Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 17 (2014) / Chapter Skim
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6 Toluene1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA)
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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 susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
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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 occupational-monitoring studies that involved exposures at up to 1,500 ppm. Those populations are presumed to be composed of healthy individuals, but they represent a broad spectrum of uptake rates (sedentary, working, and exercise conditions)
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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.
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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)
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294 Acute Exposure Guideline Levels In 1999, world production of toluene was nearly 13,000,000 tons. Approximately 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.
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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)
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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.
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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.
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298 Acute Exposure Guideline Levels 2.1. Acute Lethality Inhalation of "high concentrations" can result in paresthesia, vision disturbances, dizziness, nausea, CNS depression, and collapse (Henderson 2001)
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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 sensations)
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300 Acute Exposure Guideline Levels other solvents. Only the study by Wilson (1943)
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Toluene 301 long-term exposure to toluene below 50 ppm. Irritation of the conjunctiva and upper respiratory tract was found in only one of 11 workers exposed at 200-800 ppm (Parmeggiani and Sassi 1954)
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302 Acute Exposure Guideline Levels Two cases of accidental occupational exposure to toluene at very high concentrations were reported by Longley et al.
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Toluene 303 More than 300 individuals have been evaluated in clinical studies involving toluene exposures of 40-700 ppm. The subjects are presumed to be healthy individuals, but represent a broad spectrum of uptake rates (sedentary, working, and exercise conditions)
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304 Acute Exposure Guideline Levels ppm, the latter with exercise at 75 and 50 W for 30 min each. Toluene concentrations were measured by gas chromatography.
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Toluene 305 Twelve healthy, adult men (ages 20-50) inhaled toluene at a constant concentration of 40 ppm for 4 h or were exposed to three 30-min peaks at 110 ppm over a 4-h period (Lammers et al.
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306 Acute Exposure Guideline Levels the subjects rated the discomfort (nausea, headache, or irritation in the eyes, nose, or esophagus) during the exposure as negligible.
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Toluene 307 after the exposure. Each subject served as his or her own control.
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308 Acute Exposure Guideline Levels As part of the same study, Nielsen et al.
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Toluene 309 and 50. The subjects were healthy males and females who did not abuse alcohol or drugs and were able to exercise for 15-min periods with a load of 50, 75, or 100 W during the peak exposures.
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310 Acute Exposure Guideline Levels was a tendency for reaction time to be prolonged during the 200-ppm exposure, but there was no clear concentration-response relationship. Twelve healthy male subjects, ages 20 to 35, were exposed to successively increasing concentrations of toluene at 100, 300, 500, and 700 ppm, for four successive 20-min periods (Gamberale and Hultengren 1972)
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Toluene 311 exposed to both toluene and diazepam. During the third session, vigilance errors were increased for all groups except the control group.
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312 Acute Exposure Guideline Levels brown paper bag containing the contents of two tubes of 3/4 oz each of Testor's cement...". The estimated concentration of toluene in the paper bag was 10,000 ppm (3.6 mg of toluene/100 mL of air)
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Toluene 313 2.5. Genotoxicity Several investigators examined the effect of occupational exposures to toluene on peripheral lymphocytes.
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314 Acute Exposure Guideline Levels concentrations of toluene ranged from 450 ppm in the 1940s to as low as 30 ppm by the mid-1980s; workers were also exposed to various concentrations of benzene and other hydrocarbons for various durations. When the data were analyzed for workers who had been exposed for at least 5 years and a latency of 10 years, no significant increase in deaths from cancers was observed.
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Toluene 315 al. 1975; Andersen et al.
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316 Acute Exposure Guideline Levels 3.
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TABLE 6-4 Summary of Acute Lethal and Sublethal Toxicity of Toluene in Laboratory Animals Species Concentration (ppm) Exposure Duration Effects Reference Dog 30,000 10 min Successive tachycardia, bradycardia, and Ikeda et al.
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318 TABLE 6-4 Continued Species Concentration (ppm) Exposure Duration Effects Reference Mouse 38,465 10 min LC50 Moser and Balster 1981; 1985 21,872 30 min LC50 19,018 60 min LC50 6,000a 30 min No deaths Mouse 24,400 6h 100% mortality Cameron et al.
