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Carbon Tetrachloride
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Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could

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1This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager William Bress (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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2 Carbon Tetrachloride1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Robert Young (Oak Ridge National Laboratory), Gary Diamond (SRC, Inc.), Julie Klotzbach (SRC, Inc.), Chemical Manager William Bress (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then re- viewed by the National Research Council (NRC) Committee on Acute Exposure Guide- line Levels. The NRC committee has concluded that the AEGLs developed in this docu- ment are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 96

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Carbon Tetrachloride 97 experience notable discomfort, irritation, or certain asymptomatic, nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Carbon tetrachloride is a colorless, nonflammable, heavy liquid that is on- ly slightly soluble in water. It is used as a laboratory and industrial solvent, an intermediate in the synthesis of trichlorofluoromethane and dichlorodifluoro- methane, and was formerly used as a dry-cleaning agent, grain fumigant, an- thelmintic (destructive to worms, especially parasitic varieties), and fire sup- pressant. Numerous case reports were available on acute inhalation exposure of humans to carbon tetrachloride, but most lacked adequate exposure characteriza- tion. These reports, however, affirmed the hepatotoxic and renal toxicity of car- bon tetrachloride, as well as a delayed response for serious and fatal effects. Additionally, data from controlled exposures of humans to carbon tetrachloride were also available. Animal toxicity data on carbon tetrachloride indicate hepatotoxic and re- nal effects, as well as anesthetic-like effects, as primary end points. The most sensitive end point for evaluating the toxicity of carbon tetrachloride in animals appears to be measurement of serum-enzyme activities that reflect hepatic dam- age. Several studies provided lethality data for various concentrations and expo- sure durations, but data on nonlethal effects were few or available only from long-term exposure studies.

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98 Acute Exposure Guideline Levels Studies in animals have shown the metabolism and disposition of carbon tetrachloride to be complex and varied between species. Although the precise mechanism of toxicity is equivocal, the biotransformation of carbon tetrachlo- ride by the monooxygenase enzymes (specifically CYP2E1) to reactive interme- diates is critical for expression of toxicity. That activation process is critical in modifying the toxic response to carbon tetrachloride. Data on carbon tetrachloride were inadequate to derive AEGL-1 values, so no values are recommended. AEGL-2 values for carbon tetrachloride were derived on the basis of the highest no-effect level of 76 ppm for central nervous system (CNS) effects in humans exposed for 4 h (Davis 1934). An interspecies uncertainty factor of 1 was used because the study was conducted in humans. An intraspecies uncer- tainty factor of 10 was applied to account for individuals who may be more sus- ceptible to the toxic effects of carbon tetrachloride (e.g., variability in metabo- lism and disposition). Temporal scaling was performed using the equation Cn × t = k (ten Berge et al. 1986), where an empirical value of n was determined to be 2.5 on the basis of rat lethality data. AEGL-3 values for carbon tetrachloride were based on a 1-h LC01 (lethal concentration, 1% lethality) of 5,135.5 ppm on the basis of data from multiple studies in laboratory rats (Adams et al. 1952; Dow Chemical 1960). Results of a physiologically-based pharmacokinetic (PBPK) model predict that rodents will attain higher concentrations of carbon tetrachloride in venous blood and fat than would similarly exposed humans, with greater metabolism of carbon tetrachlo- ride by rats relative to humans (Paustenbach et al. 1988; Delic et al. 2000). PBPK models predict that at equal exposure concentrations, humans will have lower rates of production of reactive metabolites of carbon tetrachloride (human ÷ rat = 0.5). On the basis of PBPK modeling, the amount of toxic metabolites produced in humans would be approximately half the amount in the rodent. Therefore, the toxicokinetic component of the interspecies uncertainty factor is 0.5. The toxicodynamic component is 3. The total interspecies uncertainty factor is 1.5 (3 × 0.5 = 1.5). An intraspecies uncertainty factor of 10 was applied to account for individuals who may be more susceptible to the toxic effects of car- bon tetrachloride (e.g., variability in metabolism and disposition of carbon tetra- chloride). Thus, the total uncertainty factor is 15. Temporal scaling was per- formed in the same manner as that for the AEGL-2 values. The US Environmental Protection Agency (EPA 2010a, b) derived an in- halation unit risk for carbon tetrachloride of 6 × 10-6 per μg/m3, and judged that the chemical is “likely to be carcinogenic to humans” on the basis of inadequate evidence of carcinogenicity in humans and sufficient evidence in animals by oral and inhalation exposure. Hepatic tumors were found in several species (rat, mouse, and hamster) and pheochromocytomas (adrenal gland tumors) were found in mice. Carbon tetrachloride is classified as a Group 2B carcinogen (pos- sibly carcinogenic to humans) by the International Agency for Research on Can- cer. The National Toxicology Program has classified carbon tetrachloride as

