United States
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EPA/690/R-08/006F
Final
7-23-2008
Provisional Peer Reviewed Toxicity Values for
Carbazole
(CASRN 86-74-8)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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

of 1980
CNS
central nervous system
cu.m
cubic meter
DWEL
Drinking Water Equivalent Level
FEL
frank-effect level
FIFRA
Federal Insecticide, Fungicide, and Rodenticide Act
g
grams
GI
gastrointestinal
HEC
human equivalent concentration
Hgb
hemoglobin
i.m.
intramuscular
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
IUR
inhalation unit risk
i.v.
intravenous
kg
kilogram
L
liter
LEL
lowest-effect level
LOAEL
lowest-observed-adverse-effect level
LOAEL(ADJ)
LOAEL adjusted to continuous exposure duration
LOAEL(HEC)
LOAEL adjusted for dosimetric differences across species to a human
m
meter
MCL
maximum contaminant level
MCLG
maximum contaminant level goal
MF
modifying factor
mg
milligram
mg/kg
milligrams per kilogram
mg/L
milligrams per liter
MRL
minimal risk level
MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-ob served-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-ob served-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
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p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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7-23-2008
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
CARBAZOLE (CASRN 86-74-8)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
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It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD, RfC, or carcinogenicity assessment for carbazole is available on IRIS (U.S.
EPA, 2008). Carbazole is not included in the Drinking Water Standards and Health Advisories
list (U.S. EPA, 2006). The HEAST (U.S. EPA, 1997) does not include an RfD or RfC for
carbazole, but it does list carbazole as a B2 carcinogen with an oral slope factor (OSF) of 2E-02
(mg/kg/day)"1. This OSF was derived in a Health and Environmental Effects Profile (HEEP) for
carbazole (U.S. EPA, 1986) on the basis of an increased incidence of hepatocellular carcinomas
and neoplastic nodules in mice chronically exposed to carbazole through diet (Tsuda et al.,
1982). IARC (1983, 1999), however, considers the study by Tsuda et al. (1982) to provide
"limited evidence" of carcinogenicity in animals but assigned an overall classification of Group
3, "not classifiable," for the carcinogenicity of carbazole to humans. IARC uses the
classification of limited evidence of carcinogenicity when there is credible evidence of a positive
association between exposure to the chemical and cancer, but the occurrence of chance, bias, or
confounding influences cannot be ruled out with reasonable confidence, as is the case with
carbazole. The carcinogenicity of carbazole has not been assessed by NTP (2005, 2008).
Additionally, Cal EPA (2008a, 2008b, 2008c) has not derived a REL or cancer potency factor for
carbazole.
The CARA list (U.S. EPA, 1991, 1994) includes no relevant documents besides the
previously mentioned HEEP (U.S. EPA, 1986). ATSDR (2008) has not published a
Toxicol ogical Profile for carbazole and did not include it in the profile for poly cyclic aromatic
hydrocarbons (PAH) (ATSDR, 1995). In the Toxicological Profile for creosote (ATSDR, 2002),
carbazole is mentioned as a constituent of a blended creosote oil that tested positively for dermal
carcinogenicity, but it is not mentioned in the context of oral toxicity. The World Health
Organization (WHO) (2008) has not published an Environmental Health Criteria document for
carbazole, and there is no discussion of carbazole toxicity in the WHO (1998) PAH document.
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7-23-2008
OSHA (2008), NIOSH (2008), and ACGIH (2007) have not established occupational exposure
limits for carbazole.
Carbazole, and several of its derivatives, are polycyclic aromatic hydrocarbons (PAHs)
derived from fossil fuels and their incomplete combustion. The chemical shows inconsistent
toxicity data. It is negative in the Ames test, with or without activation; negative in short term
carcinogenicity tests in rats, negative in cultured hepatocytes (Weyland et al., 1993), and
negative in the CHO cell assay. However, it is positive in chromosome aberration test in Swiss
mice (Jha et al 2002), and in Syrian Hamster sperm. In two long-term studies in the same lab
(Hagiwara, et al 1979 and Tsuda et al 1982), significant increases in liver cancers were found in
mice exposed to carbazole in the diet that were somewhat dose dependent. An additional study
in Syrian Hamsters found it carcinogenic in that system (Moore et al, 1987). Unlike the well
known dibenzo and other derivatives, carbazole itself is negative in the Ames test, though the
chemical does intercalate in DNA. There is evidence for aromatic hydrocarbon receptor (AhR)
binding and P4501 Al induction in several systems, as well as peroxysome proliferation through
the PPAR. The interaction with AhR however, may be noncompetitive, as there is some
antagonism with better ligands like benzopyrene.
Literature searches were conducted from the 1960s through December 2007 for studies
relevant to the derivation of provisional toxicity values for carbazole. Databases searched
include MEDLINE, TOXLINE (Special), BIOSIS (from August 2000), TSCATS 1/TSCATS 2,
CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents (July through
December 2007).
FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR CARBAZOLE
The data are inadequate to derive a p-RfD for carbazole. No dose-response information
pertinent to any target organs is available in the current database; thus, the database lacks a study
that could serve as a suitable basis for the derivation of a p-RfD for carbazole.
FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR CARBAZOLE
No inhalation toxicity data in humans or animals is identified; thus, no p-RfC could be
derived for carbazole.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR CARBAZOLE
Because of the lack of carcinogenic data in humans or animals, under the 2005
Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), this PPRTV document classifies
carbazole as having "Inadequate Information to Assess Carcinogenic Potential."
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FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR OR
INHALATION UNIT RISK FOR CARBAZOLE
Neither a p-OSF nor a p-IUR could be derived for carbazole because of the lack of
suitable oral or inhalation data in both humans and animals.
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