6

Toluene
1

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 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

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1This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Oak Ridge National Laboratory), Chemical Manager George Woodall (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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6 Toluene1 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 Sylvia Talmage (Oak Ridge National Laboratory), Chemical Manager George Woodall (Na- tional 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). 289

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290 Acute Exposure Guideline Levels 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 Toluene is a widely used raw material in the chemical manufacturing in- dustry. It is a component of automotive and aviation gasoline and a solvent in lacquers, paint thinners, glue, and other household products. A major concern with the uncontrolled release of toluene is explosion and fire. The odor threshold for toluene ranges from 0.16 to 100 ppm for detection and 1.9 to 69 ppm for recognition; the odor is not unpleasant. Toluene is readily absorbed by the respiratory tract and distributed throughout the body, accumu- lating in tissues with high lipid content. Liquid toluene can be absorbed through intact skin and the alimentary tract. Toluene is a central nervous system (CNS) depressant and is irritating to the eyes at high concentrations. Other effects ob- served in humans after accidental or intentional inhalation of high concentra- tions of toluene include renal toxicity, cardiac arrhythmias, hepatomegaly, and developmental abnormalities. Considerable human and animal toxicity data were available for deriving AEGL values. Clinical, metabolism, and occupational-monitoring studies were available for deriving AEGL-1 values. Many of the studies evaluated sensory irritation and CNS depression. Numerous studies of neurotoxicity have also been conducted in rodents. Lethality data on toluene were available for the mouse and rat. AEGL-1 values were based on the preponderance of data from clinical and occupational studies and from metabolism studies of human subjects that indi- cated that an 8-h exposure to toluene at 200 ppm is near a threshold for AEGL-1 effects (headache), and also near a level for detectable neurologic effects (mod- erate lightheadedness and increased simple reaction time). More than 300 indi-

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Toluene 291 viduals have been evaluated in 20 clinical studies that involved exposures to toluene at 40-700 ppm, and several thousand workers were surveyed in occupa- tional-monitoring studies that involved exposures at up to 1,500 ppm. Those populations are presumed to be composed of healthy individuals, but they repre- sent a broad spectrum of uptake rates (sedentary, working, and exercise condi- tions) and individual differences in metabolism rates (Gamberale and Hulten- gren 1972; Veulemans and Masschelein 1978; Brugnone et al. 1986; Hjelm et al. 1988). Although many clinical studies tested toluene at 100 ppm, the addition of exercise to the protocol in the studies of Astrand et al. (1972), Baelum et al. (1990), and Rahill et al. (1996) more than doubled the toluene blood concentra- tion; concentrations were greater than that from a 200-ppm exposure with the subject at rest (Astrand et al. 1972; Veulemans and Masschelein 1978). The weight of evidence from these studies indicates that an 8-h exposure to toluene at 200 ppm was without adverse health effects in the tested popula- tions, and was an appropriate basis for the AEGL-1 values. At concentrations of 80-200 ppm, toluene approaches a steady-state in the blood within 15-30 min (Astrand et al. 1972; Carlsson 1982). Storage takes place in lipid-rich tissues (including the brain), but elimination is rapid. Toluene reaches a steady-state in the blood and brain fairly rapidly, and no cumulative effects were observed after repeated exposure at 100 ppm for 5 days (Stewart et al. 1975); therefore, 200 ppm was used as the basis for all AEGL-1 durations. Although there was no notable discomfort and only mild irritation (effects expected to be concentration dependent and not subject to changes in activity level), headaches (potentially related to CNS effects), dizziness, and measurable neurologic effects were re- ported after exposure to toluene at 100-200 ppm. Neurologic effects would be expected to be affected by an increase in activity level, leading to higher concen- trations in the brain (target tissue for CNS effects). As noted earlier, physical activity may double the blood concentration of toluene. On the basis of the range of alveolar concentrations among humans exposed to anesthetic gases, an uncer- tainty factor of 3 for human variability was applied to calculate an AEGL-1 val- ue of 67 ppm for all durations. That concentration is deemed protective for all observed effects, including those at 100-200 ppm. The AEGL-2 values for toluene are based on impaired neurologic function that affects the ability to escape. The point of departure was a no-observed- adverse-effect level (NOAEL) of 1,600 ppm for a doubling of the choice reac- tion time in Long-Evans rats exposed for 34 min (Bushnell et al. 2007a). The CNS effects observed during exposure were assumed to be directly related to parent material reaching the brain. Therefore, the toluene concentration in brain (BrTC) after 34 min provides an internal dose measurement correlating with the NOAEL. The physiologically-based pharmacokinetic (PBPK) model of Kenyon et al. (2008) was used to calculate the internal dose or BrTC in the rat. An inter- species uncertainty factor of 1 was applied because pharmacokinetic modeling eliminated the toxicokinetic component of the uncertainty factor, and the phar- macodynamic component was assigned a value of 1 because similar effects (CNS depression) were observed in humans and animals. An intraspecies uncer-

