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CHLOROBENZENE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Chlorobenzene (monochlorobenzene) is a liquid aromatic halogenated benzene (halobenzene), or a xenobiotic. It is lipophilic. Industrial exposure is generally via inhalation of the vapor. It is a colorless volatile liquid widely used as an organic solvent and chemical intermediate for dyes and pesticides. It is a central nervous system depressant.

Specific Substances

    1) Benzene chloride
    2) Benzene monochloride
    3) Chlorbenzene
    4) Chlorbenzol
    5) Chlorobenzol
    6) MCB
    7) Monochlorbenzene
    8) Monochlorobenzene
    9) NCI-C54886
    10) Phenyl chloride
    11) Tetrosin SP
    12) Molecular Formula: C6-H5-Cl
    13) CAS 108-90-7
    14) CHLOORBENZEEN
    15) CHLOROBENZEN
    16) CHLOROBENZEU
    17) CLOROBENZENE
    18) MONOCHLOORBENZEEN
    19) MONOCHLORBENZOL
    20) MONOCLOROBENZENE
    1.2.1) MOLECULAR FORMULA
    1) C6-H5-Cl

Available Forms Sources

    A) FORMS
    1) Chlorobenzene is a colorless to yellowish, very refractive liquid with a faint, not unpleasant odor similar to almonds (Budavari, 1996; ATSDR, 1990).
    B) SOURCES
    1) Chlorobenzene has no natural sources. It is produced by the chlorination of benzene in the presence of a catalyst. It is also produced via the Gulf oxychlorination process (benzene plus hydrogen chloride, anhydrous) (HSDB , 2002). Due to its volatility, most environmental releases occur to air. It can be released to water and the ground during the disposal of waste solvent (Anon, 1988). Chlorobenzene can persist in soil (several months), in air (3.5 days), and water (less than 1 days) (ATSDR, 1990).
    a) When released to air, chlorobenzene is expected to degrade slowly by free radical oxidation. When released to surface water, it is expected to partition rapidly to air where it degrades. Chlorobenzene is relatively resistant to biodegradation, with an estimated half-life in soil of several months. When released to soil, it is thought to bind to soil and to migrate slowly to ground water. Chlorobenzene is a rare environmental contaminant (Anon, 1988).
    C) USES
    1) This chemical is used extensively as a solvent for pesticide formulations and automobile parts degreasing; as a chemical intermediate in the production of diphenyl oxide, diisocyanates, and nitrochlorobenzene (Bingham et al, 2001). It is also used in the manufacture of phenol, aniline, and DDT; as a solvent for paints; in the manufacture of resins, dyes, perfumes, and pesticides, and as a heat transfer medium (Baselt, 2000; Budavari, 1996) Anon, 1994).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) Chlorobenzene is a skin and mucous membrane irritant. Exposures may result in central nervous system depression and liver and kidney damage. Intentional ingestions have resulted in hepatic necrosis. Acute exposures may begin, depending on dose, with headaches and dizziness followed by gastrointestinal complaints, shortness of breath, tachycardia and circulatory insufficiency.
    B) Chronic inhalation exposures may result in eye irritation, headache, dizziness, somnolence and gastrointestinal disorders. Acute inhalation exposures to high concentrations may result in narcosis. There is no evidence that severe liver damage results from acute inhalation exposures.
    0.2.6) RESPIRATORY
    A) Shortness of breath may develop following acute exposures.
    B) In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.
    0.2.7) NEUROLOGIC
    A) Chlorobenzene is a CNS depressant following high dose acute inhalation and oral exposures. In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.
    0.2.8) GASTROINTESTINAL
    A) Ingestion may result in gastric irritation.
    0.2.9) HEPATIC
    A) Acute ingestions have resulted in hepatic necrosis.
    0.2.10) GENITOURINARY
    A) Chlorobenzene is nephrotoxic in animal studies.
    0.2.20) REPRODUCTIVE
    A) In rat and rabbit inhalational studies, chlorobenzene was considered to lack embryonic and fetal toxicity.
    0.2.21) CARCINOGENICITY
    A) Existing data are inadequate to define the potential for chlorobenzene exposures to cause cancer in humans and animals.

