United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/004F
Final
11-28-2012
Provisional Peer-Reviewed Toxicity Values for
sec-Butylbenzene
(CASRN 135-98-8)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Nina Ching Y. Wang, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ambuja Bale, PhD, DABT
National Center for Environmental Assessment, Washington, DC
Paul G. Reinhart, PhD, DABT
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research
and Development's National Center for Environmental Assessment, Superfund Health Risk Technical
Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	iii
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVs	1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	6
ANIMAL STUDIES	6
Oral Exposures	6
Short-term Studies	6
Other Exposures	7
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	10
Toxicokinetics Studies	10
Toxicity of Alkylbenzenes in Various Tissues	11
Genotoxicity Studies	13
DERIVATION 01 PROVISIONAL VALUES	13
DERIVATION OF ORAL REFERENCE DOSES	13
Feasibility of Deriving Subchronic and Chronic Provisional RfDs (Subchronic and
Chronic p-RfDs)	13
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	14
DERIVATION OF PROVISIONAL ORAL AND INHALATION CANCER VALUES	14
APPENDIX A. PROVISIONAL SCREENING VALUES	15
APPENDIX B. DATA TABLES	25
APPENDIX C. POTENTIAL SURROGATES FROM DSSTOX AND CHEMIDPLUS
WITH AVAILABLE VALUES FROM IRIS, PPRTV, AND HEAST DATABASES	26
APPENDIX D. REFERENCES	27
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
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
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
sec-BUT YLBENZENE (CASRN 135-98-8)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVs
Questions regarding the contents and appropriate use of this PPRTV assessment should
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).
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INTRODUCTION
.vec-Butylbenzene is used as a solvent for coating compositions, as an organic synthesizer,
a surface active agent, and a plasticizer (HSDB, 2004). The empirical formula for
sec-butylbenzene is Ci0Hi4 (see Figure 1). A table of physicochemical properties is provided in
Table 1.
Table 1. Physicochemical Properties Table for sec-Butylbenzene (CASRN 135-98-8)
Property (unit)
Value
Boiling point (°C)
17 3.5a
Melting point (°C)
—8.27 x 10la
Density (g/cm3)
0.8580b
Vapor pressure (mm Hg at 25°C)
1.75a
Solubility in water (mg/L at 25°C)
17.6a
Relative vapor density (air = 1)
4.62b
Molecular weight (g/mol)
134.22a
Flash point (°C)
52b
Octanol/water partition coefficient (unitless)
4.57a
aChemIDplus (2010).
'"HSDB (2004).
No reference dose (RfD), reference concentration (RfC), or cancer assessment for
.vec-butylbenzene is included on the EPA's IRIS database (U.S. EPA, 2010a) or on the Drinking
Water Standards and Health Advisories List (U.S. EPA, 2006). No RfD or RfC values were
reported in the HEAST (U.S. EPA, 2003). However, EPA (U.S. EPA, 1997a) did derive a
chronic provisional RfD of 1 x 10 2 mg/kg-day for .vec-butylbenzene using isopropylbenzene
(cumene) as a structural analog. The Chemical Assessments and Related Activities (CARA) list
(U.S. EPA, 1994) does not include any health related documents for sec-butylbenzene. The
potential carcinogenicity of the chemical was also not assessed due to lack of pertinent data. The
toxicity of .vec-butylbenzene has not been reviewed by the ATSDR (2010) or the World Health
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Organization (WHO, 2010). CalEPA (2008) has not derived toxicity values for exposure to
.sfc-butylbenzene but has recommended an action level of 260 |ig/L for .vfc-butylbenzene in
drinking water (CalEPA, 2000). This derivation was based on a subchronic rat NOAEL of
110 mg/kg-day for isopropylbenzene (similar to the structural analog approach taken by U.S.
EPA, 1997a) and incorporated uncertainty factors for interspecies extrapolation, subchronic to
chronic extrapolation, human variability and database deficiencies. No occupational exposure
limits for .sfc-butylbenzene have been derived by the American Conference of Governmental
Industrial Hygienists (ACGIH, 2010), the National Institute of Occupational Safety and Health
(NIOSH, 2010), or the U.S. Occupational Safety and Health Administration (OSHA, 2006).
The HEAST (U.S. EPA, 1997a) does not report a cancer oral slope factor or an inhalation
unit risk value for .sfc-butylbenzene. The International Agency for Research on Cancer (IARC,
2000) has not reviewed the carcinogenic potential of .vfc-butylbenzene. .sfc-Butylbenzene is not
included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2008) has not derived a
quantitative estimate of carcinogenic potential for .sfc-butylbenzene.
Literature searches were conducted on sources published from 1900 through
November 17, 2011, for studies relevant to the derivation of provisional toxicity values for
sec-butylbenzene, CAS No. 135-98-8. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) database of scientific literature. HERO searches the
following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library;
DOE: Energy Information Administration, Information Bridge, and Energy Citations Database;
EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office;
Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics
& Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National
Service Center for Environmental Publications (NSCEP) and National Environmental
Publications Internet Site (NEPIS) database); PubMed: MEDLINE and CANCERLIT databases;
SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET (Toxicology Data Network):
ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP,
GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search,
NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI, and TSCATS; Virtual Health Library; Web
of Science (searches Current Content database among others); World Health Organization; and
Worldwide Science. The following databases outside of HERO were searched for health
information: ACGIH, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW, EPA
TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
Due to the limited toxicity data on sec-butylbenzene, derivation of provisional toxicity
values is not possible for this chemical. As a result, a surrogate has been applied to derive
screening toxicity values only (see Appendix A for details). Because the IRIS reassessment of
isopropylbenzene (cumene; CASRN 98-82-8) will likely use newer noncancer inhalation studies
in the consideration for selecting a principal study (last IRIS revision date: August 1997),
toxicity data on noncancer inhalation exposures to isopropylbenzene (cumene) as the surrogate
for .sfc-butylbenzene are not presented in this document. A PPRTV document on the noncancer
effects of inhalation exposure to .vfc-butylbenzene could be conducted upon the completion of
the isopropylbenzene (cumene) reassessment.
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REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides information for all of the potentially relevant studies.
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Table 2. Summary of Potentially Relevant Data for sec-Butylbenzene (CASRN 135-98-8)
Category
Number of Male/Female,
Species, Study Type, Study
Duration
Dosimetry
Critical Effects
NOAEL
BMDL/
BMCL
LOAEL'
Reference
(Comments)
Notesb
Human
Oral (mg/kg-day)a
None
Animal
Oral (mg/kg-day)a
Acute
No data, Rat
1920 mg/kg°
LD50, was 2.24 mL/kg (1920 mg/kg); no
toxic effects noted
NA
NA
NA
Carpenter et al.
