United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/049F
Final
2-04-2009
Provisional Peer-Reviewed Toxicity Values for
77-Propylbenzene
(CASRN 103-65-1)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw
body weight
cc
cubic centimeters
CD
Caesarean Delivered
CERCLA
Comprehensive Environmental Response, Compensation and Liability Act

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ft-PROPYLBENZENE (CASRN 103-65-1)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
//-Propylbenzene (Figure 1) is an alkyl aromatic hydrocarbon that occurs naturally in coal
and petroleum.
IRIS (U.S. EPA, 2008), the Health Effects Assessment Summary Tables (HEAST; U.S.
EPA, 1997a) and the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006) do
not report noncancer or cancer assessments for ^-propylbenzene. The Chemical Assessments
and Related Activities (CARA) list (U.S. EPA, 1991, 1994) includes a Drinking Water Health
Advisory for //-propylbenzene (U.S. EPA 1987) that characterizes the data for this compound as
inadequate for risk assessment. ^-Propylbenzene has not been assessed by the Agency for Toxic
Substances and Disease Registry (ATSDR, 2008), the International Agency for Research on
Cancer (IARC, 2008), or the International Programme on Chemical Safety (IPCS, 2008). The
National Toxicology Program (NTP) has not evaluated the toxicity or carcinogenicity of this
compound (NTP, 2008), and ^-propylbenzene is not included in the 11th Report on Carcinogens
(NTP, 2005). No occupational exposure limits have been established for //-propylbenzene
(ACGIH, 2007; NIOSH, 2008a,b; OSHA, 2008).
To identify toxicological information pertinent to the derivation of provisional toxicity
values for //-propylbenzene, literature searches were conducted in December 2007 using the
following databases: MEDLINE, TOXLINE, DART/ETIC, BIOSIS (January 2000-December
2007), TSCATS1/2, GENETOX, CCRIS, HSDB, RTECS and Current Contents (July -
December, 2007). Except where noted, the literature searches were not limited by date. An
INTRODUCTION
Figure 1. Structure of n-Propylbenzene
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updated literature search was conducted from December 2007 through November 2008 using
PubMed. No relevant papers were identified.
REVIEW OF PERTINENT DATA
Human Studies
No data specifically relating exposure to //-propylbenzene with health effects in humans
were located. NAS (1977) reported that in humans, //-propylbenzene is irritating to mucous
membranes, eyes, nose, throat and skin, and that systemically it causes depression of the central
nervous system, headache, anorexia, muscular weakness, incoordination, nausea, vertigo,
paresthesia, mental confusion and unconsciousness. However, review of Thienes and Haley
(1972), cited by NAS (1977) as the source of this information, suggests that the discussion
therein was a general presentation of effects for alkylbenzenes—not effects specifically based on
data for ^-propylbenzene.
Animal Studies
Oral Exposure
With regard to oral toxicity, the information provided in the NAS (1977) summary of the
//-propylbenzene rabbit study (Gerarde and Ahlstrom, 1966) lacks sufficient detail for
risk-assessment purposes. No dose-response relationship can be determined from the 2-week
ototoxicity study of Gagnaire and Langlais (2005). No other data pertaining to repeated oral
exposure are available for ^-propylbenzene.
NAS (1977) summarized the results of a 6-month oral study with //-propylbenzene in
rabbits. The study is referenced to Gerarde and Ahlstrom (1966), but the complete citation is not
provided, and efforts to identify and obtain the full reference proved unsuccessful. NAS (1977)
states that
"In a 6-month subchronic oral study (Gerarde and Ahlstrom, 1966) groups of 15
rabbits were fed propylbenzene at 0.25 and 2.5 mg/kg/day. The test animals did
not differ from the controls in general appearance, body weight, organ weights,
and protein function of the liver. There was a 7% decrease in red-cell count in the
high-dosage group that was not significant. Hemosiderin was deposited in the
spleens of the high-dosage animals, indicating red-cell destruction. There was a
nonsignificant leukocyte increase in both dosage groups. Individual animals
exhibited mild protein dystrophy of the liver and kidneys."
Gagnaire and Langlais (2005) tested the relative ototoxicity of 21 aromatic solvents,
including ^-propylbenzene. In their studies, groups of 7-8 young male Sprague-Dawley rats
were administered 8.47 mmol/kg of chemical (in a volume of 2 mL/kg [olive oil vehicle]) by
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gastric intubation for 5 days/week for a 2-week period1. For //-propylbenzene, a molar
concentration of 8.47 mmol/kg is equivalent to a dose of 1018 mg/kg-day. After dosing, body
weights were measured daily during the 2 weeks of treatment, then for a subsequent 10 days
after the period of treatment. The behavior and general health of rats was observed on a daily
basis. At the end of the 10-day recovery period, 6 rats per treatment group were chosen
randomly, deeply anesthetized and perfused with buffered paraformaldehyde and glutaraldehyde.
Subsequently, 3 left and 3 right cochleas were removed from the 6 chosen rats in each group and
processed. Organs of Corti and basilar membranes were examined by light microscopy and
scanning electron microscopy.
