Annotated Reference Outline for the Toxicological Review of Cyclohexane (cas No. 110-82-7) in Support of Summary Information on the Integrated Risk Information System (iris)


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or EPA ID for final]
www.epa.gov/iris
4>EPA
ANNOTATED REFERENCE OUTLINE
FOR THE TOXICOLOGICAL REVIEW
OF
Cyclohexane
(CAS No. 110-82-7)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
2/13/09
NOTICE
This document is a [author: insert Agency Review or external review] draft. It has not been
formally released by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency position on this chemical. It is being circulated for review of its
technical accuracy and science policy implications.
U.S. Environmental Protection Agency
Washington, DC

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REVIEWS
Anon. (1975) Toxic substances. Proposed occupational safety and health standards for alkyl benzenes, cyclohexane,
ketones, and ozone. Fed Regist 40(196):47262-47313.
Anon. (1994) Cyclohexane. New Jersey Department of Health, Right to Know Program, CN 368:08625-00368.
Anonymous. (2001) Recommendation of the Scientific Committee on occupational exposure limits for
Cyclohexane. European Commission 6
Anonymous. (2002) Cyclohexane. ACGIH. Documentation of the threshold limit values and biological exposure
indices 2
Browning, E. (1950) Industrial Solvents: The Aromatic and Cyclic Hydrocarbons. British Medical Journal 7:19-23.
Browning, E. (1965) In: Toxicity and Metabolism of Industrial Solvents. New York, NY: American Elsevier; pp.
130- 134.
Chem. Mfgs. Assn. (1986) Letter from Chem. Mfgs. Assn. to U.S. EPA regarding evaluation of environmental
exposure & toxicological testing results on cyclohexane with attachments. Submitted under TSCA Section 4; EPA
Document No. 40-8623020; NTIS No. OTS0527414.
Clayton, GD; Clayton, FE. (1994) [Cyclohexane]. In: Clayton, GD and Clayton, FE; eds. Patty's Industrial
Hygiene and Toxicology. 4th edition. New York, NY: John Wiley and Sons Inc.,; pp. 1267-1274.
CRCS Inc. (1984) Information review cyclohexane. Submitted under TSCA Section 4; EPA Document No. 40-
8423031; NTIS No. OTS0527468.
Criteria Group for Occupational Standards. (1984) Scientific basis for Swedish occupational standards. V. Alicyclic
hydrocarbons, cycloalkanes. Arbete och Halsa 44(Issue 1984:43 in Swedish):78-86.
Damg; ecirc; ard Nielsen, G; et al. (1982) Toxicological evaluation of a number of substances that may pollute the
workplace air. Arbejdstilsynet, Arbejdsmilj²
Dutch Expert Committee for Occupational Standards. (1990) Health-based recommended occupational exposure
limits for cyclohexane. Directorate General of Labour, the Netherlands 15(90)
Fairhurst, S. (1991) Cyclohexane. In: Toxicity Review 25. Cyclohexane, cumene, para-dichlorobenzene (p-DCB),
chlorodifluoromethane (CFC 22). London: Health and Safety Executive
Her Majesty's Stationery Office;
Farmer, TH. (1996) Occupational hygiene limits for hydrocarbon solvents. Ann Occup Hyg 40(2):237-242.
Gobba, F; Ghittori, S; Imbriani, M; et al. (1997) The urinary excretion of solvents and gases for the biological
monitoring of occupational exposure: A review. Sci Total Environ 199(l-2):3-12.
Grant, WM; Schuman, JS. (1993) [Cyclohexane]. In: Toxicology of the Eye. Springfield, IL: Charles C. Thomas;
p. 492.
Howe, P; Nielsen, IR. (1996) Environmental hazard assessment: cyclohexane. Toxic Substances Division.
Department of the Environment, London 26(1996)
Izmerov, NF; Sanotsky, IV; Sidorov, KK. (1982) [Cyclohexane]. In: Izmerov, NF; Sanotsky, IV and Sidorov, KK;
eds. Toxicometric Parameters of Industrial Toxic Chemicals Under Single Exposure. Moscow: Centre of
International Projects GKNT,; p. 41.
Larsen, L. (1998) Cyclohexane. In: Wexler, P; ed. Encyclopedia of Toxicology. San Diego, CA: Academic Press;
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pp. 390-391.
NIOSH. (2005) Pocket Guide to chemical hazards. National Institute for Occupational Safety and Health, U.S.
Department of Health and Human Services, Washington, D.C.
Ontario Ministry of the Environment. (2005) Ontario Air Standards for Cyclohexane. Standards Development
Branch Ontario Ministry of the Environment:46 pgs.
Oppelt, WW. (1970) Toxicity from Exposure to Solvents. Laboratory Diagnosis of Diseases Caused by Toxic
Agents, Sunderman, F. W., andF. W. Sunderman, Jr., Editors 29:296-304.
Pfannenstiel, W. (1951) Toxicity of cyclohexanes. Osterr. Apoth.-Ztg. 5:632-633.
Pryor, GT. (1995) Solvent-induced neurotoxicity effects and mechanisms. Chang, L. W. And R. S. Dyer (Ed.).
Neurological Disease and Therapy, Vol. 36. Handbook of Neurotoxicology. Xxi+1103p. Marcel Dekker, Inc.: New
York, New York, USA BASEL, SWITZERLAND. ISBN 0-8247-8873-7.; 0(0):377-400.
Sikkema, J; De Bont, JA; Poolman, B. (1995) Mechanisms of membrane toxicity of hydrocarbons. Microbiol Rev
59(2):201-222.
Simonsen, L; Lund, SP. (1992) A strategy for delineating risks due to exposure to neurotoxic chemicals. Am J Ind
Med 21(6):773-792.
Tabershaw, IR; Utidjian, HMD; Kawahara, BL. (1977) Chemical Hazards. Occupational Diseases, A Guide to
Their Recognition, Revised Edition, NIOSH, U.S. Department of Health, Education, and Welfare, NIOSH
Publication No: 131-439.
Tara, S. (1953) [Toxicity of cyclohexane.]. Arch Mai Prof 14(5):494-496.
Toscano, WAJ; McNulty, SE. (1995) Toxic and carcinogenic chemicals in biomedical laboratories. Fleming, D. O.,
Et Al. (Ed.). Laboratory Safety: Principles and Practices, Second Edition. Xiv+406p. American Society for
Microbiology (Asm): Washington, Dc, USA. Isbn 1-55581-047-0. 0(0): 133-141.
U.S. EPA. (1984) Cyclohexane.
U.S. EPA. (1994) Chemical Summary for Cyclohexane.. Prepared by Office of Pollution Prevention and Toxics.
US Environmental Protection Agency. EPA 749-F-94-01 la.
Von Oettingen, WF. (1940) Toxicity and Potential Dangers of Aliphatic and Aromatic Hydrocarbons. A Critical
Review of the Literature. U.S. Public Health Bulletin, No 255(135):318.
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2. CHEMICAL AND PHYSICAL INFORMATION
Atkinson, R. (1989) Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic
compounds. Riverside, CA: American Chemical Society American Institute of Physics for the National Institute of
Standards and Technology.
Bidleman, TF. (1988) Atmospheric processes. Environ Sci Technol 22:361-367.
Blake, NJ; Penkett, SA; Clemitshaw, KC; et al. (1993) Estimates of atmospheric hydroxyl radical concentrations
from the observed decay of many reactive hydrocarbons in well-defined urban plumes. J Geophys Res 98:2851-
2864.
Bocek, K. (1976) Relations among activity coefficients, partition coefficients and solubilities. Experientia,
Supplementum 23(Quant. Struct.-Act. Relat.):231-240.
Budavari, S. (1996) [Cyclohexane]. In: The Merck Index - An Encyclopedia of Chemicals, Drugs, and
Biologicals. Whitehouse Station, NJ: Merck and Co., Inc.; p. 459.
Chao, J; Lin, CT; Chung, TH. (1983) Vapor pressure of coal chemicals. J Phys Chem 12:1033-1063.
Clayton, GD; Clayton, FE. (1994) [Cyclohexane]. In: Clayton, GD and Clayton, FE; eds. Patty's Industrial
Hygiene and Toxicology. 4th edition. New York, NY: John Wiley and Sons Inc.,; pp. 1267-1274.
CMR. (2007) Chemical proilfe: cyclohexane. Chem Mark Rep:43.
CRCS Inc. (1984) Information review cyclohexane. Submitted under TSCA Section 4; EPA Document No. 40-
8423031; NTIS No. OTS0527468.
