EPA-540/1-86-039 Office of Emergency and Remedial Response Washington DC 20460 Superfund &EPA Off'ce of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati OH 45268 HEALTH EFFECTS ASSESSMENT FOR CARBON TETRACHLORIDE ------- EPA/540/1-86-039 September 1984 HEALTH EFFECTS ASSESSMENT FOR CARBON TETRACHLORIDE U.S. Environmental Protection Agency Office of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati, OH 45268 U.S. Environmental Protection Agency Office of Emergency and Remedial Response Office of Solid Waste and Emergency Response Washington, DC 20460 ------- DISCLAIMER This report has been funded wholly or In part by the United States Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse Research Corporation. It has been subject to the Agency's peer and adminis- trative review, and 1t has been approved for publication as an EPA document. Mention of trade names or commercial products does not constitute endorse- ment or recommendation for use. 11 ------- PREFACE This report summarizes and evaluates Information relevant to a prelimi- nary Interim assessment of adverse health effects associated with carbon tetrachloMde. All estimates of acceptable Intakes and carcinogenic potency presented In this document should be considered as preliminary and reflect limited resources allocated to this project. Pertinent toxlcologlc and environmental data were located through on-Hne literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATAL06 data bases. The basic literature searched supporting this document 1s current up to September, 1984. Secondary sources of Information have also been relied upon 1n the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The following Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized: U.S. EPA. 1980b. Ambient Water Quality Criteria for Carbon Tetra- chlorlde. Environmental Criteria and Assessment Office, Cincin- nati, OH. EPA-440/5-80-026. NTIS PB 81-117376. U.S. EPA. 1983b. Reportable Quantity Document for Carbon Tetra- chlorlde. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1983c. Review of Toxlcologlc Data 1n Support of Evalua- tion for Carcinogenic Potential of: Carbon Tetrachlorlde. Prepared by the Carcinogen Assessment Group, OHEA, Washington, DC for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1984. Health Assessment Document for Carbon Tetrachlo- rlde. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/8-82-001F. NTIS PB 85-124196. The Intent 1n these assessments Is to suggest acceptable exposure levels whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the variable data were limited 1n scope tending to generate conservative (I.e., protective) estimates. Never- theless, the Interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemlcal(s) addressed. Whenever possible, two categories of values have been estimated for sys- temic toxicants (toxicants for which cancer Is not the endpolnt of concern). The first, the AIS or acceptable Intake subchronlc, 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (I.e., for an Interval that does not constitute a significant portion of the Hfespan). This type of exposure estimate has not been extensively used or rigorously defined, as previous risk assessment efforts have been primarily directed towards exposures from toxicants 1n ambient air or water where lifetime exposure 1s 111 ------- assumed. Animal data used for AIS estimates generally Include exposures with durations of 30-90 days. Subchronlc human data are rarely available. Reported exposures are usually from chronic occupational exposure situations or from reports of acute accidental exposure. The AIC, acceptable Intake chronic, is similar 1n concept to the ADI (acceptable dally Intake). It 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the Hfespan [see U.S. EPA (1980a) for a discussion of this concept]. The AIC 1s route specific and estimates acceptable exposure for a given route with the Implicit assumption that exposure by other routes Is Insignificant. Composite scores (CSs) for noncarclnogens have also been calculated where data permitted. These values are used for ranking reportable quanti- ties; the methodology for their development 1s explained 1n U.S. EPA (1983a). For compounds for which there Is sufficient evidence of carclnogenlclty, AIS and AIC values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980a). Since cancer 1s a process that 1s not characterized by a threshold, any exposure contributes an Increment of risk. Consequently, derivation of AIS and AIC values would be Inappropriate. For carcinogens, q-|*s have been computed based on oral and Inhalation data 1f available. 1v ------- ABSTRACT In order to place the risk assessment evaluation 1n proper context the reader Is referred to the Preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appro- priate Interpretation and use of the quantitative estimates presented. Animal bloassay data 1n three species (rats, mice, hamsters) Indicate that carbon tetrachlorlde Is a hepatic carcinogen. Human data are limited and equivocal. The Cancer Assessment Group, as explained In U.S. EPA (1984), has used data from the following for risk assessment purposes: Delia Porta et al. (1961); Edwards et al. (1942); NCI (1976) (both rat and mouse). Since none of these studies were deemed adequate Individually, the geometric mean of the upper limit unit risk estimates (3.7xlO~6) has been employed. The corresponding slope estimate (q-|*) is l.SOxlCT1 (mg/kg/day)"1. A note of caution 1s provided by U.S. EPA (1984). Some evidence Indi- cates that carbon tetrachlorlde may act via a nongenotoxic mechanism. If this should be the case, then low-dose risk extrapolation using techniques developed for agents which presumably act through genotoxicity could substantially overestimate risk. The reader Is referred to U.S. EPA (1984) for a thorough discussion of this question. More experimental data are