(1974)

10, Rat, sex and purity not
specified; surviving animals
observed for 3 weeks after
dosing
4.29 g/kg-bw°
Eight of 10 animals died with pulmonary
injury the likely cause of death; enlarged
liver due to stress following
biotransformation of sec-butylbenzene
NA
NA
NA
Gerarde (1959)

4, Rat, sex, duration and purity
not specified
2.0 g/kg
No deaths noted; slight weight loss that
was noted earlier in the study
NA
NA
NA
Dow Chemical
Company (1987)
NPR
Short-term
8/0, S-D rat, gastric intubation,
5 days/week, 2 weeks followed
by 10-day observation
812 mg/kg-dayd
No deaths, changes in body-weight gain, or
evidence of ototoxicity observed; use of
control group not specified
812
None
None
Gagnaire and
Langlais (2005)

Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
aNot reported by the study author but determined from data.
bNotes: IRIS = Utilized by IRIS, date of last update; PS = Principal study, NPR = Not peer reviewed.
Dosimetric conversion: g/kg = [mL dose x (g/ml) density] + (kg body weight). Forsec-butylbenzene: 1.25 mL x 0.8580 (g/ml) + 0.250 (kg-bw) = 4.29 g/kg.
dosimetric conversion: mmol/kg-bw-day to mg/kg-day = 8.47 mmol/kg-bw-day x 134.22 (molecular weight) mg/mmol = 1136.8434 (Dose in mg)/kg-bw-day; final dose
is 1136.8434 mg/kg-bw-day x 5 + 7 = 812 mg/kg-day.
NA = Not Available; S-D = Sprague-Dawley.
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HUMAN STUDIES
No information is available regarding oral or inhalation exposure of humans to
sec-buty lb enzene.
ANIMAL STUDIES
The effects of oral or inhalation exposure of animals to sec-buty lb enzene have not been
evaluated in any subchronic-duration, chronic-duration, developmental, reproductive, or
carcinogenic studies.
Oral Exposures
The effects of oral exposure of animals to sec-buty lb enzene have been evaluated in
three acute single-dose toxicity studies (HSDB, 2004; Gerarde, 1959; Dow Chemical Company,
1987; Carpenter et al., 1974) and one short-term repeated-dose toxicity study (Gagnaire and
Langlais, 2005).
Short-term Studies
An acute oral median lethal dose (lethal dose, 50%; LD50) of 2.24 mL/kg-day
(1920 mg/kg) in rats for .vec-butylbenzene is reported by Carpenter et al. (1974; as cited in
ChemlDplus). This LD50 value was recommended by the European Chemicals Bureau with no
study details available. In an acute oral toxicity study conducted by Gerarde (1959, 1960),
several alkylbenzenes—including sec-buty lb enzene (purity not specified)—were administered as
a single dose of 2.5 mL, 1:1 v/v in olive oil (hydrocarbon:olive oil) to fasted rats (// = 10; sex not
specified; actual volume of sec-buty lb enzene is 1.25 mL, or a converted dose of 4.29 g/kg; see
Table 2, footnote d for dose conversion). The rats were observed for 3 weeks posttreatment for
toxicological effects and sacrificed. Animals were weighed once weekly. After sacrifice, liver,
spleen, and kidneys were weighed, and tissues were observed for the appearance of abnormal
morphology. Out of the 10 treated rats, 8 animals died from exposure to sec-buty lb enzene.
Histopathological findings, though not specific to sec-butylbenzene, suggest that pulmonary
injury was likely the cause of death in rats. Additionally, the study author reported a general
trend of liver enlargement, which may have been due to stress following biotransformation of
sec-buty lb enzene and other alkylbenzenes. No other chemical specific toxicological effects were
reported, and no data tables were presented. The study author did not provide an LD50 value for
sec-buty lb enzene. The dose of 4.29 g/kg is considered as a lethal dose low (LDi0) for
sec-buty lb enzene.
In another acute oral toxicity study by Dow Chemical Company (1987), no mortality was
observed in four rats (sex not specified) administered 2.0-g/kg .vec-butylbenzene (purity not
specified) in 10% solution in corn oil. Besides weight loss that was noted earlier in the study, no
other details were provided in the report and an LD50 value was not reported, possibly due to lack
of mortality in treated animals.
Gagnaire and Langlais (2005) published a study investigating the effect of several
aromatic solvents dissolved in olive oil administered via gastric intubation 5 days per week, for
2 weeks, on the ear function of groups of eight male Sprague-Dawley rats. Observations
continued for 10 days following treatment. Each administered dose was 8.47 mmol/kg-day,
which is converted to 812 mg/kg-day for .vec-butylbenzene (99% pure; see Footnote C in Table 2
for dose conversion), after adjusting for continuous exposure and the molecular weight. The use
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of a control group was not specified. Body weights, behavior, and general health were
monitored daily during the treatment period and once weekly until study termination. Following
the observation period, six randomly selected animals per group were sacrificed, and three left
and right cochleas from these rats were processed and counted. The organs of Corti and basilar
membranes were dissected and examined using light and scanning electron microscopy.
None of the animals treated with .vfc-butylbenzene died (use of control group was not
specified), and all animals appeared to gain weight normally. The study authors reported that
.sfc-butylbenzene did not cause any ototoxicity in treated animals. The relationship between the
octanol/water partition coefficient and ototoxicity was also examined, and the study authors
concluded that there was no correlation between these two parameters. Based on these results, a
NOAEL of 812 mg/kg-day is identified for .vfc-butylbenzene in this study, based on a lack of
ototoxicity at this dose. The study's short-term duration, lack of a control group, and lack of
testing at higher doses at which effects may have occurred preclude its consideration for the
derivation of an oral subchronic p-RfD for .sfc-butylbenzene. In addition, the authors did not
conduct a thorough toxicological evaluation of other organs to assess the possible toxicological
potential of .vfc-butylbenzene at the tested dose.
Other Exposures
In a report by Shell Oil Company (1987), seven hydrocarbons, including
sec-butylbenzene, were administered dermally to three male and three female rabbits and not
classified as skin irritants as a result of the semi-occlusive path test, with the exception of
1,3-di-isopropylbenzene. However, the report did state that sec-butylbenzene, among a few
other hydrocarbons, produced noticeable skin effects that persisted for several days after dosing
but did not cause any permanent skin damage. In addition to the skin irritancy test, the study
authors also conducted an eye irritancy test. The instillation of these undiluted seven
hydrocarbons, including sec-butylbenzene, into the conjunctival sac of one eye of each of six
rabbits (three male and three female rabbits) did not result in eye irritancy according to the
Official Journal of the European Communities (EEC, 1983, as cited in Shell Oil Company,
1987). As a result, these seven hydrocarbons were not classified as eye irritants.
