Annotated Reference Outline for the Toxicological Review of N-heptane (cas No. 142-82-5) in Support of Summary Information on the Integrated Risk Information System (iris)


DRAFT - DO NOT CITE OR QUOTE	lNCEA tradan" dr"f's
or EPA ID for final]
www.epa.gov/iris
4>EPA
ANNOTATED REFERENCE OUTLINE
FOR THE TOXICOLOGICAL REVIEW
OF
n-Heptane
(CAS No. 142-82-5)
In Support of Summary Information on the
Integrated Risk Information System (IRIS)
12/12/08
[author: insert current date for this draft or Agency completion date (month and year) iffinal]
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 AND SECONDARY SOURCES
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. Chem Res Toxicol 18: 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.
ACGIH (American Conference of Governmental Industrial Hygienists). (2001) Heptane, all
isomers. In: Documentation of the threshold limit values and biological exposure indices.
Cincinnati, OH: American Conference of Government Industrial Hygienists.
ACGIH. (2007) Heptane, all isomers. In: Threshold limit values for chemical substances and
physical agents and biological exposure indices. Cincinnati, OH: American Conference of
Governmental Industrial Hygienists; pp. 32.
Beall, JR; Ulsamer, AG. (1981) Toxicity of volatile organic compounds present indoors. Bull N
Y Acad Med 57(10):978-996.
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.
Bingham, E; Cohrssen, B; Powell, CH. (2001) Patty's toxicology. 5th edition. New York, NY:
John Wiley and Sons; pp. 47.
Bos, PM; Zwart, A; Reuzel, PG; et al. (1992) Evaluation of the sensory irritation test for the
assessment of occupational health risk. Crit Rev Toxicol 21(6):423-450.
Dutch Expert Committee On Occupational Standards. (1993) Health-based recommended
occupational exposure limit for n-heptane. Directorate General of Labour, The Netherlands Vol.
6
Engel Hansen, L; Jelnes, JE. (1996) Occupational exposure limits: Criteria document for
heptane. Luxembourg: Commission of the European Communities. 16866(30)
Fichera, G; Inserra, A; Parlato, G. (1968) [Hydrocarbon poisonings. 3. Anatomo-pathological
findings in experimental heptane poisonings]. Folia Med (Napoli) 51(11):854-858.
Hau, KM; Connell, DW; Richardson, BJ. (1999) Mechanism of acute inhalation toxicity of
alkanes and aliphatic alcohols. Environ Toxicol Pharmacol 7(3): 159-167.
Hau, KM; Connell, DW; Richardson, BJ. (2000) Use of partition models in setting health
guidelines for volatile organic compounds. Regul Toxicol Pharmacol 31(l):22-29.
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Hume, AS; Ho, IK. (1994) Toxicity of solvents. In: Cockerham, LG; Shane, BS; eds. Basic
environmental toxicology. Boca Raton, FL: CRC Press, Inc.; pp. 157-184.
IPCS/CEC (International Programme on Chemical Safety, Commission of the European
Communities). (2001). n-Heptane. In international chemical safety card (ICSC). International
Programme on Chemical Safety, Commission of the European Communities. Available online at
http://www.inchem.org/documents/icsc/icsc/eics0657.htm (accessed on November 13, 2008).
Laine, R. (1999) N-heptane. In: Health effects of selected chemicals. Vol. 4-5. Copenhagen:
Nordic Council of Ministers; pp. 253-268.
Lewis, RJ. (1996) Sax's dangerous properties of industrial materials. 9th edition. New York,
NY: Van Nostrand Reinhold; pp. 1770.
Lundberg, P; Lof, A; Johanson, G; et al. (1991) New Swedish occupational standards for some
organic solvents. Am J Ind Med 19(5):559-567.
NIOSH (National Institute for Occupational Safety and Health ). (1977) Criteria for a
recommended standard. Occupational exposure to alkanes (C5-C8). Cincinnati, OH: U.S.
Department of Health, Education, and Welfare. National Institute for Occupational Safety and
Health. PB273817.
NIOSH (National Institute for Occupational Safety and Health). (2008) NIOSH pocket guide to
chemical hazards. Washington, DC: National Institute for Occupational Safety and Health.
Oettel, H. (1936) Effect of organic liquids on the skin. Arch Exp Pathol Parmacal 83:641-696.
OSHA (Occupational Safety and Health Administration). (2008) Table Z-l: Limits for air
contaminants. Occupational Safety and Health Administration. Available online at
http://www.gpoaccess.gov/ecfr (accessed on November 20, 3008)
Patty, FA; Yant, WP. (1929) Odor intensity and symptoms produced by commercial propane,
butane, pentane, hexane, and heptane vapor. Pittsburgh, PA: Department of Commerce, U.S.