needed to resolve this Issue. ------- ACKNOWLEDGEMENTS The Initial draft of this report was prepared by Syracuse Research Corporation under Contract NO. 68-03-3112 for EPA's Environmental Criteria and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and Helen Ball wasithe Project Officer. The final documents In this series were prepared for the Office of Emergency and Remedial Response, Washington, DC. Scientists from the following U.S. EPA offices provided review comments for this document series: Environmental Criteria and Assessment Office, Cincinnati, OH Carcinogen Assessment Group Office of A1r Quality Planning and Standards Office of Solid Waste Office of Toxic Substances Office of Drinking Water Editorial review for the document series was provided by: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by: Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon Environmental Criteria and Assessment Office Cincinnati, OH v1 ------- TABLE OF CONTENTS 1. 2. 3. 4. 5. 6. 7. ENVIRONMENTAL CHEMISTRY AND FATE ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . 2.1. ORAL 2.2. INHALATION TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral 3.1.2. Inhalation 3.2. CHRONIC 3.2.1. Oral 3.2.2. Inhalation 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . 3.3.1. Oral 3.3.2. Inhalation 3.4. TOXICANT INTERACTIONS CARCINOGENICITY 4.1. HUMAN DATA 4.2. BIOASSAYS 4.2.1. Oral 4.2.2. Inhalation 4.3. OTHER RELEVANT DATA 4.4. WEIGHT OF EVIDENCE REGULATORY STANDARDS AND CRITERIA RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.3. CARCINOGENIC POTENCY (q-|*) 6.3.1. Oral 6.3.2. Inhalation REFERENCES Page 1 3 ... 3 ... 3 ... 4 ... 4 ... 4 ... 4 5 ... 5 5 ... 8 ... 8 , . . 9 ... 9 ... 11 ... 11 ... 11 ... 11 ... 17 ... 17 ... 17 ... 19 ... 21 ... 21 ... 21 , . 21 ... 21 ... 21 ... 22 APPENDIX: Summary Table for Carbon Tetrachlorlde 32 ------- LIST OF TABLES No. Title Page 1-1 Selected Physical and Chemical Properties and Half-lives of Carbon Tetrachlorlde 2 4-1 Survival of Rats Treated with Carbon Tetrachlorlde 14 4-2 Survival of Mice Treated with Carbon Tetrachlorlde 15 4-3 Liver Tumors 1n Mice 16 5-1 Current Regulatory Standards and Criteria for Carbon Tetrachlorlde 20 ------- LIST OF ABBREVIATIONS ADI Acceptable dally Intake AIC Acceptable Intake chronic AIS Acceptable Intake subchronlc BCF Bloconcentratlon factor bw Body weight CS Composite score PEL Frank-effect level GI Gastrolntetlnal LOAEL Lowest-observed-adverse-effect level MED Minimum effective dose ppm Parts per million SGOT Serum glutamlc oxaloacetlc transamlnase SGPT Serum glutamlc pyruvlc transamlnase STEL Short-term exposure limit TLV Threshold limit value TWA Time-weighted average 1x ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE The relevant physical and chemical properties and environmental fate of carbon tetrachlorlde (CAS No. 56-23-5), also known as tetrachloromethane, are shown In Table 1-1. The value for the retardation factor for carbon tetrachlorlde 1s esti- mated on the basis of a comparison of the octanol/water partition coeffi- cient and water solubility of this compound with chloroform and the estimated retardation factor of 1.2 for chloroform (Wilson et a!., 1981). The half-life of carbon tetrachlorlde In soil could not be located 1n the literature searched; however, evaporation 1s expected to be the predomi- nant loss mechanism from the soil surface. In subsurface soil, blodegrada- tlon of carbon tetrachlorlde will probably be a very slow process, as Is true of chloroform (Wilson et al.t 1983). Therefore, carbon tetrachlorlde Is expected to leach Into groundwater. This has been confirmed by Page (1981), who detected carbon tetrachlorlde with a 64% frequency 1n ground- water. -1- ------- TABLE 1-1 Selected Physical and Chemical Properties and Half-lives for Carbon TetrachloMde Properties Values Reference Chemical class: Molecular weight: Vapor pressure: Water solubility: Octanol/water partition coefficient: Soil mobility: (predicted as retardation factor for a soil depth of 140 cm and organic carbon content of 0.087%) BCF: Half-lives 1n A1r: halogenated aliphatic hydrocarbon 153.82 90 mm Hg at 20°C 757 mg/l at 25°C 437 537 >1.2 (estimated) Water: 30 1n blueglll (Lepomls macroschlrus) 17 1n fathead minnow (Plmephales promelas) 22 years -50 years 0.3-3 days 1n river 30-300 days 1n lake Callahan et al., 1979 Banerjee et al., 1980 Callahan et al., 1979 Banerjee et al., 1980 Wilson et al., 1981 U.S. EPA, 1980b Velth et al., 1979 Singh et al., 1981 U.S. EPA, 1984 Zoeteman et al., 1980 -2- ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2.1. ORAL No pertinent studies of absorption of carbon tetrachlorlde from the 61 tract of humans were located 1n the available literature. Little Informa- tion on absorption from the GI tract of experimental animals was available. In an early study, Robblns (1929) Investigated absorption of carbon tetra- chlorlde from the GI tract of dogs. He reported that "considerable quanti- ties" were absorbed from the small Intestine, lesser quantities from the colon and still lesser quantities from the stomach. Lamson et al. (1923) suggested that the dynamics and kinetics of absorption from the GI tract may vary from species to species. They observed more rapid GI absorption In rabbits than 1n dogs. Nielsen and Larsen (1965) determined that both the rate and the amount of carbon tetrachlorlde absorption from the GI tract were Increased by concurrent 1ngest1on of fat or alcohol. 