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Table 3. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Toxicokinetic
Male S-D rats, exposed to 100-ppm
(549 mg/m3)a'b fer/-butylbenzene
for 3 days, 12 hours/day
Accumulated rapidly and reached steady state conditions in
blood, brain, liver, and kidneys; largest hydrocarbon
concentrations found in the kidneys; in general, higher
concentrations of aromatic hydrocarbons were found in blood
compared to other hydrocarbons tested
Metabolic rate of elimination for
fcrt-butylbcnzcnc is comparatively
high
Zahlsen et al.
(1992)
Metabolism
Animal species and strain not
specified; doses not specified
Metabolism of sec-butylbenzene and alkylbenzenes in general
follows a metabolic pathway that involves oxidative changes
either at the beta, omega, or penultimate carbons on the
side-chain, forming alcohols or carboxylic acids; these
alcohols and carboxylic acids subsequently conjugate with
glucuronic acid and glycine, respectively, and are excreted in
urine
Metabolism primarily occurs on
the side-chain via the oxidative
pathway followed by conjugation
and excretion
HSDB (2004);
Gerarde (1959)
Tissue specific
toxicity
Animal species and strain not
specified; doses not specified; acute
study conducted by administering a
single oral dose of 2.5-mL
sec-butylbenzene in 1:1 v/v olive
oil (1.25 mL sec-butylbenzene;
4.29 g/kg);° surviving animals were
observed for 3 weeks post
exposure.
Irritation in the local endothelial cells leading to changes in the
capillary permeability; change in permeability may lead to
increased diapedesis, petechial and gross hemorrhage and
edema in the surrounding tissues; effects also noted in the
kidneys, liver, spleen, bladder, thymus, brain, and the spinal
cord; accumulation of alkylbenzenes in nerve cells resulting in
signs and symptoms of central nervous system (CNS)
depression such as sluggishness, stupor, coma, narcosis, and
anesthesia; 8 out of 10 animals died following oral
administration of sec-butylbenzene. Necropsy results
indicated lung involvement, with severity ranging from
hyperemia to gross hemorrhage, with pulmonary injury
reported as potential cause of death
Toxicity manifested in the
endothelial cells and CNS.
Branched alkylbenzenes were
reported to be more acutely toxic
compared to the linear
alkylbenzenes
Gerarde (1959,
1960)
Dermal
irritation
New Zealand White rabbits 3/sex,
exposed to 0.5-mL undiluted test
material in a semi-occlusive single-
application patch test (4 hours),
observations made for 14 days after
patch removal, purity of compound
not specified
Very slight to slight inflammation seen from 24 hours up to
72 hours postdosing; all reactions cleared by 14 days
Not a skin irritant based on the test
score (<2) as established in EEC
(1983, as cited in Shell Oil
Company, 1987)
Shell Oil
Company
(1987)
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Table 3. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Eye irritation
The instillation of undiluted
sec-butylbenzene into the
conjunctival sac of the one eye of
each of six rabbits
Severe initial pain; very slight conjunctival redness and
discharge
Not an eye irritant based on the
test score (<2) as established in
EEC (1983, as cited in Shell Oil
Company, 1987)
Shell Oil
Company
(1987)
amg/m3 = ppm x molecular weight ^ 24.45; HEC conversion not presented because this is an acute value.
bNot adjusted for continuous dosing.
Dose conversion: g/kg = [mL dose x (g/mL) density] ^ (kg body weight).
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Toxicokinetics Studies
Studies pertaining to the toxicokinetics of .sfc-butylbenzene in humans and animals were
not located. Zahlsen et al. (1992) investigated the toxicokinetic properties of several
alkylbenzenes, alkanes, and naphthenes in rats (see Table 3). However, a toxicokinetic study on
a structurally similar alkylbenzene, /e/7-butylbenzene, was located. Male Sprague-Dawley rats
exposed to 100-ppm (549 mg/m3; dose not adjusted for continuous dosing) fert-butylbenzene for
12 hours/day, for 3 consecutive days, exhibited the highest concentration of the chemical in fat
followed by the kidneys, liver, brain, and blood on Day 1. The /e/7-butylbenzene concentration
in fat showed a declining trend on Day 2 and 3 following chemical administration with very little
chemical remaining 12 hours after termination of exposure. In contrast, the concentrations of
/e/7-butylbenzene exhibited a slight decline in the kidney, liver, brain, and blood on Day 2 of
chemical administration, which was followed by a slight increase in concentrations on Day 3 of
chemical administration. Concentrations in these organs were either very low or could not be
detected following a 12-hour recovery period after exposure termination. These results may
suggest that the metabolic rate of elimination is high for /e/7-butylbenzene. Though the authors
did not directly measure the toxicokinetic properties of sec-butylbenzene, /e/7-butylbenzene
(CIO alkylbenzene) is also a branched alkylbenzene similar to sec-butylbenzene
(CIO alkylbenzene), thus these two isomers may share similar kinetic properties. Gerarde (1959)
corroborated absorption in the blood and stated that due to the high lipophilicity ofalkylbenzenes,
approximately 85% of the hydrocarbons in the blood is bound to the red blood cells.
Gerarde (1959, 1960) reported that alkylbenzenes tend to accumulate in tissues that have
high lipid content. Distribution results for toluene indicated that the highest amount of the
alkylbenzene was found in the adrenals followed by the cerebellum, bone marrow, brain, liver,
blood, kidney, spleen, lung, thyroid, and the pituitary. Based on the distribution of toluene, the
author suggested that the ".. .distribution and accumulation of other alkyl derivatives of benzene
would have a similar pattern" (Gerarde, 1959, p. 34).
The metabolism of .sec-butylbenzene and alkylbenzenes, in general, follow a common
metabolic pathway (HSDB, 2004; Gerarde, 1959, 1960) that involves oxidative changes either at
the beta, omega, or penultimate carbons on the side-chain, forming alcohols or carboxylic acids.
These alcohols or carboxylic acids subsequently conjugate with glucuronic acid or glycine,
respectively, and are excreted in the urine (Gerarde, 1959, 1960). Gerard also reported that
".. .ring oxidation rarely occurs if an alkyl group is present" (Gerarde, 1959, p. 34). In a later
report, Gerard and Ahlstrom (1966) showed that ring hydroxylation increases with increasing
length of the alkyl side-chain of ^-alkylbenzene, but they did not examine the biotransformation
on branched alkylbenzenes. The mechanism of side-chain oxidation seems to facilitate
detoxification and is the preferred pathway for alkylbenzenes, in general, which is exemplified
when benzene toxicity is compared with the toxicity of methyl benzene (toluene). The addition
of a methyl group to the benzene ring changes the metabolic pathway, which is reflected by the
general metabolism of alkylbenzenes.
These biotransformations may take place in the liver microsomes and also other tissues
including the brain, spinal cord, bone marrow, kidney, and adrenal glands. In summary,
hydroxylation or carboxylation can occur at various methyl groups in linear and branched chains
of alkylbenzenes, followed by conjugation with glycine or glucuronic acid for excretion in urine.