Bureau of Mines.
Rodolfo, C; Ornella, F; Cristina, P; et al. (1992) Genotoxicity of industrial solvents. MutatRes
271(2): 179.
Sheftel, VO. (2000) Indirect food additives and polymers. 1st edition. Boca Raton, FL: Lewis
Publishers; pp. 738.
Sikkema, J; De Bont, JA; Poolman, B. (1995) Mechanisms of membrane toxicity of
hydrocarbons. Microbiol Rev 59(2):201-222.
Tabershaw, IR; Utidjian, HMD; Kawahara, BL. (1977) Chemical hazards. In: Occupational
Diseases, A Guide to Their Recognition, Revised Edition. National Institute for Occupational
Safety and Health, U.S. Department of Health, Education, and Welfare.
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1	U.S. EPA (Environmental Protection Agency). (1989). Health and environmental effects
2	document for N-heptane. Cincinnati,OH: Environmental Protection Agency.
3
4	Von Oettingen, WF. (1940) Toxicity and potential dangers of aliphatic and aromatic
5	hydrocarbons. A critical review of the literature U.S. Public Health Bulletin, No 255(135):318.
6
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1	2. CHEMICAL AND PHYSICAL INFORMATION
2
3	O'Neil, MJ. (2001) The merck index - an encyclopedia of chemicals, drugs, and biologicals.
4	13th edition. Whitehouse Station, NJ: Merck and Co. Inc.; pp. 832.
5
6
7
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3. TOXICOKINETICS
3.1. ABSORPTION
Dahl, AR; Damon, EG; Mauderly, JL; et al. (1988) Uptake of 19 hydrocarbon vapors inhaled by
F344 rats. Fundam Appl Toxicol 10(2):262-269.
Roemmelt, H; Dirnagl, K. (1977) Pulmonary absorption of six hydrocarbons in relation to their
concentration in inspired air. Muenchener Medizinische Wochenschrift 119(11):367-368.
Singh, SK; Zhao, K; Singh, Jl. (2002). In vitro permeability and binding of hydrocarbons in pig
ear and human abdominal skin. Drug Chem Toxicol 25(1): 83-92.
Singh, S; Zhao, K; Singh, J. (2003) In vivo percutaneous absorption, skin barrier perturbation,
and irritation from JP-8 jet fuel components. Drug Chem Toxicol 26(2): 135-146.
Tsuruta, H. (1982) Percutaneous absorption of organic solvents: 3. Penetration rates of
hydrophobic solvents through excised rat skin. Ind Health 20(4):335-345.
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. (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.
Babanov, GP; Abramian, GG; Artem'eva, GN; et al. (1988) [Effect of elevated temperature on
animals' sensitivity to n-pentane, n-hexane, n-heptane, n-octane and toluene and their distribution
in the tissues]. Gig Tr Prof Zabol (10):23-25.
Babanov, GP; Abramyan, GG; Artem'eva, GN; et al. (1983) Toxicity and quantity of n-heptane
in tissues of experimental animals after exposure to n-heptane at high temperature. Gig Tr Prof
Zabol (9):53-55.
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.
Fateev, VA; Titov, NS; Saliaev, VN. (1984) [General inhalant anesthetics: The dependence of
the narcotic effect on the concentration in the brain], Farmakol Toksikol 47(4): 15-18.
Hansen, C; Andersen, B. (1988) The affinities of organic solvents in biological systems. Am Ind
Hyg Assoc J 49(6):301-308.
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Perbellini, L; Brugnone, F; Caretta, D; et al. (1985) Partition coefficients of some industrial
aliphatic hydrocarbons (C5-C7) in blood and human tissues. Brit J Ind Med 42(3): 162-167.
Perbellini, L; Brugnone, F; Cocheo, V; et al. (1986) Identification of the n-heptane metabolites in
rat and human urine. Arch Toxicol 58(4):229-234.
Zahlsen, K; Eide, I; Nilsen, AM; et al. (1992) Inhalation kinetics of C6 to CIO aliphatic,
aromatic and naphthenic hydrocarbons in rat after repeated exposures. Pharmacol Toxicol
71(2): 144-149.
3.3. METABOLISM
Bahima, J; Cert, A; Menendez-Gallego, M. (1984) Identification of volatile metabolites of
inhaled n-heptane in rat urine. Toxicol Appl Pharmacol 76(3):473-482.
