United States
Environmental Protection
1=1 m m Agency
EPA/690/R-09/045F
Final
3-25-2009
Provisional Peer-Reviewed Toxicity Values for
Phenanthrene
(CASRN 85-01-8)
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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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
PHENANTHRENE (CASRN 85-01-8)
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.	U.S. EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in U.S. 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 U.S. 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 U.S. EPA IRIS Program. All provisional
toxicity values receive internal review by two U.S. 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 U.S. 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 U.S. EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center for OSRTI. Other U.S. 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 or RfC for phenanthrene is listed on IRIS (U.S. EPA, 2008), in the Health
Effects Assessment Summary Tables (HEAST; U.S. EPA, 1997), or in the Drinking Water
Standards and Health Advisories list (U.S. EPA, 2006). The Chemical Assessments and Related
Activities (CARA) list (U.S. EPA 1991, 1994) includes a Health Effects Assessment (HEA)
(U.S. EPA, 1984) and a Health and Environmental Effects Profile (HEEP) (U.S. EPA, 1987) for
phenanthrene; it also includes a Drinking Water Criteria Document (DWCD) for polycyclic
aromatic hydrocarbons (PAH) (U.S. EPA, 1992). None of these documents derive an RfD or
RfC for phenanthrene because no relevant toxicity data are available for humans or animals.
Similarly, because relevant data are not available, the Agency for Toxic Substances and Disease
Registry (ATSDR, 1995) Toxicological Profile for PAH does not derive any oral or inhalation
MRLs for phenanthrene. An Environmental Health Criteria document on PAH available from
the World Health Organization (WHO, 1998) contains no subchronic or chronic oral or
inhalation toxicity data for phenanthrene. The California Environmental Protection Agency
(CalEPA, 2005a,b) has not derived oral or inhalation RELs for phenanthrene. There are no
Occupational Safety and Health Administration (OSHA, 2008), National Institute for
Occupational Safety and Health (NIOSH, 2008), or American Conference of Governmental
Industrial Hygienists (ACGIH, 2007) occupational exposure limits for phenanthrene.
Warshawsky (2001) also reviewed the health effects associated with PAHs.
The IRIS Summary for Phenanthrene (U.S. EPA, 2008) presents a cancer
weight-of-evidence characterization of Group D, not classifiable as to human carcinogenicity,
based on no human data and inadequate animal data from a single gavage study in rats and
several skin application and injection studies in mice. Phenanthrene also is classified as Group D
in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2006). Although there is
no listing for phenanthrene in the HEAST cancer table (U.S. EPA, 1997), the HEA, a HEEP, and
a DWCD all designated phenanthrene a Group D chemical or otherwise indicated that
insufficient data were available for a carcinogenicity assessment. The International Agency for
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Research on Cancer (IARC, 1983, 1987) assigned phenanthrene to Group 3—not classifiable as
to human carcinogenicity because of no adequate data in humans and inadequate evidence in
animals. Documents developed more recently by ATSDR (1995) and WHO (1998) do not
contain any previously unidentified carcinogenicity data for phenanthrene. The National
Toxicology Program (NTP) has not tested the carcinogenicity of phenanthrene or included it in
its 11th Report on Carcinogens (NTP, 2005, 2008). CalEPA (2002) has not derived a cancer
potency factor for phenanthrene.
Literature searches were conducted through December 2007 for studies relevant to the
derivation of provisional toxicity values for phenanthrene. Databases searched include the
following: MEDLINE (including cancer subset), TOXLINE (Special), BIOSIS, TSCATS
1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. An
additional PubMed Search was conducted between December 2007 and March 2009 for studies
relevant to the derivation of provisional toxicity values for phenanthrene.
REVIEW OF PERTINENT DATA
Human Studies
No studies were located regarding oral or inhalation exposure of humans to
phenanthrene. In a population-based case-control study, Croen et al. (1997) reported a
nonsignificant increase in risk for neural tube defects associated with maternal residence near
National Priority List (NPL) sites containing phenanthrene, among other pollutants.
Consequently, the association cannot be attributed to phenanthrene only.
Animal Studies
Oral Exposure
No adequate studies were located regarding chronic oral toxicity of phenanthrene in
