*>EPA
EPA/690/R-22/005F | September 2022 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
The Aromatic High Carbon Range Total Petroleum
Hydrocarbon (TPH) Fraction (Noncancer)
(various CASRNs)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United Stiles
MKHu Environmental Protection
IbbI # % Agency
EPA/690/R-22/005F
September 2022
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
The Aromatic High Carbon Range Total Petroleum
Hydrocarbon (TPH) Fraction (Noncancer)
(various CASRNs)
Center for Public Health and Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGERS
Glenn E. Rice, ScD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Elizabeth O. Owens, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Jacqueline Weinberger, Student Services Contractor
Oak Ridge Associated Universities
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
M. Margaret Pratt, PhD
Center for Public Health and Environmental Assessment, Washington, DC
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
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Aromatic high carbon range
TPH fraction (noncancer)
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
1.1. DEFINITION OF THE AROMATIC HIGH CARBON RANGE FRACTION 3
1.2. OVERVIEW OF PHYSICOCHEMICAL PROPERTIES AND ENVIRONMENTAL
FATE 4
1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS 8
1.3.1. Indicator Chemical Approach 9
1.3.2. Hazard Index Approach 10
2. SUMMARY OF TOXICITY AND DOSE-RESPONSE ASSESSMENT FOR
NONCANCER EFFECTS 11
2.1. IDENTIFICATION OF RELEVANT MIXTURES AND COMPOUNDS WITH
NONCANCER TOXICITY VALUES 13
2.2. IDENTIFICATION OF OTHER RELEVANT TOXICITY DATA 16
2.3. METHODS FOR INDICATOR CHEMICAL SELECTION 19
3. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER) 20
4. TOXICOKINETIC CONSIDERATIONS 22
5. MECHANISTIC CONSIDERATIONS 24
6. DERIVATION 01 PROVISIONAL VALUES 25
6.1. DERIVATION OF ORAL REFERENCE DOSES 25
6.1.1. Oral Noncancer Assessment Using the Indicator Chemical Method for the
Aromatic High Carbon Range Fraction 30
6.1.2. Alternative Oral Noncancer Assessment Using the Hazard Index Method for
the Aromatic Medium Carbon Range Fraction 33
6.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 33
6.2.1. Inhalation Noncancer Assessment the Indicator Chemical Method for the
Aromatic High Carbon Range Fraction 36
6.2.2. Alternative Inhalation Noncancer Assessment Using the Hazard Index Method
for the Aromatic High Carbon Range Fraction 38
6.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 38
APPENDIX A. LITERATURE SEARCH AND SCREENING 40
APPENDIX B. COMPOSITION OF MIXTURES RELEVANT TO THE AROMATIC
HIGH CARBON RANGE FRACTION 42
APPENDIX C. POTENTIALLY RELEVANT NONCANCER EVIDENCE 45
APPENDIX D. REFERENCES 79
TPH fraction (noncancer)
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IRIS
Integrated Risk Information System
ACGIH
American Conference of Governmental
IVF
in vitro fertilization
Industrial Hygienists
LC50
median lethal concentration
AIC
Akaike's information criterion
LD50
median lethal dose
ALD
approximate lethal dosage
LOAEL
lowest-observed-adverse-effect level
ALT
alanine aminotransferase
MN
micronuclei
AR
androgen receptor
MNPCE
micronucleated polychromatic
AST
aspartate aminotransferase
erythrocyte
atm
atmosphere
MOA
mode of action
ATSDR
Agency for Toxic Substances and
MTD
maximum tolerated dose
Disease Registry
NAG
7V-acetyl-P-D-glucosaminidase
BMC
benchmark concentration
NCI
National Cancer Institute
BMCL
benchmark concentration lower
NOAEL
no-observed-adverse-effect level
confidence limit
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
C#
number of carbon atoms contained in a
POD
point of departure
molecule
PODadj
duration-adjusted POD
CA
chromosomal aberration
QSAR
quantitative structure-activity
CAS
Chemical Abstracts Service
relationship
CASRN
Chemical Abstracts Service registry
RBC
red blood cell
number
RDS
replicative DNA synthesis
CBI
covalent binding index
RfC
inhalation reference concentration
CHO
Chinese hamster ovary (cell line cells)
RfD
oral reference dose
CL
confidence limit
RGDR
regional gas dose ratio
CNS
central nervous system
RNA
ribonucleic acid
CPHEA
Center for Public Health and
SAR
structure-activity relationship
Environmental Assessment
SCE
sister chromatid exchange
CPN
chronic progressive nephropathy
SD
standard deviation
CYP450
cytochrome P450
SDH
sorbitol dehydrogenase
DAF
dosimetric adjustment factor
SE
standard error
DEN
diethylnitrosamine
SGOT
serum glutamic oxaloacetic
DMSO
dimethylsulfoxide
transaminase, also known as AST
DNA
deoxyribonucleic acid
SGPT
serum glutamic pyruvic transaminase,
EC
equivalent carbon
also known as ALT
EPA
Environmental Protection Agency
SSD
systemic scleroderma
ER
estrogen receptor
TCA
trichloroacetic acid
FDA
Food and Drug Administration
TCE
trichloroethylene
FEVi
forced expiratory volume of 1 second
TWA
time-weighted average
GD
gestation day
UF
uncertainty factor
GDH
glutamate dehydrogenase
UFa
interspecies uncertainty factor
GGT
y-glutamyl transferase
UFC
composite uncertainty factor
GSH
glutathione
UFd
database uncertainty factor
GST
g 1 ut a t h i o nc - V-1 ra n s fc ra sc
UFh
intraspecies uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFl
LOAEL-to-NOAEL uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFS
subchronic-to-chronic uncertainty factor
HEC
human equivalent concentration
U.S.
United States of America
HED
human equivalent dose
WBC
white blood cell
i.p.
intraperitoneal
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR THE AROMATIC
HIGH CARBON RANGE TOTAL PETROLEUM HYDROCARBON (TPH)
FRACTION (NONCANCER)
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 U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
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.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing adverse
human-health effects. Questions regarding nomination of chemicals for update can be sent to the
appropriate U.S. EPA's eComments Chemical Safety web page
(https://ecomments.epa.gov/chemicalsafetv/).
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV was written
with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP), the QAPP
titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-Reviewed
Toxicity Values (PPRTVs) and Related Assessments/Documents (L-CPAD-0032718-QP), and the
PPRTV development contractor QAPP titled Quality Assurance Project Plan—Preparation of
Provisional Toxicity Value (PTV) Documents (L-CPAD-0031971-QP). As part of the QA
system, a quality product review is done prior to management clearance. A Technical Systems
Audit may be performed at the discretion of the QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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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. 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.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
This Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment supports a
fraction-based approach to risk assessment for mixtures of petroleum hydrocarbons (U.S. EPA.
2022. 2009b). In this approach, total petroleum hydrocarbon (TPH) fractions are defined based
on expected transport in the environment and analytical methods used to quantify environmental
contamination by TPH mixtures. TPH components were first classified into aromatics and
aliphatics, and each of these two major fractions were further separated into low, medium, and
high carbon range fractions. This PPRTV assessment describes the derivation of noncancer
toxicity values for the aromatic high carbon range fraction of TPH. The toxicity values described
herein are used in the assessment of Complex Mixtures of Petroleum Hydrocarbons that is
intended to replace current approaches used at TPH-contaminated sites (U.S. EPA. 2022. 2009b).
In general, fraction-based approaches involve: (1) dividing a complex mixture into
groups based on similarities in their chemical structures or chemical properties; (2) measuring
the concentrations of these groups (or the components within the group) in environmental media
or estimating the rates of human exposure (e.g., mg/kg-day) to these groups; (3) selecting an
approach to characterize a dose-response relationship for the group; (4) combining the
dose-response approach and the exposure estimates for all members of the group to estimate
health risks from the group; and (5) estimating risks or hazards posed by exposure to the
complex mixture using the risk characterization information from the individual groups [adapted
from AT SDR (2018)1.
1.1. DEFINITION OF I II I AROMATIC HIGH CARBON RANGE FRACTION
The aromatic high carbon range fraction includes aromatic hydrocarbons with a carbon
(C) range of C10-C32 (contains between 10 and 32 carbons, inclusive) and an equivalent carbon
(EC)1 number index range of EC11-EC35 that occur in, or co-occur with, petroleum
contamination. Hydrocarbons with a carbon number greater than C32 are not included in the
aromatic high carbon range fraction due to limited bioavailability driving a lack of toxicity
observed in in vivo studies, limited potential for transport via groundwater flow and via
volatilization to the air, and incompatibility with existing standard analytical methods (Boogaard
et at.. 2017; Shell Global Solutions International et al.. 2017; Gustafson et al.. 1997). While the
aromatic medium carbon range fraction also includes C10 compounds, the aromatic medium
carbon range fraction is restricted to those compounds with EC9-EC <11. For this reason,
naphthalene (C10, EC 11.57) is included in the aromatic high carbon range fraction. The EC
index is equivalent to the retention time of the compound on a boiling-point gas chromatography
(GC) column (nonpolar capillary column), normalized to the //-alkanes (NJ DEP. 2010). EC
numbers are the physical characteristic that underpin analytical separation of petroleum
components. EC numbers are useful because they are more closely related to environmental
mobility than carbon number. For instance, two chemicals with similar carbon numbers but
different structures (e.g., aliphatic vs. aromatic) could partition differently into environmental
media and, ultimately, have different environmental fates. Grouping based on EC numbers
provides a consistent basis for logically placing petroleum hydrocarbon compounds into
fractions, because EC measures correlate with physicochemical properties such as water
1 Based on an empirical relationship, the EC value can be estimated from a compound's boiling point (BP; °C) using
the following equation: EC = 4.12 + 0.02 (BP) + 6.5 x 10~5 (BP)2; see Gustafson et al. (1997).
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solubility, vapor pressure, Henry's law constant, and soil adsorption coefficient (log Koc).
Toxicological considerations also are a consideration when defining the aromatic high carbon
range fraction. Substituted benzenes (C9-C10; contained within the aromatic medium carbon
fraction) were grouped separately from polycyclic aromatic hydrocarbons (PAHs), naphthalenes,
and 1,1-biphenyl (contained within the aromatic high carbon range fraction), which generally
exhibit greater carcinogenicity and noncancer toxicity. Individual compounds in this fraction
have a backbone consisting of one or more aromatic rings, which can be substituted with alkane,
alkene, and other nonaromatic ring structures. Example compounds include
1,2,4-triethylbenzene, 2-methylnaphthalene, fluorene, and benzo[a]pyrene (BaP). Compounds
with two to six fused unsubstituted aromatic rings without anything other than carbon or
hydrogen in their composition are characterized as PAHs. The selection of relevant compounds
and mixtures is described in Section 2 and Appendices A and B.
1.2. OVERVIEW OF PHYSICOCHEMICAL PROPERTIES AND ENVIRONMENTAL
FATE
The systematic chemical names, synonyms [following guidance in NIST (2020b)1.
CASRNs, chemical abbreviations, chemical structures, and molecular weights for chemicals in
this document are listed in Table 1 and in Appendix B of U.S. EPA (2022). The physicochemical
properties for members of the aromatic high carbon range fraction that have noncancer toxicity
values compiled from the CompTox Chemicals Dashboard (U.S. HP A. 2021a) are provided in
Table 2. Section 2 details how the fraction members with toxicity values were identified. The
representative chemicals identified are 1,1-biphenyl and eight PAHs, including naphthalene, and
two methyl-substituted naphthalene compounds (CASRNs 91-57-6 and 90-12-0). These
chemicals are all solids except for 1-methylnaphthalene (CASRN 90-12-0), which is a liquid at
room temperature; they have moderate to low water solubility and vapor pressure. Members of
this fraction are expected to have little to no mobility in soil based on measured Koc data;
however, the Koc for naphthalene suggests potential mobility in some soil types. Volatilization of
members of this fraction from water and moist soil will be moderate based upon the measured
Henry's law constant values for the representative compounds. Volatilization from dry soil
surfaces will be low to moderate based upon the measured vapor pressure values. Measured
aerobic and anaerobic biodegradation data are available for the representative compounds. Under
aerobic conditions, the nine PAHs are expected to have slow removal by biodegradation in
unacclimated systems and more rapid biodegradation in acclimated systems. Acclimation periods
(days to months) have been observed prior to the onset of microbial degradation in tests using
soil not previously exposed to PAHs. It is thought that this occurs because small population(s) of
organisms capable of PAH degradation must attain sufficient densities before detectable PAH
reduction is observed (Mihetcic and l.uthv. 1988). 1,1 -Biphenyl undergoes biodegradation more
readily than the many PAHs, as demonstrated in a modified test where 1,1-biphenyl achieved
66% of its theoretical biochemical oxygen demand (BOD) after 14 days (compared to 0-2% after
28 days for naphthalene and acenaphthalene) (HCHA. 2019; OHCD. 2009; ('I'l l. 1992). Under
anaerobic conditions, biodegradation is slow for all fraction members. Members of the aromatic
high carbon range fraction do not contain hydrolysable functional groups; therefore, the rate of
hydrolysis is expected to be negligible for all fraction members. In the atmosphere, the rate of
photooxidation is expected to be moderate for fraction members. Many of the fraction members,
except, for example, 1,1-biphenyl, contain chromophores that absorb light at wavelengths
>290 nm, and are therefore expected to be susceptible to direct photolysis by sunlight (Nl.M.
2017a. b, c, e, £ g, 2015a. b, 2014. 2005). When the fraction members occur in the atmosphere in
the particulate phase, they will be physically removed by wet and dry deposition.
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TPH fraction (noncancer)
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Table 1. Synonyms and Abbreviations for Chemicals in this PPRTV
Assessment3
Chemical (common synonymsb)
CASRN
Abbreviation
Structure
Molecular
Weight (g/mol)
Naphthalene
(naphthalin)
91-20-3
NPT
128.174
2-Methylnaphthalene
(naphthalene, 2-methyl-)
91-57-6
2MeNPT
142.201
1-Methylnaphthalene
(naphthalene, 1-methyl-)
90-12-0
lMeNPT
142.201
1,1-Biphenyl
(biphenyl;
l,l'-biphenyl)
92-52-4
BH
// \W/ \\
154.212
Acenaphthene
(acenaphthylene, 1,2-dihydro-
1,2-dihydroacenaphthylene;
1,8-ethylenenaphthalene)
83-32-9
ANL
154.212
Fluorene
(9H-fluorene;
2,3-benzidene;
o-biphenylenemethane;
dipheny lenemethane;
2,2'-methylenebiphenyl;
o-biphenylmethane)
86-73-7
FE
166.223
Anthracene
(antliracin;
paranaphthalene)
120-12-7
AC
178.234
Pyrene
(benzo |cfe/|phcnanthrcne;
pyren)
129-00-0
Pyr
202.256
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Table 1. Synonyms and Abbreviations for Chemicals in this PPRTV
Assessment"
Chemical (common synonymsb)
CASRN
Abbreviation
Structure
Molecular
Weight (g/mol)
Fluoranthene
(ClusterCarbon;
idryl;
benzo [/l]fluorene;
1,2- [ 1,8-naphthalenediy l]benzene;
bcnz|o| acenaphthy lene;
1,2-benzoacenaphyhylene)
206-44-0
FA
202.256
Benzo[a]pyrene
(benzo \pqr] tetraphene;
benzo | clef] chry sene;
1,2-benzpyrene;
3.4-benzopyren;
4.5-benzpyrene;
6,7-benzopyrene)
50-32-8
BaP
252.316
Benzo [e]pyrene
192-97-2
BeP
252.316
aOnly chemicals with toxicity values are listed.
' Synonyms are listed according to NIST (2020b) and include valid synonyms from U.S. EPA CompTox Chemicals
Dashboard; accessed 03-30-2020; U.S. EPA (2021a).
PPRTV = Provisional Peer-Reviewed Toxicity Value; U.S. EPA = U.S. Environmental Protection Agency.
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Table 2. Physicochemical Properties of Aromatic High Carbon Range Chemicals with Noncancer Toxicity Values"
Chemical
NPT
2MeNPT
lMeNPT
BH
ANL
FE
AC
Pyr
FA
BaP
BeP
Structure
CO"
CH,
oc5
cm
(5p
cro
CCD
95)
^
^XX
opo
u
CASRN
91-20-3
91-57-6
90-12-0
92-52-4
83-32-9
86-73-7
120-12-7
129-00-0
206-44-0
50-32-8
192-97-2
Molecular formula
CioHg
CnHio
CnHio
C12H10
C12H10
C13H10
C14H10
CksHio
CksHio
C20H12
C20H12
EC numberb
11.57
12.72
12.77
13.45
14.76
15.68
18.43
22.45
21.11
29.95
27.80
Molecular weight
(g/mol)
128.174
142.201
142.201
154.212
154.212
166.223
178.234
202.256
202.256
252.316
252.316
Melting point (°C)
80.3
33.7
-3.10
69.8
93.9
115
215
150
108
177
178
Boiling point (°C)
218
241
242
255
279
295
340
399
380
495
469*
Vapor pressure
(mm Hg at 25°C)
8.50 x 10-2
5.50 x 10-2
6.70 x 10-2
8.93 x 10-3
2.15 x 10-3
6.00 x 10-4
6.53 x 10-6
4.50 x 10-6
9.22 x 10-6
5.49 x 10-9
5.70 x 10-9
Henry's law constant
(atm-m3/mole at
25°C)
4.4 x 10-4
5.18 x 10-4
5.14 x 10-4
3.08 x 10-4
1.84 x 10-4
9.62 x 10-5
5.56 x 10-5
1.19 x 10-5
8.86 x 10-6
4.57 x 10-'
1.07 x 10-6*
Water solubility
(mol/L at 25°C)
2.47 x 10~4
1.74 x 10-4
1.95 x 10-4
4.60 x 10 5
4.64 x 10 5
1.15 x 10-5
3.38 x 10~7
6.65 x 10-7
1.24 x 10-6
8.40 x 10~9
1.89 x 10-8
Log Kow
3.30
3.86
3.87
4.01
3.92
4.18
4.45
4.88
5.16
6.13
6.44
Log Koa
5.19
5.83*
5.01*
6.15
6.31
6.79
7.55
8.80
8.88
9.61*
10.3*
Log Koc
2.96
3.60
3.36
3.27
3.59
3.70
4.31
4.90
4.80
5.95
5.67*
'Data arc presented as experimental averages from U.S. EPA CompTox Chemicals Dashboard unless otherw ise stated; https://comptox.epa.gov/dashboard: updated
02-03-2021.
bEC number was developed by the TPHCWG and is proportional to the BP of a chemical. EC number is analogous to an n-paraffin retention time index and can be
estimated using: EC = 4.12 + 0.02 (BP) + 6.5 x 5 (BP)2 (NIST. 2020a: Edwards et al.. 1997: Gustafson et ai. 1997).
