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Cyclohexane
Cyclohexane SE Gad, Gad Consulting Services, Cary, NC, USA Ó 2014 Elsevier Inc. All rights reserved. l
Name: Cyclohexane Chemical Abstracts Service Registry Number: 110-82-7 l Synonyms: Benzenehexahydride, Hexahydro-benzene, Hexamethylene, Hexanaphthene l Molecular Formula: C6H12 l Chemical Structure: l
exposure to cyclohexane may occur through inhalation and dermal contact with this compound where cyclohexane is produced or used. The general population may be exposed to cyclohexane via inhalation of ambient air, ingestion of drinking water, and dermal contact with products containing cyclohexane and due to its presence in gasoline. It has been found in mother’s milk and has been detected in studies of the air in various cities.
Environmental Water Concentrations
Background Information Cyclohexane is obtained by the distillation of petroleum or by hydrogenation of benzene. It constitutes 0.5–1.0% of petroleum.
Contamination has been found in several drinking water sources including bottled water and most commonly in wells, the highest concentration found was 540 ppb. Only trace quantities of cyclohexane have been detected in bedrock and groundwater. Surface waters are generally found to contain 0.5–4.0 ppb.
Toxicokinetics Uses Cyclohexane is used as a nonpolar solvent for lacquers, resins, fats, oils, and waxes, in paint and varnish remover, in the manufacture of nylon, in the extraction of essential oils, and in analytical chemistry for molecular weight determination. In addition, it is used in the manufacture of adipic acid, benzene, cyclohexanone, cyclohexanol, cyclohexyl chloride, nitrocyclohexane, and solid fuel for camp stoves. Further, it is used in industrial recrystallization of steroids and in fungicidal formulations (it has a slight fungicidal action).
Environmental Fate and Behavior If released to air, cyclohexane will exist solely as a vapor in the ambient atmosphere, and will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals, though direct photolysis is not expected due to the lack of absorption in the environmental spectrum. Volatilization from water surfaces is expected to be an important fate for this compound, and half-lives in a model river and lake are expected to be 3 h and w3.5 days respectively. Adsorption to suspended solids and sediments is also expected, though hydrolysis in the environment is unlikely due to the lack of hydrolyzable functional groups. The potential for bioconcentration and bioaccumulation of cyclohexane in aquatic organisms is moderate. It is highly resistant to biodegradation and is catabolized chiefly by cooxidation.
Exposure and Exposure Monitoring Cyclohexane was a predominant pollutant in shoe and leather factories in Italy, associated with the use of glue. Occupational
1106
Cyclohexane is readily absorbed via inhalation and the oral routes of exposure; it is rapidly absorbed into the blood through the lungs. Animal studies indicate dermal absorption to be high, probably due to the defatting action of the compound. Cyclohexane absorption into the lungs is rapid, with the concentration in the lungs reaching 42–62% of the air concentration. Cyclohexane administered to rats either by oral gavage or by intravenous injection was rapidly absorbed and distributed to the tissues. Cyclohexane partitions preferentially to lipid-rich tissues such as fat, liver, and brain. Cyclohexane is metabolized by cytochrome P450 enzymes in the liver and other tissues. Several metabolites have been identified including cyclohexanol and transcyclohexane-1,2-diol. These compounds have been identified in the urine of human subjects and experimental animals within 48 h of exposure. Inhaled cyclohexane is excreted primarily via expiration from the lungs. A small portion partitions to and is excreted in the urine. Metabolites of cyclohexane are conjugated, primarily to glucuronides and possibly to sulfates, and excreted in the urine.
Mechanism of Toxicity The precise mechanism of toxicity of cyclohexane has not been identified, but is likely similar to other central nervous system (CNS) depressants and general anesthetics. These compounds are believed to exert their effects through a general interaction with the CNS, and interference with neuronal membrane functions has been postulated as a mechanism of action. Disruption of membrane enzymes and the corresponding alterations in cell functions may account for the behavioral and anesthetic effects observed following exposure to various solvents.