Laboratory Monitoring

    A) Serum levels are not clinically useful for guiding therapy.
    B) Monitor vital signs in all acute exposures; increased heart rate and decreased blood pressure have been reported. Monitor ECG for potential cardiac dysrhythmias.
    C) Monitor liver and renal function following significant exposures.
    D) Monitor for signs/symptoms of CNS depression and possible respiratory depression.
    E) Biological monitoring for exposure to chlorobenzene may be accomplished by means of urinalysis for 4-chlorocatechol, a major chlorobenzene metabolite.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Treatment is symptomatic and supportive. N-acetylcysteine and alprostadil have been used to treat chlorobenzene induces hepatic injury.
    B) ACTIVATED CHARCOAL: Administer charcoal as a slurry (240 mL water/30 g charcoal). Usual dose: 25 to 100 g in adults/adolescents, 25 to 50 g in children (1 to 12 years), and 1 g/kg in infants less than 1 year old.
    C) GASTRIC LAVAGE: Consider after ingestion of a potentially life-threatening amount of poison if it can be performed soon after ingestion (generally within 1 hour). Protect airway by placement in the head down left lateral decubitus position or by endotracheal intubation. Control any seizures first.
    1) CONTRAINDICATIONS: Loss of airway protective reflexes or decreased level of consciousness in unintubated patients; following ingestion of corrosives; hydrocarbons (high aspiration potential); patients at risk of hemorrhage or gastrointestinal perforation; and trivial or non-toxic ingestion.
    D) HYPOTENSION: Infuse 10 to 20 mL/kg isotonic fluid. If hypotension persists, administer dopamine (5 to 20 mcg/kg/min) or norepinephrine (ADULT: begin infusion at 0.5 to 1 mcg/min; CHILD: begin infusion at 0.1 mcg/kg/min); titrate to desired response.
    E) Do not give oils by mouth.
    F) Extracorporeal elimination techniques are probably ineffective.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    B) Toxic effects are produced by vapor inhalation. Monitor for respiratory depression. If cough or dyspnea develops, evaluate for respiratory tract irritation, bronchitis, and pneumonia.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) No case studies of human fatalities have been reported following inhalation, oral, or dermal exposures to chlorobenzene. Intentional acute ingestions have resulted in hepatic necrosis and CNS depression. 1000 ppm is considered immediately dangerous to life and health.
    B) In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.

Clinical Effects

Summary Of Exposure

    A) Chlorobenzene is a skin and mucous membrane irritant. Exposures may result in central nervous system depression and liver and kidney damage. Intentional ingestions have resulted in hepatic necrosis. Acute exposures may begin, depending on dose, with headaches and dizziness followed by gastrointestinal complaints, shortness of breath, tachycardia and circulatory insufficiency.
    B) Chronic inhalation exposures may result in eye irritation, headache, dizziness, somnolence and gastrointestinal disorders. Acute inhalation exposures to high concentrations may result in narcosis. There is no evidence that severe liver damage results from acute inhalation exposures.

Heent

    3.4.3) EYES
    A) Eye and nasal irritation are reported to occur at chlorobenzene air concentrations of 200 ppm. At that level the odor is pronounced and unpleasant (Hathaway et al, 1996). Eye irritation has been reported in humans following vapor exposure (ACGIH, 2001; (Girard et al, 1969). Contact may produce irritation, tearing, and burning pain (Material Data Safety Sheet, 1997).
    B) Transient conjunctival irritation was reported following topical application of chlorobenzene liquid to rabbit eyes. Irritation resolved within 48 hours. No corneal injury was reported (Bingham et al, 2001).
    3.4.5) NOSE
    A) Eye and nasal irritation are reported to occur at chlorobenzene air concentrations of 200 ppm. At that level the odor is pronounced and unpleasant (Hathaway et al, 1996).
    3.4.6) THROAT
    A) Following ingestion, a distinctive odor of chlorobenzene in the breath may persist for several days (Bingham et al, 2001).
    B) Chlorobenzene is a mucous membrane irritant and may cause throat and upper respiratory tract irritation following prolonged inhalation exposures or ingestions (Bingham et al, 2001) ACGIH, 2001; (Girard et al, 1969).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) Following the ingestion of 5 to 10 mL of a cleaning solution containing chlorobenzene, a 2-year-old boy developed vascular collapse and heart failure. The child recovered following supportive care (HSDB , 2002; Hathaway et al, 1996).
    B) HYPOTENSIVE EPISODE
    1) Acute ingestion exposure, depending on dose, may result in shortness of breath, tachycardia and circulatory insufficiency (Knecht & Woitowitz, 2000).

Respiratory

    3.6.1) SUMMARY
    A) Shortness of breath may develop following acute exposures.
    B) In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.
    3.6.2) CLINICAL EFFECTS
    A) CYANOSIS
    1) An accidental ingestion in a child resulted in cyanosis (Hathaway et al, 1996).
    B) ACUTE RESPIRATORY INSUFFICIENCY
    1) Following inhalation or ingestion of a toxic concentration, CNS depression may result, with respiratory failure in severe cases (Material Data Safety Sheet, 1997). Shortness of breath may occur following acute chlorobenzene exposure (Knecht & Woitowitz, 2000).
    3.6.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RESPIRATORY DEPRESSION
    a) Following inhalation exposure to concentrations of 20 milligrams/liter (4300 ppm) for 2 hours, 100% mortality was reported in mice (ATSDR, 1990). Death was a result of CNS depression resulting in respiratory failure.