animals. Rakhmanina (1964) conducted 3- and 7-month oral studies in rats and rabbits. In the
3-month study, groups of six male rabbits and six male white rats were administered 0 or
70 mg/kg of phenanthrene (strains used were not identified). The purity of phenanthrene used,
the vehicle, and the frequency of test compound administration are not reported. In rabbits,
treatment with phenanthrene resulted in significant (p < 0.05) increases (up to 5-fold higher than
controls) in serum galactose content following i.v. injection of galactose (quantity of galactose
injected and vehicle not reported) on days 45 and 90. Significantly increased (24% higher than
controls,/? = 0.05) serum sulfhydryl group content (measured after 60 days of exposure) was also
reported in rabbits. No other treatment-related changes were reported for rabbits or rats in the
3-month study (data not shown). Other endpoints evaluated included hepatic protein formation,
hypophyseal-adrenocortical system, blood cholinesterase and catalase activity, blood
composition, oxygen consumption and body weights. Specific details regarding the actual
analyses undertaken for most endpoints are unclear. While the results are reported as negative,
the data from these analyses were not shown. Given the reporting limitations, the results of the
3-month study are of limited utility due to inadequate reporting of methods and results. In the
7-month study, Rakhmanina (1964) administered 0 or 0.2 mg/kg of phenanthrene to an
unreported number of rabbits and white rats. The authors reported evaluating the "carbohydrate
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and detoxifying functions of the liver," the sulfhydryl content of serum, clinical signs, body
weight and, in rats only, conditioned reflexes. According to the study authors, no
treatment-related effects were observed; however, the data were not shown. Effect levels cannot
be determined from these data due to the poor reporting.
Huggins and Yang (1962) administered a single gavage dose of 200 mg phenanthrene
(dissolved in sesame oil; purity not specified) to 10 female Sprague-Dawley rats (50 days old) in
an effort to determine whether the compound induced mammary tumors. The authors reported
that no mammary tumors were observed in the phenanthrene-treated rats (0/10), although
mammary tumors occurred in 700/700 rats administered 7,12-dimethylbenz[a]anthracene
(20 mg) and in 8/9 rats given benzo[a]pyrene (100 mg) under the same conditions. In their
study, no other tissues or organs are evaluated for the presence of tumors. The authors generally
describe their methods for assessing tumor formation in studies of mammary carcinogenicity, but
they do not specify the methods used in the current study of phenanthrene. Thus, it is not clear
whether the occurrence of mammary tumors was evaluated exclusively by palpation or whether a
histologic examination was performed. In addition, the observation period is not specified.
Consequently, this study is not an adequate test of the carcinogenic potential of phenanthrene.
Other Studies
Fourteen additional toxicity studies are identified and described in the following sections.
These studies are not appropriate for setting PPRTVs for oral and inhalation exposures; many of
these have study-design limitations or the results are poorly reported.
Other Routes
Dermal Studies—Salaman and Roe (1956) conducted a skin-tumor initiation study in
mice. A total dose of 540 mg per mouse phenanthrene (18% solution in acetone) was applied to
the skin of 20 S-strain mice. The total dose was applied in 10 individual doses (54 mg per dose)
applied 3 times per week, followed (25 days after first initiator treatment) by 18 weekly croton
oil applications. A control group received only croton oil treatment. A week after the promotion
period ended, the study authors recorded the papilloma incidence; it is not clear whether any
histologic examination of the skin was performed. In addition, the authors sacrificed all the mice
and examined them for lung tumors. Skin papillomas were observed in 5/20 mice treated with
phenanthrene and in 4/19 control mice surviving croton oil treatment (not statistically
significant). The total number of papillomas in the tumor-bearing mice was higher in the
phenanthrene-treated animals (a total of 12 tumors) than in controls (4). The incidence of lung
tumors reportedly was not affected by phenanthrene treatment (data not shown).
Roe (1962) assessed the cocarcinogenicity of phenanthrene and benzo[a]pyrene. Groups
of 10 mice/sex were given dermal applications of 300 |ig phenanthrene (in 0.25 mL acetone)
with or without 300 |ig of benzo[a]pyrene. The applications were given on days 0, 2, 6, and 8.
Beginning on day 21, the mice were treated with dermal applications of croton oil (0.1%) once