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292 Acute Exposure Guideline Levels tainty factor of 3 was applied because the minimum alveolar concentration for volatile anesthetics should not vary by more than 2- to 3-fold among humans. A human model for toluene (Benignus et al. 2006) was then used to determine the exposure concentrations at each of the AEGL exposure durations that would yield the same brain concentration in humans. Further support for the AEGL-2 values is provided by comparisons with the results obtained from the published model of Benignus et al. (2009, 2011), which calculates the BrTC leading to an effect level comparable to an individual with a blood ethanol level of 0.10% (the legal level of incapacitation in the United States). Although the routes of exposure are different between the two chemicals (inhalation for toluene inhalation and oral for ethanol), the relative effect levels are relevant for comparison purposes. The AEGL-3 values for toluene were based on a NOAEL for lethality in rats. A 2-h exposure to toluene at 6,250 ppm was not lethal but produced pros- tration in rats (Mullin and Krivanek 1982). A 2-h exposure of rats at 10,000 ppm resulted in 20% mortality (Kojima and Kobayashi 1973). The same PBPK mod- els and uncertainty factors that were used to derive the AEGL-2 values were used to calculate the AEGL-3 values. The AEGL values for toluene are presented in Table 6-1. TABLE 6-1 AEGL Values for Toluene End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 67 ppm 67 ppm 67 ppm 67 ppm 67 ppm No-effect level for (nondisabling) (250 (250 (250 (250 (250 notable discomfort mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) and neurologic effects in 20 clinical studies.a AEGL-2 1,400 ppmb 760 ppm 560 ppm 310 ppm 250 ppm No-effect level for (disabling) (5,300 (2,900 (2,100 (1,200 (940 impaired ability to mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) escape, decrement in neurological function.c AEGL-3 5,200 ppmb 3,700 ppmb 1,800 ppmb 1,400 ppmb No-effect level for (lethal) (20,000 (14,000 (6,800 (5,300 lethality in rats –d mg/m3) mg/m3) mg/m3) mg/m3) (Mullin and Krivanek 1982) a Clinical studies include Astrand et al. (1972), Gamberale and Hultengren (1972), Stewart et al. (1975), and Baelum et al. (1990). b Concentration is one-tenth or more of the lower explosive limit of 14,000 ppm for toluene in air. Therefore, safety considerations against the hazard of explosion must be taken into account. c No-effect level for a doubling in choice reaction time in rats (Bushnell et al. 2007a). Effect level supported by comparison of toluene inhalation with ethanol consumption in humans (Benignus et al. 2011). d The 10-min AEGL-3 value of 10,000 ppm (38,000 mg/m3) is higher than 50% of the lower explosive limit of 14,000 ppm for toluene in air. Therefore, extreme safety considerations against the hazard of explosion must be taken into account.

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Toluene 293 1. INTRODUCTION Toluene is a colorless, flammable liquid with a pungent floral or aromatic odor similar to that of benzene (Henderson 2001). The odor has also been de- scribed as sour or burnt (Hellman and Small 1974), rubbery, or similar to that of moth balls (Billings and Jonas 1981; Ruth 1986). The chemical and physical properties of toluene are presented in Table 6-2. A major concern with the uncontrolled release of toluene is explosion and fire. The flash point of toluene is 4.4°C and the ignition temperature is 536°C. The saturated vapor is only slightly heavier (about 10% more) than air and may travel a considerable distance in still air to a source of ignition and flash back. Toluene may be rapidly dispersed by normal eddy currents. The vapor may ex- plode if ignited in an enclosed area (Weiss 1980). For example, a fatal explosion occurred when workers were sawing an opening in the side of an empty 10,000- gallon toluene storage tank (NIOSH 1985). TABLE 6-2 Chemical and Physical Properties of Toluene Parameter Value Reference Synonyms Methyl benzene; phenyl methane; ATSDR 2000 methyl benzol; monomethyl benzene; toluol; methacide; tolu-sol; antisal 1a CAS registry no. 108-88-3 O’Neil et al. 2006 Chemical formula C7H8 O’Neil et al. 2006 Molecular weight 92.140 O’Neil et al. 2006 Physical state Clear liquid O’Neil et al. 2006 Boiling point 110.6°C O’Neil et al. 2006 3 Density/specific gravity 0.866 g/cm O’Neil et al. 2006 Solubility in water Slightly soluble, 0.067% O’Neil et al. 2006 Vapor density (air = 1) 3.1 Henderson 2001 Vapor pressure 36.7 mmHg Henderson 2001 Log Kow 2.72 ATSDR 2000 Flash point 4.4°C (closed cup) O’Neil et al. 2006 12.8°C (open cup) Weiss 1980 Flammability limits Henderson 2001 Lower explosive limit 1.4% Upper explosive limit 7.9% Conversion factors in air 1 ppm = 3.77 mg/m3 NIOSH 2011 1 mg/m3 = 0.265 ppm

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294 Acute Exposure Guideline Levels In 1999, world production of toluene was nearly 13,000,000 tons. Approx- imately 79% of total production is from catalytic reforming of refinery streams, an additional 16% is separated from pyrolysis gasoline, and 4% is produced via separation from coal tars. Most of the toluene produced (85-90%) is not isolated but remains as a benzene-toluene-ethylbenzene-xylene (BTEX) mixture for use in gasoline as an octane booster. Of the remaining capacity, the primary use is for chemicals and solvents such as benzene (via dealkylation). In the chemical industry, toluene is used as raw material in the production of benzyl chloride, benzoic acid, phenol, cresols, vinyl toluene, trinitrotoluene (TNT), and toluene diisocyanate. Approximately 14% of toluene is also used as a solvent for paints and coatings and in adhesives, inks, and pharmaceuticals (US Air Force, 1989; EPA, 1990; Ozokwelu 1997; Chemical Week 2000). In the past, commercial toluene contained benzene and xylenes at up to 2-15% and 10%, respectively (NIOSH 1973; Low et al. 1988). Highly purified toluene (benzene at less than 0.01%) began to be produced commercially in 1973. Therefore, greater consideration was given to more recent toxicity studies, in which the toluene is more chemically pure. For both the general population and for occupationally-exposed individu- als, inhalation is the primary route of exposure to toluene. Evaporation of gaso- line and automobile exhaust is the largest source of toluene in the environment, and industries that use toluene as a solvent are the second largest source (EPA 1990). Toluene is also a common indoor-air contaminant due to releases from common household products and from cigarette smoke (ATSDR 2000). 2. HUMAN TOXICITY DATA The typical sequence of events that result from exposure to toluene at con- centrations high enough to produce unconsciousness include euphoria, delu- sions, and sedation (Benignus 1981; Bruckner and Warren 2001). Mood eleva- tion, nausea, and subtle changes in performing intricate tasks have been reported at 200 ppm and higher (ACGIH 2005), although some of the studies are poorly documented (see Table 6-3). Exposure to toluene may be occupational or recrea- tional; in the latter case it is reported to produce a pleasant euphoria with few side effects (Massengale et al. 1963). Its abuse potential may be enhanced by its apparent low irritancy in humans (von Oettingen et al. 1942; Carpenter et al. 1944; Nielsen and Alarie 1982). The major effect of toluene is its narcotic effects, manifested in muscular weakness, incoordination, and mental confusion (NIOSH 1973). Adverse effects on the liver, kidneys, lungs, and heart are limited to acute and chronic exposures at high vapor concentrations. Early reports suggesting deleterious effects on the bone marrow involved the use of toluene contaminated with benzene (NIOSH 1973). The health effects of toluene have been reviewed by Cohr and Stockholm (1979), NRC (1981, 2008), WHO (1985), CIR (1987), Low et al. (1988), EPA (1990), ATSDR (2000), Bruckner and Warren (2001), and Henderson (2001).

