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• W4235957598 abstract "Free Access Chlorobenzene [MAK Value Documentation, 1999] 1999. Documentations and Methods First published: 31 January 2012 https://doi.org/10.1002/3527600418.mb10890e0012 AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Published in the series Occupational Toxicants, Vol. 12 (1999) The article contains sections titled: Toxic Effects and Mode of Action Mechanism of Action Toxicokinetics and Metabolism Absorption Distribution Metabolism Elimination Effects in Man Single exposures Inhalation Ingestion Repeated exposure Effects on skin and mucous membranes Animal Experiments and in vitro Studies Acute toxicity Inhalation Oral and intraperitoneal administration Subacute, subchronic and chronic toxicity Inhalation Ingestion Effects on skin and mucous membranes Allergenic effects Reproductive and developmental toxicity Genotoxicity In vitro In vivo Carcinogenicity Other effects Manifesto (MAK value, classification) MAK value (1995) 10 ml/m3 (ppm) ≙ 47 mg/m3 Peak limitation (1983) Category II,1 Absorption through the skin - Sensitization - Carcinogenicity - Prenatal toxicity (1985) Pregnancy risk group C Germ cell mutagenicity - BAT value (1991) 300 mg total 4-chlorocatechol/g creatinine Sampling: end of exposure or end of shift 70 mg total 4-chlorocatechol/g creatinine Sampling: at the beginning of the next shift Synonyms benzene chloride chlorobenzol monochlorobenzene Chemical name (CAS) chlorobenzene CAS number 108–90–7 Structural formula Molecular formula C6H5Cl Molecular weight 112.56 Melting point −45°C Boiling point 132°C Vapour pressure at 20°C 11.73 hPa 1 ml/m3 (ppm) ≙ 4.68 mg/m3 1 mg/m3 ≙ 0.214 ml/m3 (ppm) The toxicology of chlorobenzene was reviewed in a BUA Report in 1990. Therefore only the results of the most important studies and the literature which has appeared since 1990 are discussed in detail here. 1 Toxic Effects and Mode of Action Chlorobenzene is taken up via the lungs and the gastrointestinal tract. Dermal absorption probably plays a less important role. The toxic effects of chlorobenzene may be ascribed largely to the metabolic formation of the epoxide which binds to macromolecules. In man, chlorobenzene is excreted mainly in the urine in the form of the glucuronic acid and sulfate conjugates of 4-chlorocatechol and 4-chlorophenol. Animals also excrete a very large proportion of a chlorophenol dose in the form of 4-chlorophenylmercapturic acid. In test persons exposed for several hours to chlorobenzene at a concentration of 60 ml/m3, subjective symptoms such as headaches and sleepiness developed. Acute intoxication leads to transient irritation in the upper airways, nausea, inebriation, unconsciousness, collapse and cyanosis. Increased levels of liver enzymes in the serum and cases of acute liver failure have been reported. In experimental animals exposed repeatedly to chlorobenzene, the main target organs were the liver and kidneys. In some cases effects were seen after exposure to concentrations as low as 50 ml/m3. At higher concentrations disorders of the haematopoietic system were also seen. Chlorobenzene is a mild irritant of skin and mucous membranes, especially after repeated exposure. There is no evidence that the substance causes sensitization. One study with rabbits yielded evidence of teratogenic effects. This result could not be confirmed in another study, nor with rats. Genotoxicity tests have yielded mostly negative results. In a carcinogenicity study with rats and mice given chlorobenzene by oral administration, the incidence of neoplastic