United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-12/005F
Final
11-28-2012
Provisional Peer-Reviewed Toxicity Values for
tert- B uty [benzene
(CASRN 98-06-6)
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
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
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 7
ANIMAL STUDIES 7
Oral Exposures 7
Acute and Short-term Studies 7
Other Exposures 9
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 12
Toxicokinetics Studies 12
Toxicity of Alkylbenzenes in Various Tissues 13
Genotoxicity Studies 15
In Vitro Cell Signaling and Carcinogenic Potential Studies 15
DERIVATION 01 PROVISIONAL VALUES 15
DERIVATION OF ORAL REFERENCE DOSES 16
Feasibility of Deriving Subchronic and Chronic Provisional RfD (Subchronic and
Chronic p-RfDs) 16
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 16
DERIVATION OF PROVISIONAL ORAL AND INHALATION CANCER VALUES 17
APPENDIX A. PROVISIONAL SCREENING VALUES 18
APPENDIX C. POTENTIAL ANALOGS FROM DSSTOX AND CHEMIDPLUS WITH
AVAILABLE VALUES FROM THE IRIS DATABASE, THE HEAST, AND THE PPRTV
DATABASE 31
APPENDIX D. REFERENCES 32
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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
NOAELhec
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
111
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
tert-BUTYLBENZENE (CASRN 98-06-6)
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 flittp://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.eov/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).
1
/£/7-Butylbenzene
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INTRODUCTION
/m-Butylbenzene—sometimes referred to as (1,1-dimethylethyl)benzene,
2-methyl-2-phenylpropane, or dimethylethylbenzene—is a colorless liquid that is used primarily
as a solvent in the synthetic organic chemistry industry and as a polymer-linking agent (HSDB,
2005a). The empirical formula for /f/V-butylbenzene is C10H14 (see Figure 1). A table of
physicochemical properties is provided in Table 1.
ch3
Figure 1. terf-Butylbenzene Structure
Table 1. Physicochemical Properties Table for
terf-Butylbenzene (CASRN 98-06-6)
Property (unit)
Value
Boiling point (°C)
169.la
Melting point (°C)
-57.8a
Density (g/cm )
0.8669b
Vapor pressure (mm Hg a at 25°C)
1.75a
pH (unitless)
NA
Solubility in water (mg/L at 25°C)
29.5a
Relative vapor density (air =1)
4.62b
Molecular weight (g/mol)
134.22a
Flash point (°C)
52b
Octanol/water partition coefficient (unitless)
4.1 la
aChemIDplus (2010).
'"HSDB (2005a).
2
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No RfD, RfC, or cancer assessment for /m-butylbenzene is included in the 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 are reported in the Health Effects Assessment Summary Tables
(HEAST; U.S. EPA, 2003). However, U.S. EPA (1997a) has derived a provisional chronic RfD
_2
of 1 x 10 mg/kg-day for /e/7-butylbenzene using cumene (isopropylbenzene) as a structural
analog. The Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1994) does
not include any health-related documents for fert-butylbenzene. The potential carcinogenicity of
the chemical has also not been assessed due to lack of pertinent data. The toxicity of
/e/7-butylbenzene has not been reviewed by the Agency for Toxic Substances and Disease
Registry (ATSDR, 2010) or the World Health Organization (WHO, 2010). The California
Environmental Protection Agency (CalEPA, 2008) has not derived toxicity values for exposure
to fert-butylbenzene but has recommended an action level of 260 |ig/L for fe/7-butylbenzene in
drinking water (CalEPA, 2000). This derivation was based on a subchronic-duration rat LOAEL
of 110 mg/kg-day for isopropylbenzene (similar to the structural analog approach taken by EPA
[1997a], and by incorporating uncertainty factors for interspecies extrapolation, subchronic to
chronic extrapolation, human variability, and database deficiencies). No occupational exposure
limits for /
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Due to the limited toxicity data on fert-butylbenzene, derivation of provisional toxicity
values is not possible for this chemical. As a result, a surrogate approach 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 /
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Table 2. Summary of Potentially Relevant Data for terf-Butylbenzene (CASRN 98-06-6)
Category
Number of
Male/Female, Species,
Study Type, Study
Duration
Dosimetry
Critical Effects
NOAEL
BMDL/
BMCL
LOAEL"
Reference
(Comments)
Human
Oral (mg/kg-day)a
None
Animal
Oral (mg/kg-day)a
Acute
10/0, ChR-CD rat,
gavage, single dose,
observed for 14 day
3000, 3400, or
3800 mg/kg
LD50 value was 3503 mg/kg (95% CI: 3308-3748 mg/kg);
mortality and body-weight decrease were dose-dependent
and observed at all dose levels. Treatment-related effects
included the following: rapid and labored respiration,
salivation, prostration, lacrimation, stained nose and mouth,
diarrhea, chromodacryorrhea, a stained and wet perineal
area, weakness, alopecia on the abdomen, stained eyes,
stained abdominal area, lethargy, and weight loss;
characterized as "slightly toxic."
None
None
None
Haskell
Laboratory
(1978)
Acute
5/5, rat (strain not
specified), method of
oral administration not
specified, observed for
14 day
1000, 2000,
3000, 4000, or
5000 mg/kg
LD50 value for male rats was 3045.4 mg/kg; LD50 value for
females was 4079.2 mg/kg; combined male and female LD50
value was 3517 mg/kg; no deaths were observed at the two
lower doses, but mortality increased beginning at the
3000-mg/kg dose with all males and four females dying at
5000 mg/kg; clinical signs included depression, urine stains,
prostration, rough coat, tremors, salivation, hunched
appearance, red stains on nose and eyes, soft feces, and
ataxia; gross pathology details were not reported, but
tabulated results indicated no gross changes at lower doses,
but some changes were noted in various organs beginning at
the 3000-mg/kg dose level.