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Carbon Tetrachloride 99 reasonably anticipated to be a human carcinogen. Extrapolation of EPA’s inha- lation unit risk to AEGL-specific exposure durations results in 10-4 cancer risk estimates at exposure concentrations that are higher than AEGL-2 values. AEGL values for carbon tetrachloride are presented in Table 2-1. 1. INTRODUCTION Carbon tetrachloride is a colorless, nonflammable, and heavy liquid (O’Neil et al. 2006). It has been used as a laboratory and industrial solvent, as an intermediate in the synthesis of trichlorofluoromethane and dichlorodifluoro- methane, and was formerly used as a dry-cleaning agent, grain fumigant, an- thelmintic (destructive to worms, especially parasitic varieties), and as a fire suppressant (Walsh 1989). Carbon tetrachloride has a sweet, pungent odor that is not unpleasant. An odor threshold of 21.4-238.5 ppm has been reported (Billings and Jones 1981; Ruth 1989). The hepatotoxicity of carbon tetrachloride is well documented and has been reviewed by Rechnagel and Glende (1973). Carbon tetrachloride is also known to affect the CNS and to induce renal toxicity. The toxicity of carbon tetrachloride has been summarized by ATSDR (2005). For derivation of AEGL values, acute exposure studies are preferentially examined in this chapter. Sub- chronic and chronic studies generally have not been included because of the uncertainty associated with extrapolating such data to acute exposure scenarios. Studies of subchronic or chronic exposure may be addressed when the data pro- vided relate to effects following acute exposures, meaningful insight into under- standing toxicity mechanisms, or for other special considerations. The primary physical and chemical data on carbon tetrachloride are presented in Table 2-2. TABLE 2-1 AEGL Values for Carbon Tetrachloride End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NRa NRa NRa NRa NRa Inadequate data. (non-disabling) AEGL-2 27 ppm 18 ppm 13 ppm 7.6 ppm 5.8 ppm No-effect level (disabling) (170 (110 (82 (48 (36 for CNS effects mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) in humans (Davi 1934). AEGL-3 700 ppm 450 ppm 340 ppm 200 ppm 150 ppm Estimated LC01 (lethal) (4,400 (2,800 (2,100 (1,300 (940 in rats (Adams mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) et al. 1952; Dow chemical 1960). a Not recommended. Absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. Abbreviations: CNS, central nervous system; LC01, lethal concentration, 1% lethality.

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100 Acute Exposure Guideline Levels TABLE 2-2 Physical and Chemical Data on Carbon Tetrachloride Parameter Value Reference Synonyms Carbon chloride; carbona; carbon tet; freon 10; Walsh 1989; methane tetrachloride; perchloromethane; HSDB 2005 tetrachloromethane; tetrachlorocarbon; tetrafinol. CAS registry no. 56-23-5 HSDB 2005 Chemical formula CCl4 HSDB 2005 Molecular weight 153.82 HSDB 2005 Physical state Liquid HSDB 2005 Boiling point 77°C HSDB 2005 Melting point -23°C HSDB 2005 Density 1.5940 at 20°C HSDB 2005 Solubility 1,160 mg/L at 25°C in water; miscible with HSDB 2005 alcohol, benzene, chloroform, ether, petroleum ether, oils, carbon disulfide. Vapor pressure 115 mmHg at 25°C HSDB 2005 Conversion factors 1 mg/m3 = 0.159 ppm NIOSH 2011 in air 1 ppm = 6.29 mg/m3 2. HUMAN TOXICITY DATA 2.1 Acute Lethality The acute toxicity and lethality of carbon tetrachloride in humans follow- ing inhalation exposure has been reviewed by Norwood et al. (1950), Umiker and Pearce (1953), and ATSDR (2005). Most human case reports lack reliable quantitative exposure data. The more relevant reports are summarized in the following sections. Most lethal cases involve renal failure and are characterized by oliguria or anuria prior to death. Norwood et al (1950) reported on two fatalities involving exposure to car- bon tetrachloride vapors. In one of the fatalities, a exposure concentration was estimated on the basis of reconstruction of the incident. The case involved a 22- year old male who was mopping a floor with carbon tetrachloride that was placed in an open bucket (approximately 1 gallon). The subject reported experi- encing headache and dizziness after mopping for approximately 15 min. The investigators reported that “exposure conditions were duplicated to the best of our ability, and the measured concentration was 250 part carbon tetrachloride per million parts of air.” The possibility of dermal contact with carbon tetrachlo- ride was not discussed in the case report. The patient was admitted to a hospital with complaints of “generalized aches and pains, nausea and vomiting” and sub- sequently experienced renal failure and died 6 days after the reported exposure. Histopathologic examination conducted at autopsy confirmed centrilobular ne-

