United States
Environmental Protection
1=1 m m Agency
EPA/690/R-13/004F
Final
7-25-2013
Provisional Peer-Reviewed Toxicity Values for
Dibenzothiophene
(CASRN 132-65-0)
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
Carrie R. Fleming, PhD
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Jason C. Lambert, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
Suryanarayana V. Vulimiri, BVSc, PhD, DABT
National Center for Environmental Assessment, Washington, DC
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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CONTENTS
COMMONLY USED ABBREVIATIONS	iv
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
Inhalation Exposures	8
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	9
DERIVATION 01 PROVISIONAL VALUES	15
DERIVATION OF ORAL REFERENCE DOSES	15
Derivation of Subchronic p-RfD	15
Derivation of Chronic p-RfD	16
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	16
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR	16
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	16
APPENDIX A. PROVISIONAL SCREENING VALUES	17
APPENDIX B. DATA TABLES	20
APPENDIX C. BMD OUTPUTS	21
APPENDIX D. REFERENCES	22
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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 confidence limit
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 inhalation reference concentration
p-RfD
provisional oral reference dose
RfC
inhalation reference concentration
RfD
oral reference dose
UF
uncertainty factor
UFa
interspecies uncertainty factor
UFC
composite uncertainty factor
UFd
database uncertainty factor
UFh
intraspecies uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PEER-REVIEWED PROVISIONAL TOXICITY VALUES FOR
DIBENZOTHIOPHENE (CASRN 132-65-0)
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 (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).
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INTRODUCTION
Dibenzothiophene, CAS No. 132-65-0, is an organosulfur compound found in crude oil
and petroleum. It is used as a chemical intermediate in cosmetics and pharmaceuticals (NLM.
2006). The empirical formula for dibenzothiophene is C^HgS (see Figure 1). A table of
physicochemical properties for dibenzothiophene is provided below (see Table 1).
Figure 1. Dibenzothiophene Structure
Table 1. Physicochemical Properties of Dibenzothiophene (CASRN 132-65-0)a
Property (unit)
Value
Boiling point (°C)
332.5
Melting point (°C)
99.5
Density (g/cm3)
ND
Vapor pressure (mm Hg at 25°C)
0.000205
pH (unitless)
ND
Solubility in water (mg/L at 25°C)
1.47
Relative vapor density (air =1)
ND
Molecular weight (g/mol)
184.26
"NLM (20061.
ND = no data.
A summary of available relevant health information for dibenzothiophene from U.S. EPA
and other agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Dibenzothiophene (CASRN 132-65-0)
Source/Parameter"
Value
(Applicability)
Notes
Source
Date Accessed
Cancer
IRIS
NV
NA
U.S. EPA
7-16-2013
HEAST
NV
NA
U.S. EPA (2011M
NA
IARC
NV
NA
IARC (2013)
NA
NTP
NV
NA
NTP (2011)
NA
Cal/EPA
NV
NA
Cal/EPA (2009)
NA
Noncancer
ACGIH
NV
NA
ACGIH
7-16-2013
ATSDR
NV
NA
ATSDR
7-16-2013
Cal/EPA
NV
NA
Cal/EPA (2012. 2009)
7-16-2013
NIOSH
NV
NA
NIOSH (2007)
NA
OSHA
NV
NA
OSHA (2006)
NA
IRIS
NV
NA
U.S. EPA
7-16-2013
Drinking water
NV
NA
U.S. EPA (2011a)
NA
HEAST
NV
NA
U.S. EPA (2011b)
NA
CARA HEEP
NV
NA
U.S. EPA (1994)
NA
WHO
NV
NA
WHO (2004)
NA
aSources: Integrated Risk Information System (IRIS) database; Health Effects Assessment Summary Tables
(HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP); California
Environmental Protection Agency (Cal/EPA); American Conference of Governmental Industrial Hygienists
(ACGIH); Agency for Toxic Substances and Disease Registry (ATSDR); National Institute for Occupational
Safety and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical Assessments and
Related Activities (CARA) list; Health and Environmental Effects Profile (HEEP); World Health Organization
(WHO).
NA = not applicable; NV = not available.
