EPA-540/1-86-040 ice of Emergency and medial Response Washington DC 20460 Off'ce of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati OH 45268 Superfund &EPA HEALTH EFFECTS ASSESSMENT FOR CHLOROBENZENE ------- EPA/540/1-86-040 September 1984 HEALTH EFFECTS ASSESSMENT FOR CHLOROBENZENE 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 H 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 chloroben- zene. All estimates of acceptable Intakes and carcinogenic potency pre- sented 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-line literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases. The basic literature searched supporting this document 1s current up to September, 1984. Secondary sources of Information have also been relied upon In the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The fol- lowing Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized: U.S. EPA. 1980b. Ambient Water Quality Criteria for Chlorinated Benzenes. Environmental Criteria and Assessment Office, Cincin- nati, OH. EPA 440/5-80-028. NTIS PB 81-117392. U.S. EPA. 1982a. Hazard Profile for Chlorobenzene. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Wash- ington, DC. U.S. EPA. 1985. Health Assessment Document for Chlorinated Ben- zenes. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/8-84-015F. NTIS PB 85-150332. The Intent In these assessments 1s 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 In 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, Is 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 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. 111 ------- The AIC, acceptable Intake chronic, 1s similar In 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 llfespan [see U.S. EPA (1980a) for a discussion of this concept]. The AIC 1s route specific and estimates acceptable expo- sure for a given route with the Implicit assumption that exposure by other routes 1s Insignificant. Composite scores (CSs) for noncardnogens have also been calculated where data permitted. These values are used for ranking reportable quanti- ties; the methodology for their development 1s explained In U.S. EPA (1983). For compounds for which there 1s sufficient evidence of cardnogenldty, 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-j*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, refer to the preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appropriate Inter- pretation and use of the quantitative estimates presented. The liver and kidneys appear to be target organs for chlorobenzene tox- Iclty. Three separate subchronlc oral exposure studies (one In dogs, two 1n rats) define comparable NOELs. The observed adverse effects Indicated a higher sensitivity of the dog to chlorobenzene than the rat. Based on these findings, the highest NOEL of 27.3 mg/kg/day from the dog study (Monsanto, 1967a) was considered appropriate to derive an ADI. The estimated AIC 1s 1.9 mg/day, estimated by applying an uncertainty factor of 1000. This esti- mate may be considered to provide adequate protection against adverse human health effects. Long-term (lifetime) animal exposure data are needed to better characterize the toxldty of this compound. A CS of 8 was calculated for the low blood sugar levels, vomiting, diarrhea and conjunctivitis observed In dogs at 55 mg/kg/day. Subchronlc Inhalation data from several species are available, but chronic Inhalation exposure assessments for chlorobenzene are lacking. A AIC for Inhalation exposure has been estimated based upon the lowest sub- chronic LOAEL reported (75 ppm) (Dllley, 1977). This AIC, 0.4 mg/day, may be conservative. More experimental data are needed addressing lower concen- trations and longer durations of exposure to more completely characterize chlorobenzene toxldty. ------- 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 1n 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 vl ------- TABLE OF CONTENTS Page 1. ENVIRONMENTAL CHEMISTRY AND FATE 1 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2 2.1. ORAL 2 2.2. INHALATION 2 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3 3.1. SUBCHRONIC 3 3.1.1. Oral 3 3.1.2. Inhalation 7 3.2. CHRONIC 10 3.2.1. Oral 10 3.2.2. Inhalation 11 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 11 3.4. TOXICANT INTERACTIONS 12 4. CARCINOGENICITY 13 4.1, HUMAN DATA 13 4.2. BIOASSAYS 13 4.3. OTHER RELEVANT DATA 15 4.4. WEIGHT OF EVIDENCE 18 5. REGULATORY STANDARDS AND CRITERIA 19 6. RISK ASSESSMENT 21 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 21 6.1.1. Oral 21 6.1.2. Inhalation 22 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 22 6.2.1. Oral 22 6.2.2. Inhalation 23 6.3. CARCINOGENIC POTENCY (q-|*) 23 6.3.1. Oral 23 6.3.2. Inhalation 23 7. REFERENCES 24 APPENDIX: Summary Table for Chlorobenzene 31 ------- LIST OF TABLES No. 3-1 3-2 4-1 4-2 4-3 5-1 Title Subchronlc Oral ToxIcHy of Chlorobenzene 1n Experimental Animals Subchronlc Inhalation ToxIcHy of Chlorobenzene In Experimental Animals . . Statistical Comparisons of Liver Tumors 1n Male Rats Treated with Chlorobenzene Pituitary Tumors 1n Rats Treated with Chlorobenzene Mutagenlcity Testing of Chlorobenzene Current Regulatory Standards and Criteria for Chlorobenzene Page 