Criteria Group for Occupational Standards. (1984) Scientific basis for Swedish occupational standards. V. Alicyclic
hydrocarbons, cycloalkanes. Arbete och Halsa 44(Issue 1984:43 in Swedish):78-86.
Eastman, AD; Mears, DE. (1995) Hydrocarbons (C1-C6). In: Kirk-Othmer Encyclopedia of Chemical
Technology. New York: John Wiley and Sons; pp. 812-837.
Fairhurst, S. (1991) Cyclohexane. In: Toxicity Review 25. Cyclohexane, cumene, para-dichlorobenzene (p-DCB),
chlorodifluoromethane (CFC 22). London: Health and Safety Executive
Her Majesty's Stationery Office;
Filov, VA. (1962) Thermodynamic activity of volatile organic compounds and their action on mammals. Biofizika
7(No. l):73-79.
Graedel, TE. (1978) In: Chemical Compounds in the Atmosphere. New York: Academic Press; p. 99.
Hansch, C; Leo, A; Hoekman, D. (1995) [Cyclohexane]. In: Exploring QSAR. Hydrophobic, electronic and steric
constant. Washington, DC: American Chemical Society; p. 23.
Lide, DR. (1995-1996) [Cyclohexane]. In: R., LD; ed. CRCHandb Chem Phys. 76th edition. Boca Raton, FL:
CRC Press Inc.; pp. 5-80, 86-61, 15-15.
Meylan, W; Howard, PH; Boethling, RS. (1992) Molecular topology/fragment contribution method for predicting
soil sorption coefficients. Environ Sci Technol 26:1560-1567.
Meylan, WM; Howard, PH. (1991) Bond contribution method for estimating Henry's Law constants. . Environ
Toxicol Chem 10:1283-1293.
NIOSH. (2005) Pocket Guide to chemical hazards. National Institute for Occupational Safety and Health, U.S.
Department of Health and Human Services, Washington, D.C.
Ontario Ministry of the Environment. (2005) Ontario Air Standards for Cyclohexane. Standards Development
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Branch Ontario Ministry of the Environment:46 pgs.
U.S. EPA. (1994) Chemical summary for cyclohexane. . Prepared by Office of Pollution Prevention and Toxics. US
Environmental Protection Agency. EPA 749-F-94-01 la.
Verschueren, K. (1996) [cyclohexane]. In: Verschueren, K; ed. Handbook of Environmental Data on Organic
Chemicals. 3rd edition. New York: Van Nostrand Reinhold; pp. 565-567.
3. TOXICOKINETICS
3.1. ABSORPTION
Brugnone, F; Perbellini, L; Gaffuri, E; et al. (1980) Biomonitoring of industrial solvent exposures in workers
alveolar air. Int Arch Occup Environ Health 47(3):1981).
Elliott, TH; Parke, DV; Williams, RT. (1959) Studies in detoxification. The metabolism of cyclo(14C)hexane and
its derivatives. Biochem J 72:193-200.
Fabre, R; Truhaut, R; Laham, S. (1959) Metabolism of cyclohexane in the rabbit. Compt. rend. 248:1081-1083.
Fiserova-Bergerova, V; Pierce, JT; Droz, PO. (1990) Dermal absorption potential of industrial chemicals: Criteria
for skin notation. Am J Ind Med 17(5):617-636.
Governa, M; Calisti, R; Coppa, G; et al. (1987) Urinary Excretion of 2,5-Hexanedione and Peripheral
Polyneuropathies in Workers Exposed to Hexane. J Toxicol Environ Health 20(3):219-228.
Iyadomi, M; Higaki, Y; Ichiba, M; et al. (1998) Evaluation of organic solvent-induced inflammation modulated by
neuropeptides in the abdominal skin of hairless rats. Ind Health 36(1):40-51.
Mraz, J; Galova, E; Nohava, H; et al. (1994) Markers of Exposure to Cyclohexanone, Cyclohexane, and
Cyclohexanol: l,2and 1,4-Cyclohexanediol. Clin Chem 40(7): 1466-1468.
Mraz, J; Galova, E; Nohova, H; et al. (1998) 1,2- and 1,4-Cyclohexanediol: major urinary metabolites and
biomarkers of exposure to cyclohexane, cyclohexanone, and cyclohexanol in humans. Int Arch Occup Environ
Health 71(8):560-565.
Mutti, A; Falzoi, M; Lucertini, S; et al. (1981) Absorption and alveolar excretion of cyclohexane in workers in a
shoe factory. J Appl Toxicol l(4):220-223.
Naruse, M. (1984) Effects on mice of long-term exposure to organic solvents in adhesives. Nagoya Medical Journal
Mar 28:3-4.
Neighbors, SM; Coleman, DP; Baldwin, JK; et al. (1998) Dermal Absorption of [C14]Cyclohexane in Fischer 344
Rats. Toxicologist 42:390.
Perbellini, L; Brugnone, F. (1980) Lung uptake and metabolism of cyclohexane in shoe factory workers. Int Arch
Occup Environ Health 45(3):261-269.
Perbellini, L; Brugnone, F; Gaffuri, E. (1987) Urinary Metabolite Excretion in the Exposure to Technical Hexane.
Biological Monitoring of Exposure to Chemicals. Organic Compounds, M. H. Ho andH. K. Dillon, Editors: 197-
205.
Perbellini, L; Brugnone, F; Pavan, I. (1980) Identification of the metabolites of n-hexane, cyclohexane, and their
isomers in men's urine. Toxicol Appl Pharmacol 53(2):220-229.
Research Triangle Inst. (1984) Adsorption, distribution, metabolism and excretion of cyclohexane (June 1984).
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Submitted under TSCA Section 4; EPA Document No. 40-8423127; NTIS No. OTS0527475.
Research Triangle Inst. (1996) Dermal aborption of 14C-Cylcohexane in Fischer 344 rats. Submitted under TSCA
Section 4; EPA Document No. 44627; NTIS No. OTS0558860.
Savolainen, H; Pfaffli, P. (1980) Burden and dose-related neurochemical effects of intermittent cyclohexane vapour
inhalation in rats. Toxicol Lett 7(1): 17-22.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of rabbits to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:199-.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of animals to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:323-.
Yasugi, T; Kawai, T; Mizunuma, K; et al. (1994) Exposure monitoring and health effect studies of workers
occupationally exposed to cyclohexane vapor. Int Arch Occup Environ Health 65(5):343-350.
Yuasa, J; Kishi, R; Eguchi, T; et al. (1996) Investigation on neurotoxicity of occupational exposure to cyclohexane:
a neurophysiological study. Occup Environ Med 53(3): 174-179.
Zahlsen, K; Eide, I; Nilsen, AM; et al. (1992) Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic
hydrocarbons in rat after repeated exposures. Pharmacol Toxicol 71(2): 144-149.
3.2. DISTRIBUTION
Abraham, MH; Ibrahim, A. (2006) Air to fat and blood to fat distribution of volatile organic compounds and drugs:
Linear free energy analyses. Eur J Med Chem 41(12): 1430-1438.
Abraham, MH; Ibrahim, A; Acree, WE, Jr. (2005) Air to blood distribution of volatile organic compounds: A linear
free energy analysis. ChemRes Toxicol 18(5):904-911.
Abraham, MH; Ibrahim, A; Acree, WE, Jr. (2006) Air to brain, blood to brain and plasma to brain distribution of
volatile organic compounds: linear free energy analyses. Eur J Med Chem 41(4):494-502.
Basak, SC; Mills, D; El-Masri, HA; et al. (2004) Predicting blood:air partition coefficients using theoretical
molecular descriptors. Environ Toxicol Pharmacol 16(l-2):45-55.
Basak, SC; Mills, D; Gute, BD. (2006) Prediction of tissue: air partition coefficients. Theoretical vs. experimental
methods. SAR QSAR Environ Res 17(5):515-532.
Beliveau, M; Krishnan, K. (2004) Molecular structure-based prediction of the steady-state blood concentrations of
inhaled organics in rats. Toxicologist 78(1-S):20.
Beliveau, M; Lipscomb, J; Tardif, R; et al. (2005) Quantitative structure-property relationships for interspecies
extrapolation of the inhalation pharmacokinetics of organic chemicals. Chem Res Toxicol 18(3):475-485.
Beliveau, M; Tardif, R; Krishnan, K. (2003) Quantitative structure-property relationships for physiologically based
pharmacokinetic modeling of volatile organic chemicals in rats. Toxicol Appl Pharmacol 189(3):221-232.
Broussilowska, AI. (1936) Sensitivity of various animals to different anesthetics. Comptes Rendus des Seances de
la Societe de Biologie et de Ses Filiales 122:893-895.