each week for 20 weeks. Papillomas were recorded for 20 weeks following initiation.
Papillomas were observed in 2/20, 4/19, and 9/19 mice in the control, phenanthrene-exposed,
and benzo[a]pyrene-exposed groups, respectively. The average numbers of papillomas per
survivor are 0.2, 0.4, and 2.5 in the control, phenanthrene-exposed, and benzo[a]pyrene-exposed
mice respectively. Other groups of mice were exposed to phenanthrene (300 |ig, in 3% aqueous
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gelatin) by subcutaneous injection on days 0, 2, 4, 6, and 8, with or without dermal application of
benzo[a]pyrene (300 |ig). In the group exposed to subcutaneous phenanthrene alone, 3/17 mice
developed papillomas (average of 0.6 papillomas per survivor). Although tumor incidence and
the number of tumors per survivor are each higher in the group exposed to both dermal
benzo[a]pyrene and subcutaneous phenanthrene, according to the study authors, coadministration
of subcutaneous phenanthrene with dermal benzo[a]pyrene exposure did not result in a
statistically significant increase in tumor formation when compared with the group exposed to
dermal benzo[a]pyrene.
Wood et al. (1979) administered a single application of phenanthrene (10 |imol in 200 |iL
acetone: ammonium hydroxide [1000:1]) to the shaved backs of 30 female CD-I mice;
30 control mice were exposed to solvent alone. (The phenanthrene was >98% pure). The study
authors began promotion with twice-weekly applications of tetradecanylphorbol acetate (TPA;
16 nmol/200 |iL acetone) 1 week after initiation. Two identical experiments were conducted. In
the first experiment, the study authors reported papilloma incidence after 35 weeks of promotion
and, in the second experiment, after 25 and 35 weeks of promotion. The numbers of animals
surviving are not reported by group; however, the study authors indicated that 27-30 animals in
each group were alive at 35 weeks. In the first experiment, the papilloma incidences were 7%
and 17% in the control and phenanthrene-treated groups, respectively, after 35 weeks. The
numbers of papillomas per mouse are 0.1 and 0.28 in the control and phenanthrene-treated
groups, respectively, after 35 weeks. In the second experiment, control animals exhibited
papilloma incidences of 3% and 7% after 25 and 35 weeks of promotion, respectively; the
incidence in phenanthrene-treated animals is 14% at both time periods. The numbers of
papillomas per mouse are 0.035 and 0.14 in the control and phenanthrene-treated groups,
respectively, after 25 weeks and 0.07 and 0.14 in the control and phenanthrene-treated groups,
respectively, after 35 weeks. The differences between the groups are not statistically significant
in either experiment.
In the only study reporting a statistically significant increase in tumor formation
associated with phenanthrene treatment, Scribner (1973) applied 10 |imol phenanthrene (in
benzene) to the shaved backs of 30 female CD-I mice, followed by twice weekly treatment with
TPA (5 |iinol'). Though the study text identifies a control group (n = 30), it does not specify the
treatment of control mice. Papilloma incidence was recorded every 5 weeks from 10 to 35
weeks after initiation. All animals survived for the 35 weeks of the study in the control and
treatment groups. In the control group, the study authors reported papillomas at only 25 weeks
and only in 1 of 30 animals (3%); no papillomas are reported in weeks 30 or 35. In the group
treated with phenanthrene, the percentage of mice with papillomas is 0%, 10%, 20%, 23%, 30%,
and 40% when measured in weeks 10, 15, 20, 25, 30, and 35, respectively. The number of
papillomas per mouse was 0, 0.1, 0.27, 0.37, 0.5, and 0.6 when measured in weeks 10, 15, 20,
25, 30, and 35, respectively. The incidence in phenanthrene-treated animals is statistically
significantly increased (p < 0.01). However, the influence of the carcinogenic vehicle (benzene)
is uncertain—especially given the apparent lack of a description of the treatment of the control
group.
1 It is not clear whether this was the total dose or the twice-weekly dose of TPA.
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In another study of skin tumor initiation, LaVoie et al. (1981) applied a total of 1.0 mg of
phenanthrene (>99.5% pure, in acetone) to the shaved backs of 20 female Swiss albino mice
(Ha/ICR). The total dose was administered through 10 doses of 0.1 mg of phenanthrene applied
every other day to each mouse. A control group received acetone application only. The study
authors began promotion by TPA (2.5 jag) 10 days after the last subdose and continued 3 times
weekly for 20 weeks. Benzo[a]pyrene was also tested at a total dose of 0.3 mg. The authors did
not specify the methods used to assess skin tumor formation (e.g., palpation, histopathology, or