No treatment-related clinical signs were observed with //-propylbenzene. Of the 21
solvents tested, the following 8 caused histological lesions (loss of hair cells) in the organ of
Corti (listed from most to least toxic based on cytocochleograms2): allylbenzene, ethylbenzene,
styrene, ^-propylbenzene, ^-xylene, toluene, /ra//.v-P-methylstyrene and a-methylstyrene.
Among the chemicals considered to be of intermediate toxicity, ^-propylbenzene is associated
with outer hair cell losses predominantly in the middle of the cochlea, with some apical loss in
4/8 animals tested and no hair loss in the basal portion.
Following an examination of octanol/water partition coefficients for the chemicals tested,
Gagnaire and Langlais (2005) concluded that there was no correlation between ototoxicity and
lipophilicity. Gagnaire and Langlais described the chemical structure-activity relationship SAR
descriptors that contribute to ototoxicity as the following: (1) single side chain on the aromatic
ring, except with /^-xylene; (2) no branch for the side-chain; (3) number of side-chain carbon
atoms of 1 to 3 (Cn-1,2,3) only; and (4) unsaturation of the side chain. Given that only one
concentration was tested, a free-standing LOAEL of 1018 mg/kg-day based on histological
evidence of hearing loss is identified for //-propylbenzene in this study.
Inhalation Exposure
No chronic, subchronic, developmental, or reproductive toxicity studies conducted by the
inhalation route of exposure were located for ^-propylbenzene.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
TOXICITY VALUES FOR n-PROPYLBENZENE (RfDs, RfCs)
Due to a lack of data, no chronic or subchronic RfDs or RfCs are developed. However,
the Appendix of this document contains Screening Values (RfD and RfC), based on an analog
treatment, that may be useful in certain instances. Please see the attached Appendix for details.
'The dose was selected on the basis of previous range-finding studies conducted with toluene. The chosen dose is
associated with outer hair cell loss in the middle turn of the organ of Corti without causing mortality or body-weight
loss.
2 Cytocochleograms are 3-dimensional graphs based on counts of the inner hair cells (IHC) and three rows of outer
hair cells (OHC) in the organ of Corti.
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PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
ft-PROPYLBENZENE
Weight-of-Evidence Descriptor
Under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), there is
"Inadequate Information to Assess the Carcinogenic Potential' of //-propylbenzene; there are no
human epidemiology studies, chronic toxicity studies, or carcinogenicity assays. The available
mutagenicity studies with Salmonella typhimurium have been negative.
Quantitative Estimates of Carcinogenic Risk
The lack of data on the carcinogenicity of //-propylbenzene precludes the derivation of
quantitative estimates of risk for either oral (p-OSF) or inhalation (p-IUR) exposure.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2007. TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. ACGIH, Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Review for
Ethylbenzene. Draft for Public Comment. Online, http://www.atsdr.cdc.gov.
ATSDR (Agency for Toxic Substances and Disease Registry). 2008. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Online, www.atsdr.cdc. gov/toxpro2.html.
Andrew, F.D., R.L. Buschbom, W.C. Cannon et al. 1981. Teratologic assessment of
ethylbenzene and 2-ethoxyethanol. Battelle Pacific Northwest Laboratory, Richland, WA.
PB83-208074.
Backes, W.L., D.J. Sequeira, G.F. Cawley et al. 1993. Relationship between hydrocarbon
structure and induction of p450: Effects on protein levels and enzyme activities. Xenobiotica.
23(12): 1353—1366.
Bardodej, Z. and Bardodejova, E. 1970. Biotransformation of ethylbenzene, styrene, and
alphamethylstyrene in man. Am. Ind. Hyg. Assoc. J. 31:206-209. (Cited by ATSDR, 1997).
ChemlDPlus. 2008. Online, http://chem. sis.nlm.nih.gov/chemidolus/.
Cruz, S.L., R.L. Balster and J.J. Woodward. 2000. Effects of volatile solvents on recombinant
N-methyl-D-aspartate receptors expressed in Xenopus oocytes. Br. J. Pharmacol. 131:1303—
1308.
5

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FINAL
2-04-2009
Dean B.J., T.M. Brooks, G. Hodson-Walker et al. 1985. Genetic toxicology testing of 41
industrial chemicals. MutatRes 153:57-77. (Cited by ATSDR, 2007).
Degirmenci E, Y. Ono, O. Kawara et al. 2000. Genotoxicity analysis and hazardousness
prioritization of a group of chemicals. Water Sci. Technol. 42(7-8): 125-131. (Cited by ATSDR,
2007).
El Masry, A.M., J.N. Smith and R.T. Williams. 1956. Studies in Detoxication. 69. The
metabolism of alkylbenzenes: //-Propylbenzene and //-butylbenzene with further observations on
ethylbenzene. Biochem. J. 64(l):50-56.
Florin, I., L. Rutberg, M. Curvall et al. 1980. Screening of tobacco smoke constituents for
mutagenicity using the Ames test. Toxicology. 18:219-232.
Gagnaire, F. and C. Langlais. 2005. Relative ototoxicity of 21 aromatic solvents. Arch.