*Predicted value.
AC = anthracene; ANL = acenaphthene; BaP = benzo[a]pyrene; BeP = benzo[e]pyrene; BH = biphenyl; BP = boiling point; EC = equivalent carbon; FA = fluoranthene;
FE = fluorene; Koa = octanol-air partition coefficient; Koc = soil adsorption coefficient; Kow = octanol-water partition coefficient; lMeNPT = 1-methylnaphthalene;
2MeNPT = 2-methylnaphthalene; NPT = naphthalene; Pyr = pyrene; TPHCWG = Total Petroleum Hydrocarbon Criteria Working Group;
U.S. EPA = U.S. Environmental Protection Agency.
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1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS
A number of different approaches have been developed and used to estimate risks and
hazards posed by exposures to chemical mixtures encountered in the environment. The two
approaches utilized in this PPRTV assessment are the indicator chemical approach and the
hazard index (HI) approach. The choice of approaches is based on the available analytical
chemistry.
The simplest of these approaches to implement is the indicator chemical approach
ATSDR (2018). The indicator chemical approach estimates the risks or hazards of a mixture by
evaluating the dose-response assessment developed for a component of the mixture and the
exposure rate of the entire mixture. The indicator chemical approach is used when there are only
measures of the concentrations of this fraction (i.e., no information is available on the
concentrations of individual chemicals in this fraction).
In addition to the indicator chemical approach, the U.S. Environmental Protection
Agency (EPA) Supplementary Guidance for Conducting Health Risk Assessment of Chemical
Mixtures (U.S. HP A. 2000. 1986) describes the following two broad categories of approaches for
assessing human health risks and health hazards associated with environmental exposures to
chemical mixtures: component methods and whole mixture methods. Component-based
approaches, which involve analyzing the toxicity of a mixture's individual components, have
more uncertainty and are recommended when appropriate toxicity data on a complex mixture of
concern, or on a sufficiently similar mixture (discussed below), are unavailable (U.S. HP A. 2000.
1986). In this PPRTV assessment, a component approach, the HI approach, is described for
assessing noncancer hazards posed by exposures to the aromatic high carbon range fraction.
Chemical mixture assessments are conducted most appropriately with quantitative
dose-response information resulting from comparable exposures to the mixture of concern. If the
dose-response data are insufficient to develop a health reference value for the specific mixture of
concern in the environment, the second option recommended by the U.S. EPA Supplementary
Guidance for Conducting Health Risk Assessment of Chemical Mixtures (U.S. HP A. 2000. 1986)
is a "sufficient similarity" approach that uses a health reference value from a characterized
surrogate mixture to estimate the hazards or risks associated with exposures to the mixture of
concern. This method requires chemistry and toxicity data on both the potential surrogate
mixture and the mixture of concern (e.g., an in vitro endpoint that is related to the apical
endpoint observed in an epidemiological study or whole animal study), and a health reference
value (e.g., from an in vivo study) on the surrogate mixture. If the chemistry and toxicity data
indicate that the mixtures are "sufficiently similar" to one another, then the health reference
value for the surrogate mixture can be used as a proxy for the mixture of concern. No data were
identified that were suitable to implement a whole mixture approach.
The choice of a chemical mixtures risk assessment method is driven by the available data.
Starting with the method requiring the least information and then discussing the method
requiring more information, the following subsections summarize the indicator chemical
approach and the HI approach. Figure 1 summarizes the two approaches and the preference for
using each approach.
8
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA 690 R-22 005F
Approaches
Available Exposure Data
Fraction Measure
Aromatic high carbon fraction
Individual
Component Measures
Ojal NPT, 2\kNPT
ISleXPT, BH. ANL. FE, AC,
Pyr, FA. or BaP
Inhalation BH, NPT or BaP
Approaeli
Indicator Chemical Approach
BaP rs indicator chrmicat
I lazard Index Approach
Component HQs. BaP is indicator chemical
for the remainder of,the fraction mass HQ
\7
Two approaches are available to estimate the noncancer hazards associated with exposure to the aromatic high
carbon range fraction. Approach selection should be driven by the available exposure data. Increased analytical
characterization of fraction components allows for more refined risk estimates with less inherent uncertainty.
Approach preference is inversely correlated with approach uncertainty.
AC = anthracene; ANL = acenaphthene; BaP = benzo[o]pyrene; BH = 1,1-biphenyl; FA = fluoranthene;
FE = fluorene; HQ = hazard quotient; lMeNPT = 1-methylnaphthalene; 2MeNPT = 2-methylnaphthalene;
NPT = naphthalene; Pyr = pyrene.
Figure 1. Provisional Peer-Reviewed Toxicity Approaches for the Aromatic High Carbon
Range TPH Fraction Noncancer Assessment
1.3.1. Indicator Chemical Approach
When the chemical composition of a mixture or a mixture fraction is not known, or
toxicity measures are only available for a few individual chemicals in a mixture, the toxicity of
an individual chemical can be used as an indicator for the toxicity of a mixture or a mixture
fraction (ATSDR. 2018). ATSDR (2018) describes an indicator chemical as "a
chemical . . . selected to represent the toxicity of a mixture because it is characteristic of other
components in the mixture and has adequate dose-response data." Indicator chemical approaches
are typically implemented to assess health risks in a health-protective manner; the chemical
chosen as an indicator is among the best characterized toxicologically and likely among the most
toxic components of the mixture. The indicator chemical needs to have adequate dose-response
data to indicate hazard potential or a dose-response relationship for noncancer outcomes,
depending on the purpose of the assessment. The health risk value of the indicator chemical is
integrated with exposure estimates for the mixture or mixture fraction to estimate health hazard
associated with the fraction (i.e., calculate fraction-specific HI for a specific exposure pathway).
This approach does not scale for potency of individual constituents; instead, it assumes that
toxicity of all measured members of the fraction can be adequately estimated, given the purpose
of the risk assessment, by the indicator chemical.
9
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
1.3.2. Hazard Index Approach
The HI approach combines estimated population exposures with toxicity information to
characterize the potential for adverse effects. The HI is not a risk estimate, in that it is not
expressed as a probability, nor is it an estimate of a toxicity measure (e.g., percentage decrement
in enzyme activity). Instead, the HI is an indicator of potential hazard. In the HI approach, a
hazard quotient (HQ) is calculated as the ratio of human exposure (E) to a health reference value
(RfV) for each mixture component chemical (/) (U.S. EPA. 1986). These HQs are summed to
yield the HI for the mixture. In health risk assessments, U.S. EPA's preferred RfVs are the
reference dose (RfD) for the oral exposure, and the reference concentration (RfC) for the
inhalation exposure route.
The HI is based on dose addition (U.S. HP A. 2000; Svendsgaard and Hertzberg. 1994);
the hazard is evaluated as the potency-weighted sum of the component exposures. The HI is
dimensionless, so E and the RfV must be in the same units.
71
71
10
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
2. SUMMARY OF TOXICITY AND DOSE-RESPONSE ASSESSMENT APPROACH
FOR NONCANCER EFFECTS
The indicator chemical approach and the HI approach are used for hazard assessment for
the aromatic high carbon range fraction. Both approaches require toxicity and dose-response
assessment data. These data depend upon the identification of component chemicals and
mixtures with existing toxicity values, and the identification of hazard information. The approach
for identifying this information is outlined here and described in additional detail in subsequent
sections. Mixtures and compounds that met structural criteria (see definition of the fraction in
Section 1.1) and had available toxicity values from designated sources were identified, as was
relevant hazard information.
Literature searches were performed for the mixtures and compounds with toxicity values
and for other mixtures and compounds that are relevant to the fraction. These literature searches
were conducted in February 2018 and date-limited to assessments and literature published after
20072. These literature searches were updated most recently in August 2021. The literature
searches were designed for several purposes. First, the literature searches were to determine
whether new information suggested that toxicity values for mixtures or compounds relevant to
the fraction (see definition of the fraction, in Section 1.1) should be updated from those
identified in the U.S. EPA (2009b) PPRTV assessment for mixtures of aliphatic and aromatic
hydrocarbons. Second, the literature searches were to determine whether new noncancer toxicity
values or data on other mixtures or compounds meeting the structural criteria of the fraction
might alter the overall understanding of the toxicity of the fraction. Third, a search of recent
comprehensive reviews was conducted on the toxicity of petroleum components or classes of
compounds relevant to the fraction, as well as Organisation for Economic Co-operation and
Development (OECD) Screening Information Data Set (SIDS) assessments3 and the Petroleum
High Production Volume (HPV) Testing Group website, to identify other mixtures or
compounds with toxicity data that may inform hazard identification for the fraction. Toxicity
data criteria included human studies of any duration by oral, inhalation, and dermal exposure,
and animal studies of oral or inhalation exposure lasting at least 28 days (or any duration of
gestational exposure). Mixture toxicity data were considered relevant only if the mixture
composition under study was quantitatively defined to enable assessment of relevance to the
fraction. Figure 2 shows a schematic depiction of the process, and further detail is provided
below.
2The literature searches were date-limited to studies published from 2007 forward in order to capture studies that
were published since the searches performed for the 2009 PPRTV assessment for TPH mixtures (U.S. EPA. 2009b').
'The OECD Existing Chemicals Database (https://hpvchemicals.oecd.org') was reviewed for C10-C13 aromatic
solvents.
11 Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA 690 II-22 005F
Step 4
Step 5
Step 2
Compound Structural Criteria:
10 < C < 32 and
11 < EC < 35 aromatic
Mixture Structural Criteria:
>99% of the mixture consists of aromatic compounds (<1% aliphatic) and
>90% of mixture consists of compounds meeting structural criteria (left) and highly
toxic lower aromatic carbons (e.g., benzene) are not present
Toxicity Data Criteria:
Human: any duration, oral, inhalation, or dermal exposure
Animal: oral or inhalation exposure for at least 28 days or any duration during gestation
Mixture toxicity data considered relevant only if mixture composition quantitatively
defined to enable assessment of relevance to the fraction
ATSDR = Agency for Toxic Substances and Disease Registry; C = carbon; EC = equivalent carbon; HPV = High Production Volume: IRIS = Integrated
Risk Information System; OECD = Organisation for Economic Co-operation and Development; PPRTV = Provisional Peer-Reviewed Toxicity Value;
RfC = reference concentration; RfD = reference dose; SIDS = Screening Information Data Set.
Compounds and mixtures relevant to the aromatic high carbon range fraction with available toxicity values or data were identified. Table 3 lists
individual compounds and mixtures and links them to their corresponding identification source during the literature search process. Table 3 also
indicates compounds with available toxicity values, or in the absence of toxicity values, available toxicity data.
Figure 2. Selection of Compounds and Mixtures for Aromatic High Carbon Range Fraction Hazard Identification and Noncancer
Dose-Response Assessment
12
Aromatic high carbon range TPIi fraction (noncancer)
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EPA/690/R-22/005F
2.1. IDENTIFICATION OF RELEVANT MIXTURES AND COMPOUNDS WITH
NONCANCER TOXICITY VALUES
In Step 1 of the assessment (see Figure 2), the U.S. EPA identified constituents of the
fraction that have existing toxicity values from any of the sources considered for the U.S. EPA
(2009b) PPRTV assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons',
these included assessments on the Integrated Risk Information System [IRIS], PPRTV
assessments, Agency for Toxic Substances and Disease Registry [ATSDR] Minimal Risk Levels
[MRLs], Massachusetts Department of Environmental Protection [MassDEP], the Total
Petroleum Hydrocarbon Criteria Working Group [TPHCWG], and Health Effects Assessment
Summary Tables [HEAST]). Of these sources, only IRIS, PPRTVs, and ATSDR MRLs have
been updated since 2009, so only these sources were consulted for updated toxicity values.
Beginning with an initial list of 41 chemicals considered relevant to the fraction [see the full list
in Table 3 as well as a description of the approach and results in Wang et al. (2012)1. the IRIS,
PPRTVs, and ATSDR MRLs were reviewed for noncancer toxicity values. At least one
subchronic or chronic oral reference value or subchronic or chronic inhalation reference value
was available for 11 chemicals (acenaphthene, anthracene, BaP, benzo[e]pyrene [BeP],
1,1-biphenyl, fluoranthene, fluorene, 1-methylnaphthalene, 2-methylnaphthalene, naphthalene,
and pyrene). Table 4 shows the noncancer toxicity values available for the 11 relevant
compounds.
Table 3. Chemicals and Mixtures Identified in Literature Searches
CASRN
Chemical Name
Literature Search
Identification Source
PubMed
Searches
Performed
Toxicity
Values
Identified
Toxicity
Data
Identified
92-52-4
1,1-Biphenyl
Initial list of 41a
X
X
26137-53-1
1,2,3-Trimethyl-4-propenyl-
naphthalene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3
X
877-44-1
1,2,4-Triethylbenzene
Recent reviews of
petroleum toxicity0, d
X
527-53-7
1,2,3,5 -Tetramethylbenzene
Initial list of 41a
X
575-41-7
1,3 -Dimethylnaphthalene
Initial list of 41a
X
102-25-0
1,3,5-Triethy lbenzene
Recent reviews of
petroleum toxicity0, d
X
202-94-8
1 lH-Benzo[/>,c]aceanthrylene
Initial list of 41a
X
90-12-0
1 -Methy lnaphthalene
Initial list of 41a
X
X
Various
16-PAH mixture
Informal PubMed
searches0, f
X
X
243-17-4
2,3 -Benzo fluorene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3
X
581-42-0
2,6-Dimethy lnaphthalene
Initial list of 41a
X
91-57-6
2-Methy lnaphthalene
Initial list of 41a
X
X
Various
21-PAH mixture®
Recent reviews of
petroleum toxicity0, h
X
202-98-2
4H-Cyclopenta[
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EPA/690/R-22/005F
Table 3. Chemicals and Mixtures Identified in Literature Searches
CASRN
Chemical Name
Literature Search
Identification Source
PubMed
Searches
Performed
Toxicity
Values
Identified
Toxicity
Data
Identified
Various
9-PAH mixture
Informal PubMed
searches6,1
X
X
83-32-9
Acenaphthene
Initial list of 41a
X
X
208-96-8
Acenaphthylene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3
X
191-26-4
Anthanthrene
Initial list of 41a
X
120-12-7
Anthracene
Initial list of 41a
X
X
56-55-3
Benzo [a] anthracene
Initial list of 41a
X
50-32-8
Be nzo |c/| pyre nc
Initial list of 41a; oral and
inhalation toxicity values'
X
205-99-2
Benzo [/>]fluoranthene
Initial list of 41a
X
X
205-12-9
Benzo [cjfluorene
Recent reviews of
petroleum toxicity0, h
X
192-97-2
Benzo [ejpyrene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3;
oral and inhalation toxicity
values'
X
191-24-2
Benzo [g/z/']perylene
Initial list of 41a
X
207-08-9
Benzo [&]fluoranthene
Initial list of 41a
X
199-54-2
Benzo [e] aceanthrylene
Initial list of 41a
X
202-33-5
Benzo [/'] aceanthrylene
Initial list of 41a
X
205-82-3
Benzo [/]fluoranthene
Initial list of 41a
X
211-91-6
Benzo [/] aceanthrylene
Initial list of 41a
X
218-01-9
Chrysene
Initial list of 41a
X
191-07-1
Coronene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3
X
27208-37-3
Cyclopenta[c, c/|pyrcne
Initial list of 41a
X
191-30-0
Dibenzo [a, /] pyrene
Initial list of 41a
X
X
215-58-7
Dibenzo [a, c] anthracene
Initial list of 41a
X
5385-75-1
Dibenzo [a, ejfluoranthene
Initial list of 41a
X
192-65-4
Dibenzo [a, e| pyrcnc
Initial list of 41a
X
53-70-3
Dibenzo [a, h\ anthracene
Initial list of 41a
X
189-64-0
Dibenzo [a, /z]pyrene
Initial list of 41a
X
189-55-9
Dibenzo [a, / Jpyrene
Initial list of 41a
X
206-44-0
Fluoranthene
Initial list of 41a
X
X
86-73-7
Fluorene
Initial list of 41a
X
X
193-39-5
Indeno [ 1,2,3 -c, d] pyrene
Initial list of 41a
X
14
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
Table 3. Chemicals and Mixtures Identified in Literature Searches
CASRN
Chemical Name
Literature Search
Identification Source
PubMed
Searches
Performed
Toxicity
Values
Identified
Toxicity
Data
Identified
91-20-3
Naphthalene
Initial list of 41a; oral and
inhalation toxicity values'
X
193-09-9
Naphtho [2,3 -ejpyrene
Initial list of 41a
X
1078-71-3
//-Hcptylbcnzcnc
Initial list of 41a
X
1077-16-3
«-Hexylbenzene
Initial list of 41a
X
2189-60-8
//-Octylbcnzcnc
Initial list of 41a
X
538-68-1
//-Pcntylbcnzcnc
Initial list of 41a
X
198-55-0
Perylene
Updated PPRTV, IRIS, and
ATSDR MRL databases'3
X
85-01-8
Phenanthrene
Initial list of 41a
X
X
827-52-1
Phenylcyclohexane
Initial list of 41a
X
129-00-0
Pyrene
Initial list of 41a
X
X
aThe U.S. EPA developed the initial list of 41 chemicals relevant to the aromatic medium carbon range. The list
included all individual hydrocarbons considered previously by the U.S. EPA's STSC in the evaluation of
hydrocarbons, as well as all those with toxicity data reviewed by the MassDEP (MassDEP. 20031 or the TPHCWG
(Edwards et at. 19971.
bDuring review of the updated IRIS, PPRTV, and ATSDR MRL databases, these compounds were identified in the
PPRTV database as meeting structural criteria for inclusion and having toxicity assessments.
These compounds/mixtures were identified in Mckee et at (2015) and Baxter and Warshawskv (2012). reviews of
petroleum toxicity.
•'Toxicity data for these compounds were found in Tshala-Katumbav et al. (2006).
"These mixtures were identified in PubMed searches using the terms '"polycyclic aromatic hydrocarbons' AND
mixture AND (rat or mouse or hamster or rabbit)."
'Toxicity data for this mixture were found in Crepeaux et al. (2014): (Crepeaux et al.. 2013. 2012).
gThe 21-PAH mixture includes 1- and 2-methylnaphthalene, which are substituted PAHs (subPAHs). For
simplicity, it is referred to as a 21-PAH mixture rather than a 19-PAH and 2-subPAH mixture.
''Toxicity data for these compounds/mixtures were found in Wevand et al. (2004).
'Toxicity data for this mixture were found in Yanetal. (2014) and Chu et al. (2013).
JBecause these compounds had IRIS, PPRTV, or ATSDR toxicity values for both oral and inhalation routes, no
additional literature searches were performed.
