EPA 749-F-94-011a CHEMICAL SUMMARY FOR CYCLOHEXANE prepared by OFFICE OF POLLUTION PREVENTION AND TOXICS U.S. ENVIRONMENTAL PROTECTION AGENCY September 1994 This summary is based on information retrieved from a systematic search limited to secondary sources (see Appendix A). These sources include online databases, unpublished EPA information, government publications, review documents, and standard reference materials. No attempt has been made to verify information in these databases and secondary sources. I. CHEMICAL IDENTITY AND PHYSICAL/CHEMICAL PROPERTIES The chemical identity and physical/chemical properties of cyclohexane are summarized in Table 1. TABLE 1. CHEMICAL IDENTITY AND CHEMICAL/PHYSICAL PROPERTIES OF CYCLOHEXANE _______________________________________________________________________ Characteristic/Property Data Reference _______________________________________________________________________ CAS No. 110-82-7 Common Synonyms hexahydrobenzene, hexamethylene, hexanaphthene Budavari et al. 1989 Molecular Formula C6H12 Chemical Structure Physical State liquid Budavari et al. 1989 Molecular Weight 84.16 Budavari et al. 1989 Melting Point 6.47øC Budavari et al. 1989 Boiling Point 80.7øC @760 mm Hg Budavari et al. 1989 Water Solubility 55 mg/L @ 25øC CHEMFATE 1994 Density d20/4 øC, 0.7781 Budavari et al. 1989 Vapor Density (air = 1) 2.90 Verschueren 1983 KOC 482 (calculated) CHEMFATE 1994 Log KOW 3.44 CHEMFATE 1994 Vapor Pressure 77 mm Hg @ 20øC Verschueren 1983 Reactivity flammable; reacts with oxidizing materials HSDB 1994 Flash Point 1øF ( 18øC) (closed cup) Budavari et al. 1989 Henry's Law Constant 0.195 atm.m3/mol @ 25øC (calculated) CHEMFATE 1994 Fish Bioconcentration Factor 240 (calculated) CHEMFATE 1994 Odor Threshold 300 ppm (in air); mild, sweet odor (chloro- form-like) HSDB 1994 Conversion Factors 1 ppm = 3.49 mg/m3 1 mg/m3 = 0.29 ppm Verschueren 1983 _______________________________________________________________________ II. PRODUCTION, USE, AND TRENDS A. Production There are four cyclohexane producers in the United States. Table 2 lists producers, plant locations, and plant capacities. Annual US capacity is approximately 378 million gallons. In 1992, an estimated 338 million gallons of cyclohexane were produced in the US. During that same year, 5 million gallons were imported into the US and 38 million gallons were exported (Mannsville 1993). B. Use Cyclohexane is used in a number of industrial applications. The primary use of cyclohexane, accounting for approximately 58 percent of all use, is in the production of adipic acid, a nylon intermediate. Cyclohexane is also used in the production of caprolactam, another nylon intermediate. Small amounts are used as a solvent for lacquers and resins; as a paint and varnish remover; as an intermediate in the manufacture of benzene, cyclohexanone, and nitrocyclohexane; as fuel for camp stoves; as an ingredient in fungicidal formulations; and in the industrial recrystallization of steroids (Mannsville 1993). Table 3 shows the estimated 1992 US end-use pattern for cyclohexane. C. Trends Demand for cyclohexane is expected to increase at a rate of 2 to 2.5 percent per year (Mannsville 1993). TABLE 2. United States Producers of Cyclohexane _______________________________________________________________________ Company Plant Location Plant Capacity (in millions of gallons) _______________________________________________________________________ Champlin Corpus Christi, TX 30 Chevron Port Arthur, TX 38 Phillips Borger, TX 45 Sweeny, TX 110 Guayama, PR 90 Texaco Port Arthur, TX 65 _______________________________________________________________________ Source: Mannsville 1993. TABLE 3. Estimated 1992 United States End-Use Pattern of Cyclohexane _______________________________________________________________________ Use of Cyclohexane Percentage of US (typical Standard Industrial Cyclohexane Use Classification (SIC) Code) (see end note 1) _______________________________________________________________________ Adipic acid (production, SIC 2869) 58% Caprolactam (production, SIC 2865) 35% Miscellaneous (including solvent) (no applicable SIC Code(s)) 7% _______________________________________________________________________ Source: Mannsville 1993. III. ENVIRONMENTAL FATE A. Environmental Release Cyclohexane occurs naturally in crude oil and may be released to the environment from sites where petroleum products are refined, stored, and used (HSDB 1994). It is also released into the atmosphere from volcanos and tobacco smoke. The chemical is present in exhaust gases from motor vehicles and in fugitive emissions and in wastewater from industrial facilities involved in its production and use (HSDB 1994). In 1992, environmental releases of the chemical, as reported to the Toxic Chemical Release Inventory by certain types of U.S. industries, totaled about 14 million pounds, including 13.6 million pounds to the atmosphere; 21,039 pounds to surface water; 230,985 pounds by underground injection; and 107,748 pounds to land (TRI92 1994). Air monitoring has detected the chemical in the air at various US locations, including Los Angeles, CA; Houston, TX; Tulsa, OK; and Jones State Forest, TX. When reported, concentrations were less than 25 ppb (CHEMFATE 1994). Water samples collected from the Hudson River Basin (28 sites), the Mississippi River Basin (Alabama and Texas, 45 sites), and the Gulf of Mexico contained less than 20 ppb of cyclohexane (CHEMFATE 1994). The chemical has also been detected in samples of mother's milk in Baton Rouge, LA; Bridgeville, PA; and Bayonne and Jersey City, NJ (CHEMFATE 1994). B. Transport Cyclohexane is volatile (vapor pressure, 77 mm Hg @ 20øC; Henry's Law constant, 0.195 atm.m3/mol @ 25øC) and is expected to partition into the atmosphere from both water and soil (HSDB 1994). The estimated KOC for cyclohexane, 482 (CHEMFATE 1994), indicates a moderate potential for soil adsorption. Cyclohexane is slightly soluble in water (55 ppm) and has the potential to leach through soil into groundwater (HSDB 1994). C. Transformation/Persistence 1. Air - In the atmosphere, cyclohexane degrades by reaction with photochemically produced hydroxyl radicals. One estimate of the rate constant for the reaction between photochemically-produced hydroxyl radicals and cyclohexane is 0.795 x 10-11 cm3/molecule- sec (CHEMFATE 1994); an estimated half-life for this type of reaction is 52 hours (HSDB 1994). The half-life is shorter in the presence of photochemical smog; in Los Angeles in sunlight, for example, 39% of the chemical was degraded in 6 hours (HSDB 1994). The products of the reaction are cyclohexyl nitrate, and unidentified carbonyl compounds (HSDB 1994). 2. Soil - Volatilization and leaching are the primary removal mechanisms for cyclohexane in soil. The chemical is resistant to biodegradation under most conditions, unless other degradable hydrocarbons, such as oil and gasoline, are present (CHEMFATE 1994; HSDB 1994). 3. Water - The primary route for the removal of cyclohexane from the aquatic environment is volatilization (half-life in a model river, 2 hours) (HSDB 1994). 4. Biota - The estimated fish bioconcentration factor for cyclohexane of 240 (CHEMFATE 1994) indicates a potential for its limited bioaccumulation in the aquatic food chain. IV. HEALTH EFFECTS A. Pharmacokinetics 1. Absorption - Cyclohexane is absorbed following inhalation (HSDB 1994) and nominally by the skin. Massive applications of the chemical to the skin of rabbits have produced microscopic changes in the liver and kidneys (effective doses not given) (Sandmeyer 1981). Systemic toxicity observed in animals exposed orally to cyclohexane (see section IV. B) indicates that gastro- intestinal absorption of the chemical also occurs . In workers exposed to atmospheric cyclohexane, 22.8% of the total respiratory intake was absorbed, and a "significant amount" of the absorbed cyclohexane was either retained or metabolized (Longacre 1987). 