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Toluene 319 Kojima and Kobayashi (1973) exposed groups of five male albino rats to concentrations of toluene ranging from 5,000 to 25,000 ppm for 2 to 2.5 h.
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320 Acute Exposure Guideline Levels exposed at 10,000 ppm for approximately 1 h or in mice exposed at 3,000 ppm for 5 h/day for 90 days (Bushnell et al.
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Toluene 321 weekly for 8 weeks, transient body weight depression and increased hepatic weights were observed. Histopathologic findings in the heart, lungs, kidneys, brain, and liver were generally unremarkable.
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322 Acute Exposure Guideline Levels tion was impaired at 2,000 ppm or higher, as indicated by an increase in response time and a decrease in accuracy of matching. Response time at 4,500 ppm increased by 0.26 sec over the control response time, and monkeys failed to respond during the second half of the session.
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TABLE 6-5 Neurbehavioral Effects of Acute Inhalation Exposure to Toluene in Rats Concentration (ppm) Duration Effects Reference 150 0.5, 1 h Stimulatory effect, multiple schedule performance.
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324 TABLE 6-5 Continued Concentration (ppm) Duration Effects Reference 1,000, 1,780, 3,000 2h 1,780 and 3,000 ppm: concentration-dependent increase in response rates to food Wood et al.
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Toluene 325 0.4 sec to 0.8 sec) compared with controls was evident at exposures of 2,000 and 2,400 ppm for 34 min and at 1,600 ppm for 46 min.
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326 Acute Exposure Guideline Levels 6,250 ppm, rats failed numerous tests at 1 h and were prostrate at 2 h, at which time the test was terminated. There were no mortalities.
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Toluene 327 difference in shock counts. Behavior recovered in an hour.
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328 Acute Exposure Guideline Levels changes in visual discrimination performance, defined as a slowing of response speed and disinhibition of responding (results presented graphically)
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TABLE 6-6 Neurobehavioral Effects of Acute Inhalation Exposure to Toluene in Mice Concentration (ppm) Duration Effects Reference 100 72 min No effect on locomotor activity.
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330 Acute Exposure Guideline Levels times with respect to maximum concentrations tested for each duration. There was only a 5-min recovery time for a 10-min exposure at 5,000 ppm.
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Toluene 331 ior were not observed. Instead, there was a concentration-related decrease in responding, which was most obvious at 4,000 ppm and higher.
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332 Acute Exposure Guideline Levels Bruckner and Peterson (1981a) also reported on recovery times of mice following 5-, 10-, or 20-min exposures to toluene at concentrations of 4,000, 8,000, or 12,000 ppm.
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TABLE 6-7 Reproductive and Developmental Toxicity of Toluene in Animals Concentration (ppm) Duration Effects Reference Rat 266 GD 1-21 (8 h/d)
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334 TABLE 6-7 Continued Concentration (ppm) Duration Effects Reference Mouse 133, 399 GD 6-13 (24 h/d)
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Toluene 335 Male F344/N rats and B6C3F1 mice evaluated in the toluene inhalation studies of NTP (1990) exhibited no compound-related effects on sperm count or motility when exposed at concentrations of 3,000 ppm or less for 14 weeks or at 1,200 ppm or less for 2 years.
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336 Acute Exposure Guideline Levels mal aberrations or DNA single-strand breaks. However, three of these studies used toluene preparations of unspecified purity and could have been contaminated with benzene (a known clastogen)
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Toluene 337 The results revealed no evidence of carcinogenicity in treated animals compared with concurrent controls. Mild degeneration of the nasal cavity olfactory and respiratory epithelium was observed at 600 and 1,200 ppm.
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338 Acute Exposure Guideline Levels exposures at higher concentrations. The lowest concentration that retarded fetal growth of the rat was 1,200 ppm when administered under developmental and reproductive guidelines suggested by EPA (6 h/day during organogenesis)
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Toluene 339 1990, 1993)
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340 FIGURE 6-1 Metabolism of to oluene in mammalian n systems (heavy arro ows indicate major pathways of metabolissm)
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Toluene 341 terminal half-life, steady-state volume of distribution, and terminal volume of distribution (Pierce et al.