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In addition, Gerarde and Ahlstrom (1966) stated that there could be a dual metabolic pathway of
side-chain oxidation and ring hydroxylation, with the former preferred in rats.
While specific excretion data for .vfc-butylbenzene were not readily available, Gerarde
(1959, 1960) reported on the excretion of several alkylbenzenes, stating that alkylbenzenes are
either eliminated from the blood as unchanged hydrocarbons or as metabolites. Unchanged
hydrocarbons may be exhaled through the lungs, with a small fraction being excreted in the
urine. Metabolites of alkylbenzenes are water soluble and are found in urine. In general, due to
their low vapor pressure, alkylbenzenes are not rapidly eliminated from blood as compared to
benzene.
Toxicity of Alkylbenzenes in Various Tissues
In addition to toxicokinetic data, Gerarde (1959, 1960) provided information regarding
the effects of alkylbenzenes in various tissues following absorption. Gerarde (1959, 1960)
reported that alkylbenzenes dissolved in blood cause local irritation of endothelial cells, resulting
in changes in capillary permeability that may lead to increased diapedesis, petechial and gross
hemorrhage, and edema in the surrounding tissues. Gerarde (1959, 1960) stated that these
changes were seen frequently in lungs of animals that were treated with alkylbenzenes
intragastrically, subcutaneously, or via intraperitoneal injection. Branched and unsaturated chain
alkylbenzenes were reported to be more irritating than the corresponding unbranched and
saturated alkylbenzene isomers. Secondary to the endothelial injury, other tissues in which
effects were noted included the kidneys, liver, spleen, bladder, thymus, brain, and spinal cord.
Alkylbenzenes have a particular affinity to nerve tissues (Gerarde, 1959, 1960). The high
lipid content of these tissues leads to accumulation of alkylbenzenes in nerve cells, resulting in
signs and symptoms of central nervous system (CNS) depression such as sluggishness, stupor,
coma, narcosis, and anesthesia. The intensity and quality of these effects were described by the
study author to be dependent upon the concentration or number of molecules of alkylbenzenes
present in the cell at any given time. Gerarde (1959, 1960) also stated that the narcotic potency
of alkylbenzenes is dependent on the chain length, branching, and diversity of alkylation.
Potency reportedly decreased with chain length, dropping off sharply at the four-carbon chain
length and decreasing steadily from thereon as the carbon chain length decreased (i.e., CNS
effects of toluene > ethylbenzene > propylbenzene > butylbenzene). Toluene and ethylbenzene
were reported to be fast-acting narcotics, whereas //-propyl and //-butylbenzene were slow in
manifesting CNS effects. The rate of initiation of CNS effects is related to the rate of absorption
of these chemicals in the blood from the portal of entry and subsequent transfer to the brain.
Because rate of absorption is dependent on water solubility, and water solubility decreases with
increasing chain length and diversity in alkylation, the rate of absorption decreases accordingly.
However, the duration of the CNS effects from exposure to alkylbenzenes increases with higher
chain length and branching of the side-chain. As a result, isopropylbenzene and ^-butylbenzene
are long-acting CNS agents compared to toluene and ethylbenzene, which are short-acting
nervous system agents. Gerarde (1959, 1960) stated that the long-lasting action of branched and
higher chain length alkylbenzenes is most likely related to the excretion rate of these
hydrocarbons from the cells in which they accumulate. Accumulation is dependent on how
quickly alkylbenzenes are biotransformed in situ and in other tissues (e.g., liver, kidney) into
water-soluble metabolites. Because the branched side-chain alkylbenzenes with the same
number of carbon atoms are oxidized more slowly compared to the linear alkylbenzenes, the
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CNS effects of branched alkylbenzenes are longer lasting in contrast to the linear alkylbenzenes.
The CNS effects of alkylbenzenes last as long as these hydrocarbons are present in the cells;
thus, a large dose of these chemicals can produce profound narcosis and coma and may result in
permanent effects in the CNS tissues, particularly in the brain.
Gerarde (1959, 1960) stated that branched alkylbenzenes such as isopropylbenzene,
/m-butylbenzene, and .vfc-butylbenzene cause more irritation than the linear alkyl groups. Such
irritation, as previously mentioned, might lead to hemorrhage in the brain and spinal cord, and
the damage could be permanent. For hematopoietic effects, in contrast to exposure to benzene,
Gerarde (1959) did not find any alkylbenzenes that cause leucopenia or injury to the
blood-forming tissues.
In acute toxicity studies conducted by Gerarde (1959, 1960), groups of 10 fasting rats
(sex and strain not specified) were administered a single oral (method of administration not
specified) dose of 2.5 mL of sec-butylbenzene (purity not specified) 1:1 v/v in olive oil (1.25 mL
of .sfc-butylbenzene) along with other alkylbenzenes. Following administration, surviving rats
were observed for a period of 3 weeks for signs of toxicity and abnormal activity. Animals were
weighed once per week during the observation period and sacrificed at study termination.
Kidneys, liver, and spleen weights were determined postmortem, and tissues were examined
histopathologically for abnormal changes. A higher rate of mortality was observed in rats treated
with branched alkylbenzenes (isopropylbenzene: 6/10; .sfc-butylbenzene: 8/10;
fert-butylbenzene: 7/10) compared to linear alkylbenzenes («-propylbenzene: 3/10;
//-butylbenzene: 2/10; toluene: 3/10) with ethylbenzene (7/10) being the only exception among
linear alkylbenzenes resulting in a higher mortality rate. Gerarde (1959) stated that necropsy
results indicated that the lungs were one of the target organs, with the severity in lung injury
ranging from hyperemia to gross hemorrhage. This lung injury was most likely the cause of
death when gross hemorrhage was observed because the author stated that the principal cause of
death was "chemical pneumonitis with pulmonary edema and hemorrhage." Additionally,
vasodilation of the blood vessels of the gastrointestinal tract and general hyperemia were
consistently noted in animals treated with alkylbenzenes. Hemorrhage in the tissues (lungs,
thymus, adrenal, and bladder) was assumed to be as a result of increased capillary permeability
due to irritation in the endothelial cells in contact with alkylbenzenes dissolved in blood.
Overall, Gerarde (1959) concluded that branched-chain mono-alkylbenzenes (isopropyl-,
sec-, /f/V-butylbenzenes) are more toxic compared with the corresponding linear isomers
(//-propylbenzene, //-butylbenzene) and dialkylbenzenes (di-isopropylbenzene,
di-fert-butylbenzene). Liver enlargement was commonly observed in animals treated with
various alkylbenzenes. Gerarde (1959) reported that this was probably due to exposure-induced
stress on the liver that resulted from biotransformations intended to eliminate the chemicals.