Neurologic

    3.7.1) SUMMARY
    A) Chlorobenzene is a CNS depressant following high dose acute inhalation and oral exposures. In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.
    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM DEFICIT
    1) Chlorobenzene is a CNS depressant (Baselt, 2000; Lewis, 2000; Hathaway et al, 1996). Inhalation or ingestions of high concentrations may result in CNS effects characterized by headache, dizziness, unconsciousness, coma and possible death due to respiratory failure (Material Data Safety Sheet, 1997).
    2) CASE REPORT - A case of coma followed by complete recovery was reported in a child following an accidental ingestion (HSDB , 2002; Hathaway et al, 1996).
    3) CASE REPORTS - Two hours after a 40-year-old chronic alcoholic male consumed 140 mL of a 90% chlorobenzene solution, drowsiness was reported. Consciousness returned to normal by day 3; however, the patient developed acute liver failure from which he subsequently recovered (Babany et al, 1991). Another patient developed drowsiness following the ingestion of a 50% chlorobenzene and 50% mineral spirit mixture (Reygagne et al, 1992).
    B) CENTRAL NERVOUS SYSTEM FINDING
    1) Occupational inhalation of chlorobenzene, above the current federal limits, has resulted in neurotoxic effects of numbness, cyanosis, hyperesthesia, and muscle spasms in humans (Bingham et al, 2001; ATSDR, 1990). Headache has been reported following vapor exposure in humans (ACGIH, 2001).
    3.7.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) CNS DEPRESSION
    a) Following inhalation exposure to concentrations of 20 milligrams/liter (4300 ppm) for 2 hours, 100% mortality was reported in mice (ATSDR, 1990). Death was a result of CNS depression resulting in respiratory failure. De Ceaurriz et al (1983) demonstrated concentration-dependent behavioral changes in mice following short-term inhalation exposures to chlorobenzene.
    b) Severe narcosis was reported in cats exposed to 8000 ppm for 30 minutes; death occurred 2 hours later. Cats tolerated exposures up to 660 ppm for 1 hour without obvious clinical signs of sedation (Hathaway et al, 1996).

Gastrointestinal

    3.8.1) SUMMARY
    A) Ingestion may result in gastric irritation.
    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) Ingestion of a concentrated chlorobenzene solution may result in digestive tract irritation with possible burns (Material Data Safety Sheet, 1997). Chronic gastritis has been reported in workers exposed to chlorobenzene in the manufacture of polyvinyl chloride (HSDB , 2002).
    3.8.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) SPLEEN DISORDER
    a) Repeated oral administration has resulted in lesions of the spleen in experimental animals (Baselt, 2000).

Hepatic

    3.9.1) SUMMARY
    A) Acute ingestions have resulted in hepatic necrosis.
    3.9.2) CLINICAL EFFECTS
    A) HEPATIC NECROSIS
    1) Benzene derivatives, including chlorobenzene, can induce severe liver cell necrosis in animals and in humans following ingestions, sometimes with acute liver failure (Baselt, 2000; Reygagne et al, 1992; Babany et al, 1991). Data has not been found that severe liver damage results from acute exposure to chlorobenzene vapor. Chronic inhalation exposures in animal studies have shown treatment-related liver congestion. It is suggested that liver toxicity may be an area of concern for chlorobenzene exposure in humans (ATSDR, 1990).
    a) Because humans preferentially metabolize chlorobenzene via the hepatotoxic 3,4-epoxide pathway, they may be more susceptible than mice to chlorobenzene-induced hepatotoxicity (Kerger et al, 1988).
    2) CASE REPORT - Acute liver failure with liver cell necrosis was reported in a 40-year-old male following an ingestion of 140 mL of a 90% chlorobenzene solution. Although the patient was a chronic alcoholic, no history of chronic liver disease (confirmed by liver biopsy) was present, although chronic alcohol consumption may have played a role in the severity of the liver lesions. Liver biopsy revealed centrilobular and mediolobular necrosis. Encephalopathy did not develop. The patient recovered following prostaglandin E1 (alprostadil) therapy and other supportive measures (Babany et al, 1991).
    3) CASE REPORT - Following the ingestion of alcohol and approximately 150 mL of an agent containing 50% chlorobenzene and 50% mineral spirits in a suicide attempt, a 40-year-old male presented with drowsiness and diarrhea. On the second day, a significant increase in hepatic enzyme levels were noted, and on day 3 a further increase in hepatic enzyme levels, as well as, diffuse erythema was reported. Treatment with NAC was started.
    a) Liver biopsy results revealed mediolobular hepatic necrosis without inflammatory infiltrates or fibrosis. On day 4 NAC therapy was replaced with alprostadil (30 mcg/hr), which was continued until day 8. The erythema resolved and hepatic laboratory values normalized by day 18. Encephalopathy did not develop (Reygagne et al, 1992).
    3.9.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) HEPATIC NECROSIS
    a) RAT - Time- and dose-dependent hepatotoxicity was reported in rats following single intraperitoneal injections. Hepatic necrosis was reported as well as increased liver weights, increased sulfobromophathalein retention, and increased serum enzyme activities. Rapid recovery occurred at lower dosages (2.0 and 4.9 mmol/kg), but prolonged recoveries were observed at doses of 9.8 or 14.7 mmol/kg (Dalich & Larson, 1985).
    b) RAT and MOUSE - In a 13-week subchronic chlorobenzene study, no clinical signs of toxicity were apparent. However, histologic examinations showed toxic lesions in the liver consisting of centrilobular hepatocellular degeneration and necrosis (Kluwe et al, 1985).