nodules in the liver was increased in the male rats of the highest dose group (120 mg/kg body weight and day). No effects were seen in the female rats or in the mice. 2 Mechanism of Action The toxic effects of chlorobenzene may be ascribed largely to the metabolic formation of the epoxides, chlorobenzene-3,4-epoxide and chlorobenzene-2,3-epoxide, which can bind to macromolecules. Binding to proteins has been demonstrated in vivo and in vitro in the liver, kidneys and lungs (BUA 1990). Binding to RNA and DNA has also been demonstrated (BUA 1990, Krewet 1991, Krewet et al. 1989). In vivo the rate of formation of these epoxides and thus the toxic effects, especially the toxic effects on the liver, may be increased by induction of the cytochrome P450 system, for example, with phenobarbital (BUA 1990). On the other hand, substances which inhibit the cytochrome P450 system or which activate epoxide hydratase reduce the adverse effects of chlorobenzene in vitro and in vivo (BUA 1990). 3 Toxicokinetics and Metabolism 3.1 Absorption Chlorobenzene is taken up by man and experimental animals via the lungs and the gastrointestinal tract. It seems likely that the substance is taken up less readily through the skin because symptoms of intoxication were seen in animal studies only after application of very large dermal doses (BUA 1990). 3.2 Distribution In persons exposed intermittently during 7 hours for a total of 4 hours to a chlorobenzene concentration of 50 ml/m3, the concentration of chlorobenzene in blood decreased by a factor of 3.5 to 4 during the 45 minutes after the end of exposure (Knecht and Woitowitz 1992). In animal studies it was demonstrated that the distribution of chlorobenzene in the organism depended largely on the fat content of the various organs (Shimada 1988, Sullivan et al. 1983, 1985). In mice, 2 hours after the end of a 1-hour exposure to 500 ml/m3, the highest concentration of chlorobenzene was found in the adipose tissue followed by the kidneys, liver, brain and blood (Shimada 1988). 3.3 Metabolism Metabolism of chlorobenzene begins with oxidation by the mixed functional oxidases of the cytochrome P450 system to yield chlorobenzene-3,4-epoxide and, to a lesser extent, chlorobenzene-2,3-epoxide and 3-chlorophenol (Figure , BUA 1990, Krewet 1991). The epoxides are then converted enzymatically by the action of glutathione transferase to water-soluble mercapturic acid derivatives, which can be eliminated in the urine, or by epoxide hydratase to dihydrodihydroxychlorobenzene and then to chlorocatechol. In addition, chlorophenols can be formed from the epoxides non-enzymatically by intramolecular rearrangement (BUA 1990, Neilson 1990). The main metabolic pathways of chlorobenzene (from BUA 1990) Chlorobenzene is metabolized not only in the liver but also in other organs which contain cytochrome P450. Thus metabolism of chlorobenzene and protein binding have been demonstrated in the lungs after intravenous and intraperitoneal administration of the substance (BUA 1990). 3.4 Elimination In all species which have been studied, chlorobenzene is excreted mainly in the form of urinary metabolites, especially as sulfate and glucuronic acid conjugates of the chlorophenols and chlorocatechols. Chlorobenzene is, however, also eliminated unchanged in the urine and in the exhaled air. In animal studies low levels of the metabolites have also been found in the faeces (BUA 1990, Ogata et al. 1991). In the urine of workers and test persons exposed to chlorobenzene, the metabolites 4-chlorocatechol, 2-chlorophenol, 3-chlorophenol, 4-chlorophenol and 