Animals dosed with branched-chain alkylbenzenes developed enlarged livers. Additionally, the
spleen was either normal or enlarged, but no thymus effects were noted. Gerarde (1959) stated
that this was in contrast to effects observed in benzene-treated animals, where a marked
involution of thymus and spleen was observed.
In conclusion, exposure to alkylbenzenes may cause various effects in various tissues.
Based on the discussion presented above, it is also notable that the branched alkylbenzenes are
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more toxic in nature in comparison to their linear counterparts in term of noncancer effects (the
same assumption may not be true for cancer effects).
Genotoxicity Studies
No studies investigating the genotoxic effects of .sfc-butylbenzene were identified.
DERIVATION OF PROVISIONAL VALUES
Table 4 below presents a summary of noncancer screening oral provisional reference
values (see Appendix A for details). Table 5 presents a summary of cancer values. IRIS data, if
available, are included in the table.
Table 4. Summary of Screening Oral Provisional Reference Values
for sec-Butylbenzene (CASRN 135-98-8)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Screening
subchronic p-RfD
(mg/kg-day)a
Rat/Female
Increased kidney
weight in female
rats
1 x KT1
NOAELadj
110
1000
Wolf et al.
(1956)
Screening chronic
p-RfD
(mg/kg-day)a
Rat/Female
Increased kidney
weight in female
rats
1 x KT1
NOAELadj
110
1000
Wolf et al.
(1956)
aIRIS (U.S. EPA, 1997b); isopropylbenzene (cumene) used as surrogate.
Table 5. Summary of Cancer Values for sec-
Butylbenzene (CASRN 135-98-8)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF
None
None
None
None
p-IUR
None
None
None
None
DERIVATION OF ORAL REFERENCE DOSES
Feasibility of Deriving Subchronic and Chronic Provisional RfDs (Subchronic and
Chronic p-RfDs)
No chronic or subchronic toxicity data were identified for the derivation of an oral
provisional RfD (p-RfD) for .sfc-butylbenzene. However, Appendix A of this document contains
Screening Values (screening oral subchronic and chronic p-RfDs) using a surrogate (e.g.,
structural and metabolic) approach, which may be of use under certain circumstances. Please see
Appendix A for details regarding the screening-level values.
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CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 6 identifies the cancer WOE descriptor for .vfc-butylbenzene (in bold).
Table 6. Cancer WOE Descriptor for sec-Butylbenzene
Possible WOE
Descriptor
Designation
Route of Entry
(Oral, Inhalation,
or Both)
Comments
"Carcinogenic to
Humans "
N/A
N/A
No studies pertaining to the
carcinogenicity of .sfc-butylbenzene in
humans are available.
"Likely to be
Carcinogenic to
Humans "
N/A
N/A
No studies pertaining to the
carcinogenicity of .sfc-butylbenzene in
multiple species of animals are available.
"Suggestive
Evidence of
Carcinogenic
Potential"
N/A
N/A
No data are available regarding the
carcinogenic potential of
.sfc-butylbenzene even in a single animal
species.
"Inadequate
Information to
Assess
Carcinogenic
Potential"
Selected
Both
There is little or no pertinent
information available to assess the
carcinogenic potential of
sec-butylbenzene.
"Not Likely to be
Carcinogenic to
Humans "
N/A
N/A
No data are available to suggest that sec-
butylbenzene is not likely to be a
carcinogen in humans following oral or
inhalation exposure.
N/A=Not applicable.
DERIVATION OF PROVISIONAL ORAL AND INHALATION CANCER VALUES
The lack of quantitative data on the carcinogenicity of .sfc-butylbenzene precludes the
derivation of a quantitative estimate of risk for either oral (p-OSF) or inhalation (p-IUR)
exposures.
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APPENDIX A. PROVISIONAL SCREENING VALUES
DERIVATION OF SCREENING ORAL PROVISIONAL REFERENCE VALUES
For reasons noted in the main PPRTV document, it is not possible to derive provisional
toxicity values for .sfc-butylbenzene. 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. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
Potential Principal Study
A NOAEL of 812 mg/kg-day (highest dose tested) was identified for .vfc-butylbenzene
from the 2-week study by Gagnaire and Langlais (2005). However, the lack of ototoxicity in
animals following exposure to sec-butylbenzene, the lack of a control group, and the lack of
testing at higher doses, which may have caused an effect, precludes the use of this study for the
derivation of an oral subchronic p-RfD for .sfc-butylbenzene. In addition, the authors did not
conduct a thorough toxicological evaluation of other organs to assess the possible toxicological
potential of .vfc-butylbenzene at the tested dose.
ALTERNATIVE APPROACH—A SURROGATE APPROACH
Three types of potential surrogates (structural, metabolic, and toxicity-like) were
identified to facilitate the final surrogate chemical selection. Details regarding searches and
methods are presented in Wang et al. (2012). The surrogate approach may or may not be
route-specific or applicable to multiple routes of exposure. In this document, it is limited to the
oral noncancer effects only based on the available toxicity information. All information was
considered together as part of the final WOE approach to select the most suitable surrogate both
toxicologically and chemically.
Structural Similarity
Structural analogs or surrogates were first identified using the National Library of
Medicine, ChemlDplus (http://chem.sis.nlm.nih.aov/ChemIDplus/) and then EPA DSSTox
(www.epa.gov/dsstox) databases. Thirty-one possible analogs (structural surrogates) were
identified using ChemlDplus (2010) with the similarity match set to >50%, and 27 possible
analogs were identified using DSSTox with the similarity match set to >70%. ChemlDplus
identified only one structural surrogate with repeated dose with a similarity match of 53% to
.sfc-butylbenzene: isopropylbenzene. DSSTox identified three structural surrogates with
repeated dose, //-butylbenzene (C10H14), isopropylbenzene (C9H12), and ethylbenzene (CgHio) as
structurally similar to .vfc-butylbenzene with similarity score of 83.8, 81.4, and 77.7%,
respectively (see Table C. 1). Based on the structural information and consensus of two
similarity search programs (ChemlDplus and DSSTox), isopropylbenzene is considered to be the
best structural surrogate.
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Toxicokinentic Data
Available information on the toxicokinetics of .sfc-butylbenzene, ethylbenzene,
//-butylbenzene, and isopropylbenzene suggests that all four chemicals are readily absorbed into
the blood following administration via different routes and excreted as unchanged hydrocarbons
or biotransformed products, primarily unchanged via the lungs or in the urine as water-soluble
metabolites (Gerarde, 1959). Gerarde (1959) also stated that the amount of alkylbenzene
exhaled via the lung was dependent on the concentration of the chemical in the blood and its
vapor pressure. Consequently, chemicals with low vapor pressures such as .vfc-butylbenzene and
isopropylbenzene are not efficiently excreted from blood unchanged. Chemical-specific
absorption and metabolic data via the oral route are presented in Table A.l. Because absorption
data for .vfc-butylbenzene were not available, a comparison of absorption between the
three possible surrogates and .vfc-butylbenzene cannot be made. However, based on the
absorption, distribution, and excretion information from Gerarde (1959), alkylbenzenes, in
general, as a chemical class, are primarily absorbed in the blood, distributed to various tissues on
the basis of blood flow and lipid content, and are excreted primarily in the urine as water-soluble
metabolites or exhaled unchanged.