Filser, JG; Csanady, GA; Dietz, W; et al. (1996) Comparative estimation of the neurotoxic risks
of n-hexane and n-heptane in rats and humans based on the formation of the metabolites
2,5-hexanedione and 2,5-heptanedione. Adv Exp Med Biol 387:411-427.
Frommer, U; Ullrich, V; Staudinger, H; et al. (1972) The monooxygenation of n-heptane by rat
liver microsomes. Biochim Biophys Acta 280:487-494.
Jaervisalo, J; Vainio, H; Heinonen, T. (1982) Induction of hepatic monooxygenases by n-heptane
and cyclohexane inhalation. Developments in Biochemistry (Cytochrome P-450, Biochem.,
Biophys. Environ. Implic.) 23:733-737.
Notten, WR; Henderson, PT. (1975) Action of n-alkanes on drug-metabolizing enzymes from
guinea-pig liver. Biochem Pharmacol 24(10): 1093-1097.
Perbellini, L; Brugnone, F; Cocheo, V; et al. (1986) Identification of the n-heptane metabolites in
rat and human urine. Arch Toxicol 58(4):229-234.
Stormer, AGC. (1997) Pyrrols and 2,5-heptanedione in rat urine and 2,5-heptanedione in
humans. Analytical determination of the excretion after exposure to n-heptane. GSF-Bericht
(14/97): 1-135 pp.
Sturaro, A; Parvoli, G; Doretti, L; et al. (1997) Biological monitoring of exposure to n-heptane
by gas chromatographic/mass spectrometric determination of its metabolites. Biomarkers
2(3): 189-192.
Szutowski, MM; Rakoto, JS. (2005) Formation of heptanediones by the rat liver monooxygenase
system with cytochrome p450. Toxicol Lett (Shannon) 158(Suppl. 1):S48.
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3.4. ELIMINATION
Bahima, J; Cert, A; Menendez-Gallego, M. (1984) Identification of volatile metabolites of
inhaled n-heptane in rat urine. Toxicol Appl Pharmacol 76(3):473-482.
Filser, JG; Csanady, GA; Dietz, W; et al. (1996) Comparative estimation of the neurotoxic risks
of n-hexane and n-heptane in rats and humans based on the formation of the metabolites 2,5-
hexanedione and 2,5-heptanedione. Adv Exp Med Biol 387:411-427.
Perbellini, L; Brugnone, F; Cocheo, V; et al. (1986) Identification of the n-heptane metabolites in
rat and human urine. Arch Toxicol 58(4):229-234.
Stormer, AGC. (1997) Pyrrols and 2,5-heptanedione in rat urine and 2,5-heptanedione in
humans. Analytical determination of the excretion after exposure to n-heptane. GSF-Bericht
(14/97): 1-135.
Sturaro, A; Parvoli, G; Doretti, L; et al. (1997) Biological monitoring of exposure to n-heptane
by gas chromatographic/mass spectrometric determination of its metabolites. Biomarkers
2(3): 189-192.
3.5. PHYSIOLOGICALLY BASED TOXICOKINETIC MODELS
Kessler, W; Kreuzer, P; Csanady, GA. (1992) Inhalation pharmacokinetics of n heptane in rat
and man. Naunyn-Schmiedeberg's Arch Pharmacol 345(Suppl. 1):R31.
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4. HAZARD IDENTIFICATION
4.1. STUDIES IN HUMANS—EPIDEMIOLOGY, CASE REPORTS, CLINICAL
CONTROLS
Burkhart, KK; Britt, A; Petrini, G; et al. (1996) Pulmonary toxicity following exposure to an
aerosolized leather protector. J Toxicol Clin Toxicol 34(l):21-24.
Cesaro, AN; Granata, A. (1955) [Blood cytochemical research on peripheral blood in
occupational benzine and heptane poisoning.]. Acta Histochem 2(3-4):88-96.
Cirla, P. (1960) Relative health hazards of benzene and heptane in a rubber factory. A clinical
study. Rassegna di Medicina Industriale 29:276-287.
Crespi, V; Di Costanzo, M; Ferrario, F; et al. (1979) Electrophysiological findings in workers
exposed to n-heptane fumes. J Neurol 222(2): 135-138.
Fichera, G; Inserra, A; Parlato, G. (1968) [Hydrocarbon poisonings. 3. Anatomo-pathological
findings in experimental heptane poisonings]. Folia Med (Napoli) 51(11):854-858.
Mason, HJ; Wheeler, JP; Purba, JS; et al. (1994) Hepatic effects of chronic exposure to mixed
solvents. Clin Chem 40(7): 1464-1466.