Genitourinary

    3.10.1) SUMMARY
    A) Chlorobenzene is nephrotoxic in animal studies.
    3.10.2) CLINICAL EFFECTS
    A) ABNORMAL URINE ODOR
    1) Following ingestion, a distinctive odor of chlorobenzene may be found in the urine which can persist for several days (Bingham et al, 2001).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) RENAL NECROSIS
    a) Repeated oral administration has resulted in necrosis of the proximal tubules in animals and is expected to result in kidney damage in humans (Baselt, 2000; ATSDR, 1990). In a small number of animal studies, it has been shown that the kidney, as well as the liver, is a target organ following repeated chlorobenzene inhalation and oral exposures, with effects including tubular dilatation, interstitial nephritis, and regenerative epithelium (ATSDR, 1990).
    b) RAT/MOUSE - A single intraperitoneal dose of chlorobenzene produced necrosis of the proximal convoluted renal tubules within 24 to 48 hours in mice and rats. Studies of the radiolabeled chemical showed that the renal necrosis was caused by a metabolite formed in the liver and transported via the circulation to binding sites in the renal tubules (Reid, 1973).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) BONE MARROW FINDING
    1) Repeated oral administration has resulted in bone marrow lesions in experimental animals and may cause bone marrow lesions and blood abnormalities in humans (Baselt, 2000; Material Data Safety Sheet, 1997; Von Burg, 1981). Bone marrow lesions, which have been reported with benzene homologues, may be reflected in anemia, leukopenia or thrombocytopenia of varying extents; this has not yet been confirmed with chlorobenzene in humans (Lisiewicz, 1993).
    B) ANEMIA
    1) An occupational exposure (6 years) to glue containing 70% chlorobenzene in the hat making industry was reported to possibly be the cause of severe anemia and medullary aplasia in a 70-year-old woman (Bingham et al, 2001; Girard et al, 1969).
    C) HEMOLYSIS
    1) Dichlorobenzene has caused hemolytic reactions following large exposures; this has not yet been reported following chlorobenzene exposure in humans (HSDB , 2002; Material Data Safety Sheet, 1997; Lisiewicz, 1993).
    3.13.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) LACK OF EFFECT
    a) MICE - Repeated high dose exposure of chlorobenzene to mouse bone marrow cells produced no DNA damage to these cells, indicating that this chemical is apparently not a major hazard to bone marrow cells (Vaghef & Hellman, 1995).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN IRRITATION
    1) Occasional short exposures during occupational use are not likely to produce more than minor skin irritation; however, prolonged or frequently repeated contact may result in defatting of the skin, dermatitis and skin burns (Material Data Safety Sheet, 1997; Hathaway et al, 1996). Chlorobenzene may cause acneiform eruptions (Material Data Safety Sheet, 1997).
    B) DERMATITIS
    1) Following an ingestion of 140 mL of a 90% chlorobenzene solution, diffuse erythema was reported in a 40-year-old male by day 3, which gradually cleared by day 12 (Babany et al, 1991). The mechanism of erythema development is not clear.
    3.14.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) IRRITATION
    a) RABBITS - Slight reddening occurred with acute chlorobenzene topical exposure to rabbits. Moderate erythema and slight superficial necrosis resulted following continuous contact for one week. There was no indication of absorption of toxic levels during prolonged dermal contact (Bingham et al, 2001).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) DISORDER OF IMMUNE FUNCTION
    1) Neutrophil chemotaxis disturbances after exposure to chlorobenzene in humans has been observed. A decrease of neutrophil alkaline phosphatase has been noted following occupational exposure. The significance and mechanism are unknown (Lisiewicz, 1993).
    B) LACK OF EFFECT
    1) No studies were found regarding immunological effects in humans or animals following inhalational or oral exposure to chlorobenzene (ATSDR, 1990).

Reproductive

    3.20.1) SUMMARY
    A) In rat and rabbit inhalational studies, chlorobenzene was considered to lack embryonic and fetal toxicity.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) In rat and rabbit inhalational studies, chlorobenzene was considered to lack embryonic and fetal toxicity (Bingham et al, 2001; John et al, 1984).

Carcinogenicity

    3.21.1) IARC CATEGORY
    A) IARC Carcinogenicity Ratings for CAS108-90-7 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):
    1) Not Listed
    3.21.2) SUMMARY/HUMAN
    A) Existing data are inadequate to define the potential for chlorobenzene exposures to cause cancer in humans and animals.
    3.21.3) HUMAN STUDIES
    A) NEOPLASM
    1) No data was found concerning carcinogenicity in humans. In chronic bioassay animal studies, doses up to 120 mg/kg/day did not produce increased tumor incidences in mice of either sex or in female rats. However, male rats showed a statistically significant increase in neoplastic nodules of the liver at the highest dose level tested (ATSDR, 1990; Kluwe, 1987; Kluwe et al, 1985). Existing data are inadequate to define the potential for chlorobenzene exposures to cause cancer in humans and animals.
    B) LACK OF EFFECT
    1) Chlorobenzene is assigned an ACGIH A3 cancer classification, "confirmed animal carcinogen with unknown relevance to humans" (ACGIH, 2002).

Genotoxicity

    A) Existing data do not support genotoxicity in humans following exposures.