Fiserova-Bergerova, V; Diaz, ML. (1986) Determination and prediction of tissue-gas partition coefficients. Int Arch
Occup Environ Health 58(l):75-87.
Gargas, ML; Burgess, RJ; Voisard, DE; et al. (1989) Partition coefficients of low-molecular-weight volatile
chemicals in various liquids and tissues. Toxicol Appl Pharmacol 98(l):87-99.
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Haddad, S; Poulin, P; Krishnan, K. (2000) Relative lipid content as the sole mechanistic determinant of the adipose
tissue:blood partition coefficients of highly lipophilic organic chemicals. Chemosphere 40(8):839-843.
Holmberg, B; Jakobson, I; Malmfors, T. (1974) The effect of organic solvents on erythrocytes during hypotonic
hemolysis. . Environ Res 7(2): 193-205.
Konoz, E; Golmohammadi, H. (2008) Prediction of air-to-blood partition coefficients of volatile organic compounds
using genetic algorithm and artificial neural network. Anal Chim Acta 619(2): 157-164.
Lehmann, I; Thoelke, A; Rehwagen, M; et al. (2002) The influence of maternal exposure to volatile organic
compounds on the cytokine secretion profile of neonatal T cells. Environ Toxicol 17(3):203-210.
Meulenberg, CJW; Vijverberg, HPM. (2000) Empirical relations predicting human and rat tissues :air partition
coefficients of volatile organic compounds. Toxicol Appl Pharmacol 165(3):206-216.
Paterson, S; Mackay, D. (1989) Correlation of tissue, blood, and air partition coefficients of volatile organic
chemicals. Br J Ind Med 46(5):321-328.
Pellizzari, ED; Hartwell, TD; Harris, BSH; et al. (1982) Purgeable organic compounds in mother's milk. Bull
Environ Contam Toxicol 28:322-328.
Perbellini, L; Brugnone, F; Caretta, D; et al. (1985) Partition coefficients of some industrial aliphatic hydrocarbons 5
carbon 7 carbon in blood and human tissues. Br J Ind Med 42(3): 162-167.
Poulin, P; Krishnan, K. (1996) A tissue composition-based algorithm for predicting tissue: air partition coefficients
of organic chemicals. [Erratum to document cited in CA124:109109], Toxicol Appl Pharmacol 140(2):521-522.
Poulin, P; Krishnan, K. (1996) A tissue composition-based algorithm for predicting tissue :air partition coefficients
of organic chemicals. Toxicol Appl Pharmacol 136(1): 126-130.
Research Triangle Inst. (1980) Acquisition and chemical analysis mother's milk for selected toxic substances
(December 1980). Submitted under TSCA Section 4; EPA Document No. 40-8023083; NTIS No. OTS0527479.
Research Triangle Inst. (1984) Adsorption, distribution, metabolism and excretion of cyclohexane (June 1984).
Submitted under TSCA Section 4; EPA Document No. 40-8423127; NTIS No. OTS0527475.
Savolainen, H; Pfaffli, P. (1980) Burden and dose-related neurochemical effects of intermittent cyclohexane vapour
inhalation in rats. Toxicol Lett 7(1): 17-22.
Sikkema, J; De Bont, JAM; Poolman, B. (1994) Interactions of cyclic hydrocarbons with biological membranes. J
Biol Chem 269(11):8022-8028.
Tham, R; et al. (1984) Vestibulo-ocular disturbance in rats exposed to organic solvents. Acta Pharmacol Toxicol
54(l):58-63.
Zahlsen, K; Eide, I; Nilsen, AM; et al. (1992) Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic
hydrocarbons in rat after repeated exposures. Pharmacol Toxicol 71(2): 144-149.
3.3. METABOLISM
Bernard, AM; de Russis, R; Normand, JC; et al. (1989) Evaluation of the subacute nephrotoxicity of cyclohexane
and other industrial solvents in the female Sprague-Dawley rat. Toxicol Lett 45(2-3):271-280.
Brugnone, F; Perbellini, L; Gaffuri, E; et al. (1980) Biomonitoring of industrial solvent exposures in workers
alveolar air. Int Arch Occup Environ Health 47(3): 1981).
Elliot, TH; Parker, DV; Williams, RT. (1957) Metabolism of cyclohexane-C14 and cyclohexanol. Biochem J
66:46P.
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Elliott, TH; Parke, DV; Williams, RT. (1959) Studies in detoxification. The metabolism of cyclo(14C)hexane and
its derivatives. Biochem J 72:193-200.
Fabre, R; Truhaut, R; Laham, S. (1959) Metabolism of cyclohexane in the rabbit. Compt. rend. 248:1081-1083.
Filippi, E. (1914) Physiological action and behavior of some derivatives of benzene compared to those of
cyclohexane. . Arch. Fermacol. Sper. 18:178-193.
Frontali, N; Amantini, MC; Spagnolo, A; et al. (1981) Experimental neurotoxicity and urinary metabolites of the
C5-C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin Toxicol 18(12): 1357-1367.
Ghittori, S; Imbriani, M; Pezzagno, G; et al. (1987) The Urinary Concentration of Solvents as a Biological Indicator
of Exposure: Proposal for the Biological Equivalent Exposure Limit for Nine Solvents. Am Ind Hyg Assoc J
48(9):786-790.
Gobba, F; Ghittori, S; Imbriani, M; et al. (1997) The urinary excretion of solvents and gases for the biological
monitoring of occupational exposure: A review. Sci Total Environ 199(l-2):3-12.
Governa, M; Calisti, R; Coppa, G; et al. (1987) Urinary Excretion of 2,5-Hexanedione and Peripheral
Polyneuropathies in Workers Exposed to Hexane. J Toxicol Environ Health 20(3):219-228.
James, SP; Jeffery, DJ; Waring, RH; et al. (1971) Reaction Of Mono-Bromo Derivatives Of Cyclopentane,
Cyclohexane And Cycloheptane And Of Related Compounds With Glutathione And The Nature Of The Sulphur-
Containing Metabolites Excreted. Biochem Pharmacol 20:897-907.
Metelitza, DI; Akhrem, AA; Belskii, SM; et al. (1978) Kinetic and spectral parameters of the hydrocarbons and
amines oxidation by rat liver microsomes. International Congress Series 440(Ind. Environ. Xenobiotics):40-42.
Mohn, G. (1976) Different phases of hydroxylase induction in liver microsomes during inhalation of cyclo hexane
and D,L-camphor by female mice. Hoppe Seyler'S Z Physiol Chem 357(8): 1041-1042.
Mohn, G. (1977) Characterization of different hydroxylase systems in liver microsomes of female mice by
difference binding spectra of amino pyrine. Hoppe Seyler'S Z Physiol Chem 358(10)
Mohn, G; Weber, M; Philipp, EM. (1980) The inactivation of hexobarbital induced preferably by cyclohexane
inhalation. Arzneimittelforschung 30(6):968-972.
Mortensen, B; Eide, I; Zahlsen, K; et al. (2000) Prediction of in vivo metabolic clearance of 25 different petroleum
hydrocarbons by a rat liver head-space technique. Arch Toxicol 74(6):308-312.
Mraz, J; Galova, E; Nohava, H; et al. (1994) Markers of Exposure to Cyclohexanone, Cyclohexane, and
Cyclohexanol: l,2and 1,4-Cyclohexanediol. Clin Chem 40(7): 1466-1468.
Mraz, J; Galova, E; Nohova, H; et al. (1998) 1,2- and 1,4-Cyclohexanediol: major urinary metabolites and
biomarkers of exposure to cyclohexane, cyclohexanone, and cyclohexanol in humans. Int Arch Occup Environ
Health 71(8):560-565.
Mraz, J; Galova, E; Nohova, H; et al. (1999) Effect of ethanol on the urinary excretion of cyclohexanol and
cyclohexanediols, biomarkers of the exposure to cyclohexanone, cyclohexane and cyclohexanol in humans. Scand J
Work Environ Health 25(3):233-237.
Mutti, A; Falzoi, M; Lucertini, S; et al. (1981) Absorption and alveolar excretion of cyclohexane in workers in a
shoe factory. J Appl Toxicol l(4):220-223.
Naruse, M. (1984) Effects on mice of long-term exposure to organic solvents in adhesives. Nagoya Medical Journal
Mar 28:3-4.
Perbellini, L; Brugnone, F. (1980) Lung uptake and metabolism of cyclohexane in shoe factory workers. Int Arch
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Occup Environ Health 45(3):261-269.