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342 Acute Exposure Guideline Levels and Nomiyama 1978; Hasegawa et al. 1983; Ogata 1984)
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TABLE 6-8 Relationship between Ambient Air and Blood Concentrations of Toluene Species Exposure Duration Air Concentration (ppm) (level of work)
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344 TABLE 6-8 Continued Species Exposure Duration Air Concentration (ppm) (level of work)
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Rat 4h 50 0.5 Haddad et al. 1999a 100 1.3 200 5.0 Rat 3h 50 0.45 Benignus et al.
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346 25 Gamberale & Hultengren, 1972 20 Blood Concentration (mg/L) 15 Astrand et al., 1972 (No Exercise)
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Toluene 347 350 300 Blood Concentration (mg/L) 250 Dog 200 Rat Mouse 150 100 50 0 0 2000 4000 6000 8000 10000 12000 Air Concentration (ppm)
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348 Acute Exposure Guideline Levels 100 End of Exposure Brain ppm 10 Blood 1 0 60 120 180 240 300 360 420 480 Time (minutes) FIGURE 6-4 Toluene concentrations in the brain and venous blood of Long-Evans rats during and after exposure to toluene at 575 ppm for 4 h.
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Toluene 349 toluene poisoning; they also stated that using a plastic bag to "concentrate" the vapors and direct inhalation from the bag contributed to the fatality. A painter who died following a fall had tissue concentrations of toluene in blood, lungs, liver, and brain of 48, 35, 65, and 80 μg/g, respectively (Takeichi et al.
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350 Acute Exposure Guideline Levels Intentional exposure to excessively high concentrations of toluene results in feelings of euphoria, which progress to lethargy and neurobehavioral deficits; these effects resemble those produced by anesthetics. Toluene is highly lipophilic and, as a nonpolar, planar molecule, can behave as an anesthetic by dissolving in the interior lipid matrix of a membrane.
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Toluene 351 duced an anesthesia-like effect with loss of righting reflex (for phenobarbital, the loss of righting reflex occurred at 30 mg/kg)
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352 Acute Exposure Guideline Levels 1985)
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Toluene 353 4.4.3. Concentration-Response Relationship The two primary effects of toluene exposure are irritation and CNS depression.
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354 Acute Exposure Guideline Levels to toluene (75, 150, and 225 ppm) and xylene (225, 150, and 75 ppm)
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Toluene 355 breathing tube. Concentrations of toluene above 300 ppm were associated with subtle differences in the speed of reacting to a stimulus or completing a task.
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356 Acute Exposure Guideline Levels ppm is a NOAEL for notable discomfort, but elicited subjective, low-severity, nonsensory effects in some studies. More than 300 individuals were involved in the clinical studies summarized in Table 6-3.
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Toluene 357 (see Section 4.4.2) , an uncertainty factor of 3 for intraspecies variability was applied to derive a value of 67 ppm.
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358 Acute Exposure Guideline Levels Cox 1995) and monkeys (Taylor and Evans 1985)
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Toluene 359 man GPAT model (Benignus et al.
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360 Acute Exposure Guideline Levels ppm for 30 min/day, 5 days/week for 7 weeks and that were deprived of food survived the exposures in apparent good health (Moser and Balster 1981)
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Toluene 361 Workers lost consciousness after being accidentally exposed to toluene at an estimated concentration of 5,000 ppm or greater for an undefined period of time (Longley et al.
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362 Acute Exposure Guideline Levels TABLE 6-12 AEGL Values for Toluene Classification 10 min 30 min 1h 4h 8h AEGL-1 67 ppm 67 ppm 67 ppm 67 ppm 67 ppm (nondisabling)
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Toluene 363 c ERPG (emergency response planning guidelines, American Industrial Hygiene Association)
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364 Acute Exposure Guideline Levels h REL-STEL (recommended exposure limit – short-term exposure limit, National Institute for Occupational Safety and Health)
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Toluene 365 centrations. Although the animal data base on lethality was limited to rodents (rats and mice)
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366 Acute Exposure Guideline Levels Anderson, D., and J.A. Styles.
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Toluene 367 Benignus, V.A., T Coleman, C.R.
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368 Acute Exposure Guideline Levels Brugnone, F
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Toluene 369 Courtney, K., J Andrews, J
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370 Acute Exposure Guideline Levels Eller, N., B Netterstrom, and P
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Toluene 371 Gibson, J.E., and J.F. Hardisty.