None
None
None
Hazelton
Laboratories
(1982)
Acute
10, rat, sex not specified;
surviving animals
observed for 3 weeks
after dosing
4.33 g/kg-bwb
Seven of 10 animals were dead; pulmonary injury likely
cause of death; enlarged liver due to stress following
biotransformation of fer/-butylbenzene and other
alkylbenzenes.
NA
NA
NA
Gerarde (1959,
1960)
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/c'/7-Butylbenzene
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Table 2. Summary of Potentially Relevant Data for terf-Butylbenzene (CASRN 98-06-6)
Category
Number of
Male/Female, Species,
Study Type, Study
Duration
Dosimetry
Critical Effects
NOAEL
BMDL/
BMCL
LOAEL"
Reference
(Comments)
Short-term
8/0, S-D rat, gastric
intubation, 5 days/week,
2 weeks followed by
10-day observation
812b
No deaths, abnormal changes in body-weight gain, or
evidence of ototoxicity observed; use of control group was
not specified.
812
None
None
Gagnaire and
Langlais
(2005)
Subchronic
None
Chronic
None
Developmental
None
Reproductive
None
Carcinogenic
None
Inhalation (mg/m3)b
Carcinogenic
None
""Dosimetric conversion: mmol/kg-bw to mg/kg-bw = 8.47 mmol/kg-bw x 134.22 (molecular weight) mg/mmol = 1136.8434 (dose in mg)/kg-bw; final dose is
1136.8434 mg/kg-bw-day x 5 + 7 = 812 mg/kg-bw.
bFor fer/-butylbenzene: 1.25 mL x 0.8669 (g/mL) + 0.250 (kg-bw) = 4.33 g/kg.
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
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In an unpublished acute toxicity study (submitted as part of Toxic Substances Control
Act [TSCA] requirements), Hazelton Laboratories (1982) administered orally a single-dose of
1000-, 2000-, 3000-, 4000-, or 5000-mg/kg fert-butylbenzene (purity not reported), respectively,
to 5 male and 5 female rats (strain not specified) per dose group (method of oral administration
not specified). Following dosing, animals were examined for 14 days for mortality, body-weight
changes, and clinical signs of toxicity. At study termination, animals were sacrificed and
examined for gross pathology. Use of a control group was not specified in the report, and a
statement of GLP compliance was not provided.
While the study is poorly reported, the tabulated results provided in the report indicate
that no mortalities were noted in any of the animals at the two lowest administered doses (1000
and 2000 mg/kg). The study authors reported that three, four, and five male rats died in the
3000-, 4000-, and 5000-mg/kg dose groups, respectively, beginning on Observation Day 3.
Mortality in females was noted in the 4000- and 5000-mg/kg dose groups with three and four
animals dead in these dose groups, respectively, beginning on Observation Day 2. Clinical signs
included depression, urine stains, prostration, rough coat, tremors, salivation, hunched
appearance, red stains on the nose and eyes, soft feces, and ataxia. The study authors stated that
all surviving rats that exhibited these clinical signs appeared normal from Days 2, 3, 4, or 5 until
study termination on Day 14. Weight gain was observed in all rats that survived until study
termination. Weight loss was observed in all animals that died except one (whether this was a
male or female is not specified) that maintained the same weight. No notable gross pathological
changes were observed in animals surviving until study termination. Pathological findings in
dead animals included dark or bright red lungs; dark livers; light tan areas on the liver; reddish
and yellowish fluid in the stomach and intestines; and distension of the stomach, intestines, and
the urinary bladder. In addition to distension, the urinary bladder also exhibited red fluid and a
foul odor. The study authors reported an LD50 of 3045.4 mg/kg (95% CI: 2542.8 to
3647.4 mg/kg) for male rats, an LD50 of 4079.2 mg/kg (95% CI: 3536.8 to 4705.1 mg/kg) for
female rats, and a combined LD50 of 3517 mg/kg (95% CI: 3093.0 to 3999.2 mg/kg) for male
and female rats.
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 (S-D) rats. Observations
continued for 10 days following treatment. Each dose administered was 8.47 mmol/kg-day,
which is converted to 812 mg/kg-day for /
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duration, lack of a control group, and lack of testing at higher doses at which effects may have
occurred precludes its consideration for the derivation of an oral subchronic p-RfD for
/m-butylbenzene. In addition, the study authors did not conduct a thorough toxicological
evaluation of other organs to assess the possible toxicological potential of /e/7-butylbenzene at
the tested dose.
Other Exposures
No studies of /t7-/-butylbenzene toxicity by other exposure pathways were identified.
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Table 3. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Toxicokinetic
Male S-D rat, exposed to 100-ppm
(549 mg/m3)ab zm-butylbcnzcnc.
3 days, 12 hours/day.
Accumulated rapidly and reached steady-state conditions in blood,
brain, liver, and kidneys; largest hydrocarbon concentrations found
in the fat followed by kidneys, liver, brain, and blood; in general,
higher concentrations of aromatic hydrocarbons found in blood
compared to other hydrocarbons tested.
Metabolic rate of elimination
for fcrt-butvlbcnzcnc
comparatively high.
Zahlsen et al.
(1992)
Metabolism
Animal species and strain not
specified; doses not specified.
Metabolism of fcrt-butylbcnzcnc and alkylbenzenes, in general,
follow a metabolic pathway that involves oxidative changes either
at beta, omega, or penultimate carbons on side-chain-forming
alcohols or carboxylic acids; these alcohols and carboxylic acids
subsequently conjugate with glucuronic acid or glycine and are
excreted in urine.
Metabolism primarily occurs
on side-chain via oxidative
pathway followed by
conjugation and excretion.