Toxicol. 79(6):346-354.
Gagnaire, F., C. Langlais, S. Grossmann et al. 2007. Ototoxicity in rats exposed to ethylbenzene
and to two technical xylene vapours for 13 weeks. Arch. Toxicol. 81(2): 127-143.
Gerarde, H.W. 1956. Toxicological studies on hydrocarbons. AM A Arch. Ind. Health. 14:468-
474.
Gerarde, H.W. 1959. Toxicological studies on hydrocarbons. AMA Arch. Ind. Health.
19:403-418.
Gerarde, H.W. 1960. Toxicological Effects in: Toxicol. Biochem. Aromat. Hydrocarbons. Pp.
52-57.
Gerarde, H.W. and D.B. Ahlstrom. 1966. (Cited in NAS, 1977, but citation not provided).
Gromiec JP, Piotrowski JK. 1984. Urinary mandelic-acid as an exposure test for ethylbenzene.
Int Arch Occup Environ Health 55(l):61-72. (Cited by ATSDR, 2007).
Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W. Niemeier. 1981.
Testing of selected workplace chemicals for teratogenic potential. Scand. J. Work Environ.
Health. 7(Suppl 4):66-75.
Henderson, R.F. 2001. Aromatic hydrocarbons-benzene and other akylbenzenes. In: Patty's
Toxicology, 5th ed., E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley and Sons, New
York. 4:231-301.
IARC (International Agency for Research on Cancer). 2008. Search IARC Monographs.
Online, www.cie.iarc.fr.
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2-04-2009
IPCS (International Programme on Chemical Safety). 2008. INCHEM. Chemical Safety
Information from Intergovernmental Organizations. Online, http://www.inchem.org/.
Jensen, T.E., W. Young, J.C. Ball et al. 1988. Direct acting mutagenicity of diesel particulate
extract is unchanged by addition of neat aromatic compounds to diesel fuel. JAPCA. 38(1):56-
58.
Kubo T, K. Urano, and H. Utsumi. 2002. Mutagenicity characteristics of 255 environmental
chemicals. J Health Sci 48(6):545-554. (Cited by AT SDR, 2007).
Lawlor, T.E. and Wagner, V.O. 1987. Salmonella/Mammalian-microsome preincubation in
mutagenicity assay (Ames test); test article: Cumene. Microbiological Associates, Inc., Study
No. T4786.502009, March 23, 1987. (Cited by U.S. EPA, 2007b).
NAS (National Academy of Sciences). 1977. Drinking Water and Health. Vol. I, Printing and
Publishing Office, National Academy of Sciences, Washington, DC. p. 761-763.
Nestmann E.R., E.G. Lee, and T.I. Matula et al. 1980. Mutagenicity of constituents identified in
pulp and paper mill effluents using the Salmonella/mammalian-microsome assay. Mutat Res
79:203-212. (Cited by AT SDR, 2007).
NTP. (National Toxicology Program) 1986. Toxicology and carcinogenesis studies of xylenes
(mixed) (60% m-xylene, 14% p-xylene, 9%-xylene, and 17% ethylbenzene) in F334/N rats and
B6C3F1 mice (gavage studies). Research Triangle Park, NC: National Toxicology Program.
NTP TR 327. (Cited by AT SDR, 2007).
NTP. (National Toxicology Program) 1999. NTP technical report on the toxicology and
carcinogenesis studies of ethylbenzene in F344/N rats and B6C3F1 mice (inhalation studies).
Research Triangle Park, NC: National Toxicology Program, U.S. Department of Health and
Human Services. NTP TR 466. (Cited by AT SDR, 2007).
NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Online, http://ntp-server.niehs.nih.gov/.
NTP (National Toxicology Program). 2008. Management Status Report. Online.
http://ntp.niehs.nih.gov/index.cfm?obiectid=78CC7E4C-FlF6-975E-72940974DE301C3F.
NIOSH (National Institute for Occupational Safety and Health). 2008a. NIOSH Pocket Guide
to Chemical Hazards. Index by CASRN. Online, http://www2.cdc.gov/nioshtic-
2/nioshtic2.htm.
NIOSH (National Institute for Occupational Safety and Health). 2008b. RTECS (Registry of
Toxic Effects of Chemical Substances). Cincinnati, OH.
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FINAL
2-04-2009
OSHA (Occupational Safety and Health Administration). 2008. OSHA Standard 1915.1000 for
Air Contaminants. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2.
Pyykko, K., S. Paavilainen, T. Metsa-Ketela et al. 1987. The increasing and decreasing effects
of aromatic hydrocarbon solvents on pulmonary and hepatic cytochrome p-450 in the rat.
Pharmacol. Toxicol. 60:288-293.
Research Triangle Institute. 1989. Metabolism, disposition and pharmacokinetics of cumene in
F-344 rats following oral, IV administration or nose-only inhalation exposure. Report No.
RTI/4353-01F. CM A Reference No. CU-5.0-PK-RTI. (Cited by U.S. EPA, 1997b).