ATSDR = Agency for Toxic Substances and Disease Registry; IRIS = Integrated Risk Information System;
MassDEP = Massachusetts Department of Environmental Protection; MRL = minimal risk level; PAH = polycyclic
aromatic hydrocarbon; PPRTV = Provisional Peer-Reviewed Toxicity Value; STSC = Superfund Technical
Support Center; TPHCWG = Total Petroleum Hydrocarbon Criteria Working Group;
U.S. EPA = U.S. Environmental Protection Agency.
15
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
Table 4. Summary of Available Noncancer Toxicity Values for Constituents
of Aromatic High Carbon Range (C10-C32, EC11-EC35) Fraction3'b
CASRN
Name
C
EC
Oral Reference Dose (mg/kg-d)
Inhalation Reference
Concentration (mg/m3)
Subchronic
Chronic
Subchronic
Chronic
91-20-3
Naphthalene
10
11.57
0.6 (ATSDR)
0.02 (IRIS)
-
0.003 (IRIS)
91-57-6
2-Methyl-
naphthalene
11
12.72
0.004 (PPRTV)
0.004 (IRIS)
-
-
90-12-0
1-Methyl-
naphthalene
11
12.77
-
0.007* (PPRTV)
-
-
92-52-4
1,1-Biphenyl
12
13.45
0.1 (PPRTV)
0.5 (IRIS)
0.004* (PPRTV)
0.0004* (PPRTV)
83-32-9
Acenaphthene
12
14.76
0.2 (PPRTV)
0.06 (IRIS)
-
-
86-73-7
Fluorene
13
15.68
0.4 (ATSDR)
0.04 (IRIS)
-
-
120-12-7
Anthracene
14
18.43
1 (PPRTV)
0.3 (IRIS)
-
-
129-00-0
Pyrene
16
22.45
0.3 (PPRTV)
0.03 (IRIS)
-
-
206-44-0
Fluoranthene
16
21.11
0.1 (PPRTV)
0.04 (IRIS)
-
-
192-97-2
Benzo[e]pyrene°
20
27.80
0.00009*
(PPRTV)
0.00009*
(PPRTV)
0.000002*
(PPRTV)
0.000002*
(PPRTV)
50-32-8
Bcn/o |fl|p\rene
20
29.95
0.0003d (IRIS)
0.0003 (IRIS)
0.000002d (IRIS)
0.000002 (IRIS)
"Toxicity values shown were selected from the following sources in order of preference: IRIS, PPRTVs, ATSDR,
HEAST, MassDEP, or TPHCWG.
'Appendix B of the TPH mixture PPRTV (U.S. EPA. 2022. 2021c) assessment provides a table containing all
chemicals with toxicity values listed in any of the individual TPH fractions. The table lists the chemical name used
in PPRTV assessments and its corresponding acronym, common synonyms listed in U.S. EPA's CompTox
Chemicals Dashboard, CASRN, structure, and molecular weight.
The screening subchronic and chronic p-RfDs and the screening subchronic and chronic p-RfCs are derived using
an alternative analogue approach in the PPRTV assessment (U.S. EPA. 2021b).
dThe chronic RfD and RfC values forbenzo[a]pyrene are based on a developmental exposure; therefore, they are
also applicable to subchronic exposures and are listed here.
* Screening toxicity value.
ATSDR = Agency for Toxic Substances and Disease Registry; C = carbon; EC = equivalent carbon;
HEAST = Health Effects Assessment Summary Tables; IRIS = Integrated Risk Information System;
MassDEP = Massachusetts Department of Environmental Protection; PPRTV = Provisional Peer-Reviewed
Toxicity Value; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; TPH = total
petroleum hydrocarbon; TPHCWG = Total Petroleum Hydrocarbon Criteria Working Group;
U.S. EPA = U.S. Environmental Protection Agency.
In Step 2 (see Figure 2), other assessments in the IRIS, PPRTV, and ATSDR databases
were reviewed to determine whether there were any other compounds or mixtures not in the
initial list that met the structural criteria for inclusion (C10-C32 and EC11-EC35 aromatics).
Searches of the IRIS and ATSDR databases did not identify any additional compounds, but
review of the PPRTV database identified five additional compounds that met structural criteria
for inclusion and had toxicity assessments: acenaphthylene, 2,3-benzofluorene, coronene,
perylene, and l,2,3-trimethyl-4-propenylnaphthalene. None of these PPRTV assessments
16
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
included toxicity value derivations or any relevant toxicity data. The U.S. EPA derived a toxicity
value for BeP, a compound that met structural criteria for inclusion in the fraction.
2.2. IDENTIFICATION OF OTHER RELEVANT TOXICITY DATA
Among the 47 compounds outlined above (41 chemicals in the U.S. EPA's initial list plus
6 chemicals [acenaphthylene, BeP, 2,3-benzofluorene, coronene, perylene, and
l,2,3-trimethyl-4-propynylnaphthalene] found during the search of PPRTV database), there were
11 compounds with noncancer toxicity values (see Table 4). Four of these compounds (BaP,
BeP, naphthalene, and 1,1-biphenyl) had IRIS or PPRTV toxicity values for both oral and
inhalation routes; no additional literature searches were performed for these compounds. For the
remaining 44 members, literature searches in PubMed were conducted in Step 3 (see Figure 2) to
identify any new studies that fill data gaps. The literature searches were date-limited to studies
published from 2007 forward in order to capture studies that were published since the searches
performed for the 2009 PPRTV assessment for TPH mixtures (U.S. EPA. 2009b). This search
was updated most recently in August 2021. A summary of the literature search strategy is
provided in Appendix A. As detailed in Appendix A, studies considered relevant to hazard
identification included animal studies using inhalation or oral exposure routes, in which
exposures continued for at least 28 days (or any duration of gestational exposure), at least one
health outcome was assessed, and an untreated or vehicle control group was included. Human
studies of any duration in which exposure was known or presumed to be through oral, inhalation,
or dermal routes and at least one health outcome was assessed were considered relevant.
The update literature search identified 11 epidemiological studies of noncancer effects in
humans exposed to undefined PAH mixtures: Agarwal et al. (2017); Alhamdow et al. (2017);
Mortamais et al. (2017); Sram et al. (2017); Yang et al. (2017); Yin et al. (2017); Rani bar et al.
(2015); Clark et al. (2012); Wang et al. (2016); Xu et al. (2010); and Suresh et al. (2009). These
studies were primarily focused on cardiovascular, immune, and neurological or
neurodevelopmental outcomes. New animal studies identified in the searches and considered
relevant include an oral developmental study of benzo[/>]fluoranthene (Kim et al.. 2011). a
28-day oral neurobehavioral study of fluorene (Peiffer et al. 2016). and a 28-day inhalation
study of 2-methylnaphthalene (Swiercz et al.. 2011).
The literature searches also identified oral studies of dibenzo[]chrysene. For example,
NLM (2017d) reported that dibenzo[defp]chrysene "occurs as a result of incomplete burning of
fossil fuels, wood, diesel oils and gasoline fuels." Therefore, it was considered to be relevant to
petroleum contamination.
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Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
In Step 4 (see Figure 2), to determine whether additional relevant compounds or mixtures
had been tested for repeat-dose and/or reproductive/developmental toxicity since 2007, recent
reviews of petroleum toxicity (Mckee et al.. 2015; Baxter and Warshawskv. 2012). an OECD
(2012) S1DS dossier, and the Petroleum HPV Testing Group website were searched.
Searches of the Mckee et al. (2015) and Baxter and Warshawskv (2012) reviews
identified three additional compounds with relevant (oral or inhalation, at least 28 days of
exposure or any duration during development) animal toxicity data: 1,2,4-triethylbenzene,
1,3,5-triethylbenzene, and benzo[c]fluorene. Both of the triethylbenzenes were tested for
neurotoxicity in a study of mice exposed orally for 5 weeks (Tshala-Katumbav et al .. 2006).
Benzo[c]fluorene, as well as a mixture of 21 PAHs, was tested for oral carcinogenicity in mice
(Wevand et al.. 2004); a few noncancer endpoints were reported. The 21-PAH mixture included
one compound that was outside the carbon range (indan, C9); however, it was present at <1% in
the mixture. The mixture composition is shown in Appendix B (see Table B-l). A subchronic
oral study (Dalbcv et al .. 2014) of heavy paraffinic distillate aromatic extract in rats was located
on the Petroleum HPV Testing Group website. However, this mixture included compounds
outside the fraction range (as high as C50) and contained approximately 15% aliphatic
compounds. Thus, it did not meet structural requirements for the aromatic high carbon range
fraction and was not considered further.
Finally, in Step 5 (see Figure 2), PubMed searches using the terms "polycyclic aromatic
hydrocarbons' AND mixture AND (rat or mouse or hamster or rabbit)" were performed to
determine whether any oral or inhalation animal studies of mixtures that met inclusion criteria
were available. Mixtures considered relevant to the fraction met the following criteria
(see Figure 2):
1. at least 90% of the mixture consisted of identified compounds within the C10-C32
and/or EC11-EC35 ranges, and highly toxic lower aromatic carbons (e.g., benzene) were
not present.
2. 99% of the mixture consisted of aromatic compounds (<1% aliphatic).
3. the mixture had been tested in animals in at least one repeat-dose (>28 days) or
reproductive/developmental toxicity study using inhalation or oral exposure routes and
included an untreated or vehicle control group.
4. human mixture studies of any duration by oral, inhalation, and dermal exposure, and
animal studies of oral or inhalation exposure lasting at least 28 days (or any duration of
gestational exposure).
In addition, mixture studies were considered relevant only if the composition of the test
material was clearly defined.
The PubMed searches identified three neurodevelopmental studies of oral exposure to a
16-PAH mixture (Crepeaux et al .. 2014. 2013. 2012). and two studies of inhalation exposure to a
nebulized 9-PAH mixture during gestation or lactation, examining adiposity (Yan et al.. 2014)
and immune (Chu et al.. 2013) endpoints in offspring. Compositions of the 16- and 9-PAH
mixtures are shown in Appendix B (see Tables B-2 and B-3, respectively).
18
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
In summary, relevant toxicity data for compounds or mixtures that lack toxicity values
were identified from reviews or literature searches for five compounds (benzo[A]fluoranthene,
benzo[c]fluorene, dibenzo[de/p]chrysene, 1,2,4-triethylbenzene, and 1,3,5-triethylbenzene) and
three defined mixtures (21-, 16-, and 9-PAH mixtures). In addition, limited toxicity data that
were not sufficient to derive a toxicity value are available in the PPRTV assessment for
phenanthrene (U.S. EPA. 2009c\ bringing the total number of compounds with available toxicity
data but no existing toxicity values to six.
2.3. METHODS FOR INDICATOR CHEMICAL SELECTION
Only compounds or mixtures with at least one U.S. EPA or ATSDR toxicity value
(see Table 4) were considered for use as potential indicator chemicals for derivation of the
fraction-specific toxicity values, although toxicity data for other compounds were used for
hazard identification and to assess consistency in effects and potency across the components of
the fraction. The method for selecting indicator chemicals was adapted from the 2009 complex
TPH mixtures document (U.S. HP A. 2009b). First, mixtures were preferred over individual
compounds, provided that the mixture exhibited in vivo toxic effects and potency similar to those
exhibited by the individual fraction components.
If suitable mixture data were lacking, but available component data indicated similar
toxicity targets and potency, a representative compound exhibiting in vivo toxic effects and
potency similar to those exhibited by other compounds in the fraction was chosen. In the event
that components of the fraction varied widely in toxic effects or potency, the toxicity value for
the most toxic component was selected as an indicator chemical for the fraction. Finally, if
toxicity values were available for many or most of the individual compounds in a fraction, and
these compounds are typically monitored at a site of hydrocarbon contamination, then an
indicator chemical would be considered. In the case of studies where the exposures or doses
occurred during fetal development, chronic toxicity values were considered representative of
both chronic and subchronic exposures and were used as the subchronic toxicity value of the
indicator chemical if they included the most sensitive endpoint.
19
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
3. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER)
Compound-specific IRIS and PPRTV assessment documents, supplemented by the
literature search findings for additional chemicals that met the structural criteria (described
above) and review articles (Mckee et al.. 2015; Baxter and Warshawskv. 2012; OHCD. 2012;
ATS DR. 2005) were assessed to evaluate the available noncancer toxicity data for compounds in
the aromatic high carbon range fraction. Critical effects identified with existing toxicity values
include developmental effects (neurodevelopmental changes, fetal skeletal anomalies),
respiratory effects (pulmonary alveolar proteinosis), increased liver weight, decreased red blood
cells (RBCs), renal effects (nephropathy, decreased kidney weights, renal papillary
mineralization), clinical signs of neurotoxicity, and decreased body weight. Additional potential
targets identified based on literature searches include the adult and developing reproductive
system and the gastrointestinal (GI) system. Table 5 presents an overview of the human and
animal data available to evaluate these primary toxicological endpoints for each aromatic high
carbon range fraction compound and three relevant mixtures. As Table 5 shows, human data and
inhalation data for animals are scarce. Animal oral data to assess consistency in effects across
members of the fraction are widely available for body-weight effects and moderate for other
endpoints. Chronic systemic toxicity information is lacking for all but five members of the
fraction: naphthalene and 1,1-biphenyl have been tested in comprehensive 2-year systemic
toxicity studies in animals (inhalation and oral, respectively); 1- and 2-methylnaphthalene have
been evaluated in comprehensive 81-week oral studies; and BaP was evaluated in a 2-year cancer
bioassay with limited reporting of nonneoplastic findings.
20
Aromatic high carbon range
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EPA/690/R-22/005F
Table 5. Overview of Human and Animal Data Availability for Evidence Integration"
CASRN
Name
Rings
C
EC
Body
Weight
Hemato-
logical
Neuro-
logical
Hepatic
Renal/
Bladder
Respir-
atory
Gastro-
intestinal
Repro-
ductive
Develop-
mental
91-20-3
Naphthalene
2
10
11.57
0,1
H, 0,1
0,1
0,1
0,1
0,1
0,1
0,1
0
877-44-1
1,2,4-Triethylbenzene
1
12
11.57
O
O
102-25-0
1,3,5-Triethy lbenzene
1
12
11.62
0
0
91-57-6
2-Methylnaphthalene
2
11
12.72
0,1
0,1
0,1
0,1
0,1
0,1
I
0,1
90-12-0
1-Methylnaphthalene
2
11
12.77
0
O
0
0
0
0
0
92-52-4
1,1-Biphenyl
2
12
13.45
0,1
O
H
H, 0,1
0,1
0,1
0
0
0
83-32-9
Acenaphthene
2
12
14.76
0
O
O
0
0
0
0
0
86-73-7
Fluorene
2
13
15.68
0
O
O
0
0
0
0
0
85-01-8
Phenanthrene
3
14
18.37
0
120-12-7
Anthracene
3
14
18.43
0
O
O
0
0
0
0
0
205-12-9
Benzo [cjfluorene
3
17
21.45
0
0
129-00-0
Pyrene
4
16
22.45
0
O
O
0
0
0
0
0
206-44-0
Fluoranthene
3
16
21.11
0
O
0
0
0
0
0
0
205-99-2
Benzo |/> | fluoranthene
4
20
25.04
0
0
50-32-8
Benzo[a]pyrene
4
20
29.95
0,1
O
H, O
0
0
0
0
H, 0,1
H, 0,1
192-97-2
Benzo [c] pyreneb
4
20
27.80
0
191-30-0
Dibenzo [defp] chry sene
6
24
33.69
0
NA
16-PAH mixture
2-6
10-22
11.57-32.62
0
NA
9-PAH mixture
4-6
16-22
22.45-32.62
I
NA
21-PAH mixture
1-6
9-22
11.57-32.62
0
0
includes human and animal studies meeting inclusion criteria. Bolded compounds have at least one oral or inhalation noncancer toxicity value available (see Table 4).
'The PPRTV assessment for benzo [e]pyrene (U.S. EPA. 2021b) discusses hepatotoxicitv studies as well as immunotoxicity, cardiovascular toxicity, and retinol cell
toxicity studies; however, as a result of the limitations of the available oral and inhalation toxicity data for benzo[e]pyrene, the U.S. EPA did not directly derive toxicity
values. Instead, screening values were derived in Appendix A of the U.S. EPA PPRTV assessment document, using an alternative analogue approach.
EC = equivalent carbon; H = human data; I = animal inhalation studies; NA = not applicable; O = animal oral studies; PAH = polycyclic aromatic hydrocarbons;
PPRTV = Provisional Peer-Reviewed Toxicity Value; U.S. EPA = U.S. Environmental Protection Agency.
21
Aromatic high carbon range TPH fraction (noncancer)
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EPA/690/R-22/005F
To evaluate consistency in endpoint-specific potencies across members of the fraction,
the dose-response data from animal studies that met selection criteria were extracted (from IRIS,
PPRTV assessment documents, and primary and secondary literature sources) and presented in
exposure-response arrays by health outcome and exposure route (see Appendix C). Based on
review of the available data presented in Appendix C, there is evidence to suggest consistency in
body-weight changes, neurological effects, hepatic effects, and hematological effects of some
aromatic high carbon range fraction members, but not enough to indicate consistency across the
entire fraction. Available data indicate that the kidney and bladder are particularly susceptible to
1,1-biphenyl toxicity, with data from other compounds generally showing increased incidence of
age-related nephropathy. There is little evidence to indicate respiratory tract effects following
oral exposure for compounds other than 1- and 2-methylnaphthalene (for which pulmonary
findings are confounded by inhalation exposure via volatilization from feedstock), although there
is limited evidence to suggest consistency in respiratory effects following inhalation exposure
across compounds with lower carbon numbers (no data for fraction members with higher carbon
numbers; CI3-35). The available data are not adequate to provide confidence in an assessment
of the consistency in effects for GI tract, reproductive toxicity, or developmental toxicity
endpoints (including neurodevelopment and reproductive development).
22
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
4. TOXICOKINETIC CONSIDERATIONS
The toxicokinetic properties of PAHs have been extensively reviewed (U.S. EPA. 2017a;
I ARC. 2010; ATSDR. 2005). In general, these compounds are well absorbed following
inhalation, oral, and dermal exposure. The lipophilicity of PAHs facilitates absorption; however,
compounds with lower molecular weight (i.e., two or three rings vs. five or six rings) are more
rapidly and extensively absorbed (IARC. 2010). PAHs are widely distributed with some
accumulation in adipose tissues. Oxidative metabolism by cytochrome P450 (CYP450) isozymes
occurs rapidly, and is followed by conjugation with sulfate, glutathione (GSH), or glucuronic
acid and excretion in urine and feces. Oxidative metabolites of PAHs include epoxides, phenols,
dihydrodiols, phenol dihydrodiols, dihydrodiol epoxides, quinones, and tetrols.
1,1 -Biphenyl is also rapidly and readily absorbed following oral exposure (U.S. EPA.