4 8 14 16 17 20 ------- LIST OF ABBREVIATIONS ADI AIC AIS BCF CAS CNS CS DNA GGTP LOAEL MED NOAEL NOEL ppm RVd RVe SAP SGOT SGPT STEL TLV TWA Acceptable dally Intake Acceptable Intake chronic Acceptable Intake subchronlc B1oconcentrat1on factor Chemical Abstract Service Central nervous system Composite score Deoxyr1bonucle1c add y-Glutamyl transpeptldase Lowest-observed-adverse-effect level Minimum effective dose No-observed-adverse-effect level No-observed-effect level Parts per million Dose-rating value Effect-rating value Serum alkaline phosphatase Serum glutamlc oxalacetlc transamlnase Serum glutamlc pyruvlc transamlnase Short-term exposure limit Threshold limit value Time-weighted average 1x ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE The relevant physical and chemical properties and environmental fate of chlorobenzene (CAS No. 108-90-7) are as follows: Chemical class: Molecular weight: Vapor pressure: Water solubility: Octanol/water partition coefficient: Soil mobility (predicted as retardation factor for soil depth of 140 cm and organic carbon content of 0.087%): BCF: monocycllc aromatic (purgeable aromatic) 112.56 11.7 mm Hg at 20°C (Mabey et al., 1981) 466.3 mg/8. at 20°C (Horvath, 1982) 692 (Hansch and Leo, 1981) Half-lives 1n A1r: Water: 1.9 (Wilson et al., 1981) 45.7 (Rainbow trout (muscle); Salmo galrdnerl) (Branson, 1978) 446.7 (Fathead minnow; P1me- phales promelas) (Velth et al., 1979) 3.5 days (Kanno and Nojlma, 1979) 0.3 days In river (Zoeteman et al., 1980) The half-life of chlorobenzene 1n soil could not be located 1n the available literature; however, evaporation 1s expected to be the predominant loss mechanism from the soil surface (Wilson et al., 1981). The halfUfe for soil evaporation should be longer than Us evaporation half-life from water. In subsurface soil, a fraction of monochlorobenzene may undergo bio- degradation, and a fraction may leach through the soil (Wilson et al., 1981). -1- ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2.1. ORAL Quantitative studies regarding absorption of chlorobenzene 1n humans or laboratory animals following 1ngest1on were not located 1n the available literature. Reports of toxic effects 1n humans following 1ngest1on or Inhalation (Reich, 1934; Rosenbaum et al., 1947; Tarkhova, 1965) suggested absorption by these routes. Delchmann (1981) reported that chlorobenzene absorption from the gastrointestinal tract was facilitated by 1ngest1on of fats and oils. Studies of the metabolism of chlorobenzene in several mam- malian species indicated that absorption from the gastrointestinal tract occurred readily (Williams, 1959). 2.2. INHALATION No quantitative studies regarding absorption 1n humans or experimental animals following inhalation exposure to chlorobenzene could be located in the available literature. Delchmann (1981) stated that chlorobenzene was absorbed rapidly from the lungs. No supporting data accompanied this statement. -2- ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. No reports of subchronlc oral exposure of humans to chloro- benzene could be located In the available literature. Table 3-1 summarizes pertinent subchronlc oral exposure data 1n laboratory animals. Most of these data were taken from summaries provided by Delchmann (1981) and U.S. EPA (1980b, 1985). The studies reviewed by these authors seemed to define similar NOELs: Monsanto Company (1967a) found no effects In dogs exposed by capsule to 27.3 mg/kg/day. Following dietary exposure for 93-99 days, no effects were reported In rats at 50 mg/kg/day (Monsanto Company, 1967b), although slight and Inconstant elevated liver and kidney weights were reported at this level In the published version of this study (Knapp et a!., 1971). Irish (1963) found no effects In rats given 14.4-18.8 mg/kg/day, 5 days/week, for 192 days. A study by Varshavskaya (1967) described CNS, liver, hematopoletlc and endocrine effects 1n groups of seven male rats exposed to 0.01 and 0.1 mg chlorobenzene/kg/day by gavage. The U.S. EPA (1980b) considered the results of Varshavskaya (1967) to be questionable primarily because these data sug- gested effects at dosages far lower than those Indicated by other Investi- gators (Table 3-1). Also, data generated by HolUngsworth et al. (1956) in a similar study of the toxlcity of o-d1chlorobenzene Indicated similar effects, but were associated with dosages >3 orders of magnitude greater than those reported by Varshavskaya (1967). The NTP (1983) conducted 13-week range-finding studies In groups of five male and five female rats and mice with chlorobenzene administered by gavage. Both species were treated with 60, 125, 250, 500 or 750 mg/kg on 5 days/week (transfomed doses 42.9, 89.3, 178.6, 357 and 538 mg/kg bw/day). -3- ------- TABLE 3-1 Subchronlc Oral Toxldty of Chlorobenzene 1n Experimental Animals Species Dogs (4M, 4F) Rats Rats Dose (mg/kg/day) 27.3 54.6 272.5 12.5 or 50 100 250 14.4 144 and 288 Duration (days) 90 90 90 93-99 93-99 93-99 192 192 Effects Reference none Monsanto Company, 1967a; Knapp et al., 1971 diarrhea and vomiting; conjunctivitis mortality 4/8 1n 3-5 weeks; Increased Immature leukocytes, SGOT, blUrubln, cholesterol; decreased blood sugar; hlstopathologlcal changes In