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00835-6
Cyclohexane
Acute and Short-Term Toxicity Animal The reported oral LD50 in rabbits is 5.5–6.0 mg kg 1 indicating the relatively low oral acute toxicity of cyclohexane. Vapor concentrations of 92 000 mg m 1 produced rapid narcosis and death in rabbits. In mice, concentrations of 51 000 mg m 3 caused narcosis and death occurred at 61 200–71 400 mg m 3. The oral LD50 was reported as 12 705 mg kg 1 for rats and 813 mg kg 1 for mice. Observations indicating CNS effects have been noted in many studies.
Human Cyclohexane is a CNS depressant and may produce mild anesthetic effects. Inhalation exposure can cause headache, nausea, dizziness, drowsiness, and confusion. Very high concentrations may cause unconsciousness, convulsions, and death. Vapors may be irritating to the nose and throat. Severe lung irritation, damage to lung tissues, or death may result from aspiration into the lungs. Direct dermal contact with liquid may cause mild irritation, which may become more severe if exposure is prolonged. Eyes may become irritated upon exposure to vapors or liquid; however, the effect is generally mild and temporary unless exposure is prolonged. Ingestion of cyclohexane may cause sore throat, nausea, diarrhea, or vomiting.
1107
Reproductive Toxicity In a prospective study in Toronto, major congenital malformations were noted in 13 of 125 fetuses of mothers exposed to organic solvents (not just cyclohexane) during pregnancy. Studies in rats have shown reduced weights in pups and diminished response to audible stimuli at high dose levels. No observed adverse effect level (NOAEL) for maternal and fetal effects has been reported as over 20 000 mg m 3 in rodents. Inhalation exposure to concentrations of 6886 and 24 101 mg m 3cyclohexane resulted in maternal toxicity in Cesaraen-derived (CD) rats, as demonstrated by a significant reduction in body weight gain. There was no evidence of developmental toxicity in rat pups at the highest concentration tested, 24 101 mg m 3. The NOAEL for developmental toxicity in rat pups was 24 101 mg m 3. Inhalation exposure to the highest concentration of 24 101 mg m 3cyclohexane resulted in no evidence of maternal or developmental toxicity in rabbits.
Genotoxicity Negative results were obtained in Ames and sister chromatid exchange, mouse lymphoma, and unscheduled DNA synthesis assays.
Carcinogenicity Chronic Toxicity
Cyclohexane is not a carcinogen.
Animal Lower doses (1.0–5.5 mg kg 1) produced mild to extensive hepatocellular degeneration and glomerulonephritis. Microscopic changes in the liver and kidneys were observed in rabbits exposed to 2700 mg m 3 for 50 exposures. No changes were noted at 1490 mg m 3. In subchronic inhalation studies in rats and mice, the no observed effect level (NOEL) in rats for acute, transient effects was 500 ppm based on a diminished/ absent response to an auditory alerting stimulus at 2000 ppm and above. The NOEL for subchronic toxicity in rats was 7000 ppm based on the lack of adverse effects on body weight, clinical chemistry, tissue morphology, and neurobehavioral parameters. In mice, the NOEL for acute, transient effects was 500 ppm based on behavioral changes during exposure at 2000 ppm and above. The NOEL for subchronic toxicity in mice was 2000 ppm based on hematological changes at 7000 ppm.
Clinical Management If inhalation exposure occurs, the source of contamination should be removed or the victim should be moved to fresh air. Artificial respiration should be administered or, if the heart has stopped, cardiopulmonary resuscitation should be provided. If dermal contact has occurred, contaminated clothing should be removed and the affected area should be washed with water and soap for at least 5 min or until the chemical is removed. Contaminated eyes should be flushed with lukewarm, gently flowing water for 5 min or until the chemical is removed. If ingestion occurs, vomiting should not be induced. Water should be given to dilute the compound. If vomiting occurs naturally, the victim should lean forward to reduce risk of aspiration. Aspiration of the compound into the lungs may produce chemical pneumonitis requiring antibiotic treatment and administration of oxygen and expiratory pressure.