Perbellini, L; Brugnone, F; Gaffuri, E. (1987) Urinary Metabolite Excretion in the Exposure to Technical Hexane.
Biological Monitoring of Exposure to Chemicals. Organic Compounds, M. H. Ho andH. K. Dillon, Editors: 197-
205.
Perbellini, L; Brugnone, F; Pavan, I. (1980) Identification of the metabolites of n-hexane, cyclohexane, and their
isomers in men's urine. Toxicol Appl Pharmacol 53(2):220-229.
Perbellini, L; Brugnone, F; Silvestri, R; et al. (1981) Measurement of the urinary metabolites of N-hexane,
cyclohexane and their isomers by gas chromatography. Int Arch Occup Environ Health 48(1):99-106.
Perbellini, L; Raineri, E; Ayyad, K; et al. (1994) Recent findings on cyclohexane metabolism. Arch Sci Lav 10(3-
4):373-375.
Perico, A; Cassinelli, C; Brugnone, F; et al. (1999) Biological monitoring of occupational exposure to cyclohexane
by urinary 1,2- and 1,4-cyclohexanediol determination. Int Arch Occup Environ Health 72(2): 115-120.
Pettersson, B; Curvall, M; Enzell, CR. (1980) Effects of tobacco smoke compounds on the noradrenaline-induced
oxidative metabolism in isolated brown fat cells. Toxicology 18(1): 1981).
Research Triangle Inst. (1984) Adsorption, distribution, metabolism and excretion of cyclohexane (June 1984).
Submitted under TSCA Section 4; EPA Document No. 40-8423127; NTIS No. OTS0527475.
Savolainen, H; Pfaffli, P. (1980) Burden and dose-related neurochemical effects of intermittent cyclohexane vapour
inhalation in rats. Toxicol Lett 7(1): 17-22.
Testa, B; Jenner, P. (1976) In: Drug Metabolism: Chemical and Biochemcial Aspects. New York, NY: Marcel
Dekker, Inc.; p. 438.
Ullrich, V. (1969) On the hydroxylation of cyclohexane in rat liver microsomes. Hoppe Seylers Z Physiol Chem
350(3):357-365.
Ullrich, V; Estabrook, RW; Schadelin, J; et al. (1968) Hydroxylation of cyclohexane by rat liver microsomes.
Hoppe Seylers Z Physiol Chem 349(11):1631-1633.
Viola, PL. (1961) Research on cyclohexane metabolism. Proc. Intern. Congr. Occupational Health, 13th, New York
1960:818.
Walker, R; Flanagan, RJ; Lennard, MS; et al. (2006) Solid-phase microextraction: Investigation of the metabolism
of substances that may be abused by inhalation. J Chromatogr Sci 44(7): 3 87-3 93.
Yasugi, T; Kawai, T; Mizunuma, K; et al. (1994) Exposure monitoring and health effect studies of workers
occupationally exposed to cyclohexane vapor. Int Arch Occup Environ Health 65(5):343-350.
3.4. ELIMINATION
Bernard, AM; de Russis, R; Normand, JC; et al. (1989) Evaluation of the subacute nephrotoxicity of cyclohexane
and other industrial solvents in the female Sprague-Dawley rat. Toxicol Lett 45(2-3):271-280.
Brugnone, F; Perbellini, L. (1980) Alveolar air concentration of solvents in occupational exposure. 2nd
International Congress on Toxicology, Brussels, Belgium, July 6-11, 1980. Toxicol Letters (Amst) 0(SPEC. ISSUE
1):43.
Brugnone, F; Perbellini, L; Gaffuri, E; et al. (1980) Biomonitoring of industrial solvent exposures in workers
alveolar air. Int Arch Occup Environ Health 47(3):1981).
Deichman, W; Thomas, G. (1943) Glucuronic Acid in the Urine as a Measure of the Absorption of Certain Organic
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Compounds. J Ind Hyg Toxicol 25(7):286-292.
Dhondt, H; Goelen, E; Koppen, G; et al. (2007) Relation between ambient air and breath volatile organic
compounds. WIT Transactions on Biomedicine and Health 11 (Environmental Health Risk IV):33-40.
Elliot, TH; Parker, DV; Williams, RT. (1957) Metabolism of cyclohexane-C14 and cyclohexanol. Biochem J
66:46P.
Elliott, TH; Parke, DV; Williams, RT. (1959) Studies in detoxification. The metabolism of cyclo(14C)hexane and
its derivatives. Biochem J 72:193-200.
Fabre, R; Truhaut, R; Laham, S. (1959) Metabolism of cyclohexane in the rabbit. Compt. rend. 248:1081-1083.
Frontali, N; Amantini, MC; Spagnolo, A; et al. (1981) Experimental neurotoxicity and urinary metabolites of the
C5-C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin Toxicol 18(12): 1357-1367.
Ghittori, S; Imbriani, M; Pezzagno, G; et al. (1987) The Urinary Concentration of Solvents as a Biological Indicator
of Exposure: Proposal for the Biological Equivalent Exposure Limit for Nine Solvents. Am Ind Hyg Assoc J
48(9):786-790.
Gobba, F; Ghittori, S; Imbriani, M; et al. (1997) The urinary excretion of solvents and gases for the biological
monitoring of occupational exposure: A review. Sci Total Environ 199(l-2):3-12.
Governa, M; Calisti, R; Coppa, G; et al. (1987) Urinary Excretion of 2,5-Hexanedione and Peripheral
Polyneuropathies in Workers Exposed to Hexane. J Toxicol Environ Health 20(3):219-228.
James, SP; Jeffery, DJ; Waring, RH; et al. (1971) Reaction Of Mono-Bromo Derivatives Of Cyclopentane,
Cyclohexane And Cycloheptane And Of Related Compounds With Glutathione And The Nature Of The Sulphur-
Containing Metabolites Excreted. Biochem Pharmacol 20:897-907.
Krotoszynski, BK; Bruneau, GM; O'Neill, HJ. (1979) Measurement of chemical inhalation exposure in urban
population in the presence of endogenous effluents. Anal Toxicol 3:225-234.
Krotoszynski, BK; O'Neal, HJ. (1982) Involuntary bioaccumulation of environmental pollutants in nonsmoking
heterogenous human population. J Environ Sci Health 17:855-883.
Mraz, J; Galova, E; Nohava, H; et al. (1994) Markers of Exposure to Cyclohexanone, Cyclohexane, and
Cyclohexanol: l,2and 1,4-Cyclohexanediol. Clin Chem 40(7): 1466-1468.
Mraz, J; Galova, E; Nohova, H; et al. (1998) 1,2- and 1,4-Cyclohexanediol: major urinary metabolites and
biomarkers of exposure to cyclohexane, cyclohexanone, and cyclohexanol in humans. Int Arch Occup Environ
Health 71(8):560-565.
Mraz, J; Galova, E; Nohova, H; et al. (1999) Effect of ethanol on the urinary excretion of cyclohexanol and
cyclohexanediols, biomarkers of the exposure to cyclohexanone, cyclohexane and cyclohexanol in humans. Scand J
Work Environ Health 25(3):233-237.
Mutti, A; Falzoi, M; Lucertini, S; et al. (1981) Absorption and alveolar excretion of cyclohexane in workers in a
shoe factory. J Appl Toxicol l(4):220-223.
Naruse, M. (1984) Effects on mice of long-term exposure to organic solvents in adhesives. Nagoya Medical Journal
Mar 28:3-4.
Neighbors, SM; Coleman, DP; Baldwin, JK; et al. (1998) Dermal Absorption of [C14]Cyclohexane in Fischer 344
Rats. Toxicologist 42:390.
Perbellini, L; Brugnone, F. (1980) Lung uptake and metabolism of cyclohexane in shoe factory workers. Int Arch
Occup Environ Health 45(3):261-269.
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Perbellini, L; Brugnone, F; Gaffuri, E. (1987) Urinary Metabolite Excretion in the Exposure to Technical Hexane.
Biological Monitoring of Exposure to Chemicals. Organic Compounds, M. H. Ho andH. K. Dillon, Editors: 197-
205.
Perbellini, L; Brugnone, F; Pavan, I. (1980) Identification of the metabolites of n-hexane, cyclohexane, and their
isomers in men's urine. Toxicol Appl Pharmacol 53(2):220-229.
Perbellini, L; Brugnone, F; Silvestri, R; et al. (1981) Measurement of the urinary metabolites of N-hexane,
cyclohexane and their isomers by gas chromatography. Int Arch Occup Environ Health 48(1):99-106.