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Carbon Tetrachloride 101 crosis of the liver and interstitial edema and tubular (loop of Henle and distal convoluted tubule) degeneration in the kidney. The findings in the liver were consistent with, but not diagnostic of, carbon tetrachloride toxicity. The case history indicated that the patient had a history of heavy alcohol consumption. His coworkers reported that he did not work on the day previous to the exposure and did not “feel well” when he reported to work. Prior history of similar expo- sures to carbon tetrachloride was not reported (in this case, carbon tetrachloride was used during a night shift without the knowledge or sanction from the super- visor). Two coworkers who continued cleaning the floor for 4 h reported only mild headaches and dizziness, which subsided after the work was completed. Those symptoms are consistent with clinical studies in which exposures to car- bon tetrachloride at approximately 300-2,400 ppm for periods of 3-30 min re- sulted in headache, nausea and dizziness, but no deaths (Davis 1934). Collec- tively, these observations suggest that the case may represent an example of ethanol potentiation of carbon tetrachloride toxicity; although other factors not- ed above may also have contributed to the severe effects observed in this case (see Section 4 for further discussion of mechanism of toxicity and interactions with ethanol). Another fatality also reported by Norwood et al. (1950) involved an etha- nol intoxicated woman with a respiratory infection who used carbon tetrachlo- ride to clean her trailer. The patient experienced nausea and vomiting, ab- dominal tenderness, and anuria, and died 12 h after admission to the hospital. Histopathologic examinations revealed fatty degeneration and centrilobular ne- crosis of the liver and tubular degeneration of the kidneys. Exposure concentra- tions and duration were not reported. 2.2 Nonlethal Toxicity 2.2.1 Acute Exposure Case Reports Although many case reports are available regarding acute exposures to carbon tetrachloride, most are deficient in exposure details. Most of the reports do, however, describe a similar clinical picture of carbon tetrachloride poisoning that includes initial dizziness and nausea, abdominal discomfort, oliguria, anu- ria, and subsequent renal failure and death (Ashe and Sailer 1942; Gray 1947; Jennings 1955; Guild et al. 1958; New et al. 1962; Ruprah et al. 1985; Manno et al. 1996). The increased potential for carbon tetrachloride-induced toxicity (both renal and hepatic) associated with alcohol consumption or abuse has been doc- umented in several of the case reports. Davis (1934) reported the results of several experiments in which human subjects were exposed to carbon tetrachloride. The carbon tetrachloride concen- trations were determined on the basis of the room volume and the amount of carbon tetrachloride necessary to achieve the desired concentration; there was no mention of air-flow rate or ventilation in the test room. In one experiment four individuals (ages 20, 28, 28, and 30 years; gender not specified) were exposed to

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102 Acute Exposure Guideline Levels carbon tetrachloride at158 ppm for 30 min. One subject experienced nervous- ness and slight nausea but the remaining three were asymptomatic. There were no physiologically significant alterations in blood pressure, heart rate, respirato- ry rate, blood counts, or hemoglobin content. Urinalyses at 24 h postexposure revealed no signs of toxicity. In the second experiment, four subjects (ages 35, 48, 22, and 30; gender not specified) were exposed to a carbon tetrachloride at 76 ppm for 2.5 h. There were no symptoms or signs of toxicity in any of the subjects. In the third exper- iment, the same subjects used in the previous experiment were exposed 24 h later to carbon tetrachloride at 76 ppm for 4 h and did not have signs or symp- toms. Urinalyses at 72 h postexposure were normal. In the fourth experiment, three additional subjects (ages 20, 45, and 36; gender not specified) were ex- posed at 317 ppm for 30 min. Although clinical tests (blood pressure, hemoglo- bin, blood count, pulse, and urinalysis) were normal, one subject experienced nausea, another nausea and vomiting, and the third complained of headache. In fifth experiment, four subjects (ages 19, 21, 28, and 40; gender not specified) were exposed for 15 min to carbon tetrachloride at 1,191 ppm. Two of the sub- jects (one of which could only tolerate a 9-min exposure) experienced headache, nausea, and vomiting, another experienced nausea and vomiting, and another reported nausea and headache. Pulse rate and blood pressure appeared somewhat elevated, but no baseline data were provided for comparison. Urinalyses at 48-h postexposure were negative except for slightly increased acidity and phosphates. In the six experiment, three subjects (ages 40, 26, and 19; gender not specified) were exposed to carbon tetrachloride at 2,382 ppm for 5, 3, and 7 min, respec- tively. The first subject became dizzy, nauseated, sleepy, and experienced a throbbing headache. The second subject became nervous, nauseated, and listless, and the third subject experienced nausea, vomiting, dizziness, and became sleepy. Clinical examination 2 weeks after exposure revealed no adverse effects. In a less controlled experiment, Davis (1934) measured the carbon tetra- chloride concentration near the faces of men asked to use the solvent in an en- closed room. Using an alcohol potassium hydroxide and combustion method, the carbon tetrachloride concentration was found to be 0.23 % (≈2,300 ppm). None of the three subjects could work for more than 10 min without becoming nause- ated and sleepy. One of the three experienced vomiting, dizziness, and a throb- bing headache. Davis (1934) also provided anecdotal data regarding compromised renal function in a worker experimentally exposed to carbon tetrachloride during an 8- h work day. The concentration was estimated at 0.02% (200 ppm). Renal func- tion was recovered 2 months after the exposure. Smyth et al. (1936) conducted surveys in various occupational settings (e.g., dry cleaning, distillation processes) and found average concentrations of carbon tetrachloride ranging from 10-650 ppm, with peak concentrations of up to 7,860 ppm. On the basis of average working time, 8-h TWA values of 5-117 ppm were calculated for these subchronic exposure settings. The effects associ- ated with these exposures were minimal (evidence of restricted visual field and