HSDB
(2005a);
Gerarde
(1959, 1960)
Metabolism
Three rabbits (sex not specified) per
dose group, exposed to 268 and
500 mg/kg.
fcrt-Butylbcnzcnc was oxidized in rabbits mainly to 2,2,-dimethyl-
2-phenylethanol (66-81% of the doses; averages from the two dose
groups tested), which was then excreted as a glucuronide in urine.
A minor metabolite, 1,1-dimethylphenylacetic acid, was detected
as traces, and it could be excreted as a glycine conjugate in urine.
2,2 -dimethyl -2 -pheny lethy 1
glucuronide "appears to be the
major if not the only
metabolite of tert
butylbenzene in the rabbit.
Robinson
and Williams
(1955)
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
fcrt-butylbcnzcnc in 1:1 v/v olive oil
(1.25-mL fer/-butylbenzene;
4.33 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 and petechial and gross hemorrhage and
edema in surrounding tissues; effects also noted in kidneys, liver,
spleen, bladder, thymus, brain, and spinal cord; accumulation of
alkylbenzenes in nerve cells resulting in signs and symptoms of
central nervous system depression such as sluggishness, stupor,
coma, narcosis, and anesthesia.
Seven out of 10 animals died following oral administration of
fer/-butylbenzene. Autopsy results indicated lung involvement
with severity ranging from hyperemia to gross hemorrhage with
pulmonary injury reported as cause of death.
Toxicity manifested in
endothelial cells and central
nervous system. Branched
alkylbenzenes were reported
to be more acutely toxic
compared to the linear
alkylbenzenes.
Gerarde
(1959, 1960)
Cell signaling
Male rat (WKY/NHsd) alveolar
macrophages, in vitro exposure,
25-400 (iM fert-butylbenzene, ROS
formation by DCF fluorescence and
TNF-alpha release by ELISA.
No effects observed at concentration <400 (iM. A 70% increase in
2,7-dichlorofluorescein observed following 400 |iM. No effect
noted on TNF-alpha.
Equivocal results.
fcr/-Butylbcnzcnc may have
potential to cause ROS
formation.
Aam et al.
(2003)
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Table 3. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Carcinogenic
potential
(genotoxic and
epigenetic)
Primary Syrian hamster embryo
cells, in vitro exposure,
transformation frequency following
exposure alone and in combination
with benzo(a)pyrene.
Morphological transformation of embryonic cells not observed
following incubation with any of the 18 hydrocarbons. Further, no
synergistic effects observed between benzo(a)pyrene and
fcr/-butylbcnzcnc.
fcrt-Butylbcnzcnc negative in
Syrian hamster embryo
transformation assay.
Rivedal et al.
(1992)
amg/m3 = ppm x molecular weight ^ 24.45; molecular weight = 134.22; HEC conversion not presented because this is an acute-duration value.
bNot adjusted for continuous dosing.
Dose conversion: g/kg = [mL dose x (g/mL) density] ^ (kg body weight). For fcrt-butvlbcnzcnc: 1.25 mL x 0.8669 (g/ml)/0.250 (kg-bw) = 4.33 g/kg.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Toxicokinetics Studies
Zahlsen et al. (1992) investigated the toxicokinetic properties of several alkylbenzenes,
alkanes, and naphthenes in rats. Four male S-D rats exposed to 100-ppm (549 mg/m3; dose not
adjusted for continuous exposure) /e/V-butylbenzene (purity > 99%) for 12 hours per 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 fert-butylbenzene concentration in fat showed a
declining trend on Days 2 and 3 of chemical administration, with very little chemical remaining
12 hours after termination of exposure. In contrast, concentrations of /e/7-butylbenzene
exhibited slight declines in the kidney, liver, brain, and blood on Day 2 of chemical
administration, 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 (see Table 3). These results may
suggest that the metabolic rate of elimination is high for /m-butylbenzene. Gerarde (1959,
1960) corroborated absorption in the blood and stated that due to the high lipophilicity of
alkylbenzenes, 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 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 /e/7-butylbenzene and alkylbenzenes, in general, follow a metabolic
pathway that involves oxidative changes either at the beta, omega, or penultimate carbons on the
side-chain-forming alcohols or carboxylic acids (HSDB, 2005a; Gerarde, 1959, 1960). These
alcohols and carboxylic acids subsequently conjugate with glucuronic acid or glycine 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, Gerarde and
Ahlstrom 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
(Gerarde and Ahlstrom, 1966). The mechanism of side-chain oxidation seems to facilitate
detoxification and is the preferred pathway for alkylbenzenes, in general, which is exemplified
when benzene is converted to 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.
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.
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Furthermore, Gerarde (1959, 1960) reported 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
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 eliminated rapidly from the blood
as compared to benzene.
In an independent toxicokinetic study for /f/V-butylbenzene, Robinson and Williams
(1955) specifically examined the metabolism of fert-butylbenzene in rabbits (3 rabbits per dose
group; 268- and 500-mg/kg dose groups). They reported that the /e/7-butylbenzene was oxidized
in rabbits mainly to 2,2,-dimethyl-2-phenylethanol (66-81% of the doses; averages from the two
dose groups of 268 and 500 mg/kg), which was then excreted as a glucuronide in urine. A minor
metabolite, 1,1-dimethylphenylacetic acid, was detected as traces, and it could be excreted as a
glycine conjugate in urine. In addition, they stated that "co-oxidation is the only possible
reaction, and it is to be noted that this oxidation hardly goes beyond the primary alcohol stage"
(Robison and Williams, 1955, p. 161). The study authors concluded that 2,2-dimethyl-
2-phenylethyl glucuronide "appears to be the major if not the only metabolite of
fert-butylbenzene in the rabbit" (Robison and Williams, 1955, p. 159).