Paolino, W; Resegotti, L. (1961) Chronic ligroine poisoning. Pathological signs in workers
exposed to hexane-heptane vapors. Minerva Medica 52:1665-1672.
Soleo, L; Coratelli, A; Iacovone, MT; et al. (1987) [Neurophysiological study of a group of
workers exposed to industrial heptane in a rubber shoe factory], Med Lav 78(l):68-74.
Valentini, F; Agnesi, R; Dal Vecchio, L; et al. (1994) Does n-heptane cause peripheral
neurotoxicity? A case report in a shoemaker. Occup Med (Lond) 44(2): 102-104.
Valentini, F; Agnesi, R; Dal Vecchio, L; et al. (1994) [Exposure to glues containing technical
heptane: A clinical and electrophysiological study], Med Lav 85(6):514-521.
4.2. LESS-THAN-LIFETIME AND CHRONIC STUDIES AND CANCER BIOASSAYS
IN ANIMALS—ORAL AND INHALATION
4.2.1. ORAL
Eastman Kodak Co. (1979) Repeated oral administration of five ketones and n-heptane to rats
with cover letter dated 021594. TSCA Section 8D. OTS 0556692.
Eastman Kodak Co. (1992) 90-day Repeated Oral Administration of five ketones and n-heptane
to rats. TSCA Section 8E. OTS 0571116.
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4.2.2. INHALATION
Albemarle Corp. (1980) Whole-animal bioassays with n-heptane and toluene, with cover letter
dated 03/23/94. Performed by Yeshiva University. TSCA Section 8D. OTS 0556825.
Albemarle Corp. (1980) A 26 week inhaltion toxicity study of heptane in the rat with cover letter
dated 03/23/94. Performed by Bio/Dynamics Inc. TSCA Section 8D. OTS 0556826.
Bahima, J; Cert, A; Menendez-Gallego, M. (1984) Identification of volatile metabolites of
inhaled n-heptane in rat urine. Toxicol Appl Pharmacol 76(3):473-482.
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. 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.
Simonsen, L; Lund, SP. (1995) Four weeks inhalation exposure to n-heptane causes loss of
auditory sensitivity in rats. Pharmacol Toxicol 76(l):41-46.
Takeuchi, Y; Ono, Y; Hisanaga, N; et al. (1980) A comparative study on the neurotoxicity of n-
pentane, n-hexane, and n-heptane in the rat. Br J Ind Med 37(3):241-247.
Takeuchi, Y; Ono, Y; Hisanaga, N; et al. (1981) A comparative study of the toxicity of n-
pentane, n-hexane, and n-heptane to the peripheral nerve of the rat. Clin Toxicol 18(12): 1395-
1402.
Truhaut, R; Laget, P; Piat, G; et al. (1973) First electrophysiological results after experimenetal
intoxication of the albino rat with technical hexane and heptane. Arch Mai Prof 34(7-8):417-
426.
4.3.	REPRODUCTIVE/DEVELOPMENTAL STUDIES—ORAL AND INHALATION
Brown-Woodman, PD; Webster, WS; Huq, F; et al. (1995) Induction of birth defects by
exposure to solvents: An in vitro study. Teratology 51(4):288.
4.4.	OTHER ENDPOINT-SPECIFIC STUDIES
4.4.1. ACUTE AND SHORT-TERM TOXICITY
Anonymous. (1952) Table VII toxicity tests. In: Chemical Biological Coordination Center,
Summary Biological Tests. Vol 4. National Research Council; pp. 106-111.
Babanov, GP; Abramian, GG; Artem'eva, GN; et al. (1988) [Effect of elevated temperature on
animals' sensitivity to n-pentane, n-hexane, n-heptane, n-octane and toluene and their distribution
in the tissues]. Gig Tr Prof Zabol (10):23-25.
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Babanov, GP; Abramyan, GG; Artem'eva, GN; et al. (1983) Toxicity and quantity of n-heptane
in tissues of experimental animals after exposure to n-heptane at high temperature. Gig Tr Prof
Zabol (9):53-55.
Dow Corning Co. (1953) Acute inhaltion toxicity of masonry water repellents and constituents-
heptane, with cover letter dated 030394. Performed by Hazleton Laboratories. TSCA Section
8D. OTS 0556733.
Goel, SK; Rao, GS; Pandya, KP. (1982) Toxicity of n-hexane and n-heptane: Some biochemical
changes in liver and serum. Toxicol Lett 14(3-4): 169-174.
Goel, SK; Rao, GS; Pandya, KP. (1988) Hepatotoxic effects elicited by n-hexane or n-heptane. J
Appl Toxicol 8(2):81-84.