Literature searches were conducted on sources published from 1900 through July 2013,
for studies relevant to the derivation of provisional toxicity values for dibenzothiophene,
CASRN 132-65-0. The following databases were searched by chemical name, synonyms, or
CASRN: ACGIH, ANEUPL, ATSDR, BIOSIS, Cal EPA, CCRIS, CDAT, ChemlDplus, CIS,
CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HERO, HMTC,
HSDB, IARC, INCHEM IPCS, IP A, ITER, IUCLID, LactMed, NIOSH, NTIS, NTP, OSHA,
OPP/RED, PESTAB, PPBIB, PPRTV, PubMed (toxicology subset), RISKLINE, RTECS,
TOXLINE, TRI, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, and
U.S. EPA TSCATS/TSCATS2. The following databases were searched for relevant health
information or exposure limits: ACGIH, ATSDR, Cal EPA, U.S. EPA IRIS, U.S. EPA HEAST,
U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and
RTECS.
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REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 3 provides an overview of the relevant database for dibenzothiophene and includes
all potentially relevant and repeated short-term, subchronic, and chronic-duration studies.
Principal studies are identified in bold and are labeled PS. The phrase "statistical significance"
used throughout the document indicates ap-walue of <0.05.
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Table 3. Summary of Potentially Relevant Data for Dibenzothiophene (CASRN 132-65-0)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry"
Critical Effects
NOAEL"
BMDL/
BMCLa
LOAEL'
Reference
Notesb
Human
1. Oral (mg/kg-d)a
Acute0
ND
Short-termd
ND
Long-term6
ND
Chronicf
ND
2. Inhalation (mg/m3)a
Acute0
ND
Short-termd
ND
Long-term0
ND
Chronicf
ND
Animal
1. Oral (mg/kg-d)a
Subchronic
ND
Chronic
Male (number not
specified), albino, rat,
diet, 165 d
0 (historical),
13,27,63
(Adjusted)
Increased liver weight8 compared
with laboratory historical controls
13
DUB
27
Thomas et al.
(1942)
PS, PR
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
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Table 3. Summary of Potentially Relevant Data for Dibenzothiophene (CASRN 132-65-0)
Category
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetry3
Critical Effects
NOAEL3
BMDL/
BMCL3
LOAEL3
Reference
Notesb
2. Inhalation (mg/m3)a
Subchronic
ND
Chronic
ND
Developmental
ND
Reproductive
ND
Carcinogenicity
ND
""Dosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects.
ADD = Total Dibenzothiophene Consumption per Animal over Study Duration x (1 Body Weight) x (1 -f- Days Dosed)
bNotes: PS = principal study; PR = peer reviewed.
cAcute = exposure for <24 hr (U.S. EPA. 2002).
''Short-term = repeated exposure for >24 hr < 30 d (U.S. EPA. 2002).
"Long-term = repeated exposure for >30 d < 10% lifespan (based on 70-yr typical human lifespan) (U.S. EPA. 2002).
'Chronic = repeated exposure for >10% lifespan (U.S. EPA. 2002).
8For liver weight evaluation, animals dosed with dibenzothiophene were compared with laboratory historical controls matched according to body weight. Therefore, the
differences from the control group approximate a change in organ weight relative to body weight.
DUB = data not amenable to BMD modeling; ND = no data.
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HUMAN STUDIES
No studies were identified.
ANIMAL STUDIES
Oral Exposures
The effects of oral exposure to dibenzothiophene in animals have not been evaluated in
subchronic, developmental, or reproductive studies although a chronic-duration study that
investigated the effects of dibenzothiophene in rats was identified (Thomas et al.. 1942).