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 depression such as sluggishness, stupor, coma,
narcosis, and anesthesia. The study author described the intensity and quality of these effects as
dependent on 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 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 decreases (i.e., central nervous system effects of toluene
> ethylbenzene > propylbenzene > butylbenzene). Toluene and ethylbenzene were reported to
be fast-acting narcotics, whereas //-propyl and //-butylbenzene were slow in manifesting central
nervous system effects. The rate of initiation of central nervous system 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 central nervous system effects
from exposure to alkylbenzenes increases with higher chain length and branching of the side
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chain. As a result, isopropylbenzene and //-butylbenzene are long-acting central nervous system
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 central nervous system effects of
branched alkylbenzenes are longer lasting in contrast to the linear alkylbenzenes. The central
nervous system 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 central nervous system tissues, particularly in the brain.
Gerarde (1959, 1960) stated that branched alkylbenzenes such as isopropylbenzene,
/^/'/-butylbenzene, and sec-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, 1960) 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 dose (method of administration not
specified) of 2.5 mL of fert-butylbenzene (purity not specified) 1:1 v/v in olive oil (1.25 mL of
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Additionally, the spleen was either normal or enlarged, but no thymus effects were noted.
Gerarde (1959, 1960) 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
more toxic in nature in comparison to their linear counterparts.
Genotoxicity Studies
HSDB (2005a) reports the results of an unpublished study (Shell Oil, 1980) that could not
be located for this review. The excerpts of the study report conclude that fert-butylbenzene was
negative for mutagenicity in the Ames test in five strains of Salmonella typhimurium, both in the
presence and absence of metabolic activation; no information regarding the genotoxic effects of
.sfc-butylbenzene was identified. /e/7-Butylbenzene was also negative in the mitotic
gene-conversion assay, performed with and without metabolic activation. fert-Butylbenzene was
also negative under all conditions tested in the chromosomal-aberration assay.
In Vitro Cell Signaling and Carcinogenic Potential Studies
Aam et al. (2003) investigated the effect of reactive oxygen species (ROS) production
following exposure to one of several hydrocarbons, including 25-400-[xM fert-butylbenzene, in
rat alveolar macrophages. TNF-alpha release, as a proinflammatory marker and indicator of
ROS, was also measured. While dose-related increases in ROS formation were observed,
particularly following exposure to alicyclic hydrocarbons, results following exposure to
fert-butylbenzene were equivocal. No concentration of /e/7-butylbenzene reportedly changed the
release of TNF-alpha; however, 400-[xM /e/7-butylbenzene increased 2,7-dichlorofluorescein
formation, an indicator of ROS, by 70%, although the data were not included in the study report.
While these results are not conclusive, they indicate that /e/7-butylbenzene may have the
potential to cause ROS formation (see Table 3).
Rivedal et al. (1992) conducted a study screening for 18 hydrocarbons using the Syrian
hamster embryo cell transformation assay. In doing so, they demonstrated a technique to detect
potential genotoxic and epigenetic rodent carcinogens. The hydrocarbons were tested alone and
in combination with benzo(a)pyrene to evaluate possible synergistic effects. None of the
hydrocarbons promoted morphological cell transformation alone; however, a naphthene and two
isoalkanes did enhance the effect of benzo(a)pyrene exposure (see Table 3). fert-Butylbenzene
tested negative in all conditions of this assay.
DERIVATION OF PROVISIONAL VALUES
Table 4 presents a summary of noncancer screening oral provisional reference values (see
Appendix A for details). Table 5 presents a summary of cancer values. IRIS values, if available,
are included in the tables.
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Table 4. Summary of Screening Oral Provisional Reference Values
for terf-Butylbenzene (CASRN 98-06-6)
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
NOAELA|,[
110
1000
Wolf et al.
(1956)
aIRIS (U.S. EPA, 1997b); isopropylbenzene (cumene) used as surrogate.
Table 5. Summary of Cancer Risk Values for terf-Butylbenzene (CASRN 98-06-6)
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 RfD (Subchronic and
Chronic p-RfDs)
No chronic or subchronic toxicity data were identified for the derivation of an oral
provisional RfD (p-RfD) for /m-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 that may be of use under certain circumstances. Please see
Appendix A for details regarding the screening values.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 6 identifies the cancer WOE descriptor for /m-butylbenzene (in bold).
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Table 6. Cancer WOE Descriptor for terf-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 fert-butylbenzene in humans are available.
"Likely to be
Carcinogenic to
Humans "
N/A
N/A
No studies pertaining to the carcinogenicity
of fert-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 terz-butyl benzene
even in a single animal species.
"Inadequate
Information to
Assess Carcinogenic
Potential"
Selected
Both
There is little or no pertinent information
available to assess carcinogenic potential of
tert-butylbenzene.
"Not Likely to be
Carcinogenic to
Humans "
N/A
N/A
No data are available to suggest that
/t'/7-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 /e/V-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 /e/7-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 fert-butylbenzene
from the 2-week study by Gagnaire and Langlais (2005). However, the lack of ototoxicity in
animals following exposure to fert-butylbenzene, the lack of a control group, and the lack of
testing at higher doses that may have caused an effect precludes the use of this study for the
derivation of an oral subchronic p-RfD for /e/7-butylbenzene. In addition, the study authors did
not conduct a thorough toxicological evaluation of other organs to assess the possible
toxicological potential of /e/7-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 ChemlDplus on the National
Library of Medicine Web site (littp ://chem. sis.nlm. nih.gov/ChemlDplus/) and then the U.S. EPA
DSSTox (www.epa.gov/dsstox) databases. Seventy-eight possible analogs (structural
surrogates) were identified using ChemlDplus (2010) with the similarity match set to >50%, and
24 possible analogs were identified using DSSTox with the similarity match set to >70%.