2.2. INHALATION Pertinent studies of pulmonary absorption of carbon tetrachlorlde In humans were not located 1n the available literature. Few studies on pulmo- nary absorption 1n experimental animals were found. Nielsen and Larsen (1965) stated that carbon tetrachlorlde is "readily absorbed" through the lungs but the species studied was not reported (U.S. EPA, 1980b). Lehmann and Hasegawa (1910) showed that the rate of absorption decreased with duration of exposure. von Oettlngen et al. (1949, 1950) studied blood concentrations in dogs following exposure to 15 or 20 g/a. in air. Peak blood concentrations of -35 or -38 mg/8. were attained after -300 minutes of exposure to 15 or 20 g/a, 1n air, respectively. -3- ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. Reports of acute toxldty from accidental, medicinal or suicidal 1ngest1on of carbon tetrachlorlde are available, but no reports of subchronlc 1ngest1on 1n man were located In the available literature. One study of subchronlc oral exposure described the toxldty of carbon tetra- chlorlde 1n Syrian golden hamsters. U.S. EPA (1983c) discussed the study by Delia Porta et al. (1961) 1n which groups of 10 male and 10 female Syrian golden hamsters were treated with 12.26 mg/week carbon tetrachlorlde by gavage for 30 weeks (-12.3 mg/kg/day). Mortality claimed 50% of the animals of each sex before treatment was completed. The survivors all developed hepatocellular carcinoma within the next 13 weeks. 3.1.2. Inhalation. Prendergast et al. (1967) performed two studies of subchronlc Inhalation exposure In animals. In the first experiment, guinea pigs and monkeys were exposed to 80 ppm carbon tetrachlorlde for 8 hours/ day, 5 days/week for 6 weeks (30 exposures). Increased mortality (3/15 guinea pigs, 1/3 monkeys) and severe liver damage were reported. In the second experiment, animals were exposed to either 1 or 10 ppm carbon tetra- chlorlde continuously for 90 days. At 10 ppm, guinea pigs showed Increased mortality (3/15 treated vs. 2/314 colony controls), growth depression and liver enlargement with fatty Infiltration, hepatocytlc degeneration, flbro- blastlc proliferation and collagen deposition. Rats, monkeys and rabbits also experienced depressed growth rates and similar hlstopathologlcal liver lesions, but no mortality occurred 1n these species. No mortality or gross signs of toxldty occurred 1n guinea pigs, rats, monkeys or rabbits exposed to 1 ppm carbon tetrachlorlde continuously for 90 days. A depression of body weight gain was observed only In rats. No changes were noted 1n -4- ------- hematologlc or hlstologlc parameters 1n any of the species tested; continu- ous exposure to 1 ppm carbon tetrachlorlde (6.3 mg/m3) was designated a LOAEL associated with depression of body weight gain. 3.2. CHRONIC 3.2.1. Oral. Pertinent data regarding chronic exposure of man to carbon tetrachloMde were not located 1n the available literature. Studies of chronic exposure of animals to carbon tetrachlorlde were designed to be cardnogenldty bloassays and, as such, used doses >12.26 mg/week, which produced 50% mortality 1n Syrian golden hamsters. These studies are, there- fore, not useful 1n deriving ADIs, and are reviewed 1n Chapter 4. 3.2.2. Inhalation. NIOSH (1975) provides an In-depth discussion of the pathology of chronic Inhalation exposure of carbon tetrachlorlde 1n man. These reports are arranged by effects on organ systems and, since exposure data are lacking, are not useful 1n risk assessment. The U.S. EPA (1983b) summarized human studies that are more relevant to risk assessment. Smyth et al. (1936) and Smyth and Smyth (1935) studied the hematology, kidney and liver function (parameters not clearly specified) and vision of carbon tetrachlorlde-exposed workers. TWA exposures were estimated to range from 5-117 ppm, with peak exposures up to a maximum of 1680 ppm. Of 77 workers examined, 9 showed severely restricted visual fields and 26 showed slightly restricted visual fields. Of 67 men tested, 13 had elevated Icterus Indices. Hematology, kidney function and other parameters of liver function showed no significant alteration associated with exposure to carbon tetra- chlorlde. Moeller (1973) evaluated the effects of chronic occupational exposure to carbon tetrachlorlde on several ophthalmologlc Indices. A cohort of 46 -5- ------- workers was exposed from 1 hour/week to 1 hour/day to an unspecified concen- tration of carbon tetrachloMde for an average of 7.7 years. Of these workers, 28 were found to have reduced corneal sensitivity. A group of 62 locksmiths exposed to 6.4-9.5 ppm carbon tetrachlorlde for a minimum of 1-3 hours/day and a control group of 82 unexposed persons were evaluated for corneal sensitivity and other visual parameters. Of the 62 exposed lock- smiths, 43 had reduced corneal sensitivity, 4 had subnormal dark adaptation corneas, 4 had restricted outer limits of white visual fields, 15 had color limits of the visual field and 7 had Instrument-detectable changes In color perception. Further Information comparing the control groups and the exposed groups was not presented 1n the available review. Barnes and Jones (1967) reported elevated urinary uroblUnogen In 6/16 and elevated urine protein In 3/16 carbon tetrachloMde-exposed workers compared with 11 unexposed controls. Z1nc turbidity and average thymol turbidity tests were elevated 1n exposed workers compared with controls. Carbon tetrachloMde-exposed workers also experienced elevated serum bH1rub1n and slightly elevated SGOT, compared with controls. Rabes (1972) associated significant elevations 1n serum Iron and glutamlc dehydrogenase with occupational exposure for >5 years to unspecified concentrations of carbon tetrachlorlde. Adams et al. (1952) exposed guinea pigs and rats to 5, 10, 25, 50, 100, 200 or 400 ppm carbon tetrachlorlde for 7 hours/day, 5 days/week for up to 184 exposures over a period of 258 days. The numbers Initially Involved and surviving were not specified, but apparently 8-9 guinea pigs of each sex were tested at each concentration and -15 rats of each sex/group were tested at dosages >25 ppm, 20 rats of each sex were tested at 10 ppm, and 23 females and 26 males were exposed to 5 ppm carbon tetrachlorlde. -6- ------- Mortality among guinea pigs was high 1n the 200 ppm group and claimed >50% of the 400 ppm