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Carbon Tetrachloride 103 elevated bilirubin) but indicative of carbon tetrachloride exposure. Actual daily exposures concentrations were unknown. Elkins (1942) summarized the findings of case reports of workers in vari- ous facilities and tasks, including dry cleaning, spot cleaning, multigraphing, and coating. Reports of nausea, vomiting, and weight loss were associated with acute, albeit probably repeated, exposures to carbon tetrachloride at concentra- tions of 20-85 ppm. Elkins proposed that the maximum allowable concentration for carbon tetrachloride should be 25-50 ppm. Norwood et al (1950) reported on 56 nonlethal cases of carbon tetrachloride poisoning resulting from various activities (e.g., use of a carbon tetrachloride fire extinguisher, degreasing operations). Exposures were to carbon tetrachloride va- pors and possibly dermal contact with liquid carbon tetrachloride. Exposure con- centrations were not reported for any of these cases. During an industrial degreas- ing operation in which carbon tetrachloride was used as the degreasing agent, 51 workers reported for first aid with complaints that included: nausea (21), headache (22), vomiting (15), vertigo and dizziness (12), malaise (7), gastric upset (5), raw- ness of throat or nasal passages (4), abdominal cramps (4), anorexia (3), nervous- ness (3), insomnia (2), nocturia (1), and cough (1). Although lacking in exposure details, Stevens and Forster (1953) provided case reports with an emphasis on the neurologic signs and symptoms of carbon tetrachloride poisoning following inhalation and oral exposures. These included CNS effects (cerebellar degeneration, encephalomyelitis, cerebral hemorrhage) and peripheral neuritis. Kazantzis and Bomford (1960) reported on the response of workers ex- posed to carbon tetrachloride vapors while cleaning quartz crystals used in elec- tronic components. Although precise exposure data were not presented, the workers (14 men and four women, 16-54 years of age) were apparently exposed for about 8 h/day at concentrations of approximately 67-97 ppm. Fifteen work- ers complained of gastrointestinal disturbances (nausea, anorexia, vomiting, flatulence, epigastric distention, and discomfort), headaches, and depression. The effects were first noticed on Tuesday or Wednesday afternoons and in- creased in severity as the week progressed. The effects were first manifested during the preceding 4 months and increased in severity a few weeks before the investigation up to the point described. The cumulative exposures were appar- ently aggravated by closed windows during the winter months. The effects de- scribed could not necessarily be attributed to acute exposure (a single 8-h expo- sure) and two subjects with prior exposures presented with no signs or symptoms. The findings, however, suggest that intermittent exposures to carbon tetrachloride at less than 100 ppm over typical occupational exposure scenarios may result in notable signs of toxicity. Groups of six male human volunteers (30-59 years of age) were subjected to carbon tetrachloride using several different exposure protocols (Stewart et al. 1961). In the first experiment, six individuals were exposed to a time-weighted- average (TWA) concentration of 49 ppm (31-87 ppm) for 70 min. During the exposure, all subjects noted a sweetish odor. There were no instances of ocular

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104 Acute Exposure Guideline Levels or soft palate irritation, no nausea, and Romberg test and heel-to-toe testing re- mained normal. The only changes observed in clinical chemistry parameters (serum iron, serum transaminases, urinary urobilinogen, and urinalysis) were a transient reduction in serum iron in two subjects during the first 48 h after expo- sure, and an elevated urinary urobilinogen in one subject 7 days postexposure. The authors suggested that the depression of serum iron and elevated urine uro- bilinogen might have been the result of minor changes in metabolism and could be indicative of minimal liver insult. Serum enzyme activities were monitored up to 7 days postexposure and remained within normal ranges. In experiment 2, six subjects were exposed at 10.9 ppm (TWA) for 180 min. That was followed 4 weeks later by a repeat 180-min exposure (experiment 3) to carbon tetrachloride at 10 ppm. No adverse effects were reported by any of the subjects and no changes in blood pressure or timed vital capacities were detected. Barnes and Jones (1967) reported on three cases of carbon tetrachloride poisoning; two in an industrial setting and one involving a tank truck driver de- livering carbon tetrachloride. Exposure durations ranged from several minutes to approximately 3 h. Signs and symptoms were typical of carbon tetrachloride poisoning and included dizziness, nausea, delirium, abdominal discomfort, and oliguria. In the first case, a worker was cleaning sludge from a carbon tetrachlo- ride tank without a respirator or other protective device during the 3-h duration of the work. Soon afterward, he experienced nausea, vomiting, drowsiness, and anuria. Following medical intervention, his condition improved over several weeks. Liver biopsy revealed indications consistent with carbon tetrachloride poisoning. No exposure concentration was provided. The second case involved a worker draining a carbon tetrachloride storage tank. The incident involved an exposure of only several minutes and produced a strong odor. By evening the worker experienced dizziness, nausea, and delirium, and medical intervention was required. Simulation of the procedure resulted in carbon tetrachloride con- centrations of in excess of 600 ppm. The third case involved a truck driver ex- posed to carbon tetrachloride during loading of the tanker. Measurement of the carbon tetrachloride concentrations up to 30 ppm were made at various breath- ing zone vicinities around the truck at the discharge end of the trip but these were made during periods of high wind and unlikely to be representative of the actual accident. Concentrations of carbon tetrachloride detected during a 20-min period in the breathing zones of pipe fitters at the plan where the cases occurred ranged from 30 ppm to over 600 ppm. For one case, the “main exposure level” was estimated at 210 ppm. Although all three subjects recovered, the exposures resulted in notable toxicity. 2.2.2 Epidemiologic Studies A cross-sectional study of hepatic function in workers occupationally ex- posed to carbon tetrachloride was conducted by Tomenson et al. (1995). Multi- variate analysis of liver function variables and various other hematologic and biochemical parameters were compared in 135 exposed workers and 276 nonex-