4-chlorophenylmercapturic acid have been detected (Krämer et al. 1994, Kumagai and Matsunaga 1994, Kusters and Lauwerys 1990, 1990üller et al. 1992, Ogata and Shimada 1983, Ogata et al. 1991, Yoshida et al. 1986). The amount of the main metabolite, 4-chlorocatechol, which was excreted was 3 to 4 times the excreted amount of 4-chlorophenol (Kumagai and Matsunaga 1994, Kusters and Lauwerys 1990, Werfel 1995). In workers exposed to an average chlorobenzene concentration of 3 ml/m3 in the workplace air, the following metabolite pattern was found in the urine: 77 % 4-chlorocatechol, 23 % chlorophenols including 12 % 4-chlorophenol and 0.4 % 4-chlorophenylmercapturic acid; chloro-phenylmethyl sulfides could not be detected (Yoshida et al. 1986). Similar results have also been obtained by other authors (Krämer et al. 1994, 1994üller et al. 1992, Ogata et al. 1991, Werfel 1995). In addition, in animal studies small amounts of the following metabolites have been detected: 2-chlorohydroquinone, phenol, 2-chlorophenylmercapturic acid and 3-chlorophenylmercapturic acid, 3-chlorocatechol, hydroquinone, 3,4-dihydro-3,4-dihydroxy-chlorobenzene, 2-chlorophenyl, 3-chlorophenyl and 4-chlorophenyl sulfide, and phenyl-mercapturic acid (BUA 1990, Krewet et al. 1989, Krewet 1991). For all the animal species which have been studied, the proportion of the chlorobenzene dose (up to 60%) excreted in the form of 4-chlorophenylmercapturic acid was much higher than for man (BUA 1990, Kumagai and Matsunaga 1994, Kusters and Lauwerys 1990, 1990üller et al. 1992, Ogata and Shimada 1983, Yoshida et al. 1986). High doses lead to a reduction in the glutathione level in the liver and, as a result, an increase in the rate of glutathione synthesis. In the urine the amount of the mercapturic acid conjugate decreases relative to that of 4-chlorophenol or 4-chlorophenol sulfate and glucuronic acid conjugates; the amount of unmetabolized chlorobenzene eliminated via the lungs is increased. Such a saturation of metabolism is seen, for example, in rats exposed once or several times to a chlorobenzene concentration of 400 ml/m3 (BUA 1990, Sullivan et al. 1983, 1985). For man the half-time for the excretion of 4-chlorocatechol and 4-chlorophenol in the urine after inhalation of chlorobenzene concentrations between 10 and 60 ml/m3 is given as 1.4 to 3.2 hours. The half-time for a second, slower excretion process is up to 17.3 hours (Ogata et al. 1991, Yunoki 1991). In another study the elimination half-time was given as 3.5 hours for 4-chlorophenylmercapturic acid, 4.2 to 5.0 hours for 4-chlorocatechol and 5.5 to 6.3 hours for 4-chlorophenol (Werfel 1995). After poisoning caused by ingestion of 120 ml chlorobenzene and simultaneous high level alcohol consumption with severe liver damage, the half-time for the elimination of chlorobenzene from the serum after the end of the second day was very much longer, 40.3 hours (Babany et al. 1991). In animal studies the elimination has also been seen to take place in two phases. For man the excretion half-time for chlorobenzene taken up by inhalation is in the region of several hours (BUA 1990, Shimada 1988, Sullivan et al. 1983, 1985). 4 Effects in Man Data are not available for allergenic effects or reproductive toxicity of chlorobenzene in man, nor have genotoxicity or carcinogenicity studies been carried out with the substance. 