Human Prolonged exposure may produce liver and kidney damage. Cyclohexane is not a carcinogen or a developmental toxicant.
Immunotoxicity Cyclohexane is not known to be immunotoxic; however, there have been few studies performed.
Ecotoxicology LC50 for fathead minnow is 95 mg l 1 (static). TLm for Fathead minnow is 43–32 mg l 1 (24–96 h); conditions of bioassay not specified. TLm for Bluegill is 43–34 mg l 1 (24–96 h); conditions of bioassay not specified. TLm for Goldfish is 42.3 mg l 1 (24–96 h); conditions of bioassay not specified.
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Cyclohexane
TLm for Guppy is 57.7 mg l 1 (24–96 h); conditions of bioassay not specified. Coho salmon; no significant mortalities were observed up to 100 ppm after 96 h in artificial seawater at 8 C.
Exposure Standards and Guidelines The American Conference of Governmental Industrial Hygienists threshold limit value (TLV), 8 h time-weighted average (TWA), is 100 ppm. Permissible exposure limit: Table Z-1 8 h TWA: 300 ppm (1050 mg m 3). 8 h TWA: 100 ppm. Excursion limit recommendation: Excursions in worker exposure levels may exceed three times the TLV–TWA for no more than a total of 30 min during a workday, and under no circumstances should they exceed five times the TLV–TWA, provided that the TLV–TWA is not exceeded. Recommended exposure limit: 10 h TWA: 300 ppm (1050 mg m 3).
Further Reading Baxter, C.S., 2001. Alicyclic hydrocarbons. In: Bingham, E., Cohrssen, B., Powell, C.H. (Eds.), Patty’s Toxicology, fifth ed., vol. 4. Wiley, New York, pp. 161–165. Bingham, E., Cohrssen, B., 2012. Patty’s Toxicology, sixth ed. John Wiley and Sons, Hoboken, NJ. Hissink, A.M., et al., 2009. Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data. Int. J. Toxicol. 28 (6), 498–509. Kreckmann, K.H., Baldwin, J.K., Roberts, L.G., et al., 2000. Inhalation developmental toxicity and reproduction studies with cyclohexane. Drug Chem. Toxicol. 23, 555–573. Lammers, J.H., Emmen, H.H., Muijser, H., Hoogendijk, E.M., McKee, R.H., Owen, D.E., Kulig, B.M., 2009. Neurobehavioral effects of cyclohexane in rat and human. Int. J. Toxicol. 28 (6), 488–497. Lewis Sr, R.J. (Ed.), 2000. Cyclohexane. Sax’s Dangerous Properties of Industrial Materials, vol. 2. Wiley, New York, pp. 1037–1038. Malley, L.A., Bamberger, J.R., Stadler, J.C., et al., 2000. Subchronic toxicity of cyclohexane in rats and mice by inhalation exposure. Drug Chem. Toxicol. 23, 513–537. Rouvière, P.E., Chen, M.W., 2003. Isolation of Brachymonas petroleovorans CHX, a novel cyclohexane degrading proteobacterium. FEMS Microbiol. Lett. 227, 101–106.
Relevant Websites Miscellaneous Cyclohexane is an indirect food additive for use only as a component of adhesives.
See also: Cyclohexene; Hexane.
http://www.echemportal.org/echemportal – OECD - The Global Portal to Information on Chemical Substances: Search for Cyclohexane. http://echa.europa.eu/documents/10162/d99cee39-82e6-4754-aac1-497106c9bd7c – European Commission (2004) Cyclohexane. European Risk Assessment Report vol. 41. http://www.epa.gov/iris/toxreviews/1005tr.pdf – Environmental Protection Agency Integrated Risk Information System. http://www.toxnet.nlm.nih.gov – Toxnet homepage
Name: Cyclohexane Chemical Abstracts Service Registry Number: 110-82-7 l Synonyms: Benzenehexahydride, Hexahydro-benzene, Hexamethylene, Hexanaphthene l Molecular Formula: C6H12 l Chemical Structure: l
exposure to cyclohexane may occur through inhalation and dermal contact with this compound where cyclohexane is produced or used. The general population may be exposed to cyclohexane via inhalation of ambient air, ingestion of drinking water, and dermal contact with products containing cyclohexane and due to its presence in gasoline. It has been found in mother’s milk and has been detected in studies of the air in various cities.