2013). Animal studies suggest a potential for absorption by inhalation as 1,1-biphenyl dust or
vapors; however, the rate and extent of absorption following inhalation are not known
(U.S. EPA. 2013). Absorption by the dermal route is also suggested, although data are limited to
an in vitro study of percutaneous absorption (U.S. EPA. 2013). 1,1-Biphenyl is widely
distributed in tissues with no indication of preferential accumulation or storage (U.S. EPA.
2013). It is rapidly metabolized by CYP450 isozymes to hydroxylated metabolites, which are
conjugated with sulphate or glucuronic acid. 1,1-Biphenyl is rapidly eliminated from the body,
primarily as conjugated hydroxylated metabolites in the urine.
1,2,4-Triethylbenzene is expected to form a y-diketone metabolite
(1,2,4-triacetyl-benzene) due to the ortho position of the ethyl moieties on the benzene ring
(Tshala-Katumbav et at.. 2006; Gagnaire et at.. 1993). Its isomer, 1,3,5-triethylbenzene, is not
expected to form a y-diketone due to the meta position of the ethyl moieties.
23
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
5. MECHANISTIC CONSIDERATIONS
Reactive oxidative metabolites of PAHs (e.g., benzo[a]pyrene diol epoxide [BPDE],
1,2-naphthoquinone) may bind covalently to proteins and nucleic acids, resulting in the cellular
toxicity responsible for some noncancer health effects (IARC. 2010; ATSDR. 2005). Using
naphthalene as an example, formation of cataracts following exposure is attributed to metabolism
of naphthene dihydrodiol into 1,2-naphthoquinone in the lens of the eye (U.S. HP A. 1998).
Additionally, GSH depletion and covalent protein binding have been implicated in the nasal and
pulmonary toxicity produced by naphthalene due to formation of epoxide intermediates,
naphthoquinones, and free radical reactive intermediates (U.S. HP A. 1998). GSH depletion is
also associated with oxidative stress and the formation of reactive oxygen species. Oxidative
stress has been suggested as a possible mechanism for several health effects of PAHs, including
developmental and neurodevelopmental effects, male and female reproductive effects,
immunotoxicity, and neurotoxicity (Agarwai et al.. 2017; U.S. HP A. 2017a; Crepeaux et al..
2012; Surcsh et al.. 2009). PAH binding to, and activation of, the aryl hydrocarbon receptor has
been shown to affect cellular growth and differentiation and has been postulated as a possible
mechanism for the developmental, neurodevelopmental, immunotoxic, and neurotoxic effects of
PAHs (U.S. HP A. 2017a). Studies provide support for several other PAH mechanisms, including
deoxyribonucleic acid (DNA) damage of somatic and/or germ cell nucleic acids, stimulation of
apoptosis, altered neurotransmitter levels, and changes in the balance of reproductive hormones
(U.S. HP A. 2017a).
The urinary bladder toxicity observed in rats following exposure to 1,1-biphenyl is
believed to be related to the formation of calculi (U.S. HP A. 2013). The liver toxicity of
1.1-biphenyl may be related to activation of peroxisome proliferation-activated receptors
(PPARs), and the reduction in body weight may be a result of an inhibition of cellular respiration
(U.S. HP A. 2013).
Formation of a y-diketone metabolite (1,2,4-triacetylbenzene) is the proposed mechanism
for peripheral neuropathy associated with exposure to 1,2,4-triethylbenzene (Tshala-Katumbav et
al.. 2006). While formation of 1,2,4-triactylbenzene has not been demonstrated, it is expected
based on ortho arrangement of ethyl moieties (Tshala-Katumbav et al .. 2006; Gagnaire et al ..
1993). There are well-established data indicating that y-diketone metabolites of
1.2-diethylbenzene and «-hexane (1,2-diacetylbenzene and 2,5-hexanedione, respectively) are
associated with peripheral neuropathy (Mckee et al.. 2015; OECD. 2007; U.S. HP A. 2005). In
support of a role for y-diketone metabolites in peripheral neuropathy, peripheral nerve damage is
not observed following oral exposure to the isomer, 1,3,5-triethylbenzene, which does not have
the potential to form a y-diketone metabolite due to meta arrangement of ethyl moieties (Tshala-
Katumbav et al.. 2006; Gagnaire et al.. 1993).
24
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
6. DERIVATION OF PROVISIONAL VALUES
6.1. DERIVATION OF ORAL REFERENCE DOSES
Tables 6 and 7 summarize the subchronic and chronic reference values for constituent
compounds, respectively, with points of departure (PODs), uncertainty factors, critical endpoints,
and confidence ratings.
25
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Table 6. Available Subchronic RfD Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator
Chemical or
Components
POD
(mg/kg-d)
POD
Type
UFc
UF
Components
p-RfD
(mg/kg-d)
Confidence
in p-RfD
Critical Effect(s)
Species,
Mode, and
Duration
Reference
Benzo [a] pyreneb
(C20 [EC29.95])
0.092
BMDL
300
UFa, UFd,
UFh
0.0003
Medium
Neurobehavioral changes
(developmental)
Rat, gavage,
PNDs 5-11
Chen et al. (2012) as
cited in U.S. EPA
(2017a)
Benzo [ejpyrene
(C20 [EC27.80])
0.092
BMDL
1,000
UFa, UFd,
UFh
0.00009°
NA
Based on benzo [a]pyrene as an
analogue; neurobehavioral
changes (developmental)
Rat, gavage,
PNDs 5-11
U.S. EPA (2021b)
Naphthalene
(CIO [EC11.57])
50
LOAEL
90
UFa, UFh,
UFl
0.6
NA
Clinical signs of toxicity and
decreased body-weight gain
(whole body effects)
Rat, gavage,
GDs 6-15
NTP (1991) as cited in
ATSDR (2005)
2-Methyl-
naphthalene
(Cll [EC12.72])
3.5
BMDLos
1,000
UFa, UFd,
UFh
0.004°
Low
Pulmonary alveolar proteinosis
(respiratory)
Mouse, diet,
81 wk
Murata et al (1997) as
cited in U.S. EPA
(2007a)
1,1-Biphenyl
(C12 [EC13.45])
9.59
BMDL05
100
UFa, UFh
0.1c
High
Increased incidence of fetal
skeletal anomalies
(developmental)
Rat, gavage,
GDs 6-15
Khera et al. (1979) as
cited in U.S. EPA
(2011a)
Acenaphthene
(C12 [EC14.76])
161
BMDL io
1,000
UFa, UFd,
UFh
0.2°
Low
Increased relative liver weight
(hepatic)
Mouse,
gavage, 13 wk
U.S. EPA (1989) as cited
in U.S. EPA (2011b)
Fluorene
(C13 [EC15.68])
125
LOAEL
300
UFa, UFh,
UFl
0.4
NA
Increased relative liver weight
(hepatic)
Mouse,
gavage, 13 wk
U.S. EPA (1989) as cited
in ATSDR (1995)
Anthracene
(C14 [EC18.43])
1,000
NOEL
1,000
UFa, UFd,
UFh
lc
Low
No effects observed
Mouse,
gavage, 13 wk
Wolfe (1989) as cited in
U.S. EPA (2009a)
26
Aromatic high carbon range TPH fraction (noncancer)
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EPA/690/R-22/005F
Table 6. Available Subchronic RfD Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator
Chemical or
Components
POD
(mg/kg-d)
POD
Type
UFc
UF
Components
p-RfD
(mg/kg-d)
Confidence
in p-RfD
Critical Effect(s)
Species,
Mode, and
Duration
Reference
Pyrene
(C16 [EC22.45])
75
NOAEL
300
UFa, UFd,
UFh
0
0
Low
Nephropathy and decreased
kidney weights (urinary)
Mouse,
gavage, 13 wk
U.S. EPA (1989) as cited
in U.S. EPA (2007b)
Fluoranthene
(C16 [EC21.11])
124
BMDL 10
1,000
UFa, UFd,
UFh
0.1c
Low
Nephropathy (urinary)
Mouse,
gavage, 13 wk
U.S. EPA (1989) as cited
in U.S. EPA (2012)
aBolded row shows the compound and toxicity value selected as the indicator chemical for the fraction if analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction.
bThe chronic RfD forbenzo[a]pyrene is based on a developmental exposure; therefore, it is also applicable to subchronic exposures and is listed here.
Toxicity values are provisional values obtained from an existing PPRTV assessment. Values in italics are screening provisional values obtained from an existing
PPRTV assessment. Screening provisional values are not assigned confidence statements; however, confidence in these values is presumed to be low. Screening
provisional values are derived when the available data do not meet the requirements for deriving a provisional toxicity value.
BMDL = benchmark dose lower confidence limit; BMDL05 = 5% benchmark dose lower confidence limit; BMDL10 = 10% benchmark dose lower confidence limit;
C = carbon; EC = equivalent carbon; GD = gestation day; LOAEL = lowest-observed-adverse-effect level; NA = not applicable, reference did not include confidence
statement; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level; PND = postnatal day; POD = point of departure; PPRTV = Provisional
Peer-Reviewed Toxicity Value; p-RfD = provisional reference dose; RfD = reference dose; SD = standard deviation; 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.
27
Aromatic high carbon range TPH fraction (noncancer)
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EPA/690/R-22/005F
Table 7. Available Chronic RfD Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator Chemical or
Components
POD
(mg/kg-d)
POD Type
UFc
UF
Components
p-RfD or
RfD
(mg/kg-d)
Confidence
in p-RfD or
RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Benzo[a]pyreneb
(C20 [EC29.95])
0.092
BMDL
300
UFa,c UFd,
UFh
0.0003
Medium
Neurobehavioral
changes
(developmental)
Rat, gavage,
PNDs 5-11
Chen et al. (2012) as
cited in U.S. EPA
(2017a)
Benzo[e]pyrene (C20
[EC27.80])
0.092
BMDL
1,000
UFa, UFd,
UFh
0.00009d
NA
Based on
benzo|c/|pyrenc as
an analogue;
neurobehavioral
changes
(developmental)
Rat, gavage,
PNDs 5-11
U.S. EPA (2021b) (in
review)
Naphthalene (CIO
[EC11.57])
71
NOAELadj
3,000
UFa, UFd,
UFh, UFs
0.02
Low
Decreased mean
terminal body
weight (other)
Rat, gavage,
5 d/wk, 13 wk
BCL (1980) as cited in
U.S. EPA (1998)
2-Methylnaphthalene
(Cll [EC12.72])
3.5
BMDLos
1,000
UFa, UFd,
UFh
0.004
Low
Pulmonary alveolar
proteinosis
(respiratory)
Mouse, diet,
81 wk
Mureta et al. (1997) as
cited in U.S. EPA (2003)
1 -Methy lnaphthalene
(Cll [EC12.77])
71.6
LOAEL
10,000
UFa, UFd,
UFh, UFl
0.007d
Low
Pulmonary alveolar
proteinosis
(respiratory)
Mouse, diet,
81 wk
Mureta et al. (1993) as
cited in U.S. EPA (2008)
1,1-Biphenyl (CI2
[EC13.45])
13.9
BMDLio
(HED)
30
UFa, UFh
0.5
Medium-high
Renal papillary
mineralization in
males F344 rats
(urinary)
Rat, diet,
104 wk
Utneda et al. (2002) as
cited in U.S. EPA (2013)
Acenaphthene (CI2
[EC14.76])
175
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.06
Low
Hepatotoxicity
(hepatic)
Mouse, gavage,
13 wk
U.S. EPA (1989) as cited
in U.S. EPA (1990a)
Fluorene
(C13 [EC15.68])
125
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.04
Low
Decreased RBCs,
packed cell volume,
and hemoglobin
(hematologic)
Mouse, gavage,
13 wk
U.S. EPA (1989) as cited
in U.S. EPA (1990d)
28
Aromatic high carbon range TPH fraction (noncancer)
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EPA/690/R-22/005F
Table 7. Available Chronic RfD Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator Chemical or
Components
POD
(mg/kg-d)
POD Type
UFc
UF
Components
p-RfD or
RfD
(mg/kg-d)
Confidence
in p-RfD or
RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Anthracene
(C14 [EC18.43])
1,000
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.3
Low
No effects observed
Mouse, gavage,
13 wk
U.S. EPA (1989) as cited
in U.S. EPA ( 1990b)
Pyrene
(C16 [EC22.45])
75
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.03
Low
Kidney effects (renal
tubular pathology,
decreased kidney
weights) (urinary)
Mouse, gavage,
13 wk
U.S. EPA (1989) as cited
in U.S. EPA (1990e)
Fluoranthene
(C16 [EC21.11])
125
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.04
Low
Nephropathy,
increased liver
weights,
hematological
alterations, and
clinical effects
(hepatic, urinary)
Mouse, gavage,
13 wk
U.S. EPA (1988) as cited
in U.S. EPA (1990c)
aBolded rows show the compound and toxicity value selected as the indicator chemical for the fraction if analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction.
bThe chronic RfD forbenzo[a]pyrene is based on a developmental exposure.
°Body-weight scaling to derive an HED was not performed because doses were administered directly to early postnatal animals (U.S. EPA. 201731.
dToxicity values are provisional values obtained from an existing PPRTV assessment. Values in italics are screening provisional values obtained from an existing
PPRTV assessment. Screening provisional values are not assigned confidence statements; however, confidence in these values is presumed to be low. Screening
provisional values are derived when the available data do not meet the requirements for deriving a provisional toxicity value.
ADJ = adjusted; BMDL = benchmark dose lower confidence limit; BMDL05 = 5% benchmark dose lower confidence limit; BMDL10 = 10% benchmark dose lower
confidence limit; C = carbon; EC = equivalent carbon; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; p-RfD = provisional reference dose; PND = postnatal day; POD = point of departure; PPRTV = provisional peer-reviewed
toxicity value; RBC = red blood cell; RfD = reference dose; SD = standard deviation; 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.
29
Aromatic high carbon range TPH fraction (noncancer)
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EPA/690/R-22/005F
Subchronic provisional reference doses (p-RfDs) and a subchronic RfD are available for
10 compounds in the fraction (see Table 6). It should be noted that the chronic RfD for BaP is
based on a developmental exposure, which is also applicable to subchronic exposures;
accordingly, the chronic RfD value for BaP is listed in Tables 4 and 6 as a proxy for subchronic
exposure. As a result of the limitations of the available oral toxicity data for BeP, the U.S. EPA
did not directly derive a subchronic p-RfD. Instead, a screening subchronic p-RfD is derived in
the U.S. EPA PPRTV assessment document, using an alternative analogue approach based on the
RfD for BaP (U.S. EPA. 2017a). The critical endpoints for the other subchronic p-RfDs are
clinical signs of toxicity and decreased body-weight gain (naphthalene), lung toxicity
(2-methylnaphthalene), developmental effects (1,1-biphenyl), liver effects (acenaphthene,
fluorene), and kidney toxicity (pyrene, fluoranthene). The subchronic p-RfD for anthracene is
based on a lack of effects.
There are 11 available chronic p-RfDs or RfDs for constituent compounds (see Table 7).
The critical endpoints for these chronic RfDs are decreased body weight (naphthalene), lung
toxicity (1-methylnaphthalene, 2-methylnaphthalene), kidney toxicity (1,1-biphenyl, pyrene,
fluoranthene), liver effects (acenaphthene, fluoranthene), hematological effects (fluorene,
fluoranthene), and developmental neurotoxicity (BaP, BeP). The chronic RfD for anthracene is
based on a lack of effects.
As suggested by the disparity in critical endpoints and values of RfDs for fraction
members and discussed in Section 3 (and Appendix C), the available oral toxicity data for
aromatic high carbon range compounds do not show much consistency across fraction members
in terms of similarity in critical or sensitive effects and potencies. There is no basis to identify a
surrogate mixture or compound that is representative of the effects and potency of the fraction as
a whole. Therefore, the compounds that resulted in the lowest RfDs were considered as the basis
for indicator chemical selection (see Section 2.3).
6.1.1. Oral Noncancer Assessment Using the Indicator Chemical Method for the Aromatic
High Carbon Range Fraction
The lowest oral subchronic and chronic RfD among the compounds in this fraction that
are not screening values is the chronic RfD for BaP (see Tables 6 and 7); this value is
recommended for chronic exposures to the aromatic high carbon range fraction if available
analytical chemistry data do not identify concentrations of individual chemicals composing this
fraction, and an indicator chemical approach is implemented. Although a subchronic toxicity
value is not available for BaP, the chronic RfD is based on a developmental exposure, so the RfD
value is applicable to subchronic exposures as well, if an indicator approach is implemented.
Accordingly, the chronic RfD for BaP is listed in Table 6 as an available subchronic oral toxicity
value for constituents in the aromatic high carbon range fraction. Subchronic and chronic toxicity
values for several other PAHs in this fraction are considerably higher (several orders of
magnitude in some cases) than the chronic RfD for BaP, raising the question of whether use of
BaP as the indicator chemical for the fraction may be toxicologically relevant. However,
emerging information on mixtures and other compounds shows effects at exposures comparable
to (or even lower than) levels at which BaP induces toxicity, suggesting that use of BaP values
for the whole fraction may be more appropriate than implied by comparisons limited to
compounds with toxicity values. For example, recent studies suggest that other PAHs may
induce altered reproductive tract development (Kim et al.. 2011). neurodevelopmental effects
(Crepeaux et at.. 2014. 2013. 2012). transgenerational changes in immune function (Chu et al..
30 Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
2013). adiposity (Yan et al.. 2014). or lethal transplacental carcinogenesis (Madeen et al.. 2016;
Benninghoff and Williams. 2013; Shorev et al.. 2013; Shorev et al.. 2012; Castro et al.. 2009;
Castro et al .. 2008c; Castro et al. 2008a; Castro et al. 2008b) at very low exposure levels. These
newer studies support the selection of BaP as the indicator chemical because it is the only
indicator chemical candidate with an oral toxicity value that will be protective against most of
these effects. However, users of the indicator chemical method should understand that there
could be more uncertainty associated with the application of this toxicity value to the aromatic
high carbon range fraction than for its derivation in U.S. EPA (2017a).
The IRIS review of BaP (U.S. EPA. 2017b) cited Chen et al. (2012) as the principal study
for the chronic RfD. The supplemental information for the toxicological review of BaP
(U.S. EPA. 2017b) provided the following summary.
Chen et al. (2012) treated male andfemale neonatal Sprague-Dawley rats
(10/sex/group) with benzo[a]pyrene (unspecifiedpurity) dissolved in peanut oil by
gavage daily on PNDs 5 11, at doses of 0.02, 0.2, or 2 mg/kg in 3 mL vehicle/kg body
weight, determined individually based upon daily measurements. This time period was
described as representing the brain growth spurt in rodents, analogous to brain
developmental occurring from the third trimester to 2 years of age in human infants.
Breeding was performed by pairs of 9-week-old rats, with delivery designated as PND 0.