4.1 Single exposures 4.1.1 Inhalation The odour threshold has been found experimentally to be 0.21 ml/m3 (Leonardos et al. 1969). Other reports indicate that chlorobenzene may be recognized by its odour from concentrations of about 60 ml/m3 and that it is unpleasant from about 200 ml/m3 (American Industrial Hygiene Association 1964). In a more recent study the unpleasant odour was detected at a concentration of 60.2 ml/m3 (Ogata et al. 1991). During a 7-hour exposure (3 hours exposure, 1 hour pause, 4 hours exposure; unclear whether the study was blind) to a chlorobenzene concentration of 60.2 ml/m3 in an exposure chamber, all four test persons complained of the unpleasant smell and sleepiness, three complained of headaches, two of pulsating pain in the eyes and one of a dry throat (Ogata et al. 1991). After the first 3 hours the values determined in the flimmer fusion frequency test were significantly reduced relative to the control values but they were no longer reduced after the second (4-hour) exposure. Workers exposed to chlorobenzene have occasionally reported transient irritation of the upper airways and transient exhaustion, nausea, vomiting and torpidity (Ehrlicher 1971). 4.1.2 Ingestion A 2-year old child who had ingested about 5 to 10 ml of a dry-cleaning fluid consisting almost entirely of chlorobenzene developed after 2.5 hours gross symptoms of inebriation, collapse, unconsciousness, cyanosis, absence of pulse and reflexes and occasional fibrillary contractions in the face. The child slowly regained consciousness after 3 hours, and felt better by the next day, but the breath, urine and clothes of the child smelled of chlorobenzene for 5 or 6 days (Reich 1934, Taeger 1934, cited from BUA 1990). After ingestion of 400 ml of the same cleaning fluid, a 56-year old woman became unconscious with cyanosis, shallow breathing, low blood pressure, reduced temperature and weak reflexes; tests for sugar, acetone, urobilinogen and urobilin in the urine yielded positive results and the blood leukocyte count was increased. The patient regained consciousness after a few hours, the clinical chemical parameters returned to normal within 2 days (Moeschlin 1956, cited from BUA 1990). A 40-year old man who consumed 200 g alcohol daily ingested 140 ml chlorobenzene (90%); 2 hours later he became sleepy and his serum liver enzyme values were increased. After 2 days the aspartate aminotransferase activity was 300 times the normal value, the serum bilirubin level was increased, prothrombin and coagulation factor V sank to 22 % and 29 % of the normal values, respectively. On the third day a diffuse erythema developed, the liver was enlarged. Histological examination of the liver revealed centrilobular and mediolobular necrosis (Babany et al. 1991). 4.2 Repeated exposure A married couple who had used a glue containing 70 % chlorobenzene for a period of 6 years experienced headaches and irritation of the upper airways and eyes. At the age of 70, the woman developed aplastic anaemia (Girard et al. 1969, cited from BUA 1990). Another report, which cannot be validated, described a reduced level of glutathione in the blood plasma of workers exposed to chlorobenzene as well as vitamin B6 deficiency (Feoktistova et al. 1989). 4.3 Effects on skin and mucous membranes According to early, inadequately documented reports, occasional contact with chlorobenzene causes slight skin irritation; after repeated or frequent contact the skin becomes light brown (American Industrial Hygiene Association 1964). Repeated contact during a period of a week results in moderate erythema and mild superficial necrosis (ILO 1971). In a study with five test persons, a burning sensation and the development of erythema, hyperaemia and weals was reported after 3 minutes contact with undiluted chlorobenzene; 12 hours later blisters were observed. After contact for 5 hours the sequelae were only slightly more severe (Oettel 1936, cited from BUA 1990). Another publication reports that contact with 5 % chlorobenzene in olive oil leads to the formation of acneiform skin eruptions (Fisher 1973). Early reports state that chlorobenzene causes slight irritation in the eye. During exposure to chlorobenzene vapour, irritation of the eyes and nose develops at concentrations of 200 ml/m3 and more (American Industrial Hygiene Association 1964). 