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TABLE 6-3 Sensory and Neurobehavioral Effects of Toluene in Controlled Human Studies Concentration (ppm) Duration Subjects/Effects Reference 10, 40, 100 6h 16 males (21-32 y): slight irritation of eyes and nose at 100 ppm; no effect Andersen et al. 1983 on mood, fatigue, or sleepiness; increased frequency of headache, dizziness, and feeling of slight to moderate intoxication; no effect on pulmonary function or nasal mucous flow; no significant effect on performance in eight psychomotor tests. 40 4h 12 males (20-50 y): no effects on measures of motor performance, attention, Lammers et al. 2005a perceptual coding and memory, or mood. 110 Three 30-min peaks over 4 h 50a 3h 10 males, 20 females (19-45 y): no subjective symptoms. Luderer et al. 1999 50 4.5 h 20 males: no increase in sleepiness; increase in scores of unpleasant smell Muttray et al. 2005 and irritation to the throat. 80 4h 8 males (22-50 y): no impairment on neurobehavioral tasks. Cherry et al. 1983 80 4h 16 males (23-38 y): no differences in subjective symptoms compared with Olson et al. 1985 controls; no impairment in tests of simple reaction time, short-term memory, or choice reaction time; no effect on heart rate. 80 4.5 h 12 males (22-44 y): increase in subjective symptoms (nausea, headache, Iregren et al. 1986 irritation), but rated negligible; no impairment in tests of simple and choice reaction time, color-word vigilance, or memory; no effect on heart rate, electroencephalograph results, or sleep latency. 100 3.5 h 18 subjects: no behavioral deficits in psychomotor tests. Winneke 1982 (Continued) 295

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296 TABLE 6-3 Continued Concentration (ppm) Duration Subjects/Effects Reference 100 4h 30 males and females: no serious impairment in neurobehavioral tests Dick et al. 1984 (small impairment in one measure of a visual-vigilance test). 100 6h 6 males and females (27-38 y): No significant effect on pulmonary function Rahill et al. 1996 (subjects exercised for 30 min); slight effect on some multitask and neuropsychologic tests (increased latency but not accuracy on neurobehavioral tasks); no symptoms reported in a double-blind questionnaire. 100 6.5 h 43 male printers and 43 referents (29-50 y). Four groups tested (two exposed Baelum et al. 1985; (printers were previously and two controls): sensory irritation (no annoyance or nausea); sleepiness; Nielsen et al. 1985 exposed for 9 to 25 y) fatigue; slightly decreased performance on four of 10 tests (manual dexterity, color discrimination, visual perception) in one or both exposed groups; no changes in renal function. 100 1, 3, or 7.5 h/d 10 males and 9 females (19-47 y): no decrement in psychomotor-test results Stewart et al. 1975 for 5 d on first day of exposure; slight decrement in performance in tests involving visual vigilance and tone detection on days 2 and 5 in females exposed for 7.5 h; similar subjective symptoms between exposed and control groups. 100 (constant) or 100 7h 32 males and 39 females (31-50 y): sensory irritation of nose and lower Baelum et al. 1990 (TWA; exposure varied (three 15-min airways; increase in dizziness and feeling of intoxication; slight decrement with peaks of 300 ppm exercise periods; in one of four psychomotor-performance tests; no differences in symptoms every 30 min) both exposures) or performance found between constant and varying exposures. 75, 150 7 h/d for 3 d 42 male and female students (18-35 y): 7% (mean) decrement in several Echeverria et al. 1989; 1991 neurobehavioral tests at 150 ppm; slight increases in headache, ocular irritation; sleepiness on first day; CNS effect demonstrated by dose-response in number of times subjects slept. No clear pattern of neurobehavioral effects. Variation in the control data across 3 d was greater than with toluene.

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100, 200a 30, 60 min 11 males and 4 females (18-46 y): no difference in heart rate, pulmonary Astrand et al. 1972; ventilation, oxygen consumption, or blood lactate, either at rest or during a Astrand 1975 work load of 50 W. 100, 200 3 h or 7 h with 23 males (23 y, average age): decrease in pulse rate at 200 ppm for 3 h; Ogata et al. 1970 1-h break tendency to have prolonged reaction time at 200 ppm; no clear concentration-response relationship. 100, 300, 500, 700a Successive 20-min 12 males (20-35 y): no effect on reaction time or perceptual speed at 100 Gamberale and exposure at increasing ppm; increase in simple reaction time at 300 ppm; increase in complex Hultengren 1972 concentrations (one reaction time at 500 ppm; decrease in perceptual speed at end of exposure at 5-min break); total 700 ppm; no effect on heart rate during total exposure; one of 12 subjects 85 min. able to distinguish between control and toluene exposures. 220b 15 min 6/6 subjects willing to work for 8 h; negligible sensory symptoms. Carpenter et al. 1976 427b 15 min 3/6 subjects willing to work for 8 h; 2 subjects reported slight “lightheadness”; 1 reported a “stuffy, drowsy feeling.” 200 6h 5 males, resting: no change in respiration; increased heart rate. Suzuki 1973 240 Three 30-min sessions 11 males (20-21 y): impaired vigilance in third session; decreased fatigue Horvath et al. 1981 during second session. a Subjects exposed via a mouthpiece. b Measured as toluene in “toluene concentrate.” 297