Perbellini, L; Raineri, E; Ayyad, K; et al. (1994) Recent findings on cyclohexane metabolism. Arch Sci Lav 10(3-
4):373-375.
Perico, A; Cassinelli, C; Brugnone, F; et al. (1999) Biological monitoring of occupational exposure to cyclohexane
by urinary 1,2- and 1,4-cyclohexanediol determination. Int Arch Occup Environ Health 72(2): 115-120.
Research Triangle Inst. (1984) Adsorption, distribution, metabolism and excretion of cyclohexane (June 1984).
Submitted under TSCA Section 4; EPA Document No. 40-8423127; NTIS No. OTS0527475.
Savolainen, H; Pfaffli, P. (1980) Burden and dose-related neurochemical effects of intermittent cyclohexane vapour
inhalation in rats. Toxicol Lett 7(1): 17-22.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of rabbits to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:199-.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of animals to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:323-.
Viola, PL. (1961) Research on cyclohexane metabolism. Proc. Intern. Congr. Occupational Health, 13th, New York
1960:818.
Yasugi, T; Kawai, T; Mizunuma, K; et al. (1994) Exposure monitoring and health effect studies of workers
occupationally exposed to cyclohexane vapor. Int Arch Occup Environ Health 65(5):343-350.
Yuasa, J; Kishi, R; Eguchi, T; et al. (1996) Investigation on neurotoxicity of occupational exposure to cyclohexane:
a neurophysiological study. Occup Environ Med 53(3): 174-179.
Zahlsen, K; Eide, I; Nilsen, AM; et al. (1992) Inhalation kinetics of C6 to C10 aliphatic, aromatic and naphthenic
hydrocarbons in rat after repeated exposures. Pharmacol Toxicol 71(2): 144-149.
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
Beliveau, M; Lipscomb, J; Tardif, R; et al. (2005) Quantitative structure-property relationships for interspecies
extrapolation of the inhalation pharmacokinetics of organic chemicals. Chem Res Toxicol 18(3):475-485.
4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL CONTROLS
Agnesi, R; Valentini, F; Mastrangelo, G. (1997) Risk of spontaneous abortion and maternal exposure to organic
solvents in the shoe industry. Int Arch Occup Environ Health 69(5):311-316.
Franco, G; Moglia, A; Ghittori, S. (1979) [Occupational polyneuropathy due to cyclohexane]. Med Lav 70(2): 118-
124.
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Hoogendijk, EMG; Emmen, HH. (1998) Model studies for evaluating the behavioural effects ofpetroleum solvents
and the role of the toxicokinetic factors: The effects of cyclohexane on behaviour in humanvolunteers. .
Lee, DH; Park, IG; Kim, JH; et al. (1998) Neurobehavioral changes in shoe manufacturing workers. Neurotoxicol
Teratol 20(3):259-263.
Lehmann, I; Thoelke, A; Rehwagen, M; et al. (2002) The influence of maternal exposure to volatile organic
compounds on the cytokine secretion profile of neonatal T cells. Environ Toxicol 17(3):203-210.
Mason, HJ; Wheeler, JP; Purba, JS; et al. (1994) Hepatic effects of chronic exposure to mixed solvents. Clin Chem
40(7 PART 2): 1464-1466.
Mutti, A; Falzoi, M; Lucertini, S; et al. (1981) Absorption and alveolar excretion of cyclohexane in workers in a
shoe factory. J Appl Toxicol l(4):220-223.
Wayne, LG; Orcutt, JA. (1960) The Relative Potentials Of Common Organic Solvents As Precursors Of Eye-
Irritants In Urban Atmospheres. J Occup Med 2:383-388.
Yasugi, T; Kawai, T; Mizunuma, K; et al. (1994) Exposure monitoring and health effect studies of workers
occupationally exposed to cyclohexane vapor. Int Arch Occup Environ Health 65(5):343-350.
Yuasa, J; Kishi, R; Eguchi, T; et al. (1996) Investigation on neurotoxicity of occupational exposure to cyclohexane:
a neurophysiological study. Occup Environ Med 53(3): 174-179.
4.2.	LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIO ASSAYS IN ANIMALS-
ORAL AND INHALATION
4.2.1.	Oral
4.2.2.	Inhalation
Fabre, R; Truhaut, R; Peron, M. (1952) Toxicological studies of solvents replacing benzene. I. Cyclohexane. Arch,
maladies profess, med. travail et securite sociale 13:437-448.
Haskell Laboratory. (1996) 90-Day inhalation toxicity study with cyclohexane in rats, with cover letter dated
11/18/96. Submitted under TSCA Section 4; EPA Document No. 44634; NTIS No. OTS0558873.
Haskell Laboratory. (1996) 90-Day Inhalation Toxicity Study With Cyclohexane In Mice, With Cover Letter Dated
8/16/96. Submitted under TSCA Section 4; EPA Document No. 44631; NTIS No. OTS0558870.
Khanin, AG. (1969) Pathohistological changes in the central nervous system and viscera of experimental animals
after chronic continuous inhalation of toxic substances. Trudy Tsentral'nogo Instituta Usovershenstvovaniya
Vrachei 135:97-106.
Malley, LA; Bamberger, JR; Stadler, JC; et al. (2000) Subchronic toxicity of cyclohexane in rats and mice by
inhalation exposure. Drug Chem Toxicol 23(4):513-537.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of animals to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:323-.
4.3.	REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rats, with cover letter dated
1/17/97. Submitted under TSCA Section 4; EPA Document No. 44637; NTIS No. OTS0558877.
Haskell Laboratory. (1997) Reproductive and fertility effects with cyclohexane inhalation multigeneration
reproduction study in rats, with cover letter dated 4/18/97. Submitted under TSCA Section 4; EPA Document No.
44640; NTIS No. OTS0558881.
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Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rabbits, with cover letter
dated 6/17/97. Submitted under TSCA Section 4; EPA Document No. 44641; NTIS No. OTS0558883.
Kreckmann, KH; Baldwin, JK; Roberts, LG; et al. (2000) Inhalation developmental toxicity and reproduction
studies with cyclohexane. Drug Chem Toxicol 23(4):555-573.
Kreckmann, KH; Roberts, LG; Baldwin, JK. (1998) Inhalation developmental toxicity studies of cyclohexane in rats
and rabbits. Toxicologist 42(1-S):256.
Kreckmann, KH; Roberts, LG; Staab, RJ. (1998) Inhalation multigeneration reproduction study with cyclohexane in
rats. Toxicologist 42(1-S): 105-106.
Tachi, N; Shimotori, S; Fujise, H; et al. (1994) Fetotoxic effects of exposure to the vapor of organic solvents from a
synthetic adhesive in mice. Bull Environ Contam Toxicol 53(3):471-478.
4.4. OTHER ENDPOINT-SPECIFIC STUDIES
Easley, JR; Holland, JM; Gipson, LC; et al. (1982) Renal Toxicity Of Middle Distillates Of Shale Oil And
Petroleum In Mice. Toxicol Appl Pharmacol 65(1):84-91.
Horton, AW; Bolewicz, LC; Bastad, AW; et al. (1981) Comparison of the promoting activity of pristane and n-
alkanes in skin carcinogenesis with their physical effects on micellar models of biological membranes. Biochim
Biophys Acta 648(1): 107-112.
Nizhegorodov, VM; Markhotskii, YL; Prokopovich, VK; et al. (1977) Effect of wastes from caprolactam production
(cyclohexane, cyclohexanol, cyclohexanone) on the vitamin provision of animals. Teor. Prakt. Vopr. Pitan., Mater.
Konf. Lit., Latv., Est. B. SSR: 106-108.
4.4.1. ACUTE AND SHORT-TERM TOXICITY
Anonymous. (1961) Acute Toxicity Data. Shell Chemical Company, New York 10:19611961.
Bernard, AM; de Russis, R; Normand, JC; et al. (1989) Evaluation of the subacute nephrotoxicity of cyclohexane
and other industrial solvents in the female Sprague-Dawley rat. Toxicol Lett 45(2-3):271-280.
Blokhina, EA; Dravolina, OA; Bespalov, AY; et al. (2004) Intravenous self-administration of abused solvents and
anesthetics in mice. Eur J Pharmacol 485(1-3):211-218.
Broussilowska, AI. (1936) Sensitivity of various animals to different anesthetics. Comptes Rendus des Seances de
la Societe de Biologie et de Ses Filiales 122:893-895.
Brown, VKH; Box, VL. (1971) The Influence of Some Alicyclic Hydrocarbons on the Arginase Activity of Guinea-
Pig Skin. Br J Dermatol 85(5):432-436.