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372 Acute Exposure Guideline Levels Occupational Exposures in Paint Manufacture and Painting. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol.
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Toluene 373 Klimisch, H.J., J Hellwig, and A
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374 Acute Exposure Guideline Levels Low, L.K., J.R. Meeks, and C.R.
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Toluene 375 MSZW (Ministerie van Sociale Zaken en Werkgelegenheid)
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376 Acute Exposure Guideline Levels Morgantown, WV [online]
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Toluene 377 Effects of inhalation exposure on fertility in rats.
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378 Acute Exposure Guideline Levels Rahill, A.A., B Weiss, P.E.
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Toluene 379 Spanggord, R.J., K.E. Mortelmans, A.F.
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380 Acute Exposure Guideline Levels Tardif, R., P.O.
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Toluene 381 Vrca, A., D Bozicevic, V
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382 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR TOLUENE Derivation of AEGL-1 Values Key studies: Astrand, I., H Ehrner-Samuel, A
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Toluene 383 Ogata, M., K Tomokuni, and Y
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384 Acute Exposure Guideline Levels Time scaling: CNS effects observed after toluene exposure were assumed to be directly related to parent material reaching the brain. Therefore, a physiologically-based pharmacokinetic (PBPK)
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Toluene 385 Uncertainty factors: 1 for interspecies differences; PBPK modeling allows a comparison of the internal dose in both rats and humans from identical external exposures, and similar CNS effects were observed in rodents and humans. 3 for intraspecies variability; the minimum alveolar concentration for volatile anesthetics differs by no more than 2- to 3-fold in the human population.
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386 APPENDIX B CATEGORY PLOT FOR TOLUENE 100000 Human ‐ No Effect Human ‐ Discomfort/ Mild Human ‐ Disabling 10000 Animal ‐ No Effect Animal ‐ AEGL‐3 Discomfort ppm 1000 Animal ‐ Disabling Animal ‐ Some AEGL‐2 Lethality Animal ‐ Lethal 100 AEGL‐1 AEGL‐3 AEGL‐2 AEGL‐1 10 0 60 120 180 240 300 360 420 480 Minutes FIGURE B-1 Category plot of animal toxicity data and AEGL values for toluene.
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TABLE B-1 Data Used in Category Plot for Toluene Source Species ppm Minutes Category AEGL-1 67 10 AEGL AEGL-1 67 30 AEGL AEGL-1 67 60 AEGL AEGL-1 67 240 AEGL AEGL-1 67 480 AEGL AEGL-2 1,400 10 AEGL AEGL-2 760 30 AEGL AEGL-2 560 60 AEGL AEGL-2 310 240 AEGL AEGL-2 250 480 AEGL AEGL-3 10,000 10 AEGL AEGL-3 5,200 30 AEGL AEGL-3 3,700 60 AEGL AEGL-3 1,800 240 AEGL AEGL-3 1,400 480 AEGL Andersen et al. 1983 Human 40 360 0, no neurobehavioral effects Andersen et al.
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388 TABLE B-1 Continued Source Species ppm Minutes Category Winneke 1982 Human 100 210 0, no behavioral deficits in psychomotor tests Dick et al. 1984 Human 100 240 0, no neurobehavioral deficits Rahill et al.
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Gamberale and Hultengren 1972 Human 300 20 0, increase in reaction time Gamberale and Hultengren 1972 Human 500 20 0, increase in complex reaction time Gamberale and Hultengren 1972 Human 700 20 0, decrease in perceptual speed at end of exposure Carpenter et al. 1944 Human 200 420 1, mild irritation Carpenter et al.
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390 TABLE B-1 Continued Source Species ppm Minutes Category Moser and Balster 1985 Mouse 19,018 60 SL, LC50 Bruckner and Peterson 1981a Mouse 12,000 20 2, no mortality Bruckner and Peterson 1981a Mouse 8,600 180 SL, LC50 Bonnet et al. 1979 Mouse 6,940 360 SL, LC50 Svirbely et al.
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Hinman 1987 Rat 15,000 60 2, no mortality Nielsen and Alarie 1982 Mouse 7,800 30 2, no mortality Nielsen and Alarie 1982 Mouse 5,300 30 2, RD50 Kojima and Kobayashi 1973 Rat 10,000 120 SL, 20% mortality Pryor et al. 1978 Rat 40,000 60 3, lethal Ikeda et al 1990 Dog 30,000 10 3, lethal Kishi et al.