ChemlDplus did not identify any structural surrogate with repeated dose data within the
alkylbenzene chemical class. To further filter these 24 possible analogs from DSSTox, only hits
identified in the IRIS data set (IRISTR lb) in DSSTox were first retained. Two potential
structural surrogates with repeated dose data were found—isopropylbenzene (C9H12) and
ethylbenzene (CxHio)—as structurally similar to fert-butylbenzene with a similarity score of 91.3
and 95.4%), respectively (see Table C. 1). One interesting hit from DSSTox was identified at
75% similarity to /f/V-butylbenzene: .scc-butylbenzene. However, .scc-butylbenzene does not
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have repeated dose information at the time of assessment (a similar surrogate approach could be
performed for sec-butylbenzene). Because of the limited number of hits (n = 2), similarity
search threshold was reset to 65%. As a result, two more hits with repeated dose data within the
alkylbenzene class were located: toluene (68.1%) and //-butylbenzene (67.7%). Finally, a total
of four structural surrogates were identified: ethylbenzene (95.4%), isopropylbenzene (91.3%),
toluene (68.1%), and //-butylbenzene (67.7%).
Toxicokinetic Data
Available information on the toxicokinetics of /
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metabolic surrogate for /m-butylbenzene at this point. Based on the toxicokinetic information,
ethylbenzene, //-butylbenzene, and isopropylbenzene are considered as metabolic surrogates. In
addition, based on both structural and toxicokinetic information, these three alkylbenzenes are
considered as potential surrogates.
Table A.l. Biological Concentration of terf-Butylbenzene in Tissues of Sprague-Dawley
Male Rats Following 12-Hour Daily Exposures to 100 ppm for 1, 2, and 3 Days and
After a 12-Hour Recovery Period"
Tissue
Time Point
Concentration (jimol/kg)
Blood
Day 1
25.5 ±6.1
Day 2
11.1 ± 1.8
Day 3
15.5 ± 1.2
Recovery Period
0.7 ±0.2
Brain
Day 1
71.2 ± 15.0
Day 2
31.3 ±4.0
Day 3
38.7 ±3.7
Recovery Period
NDb
Liver
Day 1
85.4 ± 16.1
Day 2
26.9 ±6.2
Day 3
47.0 ±4.5
Recovery Period
2.2 ±0.5
Kidney
Day 1
259.1 ±25.2
Day 2
137.5 ±42.3
Day 3
256.6 ±38.7
Recovery Period
27.9 ± 11.0
Fat
Day 1
2993 ± 642
Day 2
1323±134
Day 3
1171±134
Recovery Period
320 ±61
"Zahlsenetal. (1992).
bND = None Detected.
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Table A.2. Comparative Absorption Data for terf-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-l,2-propanediol)
Research Triangle Institute,
1989
Toluene
Oral
Rabbit
74%
Elimination of metabolites in
urine (hippuric acid)
El Masry et al., 1956
//-Butylbenzene
Oral
Rabbit
68-78%
Elimination of metabolites in
urine (hippuric acid,
phenylpropyl- and
methylpenethyl-
carbinylglucuronides, and
phenaceturic acid)
El Masry et al., 1956
fcrt-Butylbcnzcnc
Oral
Rabbit
66-81%
(average of
3 animals)
Elimination of metabolites in
urine (2,2-dimethyl-
2-phenylethanol and its
glucuronide conjugates, and
1,1,-dimethylphenylacetic acid
and its glycine conjugates)
Robinson and Williams,
1955
Acute Lethality
Because toluene was previously ailed out as a metabolic surrogate (see above), only the
acute lethality data were located for /e/7-butylbenzene, ethylbenzene, //-butylbenzene, and
isopropylbenzene (see Table A.3). The acute toxicity of /f/V-butylbenzene, isopropylbenzene,
and ethylbenzene was much higher compared to 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, 1960; see Table A.3). Two other acute oral studies for fert-butylbenzene (Haskell
Laboratory, 1987; Hazelton Laboratories, 1982) also determined a rat LD50 of approximately
3.5 g/kg, which is less acutely toxic than isopropylbenzene (1.4-2.91 g/kg) but more similar to
ethylbenzene (3.5-5.46 g/kg). Additionally, as described in the "Toxicity of Alkylbenzenes in
Various Tissues" section in the main text and in the text above, Gerarde (1959, 1960) 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 and mortality data (see Table A.3),
isopropylbenzene seems to be the most acutely toxic via the oral route.
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Table A.3. Acute Toxicity of terf-Butylbenzene and Potential Surrogates"
Chemical
w-Butylbenzene
Ethylbenzene
Isopropylbenzene
(cumene)
fert-Butylbenzene
Oral LD50 (g/kg)
Oral LDio (g/kg)
NA
4.30b,c (rat, not
specified as a LD50
by author;
considered as a LDi0)
3.5a'd (rat); 5.46a (rat)
2.91a (rat); 1.4d (rat)
3.503e (rat); 3.517f
(average; rat)
4.33b,c (not specified as a
LD50 by author;
considered as a LDi0)
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
7/10
aHSDB (2005a,b,c), unless otherwise noted.
bGerarde (1959, 1960).
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).
eHaskell Laboratory (1978).
fHazelton Laboratories (1982).
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 "Toxicokinetics Studies" sections in the main document. In the
endothelium, alkylbenzenes present in the blood cause irritation that might lead to various effects
including gross hemorrhage. These changes are often observed in the lungs of animals exposed
to alkylbenzenes via gavage, subcutaneously, or via intraperitoneal injection (Gerarde, 1959,
1960). Gerarde (1959, 1960) also states that due to the highly lipophilic nature of alkylbenzenes,
these chemicals can cause central nervous system effects that might lead to sluggishness,
narcosis, coma, and anesthesia. Based on toxicity manifestation in these tissues, Gerarde (1959,
1960) states that branched alkylbenzenes are more toxic than linear alkylbenzenes. This
information suggests that the branched surrogate (isopropylbenzene) may be more suitable over
the linear surrogates (ethylbenzene and //-butylbenzene).