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298 Acute Exposure Guideline Levels 2.1. Acute Lethality Inhalation of “high concentrations” can result in paresthesia, vision dis- turbances, dizziness, nausea, CNS depression, and collapse (Henderson 2001). Most deaths involve solvent abuse or “glue sniffing”, which involves sniffing a mixture of solvents from a plastic bag to concentrate the vapors. Solvents, such as paint thinners, may contain as much as 99% toluene (Donald et al. 1991). Prior to 1975, an estimated 125 deaths involving solvent abuse occurred per year in the United States (Winek and Collom 1975). Few deaths have been attributed solely to the inhalation of pure toluene, but are associated with paint thinners, spray paints, glues, and other products containing toluene. Few data are availa- ble on the concentrations of toluene that caused deaths in these studies. The con- centration of toluene achieved when inhaling directly from a paper bag contain- ing gauze soaked with toluene from a tube of polystyrene cement is estimated to be 10,000 ppm (Press and Done 1967). According to the authors, this concentra- tion causes unconsciousness within a few minutes, which results in cessation of exposure. Bass (1970) reviewed reports of “sudden sniffing death syndrome.” Eye- witness accounts of the events prior to death were similar and included: inhala- tion of volatile hydrocarbons from a bag, panic, physical exertion (usually in- volving running), and sudden collapse and death. This pattern was characterized by the author as being the result of severe cardiac arrhythmia associated with fulminate pulmonary edema, the excitement of a light plane anesthesia, hypera- drenergic crisis, or some combination of these and possibly unknown factors. The author suggests a mechanism of action involving sensitization of the myo- cardium by volatile hydrocarbons and subsequent physical exertion coalescing to produce sudden and severe arrhythmia. No cardiac-sensitization tests of tolu- ene in dogs was found, but dogs exposed to toluene at 30,000 ppm for 9-10 min died of ventricular fibrillation and severe hypoxia (Ikeda et al. 1990; see Section 3.1.1). 2.2. Nonlethal Toxicity The odor threshold of toluene in air ranges between 2 and 40 ppm (Amoore and Hautala 1983; Ruth 1986). According to Hellman and Small (1974), the odor can be detected at 0.17 ppm and recognized at 1.74 ppm. The American Industrial Hygiene Association (AIHA1989) reports the detectable range as 0.16-100 ppm and the odor recognition range as 1.9-69 ppm. According to a literature survey (Ruth 1986), the threshold for “irritation” is 200 ppm. In a more recent series of studies, the odor threshold and thresholds for ocular and nasal irritation were measured using squeeze bottles and a two-alternative, forced-choice procedure with an ascending method of limits (Cometto-Muniz and Cain 1995; Abraham et al. 1996). Thresholds for ocular irritation and nasal pungency were approximately >20,000 and 29,850 ppm, respectively. The nasal

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Toluene 299 pungency threshold was developed with anosmics (subjects who were clinically diagnosed as lacking a sense of smell and were, thus, unbiased by odor sensa- tions). Solvent abusers repeatedly inhale anesthetizing concentrations on a daily basis. Toluene abuse, an extreme form of exposure, has resulted in myocardial infarction and cardiac effects (Cunningham et al. 1987; Wiseman and Banim 1987; Carder and Fuerst 1997), renal toxicity that includes renal tubular acidosis (Taher et al. 1974; Reisin et al. 1975; Patel and Benjamin 1986; Gupta et al. 1991; Kamijima et al. 1994), metabolic acidosis often with “anion gap” (the sum of the cations in the blood minus the sum of the anions in the blood) (Fischman and Oster 1979; Jone and Wu 1988), acute encephalopathy in children (8-14 years old) (King et al. 1981), and cerebellar ataxia (Boor and Hurtig 1977). Streicher et al. (1981) described syndromes of toluene sniffing in adults, which included a pattern of three dominant symptoms: muscle weakness, gastrointesti- nal disorders, and neuropsychiatric disorders. Neuropsychiatric symptoms in- cluded headache, dizziness, syncope, paresthesias or peripheral neuropathy, hal- lucinations, lethargy, and cerebellar ataxia. Some exposures were to mixtures of solvents and ethanol. Exposure concentrations could not be ascertained. In a review of neurologic and psychiatric consequences of toluene abuse, Ron (1986) concluded that evidence for such sequelae remains inconclusive. Distal renal tubular acidosis is an established consequence of toluene abuse and has been reported in numerous studies. This consequence is notable with the extremely high vapor concentrations associated with chronic abuse sit- uations (O’Brien et al. 1971; Taher et al. 1974; Fischman and Oster 1979; Kroeger et al. 1980; Moss et al. 1980; Russ et al. 1981; Streicher et al. 1981; Patel and Benjamin 1986; Marjot and McLeod 1989). In life-threatening cases, patients present with severe generalized muscle weakness, nausea and vomiting, and neuropsychiatric derangements (Streicher et al. 1981; Marjot and McLeod 1989). The mechanism of action for this disorder is discussed in Section 4.2. In spite of reports of hepatic, adrenal, and renal damage, there appears to be a low incidence of these injuries among glue sniffers. Only modest elevations of serum glutamic-oxaloacetic transaminase and alkaline phosphatase and transient ab- normalities in urinalyses were observed among groups of glue sniffers (Press and Done 1967; Litt et al. 1972; Weisenberger 1977). 2.2.1. Occupational Exposures Studies of workers exposed to toluene in occupational settings have fo- cused on functional impairment. These exposures are usually not of a magnitude required to produce serious sustained effects. Even though exact exposure pa- rameters of concentration and duration are usually not determined in these stud- ies, the investigations provide information about the more common effects and at what approximate concentrations these effects are observed. Interpretation of most occupational exposure studies of toluene is confounded by co-exposure to