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Carbon Tetrachloride 105 posed controls. Exposures were categorized on the basis of mean exposures; low (≤1 ppm), medium (>1-3 ppm), and high (≥4 ppm). Four liver function variables (alanine transaminase, aspartate transaminase, alkaline phosphatase, and gamma glutamyl transferase) exhibited statistically significant differences from nonex- posed controls, but no exposure-response relationship was demonstrated. The absence of an exposure-response may have been the result of imprecision in ranking worker exposures. The biologic relevance of the observed changes in serum enzyme activities was marginal and possibly of questionable clinical sig- nificance. The authors reported that there were no clinical signs concurrent with the aforementioned changes and that a 3-year follow-up study at the site with the highest exposures showed no evidence of further changes in liver function vari- ables. 2.3 Reproductive and Developmental Toxicity Human data on the reproductive and developmental toxicity after acute exposure to carbon tetrachloride were not available. 2.4 Genotoxicity No information was available regarding the genotoxicity of carbon tetra- chloride in humans following inhalation exposure. 2.5 Carcinogenicity Information regarding the potential carcinogenicity of carbon tetrachloride in humans following acute inhalation exposure include two anecdotal case re- ports (Tracey and Sherlock 1968). In one case, a 59-year-old man (with a history of moderate alcohol usage but not to the extent of inducing cirrhosis) died of hepatocellular carcinoma 7 years after an acute exposure to carbon tetrachloride (exposure details not provided). In a second case, a 30-year-old woman died of liver cancer after 2-3 years of occupational exposure to carbon tetrachloride at concentrations sufficient to produce signs of toxicity. EPA (2010b) states that carbon tetrachloride is “likely to be carcinogenic to humans” on the basis of inadequate evidence of carcinogenicity in humans but sufficient evidence in animals by oral and inhalation exposure. The animal evidence included hepatic tumors in three species (rat, mouse, and hamster) and pheochromocytomas (adrenal gland tumors) in mice. On the basis of the in- creased incidence of pheochromocytomas in male BDF1 mice (Nagano et al. 2007), EPA (2010b) derived an inhalation unit risk of 6 × 10-6 per μg/m3. Car- bon tetrachloride is classified as a Group 2B (possibly carcinogenic to humans) carcinogen by the International Agency for Research on Cancer. NTP has classi- fied carbon tetrachloride as reasonably anticipated to be a human carcinogen.

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106 Acute Exposure Guideline Levels 2.6 Summary Case reports of human fatalities resulting from acute exposure to carbon tetrachloride provide a clinical picture of dizziness, nausea, abdominal pain, oliguria, anuria, and death being attributed to renal failure and hepatotoxicity. Also well documented is the potential for greater carbon tetrachloride-induced toxicity in individuals with histories of alcohol usage, a phenomenon that is con- sistent with the known dispositional potentiation of carbon tetrachloride toxicity by inducers of cytochrome CYP2E1 enzymes (Plaa 2000; ATSDR 2005; EPA 2010a). Most human case reports were lack information on exposure concentra- tions and durations. Controlled exposure studies by Davis (1934) and Stewart et al. (1961) showed a varied response to inhaled carbon tetrachloride among the tested subjects. Cumulative exposures to carbon tetrachloride at 30-57 ppm-h resulted in odor detection but no irritation or clinical effects in most subjects, whereas cumulative exposures at 79-2,133 ppm-h produced effects ranging from nervousness and headaches to nausea and vomiting. The variability in response to carbon tetrachloride is emphasized by the fact that an estimated exposure at 63 ppm-h was fatal in a heavy drinker whereas controlled exposures at 190 ppm- h were without effect. Quantitative data pertaining to inhalation exposures of humans to carbon tetrachloride are presented in Table 2-3. 3. ANIMAL TOXICITY DATA The discussion of animal toxicity studies on carbon tetrachloride focuses on acute exposure studies (durations of less than 24 h) or longer-term studies that provided response data for exposure periods that were of possible use in the derivation of AEGL values or as a basis for comparison with AEGL values. 3.1 Acute Lethality Lethality following acute exposures to carbon tetrachloride has been doc- umented in various laboratory species. Where available, histopathologic findings revealed hepatic injury. For some studies, data are presented that are not strictly from acute exposures, as some of the data may provide reference points with which to evaluate AEGL values. 3.1.1 Nonhuman Primates In a repeated exposure study (8 h/day, 5 days/week for 6 weeks), one of three squirrel monkeys died after the seventh exposure to carbon tetrachloride at 82 ppm (Prendergast et al. 1967).

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Carbon Tetrachloride 149 APPENDIX D ACUTE EXPOSURE GUIDELINE LEVELS FOR CARBON TETRACHLORIDE Derivation Summary AEGL-1 VALUES Although human data on AEGL-1 effects from carbon tetrachloride are available, values derived on the basis of the data greater than the corresponding AEGL-2 values. Therefore, AEGL-1 values for carbon tetrachloride are not rec- ommended. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 27 ppm 18 ppm 13 ppm 7.6 ppm 5.8 ppm Reference: Davis, P.A. 1934. Carbon tetrachloride as an industrial hazard. JAMA 103(13):962-966. Test species/Strain/Number: Humans (gender not specified); ages 20-48 years; 3-4 per exposure group Exposure route/Concentrations/Durations: Inhalation: 76 ppm for 2.5 or 4 h; 158 or 317 ppm for 30 min; 1,191 ppm for 15 min; 2,382 ppm for 3-7 min or ≤10 min; 5-117 ppm for 8 h. Effects: CNS effects at concentrations >76 ppm 76 ppm for 2.5 h: no effects 76 ppm for 4 h: no effects 158 ppm for 0.5 h: nervousness in one subject; no effect in three subjects. 317 ppm for 0.5 h: slight nausea and vomiting, headache. 1,191 ppm for 0.25 h: nausea, vomiting, headache; intolerable for one subject (9-min exposure only) 2,382 ppm for 3-7 min: nausea, vomiting, dizziness, listlessness, headache, sleepiness. 2,382 ppm for ≤10 min: nausea, vomiting, headache, sleepiness. Time scaling: Cn × t = k; n = 2.5, on the basis of regression analysis of lethality data from Adams et al. (1952). Concentration/Time Selection/Rationale: 76 ppm for 4 h; the highest no-effect level for CNS effects Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies:1, because the critical study was conducted in humans Intraspecies:10, to protect sensitive individuals (e.g., variation in cytochrome P-450) Modifying factor: none Animal-to-human dosimetric adjustment: None Data adequacy: Data are adequate to derive AEGL-2 values.