Litters were culled to eight pups/dam (four males andfour females, when possible) and
randomly redistributed at PND 1 among the nursing dams; dams themselves were rotated
every 2-3 days to control for caretaking differences, and cage-side observations of
maternal behavior were made daily. One male and female from each litter were assigned
per treatment group, and the following physical maturation landmarks were assessed
daily in all treatment groups until weaning at PND 21: incisor eruption, eye opening,
development of fur, testis decent, and vaginal opening.
Neonatal sensory and motor developmental tests were administered to pups
during the preweaningperiod at PNDs 12, 14, 16, and 18, and were behavioral tests
administered to rats as adolescents (PNDs 35 and 36) or as adults (PNDs 70 and 71):
each rat was only tested during one developmental period. All dosing was performed
from 1300 to 1600 hours, and behavioral testingwas during the "dark"periodfrom
1900 to 2300 hours, although tests were performed in a lighted environment. Pups were
observed individually and weighed daily, the order of testing litters was randomized each
day, and all observations were recorded by investigators blinded to group treatment.
Sensory and motor developmental tests, including the surface righting reflex test,
negative geotaxis test, and cliff aversion test, were performed only once, while the
forelimb grip strength test was assessed during three 60-second trials on PND 12. Rat
movements during the open-field test were recorded by camera, and two blinded
investigators scored movement and rearing separately during a 5-minute evaluation
period. Blinded investigators directly observed video monitoring of rat movements during
the elevated plus maze, and after a 5-minute free exploration period, recorded number of
entries into the closed and open arms, time spent in the open arms, and latency to the
first arm entry. Assessment of the Morris water maze was slightly different, in that the
rats were habituated to the testing pool by a 60-second swim without a platform on the
day prior to testing. The rats were then tested during a 60-second swim with a hidden
31
Aromatic high carbon range
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platform present at a constant position each day for 4 days; on the 5th day, the rats were
evaluated during a 60-secondprobe swim without a platform. The number of times each
animal crossed the original platform location and the duration of time spent in the
platform quadrant were recorded during this final evaluation. One pup/sex/litter were
assignedfor behavioral testing to each of four tracks: Track 1, surface righting reflex
test, cliff aversion test, and open-field test (PNDs 12-18); Track 2, negative geotaxis test,
forelimb grip strength test, and open-field test (PNDs 12-20); Track 3, elevated plus
maze, Morris water maze, and open-field test (PNDs 34-36); and Track 4, elevated plus
maze, Morris water maze, and open-field test (PNDs 69-71). All results were presented
in graphic form only.
No significant effects on pup body weight were observed during the 7-day
treatment period (PNDs 5-11). Three-way ANOVA (time x benzo[a]pyrene
treatment x sex) indicated that effects of benzo[a]pyrene were not sex-dependent
throughout the 71-day experiment, so both sexes were pooled together. From this pooled
analysis, pups in the 2 mg/kg-day treatment group gained significantly less weight at both
PND 36 and 71. There were no differences among treatment groups in incisor eruption,
eye opening, development of fur, testis decent, or vaginal opening.
For all measurements of neonatal sensory and motor development, results from
both sexes were analyzed together since benzo[a]pyrene was reported to have no
significant interaction with sex by 3-way ANOVA. No significant differences were
observed in either the cliff aversion or forelimb grip strength tests. In the surface righting
reflex test, latency was increased in the 0.2 mg/kg-day group at PND 12, in the 0.02 and
2 mg/kg-day groups at PND 14, and in only the high-dose group at PND 16; latency was
not significantly different in any group at PND 18. At PND 12, there was a dose-related
increase in negative geotaxis latency associated with 0.02, 2, and 2 mg/kg-day
benzo[afpyrene, which was also present in the 2 mg/kg-day group at PND 14, but
returned to control levels at PND 16 and 18. In the open field test, there were no
significant differences in either locomotion or rearing activity at PND 18 or 20. At
PND 34, the 2 mg/kg-day group exhibited significantly increased movement, but
increases in rearing were not significant. At PND 69, increased locomotion was observed
in both the 0.2 and 2 mg/kg-day groups, while rearing was significantly increased in only
the 2 mg/kg-day treatment group.
The elevated plus maze performance was only evaluated in adolescent and adult
rats. Unlike the previous tests, 3-way ANOVA revealed a statistically significant
interaction between neonatal benzo[a]pyrene treatment and sex, so male andfemale
performance was analyzed independently. No significant differences in PND 35 males
were observed, and the only significant observation in PND 35 females was increased
time spent in the open maze arms by the 2 mg/kg-day treatment group. Significantly
decreased latency time to first open arm entry was observed in PND 70 males and
females in both 0.2 and 2 mg/kg-day treatment groups; these groups also spent
significantly more time in open maze arms, along with the 0.02 mg/kg-day female group.
At PND 70, the 2 mg/kg-day males, along with the 0.2 and 2 mg/kg-day females, entered
more frequently into open arms and less frequently into closed arms than the vehicle
controls. In the Morris water maze, escape latency (time to reach the platform during
each of the four testing days) was consistently increased in the 2 mg/kg-day treatment
32
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
group of both sexes, in both adolescent and adult animals. These increases were
statistically significant in both males and females treated with 2 mg/kg-day
benzo[a]pyrene at both PNDs 39 and 74, and were also significantly elevated in
0.2 mg/kg-day animals of both sexes at PND 74. Likewise, performance during the
5th test day, in the absence of the escape platform, was significantly adversely affected by
both metrics (decreased time spent in the target quadrant and decreased number of
attempts to cross the platform location) in 2 mg/kg-day rats of both sexes at both
PNDs 40 and 75. PND 75 females treated with 0.2 mg/kg-day benzo[a]pyrene also
showed significant decreases in both performance metrics, while PND 75 0.2 mg/kg-day
males only demonstrated significant differences in "time spent in target quadrant. " Swim
speed was also assessed, but there were no differences among any treatment group at
either age evaluated.
6.1.2. Alternative Oral Noncancer Assessment Using the Hazard Index Method for the
Aromatic Medium Carbon Range Fraction
If the available analytical chemistry data quantify the concentrations of naphthalene,
2-methylnapthlalene, 1-methylnapthalene, 1,1-biphenyl, acenaphthene, fluorene, anthracene,
pyrene, fluoranthene, or BaP separately from the remainder of the aromatic high carbon range
fraction, it is recommended that HQs for the individual chemicals with existing analytical data be
calculated and an HI for the mixture be developed using the calculated HQs.
For subchronic oral exposures, the subchronic RfDs or p-RfDs as shown in Table 6 can
be used as the denominator in the HQ equations. Additionally, the chronic RfD for BaP
(0.0003 mg/kg-day) can be adopted for subchronic exposures because it is based on a
developmental study (as discussed above). In this alternative approach, the chronic RfD for BaP
(0.0003 mg/kg-day) is recommended for use with the remainder of the fraction, including any
other fraction members analyzed individually (see Table 6).
For chronic oral exposures, the chronic RfDs or p-RfDs as shown in Table 7 can be used
as the denominator in the HQ equations. In this alternative approach, the chronic RfD for BaP
(0.0003 mg/kg-day) is recommended for use with the remainder of the fraction, including any
other fraction members analyzed individually (see Table 7).
6.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The available subchronic and chronic RfC values, with PODs, uncertainty factors,
endpoints, and confidence ratings, are presented in Table 8. As shown in the table, there are two
subchronic screening p-RfCs (1,1-biphenyl and BeP), one subchronic RfC (BaP), two chronic
screening p-RfCs (1,1-biphenyl and BeP), and two chronic p-RfC or RfC values (naphthalene
and BaP). Critical effects for the aforementioned RfCs include liver and kidney toxicity
(1,1-biphenyl), nasal lesions (naphthalene), and developmental toxicity (BaP and BeP).
33
Aromatic high carbon range
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Table 8. Available RfC Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator
Chemical or
Components
POD
(mg/m3)
POD
Type
(HEC)
UFc
UF
Components
p-RfC or RfC
(mg/m3)
Confidence in
p-RfC or RfC
Critical Effect(s)
Species,
Frequency,
and Duration
Reference
Subchronic
1,1-Biphenyl
(C12 [EC13.45])
1.23
BMCLiob
300
UFa, UFd,
UFh
0.004°
Low
Congestion and edema of
liver and kidneys (hepatic,
urinary)
Mouse, 7 h/d,
5 d/wk for
13 wk
Cannon Laboratories
Inc. (1977) as cited
in U.S. EPA (2011a)
Benzo[a]pyrened
(C20 [EC29.95])
0.0046
LOAEL6
3,000
UFa, UFd,
UFh, UFl
0.000002
Low-medium
Decreased embryo/fetal
survival (developmental)
Rat, 4 h/d on
GDs 11-20
Archibons et al.
(2002) as cited in
U.S. EPA (2017a)
Benzo[e]pyrene
(C20 [EC27.80]
0.0046
LOAEL
3,000
UFa, UFd,
UFh, UFl
0.000002°
Low
Based onbenzo[a]pyrene as
an analogue; decreased
embryo/fetal survival
(developmental)
Rat, 4 h/d on
GDs 11-20
Archibong et al.
(2002) as cited in
U.S. EPA (2021b)
Chronic
Naphthalene
(CIO [EC11.57])
9.3
LOAEL
3,000
UFa, UFd,
UFh, UFl
0.003
Low-medium
Nasal effects: hyperplasia
and metaplasia in
respiratory and olfactory
epithelium, respectively
(nervous, respiratory)
Mouse, 6 h/d,
5 d/wk for 2 yr
NIP (1992) as cited
in U.S. EPA (1998)
1,1-Biphenyl
(C12 [EC13.45])
1.23
BMCLio
3,000
UFa, UFd,
UFh, UFs
0.0004c
Low
Congestion and edema of
liver and kidneys (hepatic,
urinary)
Mouse, 6 h/d,
7 d/wk for
13 wk
Cannon Laboratories
Inc. (1977) as cited
in U.S. EPA (2011a)
Benzo[a]pyrene
(C20 [EC29.95])
0.0046
LOAEL
3,000
UFa, UFd,
UFh, UFl
0.000002
Low-medium
Decreased embryo/fetal
survival (developmental)
Rat, 4 h/d on
GDs 11-20
Archibons et al.
(2002) as cited in
U.S. EPA (2017a)
34
Aromatic high carbon range TPH fraction (noncancer)
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Table 8. Available RfC Values for Aromatic High Carbon Range Fraction (C10-C32, ECll-EC35)a
Indicator
Chemical or
Components
POD
(mg/m3)
POD
Type
(HEC)
UFc
UF
Components
p-RfC or RfC
(mg/m3)
Confidence in
p-RfC or RfC
Critical Effect(s)
Species,
Frequency,
and Duration
Reference
Benzo[e]pyrene
(C20 [EC27.80])
0.0046
LOAEL
3,000
UFa, UFd,
UFh, UFl
0.000002°
NA
Based onbenzo[a]pyrene as
an analogue; decreased
embryo/fetal survival
(developmental)
Rat, 4 h/d on
GDs 11-20
Archibong et al.
(2002) as cited in
U.S. EPA (2021b)
aBolded row shows the compound and toxicity value selected as the indicator chemical for the fraction if analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction.
bU. S. EPA derived the HEC in a PPRTV based on consideration of the critical effect as extrarespiratory (using the RGDR for the extrarespiratory region).
Toxicity values are provisional values obtained from an existing PPRTV assessment. Values in italics are screening provisional values obtained from an existing
PPRTV assessment. Screening provisional values are not assigned confidence statements; however, confidence in these values is presumed to be low. Screening
provisional values are derived when the available data do not meet the requirements for deriving a provisional toxicity value.
dBecause the chronic RfC forbenzo[a]pyrene is based on a developmental exposure, it is also applicable to subchronic exposures and is listed here.
eU.S. EPA derived the HEC in an IRIS assessment based on consideration of the critical effect as extrarespiratory (using the RGDR for the extrarespiratory region).
BMCLio = 10% benchmark concentration lower confidence limit; C = carbon; EC = equivalent carbon; GD = gestation day; HEC = human equivalent concentration;
IRIS = Integrated Risk Information System; LOAEL = lowest-observed-adverse-effect level; NA = not applicable; POD = point of departure; PPRTV = Provisional
Peer-Reviewed Toxicity Value; p-RfC = provisional reference concentration; RfC = reference concentration; RGDR = regional gas dose ratio; 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; U.S. EPA = U.S. Environmental Protection Agency.
35
Aromatic high carbon range TPH fraction (noncancer)
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As suggested by the disparity in critical endpoints and values of RfCs for fraction
members and discussed in the following section, as well as in Appendix C, the available
inhalation toxicity data for aromatic high carbon range compounds do not show much
consistency across fraction members in terms of toxicological effects or potencies. Additionally,
inhalation data are limited to four members of the fraction and one PAH mixture. There is no
basis to identify a surrogate mixture or compound that is representative of the effects and
potency of the fraction as a whole. Therefore, the compounds that resulted in the lowest RfCs
were considered as the basis for indicator chemical selection (see Section 3).
6.2.1. Inhalation Noncancer Assessment the Indicator Chemical Method for the Aromatic
High Carbon Range Fraction
The lowest RfC among the compounds in this fraction that is not a screening value is the
chronic RfC for BaP (see Table 8); this value is recommended for chronic exposures to the
aromatic high carbon range fraction if available analytical chemistry data do not identify
concentrations of individual chemicals composing this fraction. Although a subchronic toxicity
value is not available for BaP, the chronic RfC is based on a developmental exposure endpoint,
so the RfC value is applicable to subchronic exposures as well. The few available subchronic
and/or chronic toxicity values for other PAHs are considerably higher (>2 orders of magnitude)
than the chronic RfC for BaP, raising the question of whether use of BaP as the indicator
chemical for the fraction may be overly conservative. However, a mixtures study suggests that
neurodevelopmental effects may occur at exposures lower than levels at which BaP induces
toxicity (Slotkin et al.. 2017). suggesting that use of BaP values for the whole fraction may be
more appropriate than implied by comparisons limited to compounds with toxicity values. At this
time, the database for members of this fraction and relevant mixtures that elicit
neurodevelopmental effects is not comprehensive. Thus, BaP is considered an appropriate
indicator because it has the lowest RfC among fraction members and the most comprehensive
database. In addition, because neurodevelopmental effects are the critical effect for oral
exposures to BaP, there is evidence that BaP can affect neurodevelopmental outcomes. However,
users of the indicator chemical method should understand that there could be more uncertainty
associated with the application of this toxicity value to the aromatic high carbon range fraction
than for its derivation in U.S. EPA (2017a).
The IRIS review of BaP (U.S. HP A. 2017a) cited Archibong et al. (2002) as the principal
study for the chronic RfC. The supplemental information for the toxicological review of BaP
(U.S. HP A. 2017b) provided the following summary.
Archibong et al. (2002) evaluated the effect of exposure to inhaled
benzo[a]pyrene on fetal survival and luteal maintenance in timed-pregnant F344 rats.
Prior to exposure on GD 8, laparotomy was performed to determine the number of
implantation sites, and confirmed pregnant rats were divided into three groups,
consisting of rats that hadfour to six, seven to nine, or more than nine conceptuses in
utero. Rats in these groups were then assigned randomly to the treatment groups or
control groups to ensure a similar distribution of litter sizes. Animals (10/group) were
exposed to benzo[a]pyrene:carbon black aerosols at concentrations of25, 75, or
100 /jg/m3 via nose-only inhalation, 4 hours/day on GDs 11-20. Control animals were
either sham-exposed to carbon black or remained entirely unexposed. Results of particle
size analysis of generated aerosols were reported by several other reports from this
laboratory (Inyang et al, 2003; Ramesh etal., 2001a; Hood etal., 2000). Aerosols
36
Aromatic high carbon range
TPH fraction (noncancer)
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EPA/690/R-22/005F
showed a trimodal distribution (average of cumulative mass, diameter) <95%, 15.85 /urn;
89%, <10 fim; 55%, <2.5 fim; and 38%, <1 fim (Inyang et al., 2003). Ramesh etal.
(2001a) reported that the MMAD (± geometric SD) for the 55% mass fraction with
diameters <2.5 fim was 1.7 ± 0.085. Progesterone, estradiol-17fi, and prolactin
concentrations were determined in plasma collected on GDs 15 and 17. Fetal survival
was calculated as the total number ofpups divided by the number of all implantation
sites determined on GD 8. Individual pup weights and crown-rump length per litter per
treatment were determined on PND 4 (PND 0 = day of parturition).
Archibong et al. (2002) reported that exposure of rats to benzo[a]pyrene caused
biologically and statistically significant (p <0.05) reductions in fetal survival compared
with the two control groups; fetal survival rates were 78.3, 38.0, and 33.8% per litter at
25, 75, and 100 /Jg/m3, respectively, and 96.7% with carbon black or 98.8% per litter in
untreated controls (see Table D-30). Consequently, the number of pups per litter was
also decreased in a concentration-dependent manner. The decrease was -50% at
75 /jg/m3 and -65% at 100 /Jg/m3, compared with sham-exposed and unexposed control
groups. No effects on hormone levels were observed on GDs 15 or 17 at the low dose.
Biologically significant decreases in mean pup weights (expressed as gper litter) of >5%
relative to the untreated control group were observed at doses >75 /jg/m3 (14 and 16%
decreases at 75 and 100 /Jg/m3, respectively, p < 0.05). There were no statistically
significant differences from the control groups in crown-rump length (see Table D-30).
Benzo[a]pyrene exposure at 75 /jg/m3 caused a statistically significant decrease
in plasma progesterone, estradiol, and prolactin on GD 17; these levels were not
determined in the rats exposed to 100 /jg/m3 (Archibong et al., 2002). Plasma prolactin is
an indirect measure of the activity of decidual luteotropin, a prolactin-like hormone
whose activity is necessary for luteal maintenance during pregnancy in rats. Control
levels of prolactin increasedfrom GD 15 to 17, but this increase did not occur in the rats
exposed to 75 /jg/m3. Although the progesterone concentration at 75 /jg/m3 was
significantly lower than in controls on GD 17, the authors thought that the circulating
levels should have been sufficient to maintain pregnancy; thus, the increased loss of
fetuses was thought to be caused by the lower prolactin levels rather than progesterone
deficiency. The reduced circulating levels of progesterone and estradiol-17fi among
benzo[a]pyrene-treated rats were thought to be a result of limited decidual luteotropic
support for the corpora lutea. The authors proposed the following mechanism for the
effects of benzo[a]pyrene on fertility: benzo[a]pyrene or its metabolites decreased
prolactin and decidual luteotropin levels, compromising the luteotropic support for the
corpora lutea and thereby decreasing the plasma levels of progesterone and
estradiol-17p. The low estradiol-17fi may decrease uterine levels of progesterone
receptors, thereby resulting in fetal mortality. Based on biologically and statistically
significant decreases in pups/litter and percent fetal survival/per litter, the LOAEL was
25 /Jg/m3; no NOAEL was identified.