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Toluene 403 !CI - Concentration TOL in inhaled air (mg/l) RAI = QP * C !Rate TOL to lung (mg/hr) AI = INTEG (RAI, 0.) !Amount TOL entering lung, mg CI = AIO * CIZONE !CA - Concentration TOL in arterial blood (mg/l) ! CA1 - Concentration part to lung !AAB - Amount TOL in arterial blood (mg) RAAB = QC * CA1 - QC * CA AAB = INTEG(RAAB, 0.) CA = AAB/VAB !AX - Amount TOL exhaled (mg) RAX = QP * CX !Rate TOL exhaled (mg/hr) AX = INTEG (RAX, 0.) CX = CA1/PB !Conc. TOL in exhaled air(mg/l) CXPPM = ((0.7 * CX) + (0.3 * CI)) * (24450/MW) !ppm AXKG = AX/BW !mg exhaled/kg body weight !AN - Amount TOL in lung (mg) RAN = QC * CV + QP * CI - QC * CA1 - QP * CX AN = INTEG (RAN, 0.) CA1 = AN/(VN * PN) CN = AN/VN !AS - Amount TOL in slowly perfused tissues (mg) RAS = QS * (CA - CVS) !Rate of change in conc. (mg/hr) AS = INTEG (RAS, 0.) CVS = AS / (VS * PS) !Conc partition to slow per. tis.(mgl) CS = AS / VS !Conc in volume slow per. tis.(mg/l) !AR - Amount TOL in rapidly perfused tissues (mg) RAR = QR * (CA - CVR) !Rate of change in conc. (mg/hr) AR = INTEG (RAR, 0.) CVR = AR / (VR * PR) !Conc partition to rap per. tis.(mg/l) CR = AR / VR !Conc in volume rap per. tis.(mg/l) !ABR - Amount TOL in brain (mg) RABR = QB * (CA - CVBR) !Rate of change in conc (mg/hr) ABR = INTEG (RABR, 0.) CVBR = ABR / (VB * PBR) !Conc partition to brain(mg/l) CBR = ABR / VB !Conc in volume brain(mg/l) AUCBR = INTEG(CBR, 0.) !AUC for TOL in brain !AF - Amount TOL in fat tissue(mg) RAF = QF * (CA - CVF) !Rate of change in conc(mg/hr) AF = INTEG (RAF, 0.) CVF = AF / (VF * PF) !Conc partition to fat(mg/l) CF = AF / VF !Conc in fat volume(mg/l)

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404 Acute Exposure Guideline Levels !AG - Amount TOL in gut tissue(mg) !RAG - rate of change TOL in gut conc, mg/hr RAG = QG * (CA - CVG) - RDSTOM AG = INTEG (RAG, 0.) CVG = AG / (VG * PG) !Conc partition to gut (mg/l) CG = AG / VG !Conc in gut volume(mg/l) !AL - Amount TOL in liver(mg) !RAL - rate of change in liver conc, mg/hr RAL = (QL * CA) + (QG * CVG) - ((QL+QG) * CVL) - RAM AL = INTEG (RAL, 0.) CVL = AL / (VL * PL) !Conc partition to liver(mg/l) CL = AL / VL !Conc in liver volume(mg/l) !AUCPO - Amount TOL oxidatively metabolized (mg) !RAM - Rate of oxidative metabolism of TOL (mg/hr) RAM = (VMAX * CVL) / (KM + CVL) AUCPO = INTEG (RAM, 0.) AUCKG = AUCPO / BW !Amount TOL metabolized/kg body weight !CV - TOL mixed venous blood concentration (mg/l) !RAVB - Rate of change in concentration (mg/hr) RAVB = (QL+QG)*CVL) + QF*CVF + QS*CVS + QR*CVR + QB*CVBR - QC * CV AVB = INTEG(RAVB, 0.) CV = AVB/VVB !Conc in venous blood volume (mg/l) AUCV = INTEG(CV,0.) !AUC for toluene in venous blood !PMASS - TOL Mass balance(mg) PMASS = AN + AF + AG + AL + AS + AR + ABR + AUCPO + AX + AVB + AAB + STOMD TERMT (T .GE. TSTOP) !terminate solution END !END OF DERIVATIVE !**Code to calculate variables used in checking mass balance** BALPC = (AI + ODTOL) - PMASS TBALPC = ABS(BALPC) END !END OF DYNAMIC END !END OF PROGRAM

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Toluene 405 APPENDIX D TOLUENE SIMULATIONS Vernon Benignus, Elaina M. Kenyon, William Boyes, and Philip Bushnell 2/22/2013 Acute exposure to toluene vapor impairs neurologic function. The degrees of neurologic impairment produced by exposures to toluene, and dose response- relationships, have been determined using a variety of behavioral procedures. Some of these behavioral procedures, such as choice reaction time tasks, have also been used to evaluate the acute consequences of exposure to another common intoxicant, ethanol. This circumstance allows the potency of toluene and ethanol to be compared relative to a common degree of behavioral impairment. Because the behavioral impairments caused by ethanol intoxication have also been associated with fatal automobile acci- dents in a dose-effect manner, it is possible to estimate the degree of toluene exposure associated with a level of impairment that might increase the probability of causing a fatal automobile accident if an exposed person were also driving at the same time. In addition to the probability of an automobile accident, this level of impairment would also be expected to put a person who was not driving at risk for other accidents or dan- gers given their unique circumstances and surroundings. With this approach, it is pos- sible to estimate the potential severity of acute behavioral impairments caused by tolu- ene in terms that are relevant for AEGL value determinations. Behavioral Consequences of Toluene Exposure Simulations comparing the behavioral effects of toluene and ethanol were made to provide context for the danger of toluene exposure in terms of the danger associated with comparable levels of intoxication with ethanol. These simulations used a behavioral effect (speed of choice reaction time) as a dependent variable. In these tests, the subject must make a decision about which response is correct as quickly as possible. Table D-1 and Figure D-1 show the severity of a decrement in reaction time (percent of maximum possible effect) as a function of brain toluene concentration, and also the blood ethanol concentrations equivalent to these brain toluene concentrations. Brain toluene concentrations are related quantitatively to blood ethanol concentrations in terms of the magnitude of change in reaction time associated with each chemical (Benignus et al. 2005). In addition, Table D-1 and Figure D-1 show corresponding increases in fatal automobile crashes as a function of degree of intoxication with either toluene or ethanol. These functions were derived from data relating the increased risk of a fatal car crash to blood ethanol concentration and the quantitative relationship between the effects of toluene and ethanol on reaction time. These relationships allow one to