Table A.l. Comparative Toxicokinetic Data for sec-Butylbenzene and Potential Surrogates
Chemical
Route
Species
Absorption
Basis
Reference
Ethylbenzene
Oral
Rabbit
73-83%
Elimination of metabolites in urine
(hippuric acid, methylphenylcarbinyl
glucosiduronic acid, and phenaceturic
acid)
El Masry et al., 1956
Isopropylbenzene
Oral
Rat
>70%
Elimination of metabolites in urine
(2-phenyl-2-propanol and its
glucuronide or sulfate conjugates,
and conjugates of 2-phenyl-
1,2-propanediol)
Research Triangle
Institute, 1989
//-Butylbenzene
Oral
Rabbit
68-78%
Elimination of metabolites in urine
(hippuric acid, phenylpropyl- and
methylpenethyl-carbinylglucuronides
and phenaceturic acid)
El Masry et al., 1956
sec-Butylbenzene
No data
No data
No data
No data
NA
NA = Not applicable.
While specific metabolism data for .sfc-butylbenzene could not be located, Gerarde
(1959) reported that metabolism of alkylbenzenes, in general, follows a metabolic pathway that
involves oxidative changes at either the beta, omega, or penultimate carbon on the side-chain
forming alcohols or carboxylic acids. These alcohols and carboxylic acids are subsequently
conjugated with glucuronic acid or glycine and excreted in the urine (Gerarde, 1959).
Hydroxylation or carboxylation can occur at various methyl groups in linear and branched
alkylbenzenes followed by conjugation with glycine or glucuronic acid for excretion in urine.
These biotransformations most likely occur in liver microsomes; however, they may also take
place in the brain, spinal cord, bone marrow, kidney, and occasionally in the adrenal glands as
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well (Gerarde, 1959). Based on the toxicokinetic information, ethylbenzene, //-butylbenzene,
and isopropylbenzene are considered as metabolic surrogates. In addition, based on the
structural and toxicokinetic information, the three alkylbenzenes are considered as potential
surrogates.
Acute Lethality
The acute oral toxicity of sec-butylbenzene, isopropylbenzene, and ethylbenzene was
much higher compared with the acute oral toxicity of //-butylbenzene in fasted rats administered
2.5 mL of each of these hydrocarbons in 1:1 v/v olive oil (Gerarde, 1959; see Table A.2).
Additionally, as described in the "Toxicity of Alkylbenzenes in Various Tissues" section above,
Gerarde (1959) clearly states that the toxicity of branched alkylbenzenes is higher in comparison
to their single-chain counterparts via oral exposures. Based on the available LD50/LDio and
mortality data (see Table A.2), isopropylbenzene seems to be the most acutely toxic via the oral
route.
Table A.2. Acute Oral Toxicity of sec-Butylbenzene and Potential Surrogates3
Chemical
M-Butylbenzene
Ethylbenzene
Isopropylbenzene
(cumene)
sec-Butylbenzene
Oral LD50 (g/kg)
Oral LDio (g/kg)
NA
4.30b c (rat, not
specified as a LD50
by author; considered
as a LDlo)
S.S3-'1 (rat); 5.46a (rat)
2.9la (rat); 1.4d (rat)
1.92°'d (rat)
4.29b'° (rat, not
specified as a LD50 by
author; considered as a
LDlo); 2.0e
Mortality in fasted
rats following a
single oral dose of
2.5 mL of each
alkylbenzene in
1:1 v/v olive oilb
2/10
7/10
6/10
8/10
aHSDB (2004), unless otherwise noted.
bGerarde (1959).
Dose Conversion: g/kg = [mL dose x (g/mL) density] ^ (kg body weight). For//-butylbenzene: 1.25 mL x
0.8601 (g/ml)/0.250 kg-bw = 4.30 g/kg.
dChemIDplus (2010).
eDow Chemical Company (1987).
Other Data
Toxicity in various tissues, acute lethality data, and toxicokinetics resulting from
exposures to alkylbenzenes, in general, are described in detail in the "Toxicity of Alkylbenzenes
in Various Tissues" and "Toxicokinetic Studies" sections of this document. In the endothelium,
alkylbenzenes present in the blood cause irritation, which may lead to various effects including
gross hemorrhage. These changes are often seen in the lungs of animals exposed to
alkylbenzenes via gavage, subcutaneously, or i.p. (Gerarde, 1959). Gerarde (1959) also states
that due to their high lipophilic nature, alkylbenzenes can cause CNS effects that can lead to
sluggishness, narcosis, coma, and anesthesia. Based on toxicity manifestation in these tissues,
Gerarde (1959) states that branched alkylbenzenes are more toxic compared to the linear
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alkylbenzenes. This information suggests that the branched surrogate (isopropylbenzene) may
be more suitable over the linear surrogates (ethylbenzene and //-butylbenzene).
Physicochemical properties among sec-butylbenzene and three potential surrogates are
generally comparable (i.e., molecular weight, melting point, boiling point, and logKow). The
major differences are water solubility and vapor pressure at room temperature (see Table A.3).
Ethylbenzene seems to be the "outlier," while the values of these two properties are more similar
among .sec-butylbenzene, isopropylbenzene, and //-butylbenzene. It is noteworthy that the
physicochemical properties of .sec-butylbenzene are most similar to those of ^-butylbenzene, but
its acute toxicities are closely aligned with those of isopropylbenzene.
Genotoxicity data for isopropylbenzene indicate that there were no genotoxic effects in
Saccharomyces cerevisiae or in Salmonella typhimurium (one or more of the five standard
strains: TA98, TA100, TA1535, TA1537, and TA1538) as a result of exposure to
isopropylbenzene (Gene-Tox, 2010). It is not clear if results were negative both in the presence
and absence of metabolic activation (±S9). Isopropylbenzene also did not induce any mutations
in a mutagenicity assay in Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) both
in the presence and absence of metabolic activation (HSDB, 2005a). Genotoxic results for
ethylbenzene were mixed with positive results seen in in vitro tests using human lymphocytes
(sister chromatid exchange) and negative results seen in Syrian hamster embryo cells (cell
transformation; HSDB, 2005b). Genotoxicity data for .sec-butylbenzene and ^-butylbenzene
were not located; thus a comparison between .sec-butylbenzene's genotoxic potential and that of
the other three alkylbenzenes (isopropylbenzene, ^-butylbenzene, and ethylbenzene) is not
feasible. However, it is likely that .sec-butylbenzene would not be genotoxic based on analogy to
isopropylbenzene.