both). No tumors were observed in the control group or in the phenanthrene-treated group.
Benzo[a]pyrene induced tumors in 14/15 animals (5 animals in this treatment group died
prematurely).
Siebert et al. (1981) applied a single dose of phenanthrene to the backs of 28 NMRI mice
(sex not specified), followed by twice-weekly TPA treatment (dose of TPA not reported). It is
not clear whether a control group is included, and no further details of the study design are
reported. The study authors indicate that phenanthrene gave negative results, as assessed by the
tumor incidence and average tumor yield. No other information is provided.
As part of a study of the complete carcinogenicity of PAH mixtures, Warshawsky et al.
(1993) exposed groups of 20 male C3H/HeJ mice to phenanthrene (99% pure; a dose of 50 |iL of
a 0.1%) solution in toluene) via dermal application to the interscapular region of the back twice
weekly for up to 104 weeks. Both untreated and toluene-treated control groups are included. A
benzo[a]pyrene-treated group was also studied, but a noncarcinogenic dose (0.001%> in toluene)
was intentionally used. The animals were observed twice daily for skin anomalies. Papilloma
appearance and progression to malignancy were recorded. Upon autopsy (when moribund or
dead, or at sacrifice at study termination), the study authors performed a gross necropsy and
collected skin samples from areas with visible lesions. Of 17 phenanthrene-treated mice that
survived to study termination, one animal had a tumor, appearing after 53 weeks of exposure.
No control or benzo[a]pyrene-exposed mice exhibited tumors.
Intraperitoneal Studies—Phenanthrene did not induce significant increases in lung or
liver tumors in a newborn mouse assay conducted by Buening et al. (1979). Phenanthrene
(98%o pure) was administered via three i.p. injections (for a total dose of 1.4 |imol, or 0.25 mg,
per mouse over) on the first, 8th and 15th day after birth to groups of 100 Swiss-Webster
BLU:Ha(ICR) mice. Control mice received i.p. injections of dimethyl sulfoxide (DMSO) on the
same schedule. The animals were sacrificed between 38 and 42 weeks of age for autopsy and
gross tumor count. The protocol called for microscopic examination of a "representative
number" of grossly identified lung tumors, all grossly identified liver tumors, as well as tissues
with "suspected pathology." No liver tumors were observed in phenanthrene-treated or control
mice. There is no statistically significant increase in the incidence of pulmonary tumors in the
phenanthrene-treated mice.
Lung Implantation Studies—Wenzel-Hartung et al. (1990) implanted phenanthrene
(99.9%o pure) in a beeswax matrix in the lungs of female Osborne-Mendel rats. Phenanthrene
doses of 1, 3, and 10 mg/animal were given to groups of 35 rats per dose. Both vehicle and
untreated control groups (n = 35) were used. Other groups of rats were exposed to additional
PAHs, including three groups exposed to benzo[a]pyrene at 0.03, 0.1, and 0.3 mg/animal.
Observations of the animals were performed twice daily, and the rats were sacrificed when
moribund or when clinical signs of tumor formation were evident. The study authors gave each
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rat a complete autopsy, and histologically examined the lungs, along with any grossly evident
tumors. No tumors were observed in vehicle or untreated control animals. Only one tumor, a
squamous-cell carcinoma, was observed in the high-dose phenanthrene-treated animals. The
authors reported that the incidence of preneoplastic lesions (squamous cell metaplasias) was
similar between the phenanthrene-exposed and control groups (data not shown). Benzo[a]pyrene
exposure resulted in a dose-related increase in the incidence of tumors (3/35, 11/35, and 27/35 in
low-, mid-, and high-dose groups).
Subcutaneous Studies—Three subcutaneous studies of the potential carcinogenicity or
cocarcinogenicity of phenanthrene are identified. Steiner (1955) injected male and female
C57BL mice (40-50 in total) with a single dose of phenanthrene (5 mg) dissolved in tricaprylin.
The animals were sacrificed 22 to 28 months after exposure. No other study design details are
given, and a control group is not reported. Benzo[a]pyrene was tested at a concentration of
0.09 mg. Phenanthrene treatment did not result in any sarcomas among the 27 mice that
survived to 4 months after exposure. In contrast, sarcomas were observed in 16/21 mice exposed
to benzo[a]pyrene. Given the limited number of details provided by the study authors and the
route of exposure, this study is of limited value for setting PPRTVs for oral exposures.
Phenanthrene was administered by subcutaneous injection in a study by Grant and Roe