group. Survivors evidenced elevated kidney and Hver weights, fatty degeneration and cirrhosis of the liver. Guinea pigs showed hepatomegaly at all concentrations tested, moderately hepatic fatty degener- ation at >10 ppm and moderate liver cirrhosis at >25 ppm. Mortality also claimed >50% of the rats exposed to 400 ppm carbon tetrachlorlde. Hepato- megaly was observed In all exposed rats but liver cirrhosis was not detected at exposure concentrations <50 ppm. Concurrently, two rabbits of each sex were exposed to 10, 25, 50 or 100 ppm carbon tetrachlorlde by the same exposure schedule (Adams et al., 1952). Exposure to 25 ppm, 178 times (248 days) resulted In moderate fatty liver degeneration and cirrhosis. Additionally, at 50 and 100 ppm, decreased growth rate, Increased kidney weights and Increased blood clotting time (Indicative of liver damage) were observed. Groups of two monkeys were exposed to 25, 50 or 100 ppm carbon tetra- chlorlde by the same schedule for 148-198 times (-30-40 weeks) (Adams et al., 1952). No abnormal findings were reported 1n monkeys exposed to 25 ppm. Exposure to 50 ppm resulted 1n weight loss and exposure to 100 ppm resulted In "some Indications of microscopic Hver change." In this study, guinea pigs appeared to be the most sensitive species. Moderate (presumably reversible) hepatomegaly occurred at all exposures tested, but evidence of fatty degeneration was not noted until concentrations reached 10 ppm. For this study, 5 ppm carbon tetrachlorlde 1n guinea pigs constituted a LOAEL. Smyth and Smyth (1935) and Smyth et al. (1936) exposed groups of 22-24 guinea pigs to 0, 50, 100, 200 or 400 ppm carbon tetrachloride 8 hours/day, 4-6 days/week for periods of up to 321 days. All guinea pigs exposed to -7- ------- >100 ppm died by 94 days of age, necessitating restructuring of the experi- ment. In the second trial, groups of 15 or 16 guinea pigs were exposed to 25, 50, 100 or 200 ppm carbon tetrachloride. A group of 7 unexposed guinea pigs served as controls. Mortality claimed 0/7, 12/15, 9/16, 11/16 and 11/15 of the 0, 25, 50, 100 and 200 ppm-exposed groups, respectively. In addition to the usual hepatic pathology, optic nerve degeneration was noted 1n 1 or 2 guinea pigs 1n each exposure group. Fatty degeneration of the ocular muscles was observed 1n 3-6 guinea pigs 1n each exposed group. Groups of 24 rats were exposed to 0, 50, 100, 200 or 400 ppm carbon tetrachloride using the same dosage schedule described above for guinea pigs (Smyth and Smyth, 1935; Smyth et al., 1936). Liver degeneration, regenera- tion and cirrhosis were observed 1n rats exposed to >50 ppm carbon tetra- chloride. Degeneration of the myelln sheath of the sciatic nerve and degenerative changes 1n ocular muscles, as well as some evidence of kidney damage, were observed sporadically In 50 ppm-exposed rats. Finally, these Investigators (Smyth and Smyth, 1935; Smyth et al., 1936) exposed four monkeys to 50 ppm and three monkeys to 200 ppm carbon tetra- chloMde by the same exposure schedule for 93-231 days. Nerve tissue appeared normal in all 50 ppm-exposed monkeys. Cloudy swelling of the kidney and fatty changes in the liver were noted at the 50 ppm level. A 28-day recovery period demonstrated the reversible nature of these mild liver and kidney changes. 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 3.3.1. Oral. No reports of teratogenldty in humans or animals orally exposed to carbon tetrachloride have been found in the available literature. -8- ------- 3.3.2. Inhalation. No reports of fetotoxldty In humans associated with Inhalation of carbon tetrachlorlde have been found In the available litera- ture. Only one Investigation of fetotoxldty caused by Inhalation exposure of animals to carbon tetrachlorlde has been found. Schwetz et al. (1974) exposed groups of Sprague-Dawley rats to 300 or 1000 ppm carbon tetrachlo- rlde for 7 hours/day on days 6-15 of gestation. A significant decrease In body weights and crown-rump lengths was found In fetuses from dams exposed to either 300 or 1000 ppm carbon tetrachlorlde, as compared with controls. Gross examination revealed no anatomical or developmental anomalies; micro- scopic examination revealed delayed ossification of the sternebrae. The authors concluded that carbon tetrachlorlde was not teratogenlc to rats at these exposures. Assuming that rats weigh 0.35 kg and Inhale 0.26 m3 of air/day, exposure to 300 ppm carbon tetrachlorlde for 7 hours/day results In an Intake of 406.7 mg/kg/day. 3.4. TOXICANT INTERACTIONS Alcohol 1ngest1on has been clearly shown to potentiate the toxlclty of carbon tetrachlorlde. Tralger and Plaa (1971) Investigated the potentlatlon of carbon tetrachlorlde toxldty by methanol, ethanol and Isopropanol In rats. The activity of SGPT was monitored to evaluate hepatotoxldty. All three alcohols tested potentiated the toxldty of carbon tetrachlorlde, with Isopropanol being the most potent. Neither carbon tetrachlorlde nor the alcohols alone elevated SGPT levels. We1 et al. (1971) Investigated the ability of ethanol and exposure to cold to potentiate hepatotoxldty of carbon tetrachlorlde In rats. Rats were pretreated with ethanol and sub- jected for 18 hours to a temperature of 4°C. Elevated SGPT Indicated that ethanol and exposure to cold potentiated carbon tetrachloMde-lnduced -9- ------- toxldty. von Oettlngen (1964) reported that persons who were habitual users or occasional users of alcoholic beverages became more seriously 111 than abstainers when exposed to carbon tetrachlorlde. In the early 1900's, carbon tetrachlorlde was used as an ant1helm1nt1c, particularly against hookworm, In both humans and animals. SmllUe and Pessoa (1923) reported on severe carbon tetrachloMde-lnduced toxldty among two alcoholics 1n a group of 34 persons treated with carbon tetrachlorlde for ancylostomlasls. Since then, other Investigators (Guild et a!., 1958; McGuIre, 1932; Smetana, 