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2 Carbon Tetrachloride Acute Exposure Guideline Levels
Pages 96-159

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From page 96...
... , Chemical Manager William Bress (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances)
From page 97...
... Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL. SUMMARY Carbon tetrachloride is a colorless, nonflammable, heavy liquid that is only slightly soluble in water.
From page 98...
... derived an inhalation 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)
From page 99...
... Subchronic 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 provided relate to effects following acute exposures, meaningful insight into understanding toxicity mechanisms, or for other special considerations.
From page 100...
... HUMAN TOXICITY DATA 2.1 Acute Lethality The acute toxicity and lethality of carbon tetrachloride in humans following inhalation exposure has been reviewed by Norwood et al.
From page 101...
... Exposure concentrations 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.
From page 102...
... also provided anecdotal data regarding compromised renal function in a worker experimentally exposed to carbon tetrachloride during an 8h work day. The concentration was estimated at 0.02% (200 ppm)
From page 103...
... 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)
From page 104...
... 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.
From page 105...
... 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 tetrachloride in humans following inhalation exposure.
From page 106...
... 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 documented in various laboratory species.
From page 107...
... (1961) Ct = 57 ppm-h postexposure; elevated urinary urobilinogen in one subject; no clinically significant effects and no irritation.
From page 108...
... Dow Chemical (1960) reported the results of acute inhalation studies in rats (age, weight, and strain not specified)
From page 109...
... , three of 15 guinea pigs died on the after 20, 22, and 30 days of exposure to carbon tetrachloride at 82 ppm (Prendergast et al.
From page 110...
... . 3.1.6 Summary of Lethal Toxicity in Animals Quantitative data regarding the lethality of carbon tetrachloride following acute inhalation exposure are available for several laboratory species (rats, mice, and guinea pigs)
From page 111...
... No data were provided that were specific to acute exposure times frames. 3.2.2 Dogs In a study submitted to the EPA Office of Toxic Substances by Union Carbide (Mellon Institute 1947)
From page 112...
... activity was used to assess the toxic response of male Wistar rats (12 per group) subjected to various exposure protocols that provided identical cumulative exposures (Ct = 300 ppm-h)
From page 113...
... The study showed measurable evidence of reversible toxic effects following various regimens of inhalation exposure to carbon tetrachloride at 63 or 80 ppm over a 4-week period. The available data were not appropriate for AEGL-specific time frames or for extrapolation to AEGL time frames.
From page 114...
... Histopathologic evaluation was limited to 1- and 2-week exposures and were not available for the shorter exposures. In studies to examine the effect of route and pattern of exposure on the pharmacokinetics and acute toxicity of carbon tetrachloride, Sanzgiri et al.
From page 115...
... conducted inhalation exposure experiments on anesthetized cats. Cats of both sexes were anesthetized with sodium pentobarbital, and were exposed by a tracheal cannula to carbon tetrachloride at 10,000 ppm for 15, 30, 60, or 240 min.
From page 116...
... was significant only at 300 ppm. Similarly, compared with the combined controls, fetal subcutaneous edema (potentially pertinent to acute exposure scenarios)
From page 117...
... 1936 Dog 400 ppm, 7 h/d for 6 mos Decreased body weight. Mellon Institute 1947 Rat 1,500 ppm, varying exposure profiles all with Hepatic vacuolation and individual cell necrosis which varied Van Stee et al.
From page 118...
... 800 ppm, 30 min No effect. 800 ppm, 60 min Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver 400 ppm, 60 min Altered liver weight, total lipid content and/or gross or microscopic changes in the liver 100 ppm, 420 min Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver.
From page 119...
... 5.64 ± 0.34 5.29 ± 0.34d 4.96 ± 0.68d d Fetal crown-rump length, mm (mean ± SD) 43.7 ± 1.0 42.2 ± 1.0 41.8 ± 2.2d a Carbon tetrachloride was administered by inhalation for 7 h/day on days 6-15 of gestation.
From page 120...