2. Distribution - Following inhalation exposure of Wistar rats to concentrations of cyclohexane ranging from 300-2000 ppm, perirenal fat concentrations of the chemical were 23- to 38-fold greater than brain concentrations after one week of exposure and 50- to 80-fold greater than brain concentrations, after two weeks. No information was found regarding distribution to other organs. 3. Metabolism - Cyclohexane is metabolized via the hepatic, vascular, and renal systems (Sandmeyer 1981). Microsomal hydroxylases oxidize cyclohexane to cyclohexanol in the presence of NADPH and oxygen (Longacre 1987). Other metabolites identified in mammalian systems include trans-cyclohexane-1,2,-diol, cyclo- hexanone, and adipic acid (HSDB 1994). 4. Excretion - Shoe factory workers exposed to atmospheric concentra- tions of cyclohexane ranging from 17 to 2484 mg/m3 excreted cyclohexanol in the urine at concentrations of 0.27 to 7.18 micrograms/mL and at the rate of 0.05 to 3.23 micrograms/min. The excretion rates of cyclohexanol correlated well with cyclo- hexane concentrations in the blood and in alveolar air (Longacre 1987). In a study of alveolar excretion, workers were exposed to cyclohexane for 4 hours and excretion was measured during a 6-hour post-exposure period. The post-exposure decline occurred in two phases: in the first, the half-life was 11.2 minutes, whereas in the second, about one hour later, the half-life was 115.3 minutes. The alveolar excretion of cyclohexane was approximately 9.1 mg for an average alveolar ventilation of 5 L/minute. Only 0.5 to 1.0% of the dose was excreted in the urine as cyclohexanol and cyclohexanone (Longacre 1987). Portions of inhaled cyclohexane are excreted unchanged in the urine and in exhaled air; the remainder is metabolized to cyclohexanol and excreted in the urine, mainly as the sulfate or glucuronide conjugate (HSDB 1994; Sandmeyer 1981). Adult chinchilla-doe rabbits given a single oral dose of 300-400 mg/kg 14C-cyclohexane excreted 35-45% of the dose in expired air (10% as CO2 and 25-35% as unchanged cyclohexane), and eliminated 33-56% of the dose in the urine (Longacre 1987). Animals given a lower dose (0.3 mg/kg) of the radiolabeled cyclohexane excreted no unchanged chemical in expired air, 5% as CO2, and 98% in the urine. The only urinary metabolites detected were the glucuronides of cyclohexanol (30-40% and 60% of the high and low dose, respectively) and transcyclohexane-1,2-diol (5-8% and 17% of the high and low dose, respectively). A total of 0.1-0.2% was excreted in the feces, and 2.4-2.6% of the dose was recovered from the tissues. B. Acute Effects Cyclohexane has low acute toxicity, producing eye irritation in humans and neurological symptoms (see section IV. G), other organ effects, and death in animals at very high doses. 1. Humans - According to one source, cyclohexane is detectable by odor and is irritating to the eyes at 300 ppm; another source suggested 25 ppm as the odor threshold (ACGIH 1991). Undiluted cyclohexane is also irritating to the skin (Longacre 1987). No other information was found in the secondary sources searched for the acute toxicity of cyclohexane to humans. 2. Animals - The oral LD50 for cyclohexane in rats ranges from 8.0 to 39 mL/kg (both greater than 5 g/kg), depending upon the age of the animals (Sandmeyer 1981). The oral LD50 for mice is 1.3 g/kg; the minimum lethal oral dose in rabbits is 5.5-6.0 g/kg; and the dermal LD50 in rabbits is >180 g/kg (Longacre 1987). Within 1 to 1.5 hours, lethal doses to animals produced severe diarrhea, vascular damage and collapse, hepatocellular degeneration and toxic glomerulonephritis (Sandmeyer 1981). Exposure of rabbits to 3330 ppm (duration not given) produced no effect; 18,500 ppm for 8 hours was non-lethal; and 26,600 ppm for 1 hour was lethal (ACGIH 1991). Application of 1.55 g/day of cyclohexane to the skin for 2 days produced minimal irritation (Longacre 1987). C. Subchronic/Chronic Effects Cyclohexane administered subchronically is of low toxicity, producing neurological effects (see section IV. G), ocular, gastrointestinal, and respiratory effects in animals at very high, lethal concentrations. 