1939; Gray, 1947) have observed that chronic alcohol 1ngest1on exacerbates carbon tetrachloMde-lnduced toxldty resulting from single medicinal doses. Alcohol Ingestlon was suspected to play a significant role In the toxlc- 1ty of carbon tetrachlorlde from nonmedldnal exposure (Abbott and Miller, 1948), particularly where renal failure was a major part of the clinical picture. The ACGIH (1980) suggested that ethanol and other substances (e.g., barbiturates and polychloMnated blphenyls) that Induce hepatic mlcrosomal enzymes enhance the toxldty of carbon tetrachlorlde. Hafeman and Hoekstra (1977) claimed that vitamin E, selenium and methlo- nlne offer partial protection from carbon tetrachloMde-lnduced toxldty. By monitoring the evolution of ethane, a peroxldatlon product of certain unsaturated fatty adds, these authors concluded that methlonlne, vitamin E and selenium protected against carbon tetrachlorlde-lnduced I1p1d peroxlda- tlon, probably by maintaining Intracellular glutathlone and glutathlone peroxldase. -10- ------- 4. CARCINOGENICITY 4.1. HUMAN DATA A few cases of "Mver cancer associated with exposure to carbon tetra- chlorlde have been reported, but no ep1dem1olog1cal studies from which risk figures can be derived have been located In the available literature. Slmler et al. (1964) reported the case of a fireman who developed eplthe- Homa of the liver 4 years after being acutely poisoned by carbon tetrachlo- rlde. Tracey and Sherlock (1968) suggested that hepatocellular carcinoma 1n a 59-year-old man was caused by a 5-day exposure to carbon tetrachlorlde used to clean his rug. The patient denied Ingesting alcohol since being exposed to carbon tetrachlorlde, but admitted to having used 1t before the exposure to carbon tetrachlorlde. Blair et al. (1979) reported 87 cancer deaths 1n a group of 330 exposed workers 1n which 67.9 cancer deaths would have been expected. Concurrent exposure to other workroom chemicals precluded attributing the observed Increase 1n cancer Incidence to carbon tetrachlorlde alone. 4.2. BIOASSAYS 4.2.1. Oral. Sufficient evidence for the carclnogenlclty of carbon tetrachlorlde 1n laboratory animals exists 1n the available literature. Many early studies, although too short 1n duration to be useful for risk assessment, demonstrated the hepatocarc1nogen1c1ty of carbon tetrachlorlde. Edwards (1941) administered by gavage 0.1 mj, of a 40% carbon tetrachlorlde solution 1n olive oil to C3H and A-stra1n mice 2-3 times/week for 23-58 doses. Necropsies performed 2-147 days after the last administration revealed a progression of events beginning with liver necrosis and followed by cirrhosis and eventually hepatomas In C3H mice. Hepatomas were found In 126/143 C3H and all 54 A-stra1n mice. Delia Porta et al. (1961) reported -11- ------- administrating 30 weekly doses of 6.25-12.5 y9. (10-20 mg) carbon tetra- chloride to five Syrian golden hamsters of each sex. Liver cell carcinomas were discovered in all animals (5 of each sex) that survived >10 weeks after the end of treatment. Subsequently, C3H and strains A, Y, C and L mice were exposed to carbon tetrachloride to further elucidate the process of carcinogenesis (Edwards and Dalton, 1942; Edwards et al., 1942). Small numbers of mice were killed and necropsied after one or more doses. Liver necrosis and regenerative processes were observed throughout the study. Atypical mitotic forms such as triple mitoses were frequent findings. In mice treated for >1 month, enlarged hepatocytes with small nuclei were concentrated along strands of fibrous tissue. Hepatic tumors were usually multiple; neither invasion of blood vessels nor metastases were seen. These authors reported finding no evidence of tumors in other organs. Eschenbrenner and Miller (1944) administered 30 doses of 0.16, 0.32, 0.64, 1.27 or 2.54 g carbon tetrachloride/kg bw by gavage to groups of 60 strain A mice. The interval between doses varied from 1-5 days; thus, the treatment period varied from 30-150 days. The incidence of hepatomas was 23/60, 23/60, 25/59, 32/60 and 33/60 in the five groups, respectively. In a later study, Eschenbrenner and Miller (1946) demonstrated that single doses of 12.5 y8./kg, but not 6.25 y9./kg, by gavage would cause liver cell necrosis in both male and female strain A mice. Administration of 6.25, 12.5, 25 or 50 y8./kg/day for 120 days resulted in hepatoma formation in mice exposed to >12.5 yi/day. Other mice were given 30 doses of 25, 50 or 100 ya./kg at 4-day intervals. Microscopic examination revealed small hepatomas in 2/10 mice given 25 yJ./kg. Grossly visible tumors were -12- ------- present in the higher-dosed groups. These Investigators theorized that a necrotlzlng action of carbon tetrachloride on the liver was an Important factor in the development of a carcinogenic response. NIOSH (1975) and U.S. EPA (1980b) discussed short-term carcinogenicity bioassays involving carbon tetrachloride. In an NCI-sponsored bioassay (NCI, 1976; Weisberger, 1977), Osborne- Mendel rats were exposed to 47 or 94 mg/kg (males) or 80 or 160 mg/kg (females) carbon tetrachloride by gavage for 78 weeks. Observations were continued for 33 additional weeks. Survival data, summarized in Table 4-1, indicate that excessive mortality had occurred in high dose rats of either sex. Although a slight increase in the incidence of hepatocellular carci- nomas was noted in both males and females, a clear dose-related response could not be demonstrated. Mice were also included in the NCI (1976) bioassay. Groups of 50 male and female 35-day-old mice were treated by gavage with 1250 or 2500 mg carbon tetrachloride in corn oil/kg bw/day, 5 days/week for 78 weeks. Observations continued for an additional 13 weeks. Vehicle control groups consisted of 20 mice of each sex. All mice were subjected to necropsy. Survival data are presented in Table 4-2. Mortality claimed most carbon tetrachloride-exposed