Physicochemical properties among fert-butylbenzene and three potential surrogates are
generally comparable (i.e., molecular weight, melting and boiling points, and log Kow). The
major differences are water solubility and vapor pressure at room temperature (see Table A.4).
Ethylbenzene seems to be the "outlier," while the values of these two properties are more similar
among fert-butylbenzene, isopropylbenzene, and //-butylbenzene. It is noteworthy that the
physicochemical properties of /^/'/-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
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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, 2005b). Genotoxic results for
ethylbenzene were mixed with positive results observed in in vitro tests using human
lymphocytes (sister chromatid exchange) and negative results observed in Syrian Hamster
embryo cells (cell transformation; HSDB, 2005c). /e/7-Butylbenzene was negative for
mutagenicity in the Ames test in five strains of Salmonella typhimurium, both in the presence
and absence of metabolic activation, and was also negative in the mitotic gene-conversion assay,
performed with and without metabolic activation. fert-Butylbenzene was also negative under all
conditions tested in the chromosomal-aberration assay (HSDB, 2005a). Because genotoxicity
data for //-butylbenzene were not located, a comparison between //-butylbenzene's genotoxic
potential and the other three alkylbenzenes (isopropylbenzene, fert-butylbenzene, and
ethylbenzene) is not feasible. However, available genotoxicity data for isopropylbenzene and
fert-butylbenzene indicate that both these alkylbenzenes may not be genotoxic.
In conclusion, an attempt was made to derive toxicity values for fert-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.l in Appendix C
provides a list of potential surrogates that have a peer-reviewed toxicity value in the IRIS
database, the HEAST, or the PPRTV database. 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 /^/'/-butylbenzene. Common target organs among the potential surrogates
include kidneys and liver, with kidneys likely to be the most sensitive endpoint for
/m-butyl benzene based on the structural information (branched vs. linear, see Table A.4).
Overall, based on weight-of-evidence of all the information presented above,
isopropylbenzene is the most appropriate surrogate for /
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• Similar pattern in ototoxicity: branched alkylbenzenes did not cause ototoxicity
(Gagnaire and Langlais, 2005)
• Similar patterns in acute toxicities (see Table A.3)
• Higher acute toxicity of isopropylbenzene compared to fert-butylbenzene (see
Table A.3)
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Table A.4. Comparison of Available Toxicity Data for terf-Butylbenzene and Potential Surrogates3
Characteristic
fe/f-Butylbenzene
Isopropylbenzene (Cumene)b
w-Butylbenzene
Ethylbenzeneb
Structure
*jO
ch3
CASRN
98-06-6
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
91.3
67.7
95.4
Melting point (°C)
-5.78 x 101
-9.6 x 101
-8.79 x 101
-9.49 x 101
Boiling point (°C)
169.1
152.4
183.3
136.1
Vapor pressure (mm Hg at
25°C)
2.2
4.5
1.06
9.6
Water solubility (mg/L) at
25°C
29.5
61.3
11.8
169
Log Kow
4.11
3.66
4.38
3.15
pKa
NA
NA
NA
NA
Oral LD50 in rat
(route: effect)
3503 mg/kg; 3517 mg/kg (oral
exposure; see Table 2)
1400 mg/kg
(oral exposure: 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.4. Comparison of Available Toxicity Data for terf-Butylbenzene and Potential Surrogates3
Characteristic
fert-Butylbenzene
Isopropylbenzene (Cumene)b
M-Butylbenzene
Ethylbenzeneb
Dermal LD50 in rabbits
(route: effect)
NA
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 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):
6.2 Dose Response
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 (3mo) 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
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
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in which thorough histopathological analyses and ancillary studies of
neurotoxicity and ocular pathology were performed. The scientific quality of this
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 fert-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, and a
UF of 10 for intraspecies variability, a partial UF of 3 to extrapolate from a less than
chronic-duration (194-day study) study to a chronic-duration study, and a partial UF of 3 for
database deficiencies (lack of reproductive information). Based on the current 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 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
tert-butylb enzene.
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Given the lack of subchronic data for /f/V-butylbenzene and the uncertainty associated
with the use of a surrogate approach for the derivation of toxicity values, the same value,
1 x 10-1 mg/kg-day, is recommended for the screening subchronic p-RfD.
While studies providing specific effects for /
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APPENDIX B. DATA TABLES
No data tables presented.
30
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APPENDIX C. POTENTIAL ANALOGS FROM DSSTOX AND CHEMIDPLUS WITH
AVAILABLE VALUES FROM THE IRIS DATABASE, THE HEAST, AND THE PPRTV
DATABASE
Table C.l. Results of DSSTox and ChemlDplus Structure Similarity Search
for terf-butylbenzene.
Chemical Name
Similarity
Search Engine
Percent
Similarity
Match
(DSSTox/
ChemlDplus)
IRIS Value
(Chronic
RfD) [Year
Updated]
PPRTV
Value
(Chronic
RfD) [Year
Updated]
PPRTV Value
(Subchronic
RfD) [Year
Updated]
HEAST Value
(Subchronic
RfD)
Oral exposure—RfD
fcrt-Butylbcnzcnc
DSSTox/
ChemlDplus
100/100
NA
NAa
NAa
NA
Isopropylbenzene
DSSTox
91.3
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
95.4
1 x 10"1
mg/kg-day
(U.S. EPA,
1991)
NAb
5 x 10~2
mg/kg-day
(U.S. EPA,
2009)
NAb
//-butylbcnzc nc
DSSTox
67.7
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).
NA = Not available.