(1963; Roe and Waters, 1967). Newborn albino mice (strain and group sizes not specified) were
given 40-[j,g phenanthrene in 0.02 mL of aqueous gelatin. Controls received either 0.02 or
0.04 mL aqueous gelatin. The study authors excluded mice that died within the first 10 weeks of
the study from analysis. At 52 weeks after exposure, the study authors sacrificed 10 mice/group
and examined them for tumors; the remaining mice were sacrificed at 62 weeks. The extent of
histologic examination is not reported. Exposure to phenanthrene did not result in an increased
incidence of pulmonary adenomas (3/49) or hepatomas (4/49) when compared to incidences in
the control groups. In controls receiving 0.02 mL aqueous gelatin, the incidence of pulmonary
adenomas and hepatomas were 8/34 and 1/34, respectively. In controls receiving 0.04 mL
aqueous gelatin, the incidence of pulmonary adenomas is 5/38 while the incidence of hepatomas
is 2/38. The study authors observed skin papillomas in 2/49 rats exposed to phenanthrene; these
incidences are not statistically significantly increased over controls (no skin papillomas were
observed in controls).
Genotoxicity and Mutagenicity Studies
An abundance of evidence suggests that phenanthrene is either very weakly genotoxic or
not genotoxic at all. Tables 1, 2, and 3 collectively summarizes the genotoxicity data for
phenanthrene: Table 1—in vitro mutagenicity and morphological transformation studies; Table
2—in vivo clastogenicity studies; and Table 3—in vitro clastogenicity and DNA damage, repair,
synthesis, and adduct studies.
The majority of the available bacterial mutagenicity assays gave results that were
negative. Six of the 17 studies available provide positive results. Bos et al. (1988),
Carver et al. (1986) and Sakai et al. (1985) observed weakly positive results for phenanthrene
(2- to 3-fold increases in revertants) in Salmonella typhimurium strains TA100 and TA97.
Sakai et al. (1985) reported a poor dose-response relationship for phenanthrene.
Dunkel et al. (1984) reported a study in which the same experiments were conducted in four
different laboratories. In mutagenicity tests conducted with or without six different metabolic
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activation preparations, phenanthrene tested negative in five strains of S. typhimurium and in
Escherichia coli WP-2 uvrA (Dunkel et al., 1984). Only one of the four laboratories reported a
positive result for phenanthrene (in TA1538 with Aroclor 1254-induced rat liver S9). When this
assay was repeated in the same laboratory, the result was negative (Dunkel et al., 1984).
Verschaeve et al. (1999) tested phenanthrene in the VITOTOX assay and reported positive
results—but at toxic concentrations. Finally, Oesch et al. (1981) report positive results in the
Ames assay (strains TA100 and TA1537) when phenanthrene was tested in combination with rat
Aroclor-induced S9 rat microsomal and cytosolic liver fractions (neither alone was active) and
when epoxide hydrolase was inhibited. Phenanthrene did not induce mitotic gene conversion in
Saccharomyces cerevisiae (Siebert et al., 1981). Phenanthrene gave negative results in four in
vitro studies of mammalian mutagenicity and in nine in vitro studies of morphological cell
transformation (see Table 1).
Both studies assessing clastogenicity after in vivo administration of phenanthrene report
positive findings (Roszinsky-Kocher et al., 1979; Bayer, 1978; see Table 2); however, in the
study by Bayer (1978), only the high dose gave a significant response. Negative results were
obtained in four in vitro studies of clastogenicity using mammalian cells (see Table 3). Of
14 studies examining DNA adducts, damage, repair, or synthesis in in vitro systems, four gave
positive results, one reported equivocal findings, and the remaining nine gave negative results
(see Table 3).
Phenanthrene also is negative in the initiator tRNA acceptance assay
(Hradec et al., 1990). In studies of DNA adduct formation with phenanthrene, no DNA adducts
are found in calf thymus DNA (Bryla and Weyand, 1992), while a low level of DNA binding is
reported by Grover and Sims (1968) when the DNA of salmon testes were assayed. In cultured
hamster fibroblasts treated with tritiated phenanthrene, a low level of DNA binding has also been
observed (Grover et al., 1971). In an in vivo study of DNA adduct formation in mice (TO strain)
exposed to a topical application of 50 mM phenanthrene, no adducts were detected in the skin
when tested 1 to 8 days after exposure (Ingram et al., 2000).
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Table 1. In vitro Mutagenicity and Morphological Transformation Studies of Phenanthrene
Reference
Test system
Activation system
Result
Comments
Bacterial Mutagenicity
Bos et al., 1988
S. typhimurium TA98, TA100
Rat Ar S9
Weakly
positive