mice by the end of the 78-week exposure period. Most carbon tetrachloride-treated mice were discovered to have hepatocellular carcinomas. The first carcinomas in female mice were found at 16 weeks and 19 weeks in low and high dose groups, respectively. Among male mice, the first carcinomas were found at 48 and 26 weeks in the low and high dose groups, respectively. The incidences of hyperplastic nodules and hepato- cellular carcinomas are presented in Table 4-3. -13- ------- Dose TABLE 4-1 Survival of Rats Treated with Carbon Tetrachlorlde* Initial *Source: NCI, 1976 78 Weeks 110 Weeks Males Control Low High Females Control Low High 100 50 50 100 50 50 67 (6754) 34 (68%) 34 (68%) 75 (75%) 38 (76%) 21 (42%) 26 (26%) 14 (28%) 7 (14%) 51 (51%) 20 (40%) 14 (28%) -14- ------- Dose TABLE 4-2 Survival of Mice Treated with Carbon Tetrachlorlde* Initial 78 Weeks 91-92 Weeks Males Control Matched Pooled Low High Females Control Matched Pooled Low High 20 77 50 50 20 80 50 50 13 (65%) 53 (69%) 11 (22%) 2 (4%) 18 (90%) 71 (89%) 10 (20%) 4 (8%) 7 (35%) 38 (49%) 0 (0%) 0 (0%) 17 (85%) 65 (81%) 0 (0%) 1 (2%) *Source: NCI, 1976 -15- ------- TABLE 4-3 Liver Tumors 1n Mice* Dose Carcinomas Males Control Matched Pooled Low High 2/19 (IT/.) 5/77 (6%) 49/49 (100%) 47/48 (98%) Females Control Matched Pooled Low High 1/20 (5%) 1/80 (1%) 40/40 (100%) 43/45 (96%) 'Source: NCI, 1976 NR = Not reported -16- ------- 4.2.2. Inhalation. Little data concerning cardnogenldty of carbon tetrachloMde from Inhalation exposure have been located 1n the available literature. Costa et al. (1963) exposed albino rats to unspecified concen- trations of atmospheric carbon tetrachloMde for up to 7 months. Rats were killed serially from 2-10 months after the beginning of exposure. Of the 30 rats that completed the experiment, 12 had adenodrrhosls and 10 had liver nodules measuring up to 1 cm, which were microscopically diagnosed as Incipient hepatocellular carcinoma. 4.3. OTHER RELEVANT DATA Scarce pertinent data regarding the mutagenlclty of carbon tetrachlorlde were located 1n the available literature. Kraemer et al. (1974) found no mutagenlclty In either the Salmonella typhimurium or Escher1ch1a coll reversion tests. Details of the experimental protocol were not available. Likewise, IARC (1979) reported a lack of mutagenlclty in S. typhimurium strains TA100, TA1535, TA1538 (McCann and Ames, 1976; McCann et al., 1975; Uehleke et al., 1976) and £. coll (Uehleke et al., 1976). 4.4. WEIGHT OF EVIDENCE There is sufficient evidence 1n mice, rats and hamsters to designate carbon tetrachlorlde a potent hepatic carcinogen in animals. Prolonged exposure (NCI, 1976; Welsburger, 1977) results 1n a very high incidence of hepatocellular carcinoma. The few case reports associated with carbon tetrachlorlde provide limited, but not sufficient, evidence to confirm human carcinogenicity. Only one epidemlologic study (Blair et al., 1979) was found in the available literature. Blair et al. (1979) observed 87 cancer deaths in a cohort of 330 exposed workers in which 67.9 cancer deaths would have been expected. -17- ------- Concurrent exposure to other chemicals precluded ascribing the observed Increase 1n cancer Incidence to carbon tetrachlorlde alone. On the basis of the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA for evaluating the overall weight of evidence for carclnogenlclty to humans (Federal Register, 1984), carbon tetrachlorlde 1s most appropriately classified as a Group B2 - Probable Human Carcinogen. -18- ------- 5. REGULATORY STANDARDS AND CRITERIA The American Conference of Governmental Industrial Hyglenlsts (ACGIH, 1980, 1983) and the U.S. EPA (1980b) have established regulating standards for carbon tetrachlorlde as dted 1n Table 5-1. -19- ------- TABLE 5-1 Current Regulatory Standards and Criteria for Carbon Tetrachlorlde Criterion TLV STEL NIOSH celling level Value 5 ppm, 30 mg/m3 20 ppm, 125 mg/m3 2 ppm Reference ACGIH, ACGIH, ACGIH, 1983 1983 1980 to prevent cancer Japan and most European nations Most eastern European nations Tolerance 1n food 10 ppm 3-7.5 ppm exempt Ambient water criteria associated with cancer risk: 10"7 10"6 lO's consumption of 6.5 g fish only 0.69 yg/8, 6.94 yg/S, 69.4 yg/8. 2 a, water + 6.5 q fish 0.04 yg/8. 0.40 vg/J. 4.0 yg/9. ACGIH, 1980 ACGIH, 1980 Code of Federal Regulations, 1982 U.S. EPA, 1980b -20- ------- 6. RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) Carbon tetrachlorlde 1s amply demonstrated to be carcinogenic 1n animals and data are sufficient for derivation of a q *. It 1s Inappropriate, therefore, to calculate an AIS for this chemical. 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) Carbon tetrachlorlde 1s amply demonstrated to be carcinogenic 1n animals and data are sufficient for derivation of a q,*. It Is Inappropriate, therefore, to calculate an AIC for this chemical. 6.3. CARCINOGENIC POTENCY (q^) 6.3.1. Oral. The Carcinogen Assessment Group, as described 1n U.S. EPA i (1984), used data from the following for risk assessment purposes: Delia Porta et al. (1961); Edwards et al. (1942); NCI (1976) (both rat and mouse). Since none of these studies was deemed adequate Individually and no study could be selected as "best" or "most appropriate", the geometric mean of the upper limit unit risk estimates (3.7xlO~6) has been calculated for drink- Ing water containing 1 vg/9.. Assuming human consumption of 2 l of water/day, a cancer risk of 3.7xlO~6 1s associated with a dose of 2 yg carbon tetrachlor1de/day. For a 70 kg human, a q * of l.SOxlO'1 (mg/kg/day)"1 can be calculated from the following formula: q.j* = 70 kg x 3.7xlO~6 * (2xlO~3) where 3.7xlO~6 1s the risk associated with a dally dose of 2 yg or 2xlO~3mg/day. U.S. EPA (1984) contains an 1n-depth explanation of the rationale applied and the calculations employed. 