1. Humans - No information was found for the subchronic/chronic toxicity of cyclohexane in humans in the secondary sources searched. 2. Animals - No effects were observed in rabbits exposed to 434 ppm cyclohexane for fifty 6-hour periods or in rhesus monkeys exposed to 1234 ppm under identical exposure conditions (Longacre 1987). Concentrations of ò7445 ppm, 6 to 8 hours/day for 2 to 26 weeks were lethal to rabbits, producing neurological effects (see section IV. G) as well as closure of the eyes, conjunctival infection, salivation, labored respiration, cyanosis and diarrhea prior to death (Longacre 1987). Rats exposed by inhalation to 1500 or 2500 ppm cyclohexane for 9-10 hours/day, 5 days/week for 7, 14, or 30 weeks exhibited no adverse effects (Longacre 1987). D. Carcinogenicity 1. Humans - No information was found in the secondary sources searched regarding the carcinogenicity of cyclohexane in humans. 2. Animals - No information was found in the secondary sources searched regarding the carcinogenicity of cyclohexane in animals. E. Genotoxicity Cyclohexane was negative for viral enhanced cell transformation in Syrian hamster embryo (SA7/SHE) cells and for histidine reverse gene mutation in Salmonella typhimurium (Ames assay) (GENETOX 1994). F. Developmental/Reproductive Toxicity 1. Humans - No information was found in the secondary sources searched regarding the developmental/reproductive toxicity of cyclohexane in humans. 2. Animals - No information was found in the secondary sources searched regarding the developmental/reproductive toxicity of cyclohexane in animals. G. Neurotoxicity The central nervous system is a major target organ for the toxicity of cyclohexane. High concentrations of the chemical produce various effects, ranging from trembling to death. 1. Humans - At high concentrations, cyclohexane is a central nervous system depressant and may cause dizziness and unconsciousness (Sandmeyer 1981). No other information was found in the secondary sources searched regarding the neurotoxicity of cyclohexane in humans. 2. Animals - Mice exposed to 50 mg/L (14,500 ppm) for 2 hours exhibited minimal narcotic effects (Longacre 1987). Exposure to 18,000 ppm produced trembling within 6 minutes, disturbed equilibrium within 15 minutes, and complete recumbency within 30 minutes (Longacre 1987). Following exposure of Wistar rats for 2 weeks to concentrations of cyclohexane ranging from 300-2000 ppm, cerebral levels of RNA, glutathione, glutathione peroxidase, and azoreductase were evaluated. The only effect noted was a decrease in azoreductase activity (Longacre 1987). The effect of cyclohexane on the vestibular function of rats was measured by recording nystagmus induced by accelerated rotation. Cyclohexane caused an excitation of the vestibulo-oculomotor reflex (threshold blood level, 1.1 mmole/L) (HSDB 1994). Concentrations of ò7445 ppm, 6 to 8 hours/day for 2 to 26 weeks were lethal to rabbits, producing convulsions, tremors, narcosis, and paresis of the legs (Longacre 1987). V. ENVIRONMENTAL EFFECTS TLm values for fish range from 32 to 57.7 mg/L, indicating that the chemical is moderately toxic to aquatic organisms in acute tests. Cyclohexane is expected to be of low toxicity to terrestrial organisms and has a smog-forming potential. A. Toxicity to Aquatic Organisms TLm values for fish (24-96 hr) are 43-32 mg/L (Pimephales promelas, fathead minnow), 43-34 mg/L (Lepomis macrochirus, bluegill), 42.3 mg/L (Crassium auratus, goldfish), and 57.7 mg/L (Poecilia reticulata, guppy) (Verschueren 1983). Mussel larvae (Mytilus edulis) exposed to 1 to 100 ppm (mg/L) cyclohexane exhibited a 10-20% increase in growth rate (Verschueren 1983). The threshold concentra- tion of cyclohexane in the cell multiplication inhibition assay, measured in the protozoa Uronema parduczi Chatton-Lwoff, was >50 mg/L (Verschueren 1983). B. Toxicity to Terrestrial Organisms Based on the low toxicity of cyclohexane to laboratory animals, the toxicity of the chemical to terrestrial animals is expected to be low. C. Abiotic Effects Limited information indicates cyclohexane may have potential to contribute to the formation of photochemical smog. U.S. EPA has denied a petition to delist cyclohexane from the Toxic Release Inventory on this basis and on the lack of adequate health effects information. The ozone-forming potential for cyclohexane has been measured as 2 on a scale of 5 (HSDB 1994). Ozone-forming potential is an indicator of the smog-forming potential of a chemical. VI. EPA/OTHER FEDERAL AND OTHER GROUP ACTIVITY The Clean Air Act Amendments of 1990 list cyclohexane as a hazardous air pollutant. Occupational exposure to cyclohexane is regulated by the Occupational Safety and Health Administration (OSHA). The permissible exposure limit (PEL) is 300 parts per million parts of air (ppm) as an 8-hour time-weighted average (TWA) (29 CFR 1910.1000). Federal agencies and other groups that can provide additional information on cyclohexane are summarized in Tables 4 and 5. TABLE 4. EPA OFFICES AND CONTACT NUMBERS FOR INFORMATION ON CYCLOHEXANE ________________________________________________________________________ EPA OFFICE LAW PHONE NUMBER ________________________________________________________________________ Pollution Prevention Toxic Substances Control Act & Toxics (Sec. 4/8A/8D/8E) (202) 554-1404 Emergency Planning and Community Right-to-Know Act (EPCRA) Regulations (Sec. 313) (800) 424-9346 Toxics Release Inventory data (202) 260-1531 Air Clean Air Act (919) 541-0888 Solid Waste & Comprehensive Environmental Emergency Response Response, Compensation, and Liability Act (Superfund)/ Resource Conservation and Recovery Act / EPCRA (Sec. 304/311/312) (800) 424-9346 Water Clean Water Act (202) 260-7588 ________________________________________________________________________ TABLE 5. OTHER FEDERAL OFFICE/OTHER GROUP CONTACT NUMBERS FOR INFORMATION ON CYCLOHEXANE _______________________________________________________________________ Other Agency/Department/Group Contact Number _______________________________________________________________________ American Conference of Governmental Industrial Hygienists Recommended TLV-TWA (see end note 2): 300 ppm (ACGIH 1993-1994)) (513) 742-2020 Consumer Product Safety Commission (301) 504-0994 Food & Drug Administration (301) 443-3170 National Institute for Occupational Safety & Health (Recommended TWA (see end note 3): 300 ppm (NIOSH 1990)) (800) 356-4674 Occupational Safety & Health Administration (Permissible TWA (see end note 2): 300 ppm (OSHA 1993)) (Check local phone book for phone number under Department of Labor) _______________________________________________________________________ VII. END NOTES 1. Standard Industrial Classification code is the statistical classification standard for all Federal economic statistics. The code provides a convenient way to reference economic data on industries of interest to the researcher. SIC codes presented here are not intended to be an exhaustive listing; rather, the codes listed should provide an indication of where a chemical may be most likely to be found in commerce. 2. TLV-TWA, Threshold Limit Value-Time Weighted Average 3. TWA, Time-Weighted Average VIII. CITED REFERENCES ACGIH. 1993-1994. American Conference of Governmental Industrial Hygienists. 1993-1994 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. ACGIH. 1991. American Conference of Governmental Industrial Hygienists. Cyclohexane. In: Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed. ACGIH, Cincinnati, OH, pp. 355-356. Budavari S, O'Neil MJ, Smith A, Heckelman PE (Eds.). 1989. The Merck Index, 11th ed. Merck & Co., Inc., Rahway, NJ, p. 426. CHEMFATE. 1994. Syracuse Research Corporation's Environmental Fate Data Bases. Syracuse Research Corporation, Syracuse, NY. Retrieved 8/15/94. GENETOX. 