Gonczi, L; Strohmayer, A; Palovics, A; et al. (2000) Acute effects of inhalation exposure to
organic solvents in rats. Cent Eur J Public Health 8(Suppl.):77-78.
Inserra, A; Parlato, G; Gesue, V. (1968) Blood indexes and experimental intoxication with
heptane. Bollettino della Societa Medico-Chirurgica di Catania 36(l-4):87-96.
Jaervisalo, J; Vainio, H; Heinonen, T. (1982) Induction of hepatic monooxygenases by n-heptane
and cyclohexane inhalation. Developments in Biochemistry (Cytochrome P-450, Biochem.,
Biophys. Environ. Implic.) 23:733-737.
Jeppsson, R. (1975) Parabolic relation between lipophilicity and biological activity of aliphatic
hydrocarbons, ethers, and ketones after intravenous injections of emulsion formulations into
mice. Acta Pharmacol Toxicol (Copenh) 37(l):56-64.
Kristiansen, U; Nielsen, GD. (1988) Activation of the sensory irritant receptor by C7-C11
n-alkanes. Arch Toxicol 61(6):419-425.
Lazarev, NV; Brusilovaskaya, Al. (1934) Dependence on the effect of volatile narcotics on
exposure and concentration. Fiziologicheskii Zhurnal SSSR 17(3):611-619.
Phillips Petroleum Co. (1982) Acute inhalation toxicity test of n-heptane in rats, final report,
with cover letter dated 030894. Performed by Hazleton Laboratories Amer Inc. TSCA Section
8D. OTS 0556754.
Singh, S; Zhao, K; Singh, J. (2003) In vivo percutaneous absorption, skin barrier perturbation,
and irritation from JP-8 jet fuel components. Drug Chem Toxicol 26(2): 135-146.
Swann, HE; Kwon, BK; Hogan, GK; et al. (1974) Acute inhalation toxicology of volatile
hydrocarbons. Am Ind Hyg Assoc J 35(9):511-518.
Tsobkallo, GI. (1974) The influence of certain hydrocarbons included in the composition of
gasoline on the respiration and blood pressure. Farmakologiia i Toksikologiia 10(l):23-30.
Yamada, C. (1980) Pathomorphological changes in the poisoning of hydrocarbons: Benzene,
toluene, p-xylene and n-heptane. J Tokyo Med Coll 38(5): 1981.
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Yamashita, M; Tanaka, J. (1995) Pulmonary collapse and pneumonia due to inhalation of a
waterproofing aerosol in female CD-I mice J Toxicol Clin Toxicol 33(6):631-637.
4.4.2 GENOTOXICITY STUDIES
Brooks, TM; Meyer, AL; Hutson, DH. (1988) The genetic toxicology of some hydrocarbon and
oxygenated solvents. Mutagenesis 3(3):227-232.
Rodolfo, C; Ornella, F; Cristina, P; et al. (1992) Genotoxicity of industrial solvents. MutatRes
271(2): 179.
4.4.3. NEUROTOXICITY STUDIES
Edelfors, S; Ravn-Jonsen, A. (1992) Effect of organic solvents on nervous cell membrane as
measured by changes in the (Ca2+/Mg2+) ATPase activity and fluidity of synaptosomal
membrane. Pharmacol Toxicol 70(3): 181-187.
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4.4.4. ENDOCRINE DISRUPTION
4.4.5. CONTACT SENSITIZATION
4.5. MECHANISTIC DATA AND OTHER STUDIES IN SUPPORT OF THE MODE OF
ACTION
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4.6.	SYNTHESIS OF MAJOR NONCANCER EFFECTS
4.6.1.	Oral
4.6.2.	Inhalation
4.6.3.	Mode of Action Information
4.7.	EVALUATION OF CARCINOGENICITY
4.7.1.	Summary of Overall Weight-of-Evidence
4.7.2.	Synthesis of Human, Animal, and Other Supporting Evidence
4.7.3.	Mode of Action Information
4.7.2.1.	Hypothesized Mode of Action
4.7.2.2.	Experimental Support for the Hypothesized Mode of Action
4.7.2.3.	Other Possible Modes of Action
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1	4.7.2.4. Conclusions About the Hypothesized Mode of Action
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3	Support for the hypothesized mode of action in test animals
4	Relevance of the hypothesized mode of action to humans
5	Populations or lifestages particularly susceptible to the hypothesized mode of action
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7	4.8. SUSCEPTIBLE POPULATIONS AND LIFE STAGES
8
9	4.8.3. OTHER
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