6.3.2. Inhalation. Sufficient data regarding the carclnogenlcHy of carbon tetrachlorlde 1n laboratory animals exposed by Inhalation, from which to calculate a q * were not located 1n the available literature. -21- ------- 7. REFERENCES Abbott, G.A. and M.J. Miller. 1948. Carbon tetrachloMde poisoning — A report on ten cases at the U.S. Marine Hospital, Seattle, WA, since 1937. Pub. Health Rep. 63: 1619-1624. (Cited in NIOSH, 1975) ACGIH (American Conference of Governmental Industrial Hygienists). 1980. Documentation of the Threshold Limit Value for Substances in Workroom Air, 4th edition with supplements through 1981. Cincinnati, OH. p. 74-75. (Cited 1n U.S. EPA, 1983b) ACGIH (American Conference of Governmental Industrial Hygienists). 1983. Threshold Limit Values for Chemical Substances and Physical Agents in the Workroom Environment with Intended Changes for 1983-84. Cincinnati, OH. Adams, E.M., H.C. Spencer, V.K. Rowe, D.D. McColHster and D.D. Irish. 1952. Vapor toxicity of carbon tetrachloride determined by experiments on laboratory animals. Arch. Ind. Hyg. Occup. Med. 6: 50-66. (Cited in U.S. EPA, 1980b; 1983b) Banerjee, S., S.H. Yalkowsky and S.C. Valvani. 1980. Water solubility and octanol/water partition coefficients of organics. Limitations of the solu- bility-partition coefficient correlation. Environ. Sci. Technol. 14: 1227-1229. Barnes, R. and R.C. Jones. 1967. Carbon tetrachloride poisoning. Am. Ind. Hyg. Assoc. J. 28: 557-560. (Cited In U.S. EPA, 1980b) -22- ------- Blair, A., P. Decoufle and D. Grauman. 1979. Causes of death among laundry and dry cleaning workers. Am. J. Publ. Health. 69: 508-511. (Cited 1n IARC, 1979) Callahan, M.A., M.W. SUmak, N.W. Gabel, et al. 1979. Water-Related Environmental Fate of 129 Priority Pollutants, Vol. II. U.S. EPA, Office of Water Planning and Standards, Office of Water and Waste Management, Washington, DC. EPA-440/4-79-029b. Code of Federal Regulations. 1982. Carbon tetrachlorlde; exemption. 180.1005. Para. 67,310.05. Costa, A., G. Weber, F.S.O. Bartolon! and G. Campana. 1963. Experimental cancerous cirrhosis from carbon tetrachlorlde 1n rats. Arch. DeVecchl. (Ita.) 39: 303-356. (Cited 1n NIOSH, 1975) Delia Porta, G., B. Terradnl and P. Shublk. 1961. Induction with carbon tetrachlorlde of liver cell carcinomas 1n hamsters. J. Natl. Cancer Inst. 26: 855-863. (Cited In U.S. EPA, 1983c) Edwards, J. 1941. Hepatomas In mice Induced with carbon tetrachlorlde. J. Natl. Cancer Inst. 2: 197-199. (Cited 1n U.S. EPA, 1980b) Edwards, J. and A. Dalton. 1942. Induction of cirrhosis of the liver and hepatomas 1n mice with carbon tetrachlorlde. J. Natl. Cancer Inst. 3: 19-41. (Cited 1n U.S. EPA, 1980b) -23- ------- Edwards, J., et al. 1942. Induction of the carbon tetrachloMde hepatoma In strain L mice. 3. Natl. Cancer Inst. 3: 297-301. (Cited In U.S. EPA, 1980b) Eschenbrenner, A.B. and E. Miller. 1944. Studies on hepatomas. I. Size and spacing of multiple doses In the Induction of carbon tetrachlorlde hepa- tomas. J. Natl. Cancer Inst. 4: 385-388. (Cited In U.S. EPA, 1983c) Eschenbrenner, A.B. and E. Miller. 1946. Liver necrosis and the Induction of carbon tetrachlorlde hepatomas 1n strain A mice. J. Natl. Cancer Inst. 6: 325-341. (Cited In U.S. EPA, 1980b) Federal Register. 1984. Environmental Protection Agency proposed guidelines for carcinogenic risk assessment. FR 49: 46294-46299. Gray, I. 1947. Carbon tetrachlorlde poisoning -- Report of seven cases with two deaths. NY State J. Med. 47: 2311-2315. (CHed In NIOSH, 1975) Guild, W.R., J.V. Young and J.P. Merrill. 1958. Anurla due to carbon tetrachlorlde Intoxication. Ann. Int. Med. 48: 1221-1227. (CHed 1n NIOSH, 1975} Hafeman, D.G. and W.G. Hoekstra. 1977. Protection against carbon tetra- chlor1de-1nduced Upld peroxldatlon 1n the rat by dietary vitamin E, selenium and methlonlne as measured by ethane evolution. J. Nutr. 107: 656-665. (CHed 1n U.S. EPA, 1980b) -24- ------- IARC (International Agency for Research on Cancer). 1979. Carbon Tetra- * chloride. In.: Some Halogenated Hydrocarbons. IARC Monographs on the Eval- uation of the Carcinogenic Risk of Chemicals to Humans. WHO: Lyon, France. 20: 371-399. (Cited In U.S. EPA, 1983b) Kraemer, M., D. Blmboes and H. Grelm. 1974. S. typhlmurlum and £. coll to detect chemical mutagens. Naunyn-Schmled. Arch. Pharmacol. 284: 46R. (Abstr.) (Cited In U.S. EPA, 1980b) Lamson, P.O., et al. 1923. No title provided. J. Pharmacol. Exp. Ther. 22: 215-288. (Cited 1n von Oettlngen, 1964; U.S. EPA, 1980b) Lehmann, K.B. and H. Hasegawa. 1910. Studies of the Absorption of Chlori- nated Hydrocarbons 1n Animals and Humans. Archlv. Fuer. Hygiene. In: National Research Council, 1978. NonfluoMnated Halomethanes In the Environment. NAS, Washington, DC. 72: 327-342. (Cited in U.S. EPA, 1980b) McCann, J. and B.N. Ames. 1976. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals: Discussion. Proc. Natl. Acad. Sci. 73: 950-954. (Cited in IARC, 1979) McCann, 0., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of car- cinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemi- cals. Proc. Natl. Acad. Sci. 72: 5135-5139. (Cited in IARC, 1979) McGuIre, L.W. 1932. Carbon tetrachloMde poisoning. JAMA. • 99: 988-989. (Cited in NIOSH, 1975) -25- ------- Moeller, W. 1973. Chronic carbon tetrachloMde poisoning from an ophthal- mologlcal viewpoint. (Ger.) Z. Ges. Hyg. 19: 127-133. (Cited 1n NIOSH, 1975; U.S. EPA, 1983b) NCI (National Cancer Institute). 1976. Report on Cardnogenesls Bloassay of Chloroform. Cardnogenesls Program, Division of Cancer Cause and Prevention. Bethesda, MD. (Cited In U.S. EPA, 1983c) Nielsen, V.K. and J. Larsen. 1965. Acute renal failure due to carbon tetrachloMde poisoning. (Scandinavia.) Acta Medlca. 178: 363-374. (Cited 1n U.S. EPA, 1980b) NIOSH (National Institute for Occupational Safety and Health). 1975. Criteria for a Recommended Standard...Occupational Exposure to Carbon Tetrachlorlde. U.S. DHEW, PHS, CDC, Rockvllle, MD. Page, G.W. 1981. Comparison of groundwater and surface water for patterns and levels of contamination by toxic substances. Environ. Scl. Techno!. 