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Serum levels are not clinically useful for guiding therapy.
    B) Monitor vital signs in all acute exposures; increased heart rate and decreased blood pressure have been reported. Monitor ECG for potential cardiac dysrhythmias.
    C) Monitor liver and renal function following significant exposures.
    D) Monitor for signs/symptoms of CNS depression and possible respiratory depression.
    E) Biological monitoring for exposure to chlorobenzene may be accomplished by means of urinalysis for 4-chlorocatechol, a major chlorobenzene metabolite.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Following significant acute exposures, monitor hepatic and renal function tests.
    4.1.3) URINE
    A) URINARY LEVELS
    1) Biological monitoring for exposure to chlorobenzene may be accomplished by means of urinalysis for 4-chlorocatechol, a major chlorobenzene metabolite, and p-chlorophenol (Kumagai & Matsunaga, 1994; Kusters & Lauwerys, 1990; Yoshida et al, 1986; Dutkiewicz & Pacholuk, 1980). Within 16 hours after the end of exposure, greater than 80% of the two main metabolites (4-chlorocatechol and 4-chlorophenol) are excreted in the urine. There does not appear to be a tendency for an increased concentration of metabolites in preshift urine samples during the workweek (Kusters & Lauwerys, 1990).
    a) Kumagai & Matsunaga (1994) found 4-chlorocatechol urinary concentrations during the last 4 hours and at the end of the work shift to be proportional to the 8-hour time-weighted chlorobenzene average airborne exposure.
    2) Goto et al (1993) suggested the detection of a protein- or a DNA-adduct of chlorobenzene is more important than measurement of urinary metabolites since the adducts are directly associated with clinical toxic manifestations and carcinogenicity. The authors recommended measurement of urinary chlorophenylmethylsulfides for detection of protein-adducts of chlorobenzene in occupational workers.
    4.1.4) OTHER
    A) OTHER
    1) RESPIRATORY MONITORING
    a) Monitor pulse oximetry and/or ABGs in all symptomatic patients.
    2) MONITORING
    a) Organic vapor air monitoring badges may be used to detect chlorobenzene in air of work places (Yoshida et al, 1986).

Methods

    A) CHROMATOGRAPHY
    1) Human serum concentrations of chlorobenzene have been measured using gas chromatography; a detection threshold of 0.5 mcg/L in serum was reported (Babany et al, 1991).
    2) Blood concentrations of chlorobenzene have been measured by gas chromatography-mass spectrometry with headspace sampling (Baselt, 2000).
    3) Chlorobenzene human blood concentrations have been determined via capillary gas chromatography using the head-space technique. Urinary metabolites have been separated by gas chromatography and determined using a mass-selective detector (Knecht & Woitowitz, 2000).
    4) Urinary 4-chlorocatechol and 4-chlorophenol (chlorobenzene metabolites) have been measured in workers exposed to chlorobenzene during a work shift via acid hydrolysis of urinary conjugates followed by liquid chromatographic analysis (Kumagai & Matsunaga, 1994). A procedure for identification of urinary metabolites following exposure to dichlorobenzene included acid hydrolysis of urinary conjugates followed by analysis with a gas chromatograph-mass spectrometer (Kumagai & Matsunaga, 1995a).
    5) HPLC and HPLC with electrochemical detection have been described for the quantitation of primary chlorobenzene metabolites in tissue and fluid samples (Kumagai & Matsunaga, 1994; Kusters & Lauwerys, 1990; Krewet et al, 1989; Kerger et al, 1988; Yoshida & Hara, 1985; Ogata & Shimada, 1983).
    6) Meharg et al (2000) described a GC-MS (Hewlett Packard 5890 gas chromatograph interfaced to a 5972A mass selective detector and a 7673 autosampler) method for the determination and quantitation of chlorobenzene in river waters draining industrial catchments.
    7) WORKPLACE AIR - A thermal desorption-gas chromatography method for the determination of chlorobenzene in workplace air has been described. Quantitative recoveries were reported in the mass range of 0.04 to 10 mcg/mcL. Air humidity appeared to have no effect on recovery (Patil & Lonkar, 1992).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Admit all patients with symptomatic CNS depression and signs of respiratory depression.