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406 Acute Exposure Guideline Levels estimate the number of fatal automobile accidents that would be produced by toluene exposure as a function of the degree of intoxication (Benignus et al. 2011). It should be noted that the increase in fatal automobile accidents is given as the number of fatalities per 1,000 drivers who had the toxicant in their bodies while driving. From Table D-1 it may be concluded that a concentration of toluene in brain of 119 µM produces a degree of intoxication associated with about 13% reduction in speed of choice reaction time. This degree of impairment is also associated with 0.08 g/dl of venous ethanol, a concentration that defines legal intoxication and is associ- ated with an increase over baseline of 305 fatal automobile accidents per 1,000 driv- ers. Almost half of drivers with 0.10 g/dl venous ethanol or a brain toluene concen- tration of 241 µM would be expected to have fatal automobile accidents. Inhaled Concentrations of Toluene Required to Produce Specific Brain Concentrations In addition to the duration of exposure, alveolar ventilation, which depends upon physical activity, affects the concentration of toluene in the inhaled air that is required to produce a given brain toluene concentration. Table D-2 and Figure D-2 give approximate concentrations of toluene in inhaled air for a person exercising at four levels of exertion for two brain concentrations and for five exposure durations of interest. This illustrates the large impact of exertion on toluene uptake. TABLE D-1 The Importance of the Behavioral Effects of Toluene Exposure Estimated via the Alcohol Effects on Fatal Automobile Accidents and Employing the Equivalent Dose of Brain Toluene Proportion of Fatal Effect on Choice Venous Blood Automobile Accidents Equivalent Brain Reaction Time Test Alcohol (g/dL) Greater Than Baselinea Toluene (µM)b (% of Maximum)c 0.10 0.478 241.0 26.2 0.09 0.386 172.0 19.1 0.08 0.305 119.0 13.1 0.07 0.216 83.1 8.9 0.06 0.132 48.8 4.9 a Fatal automobile accident estimates were obtained from Zador (1991) and Zador et al. (2000) as expressed in Figure 2 of Benignus et al. (2011). The proportion of persons who were killed in a single-car crash with a measured post-mortem blood-ethanol concentra- tion, relative to persons driving with that same blood-ethanol concentration who did not crash, is expressed as a proportional increment above baseline (0.00 g/dL). b Toluene/alcohol equivalence was computed using Equation 2 in Benignus et al. (2011). c Behavioral effect magnitudes were computed using Equation 1, with human parameters for the low motivation case, from Table 4 of Benignus et al. (2009).

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Toluene 4 407 FIGUR D-1 The effec of alcohol intoxication (top h RE ct horizontal axis) o fatal automob on bile ivers per year) compared with th equivalent am accidents (per 1,000 dri he mount of toluene in e the brain (µM). This grraph is a modifie form of Figur 3 in Benignus et al. (2011). T ed re s The alcohol axis was construucted from Figru 1c from the s ure same source. Th plotted functio he ons reflect the mean estima (solid line) and the upper a lower 95% confidence lim t ate and % mits (dashed lines). d TABLE D-2 Approxim Exposures Required to Pr E mate s roduce Brain Toluene Concen ntrations Given in Table D-1 as Determined by the GPAT Mo s y odel Concentration Required for 241 µM R Conccentration Require for 119 µM ed Brain Toluene (ppm) Brain Toluene (ppm) n Time Lying Stan nding 1 mph 2 mph Lying g Standing 1 mph 2 mph 10 min 2,290 1,860 1,350 1,000 1,150 0 930 670 500 30 min 1,320 1,000 680 480 700 520 350 240 1h 1,010 730 460 320 540 390 240 165 4h 555 390 250 200 325 230 140 110 8h 445 320 220 190 275 190 130 100 The valu in the table were approxima by iterativel applying GPA (Benignus et al. ues w ated ly AT 2006). The modeled sub T bject was lying down, standing, or walking at 1 o 2 mph. d or

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408 Ac cute Exposure Guideline Levels FIGUR D-2 Concentr RE ration of inhaled toluene (ppm) required to pro d oduce brain tolue ene concenttrations of 241 or 119 µM at four exercise levels The two brain toluene concent r s. tra- tions are equivalent to venous concentr rations of alcoh of 0.1 or 0.08 g/dl. Those co hol on- centratio are roughly approximate va ons alues of ppm geenerated by the GPAT model (B Be- nignus et al. 2006). e Inhale Air Concen ed ntrations Requiired to Produc ce Toluene Concentration of 119 or 24 µM in the Br ns 41 rain All calculations so far were made using the G A m GPAT model, because the De en- nison model does not have a brain compartment. I order to ma exposure es m t In ake sti- mates with the accepted Dennison model, (a) a GP w m PAT model was used to estimate s the vennous concentratiions of toluene required to pro duce brain conccentrations of 1 110 or 241 µM and (b) the Dennison mod was used to determine the p del ppm values neces- sary to produce these venous concen ntrations. These venous and in e nhaled-air conce en- trations are presented in Table D-3. s i