Biickeretal., 1979
S. typhimurium TA1535, TA1537,
TA1538, TA98, TA100 and B. subtilis
H17 and M45
Mouse Ar
microsomes
Negative

Carver etal., 1986
S. typhimurium TA100
Ar rat and Ar
hamster S9
Weakly
positive
S9 concentration varied; 400 |iL/plate optimal
Dunkel et al., 1984
S. typhimurium TA1535, TA1537,
TA1538, TA98, TA100, also E. coli
strains
Rat, mouse, hamster
Ar S9
Negative
Dose-response data not provided. Positive result
reported by 1/4 laboratories in 1/6 strains; repeat was
negative
Gibson etal., 1978
S. typhimurium TA1535, TA1537,
TA1538, TA98
Nonenzymatic
(gamma radiation)
Inconclusive
Toxicity interfered with mutagenicity testing
Hermann, 1981
S. typhimurium TA98
Rat Ar S9
Negative

Kadenetal., 1979
S. typhimurium TM677
Rat Ar or PB S9
Negative

Kangsadalampai et al., 1996
S. typhimurium TA98, TA100
None
Negative

LaVoie et al., 1980
S. typhimurium TA98, TA100
Rat Ar S9
Negative

McCannetal., 1975
S. typhimurium TA1535, TA1537,
TA98, TA100
Rat Ar S9
Negative

Oeschetal., 1981
S. typhimurium TA1537, TA100
Rat Ar S9
Positive
under
conditions
shown at
right
Large amounts of Rat Ar S9, or microsomal +
cytosolic liver fractions, or when epoxide hydrolase
inhibited
Pahlman and Pelkonen, 1987
S. typhimurium TA100
S9 from control,
MC- or
TCDD-treated rats
and mice
Negative

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Table 1. In vitro Mutagenicity and Morphological Transformation Studies of Phenanthrene
Reference
Test system
Activation system
Result
Comments
Probst etal., 1981
S. typhimurium TA1530, TA1535,
TA1537, TA1538, TA98, TA100
Rat Ar S9
Negative
Data reported as minimum mutagenic concentration
(nmol/mL)
Rosenkranz and Poirier, 1979
S. typhimurium TA1530, TA1535, two
E. coli strains
Uninduced rat S9
Negative

Sakaietal., 1985
S. typhimurium TA97, TA98, TA100
Rat Ar S9
Weakly
positive
Toxicity observed at 250 |ig/platc
Simmon, 1979a
S. typhimurium TA1535, TA1536,
TA1537, TA1538, TA98, TA100
Rat Ar S9
Negative

