Propargyl Alcohol 10000 Human - No Effect Human - Discomfort 1000 Human - Disabling Animal - No Effect ppm 100 Animal - Discomfort AEGL-3 Animal - Disabling 10 Animal - Some Lethality AEGL-2 AEGL-1 Animal - Lethal AEGL 1 0 60 120 180 240 300 360 420 480 Minutes FIGURE C-1 Category plot of toxicity data and AEGL values for propargyl alcohol. TABLE C-1 Data Used in Category Plot for Propargyl Alcohol No. of Source Species Sex Exposures ppm Minutes Category Comments NAC/AEGL-1 2.5 10 AEGL NAC/AEGL-1 2.5 30 AEGL NAC/AEGL-1 2.5 60 AEGL NAC/AEGL-1 2.5 240 AEGL NAC/AEGL-1 2.5 480 AEGL NAC/AEGL-2 20 10 AEGL NAC/AEGL-2 20 30 AEGL NAC/AEGL-2 16 60 AEGL NAC/AEGL-2 10 240 AEGL NAC/AEGL-2 6.6 480 AEGL NAC/AEGL-3 130 10 AEGL NAC/AEGL-3 91 30 AEGL NAC/AEGL-3 72 60 AEGL NAC/AEGL-3 29 240 AEGL NAC/AEGL-3 14 480 AEGL (Continued)

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Propargyl Alcohol 207 TABLE C-1 Continued No. of Source Species Sex Exposures ppm Minutes Category Comments Rat M 1 1,200 60 PL LC50 (Vernot et al. 1977) Rat F 1 1,000 60 PL LC50 (Vernot et al. 1977) Rat 1 850 120 PL LC50 (Kennedy and Graepel 1991); RTECS entry) Mouse 1 3,000 60 PL 30% lethality (BASF 1965) Mouse 1 220 120 PL 5% lethality (Stasenkova and Kochetkova 1966) Mouse 1 655 120 PL 5% lethality (Stasenkova and Kochetkova 1966) Mouse 1 875 120 PL 50% lethality (Stasenkova and Kochetkova 1966) Mouse 1 1,500 120 3 100% lethality (Stasenkova and Kochetkova 1966) Cat 1 1,300 60 PL 1 of 2 dead (BASF 1965) Rat 1 1,500 60 3 10/10 dead within 3 days (Hazelton Laboratories America, Inc. 1989) Rat M/F 1 80 420 1 Irritation after first 7-h exposure of 59 exposures (Dow Chem. Co. 1964) Rat M/F 1 25 360 1 No significant effects after 90 days of exposure (BASF 1965) Rat M/F 1 32 1,400 0 No significant effects after 90 days of exposure (NTP 2008) Mouse M/F 1 16 1,400 0 No significant effects after 90 days of exposure (NTP 2008) Guinea 1 1,300 60 1 Irritation of mucous pig membrane (BASF 1965) Rabbit 1 1,300 60 1 Irritation of mucous membrane (BASF 1965) Mouse 1 88 360 1 Histopathologic changes in olfactory and respiratory epithelium (Zissu 1995) Mouse 1 25 360 0 Histopathologic changes in olfactory and respiratory epithelium (Zissu 1995) For category: 0 = no effect, 1 = discomfort, 2 = disabling, PL = partially lethal, 3 = lethal.

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208 Acute Exposure Guideline Levels APPENDIX D BENCHMARK CONCENTRATION ANALYSIS FOR PROPARGYL ALCOHOL Stasenkova and Kochetkova, 1966; Propargyl alcohol; 2-h exposure; lethality study in mice. Probit Model (Version: 2.8; Date: 02/20/2007) Input Data File: C:\BMDS\PROPALC.(d) Gnuplot Plotting File: C:\BMDS\PROPALC.plt Mon Sep 14 13:38:16 2009 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 5 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -11.6925 Slope = 1.75112 Asymptotic Correlation Matrix of Parameter Estimates Background Intercept Slope Background 1 -0.4 0.39 Intercept -0.4 1 -1 Slope 0.39 -1 1 Analysis of Deviance Table Model Log(likelihood) # Param's Deviance Test d.f. P-value Full model -21.8036 5 Fitted model -22.5131 3 1.41917 2 0.4918 Reduced model -62.6869 1 81.7668 4 <.0001 AIC: 51.0263

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Propargyl Alcohol 209 Parameter Estimates 95.0% Wald Confidence Interval Variable Estimate Standard error Lower confidence limit Upper confidence limit Background 0.0252266 0.0247475 -0.0232776 0.0737309 Intercept -45.4309 21.7571 -88.074 -2.78782 Slope 6.70209 3.21983 0.391333 13.0128 Goodness of Fit Scaled Estimated Dose probability Expected Observed Size Residual 219.0000 0.0252 0.505 1 20 0.707 655.0000 0.0490 0.980 1 20 0.020 875.0000 0.5012 10.023 10 20 -0.010 1500.0000 0.9998 19.997 20 20 0.058 0.0000 0.0252 0.505 0 20 -0.719 Chi-square = 1.02 d.f. = 2 P-value = 0.6003 Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMC = 687.589 BMCL05 = 572.737 Probit Model with 0.95 Confidence Level Probit 1 BMD Lower Bound 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 200 400 600 800 1000 1200 1400 dose FIGURE B-1 Probit model with 0.95 confidence level.