1994. U.S. EPA GENETOX Program, computerized database. Retrieved September, 1993. HSDB. 1994. Hazardous Substances Data Bank. MEDLARS Online Information Retrieval System, National Library of Medicine. Retrieved June, 1994. Longacre SL. 1987. Cyclohexane. In: Ethel Browning's Toxicity and Metabolism of Industrial Solvents, 2nd ed. Snyder R, Ed. Elsevier, Amsterdam, pp. 225-235. Mannsville, 1993. Chemical Products Synopsis, Cyclohexane. Mannsville Chemical Products Corporation, 1993. NIOSH. 1990. National Institute for Occupational Safety and Health. 1990. NIOSH Pocket Guide to Chemical Hazards. NIOSH, Cincinnati, OH, pp. 76-77. OSHA. 1993. Occupational Safety and Health Administration. Table Z-2. Limits for Air Contaminants. 29 CFR Part 1910 Part 1910, p. 35343. Sandmeyer EE. 1981. Cyclic hydrocarbons. In: Clayton GD, Clayton FE. 1981-1982. Patty's Industrial Hygiene and Toxicology, 3rd ed., Vol. 2C. New York: John Wiley & Sons. pp. 3225, 3227-3228. TRI92. 1994. Toxic Chemical Release Inventory. Office of Pollution Prevention and Toxics, U.S. EPA, Washington, DC. Verschueren K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Reinhold Co., New York, pp. 418-419. APPENDIX A. SOURCES SEARCHED FOR FACT SHEET PREPARATION ACGIH. 1993-1994. American Conference of Governmental Industrial Hygienists. 11993-1994 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. AQUIRE. 1994. Aquatic Information Retrieval online data base. Chemical Information Systems, Inc., a subsidiary of Fein-Marquart Assoc. ATSDR. 1989-1994. Agency for Toxic Substances and Disease Registry. Toxicological Profiles. Chamblee, GA: ATSDR. Budavari S, O'Neil MJ, Smith A, Heckelman PE (Eds.). 1989. The Merck Index, 11th ed. Rahway, N.J.: Merck & Co., Inc. CHEMFATE. 1994. Syracuse Research Corporation's Environmental Fate Data Bases. Syracuse Research Corporation, Syracuse, NY. Clayton GD, Clayton FE. 1981-1982. Patty's Industrial Hygiene and Toxicology, 3rd ed., Vol. 2C. New York: John Wiley & Sons. GENETOX. 1994. U.S. EPA GENETOX Program, computerized database. HSDB. 1994. Hazardous Substances Data Bank. MEDLARS Online Information Retrieval System, National Library of Medicine. IARC. 1979-1994. International Agency for Research on Cancer. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Man. Lyon: IARC. NIOSH (National Institute for Occupational Safety and Health). 1992. NIOSH Recommendations for Occupational Safety and Health. Compendium of Policy Documents and Statements. Cincinnati, OH: NIOSH. NIOSH. 1990. National Institute for Occupational Safety and Health. 1990. NIOSH Pocket Guide to Chemical Hazards. NIOSH, Cincinnati, OH. NTP. 1994. National Toxicology Program. Toxicology and Carcinogenesis Studies. Tech Rep Ser. NTP. 1994. National Toxicology Program. Management Status Report. Produced from NTP Chemtrack system. April 8, 1994. National Toxicology Program, Research Triangle Park, NC. OSHA. 1993. Occupational Safety and Health Administration. Table Z-2. Limits for Air Contaminants. 29 CFR Part 1910 Part 1910, p. 35343. RTECS. 1994. Registry of Toxic Effects of Chemical Substances. MEDLARS Online Information Retrieval System, National Library of Medicine. U.S. Air Force. 1989. The Installation Restoration Toxicology Guide, Vols. 1-5. Wright-Patterson Air Force Base, OH. U.S. EPA (U.S. Environmental Protection Agency). 1991. Table 302.4 List of Hazardous Substances and Reportable Quantities 40 CFR, part 302.4:3-271. U.S. EPA. Most current. Drinking Water Regulations and Health Advisories. Office of Drinking Water, U.S. Environmental Protection Agency, Washington, D.C. U.S. EPA. Most Current. Health Effects Assessment Summary Tables. Cincinnati, OH: Environmental Criteria and Assessment Office, U.S.EPA. U.S. EPA reviews such as Health and Environmental Effects Documents, Health and Environmental Effect Profiles, and Health and Environmental Assessments. U.S. EPA. 1994. Integrated Risk Information System (IRIS) Online. Cincinnati, OH: Office of Health and Environmental Assessment.