Chronic-duration studies
Thomas et al. (1942)
The study by Thomas et al. (1942) is selected as the principal study for derivation of
the screening chronic provisional reference dose (p-RfD). In a published, peer-reviewed
study, Thomas et al. (1942) administered dibenzothiophene (purity not reported) in the diet of
male albino rats (source and number not reported) aged 25-28 days with an average body weight
of 48 g at the beginning of the study. The animals received 0.25, 0.50, or
1.00% dibenzothiophene in the diet for the first 4 days of the dosing period (number of animals
per dose group not reported). Because of low food intakes and decreases in body weight, the
doses were decreased to 0.025, 0.050, or 0.100% dibenzothiophene for the remainder of the
165-day dosing period. Adjusted daily doses are estimated to be 13, 27, and 63 mg/kg-day,
respectively, based on total dibenzothiophene consumption reported by the study authors and
time-weighted average body weights obtained by digitizing the growth curves provided by the
study authors. Animals were housed five to a cage; other details regarding animal husbandry
were not provided. Appearance and behavior were recorded by the study authors "throughout
the duration of the study." Food and water were provided ad libitum; animals and food cups
were weighed twice a week for the duration of the study. Experimental data for each exposure
group were compared with data for age- or body-weight-matched historical control animals; the
type of historical control used for each endpoint is listed below with the results for that endpoint.
At study termination, animals were sacrificed, and histopathological examinations were
performed. The study authors noted that they used an necropsy technique previously described
by Wilson et al. (1938): the spleen, liver, adrenal glands, kidneys, testes, ovaries, and heart were
weighed under this necropsy protocol. Histopathological sections of the liver, spleen, adrenal
gland, heart, bladder, intestine, lung, testis, and stomach were prepared from five animals in each
exposure group and stained with hematoxylin and eosin (Thomas et al.. 1942). Frozen sections
of the livers from three animals in the high-dose group and all animals in the low-dose group
were stained with Sudan IV. Blood was collected on Days 107 and 157 from the tails of five
high-dose animals and analyzed for hemoglobin and for erythrocyte, reticulocyte, and total and
differential white cell counts. Although the study authors indicated statistical significance of
their findings, no information was provided regarding their statistical methods. This study was
performed prior to the adoption of good laboratory practice (GLP), and little information
regarding the laboratory procedures was provided. The study authors also reported a second
experiment examining the presence of dibenzothiophene metabolites in the urine of rabbits, as
described in Table 4B.
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No deaths or clinical signs of toxicity were reported during the study. Body weights
throughout the course of the study were presented graphically, and mean terminal body weights
were provided in numerical form for each exposure group (see Table B.l). A dose-dependent
decrease in body weight was observed; however, the study authors attributed this to reduced food
consumption and did not consider it a direct effect of dibenzothiophene. For the evaluation of
organ weights, animals dosed with dibenzothiophene were compared with laboratory historical
controls matched according to body weight. As a result, the differences from the control group
approximate a change in relative (to body weight) organ weight. The only significant effects on
organ weight observed were in the liver and spleen. Although statistical significance for weight
changes in both the liver and spleen were noted by the study authors, neither an indication of the
dose at which significance occurred nor any levels of significance were reported. Data for these
organs are presented in Table B.l. Liver weights increased (7-115%) in a dose-dependent
manner, with changes greater than 10% occurring at >27 mg/kg-day. Spleen weights decreased
(29-57%) in a dose-dependent manner. The decreased spleen weight may be related to the
decreased food consumption as spleen weight has been shown to decrease disproportionately to
body weight when food consumption is decreased (Peters and Bovd. 1966). Gross examination
revealed that the livers in the mid- and high-dose animals were large and presented a yellowish,
fatty appearance. Spleens appeared normal except for a reduction in their sizes upon gross
examination. Liver and kidney histopathological lesions were reported by the study authors;
however, incidence was not reported, and no control group was examined. Histopathology of
livers from the high-dose animals revealed extensive fatty metamorphosis of the hepatic cells,
abnormal fat accumulation, and irregular vacuolation of the parenchymal cells extending
throughout the lobules. Livers from high-dose animals also had some cells with indistinct
borders where it appeared that adjacent cells had fused. Other liver cells had a rim of
homogenous, deeply stained cytoplasm surrounding groups of vacuoles. Similar changes, but
less severe, were observed in the mid-dose group. The liver effects observed in the low-dose
group were described as "still less severe" than those observed at the mid-dose. There was no
evidence of fibrosis or necrosis, and the Kupffer cells were unchanged. Kidneys of all exposed
animals had slight-to-moderate, light brown, granular pigmentation of the epithelial cells of the
proximal convoluted tubules, but there was no evidence of cell destruction. Histopathological
abnormalities in other organs, including the spleen, were not observed. Hematological effects
were compared to age-matched controls. There were no hematological effects observed based on
the blood analyses of the high-dose animals when compared with age-matched laboratory
historical controls. In addition, the study authors noted that similar blood counts were seen in
previously published hematological data from untreated animals and in animals treated with the
closely related compound, diphenylene oxide.