Environmental Water Concentrations
Background Information Cyclohexane is obtained by the distillation of petroleum or by hydrogenation of benzene. It constitutes 0.5–1.0% of petroleum.
Contamination has been found in several drinking water sources including bottled water and most commonly in wells, the highest concentration found was 540 ppb. Only trace quantities of cyclohexane have been detected in bedrock and groundwater. Surface waters are generally found to contain 0.5–4.0 ppb.
Toxicokinetics Uses Cyclohexane is used as a nonpolar solvent for lacquers, resins, fats, oils, and waxes, in paint and varnish remover, in the manufacture of nylon, in the extraction of essential oils, and in analytical chemistry for molecular weight determination. In addition, it is used in the manufacture of adipic acid, benzene, cyclohexanone, cyclohexanol, cyclohexyl chloride, nitrocyclohexane, and solid fuel for camp stoves. Further, it is used in industrial recrystallization of steroids and in fungicidal formulations (it has a slight fungicidal action).
Environmental Fate and Behavior If released to air, cyclohexane will exist solely as a vapor in the ambient atmosphere, and will be degraded in the atmosphere by reaction with photochemically produced hydroxyl radicals, though direct photolysis is not expected due to the lack of absorption in the environmental spectrum. Volatilization from water surfaces is expected to be an important fate for this compound, and half-lives in a model river and lake are expected to be 3 h and w3.5 days respectively. Adsorption to suspended solids and sediments is also expected, though hydrolysis in the environment is unlikely due to the lack of hydrolyzable functional groups. The potential for bioconcentration and bioaccumulation of cyclohexane in aquatic organisms is moderate. It is highly resistant to biodegradation and is catabolized chiefly by cooxidation.
Exposure and Exposure Monitoring Cyclohexane was a predominant pollutant in shoe and leather factories in Italy, associated with the use of glue. Occupational
1106
Cyclohexane is readily absorbed via inhalation and the oral routes of exposure; it is rapidly absorbed into the blood through the lungs. Animal studies indicate dermal absorption to be high, probably due to the defatting action of the compound. Cyclohexane absorption into the lungs is rapid, with the concentration in the lungs reaching 42–62% of the air concentration. Cyclohexane administered to rats either by oral gavage or by intravenous injection was rapidly absorbed and distributed to the tissues. Cyclohexane partitions preferentially to lipid-rich tissues such as fat, liver, and brain. Cyclohexane is metabolized by cytochrome P450 enzymes in the liver and other tissues. Several metabolites have been identified including cyclohexanol and transcyclohexane-1,2-diol. These compounds have been identified in the urine of human subjects and experimental animals within 48 h of exposure. Inhaled cyclohexane is excreted primarily via expiration from the lungs. A small portion partitions to and is excreted in the urine. Metabolites of cyclohexane are conjugated, primarily to glucuronides and possibly to sulfates, and excreted in the urine.
Mechanism of Toxicity The precise mechanism of toxicity of cyclohexane has not been identified, but is likely similar to other central nervous system (CNS) depressants and general anesthetics. These compounds are believed to exert their effects through a general interaction with the CNS, and interference with neuronal membrane functions has been postulated as a mechanism of action. Disruption of membrane enzymes and the corresponding alterations in cell functions may account for the behavioral and anesthetic effects observed following exposure to various solvents.