Sato, A. and T. Nakajima. 1979. Partition coefficients of some aromatic hydrocarbons and
ketones in water, blood and oil. Br. J. Ind. Med. 36:231-234.
Senczuk, W. and B. Litewka. 1976. Absorption of cumene through the respiratory tract and
excretion of dimethylphenylcarbinol in urine. Br. J. Ind. Med. 33: 100-105.
Smyth H., C.P. Carpenter, C.S.Weil et al. 1962. Range finding toxicity data: List VI. Am Ind.
Hyg. Assoc. J. 23:95-107.
Tegeris, J.S. and R.L. Balster. 1994. A comparison of the acute behavioral effects of
alkylbenzenes using a functional observational battery in mice. Fund. Appl. Toxicol. 22:240-
50.
Thienes, C.H. and T.J. Haley. 1972. Clinical Toxicology. Fifth Edition. Lea&Febiger:
Philadelphia, PA. p. 126.
U.S. EPA. 1987. Drinking Water Health Advisory for «-Propylbenzene. Rough External
Review Draft. Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water, Washington,
DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997a. Health Effects Assessment Summary Tables (HEAST). FY-1997 Update.
Prepared by the Office of Research and Development, National Center for Environmental
Assessment, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington,
DC. July. EPA/540/R-97/036. NTIS PB 97-921199.
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U.S. EPA. 1997b. Toxicological Review of Cumene in Support of Summary Information on the
Integrated Risk Information System. June, 1997. Online, http://www.epa.gov/iris.
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/001B. Online, http://www.epa.gov/iris/backgr-d.htm.
U.S. EPA. 2006. Drinking Water Standards and Health Advisories. Office of Water,
Washington, DC. Summer 2006. Online.
http://www.epa.gov/waterscience/criteria/drinking/dwstandards.pdf.
U.S. EPA. 2008. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa.gov/iris/.
Wolf, M.A., V.K. Rowe, D.D. McCollister et al. 1956. Toxicological studies of certain
alkylated benzenes and benzene. Arch. Ind. Health. 14:387-398.
Yuan, W., T.B. White, J.W. White et al. 1995. Relationship between hydrocarbon structure and
induction of P450: Effect on RNA levels. Xenobiotica. 25:9-1.
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APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
/i-PROPYLBENZENE (CASRN 103-65-1)
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for //-propylbenzene. However, information is available for this chemical which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an Appendix and develops a
"Screening Value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. In the OSRTI hierarchy, Screening Values are considered to be below Tier 3,
"Other (Peer-Reviewed) Toxicity Values."
Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3
values are available. Screening Values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening Values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited information. Questions or concerns about the appropriate use of
Screening Values should be directed to the Superfund Health Risk Technical Support Center.
The free-standing LOAEL based on ototoxicity of 1018 mg/kg-day (highest dose tested)
in a 2-week study (Gangnaire and Langlais, 2005) could serve as a basis for development of a
subchronic screening p-RfD. A composite UF of 10,000 would be required (10 for intra- and 10
for interspecies extrapolation, 10 for LOAEL to NOAEL extrapolation and 10 for database
deficiencies (no developmental or reproductive studies). This would provide a subchronic
screening p-RfD of 0.1 or 1E-01 mg/kg-day. Because of the large composite uncertainty factor
(UF) and inherent loss in confidence, a stronger case can be made for using the current IRIS
values for ethylbenzene toxicity, as a surrogate for //-propylbenzene. Although the screening
chronic RfD based on the IRIS value, derived by analogy to ethylbenzene, is identical to the
proposed screening subchronic p-RfD with a composite UF of 10,000, use of ethylbenzene as a
surrogate is better supported.
To evaluate the possibility of deriving toxicity values for //-propylbenzene on the basis of
structural analogs, selective information on the toxicity of cumene (isopropylbenzene) and
ethylbenzene based on structural similarity are presented in the following sections. Comparison
of these compounds is provided on the basis of toxicokinetics, acute lethality, parenteral
exposure, neurotoxicity and genotoxicity.
Toxicokinetics
The available information on the absorption and elimination of ^-propylbenzene,
ethylbenzene and cumene suggest that all three chemicals are readily absorbed and rapidly
excreted, primarily in the urine (Theienes and Haley, 1972; El Masry et al., 1956, Senczuk and
Litewka, 1976, Bardodej and Bardodejova, 1970; Gromiec and Piotrowski, 1984; Research
Triangle Institute, 1989). Table 1 presents a comparison of the available absorption data.
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Table 1. Comparative Absorption Data for «-Propylbenzene and Analogs
Chemical
Route
Species
Absorption
Basis
Reference
Ethylbenzene
Oral
Rabbit
73-83 %
Elimination of
metabolites in urine
El Masry et al., 1956
Inhalation
Human
49-64%
Retention in lungs
Bardodej and Bardodejova,
1970; Gromiec and
Piotrowski, 1984
//-Propylbenzene
Oral
Rabbit
62%
Elimination of
metabolites in urine
El Masry et al., 1956
Inhalation
No data
No data
No data
No data
Cumene
(Isopropyl benzene)
Oral
Rat
>70%
Elimination of
metabolites in urine
Research Triangle Institute,
1989
Inhalation
Rat
>70%
Elimination of
metabolites in urine
Research Triangle Institute,
1989
Human
50%
Retention in lungs
Senczuk and Litewka, 1976
The metabolism of ^-propylbenzene has been studied in rats and rabbits.