Monitoring

    A) Serum levels are not clinically useful for guiding therapy.
    B) Monitor vital signs in all acute exposures; increased heart rate and decreased blood pressure have been reported. Monitor ECG for potential cardiac dysrhythmias.
    C) Monitor liver and renal function following significant exposures.
    D) Monitor for signs/symptoms of CNS depression and possible respiratory depression.
    E) Biological monitoring for exposure to chlorobenzene may be accomplished by means of urinalysis for 4-chlorocatechol, a major chlorobenzene metabolite.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) EMESIS/NOT RECOMMENDED -
    1) Induction of emesis is not recommended because the patient may become rapidly obtunded.
    B) ACTIVATED CHARCOAL -
    1) No data were found to indicate that chlorobenzene is adsorbed to charcoal. However, until definitive quantitative data are available, use of activated charcoal is recommended.
    2) Avoid activated charcoal if gastrointestinal burns are suspected and endoscopy is anticipated.
    3) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    4) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    B) GASTRIC LAVAGE
    1) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    2) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    3) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    4) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    5) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is mainly symptomatic and supportive. Ingestion of a concentrated chlorobenzene solution may result in gastric burns. Endoscopy may be indicated in patients with signs or symptoms of gastrointestinal irritation ( abdominal pain, stridor, dysphagia, drooling) after substantial ingestion. Circulatory insufficiency has rarely been reported following significant exposure. Seizures have been reported with other halogenated benzenes, but have not been specifically reported following exposures to chlorobenzene. Patients should be monitored for possible seizures.
    B) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    C) CONTRAINDICATED TREATMENT
    1) Do NOT give oils by mouth. They tend to increase intestinal absorption of the lipophilic toxicants.
    D) PULMONARY ASPIRATION
    1) Evaluate the patient for pulmonary complications, especially if the ingested product contained a petroleum solvent.
    E) INJURY OF LIVER
    1) SUMMARY
    a) Ingestion of chlorobenzene can cause acute liver injury, probably secondary to formation of a toxic highly reactive metabolite. N-acetylcysteine and alprostadil have been used to treat chlorobenzene induced liver injury in case reports.
    2) N-ACETYLCYSTEINE
    a) Usual oral dose for acetaminophen poisoning is a loading dose of 140 milligrams/kilogram followed by 70 milligrams/kilogram every 4 hours. Duration of treatment is not established, but it should probably be continued until liver functions tests improve.
    b) Usual intravenous dose is 150 milligrams/kilogram NAC in 200 milliliters of D5W administered over 15 minutes followed by 50 milligrams/kilogram in 500 milliliters D5W infused over the next 4 hours. Finally, 100 milligrams/kilogram NAC in 1000 milliliters D5W is infused over the next 16 hour period.
    3) ALPROSTADIL
    a) Continuous infusion of alprostadil 30 micrograms/hour has been used to treat chlorobenzene induced liver injury (Babany et al, 1991).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.
    6.7.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Monitor patient for respiratory depression. If a cough or difficulty in breathing develops, evaluate for respiratory tract irritation, bronchitis, and pneumonia.
    B) PULMONARY ABSORPTION
    1) Toxic effects of chlorobenzene are produced by inhalation of the vapor.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    6.8.2) TREATMENT
    A) IRRITATION SYMPTOM
    1) Chlorobenzene is an eye irritant.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Enhanced Elimination

    A) EXTRACORPOREAL ELIMINATION
    1) Hemodialysis and hemoperfusion have not been proven effective. There is no experience reported with these procedures.
    2) Exchange transfusion, extracorporeal, and peritoneal dialysis have not proven effective in management of these poisonings. There has been little or no experience with charcoal hemoperfusion in chlorobenzene poisonings.

Abstracts

Case Reports

    A) ROUTE OF EXPOSURE
    1) ORAL - A 40-year-old chronic alcoholic male ingested 140 mL of a 90% chlorobenzene solution, with drowsiness developing within 2 hours. Laboratory tests revealed elevated AST and ALT levels (2.6 and 3.6 times the upper normal limit, respectively). By day 3, AST and ALT levels were 345 and 201 times the upper normal limit, respectively. Prothrombin time and factor V were 25% and 14% of normal, respectively. A diffuse erythema had developed. Consciousness had returned to normal by day 3. Chlorobenzene serum concentration on day 3 was reported as 500 mcg/L (Babany et al, 1991).
    a) Viral hepatitis testing proved negative. A liver biopsy revealed centrilobular and mediolobular necrosis, without inflammatory infiltration, hepatocyte ballooning, or fibrosis. On day 3, a continuous infusion of alprostadil (30 mcg/hr) was started.
    b) Erythema gradually resolved and the skin was normal by day 12. When laboratory results showed factor V level was above 50% on day 8, the alprostadil infusion was stopped. On day 15 serum chlorobenzene concentration was reported as 2 mcg/L. By day 18 all liver function tests had returned to normal. The authors speculated the chronic alcohol consumption may have potentiated the chlorobenzene-induced hepatotoxicity.

Range Of Toxicity

Summary

    A) No case studies of human fatalities have been reported following inhalation, oral, or dermal exposures to chlorobenzene. Intentional acute ingestions have resulted in hepatic necrosis and CNS depression. 1000 ppm is considered immediately dangerous to life and health.
    B) In animal lethality studies, death was attributed to CNS depression resulting in respiratory failure.

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) The minimum lethal human dose to this agent has not been delineated.
    B) ANIMAL DATA
    1) INHALATION - Cats exposed to 8000 ppm showed severe narcosis after one-half hour and died 2 hours after removal from exposure, but tolerated 660 ppm for 1 hour (Hathaway et al, 1996).
    2) INHALATION - Acute inhalation exposure at 22,000 ppm killed two of three rats in 2.3 hours, while at 9000 ppm, two of three rats died within 3 hours (ACGIH, 1991).
    3) INHALATION - Following exposure to concentrations of 20 milligrams/liter (4300 ppm) for 2 hours, 100% mortality was reported in mice (ATSDR, 1990). Death was a result of CNS depression resulting in respiratory failure.
    4) ORAL - Following a single exposure to 4000 milligrams/kilogram in corn oil by gavage in rats, death occurred within 2 to 3 days. In mice, death occurred in 2 to 3 days after a single exposure to 1000 milligrams/kilogram by gavage (ATSDR, 1990).
    5) ORAL - Some deaths occurred in dogs administered 272.5 mg/kg/day in capsule form for up to 92 days (Hathaway et al, 1996).