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150 Acute Exposure Guideline Levels AEGL-3 VALUES 10 min 30 min 1h 4h 8h 700 ppm 450 ppm 340 ppm 200 ppm 150 ppm References: Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McCollister, and D.D. Irish. 1952. Vapor toxicity of carbon tetrachloride determined by experiments on laboratory animals. AMA Arch. Ind. Hyg. Occup. Med. 6(1):50-66. Dow Chemical. 1960. Comparison of the Result of Exposure of Rats and Cavies to the Vapors of Carbon Tetrachloride and Bromochloromethane, June 11, 1960. Submitted to EPA by Dow Chemical with cover letter dated September 4, 1987. EPA Document No. 86870002363. Microfiche No. OTS0515887. Test Species/Strain/Number: Rats; albino or not specified; 5-30 per group Exposure route/Concentrations/Durations: Inhalation ; 3,000-20,000 ppm for 0.1-12 h. Effects: Lethality in rats; estimated 1-h LC01 of 5,135.5 ppm. Time scaling: Cn × t = k; n = 2.5 on the basis of regression analysis of lethality data from Adams et al. (1952). Concentration/Time selection/Rationale: Estimated 1-h LC01 of 5,153.5 ppm Uncertainty factors/Rationale: Total uncertainty factor: 15 Interspecies: 1.5, PBPK model results predict that rodents will attain higher concentrations of carbon tetrachloride in venous blood and fat than would similarly exposed humans, with greater metabolism of carbon tetrachloride by rats relative to humans (Paustenbach et al. 1988; Delic et al. 2000). PBPK models predict that, at equal exposure concentrations, humans will have lower rates of production of reactive CCl4 metabolites (human/rat = 0.5). On the basis of PBPK modeling, the amount of toxic metabolites produced in humans would be expected to be approximately half the amount in the rodent. Therefore, the toxicokinetic component of the interspecies uncertainty factor is 0.5. The toxicodynamic component is 3. The total intraspecies uncertainty factor is 1.5 (3 × 0.5 = 1.5). Intraspecies:10, to account for individual variability in the sensitivity to carbon tetrachloride-induced toxicity (e.g., alcohol-potentiated hepatotoxicity). Modifying factor: None Animal-to-human dosimetric adjustment: Insufficient data. Data adequacy: The AEGL-3 values are supported by subchronic exposure studies in animals showing that exposures above the AEGL-3 values did not result in lethality. Potential dermal absorption of carbon tetrachloride is not addressed by the AEGL values.

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Carbon Tetrachloride n e 1 151 PPENDIX E AP CATEGOR PLOTS FO CARBON TETRACHL RY OR LORIDE FIGUR E-1 Categor plot of hum toxicity dat and AEGL values for carb RE ry man ta bon tetrachlo oride. FIGUR E-2 Categor plot of anim toxicity dat and AEGL values for carb RE ry mal ta bon tetrachlo oride.

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152 TABLE E-1 Date Used in the Category Plots for Carbon Tetrachloride Source Species Sex # Exposures ppm Min. Category Comments AEGL-1 NR 10 AEGL AEGL-1 NR 30 AEGL AEGL-1 NR 60 AEGL AEGL-1 NR 240 AEGL AEGL-1 NR 480 AEGL AEGL-2 27 10 AEGL AEGL-2 18 30 AEGL AEGL-2 13 60 AEGL AEGL-2 7.6 240 AEGL AEGL-2 5.8 480 AEGL AEGL-3 700 10 AEGL AEGL-3 450 30 AEGL AEGL-3 340 60 AEGL AEGL-3 200 240 AEGL AEGL-3 150 480 AEGL Davis 1934 Human 1 76 150 0 4 subjects, no adverse effects. Davis 1934 Human 2 76 240 0 4 subjects, no adverse effects. Davis 1934 Human 1 158 30 0 4 subjects, no adverse effects. Davis 1934 Human 1 317 30 1 3 subjects: one experienced nausea, one had nausea and vomiting, and one complained of headache. Davis 1934 Human 1 1,191 9 2 4/4 subjects experienced headache, nausea, vomiting, and tolerated exposures of 9 - 15 min.