In conclusion, an attempt was made to derive toxicity values for .sec-butylbenzene using
ethylbenzene, ^-butylbenzene, and isopropylbenzene (cumene) as potential surrogates. Further
comparison of these potential surrogates is made based on the profiles of structural similarity,
toxicokinetics, acute and tissue specific toxicity, and genotoxicity. Table C. 1 in Appendix C
provides a list of potential surrogates that have a peer-reviewed toxicity value in either IRIS,
HEAST, or PPRTV databases. The chronic oral RfDs for the three potential surrogates are
generally comparable to one another, ranging from 0.05 to 0.1 mg/kg-day, and therefore, use of
any of the three potential surrogates would have resulted in a similar screening chronic p-RfD for
.sec-butylbenzene. Common target organs among the potential surrogates include kidneys and
liver, with kidneys likely to be the most sensitive endpoint for .sec-butylbenzene based on the
structural information and critical effects (branched vs. linear; see Table A.3).
Overall, based on weight-of-evidence of all the information presented above,
isopropylbenzene appears to be the most appropriate surrogate for .sec-butylbenzene (high
similarity score, similar toxicokinetic profile and target organs, and comparable acute toxicity;
see Tables A. 1-3 and C. 1). The information presented in the sections above supports
isopropylbenzene (cumene) as a better surrogate for .sec-butylbenzene than either ^-butylbenzene
or ethylbenzene. Though there are data gaps in the information compiled in the main text and in
the Appendix, the following factors are considered in support of using isopropylbenzene as the
surrogate for .sec-butylbenzene:
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Similar patterns in absorption, distribution, and excretion (Gerarde, 1959)
Similar patterns in metabolic activation and elimination (Gerarde, 1959)
Similar physicochemical properties (see Table A.3)
Similar structure
o Structural similarity of 81.4% using the DSSTox database
(www.epa.gov/dsstox) and 53% using ChemlDplus (2010)
o Both isopropylbenzene and .vfc-butylbenzene are branched alkylbenzenes, and
toxicity from branched alkylbenzenes is reported to be higher in various
tissues than that of their linear counterparts (ethylbenzene and
//-butylbenzene; Gerarde, 1959)
Similar patterns in ototoxicity: branched alkylbenzenes did not cause ototoxicity
(Gagnaire and Langlais, 2005)
Similar patterns in acute toxicities (see Table A.2)
Higher acute toxicity of isopropylbenzene compared to .vfc-butylbenzene (see
Table A.2)
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Table A.3. Comparison of Available Toxicity Data for sec-Butylbenzene and Potential Surrogates3
Characteristic
sec-Butylbenzene
Isopropylbenzene (Cumene)b
w-Butylbenzene
Ethylbenzeneb
Structure
>CH,
h3c
[A
vo
h3c x	/
kJ

CASRN
135-98-8
98-82-8
104-51-8
100-41-4
Molecular formula
C10-H14
C9-H12
C10-H14
C8-H10
Molecular weight
134.221
120.194
134.221
106.167
ChemlDplus similarity score
(%)
100
NA
NA
NA
DSSTox similarity score (%)
100
81.4
83.8
77.7
Melting point (°C)
-8.27 x 101
-9.6 x 101
-8.79 x 101
-9.49 x 101
Boiling point (°C)
173.5
152.4
183.3
131.6
Vapor pressure
(mm Hg at 25°C)
1.75
4.5
1.06
9.6
Water solubility
(mg/L) at 25°C
17.6
61.3
11.8
169
Log Kow
4.57
3.66
4.38
3.15
pKa
NA
NA
NA
NA
Oral LD50 in rats (route:
effect)
1920 mg/kg (oral; none)
1400 mg/kg
(oral: gastritis)
NA
3500 mg/kg (oral exposure:
changes in liver, kidney, ureter,
bladder)
Oral LD50 in mice (route:
effect)
NA
12,750 mg/kg (oral exposure: no
effects reported)
NA
NA
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Table A.3. Comparison of Available Toxicity Data for sec-Butylbenzene and Potential Surrogates3
Characteristic
sec-Buty lb enzene
Isopropylbenzene (Cumene)b
M-Butylbenzene
Ethylbenzeneb
Dermal LD50 in rabbits
(route: effect)
>16mL/kg
12.3 mL/kg (dermal exposure: no
effects reported)
NA
17.8 mL/kg (dermal exposure: no
effects reported)
Chronic oral RfD
Critical effect
POD
(source)
NA
1 x 10 1 mg/kg-day
Increased average kidney weight in
female rats
NOAELadj: 110 mg/kg-day
(U.S. EPA, 1997b)
5 x 10 2 mg/kg-day
Increased incidences of
hepatocellular hypertrophy in F0
and F1 parent male rats
BMDLi0: 137 mg/kg-day
(U.S. EPA, 2010b)
lx 10 1 mg/kg-day
Liver and kidney toxicity
NOELadj: 97.1 mg/kg-day
(U.S. EPA, 1991)
aFrom ChemlDplus unless otherwise noted.
bFrom DSSTox analysis.
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The summary of the IRIS Toxicological Review of Cumene (U.S. EPA, 1997c) on
dose-response (Section 6.2) is provided as an excerpt in the following (U.S. EPA, 1997b):
The quantitative estimates of human risk as a result of low-level chronic
exposure to cumene are based on animal experiments because no human data
exist.
The human dose that is likely to be without an appreciable risk of
deleterious noncancer effects during a lifetime (the RfD) is 0.1 mg/kg-day. This
amount is 1/1000 of the dose, adjusted for the stated schedule, at which no
adverse effects were noted in female rats dosed orally with cumene over a period
of about 7 mo (Wolf et al., 1956).
The overall confidence in the RfD assessment is low to medium. The
confidence in the principal study is low. For purposes of quantitative assessment,
the quality of the principal study (Wolf et al., 1956) is marginal because the group
sizes are minimal and comprise females only, and little quantitative information is
presented. The confidence in the database, judged here as medium to low, is
improved from the earlier version on IRIS, principally because of the availability
of inhalation developmental studies; some reproductive measures; corroboration
of the critical effect by other studies, including those using oral dosing; and
kinetic information. Kinetic information on oral and inhalation routes of exposure
(Research Triangle Institute, 1989) justifies utilization of inhalation
developmental studies performed in two species, rats and rabbits, in which no
adverse results were noted. However, no 2-year chronic study is available via the
oral or inhalation route. No multigeneration studies are available for this
compound. Results on some male reproductive parameters were, however,
documented in Cushman et al. (1995), the principal study for the RfC. The rapid
metabolism and excretion of cumene in both animals and humans, coupled with
the information on sperm morphology reported by Cushman et al. (1995), also
indicate cumene to have a low potential for reproductive toxicity. The critical
effect, altered tissue weights, was the same across routes of exposure (this was
also the critical effect for the RfC) and was observed in several studies giving
confidence in the consistency of this effect.