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Toluene 409 TABLE D-3 Inhaled Air and Venous Concentrations of Toluene Required to Produce Either 119 or 241 µM Brain Toluene Concentrations Computed from the Dennison PBPK Model Time For 119 µM For 241 µM Air (ppm) Venous (mg/L) 10 min 625 2.07 1,498 5.24 30 min 372 2.75 729 5.87 1h 312 3.05 597 6.49 4h 258 3.55 481 7.52 8h 239 3.66 436 7.73 Behavioral Contingencies For both rats and humans, sensitivity to a given concentration of a solvent in the brain depends upon the situation under which the exposed individual was tested (Benignus et al. 2007, 2009). When a behavioral decrement has little consequence to the subject, the behavioral disruption by the toxicant will be maximal. If the subject loses a reward for poor performance, the effect of the tested toxicant will be reduced, or more toxicant will be necessary to disrupt the behavior. If painful punishment follows poor performance, the effect of the tested toxicant is greatly reduced. For example, rats working to avoid painful shocks are less susceptible to toluene expo- sure than are rats working for a food reward. Rats working for a food reward are less susceptible than are some nonmotivated neurophysiologic procedures that are not subject to either reward or punishment. It is important to consider behavioral meas- urements that are reasonably comparable if sensitivity is to be compared across fac- tors such as different behavioral tasks or across different species. Quantitative Rat-to-Human Extrapolation Using ED10 values for various situations in rats and humans from Figure 3 in Benignus et al. (2009), a table of extrapolation ratios was created (see Table D-4). Table D-4 shows that if experimental procedures are the same in rats and humans, the same brain solvent concentrations in the two species should produce the same ED10. In contrast, if the contingencies on performance differ, then ED10s will differ accordingly. Thus, modeling studies with rats suggest that the ED10 of a subject whose behavior is minimally constrained by contingencies will be lower by a factor of 86 compared to a subject avoiding punishment (Benignus et al. 2009). Thus quan- titative rat-human extrapolation requires information about the experimental contin- gencies applied during the tests; data from animal studies suggest that if the contin- gencies differ, then the extrapolation must take into account their relative impacts of the behavioral contingencies applied to each species.

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410 Acute Exposure Guideline Levels TABLE D-4 Extrapolating Factorsa from Rats to Humans Depending on Experimental Conditions None Minimum Withhold reward Painful punishment None 1.00 7.30 19.40 86.30 Minimum – 1.00 2.70 11.80 Withhold Reward – – 1.00 4.40 Painful punishment – – – 1.00 a Divide rat ED10 for the appropriate rat experimental condition by the extrapolation factor to calculate the human ED10. Factors calculated from the data to produce Figure 3 in Be- nignus et al. (2009). REFERENCES Benignus, V.A., P.J. Bushnell, and W.K. Boyes. 2005. Toward cost-benefit analysis of acute behavioral effects of toluene in humans. Risk Anal 25(2):447-456. Benignus, V.A., T. Coleman, C.R. Eklund, and E.M. Kenyon. 2006. A general physiolog- ical and toxicokinetic (GPAT) model for simulating complex toluene exposure scenarios in humans. Toxicol. Mech. Methods 16(1):27-36. Benignus, V.A., W.K. Boyes, E.M. Kenyon, and P.J. Bushnell. 2007. Quantitative com- parison of the acute neurotoxicity of toluene in rats and humans. Toxicol. Sci. 100(1):146-155. Benignus, V.A., P.J. Bushnell, W.K. Boyes, C. Eklund, and E.M. Kenyon. 2009. Neuro- behavioral effects of acute exposure to four solvents: Meta-analyses. Toxicol. Sci. 109(2):296-305. Benignus, V.A., P.J. Bushnell, and W.K. Boyes. 2011. Estimated rate of fatal automobile accidents attributable to acute solvent exposure at low inhaled concentrations. Risk Anal. 31(12):1935-1948. Zador, P.L. 1991. Alcohol-related relative risk of fatal driver injuries in relation to driver age and sex. J. Stud. Alcohol 52(4):302-310. Zador, P.L., S.A. Krawchuck, and R.B. Voas. 2000. Alcohol-related relative risk of driv- er fatalities and driver involvement in fatal crashes in relation to driver age and gender: An update using 1996 data. J. Stud. Alcohol 61(3):387-395.

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Toluene 411 APPENDIX E ACUTE EXPOSURE GUIDELINE LEVELS FOR TOLUENE AEGL-1 VALUES 10 min 30 min 1h 4h 8h 67 ppm 67 ppm 67 ppm 67 ppm 67 ppm (250 mg/m3) (250 mg/m3) (250 mg/m3) (250 mg/m3) (250 mg/m3) Key references: Multiple clinical studies, including: (1) Astrand, I., H. Ehrner-Samuel, A. Kilbom, and P. Ovrum. 1972. Toluene exposure. I. Concentration in alveolar air and blood at rest and during exercise. Scand. Work Environ. Health 9:119-130. (2) Gamberale, F., and M. Hultengren. 1972. Toluene exposure. II. Psychophysiological functions. Work Environ. Health. 9(3):131-139. (3) Baelum, J., G.R. Lundqvist, L. Molhave, and N.T. Andersen. 1990. Human response to varying concentrations of toluene. Int. Arch. Occup. Environ. Health 62(1):65-72. Test species/Strain/Number: Humans, (1) 15, both sexes; (2) 12 males; (3) 71 subjects Exposure route/Concentrations/Durations: Inhalation; (1) 100 or 200 ppm for 60 min, exercise incorporated into protocol; (2) 100, 300, 500, or 700 ppm, successive 20-min exposures for a total of 85 min (one 5-min break), exposure via a mouthpiece; (3) 100 ppm for 7.5 h, varying exposures of 50-300 ppm (TWA of 100 ppm) for 7.5 h. Effects: (1) 100 or 200 ppm with exercise: no effect on heart rate, pulmonary ventilation, oxygen consumption, or blood lactate; subjective symptoms not assessed. (2) One of 12 subjects able to distinguish between control and toluene exposure 100 ppm: no effect on reaction time 300 ppm: increase in simple reaction time 500 ppm: increase in complex reaction time 700 ppm: decrease in perceptual speed at end of exposure (3) 100 ppm: no ocular irritation, complaints of “poor air quality,” irritation of nose and lower airways. 50-300 ppm (TWA of 100 ppm): same symptoms as above. End point/Concentration/Rationale: Weight of evidence from multiple clinical studies indicated that toluene at 200 ppm for up to 8 h would be without effects that exceed the definition of AEGL-1. Slight irritation reported in some studies, but not others. Uncertainty factors/Rationale: Intraspecies: 3, the minimum alveolar concentration for volatile anesthetics differs by no more than 2- to 3-fold in the human population. Modifying factor: None Animal-to-human dosimetric adjustment: None Time scaling: Not applied; steady-state at 67 ppm is approached fairly rapidly. Data adequacy: Twenty clinical studies, many of them recent and well-conducted, addressed sensory irritation and the threshold for CNS effects. Metabolism and monitoring studies also indicate a lack of substantial effects at 200 ppm.