Liver effects seen at the low dose as well as decreased spleen weight and granular
pigmentation of the renal epithelial cells were not considered adverse effects of
dibenzothiophene exposure. Therefore, based on increased liver weight and histopathological
changes in the liver, the NOAEL and LOAEL identified for this study are 13 and 27 mg/kg-day,
respectively.
Inhalation Exposures
No studies were identified.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Dibenzothiophene is deemed not mutagenic based on the few available studies on its
mutagenic potential. Dibenzothiophene was negative for mutagenicity in the Ames test for doses
up to 500 jug (Mct'all et al.. 1984; Pelrov et al.. 1983; Dickson and Adams. 1980) and was
negative in the Chinese hamster ovary cell (CHO) mutation assay for doses up to 100 |ag/m L
(Rasmussen et al.. 1991). These data are further described in Table 4A.
Additional studies investigating the metabolism of dibenzothiophene in rats (Jacob et al..
1991; Vignier et ai, 1985), the elimination of dibenzothiophene in the urine of rabbits (Thomas
et al.. 1942). and the acute toxicity of dibenzothiophene in mice (Leighton. 1989) are also
available. See Table 4B for the details of these studies.
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Table 4A. Summary of Dibenzothiophene Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Genotoxicity studies in prokaryotic organisms
Reverse mutation
Ames assay using Salmonella typhimurium
strain TA98 treated with 10-100 |ig
dibenzothiophene per plate dissolved in DMSO
and incubated at 37°C for 48 hr with Aroclor
1254-induced rat-liver S9 homogenate
activation (S9 concentrations of 4, 10, or 20%)
100 ng
ND

Not mutagenic at any dose; S9 volume
did not affect activity
Mcfall et al.
(1984)
Ames assay using S. typhimurium strains TA98,
TA100, TA1535, TA1537, and TA1538 treated
with an unreported quantity of
dibenzothiophene dissolved in DMSO with
Aroclor 1254-induced rat-liver S9 homogenate
activation
NR
ND

Not mutagenic; mutagenicity results
presented as revertant ratio (number of
revertants per plate/number of
spontaneous revertants);
dibenzothiophene reportedly had "no
mutagenic response" with an average
revertant ratio <2.0
Dickson and
Adams
(1980)
Ames assay using S. typhimurium strains TA98,
TA100, TA1535, and TA1537 treated with
2-500 |ig dibenzothiophene per plate dissolved
in DMSO with and without Aroclor
1254-induced rat-liver S9 homogenate
activation
500 ng


Not mutagenic at any dose
Pelrov et al.
(1983)
SOS repair
induction
ND
Genotoxicity studies in nonmammalian eukaryotic organisms
Mutation
ND
Recombination
induction
ND
Chromosomal
aberration
ND
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Table 4A. Summary of Dibenzothiophene Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without
Activation
With
Activation
Chromosomal
malsegregation
ND
Mitotic arrest
ND
Genotoxicity studies in mammalian cells—in vitro
Mutation
Chinese hamster ovary (CHO-K1BH4) cells
treated with 1-100 ng/mL dibenzothiophene
with Ham's F12 medium, activated with
4% Aroclor-induced rat-liver S9 solution and
incubated for 5 hr; control experiments
conducted with DMSO as the control and
methyl methane sulfonate as a positive control
100 iig/mL
ND

Not mutagenic at any dose
Rasmussen
et al. ("19911
Chromosomal
aberrations
ND
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
Genotoxicity studies in mammals—in vivo
Chromosomal
aberrations
ND
Sister chromatid
exchange (SCE)
ND
DNA damage
ND
DNA adducts
ND
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Table 4A. Summary of Dibenzothiophene Genotoxicity
Endpoint
Test System
Dose
Concentration"
Resultsb
Comments
References
Without With
Activation Activation
Mouse
biochemical or
visible specific
locus test
ND
Dominant lethal
ND
Genotoxicity studies in subcellular systems
DNA binding
ND
"Low est effective dose for positive results or highest dose tested for negative results.
b+ = positive; ± = equivocal or weakly positive; - = negative; ND = no data; NR = not reported; DMSO = dimethyl sulfoxide.