... caused a 23-fold increase in replicative DNA synthesis at 48 h. 3.5 Carcinogenicity Data on tumorigenic responses to carbon tetrachloride following inhalation exposure were limited.
From page 121...
... 3.6 Summary Animal toxicity data for inhaled carbon tetrachloride affirm hepatotoxic and renal effects, as well as anesthetic-like effects, as primary end points. The findings are consistent with those associated with human exposures, although carbon tetrachloride-induced nephrotoxicity appears to be more prevalent in humans than in laboratory species.
From page 122...
... Sprague-Dawley rats were exposed to carbon tetrachloride at 100 ppm for either 8 h/day or 11.5 h/day. The daily exposure regimens were adjusted such that cumulative exposures were identical.
From page 123...
... found that fecal elimination of carbon tetrachloride (as parent compound) by Sprague-Dawley rats did not significantly contribute to overall elimination of carbon tetrachloride following single or repeated inhalation exposure.
From page 124...
... but the precise mechanism of action is unknown. 4.3 Structure-Activity Relationships Assessment of structure-activity relationships were not instrumental is deriving AEGL values for carbon tetrachloride.
From page 125...
... In contrast, rats exhibited mild elevations in serum enzyme activities following exposures at 250 ppm for 4 h (Cornish and Block 1960) and at 250 ppm for 70 min (David et al.
From page 126...
... (1976) reported on an individual who exhibited only a modest, transient increase in serum transaminase activity, but experienced renal failure following acute exposure to carbon tetrachloride.
From page 127...
... (1995) affirmed that occupational exposure to carbon tetrachloride at mean concentrations of up to 4 ppm resulted in only minor alterations in serum enzyme activity.
From page 128...
... 6. DATA ANALYSIS FOR AEGL-2 6.1 Human Data Relevant to AEGL-2 Several reports provided data describing nonlethal effects of acute exposure of humans to carbon tetrachloride.
From page 129...
... However, no data were provided relative to acute exposures. Mice exposed at 4,770 ppm for 4 h exhibited centrilobular necrosis in the liver (Belyaev et al.
From page 130...
... Similarly, compared with the combined controls, fetal subcutaneous edema (potentially pertinent to acute exposure scenarios) was only significant at 300 ppm; however, no significant increase in total soft tissue abnormalities was detected at either dose.
From page 131...
... 7.2 Animal Data Relevant to AEGL-3 Lethality data are available from studies of squirrel monkeys, dogs, rats, mice, and guinea pigs. The squirrel monkey and guinea pig data did not involve acute exposures, and the dog study involved only one animal.
From page 132...
... Overall, PBPK models affirm greater sensitivity of rodent species to carbon tetrachloride on the basis of metabolism and disposition considerations for carbon tetrachloride. 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)
From page 133...
... Data from nonhuman primates indicate that chronic exposures to carbon tetrachloride at concentrations greater than the 8-h AEGL-3 value were not lethal. Extrapolation of EPA's inhalation unit risk to AEGL-specific exposure durations yield 10-4 cancer risk estimates at exposure concentrations that are higher than AEGL-2 values (see Appendix C)
From page 134...
... However, absence of AEGL-1 values does not imply that exposures below the AEGL-2 values are without adverse effects. TABLE 2-16 Standards and Guidelines for Carbon Tetrachloride Guideline 10 min 30 min 1h 4h 8h AEGL-1 NRa NRa NRa NRa NRa AEGL-2 27 ppm 18 ppm 13 ppm 7.6 ppm 5.8 ppm AEGL-3 700 ppm 450 ppm 340 ppm 200 ppm 150 ppm ERPG-1(AIHA)
From page 135...
... 1952. Vapor toxicity of carbon tetrachloride determined by experiments on laboratory animals.
From page 136...
... 1967. Carbon tetrachloride poisoning.
From page 137...
... Submit ted to EPA by Dow Chemical with cover letter dated September 4, 1987. EPA Document No.
From page 138...
... 1955. Fatal fulminant acute carbon tetrachloride poisoning.
From page 139...
... 1986a. A comparative study of the pharmacokinetics, of carbon tetrachloride in the rat following repeated inhalation exposures of 8 and 11.5 hr/day.