El Masry et al. (1956) fed //-propylbenzene to rabbits (3 mmol/kg [361 mg/kg] for a total of 13.8
grams/rabbit) and collected the urine for 24 hours after dosing. Based on the administered dose,
15% was excreted in the urine as hippuric acid and 47% was excreted in the urine as conjugates
of glucuronic acid (glucuronides of ethylphenyl carbinol and benzylmethylcarbionol). In a
similar protocol with ethylbenzene, 31% of the administered dose (also 3 mmol/kg [318 mg/kg])
was excreted in the urine as hippuric acid, 32% was excreted as conjugates of glucuronic acid,
and 10-20%) was excreted in the urine as phenaceturic acid.
Using microsomes isolated from male rabbits, Sato and Nakajima (1979) determined the
rate of metabolism of various solvents in lung and liver tissue. Table 2 summarizes the results
for //-propylbenzene, ethylbenzene and cumene.
Table 2. Mean Rates of Metabolism In Vitro in Tissues Isolated from Five Male Rabbits3

Rate of Metabolism
nmol/g-10 min
jimol/organ-10 min
nmol/nmol cytp450-10 min
Substrate
Liver
Lung
Liver
Lung
Liver
Lung
Ethylbenzene
453.0
680.3
34.4
5.3
11.7
200.1
//-Propylbenzene
740.2
1187.6
56.2
9.2
19.1
349.3
Cumene
1021.1
12,436.2
77.6
11.1
26.4
422.4
aSato and Nakajima, 1979
Pyykko et al. (1987) demonstrated that various aromatic hydrocarbons induce pulmonary
and hepatic enzymes following a single i.p. injection (5 mmol/kg) of each solvent. Table 3
summarizes the significant results for //-propylbenzene, ethylbenzene and cumene.
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Table 3. Induction or Depression of Pulmonary and Liver Enzymes in Microsomes
Isolated from Male Rats3

Significantly Increased or Decreased Enzymes Relative to Controls
Ethylbenzene
w-Propylbenzene
Cumene
Enzyme
Liver
Lung
Liver
Lung
Liver
Lung
Cytochrome P450
Yes
increase
Yes
decrease
Yes
increase
Yes
decrease
Yes
increase
Yes
decrease
Aryl hydrocarbon hydroxylase
Yes
increase
Yes
decrease
Yes
increase
No
change
Yes
increase
No
change
7 -Ethoxy cumarin-O-deethylase
Yes
increase
Yes
decrease
Yes
increase
Yes
decrease
Yes
increase
No
change
Cytochrome b5
No
change
No
change
No
change
No
change
Yes
increase
No
change
NADPH cytochrome c
reductase
Yes
increase
No
change
Yes
increase
No
change
Yes
increase
No
change
aPyykko et al., 1987
Further studies (Backes et al., 1993; Yuan et al., 1995) conducted with male rats injected
intraperitoneally with various aromatic hydrocarbons demonstrate that the effects of the various
hydrocarbons on the different isozymes of cytochrome p450 and p450 mRNA are complicated.
Both //-propylbenzene and ethylbenzene have a similar protein induction pattern: both substrates
induced p4502Bl and -2B2 but suppressed -2C11 in rat liver (Backes et al., 1993). However, the
pattern of mRNA induction is different for //-propylbenzene and ethylbenzene and does not
correlate with the observed effects of these chemicals on induction of the enzymes (Yuan et al.,
1995). mRNA associated with p4502Bl is not elevated for any hydrocarbon tested and mRNA
associated with p4502B2 is elevated relative to controls only for the larger hydrocarbons,
including ethylbenzene and ^-propylbenzene. P450C11 mRNA is not suppressed by n-
propylbenzene or any other hydrocarbon tested except for ethylbenzene.
Sato and Nakajima (1979) report a human blood:air partition coefficient of 47 for
propylbenzene measured using preserved human blood containing 13% by volume (v/v) of blood
preserving solution (2.2 g sodium citrate, 0.8 g citric acid and 2.2 g glucose in 100 mL).
Blood:air partition coefficients of 28.4 and 37.0 were measured in the same system for
ethylbenzene and cumene, respectively.
Acute Lethality
Table 4 presents acute oral and inhalation toxicity values for //-propylbenzene,
ethylbenzene and cumene. When exposure is by the oral route, ethylbenzene and cumene are
clearly more acutely toxic to rats than ^-propylbenzene. However, the relative acute toxicity of
the three analogs is not strictly comparable for inhalation exposure due to a lack of studies that
use the same species and exposure duration.