Brownlee, LJ; Hollebone, BR. (1986) A Correlation of Induced Mixed-Function Oxidase Specific Activity to C-H
Bond Strengths in Partially Chlorinated Monocyclic Hydrocarbons. J Appl Toxicol 6(l):61-66.
de Wolf, W; Lieder, PH; Walker, JD. (2004) Application of QSARs: Correlation of acute toxicity in the rat
following oral or inhalation exposure. QSAR Comb Sci 23(7):521-525.
Fabre, R; Truhaut, R; Peron, M. (1952) Toxicological studies of solvents replacing benzene. I. Cyclohexane. Arch,
maladies profess, med. travail et securite sociale 13:437-448.
Fang, JF; Kitagawa, Y; Ishikawa, S; et al. (1986) Toxicity assessments of chemical substances using primary culture
of rat hepatocytes. Jpn J Ind Health 28(6):438-444.
Flury, F; Zernik, F. (1931) Schaliche gase dampfe, nebel, rauch and staubarten. Verlag von Julius Springer:257-
264.
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Gerarde, HW. (1963) Toxicological studies on hydrocarbons. IX. The aspiration hazard and toxicity of
hydrocarbons and hydrocarbon mixtures. Arch Environ Health 6(3):329-341.
Haskell Laboratory. (1995) Support, Final Report, Two week inhalation range-finding with cyclohexane in rats and
mice, with cover letter dated 6/13/96. Submitted under TSCA Section 8E; EPA Document No. 89960000172; NTIS
No. OTS0572154-1.
Hazleton Labs Inc. (1986) Letter from Phillips Petroleum Co. to U.S. EPA submitting unpublished studies on
cyclohexane with attachments. Submitted under TSCA Section 4; EPA Document NO. 40-8623065; NTIS No.
OTS0527456.
Jacobs, G; Martens, M. (1987) Evaluation of the test method for skin irritation as prescribed by oecd and eec. J
Toxicol Cutaneous Ocul Toxicol 6(3):215-226.
Jaervisalo, J; Vainio, H; Heinonen, T. (1982) Induction of hepatic monooxygenases by n-heptane and cyclohexane
inhalation. Developments in Biochemistry 23(Cytochrome P-450, Biochem., Biophys. Environ. Implic.):733-737.
Jeon, TW; Cho, HG; Yoon, CG. (2002) Effect of cyclohexane application to rat skin on the skin toxicity. Han'guk
Hwankyong Uisaeng Hakhoechi 28(2):71-80.
Kennedy, GLJ; Graepel, GJ. (1991) Acute toxicity in the rat following either oral or inhalation exposure. Toxicol
Lett (Amst) 56(3):317-326.
Kimura, ET; Ebert, DM; Dodge, PW. (1971) Acute Toxicity and Limits of Solvents Residue for Sixteen Organic
Solvents. Toxicol Appl Pharmacol 19:699-704.
Kopeika, IG. (1989) Quantitative evaluation of resistance of the body to the effect of chemical substances. Vrach
Delo 0(6): 107-109.
Launoy, L; Briul, ML. (1920) The Comparative Action of Benzene and Cyclohexane on the Hematopoietic Organs.
Comptes Rendus des Seances de la Societe de Biologie et des Filiales 83:215-217.
Lazarew, NW. (1929) The Toxicology of Gasoline. Archiv fuer Hygiene, pages:19291929.
Luan, F; Ma, W; Zhang, X; et al. (2006) Quantitative structure-activity relationship models for prediction of sensory
irritants (logRD50) of volatile organic chemicals. Chemosphere 63(7): 1142-1153.
Mohn, G; Kessler, C. (1978) Induction Of The Microsomal System Of Hydroxylases In Mouse Liver By Exposure
Of The Animals To Vapor Of Camphor Or Cyclohexane. Industrial and Environmental Xenobiotics, In Vitro
Versus In Vivo Biotransformation and Toxicity, Fouts, J. R., and I. Gut, Editors: 168-172.
Phillips Petroleum Co. (1984) Initial submission: Letter from Phillips Petroleum Co. to U.S. EPA submitting
production & processing, safety & handling and toxicity info re: cyclohexane w/attachments, dated 10/2/84.
Submitted under TSCA Section FYI; EPA Document No. FYI-OTS-0794-1039; NTIS No. OTS0001039.
RTECS. (2008) Cyclohexane. In: Registry of toxic effects on chemical substances. National Institute of
Occupational Saftey and Health. MDL Information Systems, Inc;
Schutz, E. (1960) Effects of organic liquids on the skin. Arzneimittel-Forschung 10:1027-1029.
Sugai, S; Murata, K; Kitagaki, T; et al. (1990) Studies on eye irritation caused by chemicals in rabbits. 1. A
quantitative structure-activity relationships approach to primary eye irritation of chemicals in rabbits. J Toxicol Sci
15(4):245-262.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of rabbits to cyclohexane,
methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:199-.
Treon, JF; Crutchfield, WE; Kitzmiller, KV. (1943) The physiological response of animals to cyclohexane,
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methylcyclohexane, and certain derivatives of these compounds. J Ind Hyg Toxicol 25:323-.
White Eagle Toxicology Labs. (1996) Guinea pig dermal sensitization - modified Buehler Method with cyclohexane
(H-21174), with cover letter dated 5/17/96. Submitted under TSCA Section 4; EPA Document No. 44627; NTIS
No. OTS0558861.
Yoon, C-G; Kim, H-H. (2003) Effect of cyclohexane treatment on the liver damage in CC14-pretreated rats. J
Toxicol Public Health 19(2): 105-114.
4.4.2. NEUROTOXICITY STUDIES
Bespalov, AY; Sukhotina, IA; Medvedev, 10; et al. (2003) Facilitation of electrical brain self-stimulation behavior
by abused solvents. Pharmacol BiochemBehav 75:199-208.
Blokhina, EA; Dravolina, OA; Bespalov, AY; et al. (2004) Intravenous self-administration of abused solvents and
anesthetics in mice. Eur J Pharmacol 485(1-3):211-218.
Broussilowska, AL (1936) Sensitivity of various animals to different anesthetics. Comptes Rendus des Seances de
la Societe de Biologie et de Ses Filiales 122:893-895.
Christoph, GR; Kelly, DP; Krivanek, N. (2000) Acute inhalation exposure to cyclohexane and schedule-controlled
operant performance in rats: comparison to d-amphetamine and chlorpromazine. Drug Chem Toxicol 23(4):539-
553.
Cronin, MT. (1996) Quantitative structure-activity relationship (QSAR) analysis of the acute sublethal neurotoxicity
of solvents. Toxicol In Vitro 10(2): 103-110.
De Rosa, E; Bartolucci, GB; Brighenti, F; et al. (1985) The industrial use of solvents and risk of neurotoxicity. Ann
Occup Hyg 29(3):391-398.
Donelli, G; Frontali, N; Guarcini, AM; et al. (1978) Light microscope and electron microscope observations on
peripheral nerves of rats treated with n hexane and cyclo hexane. J Submicrosc Cytol 10(1): 125-126.
Edelfors, S; Ravn-Jonsen, A. (1992) Effect of organic solvents on nervous cell membrane as measured by changes
in the calcium, magnesium ATPase activity and fluidity of synaptosomal membrane. Pharmacology & Toxicology
(Oxford, United Kingdom) 70(3): 181-187.
Fang, Z; Sonner, J; Laster, MJ; et al. (1996) Anesthetic and convulsant properties of aromatic compounds and
cycloalkanes: implications for mechanisms of narcosis. Anesth Analg 83(5): 1097-1104.
Filov, VA. (1962) Thermodynamic activity of volatile organic compounds and their action on mammals. Biofizika
7(No. l):73-79.
Flury, F; Zernik, F. (1931) Schaliche gase dampfe, nebel, rauch and staubarten. Verlag von Julius Springer:257-
264.
Frantik, E; Hornychova, M; Horvath, M. (1994) Relative acute neurotoxicity of solvents: Isoeffective air
concentrations of 48 compounds evaluated in rats and mice. Environ Res 66(2): 173-185.
Frontali, N; Amantini, MC; Spagnolo, A; et al. (1979) Poly neuropathy in rats treated with the different solvent
components of the glues used in shoe factories. 3rd European Neuroscience Meeting, Rome, Italy, Sept. 11-14,
1979. Neurosci Lett SUPPL.(3):S217.
Frontali, N; Amantini, MC; Spagnolo, A; et al. (1981) Experimental neurotoxicity and urinary metabolites of the
C5-C7 aliphatic hydrocarbons used as glue solvents in shoe manufacture. Clin Toxicol 18(12): 1357-1367.