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term
studies
CD-I mice treated via gavage
Pilot range-finding studies: 4 mice/sex/dose, single
dose of 0-3,250 mg/kg or 4 consecutive daily
doses of 0-325 mg/kg; necropsy performed 24 hr
after last dose; blood taken from hearts of mice and
examined for hematological effects; liver, kidney,
spleen, heart, lungs, thymus, and duodenum
examined at necropsy
LDsn Experiment 1: 12 male mice/dose. 12 vehicle
controls, 8 untreated controls; single doses of 0;
260; 374; 540; 777; 1,118; or 1,609 mg/kg; LD50
determined at 7 d; surviving mice sacrificed on
Day 14 and performed histology of liver, lung,
heart, and thymus
LD™ Experiment 2: 12 mice/treatment aroiiD.
5 preinduced vehicle controls; mixed-function
oxidase (MFO) pretreatment (one intraperitoneal
[i.p.] injection of 3-methylcholanthrene [80 mg/kg]
followed by daily i.p. injections of phenobarbital
[50 mg/kg] in sterile saline for 3 d) followed 24 hr
later by single doses of 0, 215, 265, 325, 400, 492,
605, or 744 mg/kg
Pilot ranee finding studies: No treatment-related
hematological changes seen; no treatment-related
histological lesions seen in the kidney, duodenum,
spleen, or heart; liver lesions included centrilobular
or periacinar degeneration and necrosis
LD™ experiments: All mortality occurred within
72 hr of treatment and was increased in groups with
prior induction of MFO; animals were sluggish;
gross lesions in mice found dead included
pulmonary congestion and edema, mild to moderate
hydrothorax, intestinal hemorrhage, and mottled
livers; all MFO-induced mice had mild fibrinous
peritonitis; histological lesions included severe
centrilobular hepatic necrosis across doses in both
experiments, necrosis of lymphocytes in thymic
cortices at >540 mg/kg in Exp. 1 and >265 mg/kg in
Exp. 2, and degenerative changes in the walls of
small arteries in the lung in 5 mice dosed with
265-492 mg/kg (Exp. 2)
Without induction: acute LD50
of 470 mg/kg; with prior
induction of MFO, acute LD50
of 335 mg/kg; preinduction of
MFO potentiated the toxicity of
dibenzothiophene
Leighton
(1989)
Metabolism/
toxicokinetic
Male Wistar rat (number not specified), treated
with daily i.p. injections of 40 mg/kg
dibenzothiophene for 3 d, 3-methylcholanthrene
for 3 d, 500 mg/kg Aroclor 1254 for 5 d, or twice
daily i.p. injections of 40 mg/kg phenobarbital for
4 d, then starved for 24 hr after final injection; liver
microsomes isolated; in vitro oxidation assay
performed using dibenzothiophene
(0.02-0.50 mM) and rat liver microsomal
suspension (10 |iL)
Dibenzothiophene metabolic pathway determined
to be S-oxidation with metabolites of
dibenzothiophene-5-oxide (primary) and
dibenzothiophene-5 -dioxide (secondary);
Aroclor 1254, 3-methylcholanthrene, and
phenobarbital increased rate of formation of
sulfoxide, but dibenzothiophene pretreatment had
no effect; carbon monoxide inhibited sulfoxidation
Dibenzothiophene metabolite
dibenzothiophene-5-oxide was
further oxidized to
dibenzothiophene-5 -dioxide;
P-450 monooxygenases most
likely involved in the
metabolism
Vignier et
al. C1985)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Metabolism/
toxicokinetic
Male Wistar rat (number not specified), treated
with i.p. injections of 40 mg 5,6-benzoflavone/kg
for 3 d, 200 mg Aroclor/kg once, or 80 mg
phenobarbital/kg in 0.9% NaCl over 3 d and
sacrificed 24 hr after last dose; microsomes from
4 animals per group were incubated with
50 |imol/L dibenzothiophene for 20 min at 37°C
and analyzed; solvent-only controls
Metabolic products were sulfoxide (main product)
and sulfone; no pretreatments affected sulfoxide
formation, but pretreatments with phenobarbital and
Aroclor increased sulfone formation
Dibenzothiophene metabolites
(using rat microsomes) were
sulfoxide and sulfone,
controlled by different enzymes;
only the one responsible for
sulfone formation can be
induced by P-450 inducers such
as phenobarbital
Jacob et al.