Maximum Tolerated Exposure

    A) GENERAL/SUMMARY
    1) An odor threshold for chlorobenzene is reported as 0.5 ppm, while the current threshold limit value is 10 ppm (46 mg/m(3)) (Baselt, 2000).
    2) In humans, eye and nasal irritation occur at 200 ppm, and at that level the odor is pronounced and unpleasant (Hathaway et al, 1996).
    B) CASE REPORTS
    1) ADULT
    a) Acute liver failure with liver cell necrosis was reported in a 40-year-old male following an ingestion of 140 mL of a 90% chlorobenzene solution. Liver biopsy revealed centrilobular and mediolobular necrosis. Encephalopathy did not develop. The patient recovered following prostaglandin E1 (alprostadil) therapy and other supportive measures (Babany et al, 1991).
    b) Following the ingestion of alcohol and approximately 150 mL of an agent containing 50% chlorobenzene and 50% mineral spirits in a suicide attempt, a 40-year-old male developed elevated hepatic enzyme levels, and mediolobular hepatic necrosis was seen on liver biopsy. He recovered following NAC and alprostadil therapy (Reygagne et al, 1992).
    c) Headaches and both upper respiratory tract and eye irritation were reported in a 70-year-old woman exposed to chlorobenzene contained in a glue preparation used in hat making. The glue contained 70% chlorobenzene (Girard et al, 1969).
    2) PEDIATRIC
    a) A two-year-old boy who swallowed 5 to 10 mL of Puran, a cleaning agent containing chlorobenzene, showed no ill effect for 2.5 hours, but after eating lunch he quickly lost consciousness and suffered vascular collapse as well as heart failure. He recovered and survived (Clayton & Clayton, 1981).
    3) OCCUPATIONAL
    a) A 1947 study of people who were occupationally exposed to chlorobenzene reported that many of the individuals who had worked in the factory for 1 to 2 years suffered from headache, dizziness, somnolence, and dyspeptic disorders. Twenty-eight of the 52 people studied were employed in a factory where the only vapors they were exposed to were those of chlorobenzene (Clayton & Clayton, 1981).
    C) ANIMAL DATA
    1) Several species of animals exposed daily to 1000 ppm for 44 days showed injury to the lungs, liver, and kidneys, but at 475 ppm there was only slight liver damage in guinea pigs (Hathaway et al, 1996).
    2) Cats tolerated 660 ppm for 1 hour, but at 8000 ppm showed severe narcosis after one-half hour and died 2 hours after removal from the exposure (Hathaway et al, 1996).
    3) In 91-day gavage studies, no toxic effects were observed at doses of 125 mg/kg/day or less for both sexes of rats and mice (Hathaway et al, 1996).
    4) No consistent effects were observed in dogs administered 54.5 mg/kg/day in capsule form for up to 92 days (Hathaway et al, 1996).
    5) Gastric intubation of 120 mg/kg/day for 2 years produced a slight but statistically significant increase in tumor frequencies in male rats (Hathaway et al, 1996).
    6) Concentrations up to 450 ppm, 7 days/week, 6 hours/day, did not adversely affect reproductive performance or fertility in a two-generation rat study. In rats and rabbits, inhalation of 590 ppm, 6 hours/day, during periods of major organogenesis did not produce structural malformations (Hathaway et al, 1996).
    7) Dermal doses of 10 mL/kg were not lethal to guinea pigs (ACGIH, 1991).
    8) Daily doses of 500 mg/kg body weight of chlorobenzene were tolerated for 14 days by both mice and rats, while rats died following repeated 1000 mg/kg doses (ACGIH, 1991).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CASE REPORTS
    a) ADULT
    1) Following an ingestion of 140 milliliters of a 90% chlorobenzene solution, serum chlorobenzene concentration was reported to be 500 micrograms/liter on day 3 and 2 micrograms/liter on day 15 (Babany et al, 1991).
    2) Following a 7 hour exposure to 11.8 ppm chlorobenzene in air, 5 resting male adults developed end-of-exposure blood chlorobenzene concentration averaging 54 micrograms/liter (Baselt, 2000).

Workplace Standards

    A) ACGIH TLV Values for CAS108-90-7 (American Conference of Governmental Industrial Hygienists, 2010):
    1) Editor's Note: The listed values are recommendations or guidelines developed by ACGIH(R) to assist in the control of health hazards. They should only be used, interpreted and applied by individuals trained in industrial hygiene. Before applying these values, it is imperative to read the introduction to each section in the current TLVs(R) and BEI(R) Book and become familiar with the constraints and limitations to their use. Always consult the Documentation of the TLVs(R) and BEIs(R) before applying these recommendations and guidelines.
    a) Adopted Value
    1) Chlorobenzene
    a) TLV:
    1) TLV-TWA: 10 ppm
    2) TLV-STEL:
    3) TLV-Ceiling:
    b) Notations and Endnotes:
    1) Carcinogenicity Category: A3
    2) Codes: BEI
    3) Definitions:
    a) A3: Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    b) BEI: The BEI notation is listed when a BEI is also recommended for the substance listed. Biological monitoring should be instituted for such substances to evaluate the total exposure from all sources, including dermal, ingestion, or non-occupational.
    c) TLV Basis - Critical Effect(s): Liver dam
    d) Molecular Weight: 112.56
    1) For gases and vapors, to convert the TLV from ppm to mg/m(3):
    a) [(TLV in ppm)(gram molecular weight of substance)]/24.45
    2) For gases and vapors, to convert the TLV from mg/m(3) to ppm:
    a) [(TLV in mg/m(3))(24.45)]/gram molecular weight of substance
    e) Additional information:

    B) NIOSH REL and IDLH Values for CAS108-90-7 (National Institute for Occupational Safety and Health, 2007):
    1) Listed as: Chlorobenzene
    2) REL:
    a) TWA:
    b) STEL:
    c) Ceiling:
    d) Carcinogen Listing: (Not Listed) Not Listed
    e) Skin Designation: Not Listed
    f) Note(s): See Appendix D
    3) IDLH:
    a) IDLH: 1000 ppm
    b) Note(s): Not Listed

    C) Carcinogenicity Ratings for CAS108-90-7 :
    1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): A3 ; Listed as: Chlorobenzene
    a) A3 :Confirmed Animal Carcinogen with Unknown Relevance to Humans: The agent is carcinogenic in experimental animals at a relatively high dose, by route(s) of administration, at site(s), of histologic type(s), or by mechanism(s) that may not be relevant to worker exposure. Available epidemiologic studies do not confirm an increased risk of cancer in exposed humans. Available evidence does not suggest that the agent is likely to cause cancer in humans except under uncommon or unlikely routes or levels of exposure.
    2) EPA (U.S. Environmental Protection Agency, 2011): D ; Listed as: Chlorobenzene
    a) D : Not classifiable as to human carcinogenicity.
    3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): Not Listed
    4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed ; Listed as: Chlorobenzene
    5) MAK (DFG, 2002): Not Listed
    6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

    D) OSHA PEL Values for CAS108-90-7 (U.S. Occupational Safety, and Health Administration (OSHA), 2010):
    1) Listed as: Chlorobenzene
    2) Table Z-1 for Chlorobenzene:
    a) 8-hour TWA:
    1) ppm: 75
    a) Parts of vapor or gas per million parts of contaminated air by volume at 25 degrees C and 760 torr.
    2) mg/m3: 350
    a) Milligrams of substances per cubic meter of air. When entry is in this column only, the value is exact; when listed with a ppm entry, it is approximate.
    3) Ceiling Value:
    4) Skin Designation: No
    5) Notation(s): Not Listed

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) References: Lewis, 1992 RTECS, 2002
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 515 mg/kg
    2) LD50- (ORAL)MOUSE:
    a) 2300 mg/kg
    3) LD50- (ORAL)RAT:
    a) 2290 mg/kg
    4) LD50- (SUBCUTANEOUS)RAT:
    a) 1110 mg/kg
    5) TCLo- (INHALATION)RAT:
    a) 210 ppm for 6H -- 6-15D preg,TER

Pharmacology Toxicology

Toxicologic Mechanism

    A) Chlorobenzene has been shown in animal studies to be toxic to the central nervous system, kidney, and liver. It is unclear whether the toxicity is due to parent chemical or its metabolites; however, the chlorobenzene concentration in blood may be significantly related to the toxic intensity on the organs (Kumagai & Matsunaga, 1995).
    B) HEPATOTOXICITY - Chlorobenzene exposures may cause severe centrilobular liver necrosis and failure probably due to a toxic metabolite. It is reasonable to assume that the metabolism of chlorobenzene is similar to bromobenzene, which has been shown to be transformed by cytochrome P450 into 3-4 bromobenzene epoxide which leads to reactive metabolite formation (metabolite covalently binds to macromolecules), glutathione depletion, and liver damage (Babany et al, 1991).
    1) Because humans preferentially metabolize chlorobenzene via the hepatotoxic 3,4-epoxide pathway, they may be more susceptible than mice to chlorobenzene-induced hepatotoxicity (Kerger et al, 1988).
    C) RENAL TOXICITY - A single intraperitoneal dose of chlorobenzene produced necrosis of the proximal convoluted renal tubules within 24 to 48 hours in mice and rats. Studies of the radiolabeled chemical showed that the renal necrosis was caused by a metabolite formed in the liver and transported via the circulation to binding sites in the renal tubules (Reid, 1973).

Physicochemical

Physical Characteristics

    A) ODOR: Almond-like (ACGIH, 2001); Faint, not unpleasant odor (Lewis, 2000; Budavari, 1996); Pronounced and unpleasant at 200 ppm (Hathaway et al, 1991); Like that of mothballs or benzene (Bingham et al, 2001); Mild amine; mild aromatic (HSDB , 2002);
    B) COLOR: Colorless to yellowish, very refractive liquid (ACGIH, 2001; (Budavari, 1996)
    C) SOLUBILITY: Virtually insoluble in water (sinks to bottom); freely soluble in ether, chloroform, alcohol, and benzene (ACGIH, 2001).

Ph

    1) No information found at the time of this review.

Molecular Weight

    A) 112.56 (Lewis, 2000)

References

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