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Aromatic high carbon range
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6.2.2. Alternative Inhalation Noncancer Assessment Using the Hazard Index Method for
the Aromatic High Carbon Range Fraction
If the available analytical chemistry data quantify the concentrations of 1,1-biphenyl,
naphthalene, BaP, or BeP in the air separately from the remainder of the aromatic high carbon
range fraction, it is recommended that HQs for the individual chemicals with analytical data be
calculated and an HI for the mixture be developed using the calculated HQs.
For subchronic inhalation exposures, the subchronic p-RfC for 1,1-biphenyl
(0.004 mg/m3), the p-RfC for BeP (2 x 10 6 mg/m3), and the chronic RfC for BaP
(2 x 10~6 mg/m3) can be used as the denominator in the HQ equations; as discussed above, use of
the chronic BaP value is appropriate because it is based on a developmental study. In this
alternative approach, the chronic RfC for BaP (2 x 10 6 mg/m3) is recommended for use with the
remainder of the fraction, including any other fraction members analyzed individually.
For chronic inhalation exposures, the chronic RfCs or p-RfCs as shown in Table 8 can be
used in the denominator of the HQ equations. In this alternative approach, the chronic RfC for
BaP (2 x 10 6 mg/m3) is recommended for use with the remainder of the fraction, including any
other fraction members analyzed individually.
6.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
Table 9 summarizes the noncancer health reference values for indicator chemicals used
when available analytical data and exposure estimates are limited to either air concentrations of,
or oral exposure rates associated with, the whole fraction. When analytical results, air
concentrations, or exposure rate measures for individual compounds with reference values are
available, then the hazards associated with these compounds are assessed separately, using the
HI approach and reference values reported in Tables 6, 7, and 8. The mass of those compounds is
then subtracted from the total mass of the fraction, and the risks associated with the remaining
mass are assessed using the values in Table 9.
Table 9. Summary of Noncancer Reference Estimates for Aromatic High
Carbon Range (C10-C32, EC11-EC35) Fraction of TPHs
Toxicity Type
(units);
Indicator
Chemical
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UFc
Reference
Subchronic
p-RfD (mg/kg-d);
Bcnzo|fl|pyrcnc
Rat/M, F
Neuro-
development
3 x 1(T4
BMDLi sd
0.092
300
Chenetal. (2012)
as cited in U.S.
EPA (2017a)
Chronic p-RfD
(mg/kg-d);
Bcnzo|fl|pyrcnc
Rat/M, F
Neuro-
development
3 x 1(T4
BMDLi sd
0.092
300
Chenetal. (2012)
as cited in U.S.
EPA (2017a)
Subchronic
p-RfC
(mg/m3)
Bcnzo|fl|pyrcnc
Rat/M, F
Decreased
embryo/fetal
survival
2 x 1(T6
LOAEL
(HEC)
0.0046
3,000
Archibong et al.
(2002) as cited in
U.S. EPA (2017a)
38
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TPH fraction (noncancer)
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Table 9. Summary of Noncancer Reference Estimates for Aromatic High
Carbon Range (C10-C32, EC11-EC35) Fraction of TPHs
Toxicity Type
(units);
Indicator
Chemical
Species/
Sex
Critical
Effect
p-Reference
Value
POD
Method
POD
UFc
Reference
Chronic p-RfC
(mg/m3)
Bcnzo|fl|pyrcnc
Rat/M, F
Decreased
embryo/fetal
survival
2 x 1(T6
LOAEL
(HEC)
0.0046
3,000
Archibone et al.
(2002) as cited in
U.S. EPA (2017a)
BMDLisd = lower confidence limit on benchmark dose using benchmark response of 1 standard deviation change
from control mean; C = carbon; EC = equivalent carbon; F = female(s); HEC = human equivalent concentration;
M = male(s); POD = point of departure; p-RfC = provisional inhalation reference concentration;
p-RfD = provisional oral reference dose; TPH = total petroleum hydrocarbon; UFC = composite uncertainty factor.
39
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
APPENDIX A. LITERATURE SEARCH AND SCREENING
Literature searches were conducted in February 2018 and updated in August 2021 for
studies relevant to the derivation of provisional toxicity values for 44 constituents of the aromatic
high carbon range fraction of total petroleum hydrocarbons (TPHs). This included the
U.S. Environmental Protection Agency (U.S. EPA) initial list of 41 relevant chemicals and
6 additional chemicals identified in the search of the Provisional Peer-Reviewed Toxicity Value
(PPRTV) database (total 47) less benzo[a]pyrene (BaP) and naphthalene that had chronic and
subchronic health risk values on the Integrated Risk Information System (IRIS) and
benzo[e]pyrene (BeP) that had PPRTV health risk values (see Table 3). Database searches for
PubMed and Web of Science were conducted by an information scientist. Initial searches were
date limited from 2007 to 2018. The records were stored using the U.S. EPA's Health and
Environmental Research Online (HERO) database of scientific literature. The PubMed database
was searched using the HERO interface. The updated search was conducted similarly using the
same search strings in PubMed and Web of Science from February 2018 through August 2021.
There was an additional search of Agency for Toxic Substances and Disease Registry (ATSDR)
and U.S. EPA documents for health risk values for fraction members.
The results of the PubMed searches were screened (title and abstract) for relevance using
the Population, Exposure, Comparator, and Outcome (PECO) criteria outline in Table A-l.
Full-text screening for relevance to hazard identification was performed using the refined PECO
criteria shown in Table A-2.
Table A-l. PECO Criteria for Screening of TPH Constituent Literature
Search Results
PECO Element
Inclusion Criteria
Population
Humans (any population) or laboratory mammals (any life stage)
Exposure
Human: Exposure to the subject material alone or as the primary component of a mixture,
known or presumed to occur by oral, inhalation, and/or dermal routes.
Animal: In vivo, exposure to the subject material alone, by oral or inhalation (including
instillation) routes, for all durations of exposures (durations <28 days will be captured as
supporting information), including any duration during gestation. Other routes of exposure will
be captured as supporting information.
Comparison
Human: Includes any comparison/referent group (no exposure, lower exposure).
Animal: Includes concurrent negative (untreated, sham-treated, or vehicle) control.
Outcomes
Assesses any cancer or noncancer endpoint in any tissue, organ, or physiological system.
PECO = Population, Exposure, Comparator, and Outcome; TPH = total petroleum hydrocarbon.
40
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Table A-2. PECO Criteria for Relevance to Hazard Identification
PECO Element
Inclusion Criteria
Population
Humans (any population) or laboratory mammals (any life stage)
Exposure
Human: Exposure to the subject material alone or as the primary component of a mixture,
known or presumed to occur by oral or inhalation routes.
Animal: In vivo, exposure to the subject material alone, by oral or inhalation routes, for
durations >28 days3 or any duration during gestation.
Comparison
Human: Includes any comparison/referent group (no exposure, lower exposure).
Animal: Includes concurrent negative (untreated, sham-treated, or vehicle) control.
Outcomes
Assesses any noncancer health outcome in any tissue, organ, or physiological system.
aIt is noted that the PPRTV program often considers studies of shorter duration. However, given the database and
the described relative potency of benzo[a]pyrene (which was selected as the indicator chemical), it is unlikely that
a more sensitive endpoint than those captured in studies >28 days in duration will be identified in data from acute
studies.
PECO = Population, Exposure, Comparator, and Outcome; PPRTV = Provisional Peer-Reviewed Toxicity Value.
41
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
APPENDIX B. COMPOSITION OF MIXTURES RELEVANT TO THE AROMATIC
HIGH CARBON RANGE FRACTION
Table B-l lists information on the 21 -PAH mixture composition for the Wevand et al.
(2004) oral carcinogenicity study. The composition of the 16-PAH mixture in the Crepeaux et al.
(2014. 2013. 2012) oral neurodevelopmental toxicity studies is shown in Table B-2. Information
on the composition of the 9-PAH mixture in the Van et al. (2014) and Chu et al. (2013)
inhalation developmental studies is provided in Table B-3.
Table B-l. Composition of PAH Mixture Tested in Dietary Carcinogenesis
Study (Limited Noncancer Endpoints)a
Chemical
C
EC
Level in
Diet (mg/kg
food)
PAH Mix
PAH Mix with
Benzo [cjfluorene
Dose
(ng/mouse/d)
mg/Mouse
over 260 d
Dose
(ng/mouse/d)
mg/Mouse
over 260 d
Indan
9
9.74
1.23
2.6
0.7
2.8
0.7
Naphthalene
10
11.57
80.8
170
43.7
186
48.7
2-Methylnaphthalene
11
12.72
26.8
56.2
14.5
61.5
16.1
1 -Methy lnaphthalene
11
12.77
14.2
29.7
7.7
32.5
8.5
Acenaphthylene
12
14.82
14.3
30
7.7
32.8
8.6
Acenaphthene
12
14.76
3.18
6.7
1.7
7.3
1.9
Dibenzofuran
12
13.24
4.53
9.5
2.4
10.4
2.7
Fluorene
13
15.68
11.9
25
6.5
27.4
7.2
Phenanthrene
14
18.37
25.3
53
13.7
58.1
15.2
Anthracene
14
18.43
7.25
15.2
3.9
16.7
4.4
Fluoranthene
16
21.11
15.9
33.4
8.6
36.6
9.6
Pyrene
16
22.45
18.1
37.9
9.8
41.5
10.9
B enz [a] anthracene
18
25.27
8.35
17.5
4.5
19.2
5
Chrysene
18
26.13
7.4
15.5
4
17
4.5
Benzo [/>]fluoranthene
20
25.04
7.23
15.2
3.9
16.6
4.4
Benzo [&]fluoranthene
20
28.70
2.53
5.3
1.4
5.8
1.5
Benzo [a]pyrene
20
29.95
6.9
14.5
3.7
15.9
4.2
Indeno [ 1,2,3 -cd\ pyrene
22
32.62
4.98
10.4
2.7
11.4
3
Dibcnz|fl, h\ anthracene
22
32.45
0.93
1.9
0.5
2.1
0.6
Bcn/o\ghi | pen lcne
22
30.37
5.73
12
3.1
13.2
3.5
Benzo [c]fluorene
17
21.45
5.6
-
-
13.6
3.6
Sum
561.5
144.7
628.4
164.8
aWevand et al. (2004).
C = carbon; EC = equivalent carbon; PAH = polycyclic aromatic hydrocarbon.
42
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Table B-2. Composition of 16-PAH Mixture Tested in Oral
Neurodevelopmental Studies"
CASRN
Name
Rings
C
EC
Percent in
16-PAH
Mixture (%)
PAH Dose in
Low-Dose
Mixture
(mg/kg-d)
PAH Dose in
High-Dose
Mixture (mg/kg-d)
91-20-3
Naphthalene
1
10
11.57
17
0.00034
0.034
208-96-8
Acenaphthylene
2
12
14.82
1.5
0.00003
0.003
83-32-9
Acenaphthene
2
12
14.76
10
0.0002
0.02
86-73-7
Fluorene
2
13
15.68
2.5
0.00005
0.005
85-01-8
Phenanthrene
3
14
18.37
25
0.0005
0.05
120-12-7
Anthracene
3
14
18.43
3.5
0.00007
0.007
129-00-0
Pyrene
4
16
22.45
8.5
0.00017
0.017
206-44-0
Fluoranthene
3
16
21.11
11.5
0.00023
0.023
218-01-9
Chrysene
4
18
26.13
4
0.00008
0.008
56-55-3
Benzo [a] anthracene
4
18
25.27
2
0.00004
0.004
205-99-2
Benzo |/> | fluoranthene
4
20
25.04
2.5
0.00005
0.005
207-08-9
Benzo [&]fluoranthene
4
20
28.70
2
0.00004
0.004
50-32-8
Benzo [a]pyrene
4
20
29.95
2.5
0.00005
0.005
193-39-5
Indeno( 1,2,3 -c, d) pyrene
5
22
32.62
6
0.00012
0.012
53-70-3
Dibenzo [a, h\ anthracene
5
22
32.45
0.5
0.00001
0.001
191-24-2
Benzo [g/z/']perylene
6
22
30.37
1
0.00002
0.002
Sum/mixture dose
0.002
0.2
aCrepeaux et at (2014. 2013. 2012).
C = carbon; EC = equivalent carbon; PAH = polycyclic aromatic hydrocarbon.
43
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Table B-3. Composition of PAH Aerosol Mixture Tested in Inhalation
Developmental Studies"
CASRN
Name
Rings
C
EC
Percent in
Mixture (%)
Mean
Concentration
(ng/m3)
Mean
Concentration
(mg/m3)
129-00-0
Pyrene
4
16
20.8
3.99
0.27
0.00027
218-01-9
Chrysene
4
18
26.13
5.13
0.42
0.00042
56-55-3
Benzo [a] anthracene
4
18
26.37
7.62
0.59
0.00059
205-99-2
Benzo [/>]fluoranthene
4
20
30.14
1.79
0.15
0.00015
207-08-9
Benzo [&]fluoranthene
4
20
30.14
13.02
1.12
0.00112
50-32-8
Be nzo |c/| pyre nc
4
20
31.34
4.82
0.35
0.00035
193-39-5
Indeno( 1,2,3 -c, d) pyrene
5
22
33.51
0.89
0.06
0.00006
53-70-3
Dibenzo [a, h\ anthracene
5
22
33.92
7.42
0.64
0.00064
191-24-2
B e n /o (gh /) pc ry 1 c nc
6
22
34
54.59
3.69
0.00369
Sum/mixture concentration
7.29
0.00729
aYan et al. (2014): Chuetal. (2013).
C = carbon; EC = equivalent carbon; PAH = polycyclic aromatic hydrocarbon.
44
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
APPENDIX C. POTENTIALLY RELEVANT NONCANCER EVIDENCE
In order to assess consistency in effects and potency across the components of the
fraction, experimental data from compound-specific Integrated Risk Information System (IRIS)
and Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment documents and primary
data sources (identified from literature searches) were used to create exposure-response arrays.
Data were extracted only from studies meeting existing IRIS and PPRTV program standards that
provided dose-response data enabling the identification of no-observed-adverse-effect levels
(NOAELs) and lowest-observed-adverse-effect levels (LOAELs). Target organ-specific
NOAELs and LOAELs were determined using the following methodology.
1. Whenever possible, NOAELs and LOAELs were identified from existing IRIS or
PPRTV assessments. For chemicals in which both types of assessments were
available, preference was given to IRIS (in accordance with the U.S. Environmental
Protection Agency [U.S. EPA] Office of Superfund Remediation and Technology
Innovation [OSRTI] hierarchy of human health toxicity values for Superfund
assessments). In general, these assessments explicitly identified NOAEL and LOAEL
values only for the most sensitive target of toxicity.
2. All other target-organ-specific effect levels (i.e., for targets other than the most
sensitive target identified in IRIS or PPRTV assessments, and all targets evaluated in
newly identified studies) were determined using professional judgment, taking into
consideration factors such as statistical significance (at ap-walue < 0.05), biological
significance (e.g., a greater than 10% increase in liver weight), magnitude and
direction of change, and study quality. In the case of chemicals with existing IRIS or
PPRTV assessments, NOAELs and LOAELs could often be identified from existing
study summaries.
Dose-response data were presented in exposure-response arrays by health outcome and
exposure route. From left to right, compounds exhibiting an effect typically are shown before
those not exhibiting an effect, to enable identification of patterns. For compounds that do not
exhibit an effect, NOAELs in the arrays are ordered by equivalent carbon (EC) number (low to
high from left to right), with mixtures shown last. Both administered doses and exposure
concentrations reported in the arrays and in the text reflect time-weighted average (TWA)
exposures to facilitate comparisons across studies and compounds. Consistency across the
fraction was evaluated by assessing if comparable outcomes were observed for members of the
fraction, and if these effects were observed at similar dose levels.
Unless otherwise specified, the term "significant," used throughout this appendix, refers
to statistical significance at a p-w alue of <0.05.
45
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
BODY-WEIGHT EFFECTS
Decreased body-weight gain was the critical effect in the study used to derive the chronic
reference dose (RfD) for naphthalene (U.S. EPA. 1998). No human studies examining
body-weight effects of aromatic high carbon range compounds were identified in the sources
reviewed. As shown in Table 5, animal studies that examined body-weight gain as an endpoint
are available for nearly all of the compounds and mixtures with toxicity data; exceptions are
benzo[e]pyrene [BeP], dibenzo[de/p]chrysene, and the 16- and 9-polycyclic aromatic
hydrocarbon (PAH) mixtures. In this section, body-weight decreases of at least 10% relative to
controls in adult animals are considered LOAELs, and smaller changes are not. For studies that
reported body-weight gain but did not report absolute body weights, and for studies of maternal
weight gain during gestation, statistically significant changes from control are described.
Animal Studies
Figures C-l, C-2, and C-3 show the effects of orally-administered aromatic high carbon
range compounds on body weight following subchronic exposure, body weight following
chronic exposure, and maternal body weight after gestational exposure, respectively. Data are
available for 14 compounds, including compounds with carbon (C) numbers C10-C20.
Body-weight decreases were observed after exposure to several compounds across the fraction,
including naphthalene, 1,1-biphenyl, 1,2,4-triethylbenzene, fluorene, fluoranthene, and
benzo[a]pyrene (BaP) (U.S. EPA. 2017a. b, 2013. 2012. 2011a; Tshala-Katumbav et at.. 2006;
U.S. EPA. 1998. 1990d). The lowest reported LOAELs (by compound) ranged from
0.7 mg/kg-day (BaP) to 1,500 mg/kg-day (fluoranthene) in subchronic studies (see Figure C-l).
Body-weight data for chronic exposures were limited, with significant body-weight reductions
reported for 1,1-biphenyl at a wide range of LOAELs (7-378 mg/kg-day in rats, >291 mg/kg-day
in mice) (U.S. EPA. 2013) and for BaP at a LOAEL of 21 mg/kg-day in rats (U.S. EPA. 2017a.
b). No body-weight effects were reported after chronic exposure for the remaining tested
compounds (see Figure C-2). In gestational studies, the lowest reported LOAELs, for reduced
maternal body weight or body-weight gain, were 150 mg/kg-day for naphthalene and
1,000 mg/kg-day for 1,1-biphenyl. No body-weight effects were reported after gestational
exposure for the remaining tested compounds (see Figure C-3).
46
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA 690 II-22 005F
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Compounds
47
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA 690 R-22 005F
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48
Aromatic high carbon range TPH fraction (noncancer)
-------
EPA 690 II-22 005F
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Figure C-3. Maternal Body-Weight Effects in Animals after Gestational Oral Exposure to Aromatic High Carbon Range Compounds
49
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Data for body-weight effects following oral exposure to mixtures are available from one
study (not included in the body-weight exposure-response graphs). In this study, no body-weight
effects were noted in mice exposed to a 21-PAH mixture with or without benzo[c]fluorene in the
diet for 37 weeks at doses of approximately 15-17 mg/kg-day (Wevand et al.. 2004).