Verschaeve et al., 1999
S. typhimurium TA104recN2-4 and
TA104/?rl
S9 (unspecified)
Positive
Toxicity observed at mutagenic doses. VITOTOX
assay tests expression of lux bioluminescent operon
Mammalian Mutagenicity
Barfknecht et al., 1982
TK6 human lymphoblast cells
Rat Ar S9
Negative
Trifluorothymidine resistance (TK)
Durantetal., 1996
Human B-lymphoblastoid hlAlv2 cells
Intrinsic
Negative
Trifluorothymidine resistance (TK)
Hubermanand Sachs, 1976
V79 Chinese hamster cells
Hamster embryo
cells
Negative
Ouabain and 8-azaguanine resistance (HPRT)
Mishraetal., 1978
Fischer rat embryo cells infected with
Rauscher leukemia virus
Rat Ar S9
Negative
Ouabain resistance (HPRT)
Morphological Transformation
DiPaolo et al., 1969
Syrian golden hamster embryo cells
Cocultivated
irradiated
Sprague-Dawley rat
fetal cells
Negative

DiPaolo et al., 1973
Syrian golden hamster embryo cells
In vivo
(transplacental)
exposure
Negative
Positive results confirmed with tumor induction
Dunkeletal., 1981
Balb/3T3, Syrian golden hamster
embryo and Rauscher murine leukemia
virus-infected F344 rat embryo cells
None
Negative

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Table 1. In vitro Mutagenicity and Morphological Transformation Studies of Phenanthrene
Reference
Test system
Activation system
Result
Comments
Evans and DiPaolo, 1975
Strain 2 guinea pig fetal cells
None
Negative
Positive results confirmed with tumor induction
Greb et al., 1980
BHK21/CL 13
Rat Ar S9
Negative

Kakunaga, 1973
BALB/3T3 subclone A31-714
None
Negative
Positive results confirmed with tumor induction
Lubetetal., 1983
C3H10T1/2CL8 mouse embryo
fibroblasts
None
Negative

Mishraetal., 1978
Rauscher leukemia virus-infected
Fischer rat embryo
None
Negative

Pientaetal., 1977
Syrian golden hamster embryo
Cocultivated
X-irradiated cells of
same type
Negative

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Table 2. In vivo Clastogenicity Studies of Phenanthrene
Reference
Species
Strain
Route of
administration
Vehicle
Exposure
Hours between
dosing and
sacrifice
Tissue
analyzed
Clastogenic
endpoint
Result
Comments
Bayer, 1978
Hamsters
Chinese
Intraperitoneal
Tricaprylin
Single
24 hr for
aberrations; 30 hr
for micronuclei
Bone
marrow
Gaps, breaks,
micronuclei,
SCEs
Positive at
high dose

Roszinsky-
Kocher et al.,
1979
Hamsters
Chinese
Intraperitoneal
Tricaprylin
2 doses 24 hr
apart
24 hr after 2nd
treatment
Bone
marrow
SCEs,
aberrations
Positive for
Sister
Chromatid
Exchanges
Negative for
aberrations
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Table 3. In vitro Clastogenicity, DNA Adducts, DNA Damage, DNA Repair, and DNA Synthesis Studies of Phenanthrene
Reference
Test system
Metabolic activation
Endpoint
Result
Comments
Clastogenicity
Crofton-Sleigh et
al., 1993
Human lymphoblastoid
MCL-5 cells
Intrinsic
Micronuclei
Negative

Matsuoka et al.,
1979
Male Chinese hamster lung
(CHL)
Rat Ar S9
Aberrations and SCEs
Negative
No untreated
control
Popescu et al.,
1977
Chinese hamster V79-4 cells
With or without irradiated
Syrian golden hamster
secondary embryo feeder
cells
Aberrations and SCEs
Negative

Piatt et al., 2007
Chinese hamster V79-4 cells
V79 lung fibroblasts
With and without Rat Ar S9
DNA strand breaks in Comet assay
Negative