31
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APPENDIX D. REFERENCES
Aam, BB; Myhre, O; Fonnum, F. (2003) Transcellular signalling pathways and TNF-alpha
release involved in formation of reactive oxygen species in rat alveolar macrophages exposed to
/c'/7-butylcyclohexane. Arch Toxicol 77:678-684. 598116
ACGIH (American Conference of Governmental Industrial Hygienists). (2010) 2010 TLVs and
BEIs: Threshold limit values for chemical substances and physical agents and biological
exposure indices. Cincinnati, OH: ACGIH. 594528
ATSDR (Agency for Toxic Substances and Disease Registry). (2010) Toxicological profile
information sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed on
5/14/2010. 684152
CalEPA (California Environmental Protection Agency). (2000) Proposed action levels for
sec-butylbenzene and tert-butylbenzene. Office of Environmental Health Hazard Assessment,
Sacramento, CA. Available online at http://www.oehha.org/water/pals/sec tert6benz.html.
Accessed on 5/14/2010. 625582
CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as on December 18, 2008. Office of Environmental
Health Hazard Assessment, Sacramento, CA. Available online at
http://www.oehha.ca.gov/air/allrels.html. Accessed on 5/14/2010. 595416
ChemlDplus. (2010) Chemical identification file. U.S. National Library of Medicine.
Available online at http://chem.sis.nlm.gov/chemidplus. Accessed on 7/6/2010. 629639
Cushman, JR; Norris, JC; Dodd, DE; et al. (1995) Subchronic inhalation toxicity and
neurotoxicity assessment of cumene in Fischer 344 rats. Int J Toxicol 14(2): 129-147. 075034
Gagnaire, F; Langlais, C. (2005) Relative ototoxicity of 21 aromatic solvents. Arch Toxicol
79(6):346-354. 598134
Gene-Tox. (2010) Genetic Toxicology Data Bank. National Library of Medicine, National
Institutes of Health, U.S. Department of Health and Human Services, Bethesda, MD. Available
online at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7GENETOX. Accessed on 7/6/2010.
629638
Gerarde, HW. (1959) Toxicological studies on hydrocarbons. III. The biochemorphology of
the phenylalkanes and phenylalkenes. AMA Arch IndHealth 19(4):403-418. 597515
Gerarde, HW. (1960) Toxicological effects. In: Threlfall, CJ; ed. Toxicology and biochemistry
of aromatic hydrocarbons. Amsterdam, Netherlands: Elsevier Publishing Company; pp. 52-57.
628707
32
/£/7-Butylbenzene
-------
FINAL
11-28-2012
Gerarde, HW; Ahlstrom, DB. (1966) Toxicologic studies on hydrocarbons: XI. Influence of
dose on the metabolism of mono-n-alkyl derivatives of benzene. Toxicol Appl Pharmacol
9:185-190.
Haskell Laboratory of Toxicology and Industrial Medicine. (1978) Oral tert butyl-benzene
testing in male rats. E.I. Dupont de Nemours & Co. Newark, DE. EPA 86-870000981.
Available online at http://www.ntis.gov/search/product.aspx'">ABBR=GTS0514883. Accessed
on 5/14/2010. 598098
Hazelton Laboratories. (1982) Initial submission: Acute oral toxicity in rats using t butyl
benzene (with cover letter dated 08/24/92). Hazelton Laboratories No. 88920010733. Available
online at http://www.ntis.gov/search/product. aspx?ABBR=OTSQ571879. Accessed on
5/14/2010. 625141
HSDB (Hazardous Substances Data Bank). (2005a) tert-Butylbenzene. National Library of
Medicine, National Institutes of Health, U.S. Department of Health and Human and Human
Services, Bethesda, MD. Available online at http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+98-06-6. Last revised on December 19, 2005.
Accessed on 5/14/2010. 594343
HSDB (Hazardous Substances Data Bank). (2005b) Cumene. National Library of Medicine,
National Institutes of Health, U.S. Department of Health and Human and Human Services,
Bethesda, MD. Available online at http://toxnet.nlm.nih.gov/cgi-
bin/sis/search/r?dbs+hsdb:@term+@rn+@rel+98-82-8. Last revised on June 24, 2005.
Accessed on 5/14/2010.
HSDB (Hazardous Substances Data Bank). (2005c) Ethylbenzene. National Library of
Medicine, National Institutes of Health, U.S. Department of Health and Human and Human
Services, Bethesda, MD. Available online at http://toxnet.nlm.nih.gov/cgi-
bin/si s/ search/r? db s+hsdb: @term+@rn+@rel+100-41-4. Last revised on July 7, 2005.
Accessed on 5/14/2010.
IARC (International Agency for Research on Cancer). (2000) Some industrial chemicals.
IARC monographs on the evaluation of carcinogenic risks to humans, volume 77. Geneva:
WHO. Available online at http://monographs.iarc.fr/ENG/Monographs/vol77/index.php.
Accessed on 5/14/2010. 201837
El Masry, AM; Smith, JN; Williams, RT. (1956) Studies in detoxication. 69. The metabolism
of alkylbenzenes: n-propylbenzene and n-butylbenzene with further observations on
ethylbenzene. Biochem J64(l):50-56.
NIOSH (National Institute for Occupational Safety and Health). (2010) NIOSH pocket guide to
chemical hazards. Index of chemical abstracts service registry numbers (CAS No.). Center for
Disease Control and Prevention, U.S. Department of Health, Education and Welfare,
Atlanta, GA. Available online at http://www.cdc.gov/niosh/npg/npgdcas.html. 625692
33
/£/7-Butylbenzene
-------
FINAL
11-28-2012
NTP (National Toxicology Program). (2011) 12th Report on carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp.niehs.nih.eov/?obiectid=03C9AF75-ElBF-
FF40-DBA9EC0928DF8B15. Accessed on 11/17/2011. 737606
OSHA (Occupational Safety and Health Association). (2006) Table Z-l limits for air
contaminants: occupational safety and health standards, subpart Z, toxic and hazardous
substances. U.S. Department of Labor, Washington, DC; OSHA Standard 1910.1000. Available
online at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2. Accessed on 5/14/2010. 670067
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.