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Table 4. Acute Toxicity of ft-Propylbenzene and Possible Analogs21
Chemical
Ethylbenzene
M-Propylbenzene
Cumene
Oral LD50 (mg/kg-day)
3500b, rat
6040, rat
1400b, rat
Mortality in fasted rats following single
gavage dose of 2.5 ml in olive oil0
7/10
3/10
6/10
Inhalation LC50 (ppm)
4000 (4 hr)d, mouse
65,000 (2 hr), rat
8000 (4 hr)e, rat
aChemIDPlus (2008) unless noted otherwise
bWolf et al., 1956
°Gerarde, 1959
dSmythetal. 1962
eGerarde, 1960; ChemlDplus incorrectly cites this value as an LClo
Parenteral Exposure
Six groups of Wistar rats (40 males/group) weighing 125-150 grams each were given
daily subcutaneous injections of olive oil (control), benzene, toluene, ethylbenzene,
//-propylbenzene, or //-butylbenzene (all chemicals were 99% pure) for a period of 2 weeks
(Gerarde, 1956). The dose for each chemical was 1 mL/kg in an equal volume of olive oil, and
injections were given in a different area of skin each day. Assuming the densities shown in
Table 5 (below), the doses for //-propylbenzene and ethylbenzene were 862 and 867 mg/kg-day,
respectively. Groups of 10 animals per chemical were sacrificed at weekly intervals during
exposure and at 10-day intervals over a 3-week recovery period. The following observations
were made for each animal: appearance, behavior, activity, and food/water consumption, stool
appearance, body weight, fur and skin appearance, irritation of subcutaneous tissues at site of
injection, hematology (peripheral leukocyte count, microhematocrit, total femoral marrow
nucleated cell count) and bone marrow biochemistry (total femoral marrow RNA and DNA). A
gross and microscopic examination of tissues and internal organs, thymus and spleen weight and
an examination of site of injection tissue as well as a gross and microscopic examination of bone
marrow was also conducted.
The authors considered the responses observed following treatment with all chemicals—
except benzene—to be similar and, therefore, grouped them together as //-alkylbenzenes for the
purposes of presentation of results and discussion (Gerarde, 1956). Rats exposed to
//-propylbenzene, ethylbenzene and the other //-alkylbenzenes had 5% mortality and diminished
activity (attributed to CNS depression) but were considered to be normal in appearance. The
^-alkylbenzenes were considered to be more irritating than benzene and caused induration of
subcutaneous tissue at the sites of injection. The ^-alkylbenzenes had no effect on body-weight
gain relative to controls throughout the treatment and recovery periods. The ^-alkylbenzenes had
no effect on hematocrit, leukocyte count, or the femoral bone marrow nucleated cell population
during any period of treatment or recovery. Rats treated with ^-alkylbenzenes had slightly
elevated femoral marrow DNA and RNA relative to controls during the exposure period. The
authors considered elevated nucleic acids to be indicative of hyperplastic marrow resulting from
inflammatory response to the injected materials. The study authors contend that ^-alkylbenzenes
caused subcutaneous irritation, but they did not report treatment-related pathological changes in
other tissues or organs (specifics not reported other than for spleen and thymus). These results
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suggest that the toxic effects caused by //-propylbenzene and ethylbenzene (and other
//-alkylbenzenes) are qualitatively similar.
Neurotoxicity
The acute neurobehavioral toxicity of 6 different alkylbenzenes was evaluated by a
functional observational battery (FOB) (Tegeris and Balster, 1994). Groups of adult male
Charles River/Swiss mice (8/group) were exposed by whole-body inhalation for 20 minutes to
benzene, toluene, ethylbenzene, //-propylbenzene, m-xylene, or cumene over a range of 3
concentrations (2000, 8000 or 14,000 ppm for ^-propylbenzene; 2000, 4000 or 8000 for cumene
and ethylbenzene). Two additional groups were used as air-exposed controls. In order to
compare the results of alkylbenzene exposure with the known effects of pentobarbital, a separate
group of 8 mice was injected intraperitoneally with pentobarbital (each mouse tested sequentially
with 0, 5, 10, 20, 30 or 40 mg/kg). The authors point out that the purpose of their study was to
make qualitative—rather than quantitative—comparisons between the chemicals tested with
pentobarbital, a known CNS depressant. Therefore, strict quantitative comparisons between the
chemicals are not supported by their results. That said, general comparisons are possible for
ranges of concentrations as follows.
All of the alkylbenzenes tested and pentobarbital exhibited nearly identical profiles of
effects at a concentration range of 2000-8000 ppm when the individual measures of the FOB are
taken into account (Tegeris and Balster, 1994). Relative to air-exposed controls, these effects
include changes in posture, decreased arousal and rearing, increased ease of handling,
disturbances in gait, mobility and righting reflex, decreased forelimb grip strength, increased
landing foot splay, and impaired psychomotor coordination. Results for
//-propylbenzene-exposed rats are statistically different from controls for 15/23 assessed
endpoints. Detailed results for 6/23 assessed endpoints are presented for each of the chemicals
tested in the report. Based on the reported results, the LOAEL for //-propylbenzene in the study
is 2000 ppm (lowest dose tested) for statistically significant decreases in rearing effect in
mobility (during exposure), righting reflex and forelimb grip strength, and a signficant increase
in hindlimb foot splay, relative to controls. Other endpoints may have achieved statistical
significance at this concentration, but because they are not reported individually for each
chemical, the dose-response details are not discernable. Of the two remaining endpoints reported
in detail for each chemical (inverted screen test of motor coordination, touch response), a
dose-related statistical difference from controls was achieved at the 8000- and 14,000-ppm
concentrations, but not at 2000 ppm, for ^-propylbenzene. Similar dose-response patterns (i.e.,
similar shapes of dose-response curves and nearly identical exposure concentrations that were
statistically significant for the endpoints discussed above with regard to ^-propylbenzene) were
observed for cumene and ethylbenzene, with LOAEL values of 2000 ppm for each of those
chemicals. Similar results were also obtained for pentobarbital in terms of the direction of
response and general shape of the dose-response curve, suggesting that these findings might be
generally applicable to CNS depressants.