liver, kidneys, spleen none Monsanto Company, 1967b Increased liver and kidney weights Increased liver and kidney weights; retarded growth In males none Irish, 1963 Increased liver, kidney weights, given 5 days/ week salivation; partial alopecia ------- TABLE 3-1 (cont.) Species Rats House Dose (mg/kg/day) 12.5 50 or 100 250 42.9 89.3 Duration (days) 93-99 93-99 93-99 13 weeks 13 weeks Effects Reference none Knapp et al., 1971 Increased liver and kidney weights Increased liver and kidney weights, retarded growth In males one male with hepatic necrosis NTP, 1983 Increased liver weights 1n males; I en I 178.6 357 538 one male with hepatic necrosis 13 weeks >505C reduction 1n weight gain, Increased excretion of coproporphyrlns In females, Increased liver weights, lesions of the liver, kidney, bone marrow, spleen and thymus 13 weeks 100% lethal to males within 1 week, reduced body weight gains, polyurla In females. Increased liver weights, lesions of the liver, kidney, bone marrow, spleen and thymus 10 weeks 100% lethal to males within 1 week and to female mice within 10 weeks, lesions of the liver, kidney, bone marrow, spleen and thymus at death ------- TABLE 3-1 (cont.) Species Dose (mg/kg/day) Duration (days) Effects Reference Rat 42.9 89.3 178.6 357 538 13 weeks none NTP, 1983 13 weeks none 13 weeks minimal centrolobular hepatocellular necrosis 13 weeks decreased body weight gain, Increased GGTP and alkaline phosphatase In females, Increased excretion of porphyrlns, cen- trolobular hepatocellular necrosis, nephropathy 1n males, myelold depletion of bone marrow 13 weeks decreased body weight gain and survival of animals, hematologlc effects, Increased GGTP and alkaline phosphatase In females, polyurla In males, Increased excretion of porphyrlns, centrolobular hepatocellular necrosis, nephropathy, lymphold depletion of thymus and spleen, myelold depletion of bone marrow ------- In mice, 100% lethality to males within 1 week occurred at >500 mg/kg, accompanied by hlstopathologlcal lesions In many organs. All females 1n the 750 mg/kg group died by week 10. A 50% reduction In body weight gain and hlstopathologlcal lesions were noted at 250 mg/kg. Increased liver weights In males were noted at 125 mg/kg and liver necrosis was noted In 1 male In the 125 and 1 male In the 60 mg/kg group. Hale mice appeared to be affected more severely than females. In rats, decreased body weight gain 1n both sexes, altered serum bio- chemistries 1n females and hlstopathologlcal alterations were observed at 500 and 750 mg/kg. Decreased survival was observed at 750 mg/kg. The only effect reported at 250 mg/kg was minimal centrolobular hepatocellular necro- sis. No effects were observed at the two lowest levels. 3.1.2. Inhalation. No studies regarding subchronlc Inhalation exposure of humans to chlorobenzene could be located 1n the available literature. Because of the potential for being long-term, reports of occupational expo- sure are discussed In Section 3.2.2. Several studies of subchronlc Inhalation exposure of laboratory animals to chlorobenzene have been reviewed by Delchmann (1981) and U.S. EPA (1985) and are summarized In Table 3-2. Ollley (1977) demonstrated small, focal lesions In the adrenal cortex and kidney tubules and decreased SCOT 1n rats exposed to 75 ppm chlorobenzene 7 hours/day, 5 days/week for 120 days. This dosage, corresponding to an Intake of 53 mg/kg/day, defined a LOAEL In rats from Inhalation exposure to chlorobenzene. In an earlier study, no effects were seen In rats exposed to 142 mg/kg bw/day for 44 days (Irish, 1963). Several reports from the foreign literature Indicate effects In rats at exposures leading to dosages far below those associated with no effects 1n -7- ------- TABLE 3-2 Subchronlc Inhalation Toxtclty of Chlorobenzene In Experimental Animals oo i Species Rats Rats Rats Rats Rats Rats Exposure 200 ppm, 7 hours/day. 5 days/week 475 and 1000 ppm, 7 hours/day, 5 days/week 0.75. 1.50 or 2 rag/I 6 hours/day, 5 days/week 0.1 or 1.0 mg/m9 continuous 0.1 mg/rn3 continuous 1.0 mg/m' continuous 0.1. 1.25 or 1.5 rag/lb 0.1 mg/l, 3 hours /day every other day Dose3 (ing/kg/day) 142 338 and 713 99. 199 or 265 0.7 or 7.0 0.07 0.7 NO 4.6 Duration (days) 44 44 87 72-80 60 60 49-98 259 Effects none Increasing severity of hepatomegaly, hlstopathologlcal changes none liver necrosis and regenerations; kidney hyperplasla. encephalopathy, pneumonia none Inhibited chronaxla of antlgonlstlc muscles at 39 days; Increased blood chollnesterase chronaxlmetrlc Inhibition Inhibition of extensor tlblalls at 7-14 weeks, normal by 20 weeks Reference Irish. 1963 Monsanto Company, 1976 Khanln. 1977 Tarkhova, 1965 Ptslaru, 1960 Gabor and Raucher, 1960 Rats 75 or 250 ppm 7 hours/day. 53 or 178 5 days/week Rabbits 75 or 250 ppm. 7 hours/day, 102 or 340 5 days/week Rabbits 200 ppm. 7 hours/day, 271 5 days/week Guinea pigs , 200 ppm, 7 hours/day, 102 5 days/week 120 120 44 44 focal lesions In adrenal cortex and Dllley, 1977 and kidney tubules; congestion of liver and kidney, decreased SCOT decreased SGOT Dllley. 