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Davis 1934 Human 2,300 10 2 3/3 subjects could not tolerate more than 10 min without becoming nauseated and sleepy. One experienced vomiting, dizziness, and a throbbing headache. Davis 1934 Human 1 2,382 3 2 3/3 subjects experienced nausea, vomiting, dizziness, and listlessness or sleepiness and tolerated exposure for 3 - 7 min. Norwood et al 1950 Human M 1 250 15 SL 1/3 subjects experienced headache and dizziness, aches and pains, nausea and vomiting, renal failure and death, centrilobular necrosis of the liver and interstitial edema and tubular (loop of Henle and distal convoluted tubule) degeneration in the kidney. Norwood et al 1950 Human 1 250 240 1 2/3 workers experienced mild headache and dizziness during exposure. Smyth et al 1936 Human 117 480 2 Elevated bilirubin, restricted visual field (imprecise assessments for both). Stewart et al. 1961 Human 10.1 180 0 6 subjects; no adverse effects. Stewart et al. 1961 Human 10.9 180 0 6 subjects; no adverse effects. Stewart et al. 1961 Human 49 70 0 6 subjects; no clinically significant effects; no irritation; odor detection; transient decline in serum iron 20-68 h postexposure; elevated urinary urobilinogen in one subject. McCollister et al. 1951 Monkey 1 485 240 1 Negligible absorption as determined by radioactivity in the blood and expired air. Dow Chemical 1960 Mouse F 1 8,500 680 SL LCt50 Gehring 1968 Mouse 1 8,500 0.16 1 ECt50 for SGPT activity Gehring 1968 Mouse 1 8,500 21 1 ECt50 for anesthesia (Continued) 153

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154 TABLE E-1 Continued Source Species Sex # Exposures ppm Min. Category Comments Merck 1983 Mouse 1 9,400 3.5 2 Mortality (0/5) Merck 1983 Mouse 1 18,800 3.5 2 Mortality (0/5) Merck 1983 Mouse 1 37,500 3.5 2 Mortality (0/5) Merck 1983 Mouse 1 75,000 3.5 SL Mortality (2/6) Merck 1983 Mouse 1 150,000 3.5 3 Mortality (6/6) Nagano et al. 2007 Mouse B 520 5 360 Nagano et al. 2007 Mouse B 520 25 360 Nagano et al. 2007 Mouse B 520 125 360 Svirbaly et al. 1947 Mouse 1 6,340 480 2 Mortality (0/20) Svirbaly et al. 1947 Mouse 1 7,628 480 SL Mortality (2/20) Svirbaly et al. 1947 Mouse 1 8,088 480 SL Mortality (19/20) Svirbaly et al. 1947 Mouse 1 8,787 480 SL Mortality (10/20) Svirbaly et al. 1947 Mouse 1 9,327 480 3 Mortality (20/20) Ugazio et al. 1995 Rabbit 23 100 120 0 Increased hexobarbital sleeping time; hepatic fibrosis. Adams et al. 1952 Rat 1 50 420 0 No effects. Adams et al. 1952 Rat 1 100 420 2 Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver. Adams et al. 1952 Rat 1 400 60 2 Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver. Adams et al. 1952 Rat 1 800 30 0 No effects. Adams et al. 1952 Rat 1 800 60 2 Altered hepatic weight, total lipid content,

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and/or gross or microscopic changes in the liver. Adams et al. 1952 Rat 1 3,000 6 0 No effects. Adams et al 1952 Rat 1 3,000 9 1 Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver. Adams et al. 1952 Rat 1 3,000 480 2 Mortality (0/20) Adams et al. 1952 Rat 1 3,000 600 SL Mortality (1/30) Adams et al. 1952 Rat 1 3600 480 SL Mortality (4/10) Adams et al. 1952 Rat 1 3,600 720 SL Mortality (1/10) Adams et al. 1952 Rat 1 4,600 300 2 Mortality (0/20) Adams et al. 1952 Rat 1 4,600 360 SL Mortality (1/11) Adams et al. 1952 Rat 1 4,600 480 SL Mortality (2/10) Adams et al. 1952 Rat 1 7,300 60 2 Mortality (0/20) Adams et al. 1952 Rat 1 7,300 90 2 Mortality (0/20) Adams et al. 1952 Rat 1 7,300 120 SL Mortality (1/10) Adams et al. 1952 Rat 1 7,300 180 SL Mortality (1/10) Adams et al. 1952 Rat 1 7,300 240 SL Mortality (4/10) Adams et al. 1952 Rat 1 7,300 360 SL Mortality (6/10) Adams et al. 1952 Rat 1 7,300 420 SL Mortality (4/10) Adams et al. 1952 Rat 1 7,300 480 3 Mortality (20/20) Adams et al. 1952 Rat 1 12,000 3 2 Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver. Adams et al. 1952 Rat 1 12,000 15 2 Mortality (0/20) Adams et al. 1952 Rat 1 12,000 30 SL Mortality (1/10) (Continued) 155

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156 TABLE E-1 Continued Source Species Sex # Exposures ppm Min. Category Comments Adams et al. 1952 Rat 1 12,000 60 SL Mortality (3/10) Adams et al. 1952 Rat 1 12,000 120 SL Mortality (7/10) Adams et al. 1952 Rat 1 12,000 180 SL Mortality (8/10) Adams et al. 1952 Rat 1 12,000 240 3 Mortality (20/20) Adams et al. 1952 Rat 1 19,000 6 SL Mortality (1/10) Adams et al. 1952 Rat 1 19,000 12 SL Mortality (1/5) Adams et al. 1952 Rat 1 19,000 18 SL Mortality (3/5) Adams et al. 1952 Rat 1 19,000 30 SL Mortality (2/5) Adams et al. 1952 Rat 1 19,000 36 SL Mortality (14/15) Adams et al. 1952 Rat 1 19,000 42 3 Mortality (5/5) Adams et al. 1952 Rat 1 19,000 48 SL Mortality (4/5) Adams et al. 1952 Rat 1 19,000 60 SL Morality (9/19) Adams et al. 1952 Rat 1 19,000 132 3 Mortality (20/20) Appelman et al. 1985 Rat 2 63 180 0 Transient hepatic effects; 2- to 9-fold increase in SGOT, SGPT. Appelman et al. 1985 Rat 20 63 360 0 Transient hepatic effects; 2- to 9-fold increase in SGOT, SGPT. Appelman et al. 1985 Rat 2 80 180 0 Transient hepatic effects; 2- to 9-fold increase in SGOT, SGPT. Appelman et al. 1985 Rat 20 80 360 0 Transient hepatic effects; 2- to 9-fold increase in SGOT, SGPT. Cornish and Block 1960 Rat B 1 50 240 0 Cornish and Block 1960 Rat B 1 50 240 0