Rivedal, E; Mikalsen, SO; Roseng, LE; et al. (1992) Effects of hydrocarbons on transformation
and intercellular communication in Syrian hamster embryo cells. Pharmacol Toxicol
71(1):57—61. 598152
Robinson, D; Williams, RT. (1955) Studies in detoxification. 61. The metabolism of
alkylbenzenes: tert-Butylbenzene. Biochem J 59(1): 159—161.
Shell Oil Company. (1980) Toxicity studies with fine chemicals - in vitro genotoxicity studies
with tertiary butyl benzene. Shell Research Limited, London, Sittingbourne Research Centre,
Shell Toxicology Laboratory (Tunstall). Sittingbourne, Kent, United Kingdom. OTS0515723;
86 870001647. Available online at
http://www.ntis.gov/search/product.aspx?ABBR=OTSQ515723. 629644
U.S. EPA (Environmental Protection Agency). (1991) IRIS summary for ethylbenzene
(CASRN 100-41-4). National Center for Environmental Assessment, Washington, DC.
Available online at http://www.epa.gov/IRIS/subst/0051 .htm. Accessed on 7/8/2010. 629645
U.S. EPA (Environmental Protection Agency). (1994) Chemical assessments and related
activities (CARA). Office of Health and Environmental Assessment, Washington, DC;
EPA/600/R-94/904. Available online at
http://nepis.epa.gov/Exe/ZyPURL.cgi?Dockev=6000lG8L.txt. 596444
U.S. EPA (Environmental Protection Agency). (1997a) Risk assessment issue paper for:
Derivation of provisional chronic RfDs for n-butylbenzene (CASRN 104-51-8),
sec-butylbenzene (CASRN 135-98-8), tert-butylbenzene (CASRN 98-06-6), and
n-propylbenzene (CASRN 103-65-1). National Center for Environmental Assessment,
Washington, DC; EPA/97-009/6-5-97. 597097
U.S. EPA (Environmental Protection Agency). (1997b) IRIS summary for cumene. Integrated
risk information system (IRIS). Office of Research and Development, National Center for
Environmental Assessment, Washington, DC. Last revised 4/11/2003. Available online at
http://www.epa.gOv/iris/subst/0306.htm. Accessed on 7/8/2010. 628708
34
/£/7-Butylbenzene
-------
FINAL
11-28-2012
U.S. EPA (Environmental Protection Agency). (1997c) Toxicological review of cumene
(CAS No. 98-82-8). In support of the Integrated Risk Information System. National Center for
Environmental Assessment, Research Triangle Park, NC. Available online at
http ://www. epa. gov/iri s/toxreviews/03 06tr.pdf. Accessed on 5/6/2011.
U.S. EPA (Environmental Protection Agency). (2003) Health effects assessment summary
tables (HEAST). 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. Available online at http://epa-heast.ornl.gov/. Accessed on 5/14/2010.
595422
U.S. EPA (Environmental Protection Agency). (2005) Guidelines for carcinogen risk
assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register
70(66): 17765-17817. Available online at
http://www.epa.eov/raf/publications/pdfs/CANCER GUIDELINES FINAL 3-25-05.PDF.
Accessed on 5/14/2010. 086237
U.S. EPA (Environmental Protection Agency). (2006) 2006 Edition of the drinking water
standards and health advisories. Office of Water, Washington, DC; EPA/822/R-06/013.
Available online at http://www.epa.eov/waterscience/drinking/standards/dwstandards.pdf.
Accessed on 5/14/2010. 091193
U.S. EPA (Environmental Protection Agency). (2009) Provisional peer-reviewed toxicity
values for ethylbenzene (CASRN 100-41-4). Derivation of a subchronic oral provisional-RfD
and subchronic inhalation provisional-RfC. Superfund Health Risk Technical Support Center,
National Center for Environmental Assessment, Cincinnati, OH. Accessed on 7/19/2010.
U.S. EPA (Environmental Protection Agency). (2010a) Integrated risk information system
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http://www.epa.eov/iris/. Accessed on 5/14/2010. 595423
U.S. EPA (Environmental Protection Agency). (2010b) Provisional peer reviewed toxicity
value for n-butylbenzene (CASRN 104-51-8), sec-butylbenzene (CASRN 135-98-8), and
tert-butylbenzene (CASRN 98-06-6). Derivation of a subchronic oral provisional-RfD and
subchronic inhalation provisional-RfC. Superfund Health Risk Technical Support Center,
National Center for Environmental Assessment, Cincinnati, OH. Accessed on 9/13/2010.
Wang, NCY; Zhao, QJ; Wesselkamper, SC; et al. (2012) Application of computational
toxicological approaches in human health risk assessment. I. A tiered surrogate approach. Regul
Toxicol Pharmacol 63(1): 10-19. Available online at
http://www.sciencedirect.com/science/article/pii/S027323001200Q323. 1239453
WHO (World Health Organization). (2010) Online catalogs for the Environmental Health
Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed on
5/14/2010. 595424
Wolf, MA; Rowe, VK; McCollister, DD; et al. (1956) Toxicological studies of certain alkylated
benzenes and benzene: Experiments on laboratory animals. AMA Arch IndHealth
14(4):3 87-398. 062279
35
/£/7-Butylbenzene
-------
FINAL
11-28-2012
Zahlsen, K; Eide, I; Nilsen, AM; et al. (1992) Inhalation kinetics of C6 to CIO aliphatic,
aromatic and naphthenic hydrocarbons in rat after repeated exposures. Pharmacol Toxicol
71(2): 144-149. 068948
36
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