5 Animal Experiments and in vitro Studies 5.1 Acute toxicity Data for the LD50 of chlorobenzene are shown in Table 1. Table 1. Acute toxicity of chlorobenzene (cited from BUA 1990) Species Sex Dose or concentration Effect References inhalation rat ♂ 13870 mg/m3, 6 h LC50 Bonnet et al. 1982 rat n.s. 18016 mg/m3, n.s. LC50 Eitingon 1975 rat n.s. 20000 mg/m3, 2 h LC100 Rosenbaum et al. 1947, Deichmann 1981 mouse ♀ 8822 mg/m3, 6 h LC50 Bonnet et al. 1979 cat n.s. 3000 mg/m3, 7 h no symptoms Götzmann 1904 cat n.s. 11000 mg/m3, 7 h not lethal, tremor, Götzmann 1904 spasms cat n.s. 17000 mg/m3, 7 h lethal Götzmann 1904 oral administration rat n.s. 2390 mg/kg body weight LD50 Varshavskaya 1967a rat n.s. 2910 mg/kg body weight LD50 Irish 1962 rat ♂ 1427 mg/kg body weight LD50 Löser 1982a rat ♀ 2455 mg/kg body weight LD50 Löser 1982b rat ♂ 3400 mg/kg body weight LD50 Vecerek et al. 1976 rat n.s. 2300 mg/kg body weight LD50 Eitingon 1975 mouse n.s. 1445 mg/kg body weight LD50 Varshavskaya 1967a guinea pig n.s. 5060 mg/kg body weight LD50 Varshavskaya 1967a rabbit n.s. 2250 mg/kg body weight LD50 Varshavskaya 1967a rabbit n.s. 2830 mg/kg body weight LD50 Irish 1962 dermal application rabbit ♂ 2212 mg/kg body weight not lethal Kinkead and Leahy 1987 subcutaneous injection rat n.s. 4000 mg/kg body weight lethal von Oettingen 1955 intraperitoneal injection rat n.s. 570 mg/kg body weight LD50 Kocsis et al. 1975 rat ♂ 1655 mg/kg body weight LD50 Dalich and Larson 1985 mouse ♂ 1355 mg/kg body weight LD50 Mohtashamipur et al. 1987 a n.s. not specified 5.1.1 Inhalation Inhaled chlorobenzene is of low acute toxicity, the LC50 values determined after exposure of rat, mouse and cat for at least 6 hours being more than 8000 mg/m3 (BUA 1990). When mice were exposed for 4 hours to chlorobenzene concentrations between 650 and 1000 ml/m3, behavioural changes were detected in the “behavioural despair swimming test” (de Ceaurriz et al. 1983). Exposure of mice to 854 ml/m3 caused a 50 % reduction in the threshold for induction of spasms with Pentetrazole (de Ceaurriz et al. 1981b). A 50 % reduction in the respiration rate was seen in mice exposed to a chlorobenzene concentration of 1054 ml/m3 (de Ceaurriz et al. 1981a). 5.1.2 Oral and intraperitoneal administration The acute oral toxicity of chlorobenzene has also been shown to be low, with LD50 values of more than 1000 mg/kg to more than 5000 mg/kg body weight (BUA 1990). After administration of single oral doses of chlorobenzene to rats and mice, an increase in respiration rate was observed at doses of 250 mg/kg body weight and more (Kluwe et al. 1985, NTP 1985). The other symptoms of intoxication included weight loss, apathy, somnolence, narcosis, trembling, muscle spasms, ataxia, paralysis of the hind limbs and respiratory distress (BUA 1990, Kluwe et al. 1985, NTP 1985). After administration of doses of 276 to 4180 mg/kg body weight to male rats, increases in the serum glutamate oxalacetate transaminase, lactate dehydrogenase, alkaline phosphatase, uric acid and sugar levels in the blood were found (Vecerek et al. 1976). Single