1977 none Irish, 1963 none Irish, 1963 ------- TABLE 3-2 (cont.) Species Dogs Exposure 0.75 my/I, 6 hours/day, 5 days/week Dosed (mg/kg/day) 15.8 Duration Effects (days) 87 none Reference Honsanto Company, 1978 l.SO mg/i, 6 hours/day, 5 days/week 200 mg/t, 6 hours/day, 5 days/week 31.6 4218 87 87 weight loss, conjunctivitis, moribund by 31 days weight loss, hypoactlvlty and conjunctiv- itis; vacuolated hepatocytes, cytoplasmlc vacuolation of renal tubules, bilateral atrophy of seminiferous tubules; leukocyto- poenla; elevated SAP, SGOT, SGPT; aplastlc bone narrow, mortality In 5/8 dogs by 25-29 days aDose In mg/kg was calculated assuming the following inhalation rates and body weights: rats - 0.26 mVday and 0.35 kg; rabbits - 1.6 mVday, 1.13 kg; guinea pigs - 0.23 mVday, 0.43 kg; dogs - 1.5 mVday, 12.7 kg ^Exposure data insufficient for calculation of dose ND = Not derived because exposure data are insufficient ------- reports from the domestic literature. For example, Khanln (1977) reported hlstopathological lesions 1n several organs at 0.7 mg/kg bw/day. Neuro- muscular dysfunction was reported 1n rats at exposures leading to dosages of 0.7-4.6 mg/kg bw/day (Tarkhova, 1965; Plslaru, 1960; Gabor and Raucher, 1960). In the absence of corroborating evidence from the domestic liter- ature, the data are not considered reliable for use 1n risk assessment. In subchronlc Inhalation experiments 1n other species, no adverse effects were observed 1n rabbits at 102-340 mg/kg bw/day (DUley, 1977; Irish, 1963), 1n guinea pigs at 102 mg/kg bw/day (Irish, 1963) or In dogs at 15.8 mg/kg bw/day (Monsanto Company, 1978). Dogs appear to be the most sensitive species tested, however, as weight loss and morlbundlty occurred 1n this species by 31 days of exposure to 31.6 mg/kg bw/day (Monsanto Company, 1978). 3.2. CHRONIC 3.2.1. Oral. No reports of chronic oral exposure of humans to chloroben- zene could be located 1n the available literature. Minimal toxldty data are available from the 103-week cardnogenlcHy bloassay 1n rats and mice (NTP, 1983). Groups of 50 male and 50 female B6C3F, mice were treated by gavage with chlorobenzene In corn oil at 0, 60 and 120 mg/kg for females and 0, 30 and 60 mg/kg for males. Groups of 50 male and 50 female F344/N rats were treated with 0, 60 and 120 mg/kg. Treatments were performed 5 days/ week for 103 weeks. Both untreated and vehicle-treated controls were maintained. Neither mice nor rats had clinical signs of toxldty related to treat- ment with chlorobenzene. Statistically significant reduced survival was observed In low-dose male mice and high-dose male rats. Increased body weights In both treated groups of female rats were noted during the second -10- ------- year of the experiment. No histopathologic evidence of toxldty was was observed In mice; however, rats had "equivocal evidence for mild chloro- benzene-lnduced hepatocellular necrosis." 3.2.2. Inhalation. The only available reports of chronic human exposure to monochlorobenzene were summaries by U.S. EPA (1985) and Delchmann (1981), from which this discussion was adapted. Glrard et al. (1969) reported the case of a 70-year-old woman exposed for 6 years to a glue containing 70% chlorobenzene. From the time she began using the glue, she experienced headaches and Irritation of the mucosa of the upper respiratory tract and eyes. After 6 years, she had developed medullary aplasia. No exposure data were available. Rosenbaum et al. (1947) examined 28 factory workers, many of whom com- plained of headaches and showed signs of somnolescence and dyspepsia. Other complaints Included tingling, numbness and stiffness of the extremities (8 workers), hyperesthesia of the hands (4 workers), and spastic contractions of the finger muscles (9 workers) or of the gastrocnemius (2 workers). These workers had reportedly been exposed for 1-2 years, but details of exposure were not specified. No neurotoxlc signs were displayed by 26 workers exposed to benzene and/or chlorobenzene fumes for <1 year. No reports of chronic Inhalation exposure of laboratory animals to chlorobenzene could be located in the available literature. 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS No reports of fetotoxlcity or teratogenlcity In humans or animals asso- ciated with either oral or Inhalation exposure to chlorobenzene could be located in the available literature. -11- ------- 3.4. TOXICANT INTERACTIONS No pertinent data confirming the Interaction of chlorobenzene with other xenoblotlcs could be located 1n the available literature. Generalizing that the halogenated benzenes appeared to Increase the activity of mlcrosomal cytochrome P-450-dependent enzyme systems, the U.S. EPA (1980b) suggested that exposure to chlorobenzene might be expected to hasten metabolism of other xenoblotlcs to either more or less toxic metabolites. Shelton and Weber (1981) Investigated the hepatotoxiclty of a 1:38 molar ratio mixture of carbon tetrachlorlde and chlorobenzene in male CF-1 mice. The dosages used (not specified) were given by 1ntraper1toneal Injection. Although parameters of hepatotoxiclty were not mentioned, the U.S. EPA (1985) stated that the dose-response did not deviate from that predicted by addition alone. -12- ------- 4. CARCINOGENICITY 4.1. HUMAN DATA No reports associating chlorobenzene with cancer 1n humans could be located In the available literature. 