Justification for the use of a partial uncertainty factor for subchronic to
chronic extrapolation was twofold: (1) the duration of the principal study (6 to
7 mo) was intermediate, between subchronic (3 mo) and chronic (24 mo)
duration, and (2) toxicokinetic data (Section 3) indicate that inhaled cumene and
its metabolites are cleared quickly from both humans and rats, which also could
indicate low potential for cumulative damage.
The daily exposure to the human population that is likely to be without an
3
appreciable risk of deleterious effects during a lifetime (the RfC) is 4E-1 mg/m .
This concentration is 1/1000 of the adjusted no-effect level for significant
increases (>10%) in renal and adrenal weights in rats exposed to cumene in the
subchronic inhalation study of Cushman et al. (1995).
The overall confidence in the RfC assessment is medium. The RfC is based
on rat subchronic inhalation studies performed with relatively large group sizes
in which thorough histopathological analyses and ancillary studies of
neurotoxicity and ocular pathology were performed. The scientific quality of this
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evidence is high. The confidence in the database for the cumene RfC is rated as
medium. Acceptable developmental studies were carried out (via inhalation route)
in two species, rats and rabbits, with no adverse results noted; however, no
2-year chronic studies are available. As with the RfD database, full-scale
multigeneration reproductive studies are lacking. The critical effect, altered tissue
weights, is consistent across routes of exposure (altered kidney weight was also a
critical effect for the RfD).
The use of a partial uncertainty factor for interspecies extrapolation is
justified because species-to-species dosimetric adjustments were made and an
HEC was calculated.
An area of scientific uncertainty and controversy in this assessment
concerns the renal lesions in the male rats observed in the principal study. The
descriptions of these lesions strongly suggest the male-specific rat nephropathic
response elicited by compounds such as d-limonene anddecalin (U.S. EPA,
1991a). This assessment has discounted these histopathological lesions in
establishing an effect level for derivation of the RfC because EPA does not
consider such lesions to be an appropriate endpoint for determining noncancer
toxicity. If the male rat renal effects had not been discounted, then the RfD would
have been approximately fivefold lower, because the NOAEL would be 100 ppm
versus 496ppm. What has been accepted as toxicologically relevant from the
profile of renal toxicity in the principal study is the increase in female renal
weight. Other repeated-dose studies with cumene also have reported increased
renal weights among female rats (Wolf et al., 1956; Monsanto, 1986; Chemical
Manufacturer's Association, 1989). These independent observations, coupled with
the uncertainty about the progression and outcomes of these alterations (because
of the absence of any true lifetime studies) further justifies considering these
weight alterations as toxicologically significant.
Oral Toxicity Values
Screening Subchronic and Chronic p-RfDs
For .sfc-butylbenzene, the IRIS chronic value for isopropylbenzene (1 x 10 1 mg/kg-day)
based on increased average kidney weight in female Wistar rats from a 194-day study
(Wolf et al., 1956) is recommended as a screening p-RfD based on the chemical-class specific
information (e.g., metabolic profile) and overall surrogate approach presented in this document.
IRIS used a NOAEL of 154 mg/kg-day (converted to 110 mg/kg-day for continuous exposure)
and applied a composite UF of 1000 including a UF of 10 for interspecies extrapolation, a UF of
10 for intraspecies variability, a partial UF of 3 to extrapolate from a less than chronic (194-day
study) study to a chronic duration, and a partial UF of 3 for database deficiencies (lack of
reproductive information). Based on the current understanding of the surrogate approach, it is
assumed that all attributes such as critical effect, POD, and all UFs of the surrogate chemical be
adopted for the chemical of concern (unless a different [surrogate] adverse effect was used).
Based on the surrogate analysis presented in this appendix, the IRIS chronic RfD of
1 x 10-1 mg/kg-day for isopropylbenzene is recommended for the screening chronic p-RfD for
sec-buty lb enzene.
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Given the lack of subchronic data for isopropylbenzene (cumene) as the surrogate
chemical for .vfc-butylbenzene and the uncertainty associated with the use of a surrogate
approach for the derivation of toxicity values, the same value of 1 x 10_1mg/kg-day is
recommended for the screening subchronic p-RfD.
While studies providing specific effects for .vfc-butylbenzene following oral exposures
could not be located, the information regarding metabolism, absorption, and tissue specific
toxicity provided in the Gerarde (1959) study, and the lack of ototoxicity in both
.sfc-butylbenzene and isopropylbenzene (Gagnaire and Langalais, 2005), provide some
confidence that the observed effects, or lack thereof, following long-term oral exposures to
isopropylbenzene may also be expected following long-term oral exposures to .sfc-butylbenzene.
Because the toxicity of short-chain alkylbezenes was not dependent upon the molecular weight
and the actual mechanism of action is not elucidated, a molecular weight-adjustment was not
applied (in general, an adjustment is not considered when the difference in molecular weights is
less than 2-fold).
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APPENDIX B. DATA TABLES
No data tables are presented.
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APPENDIX C. POTENTIAL SURROGATES FROM DSSTOX AND CHEMIDPLUS
WITH AVAILABLE VALUES FROM IRIS, PPRTV, AND HEAST DATABASES
Table C.l. Results of DSSTox and ChemlDplus Structure Similarity Search
for .sec-Butyl benzene
Oral Exposure—Rt'D
Chemical Name
Similarity
Search Engine
Percent
Similarity
Match
(DSSTox/
ChemlDplus)
IRIS Value
(Chronic
RID)
PPRTV
Value
(Chronic
RID)
PPRTV
Value
(Subchronic
RID)
HEAST Value
(Subchronic
RID)
sec-Butylbenzene
DSSTox/
ChemlDplus
100
NA
NAa
NAa
NA
Isopropylbenzene
DSSTox/
ChemlDplus
81.4/53.0
1 x 10"1
mg/kg-day
(U.S. EPA,
1997b)
NA
NA
4 x 10"1
mg/kg-day
(U.S. EPA,
2003)
Ethylbenzene
DSSTox
77.7
1 x 10"1
mg/kg-day
(U.S. EPA,
1991)
NAb
5 x 10~2
mg/kg-day
(U.S. EPA,
2009)
NAb
//-butylbcnzcnc
DSSTox
83.8
NA
5 x 10~2
mg/kg-day
(U.S. EPA,
2010b)
0.1 mg/kg-day
(U.S. EPA,
2010b)
NA
Surrogate approach used to develop toxicity values in this PPRTV.
bValue not derived because of the existing IRIS value(s).
Note: NA = Not available.
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