intraperitoneal injections of chlorobenzene into rats produced effects on the liver from doses of about 200 mg/kg body weight. The relative liver weights were increased (den Besten et al. 1991, Yoshida and Hara 1984). There was a marked transient decrease in the level of GSH (den Besten et al. 1991, Dalich and Larson 1985, Koizumi et al. 1984, Yoshida and Hara 1984). The aminotransferase activity in blood was increased (Ariyoshi et al. 1975, den Besten et al. 1991, Dalich and Larson 1985, Koizumi et al. 1984) and centrilobular liver cell necrosis was detected (den Besten 1991, Koizumi et al. 1984, Reid et al. 1973). Pretreatment with phenobarbital increased the liver toxicity (Reid and Krishna 1973). The reduction in cytochrome P450 concentration which also developed in this dose range was associated with increased activities of cytochrome P450-synthesizing enzymes (Ariyoshi et al. 1975, 1981). 5.2 Subacute, subchronic and chronic toxicity The subacute, subchronic and chronic toxicity of chlorobenzene has been studied in several animal species given the substance by inhalation or by oral administration; the results are shown in Tables 2 and 3. Table 2. Effects of repeated inhalation of chlorobenzene (cited from BUA 1990) Species, strain, number per dose, sex Administration Concentration mg/m3 (ml/m3) Effects References rat 44 days, 936 (200), 200 ml/m3: no effects Irish 1962 7 h/day, 2220 (475), 475 ml/m3: increased liver weights, 5 days/week, 4678 (1000) pathological liver changes 32 single exposures 1000 ml/m3: decreased body weights, pathological changes in the lungs, liver, kidneys rat 5 weeks, 351 (75), from 75 ml/m3: increased food consumption, Dilley 1977, SD 7 h/day, 1169 (250) increased relative brain weights, decreased haematocrit 10 ♂ 5 days/week Dilley and Lewis 1978 250 ml/m3: increased relative kidney weights, AST and LDH decreased rat 60 days, 0.1 (0.02), 0.02 ml/m3: no effects Tarkhova 1965 15 ♂ 24 h/day 1 (0.2) 0.2 ml/m3: disturbance of the chronaxy of antagonistic muscles, increased cholinesterase, decreased alpha-globulin rat 70–80 days, 1 (0.2) 0.2 ml/m3: encephalopathy, pathological Khanin 1969 24 h/day changes in liver and kidneys, inflammation of the internal organs rat 1 year, 100 (20) 20 ml/m3: disturbance of the chronaxy of Gabor and Raucher 1960 3 h/day every second day antagonistic muscles, increased catalase and indophenoloxidase, decreased peroxidase and carbon dioxide anhydrase rat 11 weeks, 351 (75), from 75 ml/m3: increased food consumption, Dilley 1977, SD 7 h/day, 1169 (250) increased liver weights, pathological changes 10 ♂ 5 days/week in adrenals and kidneys, AST decreased, haematocrit and thrombocytes increased, reticulocytes increased Dilley and Lewis 1978 250 ml/m3: increased liver and kidney weights, leukocyte counts decreased rat 24 weeks, 351 (75), from 75 ml/m3: increased food consumption Dilley 1977, SD 7 h/day, 1169 (250) 250 ml/m3: increased liver and kidney 10 ♂ 5 days/week weights, reticulocyte counts increased, AST decreased, liver changes and slight kidney changes Dilley and Lewis 1978 rat, SD F0: 234 (50) 50 ml/m3: increased relative liver weights Nair et al. 1987 F0 and >10 weeks, 702 (150) (♂)(F1), renal tubular dilation with F1: 30 ♂ 30 ♂, F1: 2105 (450) eosinophilic material (♂) >11 weeks*, from 150 ml/m3: increased liver weights, 6 h/day, histopathological changes (♂) in liver, kidneys, testes 7 days/week mouse, 5 days, 350 (75) 75 ml/m3: no reduction in pulmonary Aranyl et al. 1986 CD1 135 ♀ 3 h/day bactericidal activity mouse 5 ♂, 5 ♀ 3 weeks, 7h/day 2500 (535) 535 ml/m3: 50% mortality, somnolence, decreased