(1991)

1 rabbit (sex and strain not specified) given an
emulsion of 2 g dibenzothiophene in water
administered via stomach tube; urine collected
(time not specified) and analyzed
Main excretion product was mono-hydroxy-
diphenylene sulfone
Dibenzothiophene oxidized to
mono-hydro xy-diphenylene
sulfone in the rabbit
Thomas et
al. f1942s)
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DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer reference values, respectively.
IRIS data are indicated in the tables, if available.
Table 5. Summary of Noncancer Reference Values for Dibenzothiophene
(CASRN 132-65-0)
Toxicity Type (units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
PODhed
UFC
Principal
Study
Subchronic p-RfD
(mg/kg-d)
NDr
Screening chronic p-RfD
(mg/kg-d)
Rat/M
Increased
liver weight
1 x 1(T2
NOAEL
3.1
300
Thomas et
al. f 1942s)
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
NDr = not determinable.
Table 6. Summary of Cancer Values for Dibenzothiophene (CASRN 132-65-0)
Toxicity Type
(units)
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3) 1
NDr
NDr = not determinable.
DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic p-RfD
No subchronic p-RfD value can be derived because no subchronic oral studies on
exposure to dibenzothiophene were identified. The only available chronic oral study is a
peer-reviewed, published study by Thomas et al. (1942). in which male albino rats were exposed
to dibenzothiophene by oral administration for 165 days. This study relied on historical
laboratory control groups instead of a concurrent control group, and information regarding
statistical methods was not provided. Due to the shortcomings of this study, a chronic p-RfD
cannot be confidently derived here. However, the effects in the liver (increased liver weight and
fatty metamorphosis of the liver) reported by Thomas et al. (1942) are pronounced and are
supported by liver pathology observed by Leighton (1989) during acute and short-term studies in
mice (see Table 4B for details). A "screening-level" value for chronic oral exposure based on
these liver effects is provided in Appendix A. This value is thought to be protective of shorter
duration exposures as well.
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Derivation of Chronic p-RfD
As described above, no chronic p-RfD value can be derived because no adequate,
well-described studies are available. A "screening-level" value for chronic oral exposure based
on these liver effects is provided in Appendix A.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No subchronic or chronic provisional reference concentration (p-RfC) can be derived
because no inhalation studies on exposure to dibenzothiophene were identified. Furthermore,
sufficient information on the oral toxicity and metabolism of dibenzothiophene and the potential
role of first-pass effects in this toxicity does not exist to support route-to-route extrapolation.
CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 7 identifies the cancer WOE descriptor for dibenzothiophene.
Table 7. Cancer WOE Descriptor for Dibenzothiophene
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation, or
both)
Comments
"Carcinogenic to
Humans "
NS
NA
No human carcinogenicity studies were
identified.
"Likely to Be
Carcinogenic to Humans"
NS
NA
No animal carcinogenicity studies were
identified.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No animal carcinogenicity studies were
identified.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
Selected due to the lack of any data on
carcinogenicity.
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
There are no data to indicate that
dibenzothiophene is not likely to be
carcinogenic to humans.
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Although several studies have produced negative results regarding the mutagenicity of
dibenzothiophene in bacteria and CHO cells (Rasmussen et al.. 1991; Mcfall et al.. 1984; Pelrov
et al.. 1983; Dickson and Adams. 1980). no data were located on the carcinogenicity of
dibenzothiophene in whole animals. The lack of data on the carcinogenicity of dibenzothiophene
precludes the derivation of quantitative estimates for either oral (p-OSF) or inhalation (p-IUR)
exposure.
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APPENDIX A. PROVISIONAL SCREENING VALUES
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for dibenzothiophene. 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.