Encyclopedia of Toxicology, Volume 1
http://dx.doi.org/10.1016/B978-0-12-386454-3.00835-6
Cyclohexane
Acute and Short-Term Toxicity Animal The reported oral LD50 in rabbits is 5.5–6.0 mg kg 1 indicating the relatively low oral acute toxicity of cyclohexane. Vapor concentrations of 92 000 mg m 1 produced rapid narcosis and death in rabbits. In mice, concentrations of 51 000 mg m 3 caused narcosis and death occurred at 61 200–71 400 mg m 3. The oral LD50 was reported as 12 705 mg kg 1 for rats and 813 mg kg 1 for mice. Observations indicating CNS effects have been noted in many studies.
Human Cyclohexane is a CNS depressant and may produce mild anesthetic effects. Inhalation exposure can cause headache, nausea, dizziness, drowsiness, and confusion. Very high concentrations may cause unconsciousness, convulsions, and death. Vapors may be irritating to the nose and throat. Severe lung irritation, damage to lung tissues, or death may result from aspiration into the lungs. Direct dermal contact with liquid may cause mild irritation, which may become more severe if exposure is prolonged. Eyes may become irritated upon exposure to vapors or liquid; however, the effect is generally mild and temporary unless exposure is prolonged. Ingestion of cyclohexane may cause sore throat, nausea, diarrhea, or vomiting.
1107
Reproductive Toxicity In a prospective study in Toronto, major congenital malformations were noted in 13 of 125 fetuses of mothers exposed to organic solvents (not just cyclohexane) during pregnancy. Studies in rats have shown reduced weights in pups and diminished response to audible stimuli at high dose levels. No observed adverse effect level (NOAEL) for maternal and fetal effects has been reported as over 20 000 mg m 3 in rodents. Inhalation exposure to concentrations of 6886 and 24 101 mg m 3cyclohexane resulted in maternal toxicity in Cesaraen-derived (CD) rats, as demonstrated by a significant reduction in body weight gain. There was no evidence of developmental toxicity in rat pups at the highest concentration tested, 24 101 mg m 3. The NOAEL for developmental toxicity in rat pups was 24 101 mg m 3. Inhalation exposure to the highest concentration of 24 101 mg m 3cyclohexane resulted in no evidence of maternal or developmental toxicity in rabbits.
Genotoxicity Negative results were obtained in Ames and sister chromatid exchange, mouse lymphoma, and unscheduled DNA synthesis assays.
Carcinogenicity Chronic Toxicity
Cyclohexane is not a carcinogen.
Animal Lower doses (1.0–5.5 mg kg 1) produced mild to extensive hepatocellular degeneration and glomerulonephritis. Microscopic changes in the liver and kidneys were observed in rabbits exposed to 2700 mg m 3 for 50 exposures. No changes were noted at 1490 mg m 3. In subchronic inhalation studies in rats and mice, the no observed effect level (NOEL) in rats for acute, transient effects was 500 ppm based on a diminished/ absent response to an auditory alerting stimulus at 2000 ppm and above. The NOEL for subchronic toxicity in rats was 7000 ppm based on the lack of adverse effects on body weight, clinical chemistry, tissue morphology, and neurobehavioral parameters. In mice, the NOEL for acute, transient effects was 500 ppm based on behavioral changes during exposure at 2000 ppm and above. The NOEL for subchronic toxicity in mice was 2000 ppm based on hematological changes at 7000 ppm.
Clinical Management If inhalation exposure occurs, the source of contamination should be removed or the victim should be moved to fresh air. Artificial respiration should be administered or, if the heart has stopped, cardiopulmonary resuscitation should be provided. If dermal contact has occurred, contaminated clothing should be removed and the affected area should be washed with water and soap for at least 5 min or until the chemical is removed. Contaminated eyes should be flushed with lukewarm, gently flowing water for 5 min or until the chemical is removed. If ingestion occurs, vomiting should not be induced. Water should be given to dilute the compound. If vomiting occurs naturally, the victim should lean forward to reduce risk of aspiration. Aspiration of the compound into the lungs may produce chemical pneumonitis requiring antibiotic treatment and administration of oxygen and expiratory pressure.