food consumption and body weights, pathological liver changes, decreased neutrophilic leukocyte counts Zub 1978 mouse 5 ♂, 5 ♀ 3 months, 7h/day 100 (21) 21 ml/m3: excitation, decreased neutrophilic leukocyte counts Zub 1978 Dilley 1977 ,Dilley and Lewis 1978 rabbit 10 ♂ 5 weeks, 7h/day, 5 days/week 351(75), 1169 (250) in all animals (including controls): diarrhoea 75 ml/m3: decreased uric acid, increased LDH 250 ml/m3: increased leukocyte counts, decreased uric acid, pathological changes in liver and kidneys (hyperaemia) rabbit 44 days ,7h/day, 5 days/week, 32 single exposures 936(200), 2220(475), 4678 (1000) 200 ml/m3: no effects 475 ml/m3: increased liver weights, pathological liver changes 1000 ml/m3: decreased body weights, pathological changes in lungs, liver and kidneys Irish 1962 rabbit 10(11) ♂ 11 weeks, 7h/day, 5 days/week 351 (75), 1169 (250) in all animals (including controls): diarrhoea 75ml/m3:decreased uric acid Dilley 1977 ,Dilley and Lewis 1978 rabbit 10 ♂ 24 weeks, 7h/day, 5 days/week 351 (75), 1169 (250) in all animals (including controls): diarrhoea 75 ml/m3: LDH decreased 250 ml/m3: increased weights of lungs, liver and spleen, AST decreased, thrombocyte count increased Dilley 1977 ,Dilley and Lewis 1978 guinea pig 44 days, 7h/day, 5days/week, 32 single exposures 936 (200) ,2220(475), 4678 (1000) 200 ml/m3: no effects 475 ml/m3: increased liver weights, pathological liver changes 1000 ml/m3: decreased body weights, pathological changes in lungs, liver and kidneys Irish 1962 * F0 exposed from 10 weeks before mating until end of lactation; ♀ not exposed from gestation day 20 to lactation day 4; b F1 exposed from 1 week after weaning for at least 11 weeks until mating AST aspartate aminotransferase LDH lactate dehydrogenase Table 3. Effects of repeated oral administration of chlorobenzene (cited from BUA 1990) Species, strain, number/dose, sex Administration Dose mg/kg body weight Effects References rat 3 days 250 250 mg/kg: relative liver weights increased, Ariyoshi et al. 1975 ♀ liver phospholipids increased, delta-aminolaevulinic acid increased, cytochrome P450 (liver) decreased, aminopyrine demethylase and aniline hydroxylase decreased rat 5 days 1140 1140 mg/kg: body weights decreased, Rimington 2 ♂ histopathological liver changes, increased porphyrin excretion and Ziegler 1963 rat, SD 7 days 300 300 mg/kg: liver cell necrosis Chadwick et al. 1984 12 ♀ rat, F344/N 14 days 125, from 125 mg/kg: body weights increased (♂), Kluwe et al. 1985, 5 ♂, 5 ♀ 250, body weights decreased (♀) 500, from 1000 mg/kg: 100% mortality NTP 1985 1000, 2000 rat, albino 14 days 200, from 200 mg/kg: increased glucose transferase Carlson and 6 ♂ 400, 800 mg/kg: decreased glucose-6-phosphatase Tardiff 1976 800 and cytochrome P450, body weights decreased rat 93–99 days 12.5, 12.5 mg/kg: NOEL Knapp et al. 1971 50, from 50 mg/kg: liver and kidney weights 250 increased from 250 mg/kg: body weights decreased (♂) rat, F344/N 13 weeks, 60, from 60 mg/kg: body weights decreased (♂), Kluwe et al. 1985, 10 ♂, 10 ♀ 5 days/week 125, spleen weights decreased (♂) 250, from 125 mg/kg: liver weights increased (♀) NTP 1985 500, from 250 mg/kg: liver weights increased, 750 pathological liver changes from 500 mg/kg: kidney weights increased, pathological changes in the kidneys (♂) and bone marrow, porphyrin excretion increased, mortality increased, γ-glutamyl transpeptidase increased (♀), alkaline phosphatase increased (♀) 750 mg/kg: pathological changes in thymus and spleen, increased reticulocyte counts (♂) and diuresis (♂), decreased leukocyte counts (♀) rat 