Body-weight data following inhalation exposure were only available for four aromatic
high carbon range compounds with carbon numbers C10-C20: naphthalene, 1,1-biphenyl,
2-methylnaphthalene, and BaP. An exposure-response graph to compare potencies across
compounds was not included due to limited data. Decreased body weight was reported in rats
exposed to 1,1-biphenyl at 60 mg/m3, a concentration associated with 50% mortality. Mice and
rabbits exposed to similar concentrations did not show body-weight effects (or changes in
survival) (U.S. HP A. 2013). No body-weight effects were reported following inhalation exposure
to other tested compounds (U.S. HP A. 2017a. b; Dodd et al.. 2012; Swiercz et al.. 2011; AT SDR.
2005; U.S. HP A. 1998).
Summary of Potentially Relevant Evidence
No human data are available for body-weight effects. Compounds across the aromatic
high carbon range fraction have been shown to reduce body weights in rats, mice, and rabbits
following oral exposure. Compounds associated with body-weight effects following oral route
exposures include carbon numbers C10 (naphthalene) to C20 (BaP), with naphthalene having the
lowest LOAEL following gestational exposure, BaP having the lowest LOAEL following
subchronic exposure, and 1,1-biphenyl (CI2) having the lowest LOAEL following chronic
exposure. Compounds not associated with body-weight effects also spanned the high carbon
range, including carbon numbers Cll (1,3,5-triethylbenzene) to C20 (benzo[A]fluoranthene).
Taken together, these data suggest that oral exposure to many aromatic high carbon range
fraction compounds can cause decreases in body weight, but no apparent pattern of sensitivity is
observed based on number of carbons or ring structure. Available inhalation data do not report
body-weight effects following inhalation exposure to naphthalene, 1,1-biphenyl,
2-methylnaphthalene, or BaP at nonlethal concentrations.
HEMATOLOGICAL EFFECTS
Decreased red blood cells (RBCs), hemoglobin (Hb), and packed cell volume (PCV)
were the critical effects in the study used to derive the chronic reference dose (RfD) for fluorene
(U.S. HP A. 1997. 1990d). Hematological alterations (decreased PCV) were also considered
cocritical effects in the study used to derive the chronic RfD for fluoranthene (U.S. HP A. 1990c).
Human data pertaining to hematological effects of aromatic high carbon range fraction members
are limited primarily to case reports of naphthalene exposure. As shown in Table 5, data on
hematological effects in animals were located for 10 members of the fraction.
Human Studies
Hemolytic anemia has been reported in adults, children, and neonates exposed to
naphthalene by ingestion, inhalation, and dermal contact with clothes and bedding impregnated
with naphthalene from moth balls (ATSDR. 2005; U.S. HP A. 1998). It has also been reported in
newborns exposed transplacental^ during pregnancy. Blood samples from patients with anemia
exhibited reduced Hb, hematocrit (Hct), and RBC values and increased reticulocytes, Heinz
bodies, serum bilirubin, and fragmented RBCs. Hemolytic anemia was accompanied by jaundice,
cyanosis, and kernicterus with neurological signs in severe cases (U.S. HP A. 1998). Individuals
with a deficiency in the enzyme, glucose-6-phosphate dehydrogenase (G6PDH), are particularly
50
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
susceptible to naphthalene-induced hemolytic anemia (ATSDR. 2005; U.S. EPA. 1998). No data
are available regarding potential hematological effects in humans for other members of the
fraction.
Animal Studies
Hemolytic anemia was reported in one dog given a single oral dose of 1,525 mg/kg
naphthalene in food and in another given 263 mg/kg-day naphthalene in food for 7 days
(ATSDR. 2005). These data provide limited evidence of hemolytic anemia in dogs following
acute or short-term exposure to naphthalene at high doses. Studies in rats and mice did not find
evidence of hemolytic anemia following acute naphthalene exposure (ATSDR. 2005).
Figure C-4 shows the effects of orally-administered naphthalene and other aromatic high carbon
range compounds on hematological parameters in subchronic and chronic animal studies (studies
available only in rodents). Data are available for 10 compounds, including compounds with
carbon numbers C10-C20. Hematological alterations were seen with several compounds across
the fraction following subchronic oral exposure, including decreases in RBC, Hct/PCV, and/or
Hb (BaP, fluorene, fluoranthene) and inconsistent alterations in white blood cell (WBC)
populations (naphthalene, fluoranthene, acenaphthene) (U.S. EPA. 2017a. b, 2012. 1998. 1990a.
c, d). The lowest LOAELs (by compound) for RBC effects ranged from 7.1 to 250 mg/kg-day,
and the lowest LOAELs for WBC effects ranged from 143 to 1,500 mg/kg-day. No
hematological alterations were observed following subchronic oral exposure to pyrene or
anthracene (NOAELs of 250 and 1,000 mg/kg-day, respectively) (U.S. EPA. 1990b. e). Chronic
oral data are limited to three compounds (1-methylnaphthalene, 2-methylnaphthalene,
1,1-bi phenyl), none of which showed hematological effects (see Figure C-4) (U.S. EPA. 2013;
ATSDR. 2005).
51
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Figure C-4. Hematological Effects in Animals after Oral Exposure to Aromatic High Carbon Range Compounds
52
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Data pertaining to the effects of inhalation exposure to aromatic high carbon range
compounds on hematological parameters are limited to naphthalene and 2-methylnaphthalene.
An exposure-response graph to compare potencies across compounds was not included due to
the limited data. In contrast to effects seen after oral exposure to fraction components,
stimulation of the hematopoietic system was observed following inhalation exposure to
2-methylnaphthalene at concentrations ranging from 0.4 to 8.9 mg/m3 for 4 weeks (Swiercz ct
al.. 2011). Observed effects included exposure-related trends for increased RBC counts, Hct, and
Hb in male rats, as well as increased reticulocyte abundance in male and female rats. No
exposure-related changes in hematological parameters were observed in mice following exposure
to naphthalene at 28 mg/m3 for 2 weeks (ATSDR. 2005; U.S. EPA. 1998).
Summary of Potentially Relevant Evidence
Available human data indicate that acute exposures to high levels of naphthalene via oral,
inhalation, or dermal routes may cause hemolytic anemia, particularly in individuals with
G6PDH enzyme deficiency. Available animal data indicate that dogs, but not rodents, may also
be susceptible to hemolytic anemia following acute oral exposure to naphthalene. Data in
laboratory animals indicate that anemia (decreased RBC count, Hct/PCV, and/or Hb) may occur
following subchronic oral exposure to compounds from across the high fraction, including BaP,
fluorene, and fluoranthene (C13-C20). Data regarding potential alterations in WBC parameters
following oral exposure are inconsistent between and within studied fraction members
(see Figure C-4). Too few studies are available to evaluate effects and potencies in animals after
inhalation exposure. Taken together, the data indicate that oral exposure to some aromatic high
carbon range fraction compounds may result in anemia, and effects may be severe in humans
following acute exposure to high levels of naphthalene via any route.
NEUROLOGICAL EFFECTS
Clinical signs of toxicity in pregnant dams, including central nervous system (CNS)
depression, are the critical effects for the intermediate minimal risk level (MRL) for naphthalene
(ATSDR. 2005). Neurodevelopmental effects are the critical effect for the chronic RfD for BaP;
however, these effects are discussed below in the developmental section. Neurological effects in
humans have been studied in coke oven workers exposed to complex PAH mixtures and workers
exposed to 1,1-biphenyl during production of 1,1-biphenyl-impregnated fruit wrapping paper. As
shown in Table 5, data on neurological effects in animals were identified for 12 members of the
fraction; however, the studies varied widely with respect to the nature of the neurological
endpoints evaluated.
Human Studies
Neurobehavioral examinations of coke oven workers exposed to complex PAH mixtures
demonstrated impairments in short-term memory and attention and deficits in sensorimotor
coordination, and some effects were directly correlated with measured air levels of BaP
(U.S. EPA. 2017a. b). Occupational workers exposed to 1,1-biphenyl in Finland had abnormal
electroencephalography (EEG), nerve conduction velocity, and electromyographic (EMG) test
results. A study of similarly exposed workers in Sweden did not demonstrate neurological test
abnormalities; however, an increase in the relative risk of Parkinson's disease was reported
(U.S. EPA. 2013).
53
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Animal Studies
Figure C-5 shows the effects of subchronic oral exposure to aromatic high carbon range
compounds on neurological parameters. Subchronic data are available for eight compounds,
including compounds with carbon numbers C10-C20. Neurobehavioral alterations and/or
clinical signs of neurotoxicity were observed with several compounds across the fraction,
including BaP (impaired learning and memory, decreased activity), naphthalene (clinical signs,
including CNS depression), fluorene (impaired learning, clinical signs), and
1,2,4-triethylbenzene (impaired gait, muscular weakness) (U.S. EPA. 2017a. b; Peiffer et at..
2016: Tshala-Katumbav et at.. 2006; U.S. EPA. 1998. 1990d). The lowest LOAELs (by
compound) ranged from 2 to 114 mg/kg-day. Peripheral nerve damage was associated with
observed impaired gait and muscular weakness in mice following exposure to
1,2,4-triethylbenzene at >129 mg/kg-day (Tshala-Katumbav et at.. 2006). Impaired sensory and
motor nerve conduction were also observed in rats following subchronic oral exposure to
1.2.4-triethylbenzene at >114 mg/kg-day (Gagnaire et at.. 1993). However, no changes in
peripheral nerve conduction or histology were observed in rats or mice similarly exposed to
1.3.5-triethylbenzene at doses up to 257 or 386 mg/kg-day, respectively (Tshala-Katumbav et at..
2006; Gagnaire et at.. 1993). Histopathological findings in the peripheral nervous system (PNS)
were not observed following subchronic oral exposure to fluoranthene or acenaphthene at doses
of 500 and 700 mg/kg-day, respectively (U.S. EPA. 1990a. c). No changes in CNS histology
were observed in animals following subchronic oral exposure to any tested compound
(see Figure C-5). Decreased brain weight was observed following subchronic oral exposure to
naphthalene at 133 mg/kg-day (U.S. EPA. 1998). but not following subchronic exposure to
acenaphthene, anthracene, or fluorene (Peiffer et at.. 2016; U.S. EPA. 1990a. b).
54
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No adverse neurological effects were observed in a limited number of chronic oral
studies; therefore, chronic data are not included in Figure C-5. No changes in brain weight or
histology were observed following chronic exposure to 1,1-biphenyl at doses up to
1,420 mg/kg-day, 1-methylnaphthalene at doses up to 144 mg/kg-day, or 2-methylnaphthalene at
doses up to 114 mg/kg-day (U.S. EPA. 2013. 2011a. 2008. 2007a. 2003). No changes in PNS
histology were observed following chronic exposure to 1,1-biphenyl at doses up to
1,420 mg/kg-day (U.S. EPA. 2013. 2011a). Neurological function was not evaluated in available
chronic oral studies.
No data pertaining to neurological function were located following inhalation exposure to
aromatic high carbon range compounds. No histopathological changes were observed in the
brain following subchronic exposure to 2-methylnaphthalene at concentrations up to 8.9 mg/m3
or chronic exposure to naphthalene at concentrations up to 56 mg/m3 (Swiercz et at.. 2011;
ATSDR. 2005). An exposure-response graph to compare potencies across compounds was not
included due to limited data.
Summary of Potentially Relevant Evidence
Human evidence suggests that occupational exposure to PAH mixtures containing
members of the aromatic high carbon range fraction, namely BaP, may alter neurobehavior, and
occupational exposure to 1,1-biphenyl may damage nerve function. Available animal data show
that oral exposure to compounds from across the aromatic high carbon range fraction (C10-C20)
can alter neurobehavior in animals, including BaP, naphthalene, fluorene, and
1,2,4-triethylbenzene. Other effects reported in animal studies of one or more compounds
include clinical signs of neurotoxicity, peripheral nerve damage, and decreased brain weight.
Available data are too limited to assess potential neurological effects in animals following
inhalation exposure. Considering human and animal evidence together, the available data
indicate that some members of the aromatic high carbon range fraction induce neurological
effects. BaP appears to be the most potent neurotoxicant, as the LOAEL for BaP is 1-2 orders of
magnitude lower than the lowest LOAELs observed for other compounds see Figure C-5).
However, there are a number of compounds within the aromatic high carbon range fraction that
have not been evaluated for sensitive measures of neurological function, particularly
1,1-biphenyl. Additionally, no NOAEL values for neurofunctional endpoints were identified for
BaP (however, there are BaP studies that did not report neurological effects at higher doses) or
1,2,4-triethylbenzene.
HEPATIC EFFECTS
Hepatic effects are the critical endpoints for the subchronic p-RfD and chronic RfD for
acenaphthene (U.S. EPA. 2011b) and the intermediate MRL for fluorene (ATSDR. 1995). and
cocritical effects for the chronic RfD for fluoranthene (U.S. EPA. 1990c). and the subchronic
provisional reference concentration (p-RfC) and chronic p-RfC for 1,1-biphenyl (U.S. EPA.
2011a). Critical hepatic effects of exposure included increased liver weight and hepatocellular
hypertrophy for acenaphthene, increased liver weight for fluorene, and liver congestion and
edema for 1,1-biphenyl. Human data pertaining to the hepatotoxicity of aromatic high carbon
range fraction members are limited to a single case study of hepatotoxicity following
occupational exposure to 1,1-biphenyl. As shown in Table 5, data on hepatic effects in animals
were located for 11 members of the fraction. In general, the hepatic endpoints evaluated in the
studies were liver weight and histology, with most studies also measuring clinical chemistry.
56
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Human Studies
A case report of a female worker exposed to 1,1-biphenyl indicated the presence of
chronic hepatitis. The diagnosis was suggested by the presence of hepatomegaly and altered
clinical chemistry findings and was confirmed by liver biopsy. Neutrophilic leukocytosis was
also reported, suggesting an immunological or inflammatory response to liver injury. Serum
enzymes returned to normal following cessation of exposure to 1,1-biphenyl (U.S. EPA. 2013).
Animal Studies
Figures C-6 and C-7 show the effects of orally-administered aromatic high carbon range
compounds on liver weight and histology, respectively. Data are available for 11 compounds,
including compounds with carbon numbers C10-C204. Hepatic alterations were observed with
several compounds across the fraction, including naphthalene, 1,1-biphenyl, acenaphthene,
fluorene, fluoranthene, and BaP (U.S. EPA. 2017a. b; Peiffer et at.. 2016; U.S. EPA. 2013. 2012.
2011b. 1998. 1990c. d). The most sensitive and commonly observed effect following sub chronic
exposure was increased liver weight, with the lowest LOAELs (by compound) ranging from
7.1 to 2,989 mg/kg-day for all compounds listed above except naphthalene, which caused
decreased liver weight at 133 mg/kg-day (see Figure C-6). No liver-weight effects were observed
following subchronic exposure to anthracene at doses up to 1,000 mg/kg-day (U.S. EPA. 1990b).
Liver-weight data for chronic oral exposure are limited to 1,1-biphenyl, 1-methylnaphthalene,
and 2-methylnaphthalene. Increased liver weight was observed following chronic exposure to
1,1-biphenyl at 732 mg/kg-day (U.S. EPA. 2013). but not following chronic oral exposure to
1 - or 2-methylnapthanene at doses up to 1 14-144 mg/kg-day (U.S. EPA. 2008. 2007a).
4Based on the U.S. EPA PPRTV for BeP, no short-term, subchronic, chronic, or reproductive and developmental
toxicity studies of BeP in humans or animals exposed by oral or inhalation routes were adequate for the derivation of
a toxicity value. The toxicity values for BeP are based on a read-across approach that used BaP as a surrogate.
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58
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Figure C-7. Liver Histology Effects in Animals after Oral Exposure to Aromatic High Carbon Range Compounds
59
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Histopathological lesions were reported following oral exposure to BaP, fluoranthene,
1,1-biphenyl, and acenaphthene, but findings were generally proliferative effects associated with
enzyme induction and were often inconsistent between studies for the same compound. Oval cell
hyperplasia was reported in rats following exposure to BaP for 7 weeks at 64 mg/kg-day, but no effects
were reported following 13-week exposure to BaP doses up to 100 mg/kg-day (U.S. HP A. 2017a. b).
Following chronic exposure to BaP, clear cell foci were observed at >2 mg/kg-day (U.S. HP A. 2017a.
b). For 1,1-biphenyl, degenerative changes and hepatic hyperplasia were reported in rats at doses
>250 mg/kg-day for 8 or 56 weeks and hepatocellular hypertrophy and peroxisomal proliferation were
observed in mice exposed at 2,989 mg/kg-day for 13 weeks, but no treatment-related liver lesions were
observed after exposure for 104 weeks at doses up to 732 and 1,420 mg/kg-day in rats and mice,
respectively (U.S. HP A. 2013). Hepatocellular hypertrophy was also reported following exposure to
acenaphthene at >350 mg/kg-day for 13 weeks (U.S. HP A. 2011b). For fluoranthene, centri lobular
pigmentation was reported in mice exposed at >250 mg/kg-day for 13 weeks, but not in similarly
exposed rats at doses up to 1,500 mg/kg-day (U.S. HP A. 2012. 1990c). No histopathological hepatic
lesions were noted following exposure to naphthalene, 1-methylnaphthalene, 2-methylnaphthalene,
pyrene, fluorene, or anthracene (see Figure C-7).
Increased plasma aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) were
observed in mice (but not rats) exposed to 1,1-biphenyl or fluoranthene at oral doses >414 mg/kg-day
(U.S. HP A. 2013. 1990c). and increased total cholesterol was observed in mice exposed to acenaphthene
at doses >350 mg/kg-day (U.S. HP A. 2011b). No significant alterations in hepatic serum chemistry were
observed following subchronic exposure to BaP, naphthalene, pyrene, fluorene, or anthracene, or
chronic exposure to 1 -methylnaphthalene or 2-methylnaphthalene (U.S. HP A. 2017a. b, 2007a. b, 2003.
1998. 1990b. d, e). An exposure-response graph to compare potencies across compounds was not
included due to lack of exposure-related effects in the majority of tested compounds.
Figure C-8 shows the effects of inhalation exposure to aromatic high carbon range compounds
on hepatic endpoints. Data are available only for naphthalene, 2-methylnaphthalene, and 1,1-biphenyl,
which represent compounds with carbon numbers C10-C12. Hepatic alterations were reported following
subchronic exposure to 2-methylnaphthalene at >1.8 mg/m3 (decreased liver weight, altered serum
chemistry, and bile duct hyperplasia) (Swiercz et at.. 2011) and 1,1-biphenyl at >32.9 mg/m3, which was
the lowest concentration tested (liver congestion and edema) (U.S. HP A. 2013). No histopathological
hepatic findings were reported following chronic exposure to naphthalene at concentrations up to 28 and
56 mg/m3 in mice and rats, respectively (ATSDR. 2005; U.S. HP A. 1998).