4.2. BIOASSAYS The NTP (1983) conducted a study of the cardnogenldty of chlorobenzene in rats and mice. Based on data from a 13-week dose range-finding experi- ment, 50 rats of each sex were treated by gavage with 60 or 120 mg/kg, 5 days/week for 103 weeks. Both untreated and vehicle-treated control groups of 50 rats of each sex were maintained. Throughout the study, body weight of treated and control animals remained comparable. Survival rates were similar until about 70 weeks of treatment, at which time survival 1n high-dose group males was significantly reduced. Survival at the end of 2 years was 68, 78, 64 and 52% 1n untreated control, vehicle-treated control, low-dose and high-dose males, respec- tively. Among female rats, 2-year survival data were 74, 58, 60 and 62% In untreated control, vehicle-treated control, low-dose and high-dose groups, respectively. Although there was some disagreement 1n the Interpretation of liver lesions, pathologists evaluating the slides seemed to agree that Inflamma- tion and cytoplasmic basophilla, manifestations of hepatic degeneration, were less severe In chlorobenzene-treated rats than in the control groups. In male rats, a significant Increase in neoplastlc nodules 1n the liver was observed in the high-dose group (Table 4-1) as determined by both the Inci- dental tumor test (p=0.021) and the Cochran-Armitage test for dose-related trend (p=0.043). Liver carcinomas in male rats were found only in the vehicle-treated group (2/50). Combining the incidences of neoplastic -13- ------- TABLE 4-1 Statistical Comparisons of Liver Tumors 1n Male Rats Treated with Chlorobenzene* Tumor Type Neoplastlc nodule Incidental tumor test Cochran-Armltage test Fisher exact test Carcinoma Incidental -tumor test Cochran-Armltage test Fisher exact test Neoplastlc nodule or carcinoma Incidental tumor test Cochran-Armltage test Fisher exact test Untreated Vehicle Control Control 4/50 (8%) 2/50 (4%) p=0.011 p=0.027 NA 0/50 (0%) 2/50 (4%) p=0.139 p=0.098 NA 4/50 (8%) 4/50 (8%) p=0.054 p=0.121 NA 60 mg/kg 4/49 (8%) p=0.290 NA p=0.329 0/49 (0%) p=0.283 NA p=0.253 4/49 (8%) p=0.570 NA p=0.631 120 mg/kg 8/49 (16%) p=0.021 NA p=0.043 0/49 (0%) p=0.331 NA p=0.253 8/49 (16%) p=0.083 NA p=0.168 *Source: NTP, 1983 NA = Not applicable -14- ------- nodules and carcinomas failed to create an overall tumor Incidence that was statistically significant. There was no evidence of neoplastlc nodule or liver tumor formation 1n female rats. The Incidence of pituitary tumors (adenoma, adenocarclnoma and car- cinoma) In both male and female rats was found to be significantly Inversely related to treatment with chlorobenzene (Table 4-2). The carclnogenlclty of chlorobenzene has also been tested 1n B6C3F.. mice (NTP, 1983). Males were treated with 30 or 60 mg/kg and females were subjected to 60 or 120 mg/kg, 5 days/week for the 2-year (103-week) treat- ment period. These dosages were chosen on the basis of a preliminary 13-week dose range-finding study. It appeared that the doses chosen for the chronic bloassay were too low based on the data generated by the 13-week preliminary study, and that the accepatable Intake had not been approached (U.S. EPA, 1985). No tumors occurred with frequencies that differed sig- nificantly from those 1n the control groups. The U.S. EPA (1985) stated that the data generated by these studies were not sufficient to draw conclusions about the carclnogenlclty of chloro- benzene. 4.3. OTHER RELEVANT DATA Studies of the mutagenlclty of chlorobenzene 1n microorganisms have yielded mixed results, with positive results observed only in tests with Saccharomyces cerevlslae (Simmon et al., 1979) and Streptomyces antlbloticus (Kesklnova, 1968) (Table 4-3). In a sex-Hnked recessive lethal test 1n DrosophUa melanogaster (Bio- assay Systems Corp., 1982), male flies were exposed to 36,000 or 128,400 ppm of chlorobenzene for 1 hour. The exposed flies were mated at 1-3 days -15- ------- TABLE 4-2 Pituitary Tumors In Male Rats Treated with Chlorobenzene* cr> i Untreated Tumor Type Control Adenoma 20/49 (4154) Incidental tumor test Cochran-Armltage test Fisher exact test Adenoma, adenocarclnoma or carcinoma 20/49 (4154) Incidental tumor test Cochran-Armltage test Fisher exact test • Vehicle Control 10/50 (20%) p=0.109 p=0.047 NA 12/50 (2454) p=0.044 p=0.016 NA 60 mg/kg 9/42 (2154) p=0.532 NA p=0.534 9/42 (2154) p=0.462 NA p=0.484 120 mg/kg 3/47 (654) p=0.101 NA p=0.046 3/47 (654) p=0.044 NA p=0.015 *Source: NTP, 1983 NA -- Not applicable ------- TABLE 4-3 Mutagenicity Testing of Chlorobenzene* Test System Metabolic Activation Concentration Result Reference Asperlqlllus nldulans Salmonella strains TA1535, TA1537, TA1538, TA92, TA98, TA100 Salmonella typhirourium strains *Source: U.S. EPA. 1985 NR = Not reported 200 0.1-0.5 pi/plate 100 yg/plate negative Prasad, 1970 negative Simmon et al., 1979 negative Merck and Company, 1978 Saccharomyces cerevislao S. cerevlslae Mouse lymphoma L5178Y (forward mutation of TK) Escherlchla coll (polAVpolA-) Bacillus subtilis (rec~/recf) Streptomyces antlblotlcus f 0.05-654 t- 0.01-5 ul/plate 0.001-0.1 til/mi H 0.0001-0.01 jii/mfc 10^20 pi/plate 10-20 yi/plate NR positive negative negative negative negative negative positive Simmon et al., 1979 Monsanto Company, 1976 Monsanto Company, 1976 Simmon et al., 1979 Simmon et al., 1979 Keskinova. 