DERIVATION OF SCREENING PROVISIONAL ORAL REFERENCES DOSES
Derivation of Screening Chronic p-RfD
The published, peer-reviewed study by Thomas et al. (1942) represents the only
chronic-duration oral study available for dibenzothiophene and is selected as the principal
study for derivation of the screening chronic p-RfD. The critical effect is increased liver
weight in male rats. Details of the study are provided in the "Review of Potentially Relevant
Data" section of this document and briefly described below.
Following dietary dibenzothiophene exposure of rats for 165 days, effects were reported
in the liver, kidney, and spleen (Thomas et al.. 1942). Decreased spleen weight was reported;
however, this could be explained by the dose-related decrease in food consumption that
occurred. According to Peters and Boyd (1966). spleen weight decreases disproportionately to
body weight in instances of decreased food consumption. There were neither histopathological
changes to the spleen nor any hematological changes that could have indicated functional
impairment. In addition, no histopathological changes in the spleen were seen in mice following
gavage treatment of 3,250 mg/kg dibenzothiophene (single dose) or 325 mg/kg-day
dibenzothiophene for 4 consecutive days (Leighton. 1989). Therefore, the changes in spleen
weight are not considered a direct, adverse effect of dibenzothiophene exposure. Renal effects
observed in the Thomas et al. (1942) study included only a slight-to-moderate, light brown,
granular pigmentation of the epithelial cells of the proximal convoluted tubules with no evidence
of cell destruction in all treated animals. These renal changes are also not considered adverse. A
dose-dependent, biologically relevant increase in liver weight was observed with changes of
>10% (over body weight-matched laboratory historical controls) at the middle dose of
27 mg/kg-day. Histopathological lesions in the liver (fat accumulation, irregular vacuolation of
the parenchymal cells [hepatocytes] throughout the lobules, and indications that adjacent cells
had fused) were also observed at all doses; however, incidence of lesions was not provided, and
severity was described as much less in the low-dose group (13 mg/kg-day) animals. The
LOAEL in the study by Thomas et al. (1942) is 27 mg/kg-day based on increased liver weight
(relative to body weight-matched laboratory historical controls) and histopathological changes in
the liver. There is also support that the liver is a target organ of dibenzothiophene toxicity
provided by the reported severe centrilobular hepatic lesions (degeneration and necrosis) in CD-I
mice following a single lethal oral dose and during a 4-day range finding study (Leighton, 1989).
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Data from the Thomas et al. (1942) study are not amenable to BMD modeling because
the required information (i.e., number of animals per dose group) is not available. Therefore, a
NOAEL/LOAEL approach is employed to identify the point of departure (POD). The POD is a
NOAEL of 13 mg/kg-day based on changes in liver weight and liver histopathology at
>27 mg/kg-day.
In EPA's Recommended Use of Body Weight3/4 as the Default Method in Derivation of
the Oral Reference Dose (U.S. EPA. 201 1c). the Agency endorses a hierarchy of approaches to
derive human equivalent oral exposures using data from laboratory animal species, with the
preferred approach being physiologically based toxicokinetic modeling. Other approaches might
include using some chemical-specific information without a complete physiologically based
toxicokinetic model. In lieu of chemical-specific models or data to inform the derivation of
human equivalent oral exposures, EPA endorses the use of body-weight scaling to the 3/4 power
(i.e., BW3 4) to extrapolate toxicologically equivalent doses of orally administered agents from
all laboratory animals to humans for the purpose of deriving an RfD under certain exposure
conditions. More specifically, the use of BW3 4 scaling for deriving an RfD is recommended
when the observed effects are associated with the parent compound or a stable metabolite, but
not for portal-of-entry effects or developmental endpoints.