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Cornish and Block 1960 Rat B 1 100 240 0 Cornish and Block 1960 Rat B 1 250 240 1 Cornish and Block 1960 Rat B 1 1,000 240 1 Cornish and Block 1960 Rat B 1 1,500 240 1 David et al. 1981 Rat 13-18 50 360 1 Minor increase in SGPT, minor histologic changes in the liver. David et al. 1981 Rat 13-18 250 72 1 Minor increase in SGPT, minor histologic changes in the liver. David et al. 1981 Rat 13-18 1,000 3 1 Minor increase in SGPT, minor histologic changes in the liver. David et al. 1981 Rat 13-18 1,000 18 1 Minor increase in SGPT, minor histologic changes in the liver. Dow Chemical 1960 Rat 1 10,000 60 2 Mortality (0/5) Dow Chemical 1960 Rat 1 10,000 90 2 Mortality (0/5) Dow Chemical 1960 Rat 1 10,000 120 SL Mortality (5/10) Dow Chemical 1960 Rat 1 10,000 150 3 Mortality (5/5) Dow Chemical 1960 Rat 1 20,000 6 2 Mortality (0/10) Dow Chemical 1960 Rat 1 20,000 15 SL Mortality (5/10) Dow Chemical 1960 Rat 1 20,000 30 SL Mortality (8/10) Nagano et al. 2007 Rat B 520 5 360 Nagano et al. 2007 Rat B 520 25 360 Nagano et al. 2007 Rat B 520 125 360 Increased hepatocellular adenomas and carcinomas. Paustenbach et al. 1986b Rat 1 100 480 0 No significant effect on SDH. (Continued) 157

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158 TABLE E-1 Continued Source Species Sex # Exposures ppm Min. Category Comments Paustenbach et al. 1986b Rat 1 100 690 1 Marginally increased SDH. Sakata et al. 1987 Rat 1 180 15 2 "Comatose"; increased ALT at 24-h postexposure. Sanzgini et al. 1995 Rat 1 100 120 0 No effects. Sanzgini et al. 1995 Rat 1 1,000 120 1 Increased ALT and SDH, decreased P-450. Schwetz et al. 1974 Rat F 10 300 420 2 Fetoxicity. Schwetz et al. 1974 Rat F 10 1,000 420 2 Fetoxicity. Smyth et al. 1936 Rat 210 200 480 0 No significant effects. Mellon Institute 1947 Rat 1 1,000 480 2 Mortality (0/12) Mellon Institute 1947 Rat 1 3,000 480 2 Mortality (0/12) Mellon Institute 1947 Rat 1 4,000 480 SL Mortality (2/12) Mellon Institute 1947 Rat 1 8,000 390 3 Mortality (12/12) Van Stee et al. 1982 Rat 1 Hepatic vacuolation and individual cell necrosis which varied with exposure profile. Wang et al. 1997 Rat 1 50 360 0 No effects. Wang et al. 1997 Rat 1 500 360 1 Minor increase in SGOT and SGPT. Smyth et al. 1936 Rhesus monkey 210 200 480 1 Transient hepatic injury. Prendergast et al. 1967 Squirrel monkey 1 82 480 0 One of three monkeys died after the 7th exposure at 82 ppm (8h/day; 5d/wk for 6 wk). Wong and DiStefano 1966 Cat 1 10,000 15 2 Increased total lipids in renal cortex. Wong and DiStefano 1966 Cat 1 10,000 30 2 Increased relative adrenal weight. Wong and DiStefano 1966 Cat 1 10,000 60 2

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Wong and DiStefano 1966 Cat 1 10,000 240 2 Central necrosis in liver. Mellon Institute 1947 Dog 168 400 420 1 Decreased body weight. Dow Chemical 1960 Guinea pig 1 10,000 0.25 2 Mortality (0/5) Dow Chemical 1960 Guinea pig 1 10,000 1 2 Mortality (0/5) Dow Chemical 1960 Guinea pig 1 10,000 1.5 SL Mortality (1/10) Dow Chemical 1960 Guinea pig 1 10,000 2 SL Mortality (4/5) Dow Chemical 1960 Guinea pig 1 10,000 2.5 SL Mortality (1/5) Dow Chemical 1960 Guinea pig 1 10,000 3 SL Mortality (1/5) Dow Chemical 1960 Guinea pig 1 20,000 0.5 SL Mortality (2/5) Dow Chemical 1960 Guinea pig 1 20,000 1 SL Mortality (4/5) For category: 0 = no effect, 1 = discomfort, 2 = disabling, SL = some lethality, 3 = lethal. 159