1968 ------- (to sample effects on spermatozoa), 4-5 days (to sample effects on sper- matlds) and 6-7 days (to measure effects on spermatocytes) after exposure. No evidence of mutagenldty was found 1n 11,543 chromosomes from treated flies compared to 9430 chromosomes from control flies. A positive response was obtained 1n a test for 1j\ vitro Induction of chromosomal aberrations 1n Chinese hamster ovary cells (U.S. EPA, 1982b). Concentrations of 444, 266 and 178 yg/ms, were tested 1n assays not Incorporating a metabolic activating system and concentrations of 493, 296, 197 and 99 yg/mj. were assayed with an S-9 activating system. A positive response was observed 1n the S-9 activated system after a 4-hour exposure but not after a 2-hour exposure. 4.4. WEIGHT OF EVIDENCE No evidence of cardnogenldty associated with exposure to chlorobenzene In humans could be located 1n the available literature. The NTP (1983) bio- assay failed to confirm or deny the cardnogenldty of chlorobenzene 1n rats or mice. IARC has not evaluated the risk to humans associated with oral or Inhalation exposure to chlorobenzene. By applying the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA for evaluating the overall weight of evidence for cardnogenldty to humans (Federal Register, 1984), a designation of chlorobenzene as a Group D - Not Classified chemical seems most appropriate. -18- ------- 5. REGULATORY STANDARDS AND CRITERIA A summary of regulatory standards and criteria for chlorobenzene 1s presented in Table 5-1. Both the ACGIH (1980) and NIOSH (1982) have set the TWA for chlorobenzene at 75 ppm. No STEL has been set. The U.S. EPA (1980b) has suggested an ambient water quality criterion of 488 yg/a. to protect human health. This criterion Is based on an ADI of 1.008 mg/day, assumes consumption of 2 i water/day and takes Into con- sideration consumption by fish and shellfish. -19- ------- TABLE 5-1 Current Regulatory Standards and Criteria for Chlorobenzene Standard or Criterion Value Reference TLV TWA Ambient water quality criteria: Freshwater aquatic life Acute toxlclty Saltwater aquatic life Acute toxldty Chronic toxlclty Ambient water quality criterion: Human life Organoleptlc 75 ppm (-350 mg/m3) 75 ppm 250 pg/8, 160 129 488 vg/l 20 AC6IH, 1980 U.S. EPA, 1985 U.S. EPA, 1985 U.S. EPA, 1985 U.S. EPA, 1985 U.S. EPA, 1985 U.S. EPA, 1985 -20- ------- 6. RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.1.1. Oral. NOAELs from subchronlc oral studies Include 14.4 mg/kg/day In rats (Irish, 1963), 50 mg/kg/day in rats (Monsanto Company, 1967b), 89.3 mg/kg/day 1n rats (125 mg/kg, 5 days/week) (NTP, 1983), 12.5 mg/kg/day In rats (Knapp et a!., 1971) and 27.3 mg/kg/day In dogs (Monsanto Company, 1967a; Knapp et al.. 1971). The Irish (1963) study reported a NOEL of 14.4 mg/kg/day and LOAEL of 144.4 mg/kg/day, however, Intermediate doses were not evaluated. The Monsanto (1967a,b) study defined a NOAEL of 50 mg/kg/day and LOAEL of 100 mg/kg/day In the rat. In contrast, a NOEL of 27.3 mg/kg/day and a LOAEL of 55 mg/kg/day were defined for the dog. The observed adverse effects Indicated a higher sensitivity of the dog to chlorobenzene than the rat. Based on these findings the highest dog NOEL of 27.3 mg/kg/day (Mon- santo, 1967b) was considered appropriate to derive an ADI for subchronlc exposure. An uncertainty factor of 100 1s applied, a factor of 10 to account for Interspecles extrapolation and a factor of 10 to provide greater protection for especially sensitive populations. Assuming a body weight 1n man of 70 kg, an AIS for man can be calculated as follows: AIS = (27.3 mg/kg/day days x 70 kg) f 100 (the uncertainty factor derived above) AIS =19.1 mg/day In dogs Immature leukocytes, low blood sugar, conjunctivitis, vomiting and diarrhea were reported at 55 mg/kg/day, whereas higher doses caused mortality and histopathologlcal lesions In liver and kidneys (Monsanto, 1967a). A human MED was calculated by multiplying the dog MED by the cube root of the ratio of the body weight of dogs (assumed: 12.7 kg) to that of humans (assumed: 70 kg) and dividing the result by 10, an uncertainty -21- ------- factor chosen to reflect the unknowns 1n extrapolating from a subchronlc study to chronic application. The result, 3.1 mg/kg/day, 1s multiplied by 70, resulting in an MED of 218 mg/day for a 70 kg man. This MED corresponds to an RVd of 2.0; the effects of vomiting, diarrhea, conjunctivitis and Immature luekocytes rate an RV of 4. A CS of 8, the product of RV. and RVe, 1s calculated. 6.1.2. Inhalation. No pertinent data regarding the effects of subchronlc Inhalation exposure of humans to chlorobenzene could be located 1n the available literature. Studies by Irish (1963) defined NOELs in rats, rab- bits and guinea pigs of 142, 271 and 102 mg/kg/day, respectively. Dilley (1977) found small focal lesions 1n the adrenal cortex and kidney tubules, congestion of the liver and kidney, and decreased SGOT in rats exposed to 75 ppm chlorobenzene for 7 hours/day, 5 days/week for 120 days. This concen- tration resulted in an intake of 53 mg/kg/day (applying the assumptions stated in Table 3-2), which was designated as a LOAEL in this study. An interim AIS can be calculated from these data by assuming a body weight of man of 70 kg and using an uncertainty factor of 1000; a factor of 10 to account for interspecies conversion, another factor of 10 to convert from a LOAEL to a NOEL and a final factor of 10 to afford greater protection to unusually sensitive populations. The resultant interim AIS is 3.7 mg/day. 