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//-Methyl-D-aspartate (NMDA) receptors are ionotropic receptors that have been studied
as targets of CNS depression. Using recombinant NMDA receptors expressed in Xenopus
oocytes, Cruz et al. (2000) tested the inhibition of these receptors by commonly abused inhalant
solvents—including //-propylbenzene—to determine whether a common mechanism of action
mediated through the NMDA receptor was possible. All of the solvents tested—including
//-propylbenzene—caused a reversible inhibition of NMDA-induced membrane currents that was
dose- and subunit-dependent. The median inhibition concentrations (IC50) for //-propylbenzene
and ethylbenzene, corrected for solvent evaporation, are 0.35 and 0.17 mM, respectively.
Cumene is not tested in this study. The results of this study are congruent with the observation
that ^-propylbenzene is a CNS depressant that, along with some other abused inhalants, displays
pharmacological selectivity for specific NMDA receptors, but this do not provide sufficient
evidence to conclude that a common mechanism of action is appropriate for the solvents tested.
However, this study does provide a basis for the CNS effect using ethylbenzene as the surrogate
for the derivation of an RfD—provided that the CNS effect is the most sensitive endpoint.
Genotoxicity
//-Propylbenzene, ethylbenzene and cumene each were not found to be mutagenic in
Ames tests conducted with Salmonella typhimurium—regardless of the presence or absence of
metabolic activation (Florin et al., 1980; Jensen et al., 1988; Dean et al. 1985; Degirmenci et al.
2000, Kubo et al. 2002; Nestmann et al. 1980; NTP 1986, 1999; Lawlor and Wagner, 1987).
No further tests of genotoxicity have been reported for ^-propylbenzene. A fairly complete battery of
in vitro and in vivo genotoxicity tests, in addition to those reported above, have been conducted
for cumene and ethylbenzene, with predominantly negative results (ATSDR, 2007; U.S. EPA,
1997b).
Ethylbenzene (CgHio) and cumene (C9H12) are structurally similar to ^-propylbenzene,
but ethylbenzene appears to be the more appropriate analog for //-propylbenzene (Table 5).
Table 5. Structures and Physical/Chemical Properties of «-Propylbenzene and Possible
Analogs21
Chemical
Ethylbenzene
M-Propylbenzene
Cumene
Structure
/	\
/	\
/	\ /




CASRN
100-41-4
103-65-1
98-82-8
ChemID Plus Similarity Searchb
56%
-
<50%
Molecular formula
O
00
K
0
C9H12
C9H12
Molecular weight
106.16
120.19
120.19
Melting point (°C)
-94.9
-99.5
-96.03
Boiling point (°C)
136.1
159.2
152.39
Vapor Pressure (mmHg)
9.6 @ 25 °C
3.42 @25 °C
4.5 @ 25 °C
Henry's Law Constant (atm-m3/mole)
0.00788 @ 25 °C
0.0105 @25 °C
0.0115 @25 °C
Water solubility (g/L)
169 @ 25 °C
52.2 @ 25 °C
61.3 @25 °C
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Table 5. Structures and Physical/Chemical Properties of n-Propylbenzene and Possible

Analogs21


Chemical
Ethylbenzene
M-Propylbenzene
Cumene
Specific gravity /density
0.8670 @20 °C/4 °C
0.8620 @ 20 °C/4 °C
0.8620 @ 20 °C/4 °C
Log Kow
3.15 @25 °C
3.69 @25 °C
3.66
aChemIDPlus (2008)
bThe ChemID Plus Similarity Search function characterizes the similarity of compounds. In this case, it was used
to determine the similarity of ethylbenzene and Cumene to //-propylbenzene. Note that 100% indicates an exact
match; 56% is not high, but it is high enough to suggest that some structural-related property can be applied using
SAR analysis. The low similarity score (<50%) for cumene suggests that cumene is not a strong surrogate
candidate.
The scope of information available in support of using either cumene or ethylbenzene as
an analog for //-propylbenzene is limited. However, based on information presented in the
previous sections, the following factors can be considered.
Factors supporting the use of ethylbenzene as an analog for n-propylbenzene:
•	Similar patterns of gastrointestinal and pulmonary absorption and elimination of
metabolites in the urine (Table 1).