DNA Damage, Repair, and Synthesis
Casto, 1979
Syrian golden hamster
embryo
Intrinsic
Unscheduled DNA synthesis measured by [3H]
thymidine uptake
Negative

Lake et al., 1978
Human foreskin epithelial
cells
None
Unscheduled DNA synthesis measured by [3H]
thymidine uptake
Negative

McCarroll et al.,
1981
E. coli WP2, WP2 uvrA,
WP67, CM611, WP100,
W3110polA+ and
p3478pola-
Rat Ar S9
DNA damage measured by differential killing of
repair-deficient strains
Negative

Mersch-
Sundermann et
al., 1992, 1993
E. coli PQ37
Rat Ar S9
Induction of SOS system measured by SOS
chromotest
Positive

Milo et al., 1978
Human skin fibroblast NF
and Detroit 550 cells
None
DNA damage measured by alkaline elution
Negative

Probst etal., 1981
Rat hepatocyte primary
culture
None
Unscheduled DNA synthesis measured by [3H]
thymidine uptake
Negative

13

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Table 3. In vitro Clastogenicity, DNA Adducts, DNA Damage, DNA Repair, and DNA Synthesis Studies of Phenanthrene
Reference
Test system
Metabolic activation
Endpoint
Result
Comments
Rosenkranz and
Leifer, 1980
E coli pol Al-
Rat liver S9
DNA damage measured by differential killing of
repair-deficient strains
Negative

Rossman et al.,
1991
Ecoli WP2s(X)
Rat liver S9
DNA damage measured by A prophage induction
Positive

Selden et al.,
1994
Rat hepatocyte primary
culture
Intrinsic
Unscheduled DNA synthesis measured by
bromodeoxyuridine uptake
Negative

Simmon, 1979b
Saccharomyces cerevisiae
D3
Rat Ar S9
Induced recombination
Negative

Storeretal., 1996
Rat hepatocyte primary
culture
Intrinsic
DNA damage measured by alkaline elution
Equivocal

DNA Adducts
Bryla and
Weyand, 1992
Calf thymus DNA

DNA adducts measured by [32P] postlabeling
Negative
No measurable
DNA adducts
Grover and Sims,
1968
Salmon testes DNA
Rat liver microsomes
DNA binding measured by [3H] prelabeling
Low-level
DNA binding
detected

Grover etal.,
1971
BHK 21 and PyY hamster
fibroblasts

DNA binding measured by [3H] prelabeling
Low-level
DNA binding
detected

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FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR PHENANTHRENE
Due to the lack of suitable human and animal data, provisional RfDs for phenanthrene
cannot be derived.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR PHENANTHRENE
Due to the lack of suitable human and animal data, provisional RfCs for phenanthrene
cannot be derived
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR PHENANTHRENE
Weight-of-Evidence Descriptor
On IRIS (U.S. EPA, 2008), phenanthrene is classified as Group D—not classifiable as to
human carcinogenicity—under the U.S. EPA (1986) Guidelines for Carcinogen Risk
Assessment. The IRIS Summary cites a lack of human data and inadequate animal data from a
single gavage study in rats and several skin application and injection studies in mice. Under the
U.S. EPA (2005) Guidelines, there is "Inadequate Information to Assess [the] Carcinogenic
Potential" of phenanthrene. As indicated in IRIS, there are no human data, and the single oral
bioassay of phenanthrene (Huggins and Yang, 1962) is inadequate. Most of the studies that are
available (both in vivo and in vitro) for evaluating the carcinogenicity of phenanthrene are
nonpositive. Overall, the database for phenanthrene is substantial, and the weight-of-evidence
suggests that this chemical is either very weakly carcinogenic or not carcinogenic at all. An
abundance of data indicates that phenanthrene exhibits little or no genotoxicity. However, given
the limitations of the bioassays and the absence of human data and cancer bioassays conducted in
additional species, the data are inadequate to classify the human carcinogenicity of phenanthrene.
Quantitative Assessment of Carcinogenic Risk
A provisional oral slope factor and inhalation unit risk for phenanthrene cannot be
derived because human data are lacking and the animal data are inadequate for developing such
estimates.
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