Haskell Laboratory. (1996) Final Report, Acute operant behavior study of cyclohexane inhalation in rats, with cover
letter dated 2/16/96. Submitted under TSCA Section 4; EPA Document No. 44622; NTIS No. OTS0558850.
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Haskell Laboratory. (1996) 90-Day Inhalation neurotoxicity study with cyclohexane in rats, with cover letter dated
8/16/96. Submitted under TSCA Section 4; EPA Document No. 44631; NTIS No. OTS0558869.
Henderson, VE; Johnston, JFA. (1931) Anaesthetic Potency in the Cyclo Hydrocarbon Series. J Pharmacol Exp
Ther 43:89-92.
Khanin, AG. (1969) Pathohistological changes in the central nervous system and viscera of experimental animals
after chronic continuous inhalation of toxic substances. Trudy Tsentral'nogo Instituta Usovershenstvovaniya
Vrachei 135:97-106.
Lazarew,NW. (1929) On the toxicity of various hydrocarbon vapors. Arch Exp Pathol Pharmakol 143:223-233.
Malley, LA; Bamberger, JR; Stadler, JC; et al. (2000) Subchronic toxicity of cyclohexane in rats and mice by
inhalation exposure. Drug Chem Toxicol 23(4):513-537.
Tham, R; et al. (1984) Vestibulo-ocular disturbance in rats exposed to organic solvents. Acta Pharmacol Toxicol
54(l):58-63.
4.4.3. GENOTOXICITY STUDIES
Arimoto, S; Nakano, N; Ohara, Y; et al. (1982) A solvent effect on the mutagenicity of tryptophan-pyrolysate
mutagens in the salmonella/mammalian microsome assay. Mutat Res 102:105-112.
Hazleton Labs Inc. (1986) Letter from Phillips Petroleum Co. to U.S. EPA submitting unpublished studies on
cyclohexane with attachments. Submitted under TSCA Section 4; EPA Document NO. 40-8623065; NTIS No.
OTS0527456.
Kier, LE; Brusick, DJ; Auletta, AE; et al. (1986) The Salmonella typhimurium/mammalian microsomal assay. A
report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutation Research 168:69-240.
Kubinski, H; Gutzke, GE; Kubinski, ZO. (1981) Dna-cell-binding (deb) assay for suspected carcinogens and
mutagens. Mutat Res 89:95-136.
Litton Bionetics Inc. (1981) Mutagenicty evaluation of certified cyclohexane in the rat bone marrow cytogenetic
assay. Submitted under TSCA Section FYI; EPA Document No. FYI-AX-1081-0142; NTIS No. OTS0000142-0.
Litton Bionetics Inc. (1982) Mutagenicity evaluation of certified cyclohexane in the mouse lymphoma forward
mutation assay final report. Submitted under TSCA FYI; EPA Document No. FYI-AX-0482-0142; NTIS No.
OTS0000142-0.
Maron, D; Katzenellenbogen, J; Ames, BN. (1981) Compatibility of organic solvents with the
salmonella/microsome test. Mutat Res 88:343-350.
McCann, J; Choi, E; Yamasaki, E; et al. (1975) Detection of carcinogens as mutagens in the salmonella/microsome
test: assay of 300 chemicals. Proc Natl Acad Sci USA 72:5135-5139.
McElroy, NR; Thompson, ED; Jurs, PC. (2003) Classification of Diverse Organic Compounds That Induce
Chromosomal Aberrations in Chinese Hamster Cells. J Chem Inf Comput Sci 43(6):2111-2119.
Mortelmans, K; Haworth, S; Lawlor, T; et al. (1986) Salmonella mutagenicity tests: II. Results from the testing of
270 chemicals. Environ Mutagen 8(SUPPL 7): 1-119.
Perocco, P; Bolognesi, S; Alberghini, W. (1983) Toxic activity of seventeen industrial solvents and halogenated
compounds on human lymphocytes cultured in vitro. Toxicol Lett (Amst) 16(l-2):69-76.
Phillips Petroleum Co. (1984) Initial submission: Letter from Phillips Petroleum Co. to U.S. EPA submitting
production & processing, safety & handling and toxicity info re: cyclohexane w/attachments, dated 10/2/84.
Submitted under TSCA Section FYI; EPA Document No. FYI-OTS-0794-1039; NTIS No. OTS0001039.
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Rodolfo, C; Ornella, F; Cristina, P; et al. (1992) Genotoxicity of industrial solvents. Mutat Res 271(2): 179.
Salmeen, IT; Young, WC; Zacmanidis, P; et al. (1989) Evidence from ames assays of laboratory pulse-flame
combustor samples that direct-acting mutagens are not an inevitable consequence of hydrocarbon fuel combustion.
Mutat Res 227(1):7-12.
Shetty, GH; Rangaswamy, V. (1984) Mutagenic effects of cyclohexane in drosophila-melanogaster. Egypt J Genet
Cytol 13(1): 1985).
4.4.4.	ENDOCRINE DISRUPTION
4.4.5.	CONTACT SENSITIZATION
4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF ACTION
Brownlee, LJ; Hollebone, BR. (1986) A Correlation of Induced Mixed-Function Oxidase Specific Activity to C-H
Bond Strengths in Partially Chlorinated Monocyclic Hydrocarbons. J Appl Toxicol 6(l):61-66.
Chou, C-C; Riviere, JE; Monteiro-Riviere, NA. (2002) Differential Relationship between the Carbon Chain Length
of Jet Fuel Aliphatic Hydrocarbons and Their Ability to Induce Cytotoxicity vs. Interleukin-8 Release in Human
Epidermal Keratinocytes. Toxicol Sci 69(l):226-233.
Comba, P; Maurer, M; Vadivelu, P. (2008) Oxidation of Cyclohexane by a High-Valent Iron Bispidine Complex: A
Combined Experimental and Computational Mechanistic Study. J Phys Chem A
Dreiem, A; Myhre, O; Fonnum, F. (2002) Relationship between lipophilicity of C6-10 hydrocarbon solvents and
their ROS-inducing potency in rat cerebellar granule cells. Neurotoxicology (Little Rock) 23(6):701-709.
Dreiem, A; Myhre, O; Fonnum, F. (2003) Involvement of the extracellular signal regulated kinase pathway in
hydrocarbon-induced reactive oxygen species formation in human neutrophil granulocytes. Toxicol Appl
Pharmacol 190(2): 102-110.
Engelke, M; Tahti, H; Vaalavirta, L. (1996) Perturbation of artificial and biological membranes by organic
compounds of aliphatic, alicyclic and aromatic structure. Toxicol In Vitro 10(2): 111-115.
Gupta, KP; Mehrotra, NK. (1990) Mouse skin ornithine decarboxylase induction and tumor promotion by
cyclohexane. Cancer Lett 51(3):227-233.
Hermans, I; Jacobs, P; Peeters, J. (2007) The formation of byproducts in the autoxidation of cyclohexane.
Chemistry 13(3):754-761.
Hermans, I; Peeters, J; Jacobs, PA. (2008) Origin of byproducts during the catalytic autoxidation of cyclohexane. J
Phys Chem A 112(8): 1747-1753.
Horton, AW; Bolewicz, LC; Bastad, AW; et al. (1981) Comparison of the promoting activity of pristane and n-
alkanes in skin carcinogenesis with their physical effects on micellar models of biological membranes. Biochim
Biophys Acta 648(1): 107-112.
Kim, B-R; Yoon, C-G; Hyun, GC. (2006) Ultrastructural Changes of Endoplasmic Reticulum on Hepatocytes by
Cyclohexane Injection in Alcohol-pretreated Rats. Korean J. Electron Microscopy 36(4):291-297.
King, JR; Monteiro-Riviere, NA. (1991) Effects of organic solvent vehicles on the viability and morphology of
isolated perfused porcine skin. Toxicology 69(1): 11-26.
Kopeika, IG. (1989) Quantitative evaluation of resistance of the body to the effect of chemical substances. Vrach
Delo 0(6): 107-109.
Maldotti, A; Molinari, A; Amadelli, R; et al. (2008) Photocatalytic activity of MCM-organized TiO(2) materials in
the oxygenation of cyclohexane with molecular oxygen. Photochem Photobiol Sci 7(7):819-825.
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Mohn, G; Philipp, EM. (1981) Effects Of Syphacia Muris And The Anthelmintic Fenbendazole On The Microsomal
Monooxygenase System In Mouse Liver. Lab Anim 15(2):89-94.