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412 Acute Exposure Guideline Levels AEGL-2 VALUES 10 min 30 min 1h 4h 8h 1,400 ppma 760 ppm 560 ppm 310 ppm 250 ppm (5,300 mg/m3) (2,900 mg/m3) (2,100 mg/m3) (1,200 mg/m3) (940 mg/m3) Reference: Bushnell, P.J., W.M. Ohiro, T.E. Samsam, V.A. Benignus, Q.T. Krantz, and E.M. Kenyon. 2007a. A Dosimetric analysis of the acute behavioral effects of inhaled toluene in rats. Toxicol. Sci. 99(1):181-189. Test species/Strain/Number: Rat; Long-Evans; 16 male rats exposed in groups of 4. Exposure route/Concentrations/Durations: Inhalation; 0, 1,200, 1,600, 2,000, or 2,400 ppm for up to 70 min. Effects: Reaction time doubled compared with air-exposed controls. Concentration- related increase in reaction time. NOAEL for a doubling of reaction time was 1,600 ppm for a 34-min exposure. End point/Concentration/Rationale: Doubling of reaction time, threshold of 1,600 ppm for 34-min exposure Uncertainty factors/Rationale: Interspecies: 1, PBPK modeling eliminated the toxicokinetic component of the uncertainty factor; the pharmacodynamic component was assigned a factor of 1 because similar central-nervous-system effects were observed in rodents and humans. Intraspecies: 3, the minimum alveolar concentration for volatile anesthetics differs by no more than 2- to 3-fold in the human population. Modifying factor: None Animal-to-human dosimetric adjustment: PBPK modeling performed Time scaling: PBPK modeling was used to determine the equivalent exposure concentrations that yield the dose metric at each of the AEGL exposure durations. Data adequacy: The values are supported by a comparison of the AEGL values and corresponding effect levels from ethanol consumption in humans (Benignus et al. 2011). a Concentration is one-tenth or more of the lower explosive limit of 14,000 ppm for tolu- ene in air. Therefore, safety considerations against the hazard of explosion must be taken into account. AEGL-3 VALUES 10 min 30 min 1h 4h 8h b b b 5,200 ppm 3,700 ppm 1,800 ppm 1,400 ppmb –a (20,000 mg/m3) (14,000 mg/m3) (6,800 mg/m3) (5,300 mg/m3) Reference: Mullin, L.S., and N.D. Krivanek. 1982. Comparison of unconditioned reflex and conditioned avoidance tests in rats exposure by inhalation to carbon monoxide, 1,1,1- trichloroethane, toluene or ethanol. Neurotoxicity 3(1):126-137. Test species/Strain/Number: Rats, CD, 6 males per group Exposure route/Concentrations/Durations: Inhalation, 810, 1,660, or 3,100 ppm for 4 h; 6,250 ppm for 2 h Effects: No deaths after a 2-h exposure at 6,250 ppm End point/Concentration/Rationale: NOAEL for lethality, 6,250 ppm for 2 h

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Toluene 413 Uncertainty factors/Rationale: Interspecies: 1, PBPK modeling eliminated the toxicokinetic component of the uncertainty factor; the pharmacodynamic component was assigned a factor of 1 because similar central-nervous-system effects were observed in rodents and humans. Intraspecies: 3, the minimum alveolar concentration for volatile anesthetics differs by no more than 2- to 3-fold in the human population. Modifying factor: None Animal-to-human dosimetric adjustment: PBPK modeling performed Time scaling: PBPK modeling was used to determine the equivalent exposure concentrations that yield the dose metric at each of the AEGL exposure durations. Data adequacy: There are multiple lethality studies in rats and mice. The AEGL-3 values are supported by the 20-min NOAEL of 12,000 ppm for lethality in the mouse (Bruckner and Peterson 1981a), the 2-h NOAEL of 5,000 ppm for lethality in rats (Kojima and Kobayashi 1973), the 4-h NOAEL of 6,000 ppm for lethality in rats (Wada et al. 1989), the NOAEL of 6,000 ppm in mice repeatedly exposed for 30 min/day (Moser and Balster 1981), and the chronic NOAEL of 1,200 ppm for mice and rats (NTP 1990). a The 10-min AEGL-3 value of 10,000 ppm (38,000 mg/m3) is higher than 50% of the lower explosive limit of 14,000 ppm for toluene in air. Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. b Concentration is one-tenth or more of the lower explosive limit of 14,000 ppm for tolu- ene in air. Therefore, safety considerations against the hazard of explosion must be taken into account.