Human Prolonged exposure may produce liver and kidney damage. Cyclohexane is not a carcinogen or a developmental toxicant.
Immunotoxicity Cyclohexane is not known to be immunotoxic; however, there have been few studies performed.
Ecotoxicology LC50 for fathead minnow is 95 mg l 1 (static). TLm for Fathead minnow is 43–32 mg l 1 (24–96 h); conditions of bioassay not specified. TLm for Bluegill is 43–34 mg l 1 (24–96 h); conditions of bioassay not specified. TLm for Goldfish is 42.3 mg l 1 (24–96 h); conditions of bioassay not specified.
1108
Cyclohexane
TLm for Guppy is 57.7 mg l 1 (24–96 h); conditions of bioassay not specified. Coho salmon; no significant mortalities were observed up to 100 ppm after 96 h in artificial seawater at 8 C.
Exposure Standards and Guidelines The American Conference of Governmental Industrial Hygienists threshold limit value (TLV), 8 h time-weighted average (TWA), is 100 ppm. Permissible exposure limit: Table Z-1 8 h TWA: 300 ppm (1050 mg m 3). 8 h TWA: 100 ppm. Excursion limit recommendation: Excursions in worker exposure levels may exceed three times the TLV–TWA for no more than a total of 30 min during a workday, and under no circumstances should they exceed five times the TLV–TWA, provided that the TLV–TWA is not exceeded. Recommended exposure limit: 10 h TWA: 300 ppm (1050 mg m 3).
Further Reading Baxter, C.S., 2001. Alicyclic hydrocarbons. In: Bingham, E., Cohrssen, B., Powell, C.H. (Eds.), Patty’s Toxicology, fifth ed., vol. 4. Wiley, New York, pp. 161–165. Bingham, E., Cohrssen, B., 2012. Patty’s Toxicology, sixth ed. John Wiley and Sons, Hoboken, NJ. Hissink, A.M., et al., 2009. Physiologically based pharmacokinetic modeling of cyclohexane as a tool for integrating animal and human test data. Int. J. Toxicol. 28 (6), 498–509. Kreckmann, K.H., Baldwin, J.K., Roberts, L.G., et al., 2000. Inhalation developmental toxicity and reproduction studies with cyclohexane. Drug Chem. Toxicol. 23, 555–573. Lammers, J.H., Emmen, H.H., Muijser, H., Hoogendijk, E.M., McKee, R.H., Owen, D.E., Kulig, B.M., 2009. Neurobehavioral effects of cyclohexane in rat and human. Int. J. Toxicol. 28 (6), 488–497. Lewis Sr, R.J. (Ed.), 2000. Cyclohexane. Sax’s Dangerous Properties of Industrial Materials, vol. 2. Wiley, New York, pp. 1037–1038. Malley, L.A., Bamberger, J.R., Stadler, J.C., et al., 2000. Subchronic toxicity of cyclohexane in rats and mice by inhalation exposure. Drug Chem. Toxicol. 23, 513–537. Rouvière, P.E., Chen, M.W., 2003. Isolation of Brachymonas petroleovorans CHX, a novel cyclohexane degrading proteobacterium. FEMS Microbiol. Lett. 227, 101–106.
Relevant Websites Miscellaneous Cyclohexane is an indirect food additive for use only as a component of adhesives.
See also: Cyclohexene; Hexane.
http://www.echemportal.org/echemportal – OECD - The Global Portal to Information on Chemical Substances: Search for Cyclohexane. http://echa.europa.eu/documents/10162/d99cee39-82e6-4754-aac1-497106c9bd7c – European Commission (2004) Cyclohexane. European Risk Assessment Report vol. 41. http://www.epa.gov/iris/toxreviews/1005tr.pdf – Environmental Protection Agency Integrated Risk Information System. http://www.toxnet.nlm.nih.gov – Toxnet homepage