192 days, 14.4, 14.4 mg/kg: NOEL Irish 1962 5 days/week 144, from 144 mg/kg: liver and kidney weights (137 doses) 288 increased, pathological liver changes rat F344/N 103 weeks, 60, 60 mg/kg: NOEL Kluwe et al. 1985, 50 ♂, 50 ♀ 5 days/week 120 120 mg/kg: pathological liver changes (♂) NTP 1985 rat “long-term” 0.001, 0.001 mg/kg: no effects Varshavskaya 1967 7 ♂ 0.01, from 0.01 mg/kg: CNS and haematopoietic 0.1 organs affected, liver enzyme changes (poor documentation) mouse 14 days 30, from 30 mg/kg: body weights decreased (♂) Kluwe et al. 1985, B6C3F1 60, from 60 mg/kg: body weights increased (♀) 5 ♂, 5 ♀ 125, 500 mg/kg: mortality increased (♂) NTP 1985 250, 500 mouse 13 weeks, 60, from 60 mg/kg: body weights decreased (♂), Kluwe et al. B6C3F1 5 days/week 125, heart weights decreased (♂), pathological liver changes (♂) 1985, 10 ♂, 10♀ 250, NTP 1985 500, from 125 mg/kg: liver weights increased (♂) 750 from 250 mg/kg: body weights decreased (♀), liver weights increased (♀), pathological changes in liver, kidney, thymus, spleen, bone marrow, porphyrin excretion increased (♀), mortality increased from 500 mg/kg: 100% mortality (♂), diuresis increased (♀) 750 mg/kg: 100% mortality (♀) mouse 103 weeks, 30, 60 mg/kg: NOEL Kluwe et al. 1985, B6C3F1 5 days/week 60 50 ♂, 50 ♀ NTP 1985 dog 93 days, 27.25, 54.5 mg/kg: NOEL Knapp et al. 1971 5 days/week 54.5, 272.5 mg/kg: mortality increased, pathological 272.5 changes in liver, kidneys, haematopoietic tissue, stomach mucosa, decreased blood sugar, increased alanine aminotransferase, alkaline phosphatase, bilirubin, immature leukocytes and cholesterol In animals given the substance by repeated ingestion or inhalation, the liver and kidney proved to be the main target organs of chlorobenzene. It is noteworthy that the effects are more pronounced after short exposures than after longer exposures. In the liver, degeneration and necrosis of the centrilobular cells, lipid accumulation, increased liver enzyme values and increased organ weights were detected. Lethal doses produced increased urinary levels of porphyrin and porphobilinogen. In the kidney diffusely distributed focal coagulative degeneration and necrosis of the proximal tubules and increased organ weights were detected together with increased diuresis. 5.2.1 Inhalation In a multi-generation study in which chlorobenzene was administered to rats for several weeks, slight effects on the liver (F1 generation) and kidneys (F0 generation) were observed at 50 ml/m3, the lowest concentration studied, and significant effects from 150 ml/m3 (Table 2: Nair et al. 1987, Section 6.5 below). In another study in which rats were exposed to 75 ml/m3 for 11 weeks, the liver weights were increased at the end of exposure and there were histopathological changes in the kidneys and adrenal glands and also changes in the blood count. After exposure for 24 weeks the only changes seen at 75 ml/m3 were reduced lactate dehydrogenase values; at 250 ml/m3 the weights of the lungs, liver and spleen were also increased as was the thrombocyte count (Table 2: Dilley 1977, Dilley and Lewis 1978). In rabbits exposed to 75 ml/m3 the same authors found only slight changes in clinical chemical parameters. The lowest concentration seen to produce effects on liver, lungs and kidneys was 250 ml/m3 (Table 2: Dilley 1977, Dilley" @default.
• W4235957598 created "2022-05-12" @default.
• W4235957598 date "2012-01-31" @default.
• W4235957598 modified "2023-09-23" @default.
• W4235957598 title "Chlorobenzene [MAK Value Documentation, 1999]" @default.
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