15: 1475-1481. Prendergast, J.A., R.A. Jones, L.J. Jenkins and J. Slegel. 1967. Effects on experimental animals of long-term Inhalation of trlchloroethylene, carbon tetrachloMde, 1,1 ,l-tr1chloroethane, d1chlorod1fluoromethane and I,l-d1chloroethylene. Toxlcol. Appl. Pharmacol. 10: 270-289. (Cited 1n U.S. EPA, 1983c) -26- ------- Rabes, U. 1972. Results of occupational medical examinations of workers exposed for many years to carbon tetrachlorlde. W1ss. Z. Univ. Halle. 21: 73-80. (Cited In U.S. EPA, 1983b) Robblns, 8.H. 1929. The absorption, distribution and excretion of carbon tetrachlorlde In dogs under various conditions. J. Pharmacol. 37: 203-216. (Cited 1n U.S. EPA, 1980b) Schwetz, B.A., B.K.J. Leong and P.J. Gehrlng. 1974. Embryo and fetotoxl- dty of Inhaled carbon tetrachlorlde, 1,l-d1chloroethane and methyl ethyl ketone In rats. Toxlcol. Appl. Pharmacol. 28: 452-464. (Cited in NIOSH, 1975) Slmler, M., M. Mauer and J.C. Mandard. 1964. Liver cancer with cirrhosis due to carbon tetrachlorlde. Strasbourg Med. (Fre.) 15: 910-918. (Cited In IARC, 1979; U.S. EPA, 1983c) Singh, H.B., L.O. Salas, A-J Smith and H. Sh1ge1sh1. 1981. Measurements of some potentially hazardous organic chemicals In urban environments. Atmos. Environ. 15: 601-612. Smetana, H. 1939. Nephrosls due to carbon tetrachlorlde. Arch. Int. Med. 63: 760-777. (Cited In NIOSH, 1975) Sm1ll1e, W.G. and S.B. Pessoa. 1923. Treatment of hookworm disease with carbon tetrachlorlde. Am. J. Hyg. 3: 35-45. (Cited 1n NIOSH, 1975) -27- ------- Smyth, H.F. and H.F. Smyth, Jr. 1935. Investigation of the Chronic Toxlc- Hy of Carbon Tetrachlorlde -- Final Report to the Producers Committee. (Cited In NIOSH, 1975; U.S. EPA, 1983b) Smyth, H.F., H.F. Smyth, Jr. and C.P. Carpenter. 1936. The chronic toxlc- 1ty of carbon tetrachlorlde ~ Animal exposures and field studies. J. Ind. Hyg. Toxlcol. 18: 277-298. (Cited 1n NIOSH, 1975; U.S. EPA, 1983c) Tracey, J.P. and P. Sherlock. 1968. Hepatoma following carbon tetrachlo- rlde poisoning. NYS J. Med. 68: 2202-2204. (Cited 1n U.S. EPA, 1983c) Tralger, G.J. and G.L. Plaa. 1971. Differences 1n the potentlatlon of carbon tetrachlorlde 1n rats by ethanol and Isopropanol pretreatment. Toxlcol. Appl. Pharmacol. 20: 105-112. (Cited 1n U.S. EPA, 1980b) Uehleke, H., H. Grelm, M. Kramer and T. Werner. 1976. Covalent binding of haloalkanes to liver constltutents, but absence of mutagenldty on bacteria In a metabolizing test system (Abstract No. 25). Mutat. Res. 38: 114. (Cited In IARC, 1979} U.S. EPA. 1980a. Guidelines and Methodology Used 1n the Preparation of Health Effects Assessment Chapters of the Consent Decree Water Quality Criteria. Federal Register. 45: 79347-79357. U.S. EPA. 1980b. Ambient Water Quality Criteria for Carbon Tetrachlorlde. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA-440/5- 80-026. NTIS PB 81-117376. -28- ------- U.S. EPA. 1983a. -Methodology and Guidelines for Reportable Quantity Determinations Based on Chronic Toxldty Data. Prepared by Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1983b. Reportable Quantity Document for Carbon Tetrachlorlde. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1983c. Review of Tox1colog1c Data 1n Support of Evaluation for Carcinogenic Potential of: Carbon Tetrachlorlde. Prepared by the Carcinogen Assessment Group, OHEA, Washington, DC for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1984. Health Assessment Document for Carbon Tetrachlorlde. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA-600/8-82- 001F. NTIS PB 85-124196. Velth, G.D., D.L. Derfoe and B.V. Bergstedt. 1979. Measuring and estimat- ing the bioconcentratlon factor of chemicals 1n fish. J. Fish Res. Board. 36: 1040-1048. von Oettlngen, W.F. 1964. The Halogenated Hydrocarbons of Industrial and Tox1colog1cal Importance. In: Elsevler Monographs on Toxic Agents, E. Browning, Ed. Elsevler Publishing Co., NY. (Cited In U.S. EPA, 1980b) -29- ------- von Oettlngen, W.F., et al. 1949. Relation Between the Toxic Action of Chlorinated Methanes and Their Chemical and Physlochemlcal Properties. Natl. Inst. Health Bull. No. 191. In: National Research Council. 1978. Non-fluorl- nated Halomethanes 1n the Environment. NAS, Washington, DC. p. 1-85. (Cited 1n U.S. EPA, 1980b) von Oettlngen, W.F., et al. 1950. Comparative studies of the toxldty and pharmacodynamlc action of chlorinated methanes with special reference to their physical and chemical characteristics. Arch. Int. de Pharmacodynamle et de Theraple. ITK National Research Council. 1978. Non-fluorlnated Halomethanes 1n the Environment. NAS, Washington, DC. 81: 17-34. {Cited In U.S. EPA, 1980b) We1, E., et al. 1971. Potent1at1on of carbon tetrachloMde hepatoxldty by ethanol and cold. Toxlcol. Appl. Pharmacol. 18: 329-334. (CHed 1n U.S. EPA, 19805) Welsburger, E.K. 1977. Cardnogenldty studies on halogenated hydrocar- bons. Environ. Health Perspect. 21: 7-16. (CHed 1n U.S. EPA, 1983c) Wilson, J.T., C.6. EnHeld, W.J. Dunlap, R.L. Cosby, D.A. Foster and L.B. Baskln. 1981. Transport and fate of selected organic pollutants In a sandy soil. J. Environ. Qual. 10: 501-506. Wilson, J.T., J.F. McNabb, B.H. Wilson and M.J. Noonan. 1983. Blotrans- formatlon of selected organic pollutants In groundwater. Dev. Ind. M1crob1ol. 24: 225-233. -30- ------- Zoeteman, B.C.J., K. Harmensen, J.B.H.J. Unders, C.F.H. Morra and W. Slooff. 1980. Persistent organic pollutants 1n river water and groundwater of The Netherlands. Chemosphere. 9: 231-249. -31- ------- APPENDIX Summary Table for Carbon Tetrachlorlde ro I Carcinogenic Potency Inhalation Oral Experimental Species Dose/Exposure Effect (mg/kg/day) mice 1250-2500 liver tumors Ql* ND 1.3X10"1 (mg/kg/day) * Reference Delia Porta et al., 1961; Edwards et al., 1942; NCI, 1976; U.S. EPA, 1984 ND = Not derived ------- |