Naskali, L; Engelke, M; Tahti, H; et al. (1993) The effects of selected organic solvents on rat synaptosomal
membrane fluidity and integral enzyme activities. Neurosci Res Commun 13(l):27-35.
Naskali, L; Oksanen, H; Tahti, H. (1994) Astrocytes as targets for CNS effects of organic solvents in vitro.
Neurotoxicology (Little Rock) 15(3):609-612.
Naskali, L; Tahti, H. (1993) Astrocytes as targets for ens effects of organic solvents in vitro. Fourth Meeting of the
International Neurotoxicology Association, Helsingor, Denmark, June 6-11, 1993. Neurotoxicology (Little Rock)
14(4):546.
Nesnow, S; Garland, H; Curtis, G. (1984) Inhibition and enhancement of oncogenic cell transformation in
C3H10T1/2C18 cells. Report (EPA/600/D-84/277; Order No. PB85-124709/GAR):14 pp., Gov.
Pettersson, B; Curvall, M; Enzell, CR. (1980) Effects of tobacco smoke compounds on the noradrenaline-induced
oxidative metabolism in isolated brown fat cells. Toxicology 18(1): 1981).
Senler, TI; Dean, WL; Pierce, WM, Jr.; et al. (1985) Procedures for measuring cytochrome P-450-dependent
hydroxylation activity in reproductive tissues. Anal Biochem 144(1): 152-158.
Senler, TI; Hofmann, GE; Sanfilippo, JS; et al. (1985) Cytochrome P-450 activity in human leiomyoma and normal
myometrium. Am J Obstet Gynecol 153(5):551-555.
Sikkema, J; De Bont, JA; Poolman, B. (1995) Mechanisms of membrane toxicity of hydrocarbons. Microbiol Rev
59(2):201-222.
Sikkema, J; De Bont, JAM; Poolman, B. (1994) Interactions of cyclic hydrocarbons with biological membranes. J
Biol Chem 269(11):8022-8028.
Tahti, H; Engelke, M; Vaalavirta, L. (1996) Mechanisms of the CNS depressing effects of organic solvents. 11th
Biennial Meeting of the International Society for Developmental Neuroscience, Tampere, Finland, July 30-August
3, 1996. International Journal of Developmental Neuroscience 14(SUPPL. 1):95.
Tahti, H; Naskali, L. (1992) The effects of organic solvents on neural membrane integral protein tested in neural cell
cultures. Neurosci Res Commun 10(2):71-77.
Thalhammer, T; Kaschnitz, R; Mittermayer, K; et al. (1993) Organic Solvents Increase Membrane Fluidity and
Affect Bile Flow and K+ Transport in Rat Liver. Biochem Pharmacol 46(7): 1207-1215.
Uribe, S; Rangel, P; Espinola, G; et al. (1990) Effects of cyclohexane, an industrial solvent, on the yeast
Saccharomyces cerevisiae and on isolated yeast mitochondria. Appl Environ Microbiol 56(7):2114-2119.
Vaalavirta, L; Tahti, H. (1995) Effects of selected organic solvents on the astrocyte membrane ATPase in vitro.
Clin Exp Pharmacol Physiol 22(4):293-294.
Wang, H; Yang, H; Chuang, W; et al. (2007) Pyrolysis mechanism of carbon matrix precursor cyclohexane~the
formation of condensed-ring aromatics and the growing process of molecules. J Mol Graph Model 25(6):824-830.
Yoon, C-G; Kim, H-H. (2003) Effect of cyclohexane treatment on the liver damage in CC14-pretreated rats. J
Toxicol Public Health 19(2): 105-114.
4.6. SYNTHESIS OF MAJOR NONCANCER EFFECTS
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3 4.6.2. Inhalation
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5 4.6.3. Mode of Action Information
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7 4.7. EVALUATION OF CARCINOGENICITY
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9 4.7.1. Summary of Overall Weight-of-Evidence
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11 4.7.2. Synthesis of Human, Animal, and Other Supporting Evidence
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13 4.7.3. Mode of Action Information
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15 4.7.2.1. Hypothesized Mode of Action
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17 4.7.2.2. Experimental Support for the Hypothesized Mode of Action
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19 4.7.2.3. Other Possible Modes of Action
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21 4.7.2.4. Conclusions About the Hypothesized Mode of Action
22
23 Support for the hypothesized mode of action in test animals
24 Relevance of the hypothesized mode of action to humans
25 Populations or lifestages particularly susceptible to the hypothesized mode of action
26
27 4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES
28
29 4.8.1 POSSIBLE CHILDHOOD SUSCEPTIBILITY
30
31 Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rats, with cover letter dated
32 1/17/97. Submitted under TSCA Section 4; EPA Document No. 44637; NTIS No. OTS0558877.
33
34 Haskell Laboratory. (1997) Reproductive and fertility effects with cyclohexane inhalation multigeneration
35 reproduction study in rats, with cover letter dated 4/18/97. Submitted under TSCA Section 4; EPA Document No.
36 44640; NTIS No. OTS0558881.
37
38 Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rabbits, with cover letter
39 dated 6/17/97. Submitted under TSCA Section 4; EPA Document No. 44641; NTIS No. OTS0558883.
40
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Kreckmann, KH; Baldwin, JK; Roberts, LG; et al. (2000) Inhalation developmental toxicity and reproduction
studies with cyclohexane. Drug Chem Toxicol 23(4):555-573.
Lehmann, I; Thoelke, A; Rehwagen, M; et al. (2002) The influence of maternal exposure to volatile organic
compounds on the cytokine secretion profile of neonatal T cells. Environ Toxicol 17(3):203-210.
Pellizzari, ED; Hartwell, TD; Harris, BSH; et al. (1982) Purgeable organic compounds in mother's milk. Bull
Environ Contam Toxicol 28:322-328.
Research Triangle Inst. (1980) Acquisition and chemical analysis mother's milk for selected toxic substances
(December 1980). Submitted under TSCA Section 4; EPA Document No. 40-8023083; NTIS No. OTS0527479.
4.8.2.	POSSIBLE GENDER DIFFERENCES
Haskell Laboratory. (1996) 90-Day Inhalation neurotoxicity study with cyclohexane in rats, with cover letter dated
8/16/96. Submitted under TSCA Section 4; EPA Document No. 44631; NTIS No. OTS0558869.
Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rats, with cover letter dated
1/17/97. Submitted under TSCA Section 4; EPA Document No. 44637; NTIS No. OTS0558877.
Haskell Laboratory. (1997) Reproductive and fertility effects with cyclohexane inhalation multigeneration
reproduction study in rats, with cover letter dated 4/18/97. Submitted under TSCA Section 4; EPA Document No.
44640; NTIS No. OTS0558881.
Haskell Laboratory. (1997) Inhalation developmental toxicity study of cyclohexane in rabbits, with cover letter
dated 6/17/97. Submitted under TSCA Section 4; EPA Document No. 44641; NTIS No. OTS0558883.
Kreckmann, KH; Baldwin, JK; Roberts, LG; et al. (2000) Inhalation developmental toxicity and reproduction
studies with cyclohexane. Drug Chem Toxicol 23(4):555-573.
Malley, LA; Bamberger, JR; Stadler, JC; et al. (2000) Subchronic toxicity of cyclohexane in rats and mice by
inhalation exposure. Drug Chem Toxicol 23(4):513-537.
4.8.3.	Other
5. DOSE-RESPONSE ASSESSMENTS
5.1. ORAL REFERENCE DOSE (RfD)
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5.1.1. Choice of Principal Study and Critical Effect—with Rationale and Justification
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5.1.2. Methods of Analysis—Including Models (PBPK, BMD, etc.)
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5.1.3. RfD Derivation—Including Application of Uncertainty Factors (UFs)
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5.1.4. Previous RfD Assessment (if any)]
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5.2.	INHALATION REFERENCE CONCENTRATION (RfC)
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5.2.1.	Choice of Principal Study and Critical Effect—with Rationale and Justification
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5.2.2.	Methods of Analysis—Including Models (PBPK, BMD, etc.)
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5.2.3.	RfC Derivation—Including Application of Uncertainty Factors (UFs)
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5.2.4.	Previous RfC Assessment (if any)]
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5.3.	CANCER ASSESSMENT
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5.3.1. Choice of Study/Data—with Rationale and Justification
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5.3.2.	Dose-response Data
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5.3.3.	Dose Conversion
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5.3.4. Extrapolation Method(s)
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6. MAJOR CONCLUSIONS IN Till CHARACTERIZATION OF HAZARD AND DOSE
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6.1.	HUMAN HAZARD POTENTIAL
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6.2.	DOSE RESPONSE
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