From page 140...
... 1985. Acute carbon tetrachloride poisoning in 19 patients: Implications for diagnosis and treatment.
From page 141...
... 1953. Nature and genesis of pulmonary alterations in carbon tetrachloride poisoning.
From page 142...
... Thus, not values are recommended. Derivation of AEGL-2 Values Key study: Davis 1934 Toxicity end point: No-effect level for CNS effects in human volunteers, 76 ppm for 4 h Scaling: C2.5 × t = k; n = 2.5 (see Appendix B for how the value for n was determined)
From page 143...
... (5,153.5 ppm) 2.5 × 1 h = 1,906,582,933 ppm-h Uncertainty factors: 1.5 for interspecies variability; results of PBPK models clearly indicate that the kinetics of carbon tetrachloride in rodents are markedly different from that in humans; rodents exhibit greater sensitivity in toxic responses.
From page 144...
... 144 Acute Exposure Guideline Levels 8-h AEGL-3: C2.5 × 8 h = 1,906,582,933 ppm-h C = 2,243 ppm 2,243 ppm ÷ 15 = 149.5 ppm, rounded to 150 ppm (940 mg/m3)
From page 145...
... Carbon n Tetrachloridee 1145 PPENDIX B AP DERIVATION OF O EXPONENNTIAL FUNC CTION FOR T TEMPORAL LING AND DE SCAL ERIVATION OF LETHAL LITY THRESH HOLD VALU UE Concentration-Time Morta ality Responsee Relationship p for Rats Time Concentration C Log Time Logg Concentration 6 20,000 0.7782 4.30010 15 12,000 1.1761 4.07792 60 10,000 1.7782 4.00000 90 7,300 1.9542 3.86633 300 4,600 4 2.4771 3.66628 480 3,000 2.6812 3.47771 Regresssion Output Intercept 4.6106 Slope -0.3947 R Squarred 0.9545 Correlattion -0.9770 Degrees of Freedom 4 Observaation 6 3 n = 2.53 k = 4.813E+11 Data So ources: Adams ett al. 1952; Dow Chemical 1960.
From page 146...
... 1952; Dow Chemical 1960.
From page 147...
... A comparison of the AEGL-2 and AEGL-3 values with the estimated concentration of carbon tetrachloride associated with a 10-4 cancer risk is presented in Table C-2. Estimated cancer risks for AEGL-2 and AEGL-3 values are also provided, obtained by assuming a linear relationship between exposure concentration and cancer risk.
From page 148...
... (1.5 mg/m3) TABLE C-2 Comparison of AEGL Values and Potential Cancer Risk Associated with Acute Inhalation of Carbon Tetrachloride Exposure Duration Value 10 min 30 min 1h 4h 8h 24 h Cancer risk (10-4)
From page 149...
... . 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)
From page 150...
... . 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.
From page 151...
... Carbon n Tetrachloridee 1151 PPENDIX E AP CATEGOR RY PLOTS FO OR CARBON TETRACHL LORIDE FIGUR RE E-1 Categorry plot of hum man toxicity datta and AEGL values for carbbon tetrachlo oride. FIGUR RE E-2 Categorry plot of anim mal toxicity datta and AEGL values for carbbon tetrachlo oride.
From page 152...
... 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.
From page 153...
... 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.
From page 154...
... 1952 Rat 1 400 60 2 Altered hepatic weight, total lipid content, and/or gross or microscopic changes in the liver. Adams et al.
From page 155...
... 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.
From page 156...
... 1985 Rat 2 80 180 0 Transient hepatic effects; 2- to 9-fold increase in SGOT, SGPT. Appelman et al.
From page 157...
... Dow Chemical 1960 Rat 1 20,000 6 2 Mortality (0/10) Dow Chemical 1960 Rat 1 20,000 15 SL Mortality (5/10)
From page 158...
... 1936 Rat 210 200 480 0 No significant effects. Mellon Institute 1947 Rat 1 1,000 480 2 Mortality (0/12)
From page 159...
... 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)


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