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392 Acute Exposure Guideline Levels APPENDIX C PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODELING OF TOLUENE Summary The method used in this appendix to determine human equivalent AEGL values is similar to that previously reported (Bruckner et al. 2004; Krewski et al.
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Toluene 393 Step 3) Calculate the dose metric amount under conditions that correspond to the critical study.
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394 Acute Exposure Guideline Levels Additional information and justification of these choices of critical studies is available in the technical support document. The target tissue dose (venous blood concentration)
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Toluene 395 Model Structure The model structure is shown in Figure C-1. The tissue groups/compartments specified are consistent with models for other inhaled volatile organic solvents (Reddy et al.
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396 Acute Exposure Guideline Levels TABLE C-2 Physiologic Parameters for the Toluene Rat Model Parameter, units Symbol Value Footnote 1 Body weight, kg BW 0.237-0.508 Cardiac output, L/h-kg0.75 QCC 2 Normal 11.2 Sedentary, day acclimated 11.2 Active, day-acclimated 13.2 Alveolar ventilation, L/h-kg0.75 QPC 2 Normal 9.9 Ratio = 0.9 Sedentary, day-acclimated 12.2 Ratio = 1.1 Active, day-acclimated 22.4 Ratio = 1.7 Flow (fraction QC) 3 4 Lung QCC 1.0 Liver QLC 0.02 Fat QFC 0.082 Brain QBC 0.027 Gut QGC 0.16 SPTG QSC 0.257 RPTG QRC 1-Qi Volumes (fraction body weight)
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Toluene 397 TABLE C-3 Chemical-Specific Parameters for the Toluene Rat Model Parameter Symbol Units Value Reference Partition coefficients Blood:air PB None 21.0 Thrall et al. 2002 Lung:blood PN None 1.14 Liver:blood PL None 2.01 Brain:blood PBR None 1.72 Fat:blood PF None 86.19 Gut:blood PG None 2.62 RPTG:blood PR None 2.62 SPTG:blood PS None 1.32 Metabolism parameters Vmax VMAXC L/h/kg0.75 4.55 Tardif et al.
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398 Acute Exposure Guideline Levels TABLE C-4 Toluene Concentrations in Air Associated with Relevant Brain Toluene Concentrations in Rats and Humans as Determined by PBPK Modeling 10 min 30 min 1h 4h 8h Duration extrapolation at the critical brain toluene concentration (BrTC) in rats, and extrapolation to humans using one-third of the critical internal dose (per guidance in NRC 2002)
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Toluene 399 TABLE C-5 AEGL-2 Values for Toluene Determined with PBPK Model of Human Data 10 min 30 min 1h 4h 8h UF = 1 1,855 805 601 426 378 UF = 3, applied to human 618 268 200 142 126 equivalent concentration UF = 3, applied to dose metric 655 305 239 180 166 Source: Based on Gamberale and Hultengren 1972. The AEGL-3 values were based on a rat NOAEL for lethality and were determined in the same manner as the AEGL-2 values: the determination of the internal dose metric used the rat PBPK model and the determination of the HEC used the human GPAT model.
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400 Acute Exposure Guideline Levels Attachment 1 PBPK Model Code for Toluene AEGL Rat Model Models used were published models for the rat (Kenyon et al.
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Toluene 401 CONSTANT BW = 0.350 ! Body Weight(kg)
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402 Acute Exposure Guideline Levels !
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Toluene 403 ! CI - Concentration TOL in inhaled air (mg/l)
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404 Acute Exposure Guideline Levels ! AG - Amount TOL in gut tissue(mg)
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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.
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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.
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Toluene 4407 FIGUR RE D-1 The effecct of alcohol intoxication (top hhorizontal axis) oon fatal automobbile accidents (per 1,000 driivers per year)
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408 Accute Exposure Guideline Levels FIGUR RE D-2 Concentrration of inhaled d toluene (ppm) required to prooduce brain tolueene concenttrations of 241 orr 119 µM at four exercise levelss.
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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)
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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 Benignus et al.
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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)
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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)
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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.
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