Following U.S. EPA (2011c) guidance, the POD of increased liver weight and liver
histopathology in male albino rats is converted to an HED through application of a dosimetric
adjustment factor (DAF)1 derived as follows:
DAF = BWa1/4 - BWh1/4
Where:
DAF	=	dosimetric adjustment factor
BWa	=	animal body weight
BWh	=	human body weight
Using a BWa of 0.25 kg for rats and a BWh of 70 kg for humans (U.S. EPA. 1988). the
resulting DAF is 0.24. Applying this DAF to the NOAEL identified for the critical effect in
male albino rats yields a NOAELhed as follows:
NOAELhed = NOAEL (mg/kg-day) x DAF
= 13 mg/kg-day x 0.24
= 3.1 mg/kg-day
The screening chronic p-RfD for dibenzothiophene based on a NOAELhed of
3.1 mg/kg-day in male rats is derived as follows:
Screening Chronic p-RfD = NOAELhed UFc
= 3.1 mg/kg-day -^300
= 1 x 10~2 mg/kg-day
:As described in detail in Recommended Use of Body Weight3/4 as the Default Method in Derivation of the Oral
Reference Dose (U.S. EPA. 2011c'). rate-related processes scale across species in a manner related to both the direct
(BW11) and allometric scaling (BW3'4) aspects such that BW34 BW11 = BW converted to a DAF of
BWa1/4 + BWh1/4.
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Table A. 1 summarizes the uncertainty factors (UFs) for the screening chronic p-RfD for
dib enzothi ophene.
Table A.l. UFs for the Screening Chronic p-RfD for Dibenzothiophene
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) has been applied to account for uncertainty in characterizing the toxicodynamic
differences between rats and humans following oral dibenzothiophene exposure. The toxicokinetic
uncertainty has been accounted for by calculation of a human equivalent dose (HED) through
application of a dosimetric adjustment factor (DAF) as outlined in the EPA's Recommended Use of
Body Weight3'4 as the Default Method in Derivation of the Oral Reference Dose (U.S. EPA. 20 lie).
ufd
10
A UFd of 10 has been applied because there are no acceptable two-generation reproductive toxicity
or developmental toxicity studies.
UFh
10
A UFh of 10 has been applied for inter-individual variability to account for human-to-human
variability in susceptibility in the absence of quantitative information to assess the toxicokinetics
and toxicodynamics of dibenzothiophene in humans.
ufl
1
A UFl of 1 has been applied for LOAEL-to-NOAEL extrapolation because the POD is a NOAEL.
UFS
1
A UFS of 1 has been applied because a chronic-duration study was selected as the principal study.
UFC
300

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APPENDIX B. DATA TABLES
Table B.l. Body, Liver, and Spleen Weights of Male Albino Rats After Dietary Exposure to
Dibenzothiophene for 165 Daysa'b
Parameter
Exposure Group, % (ADD, mg/kg-d)d'e
0f
0.025 (13)
0g
0.050 (27)
0h
0.100 (63)
Terminal body
weight (g)
310
310
273
273
212
212
Absolute liver
weight (g)c
10.00 ±0.11
10.70 ±0.29
(107)
9.50 ±0.27
12.80 ±0.48
(135)
8.40 ± 0.22
18.10 ±0.74
(215)
Absolute spleen
weight (g)c
0.97 ± 0.062
0.69 ±0.015
(71)
0.92 ± 0.072
0.64 ± 0.067
(70)
0.83 ±0.041
0.36 ±0.010
(43)
"Thomas et al. (19421.
Statistical analysis was not reported and is not conducted because number of animals per group was not reported.
0Weights are expressed as mean ± probable errors (% of laboratory historical control).
dAnimals were provided dibenzothiophene in the food at 0.25, 0.50, or 1.00% for the first 4 d. Because of low food
intakes and decreases in body weight, doses were then decreased to 0.025, 0.050, or 0.100% dibenzothiophene for
the remainder of the 165-d study period. The study authors provided the amount of dibenzothiophene consumed.
The following equation was used to convert that information to mg/kg-d:
ADD = Total Dibenzothiophene Consumption per Animal over Study Duration x (1 Body Weight) x
(1 ^ Days Dosed)
eData for each exposure group were compared with data for laboratory historical controls. For the evaluation of
organ weights, historical controls were matched according to body weight.
fMatched laboratory historical controls for 13-mg/kg-d dose group.
8Matched laboratory historical controls for 27-mg/kg-d dose group.
hMatched laboratory historical controls for 63-mg/kg-d dose group.
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APPENDIX C. BMD OUTPUTS
There are no BMD outputs for dibenzothiophene.
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APPENDIX D. REFERENCES
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Dickson. JG: Adams. YD. (1980). Evaluation of mutagenicity testing of extracts from processed
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Leighton. FA. (1989). Acute oral toxicity of dibenzothiophene for male CD-I mice: LD50,
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