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.2.1. Oral. No reports of chronic oral exposure of humans or animals to chlorobenzene could be located 1n the available literature. An Interim AIC for chronic oral exposure can be derived from the subchronic AIC by applying an additional uncertainty factor of 10 to convert from a subchronic study to chronic exposure; this results 1n an overall uncertainty factor of 1000. The resultant AIC is 1.9 mg/day. -22- ------- 6.2.2. Inhalation. No reports of chronic exposure of humans to chloro- benzene that were satisfactory for risk assessment, or studies of chronic animal exposure could be located In the available literature. The study by Dllley (1977), used to derive an AIS, can be used to derive an AIC for Inhalation exposure. An additional uncertainty factor of 10 to account for derivation of an AIC from subchronlc data results 1n an AIC of 0.4 mg/day, starting with the AIS of 3.7 mg/day (see Section 6.1.2). 6.3. CARCINOGENIC POTENCY (q^) 6.3.1. Oral. The NTP (1983) bloassay failed to demonstrate conclusively the cardnogenldty, or lack of cardnogenldty, of chlorobenzene admin- istered to rats and mice by gavage. No other reports of cardnogenldty 1n humans or animals resulting from oral exposure to chlorobenzene could be located 1n the available literature. Therefore, Insufficient data are available from which to estimate carcinogenic potency. 6.3.2. Inhalation. No reports of cardnogenldty 1n humans or animals associated with Inhalation exposure to chlorobenzene could be located 1n the available literature; hence, no estimation of carcinogenic postency has been made. -23- ------- 8. REFERENCES ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1980. Documentation of the Threshold Limit Values for Substances In Workroom A1r, 4th ed. Cincinnati, OH. p. 84-85. (Cited In U.S. EPA, 1982a) Bloassay Systems Corp. 1982. DrosophHla sex-linked recessive lethal test on monochlorobenzene. U.S. EPA, Office of Pesticides and Toxic Substances, Washington, DC. TSCA Section 8(d) submission. (Cited 1n U.S. EPA, 1985) Branson, D.R. 1978. Predicting the fate of chemicals In the aquatic environment from laboratory data. ASTM STP 657. American Society for Testing and Materials, Philadelphia, PA. p. 55-76. Delchmann, W.B. 1981. Halogenated Cyclic Hydrocarbons. In_: Toxicology. Patty's Industrial Hygiene and Toxicology, 3rd ed.. Vol. 2B, G.O. Clayton and E.E. Clayton, Ed. John Wiley and Sons, Inc., NY. p. 3605-3611. (Cited In U.S. EPA, 1982a) DUley, J.V. 1977. Toxic Evaluation of Inhaled Chlorobenzene. NIOSH, DHEW, Cincinnati, OH. Contract 210-76-0126. (Cited In U.S. EPA, 1985) Federal Register. 1984. Environmental Protection Agency. Proposed guide- lines for carcinogenic risk assessment. 49 FR 46294-46299. -24- ------- Gabor, S. and K. Raucher. 1960. Studlen zur Bestlmmung der zulasslgne benzol und monochorbenzol grenzkonzentratlonen. J. Hyg. Epidemic!. Mlcrobiol. Immunol. 4: 223-231. (Ger.) (CHed In U.S. EPA, 1985) Glrard, R., F. Tolot, P. Martin and J. Bourret. 1969. Serious blood dis- orders and exposure to chlorine derivatives of benzene (A report of 7 cases). J. Med. Lyon. 50: 771-773. (CHed 1n U.S. EPA, 1985) Hansch, C. and A.J. Leo. 1981. Medchem Project. Issue No. 19. Pomona College, Claremont, CA. Holllngsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer. 1956. Toxldty of paradlchlorobenzene: Determination on experimental animals and human subjects. AMA Arch. Ind. Health. 14: 138-147. (Cited In U.S. EPA, 1980b) Horvath, A.L. 1982. Halogenated Hydrocarbons: Solub1lity-H1sc1b1l1ty with Water. Marcel Dekker, Inc., New York, NY. p. 889. Irish, D.D. 1963. Halogenated Hydrocarbons: II. Cyclic. ITK Industrial Hygiene and Toxicology, Vol. II, 2nd ed., F.A. Patty, Ed. Intersclence, NY. p. 1333-1361. (Cited 1n U.S. EPA, 1980b) Kanno, S. and K. Nojima. 1979. Studies on photochemistry of aromatic hydrocarbons. V. Photochemical reaction of chlorobenzene with nitrogen oxides In air. Chemosphere. 8: 225-232. -25- ------- Keskinova, D.V. 1968. The effect of d1methylcyclod1azomethane In chloro- benzene solution on mutagenesls In Actlnomyces antlbiotlcus 400. Genetlka. 4(8): 121-125. (Cited In U.S. EPA, 1985) Khanln, A.6. 1977. Pathological changes In the general nervous system and Internal organs of experimental animals after chronic continuous Inhalation of toxic substances. Chem. Abstr. 74: 97-106. (Cited In U.S. EPA, 1985) Knapp, W.K., Jr., W.M. Busey and W. Kundzlns. 1971. Subacute oral toxldty of monochlorobenzene 1n dogs and rats. Toxlcol. Appl. Pharmacol. 19: 393. (Abstr.) (Cited In U.S. EPA, 1980b) Mabey, W.R., J.H. Smith and R.T. Podoll. 1981. Aquatic Fate Process Data for Organic Priority Pollutants. Monitoring and Data Support Division, Office of Water Regulations and Standards, Washington, DC. EPA 440/4-81-014. Merck and Company. 