•	Similar, but not identical, patterns of metabolism (El Masry et al., 1956) and
pulmonary and liver metabolic enzyme induction (Pyykko et al., 1987; Sato and
Nakajima, 1979; Backes et al., 1993).
•	A similar pattern of ototoxicity (Gagnaire and Langlais, 2005). In addition, the
ototoxicity of 21 solvents was not related to lipophilicity, suggesting that
structural—rather than physical/chemical properties—have a greater influence on
this critical endpoint.
•	A similar pattern of neurological effects (Tegeris and Balster, 1994; Cruz et al.,
2000). However, these findings appear to be broadly applicable to CNS
depressants, and, therefore, are too general to provide strong support for use of
ethylbenzene as a surrogate for //-propylbenzene.
•	Ethylbenzene is more toxic than //-propylbenzene with regard to acute oral
toxicity (Table 4) and ototoxicity (Gagnaire and Langlais, 2005); therefore, using
ethylbenzene as a surrogate would likely be protective of potential
//-propylbenzene toxicity.
•	Structural similarity = 56%
Factors inconsistent with the use of cumene as an analog for n-propylbenzene:
•	Branched chain structure.
•	No ototoxicity because of the branched chain structure (Gagnaire and Langlais,
2005).
Taken together, the above factors support the selection of ethylbenzene over cumene as
the basis for toxicity screening values for ^-propylbenzene. Further considerations are discussed
with regard to the derivation of oral and inhalation values below.
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Oral Toxicity Values
Screening subchronic RfD and screening chronic RfD
For //-propylbenzene, the IRIS chronic RfD for ethylbenzene (1E-01 or 0.1 mg/kg-day),
derived in June 1991 and based on liver and kidney toxicity in a subchronic rat study
(Wolf et al., 1956), is recommended as a screening RfD based on the surrogate analysis
presented here. IRIS used a NOEL of 136 mg/kg-day (converted to 97.1 mg/kg-day) and applied
a composite UF of 1000 including 10 for interspecies- and 10 for intraspecies extrapolation and
10 to extrapolate from subchronic to chronic exposure duration.
Based on the analysis of structure-activity relationships presented here, the IRIS chronic
RfD of 1E-01 or 0.1 mg/kg-day for ethylbenzene is recommended for the screening chronic
RfD for n-propylbenzene. Also, as indicated earlier, using a 2-week LOAEL of 1080 mg/kg-
day for ototoxicity induced by n-propylbenzene with the application of a composite UF of
10,000 would give an identical value.
Given the lack of data on n-propylbenzene and the uncertainty associated with the
use of a surrogate for the derivation of the toxicity values, the same value, 1E-01 or 0.1
mg/kg-day, is recommended for the screening subchronic RfD.
While the Gerarde and Ahlstrom (1966) study cited by NAS (1977) suggests the
possibility of mild liver and kidney effects attributable to //-propylbenzene following repeated
oral exposure, the study cannot be located for detailed scrutiny. The similarities between
ethylbenzene and //-propylbenzene observed in short-term studies (e.g., Gagnaire and Langlais,
2005) and the suggestion of liver or kidney toxicity tentatively identified in the Gerarde and
Ahlstrom (1966) study cited by NAS (1977) raise confidence that these effects would also be
observed following longer-term exposures, as they are with ethylbenzene.
Inhalation Toxicity Values
Inhalation values are based on using ethylbenzene as a surrogate.
For ethylbenzene, IRIS provides a chronic RfC of 1 or 1E+0 mg/m3 (100 ppm) based on
Andrews et al. (1981) and Hardin et al. (1981) on developmental toxicity. IRIS chose a
composite UF of 300 (10 for intra- and 3 for interspecies extrapolation and 10 for database
deficiencies (lack of multigenerational reproductive and chronic studies). Based on the
-2
argument by analogy presented here, the chronic screening value RfC of 1 or 1E+0 mg/m
is recommended for n-propylbenzene.
Because the IRIS RfC (for ethylbenzene) is based on developmental studies, the
same value is recommended as a screening subchronic RfC: 1 or 1E+0 mg/m3.
The ototoxicity observed in rats by Gagnaire and Langlais (2005) was investigated
further in a subchronic rat study using ethylbenzene by the inhalation route of exposure
(Gagnaire et al., 2007). Given that the ototoxicity of ethylbenzene was shown to be
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quantitatively greater, but qualitatively similar to that shown by //-propylbenzene following
short-term oral exposure (Gagnaire and Langlais, 2005), it is probable that a similar result would
be obtained following inhalation exposure if //-propylbenzene had been tested in parallel with
ethylbenzene.
The current IRIS RfC of 1 mg/m3 for ethylbenzene is based on developmental toxicity
studies (Andrew et al., 1981; Hardin et al., 1981). Subsequent developmental toxicity studies
support the results of these earlier studies. The subchronic ototoxicity study by
Gagnaire et al. (2007) suggests that ototoxicity may be the most sensitive endpoint for inhalation
exposure to ethylbenzene. However, at this time, the best available information supports
utilization of the existing IRIS values.
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