1978. Summary of Monochlorobenzene Bacterial Mutagen Test (Ames Test). Office of Pesticides and Toxic Substances, U.S. EPA, Washington, DC. TSCA Sec 8(d) submission 8DHQ-1078-0302. (Cited 1n U.S. EPA, 1985) Monsanto Company. 1967a. 13-Week oral administration - dogs, monochloro- benzene. U.S. EPA, OPTS, Washington. DC. TSCA Sec 8(d) submission 8DHQ-1078-0202(2). (Cited 1n U.S. EPA, 1985) -26- ------- Monsanto Company. 1967b. 3-Month subacute oral study of monochlorobenzene in rats. U.S. EPA, Washington. DC. TSCA Sec 8(d) submission 8DHQ-1078-Q212(3). (Cited 1n U.S. EPA, 1985) Monsanto Company. 1976. Litton Blonetlcs mutagenldty evaluation of B10-76-86-CP 5535 (WGK): Monochlorobenzene. Office of Pesticides and Toxic Substances, U.S. EPA, Washington, DC. TSCA Sec 8(d) submission 8DHQ-1078- 0214(1). (Cited 1n U.S. EPA, 1985) Monsanto Company. 1978. Industrial Bio-Test draft report of 90-day subacute vapor Inhalation toxldty study with monochlorobenzene In beagle dogs and albino rats. U.S. EPA, OPTS, Washington, DC. TSCA Sec 8{d) submission 8DHQ-1078-0202(1). (Cited In U.S. EPA, 1985) NIOSH (National Institute for Occupational Safety and Health). 1972. The 1982 Registry of Toxic Effects of Chemical Substances, R.L. Lewis and R.L. Tatken, Ed. Cincinnati, OH. (Cited 1n U.S. EPA, 1985) NTP (National Toxicology Program). 1983. Cardnogenesls studies of chloro- benzene (CAS No. 108-99-7) In F344/N rats and B6C3F1 mice (gavage studies). NTP-82-90. NIH Publ. 83-2517. (Draft) Plslaru, V. 1960. Modlflcarl cronaxlmetrlce In 1ntox1cat1a cronlca cu benzen s1 monochlorobenzen. Iglena. 9: 127-135. (Cited In U.S. EPA, 1985) -27- ------- Prasad, I. 1970. Mutagenlc effects of the herbicide 3',4'-d1chloroprop1o- anHlde and Its degradation products. Can. J. M1crob1ol. 16: 369-372. (CHed 1n U.S. EPA, 1985) Reich, H. 1934. Puran (Monochlorobenzol)-Verg1ftung bel elnem zweljahrlgen K1nde. Verglftungsfalle. 5: 193-194. (Ger.) (CHed In U.S. EPA, 1985) Rosenbaum, N.D., R.S. Block, S.N. Kremneva, S.L. Glnzburg and I.V. PozhaMskll. 1947. The use of chlorobenzene as a solvent from the point of view of industrial hygiene. G1g. Sanlt. 12(1): 21-24. (Cited In U.S. EPA, 1985) Shelton, D.W. and L.J. Weber. 1981. Quantification of the joint effects of mixtures of hepatotoxlc agents: Evaluation of a threshold model In mice. Environ. Res. 26: 33-41. (CHed 1n U.S. EPA, 1985) Simmon, V.F., E.S Rlccio and M.V. Pelrce. 1979. In. vitro microbiological genotoxiclty assays of chlorobenzene, m-d1chlorobenzene, o-dlchlorobenzene and p-d1chlorobenzene. Contract No. 68-02-2947. U.S. EPA, ORD, Washington, DC. (CHed In U.S. EPA, 1985) Tarkhova, L.P. 1965. Maximum permissible concentration of chlorobenzene In the atmosphere. G1g. Sanlt. 30: 8. (CHed 1n U.S. EPA, 1985) U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of Health Effects Assessment Chapters of the Consent Decree Water Quality Criteria. Federal Register. 45:79347-79357. -28- ------- U.S. EPA. 19805. Ambient Water Quality Criteria for Chlorinated Benzenes. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 440/5-80-028. NTIS PB 81-117392. U.S. EPA. 1982a. Hazard Profile for Chlorobenzene. 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. 1982b. Effects of Monochlorobenzene on the In vitro Induction of Chromosomal Aberrations 1n Chinese Hamster Ovary Cells. Prepared for U.S. EPA by Bloassay Systems Corp. (Cited In U.S. EPA, 1985) U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter- minations Based on Chronic Toxldty Data. 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. 1985. Health Assessment Document for Chlorinated Benzenes. Environmental Criteria and Assessment Office, Cincinnati, OH. EPA 600/8-84-015F. NTIS PB 85-150332. Varshavskaya, S.P. 1967. Comparative toxlcologlcal characteristics of Chlorobenzene and dlchlorobenzene (ortho- and para-1somers) 1n relation to the sanitary protection of water bodies. (Rus. trans.) Hyg. San. 33(10): 17-23. (Cited In U.S. EPA, 1980b) -29- ------- - -I Velth, G.D., D.L. DeFoe and B.V. Bergstedt. 1979. Measuring and estimating the bloconcentratlon factor of chemicals 1n fish. J. Fish Res. Board Can. 36: 1040-1048. Williams, R.T. 1959. The Metabolism of Halogenated Aromatic Hydrocarbons. Detox1cat1on of Mechanisms, 2nd ed. John WHey and Sons, Inc., NY. p. 237. (Cited In U.S. EPA, 1985) Wilson, J.T., C.G. Enfleld, 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. Zoeteman, B.C.J., K. Harmsen, 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. -30- ------- APPENDIX Summary Table for Chlorobenzene Species Inhalation AIS rat AIC rat Oral AIS dog AIC dog Maximum dog composite score Experimental Dose/Exposure 53 mg/kg/day 53 mg/kg/day 27.3 mg/kg/day for 90 days 27.3 mg/kg/day for 90 days 55 mg/kg/day for 90 days (RVd = 2.0) Acceptable Intake Effect (AIS or AIC) focal lesions In liver, 3.7 mg/day kidney tubules; hepatic and renal congestion; decreased SGOT focal lesions In liver. 0.4 mg/day kidney tubules; hepatic and renal congestion; decreased SGOT none 19.1 mg/day none 1.9 mg/day Immature leukocytes, con- 8 junctlvltls, vomiting and diarrhea (RVe=4) Reference Dllley, 1977 Dllley, 1977 Monsanto, 1967a Monsanto. 1967a Monsanto, 1967a ND = Not derived ------- |