60
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fraction (noncancer)
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61
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Summary of Potentially Relevant Evidence
Human data are inadequate to assess potential hepatotoxic effects of aromatic high
carbon range compounds. In animals, hepatic effects were primarily elevated liver weights
following oral exposure to compounds from across the aromatic high carbon range fraction
(CI 1-C20), with inconsistent evidence of histopathological damage for some compounds at
higher doses (generally proliferative effects). A few compounds showed altered serum chemistry
values at high oral doses. In aggregate, the data suggest that many aromatic high carbon range
fraction compounds can produce increases in rodent liver weight following oral exposure, which
is sometimes accompanied by serum chemistry and/or histological changes. No apparent pattern
of sensitivity is observed based on number of carbons or ring structure. Available data are too
limited to assess potential hepatic effects in animals following inhalation exposure.
RENAL/BLADDER EFFECTS
Renal effects are the critical endpoints for the subchronic p-RfDs for pyrene and
fluoranthene (U.S. EPA. 2012. 2007b) and the chronic RfDs for 1,1-biphenyl and pyrene (U.S.
EPA. 2013. 1990e). and cocritical effects for the chronic RfD for fluoranthene (U.S. EPA.
1990c) and the subchronic p-RfC and chronic RfC for 1,1-biphenyl (U.S. EPA. 2011a). Critical
renal effects of exposure included renal tubular nephropathy (pyrene, fluoranthene), renal
mineralization (1,1-biphenyl), and decreased kidney weights (pyrene). No human studies
examining renal or bladder effects of aromatic high carbon range compounds were identified in
the sources reviewed. As shown in Table 5, data on renal and/or bladder effects in animals were
located for 10 members of the fraction. In general, the renal endpoints evaluated in the studies
were kidney weight and histology, with some studies also conducting urine and serum chemistry
analyses. A few studies also evaluated histology of the bladder.
Animal Studies
Figures C-9 and C-10 show the effects of orally-administered aromatic high carbon range
compounds on renal and bladder endpoints following subchronic or chronic exposure,
respectively. Data are available for 10 compounds, including compounds with carbon numbers
C10-C20. Renal alterations were observed with several compounds across the fraction,
including BaP, pyrene, fluorene, fluoranthene, and 1,1-biphenyl (U.S. EPA. 2017a. b, 2013.
2011a. b, 1990c. d, e). The most sensitive finding following subchronic exposure was altered
kidney weight, with decreased kidney weight reported at BaP doses >21 mg/kg-day or pyrene
doses >125 mg/kg-day and increased kidney weight reported at fluorene doses >250 mg/kg-day.
Nephropathy was observed following subchronic exposure to pyrene at >125 mg/kg-day or
fluoranthene at >250 mg/kg-day.
62
Aromatic high carbon range
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EPA/690/R-22/005F
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Figure C-10. Renal Effects in Animals after Chronic Oral Exposure to Aromatic High Carbon Range Compounds
64
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Additional renal and bladder effects were only observed following oral exposure to
1,1-biphenyl, including renal tubule degeneration and hyperplasia, focal calcification of the renal
medulla, renal mineralization, tubule dilation and inflammation, hyperplastic and metaplastic
lesions of the renal pelvis, desquamation of renal pelvis, papillary necrosis, urinary microcalculi,
and bladder lesions (hyperplasia, papillomatosis, epithelial proliferation) at subchronic or chronic
doses >250 mg/kg-day. Additionally, transitional cell hyperplasia in renal pelvis, pyelonephritis,
kidney stones, and hemosiderin deposits were reported following chronic exposure to
1,1-biphenyl at LOAELs ranging from 128 to 732 mg/kg-day. Alterations in blood urea nitrogen
(BUN) were sporadically reported following exposure to naphthalene, fluoranthene, and
fluorene, and were not considered a clear indication of renal effects in the absence of additional
renal effects (U.S. EPA. 2012. 1998. 1990d). No clearly adverse renal effects were observed
following subchronic exposure to naphthalene, acenaphthene, or anthracene (see Figure C-9)
(U.S. EPA. 1998. 1990a. b) or chronic oral exposure to 1 - or 2-methylnapthalene
(see Figure C-10) (U.S. EPA. 2008. 2007a. 2003).
Refer to Figure C-8 for the reported effects on renal endpoints following inhalation
exposures to individual aromatic high carbon range compounds. Data are available only for
naphthalene, 2-methylnaphthalene, and 1,1-biphenyl, which represent compounds with carbon
numbers C10-C12. Decreased kidney weight was reported in rats exposed to
2-methylnaphthalene at >1.8 mg/m3 for 4 weeks (Swiercz et at.. 2011) and kidney congestion
and edema were observed in mice exposed to 1,1-biphenyl at >32.9 mg/m3 for 13 weeks
(U.S. EPA. 2013). No exposure-related changes in renal histology were observed in rats or mice
exposed to naphthalene at 56 or 28 mg/m3, respectively, for 2 years (ATSDR. 2005; U.S. EPA.
1998).
Summary of Potentially Relevant Evidence
No human data are available. In animals, renal effects appear to be limited to organ
weight changes and exacerbation of age-related nephropathy after exposure to high oral doses for
compounds from across the aromatic high carbon range fraction (CI 1-C20), with the exception
of 1,1-biphenyl (C12). Oral exposure to high doses of 1,1-biphenyl is associated with
histopathological changes in both the kidney and bladder. Available data indicate that renal
damage can also occur following inhalation exposure to 1,1-biphenyl. Data for other compounds
are too limited to assess potential renal effects in animals following inhalation exposure. Taken
together, the kidney and bladder appear to be a target of 1,1-biphenyl toxicity. Other high
aromatic carbon range compounds may alter kidney weight and increase age-related nephropathy
following oral exposure.
RESPIRATORY
Pulmonary alveolar proteinosis is the critical endpoint for the subchronic p-RfD and
chronic RfD for 2-methylnaphthalene, as well as the screening chronic p-RfD for
1-methylnaphthene (U.S. EPA. 2008. 2007a. 2003) (see Tables 6 and 7). Nasal lesions are the
critical endpoint for the chronic RfC (see Table 8) and inhalation MRL5 for naphthalene
5The ATSDR chronic inhalation MRL for naphthalene is based on the 105-week study in Fischer 344 rats (N I P.
2000). The study reported inflammation of the nose (including, olfactory epithelium, atypical hyperplasia, atrophy,
degeneration); nasal respiratory epithelium (including hyperplasia, squamous metaplasia, and degeneration); and
Bowman's glands hyperplasia observed in the 10 PPM dose group. The chronic MRL of 0.0007 ppm was based on a
human equivalent concentration LOAEL of 0.2 ppm, which was divided by an uncertainty factor of 300 (10 for
65
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
(ATSDR. 2005; U.S. EPA. 1998). No human studies examining respiratory effects of aromatic
high carbon range compounds were identified in the sources reviewed. As shown in Table 5, data
on respiratory effects in animals were located for 10 members of the fraction. In general, the
respiratory endpoints evaluated in the studies were lung weight and histology, with a few studies
evaluating the entire respiratory tract (including nasal tissue).
Animal Studies
Respiratory data following oral exposure are available for 10 compounds, including
compounds with carbon numbers C10-C20. Respiratory findings were limited to pulmonary
alveolar proteinosis alterations in mice following oral exposure to 1- or 2-methylnaphthalene at
doses >50 or 72 mg/kg-day, respectively, for 81 weeks (no NOAEL was identified) (U.S. EPA.
2008. 2007a. 2003). However, pulmonary findings following oral exposure to 1 - or
2-methylnapthalene were likely confounded by unquantified volatilization of these compounds
from the feedstock (U.S. EPA. 2008. 2007a. 2003). No effect was observed on lung weight
and/or histology following oral exposure to BaP, naphthalene, pyrene, fluoranthene, fluorene,
1,1-biphenyl, acenaphthene, or anthracene (U.S. EPA. 2017a. b, 2013. 201 1 a. 2007b. 1998.
1990a. b, c, d, e). Additionally, no histopathological changes were found in the upper respiratory
tract following exposure to naphthalene or acenaphthene (U.S. EPA. 1998. 1990a). An
exposure-response graph to compare potencies across compounds was not included due to lack
of exposure-related effects in the majority of tested compounds.
Figure C-l 1 shows the effects of inhalation exposure to aromatic high carbon range
compounds on respiratory endpoints. Data are available for naphthalene, 2-methylnaphthalene,
and 1,1-biphenyl only, representing compounds with carbon numbers C10-C12. Respiratory
effects were reported for all three compounds (U.S. EPA. 2013; Dodd et at.. 2012; Swiercz et at..
2011; U.S. EPA. 201 lb; ATSDR. 2005; U.S. EPA. 1998). The predominant respiratory effect
associated with naphthalene exposure was nasal lesions following subchronic exposure to
>0.9 mg/m3 in rats or chronic exposure to >9.3 mg/m3 (lowest concentration tested) in rats and
mice. Lung inflammation was also observed in mice after chronic exposure to >9.3 mg/m3. Less
severe nasal effects, characterized as nasal or upper respiratory irritation, were observed in rats
and mice following subchronic exposure to 1,1-biphenyl at >1 mg/m3. Tracheal hyperplasia and
inflammation, as well as lung congestion and edema, were observed in mice after subchronic
exposure to higher concentrations of 1,1-biphenyl (>32.9 mg/m3). However, no evidence of
respiratory tract irritation was observed in rabbits after subchronic exposure to concentrations up
to 60 mg/m3. Lung lesions (increased goblet cells, interstitial infiltration, hyperplasia of
peribronchial tissue) were the primary respiratory effect in rats exposed to 2-methylnapthalene at
>1.8 mg/m3 for 4 weeks (Swiercz et at.. 2011).
using the LOAEL, 3 for extrapolating from rodents to humans using an interspecies dosimetric adjustment, and
10 for human interindividual variability).
Aromatic high carbon range
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Figure C-11. Respiratory Effects in Animals after Inhalation Exposure to Aromatic High Carbon Range Compounds
67
Aromatic high carbon range TPIi fraction (noncancer)
-------
EPA/690/R-22/005F
Summary of Potentially Relevant Evidence
There were no relevant human data identified. Available animal data indicate that the
respiratory tract is only a target of toxicity following oral exposure for methylated naphthalene
compounds, 1- and 2-methylnaphthalene. For these two compounds, pulmonary alveolar
proteinosis was observed at doses >72 or 50 mg/kg-day, respectively. Eight other compounds
from across the fraction (C10-C20) did not show respiratory tract damage following oral
exposure.
Inhalation data are limited but indicate that the lung is also a target of
2-methylnaphthalene following subchronic inhalation exposure; there are no data for
1-methylnapthalene. Subchronic inhalation studies also indicate that exposure to concentrations
of naphthalene >0.9 mg/m3 results in damage to the nasal epithelium; concentrations of
1,1-biphenyl reportedly can result in irritation and irritation of the upper respiratory tract as well
as lung congestion and edema. Taken together, data indicate that the respiratory tract
(particularly nasal tissue) is a target of at least some aromatic high carbon range compounds
following inhalation exposure; however, inhalation data are limited to compounds with carbon
numbers ranging from CIO to C12 only. Other than the methylated naphthalene compounds, the
respiratory system does not appear to be a target of oral toxicity for aromatic high carbon range
compounds.
GASTROINTESTINAL EFFECTS
No reference values for aromatic high carbon range compounds are based on
gastrointestinal (GI) effects; however, the point of departure (POD) of 0.663 mg/kg-day based on
GI effects reported for benzo[c]fluorene (which does not have any reference values) is lower
than the currently available subchronic PODs for all fraction members except BaP (see Table 6).
Available human studies are limited to reports of side effects in patients taking laxatives
containing anthracene (U.S. EPA. 2009a). As shown in Table 5, data on GI effects in animals
were located for 10 members of the fraction and a 21-PAH mixture. In general, the GI endpoints
evaluated in the studies were GI histology, with a few studies evaluating stomach weight.
Human Studies
Melanosis or hyperpigmentation of the lining of the colon and rectum was reported in
patients taking anthracene-based laxatives for treatment of constipation (U.S. HP A. 2009a).
Animal Studies
Figure C-12 shows the effects of orally-administered aromatic high carbon range
compounds on GI endpoints. Data are available for nine compounds, including compounds with
carbon numbers C10-C20. GI effects, specifically forestomach lesions, were observed following
oral exposure to benzo[c]fluorene, BaP, and 1,1-bi phenyl (U.S. HP A. 2017a. b, 2013; Wevand et
at.. 2004). Squamous hyperplasia was observed after subchronic exposure to benzo[c ]fluorene at
dietary doses >0.663 mg/kg-day (Wevand et at.. 2004). Basal cell hyperplasia was observed after
exposure to BaP at subchronic gavage doses >21 mg/kg-day and chronic gavage doses
>2 mg/kg-day, but not after subchronic dietary doses up to 100 mg/kg-day (U.S. HP A. 2017a. b).
For 1,1-biphenyl, epithelial hyperkeratinization was observed in rats after dietary exposure to
doses >250 mg/kg-day for 8 or 56 weeks in one study, but not after chronic dietary exposure to
doses up to 732 mg/kg-day in rats or 1,420 mg/kg-day in mice in three additional studies (U.S.
HP A. 2013). No effects on GI histology were observed following subchronic gavage exposure to
naphthalene, pyrene, fluoranthene, fluorene, acenaphthene, or anthracene (see Figure C-12).
68 Aromatic high carbon range
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Data for GI effects following oral exposure to mixtures are available from one study (not
included in Figure C-12). In this study, squamous hyperplasia of the forestomach was noted in
mice exposed to a 21-PAH mixture with or without benzo[c]fluorene in the diet for 37 weeks at
doses of approximately 15-17 mg/kg-day (Wevand et al.. 2004).
The potential effects of inhalation exposure to aromatic high carbon range compounds on
the GI system were only evaluated for naphthalene and 2-methylnaphthalene (Swiercz et al..
2011; ATSDR. 2005). No changes were observed in GI histology following sub chronic exposure
to 2-methylnapthalene at concentrations up to 8.9 mg/m2 or chronic exposure to naphthalene at
concentrations up to 56 mg/m3. An exposure-response graph to compare potencies across
compounds was not included due to limited data.
Summary of Potentially Relevant Evidence
Available human data are insufficient to assess potential GI effects following exposure to
aromatic high carbon range compounds. Animal data report damage to the forestomach
following exposure to three compounds from across the aromatic high carbon range fraction
(C12-C20). Forestomach lesions were observed following subchronic exposure to
benzo[c]fluorene at dietary doses >0.663 mg/kg-day (lowest dose tested, only available study),
subchronic BaP at gavage doses >21 mg/kg-day, but not dietary doses up to 100 mg/kg-day,
chronic BaP at gavage doses >2 mg/kg-day (no chronic dietary studies identified for BaP), and
subchronic or chronic exposure to 1,1-biphenyl at doses >250 mg/kg-day in one of four available
dietary studies (no gavage studies identified for 1,1-biphenyl). There was no evidence for GI
lesions from six other compounds following subchronic exposure via gavage (C10-C16). Taken
together, these data indicate that some aromatic high carbon range fraction compounds may
cause hyperplastic lesions in the GI tract following oral exposure. Data are too limited to assess
potential GI effects in animals following inhalation exposure.
REPRODUCTIVE EFFECTS
No existing health reference values for aromatic high carbon range compounds are based
on reproductive effects; however, available data from workers occupationally exposed to PAH
mixtures indicates that the male and female reproductive systems may be a target of some
members of this fraction. Human studies with data on PAH mixtures, often with a focus on BaP,
include both occupational and smoking exposure studies. As shown in Table 5, data on
reproductive endpoints in animals were located for 10 members of the fraction. However, data on
reproductive function were only located for two members; the remaining studies evaluated
reproductive organ weight and/or histology but did not assess reproductive function or capacity.
Human Studies
Exposure to PAH mixtures has been associated with effects on male and female
reproductive function (U.S. HP A. 2017a. b). Decreased sperm quality has been demonstrated in
cigarette smokers, coke oven workers, and other men occupationally exposed to PAHs (U.S.
EPA. 2017a. b). A study in coke oven workers reported oligospermia and an increase in the
proportion of morphologically abnormal sperm (U.S. EPA. 2017a. b). Associations were also
reported between exposure to PAHs (occupational exposure and smoking), PAH-adduct
formation, and increased deoxyribonucleic acid (DNA) fragmentation in sperm (U.S. EPA.
2017a. b). A relationship was observed between the level of benzo[a]pyrene diol epoxide
(BPDE)-DNA adducts in sperm and altered motility and morphology in patients at fertility
clinics (U.S. EPA. 2017a. b). Higher levels of PAH-DNA adducts in sperm and higher urinary
70
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
levels of PAHs were also associated with infertility (U.S. EPA. 2017a. b). The fertilizing
capacity of sperm and the implantation rates of embryos were reduced in cigarette smokers (U.S.
EPA. 2017a. b).
Reproductive effects related to ovulation, pregnancy, and spontaneous abortion have been
reported in women who smoked cigarettes (U.S. EPA. 2017a. b). In utero exposure to maternal
tobacco smoke may also affect the future fertility of female offspring (U.S. EPA. 2017a. b).
Associations were reported between follicular fluid BaP levels and reduced conception and
maternal blood BaP-DNA adduct levels and risk of miscarriage (U.S. EPA. 2017a. b). The level
of BaP in placental tissue was significantly increased in women that experienced preterm birth
(<36 weeks, n = 29) compared to women with full-term delivery (>36 weeks, n = 55) (Agarwat
et al.. 2017).
Animal Studies
Oral and inhalation data on reproductive function are only available for a limited number
of aromatic high carbon range fraction compounds. Therefore, exposure-response graphs were
not generated to compare potencies across compounds for reproductive data.
Reproductive function studies following oral exposure were only available for two
compounds: 1,1-biphenyl and BaP (U.S. EPA. 2017a. b, 2013. 2011a). Decreased fertility and
litter size were observed in Fo and Fi parental rats exposed to 1,1-biphenyl in a multigenerational
study at dietary doses of 887-1,006 mg/kg-day, but not <101 mg/kg-day. In one-generation
studies in rats, no effects on reproductive performance were reported at doses up to
525 mg/kg-day; however, endpoints evaluated were very limited and considered insufficient for
a full evaluation of reproductive performance. For BaP, male mice exposed to >1 mg/kg-day had
low sperm counts, and sperm had decreased ability to penetrate ova in vitro; however,
reproductive performance in vivo was not evaluated. Other reproductive studies reported sperm
effects in male rats and mice following exposure to BaP at doses >0.01 mg/kg-day. Additional
effects reported at >5 mg/kg-day include decreased testosterone levels, decreased testicular
testosterone production, decreased sperm motility, increased percentage of abnormal sperm, and
histopathological changes in the testes. In females, adverse effects were noted in rats (decreased
ovary weight, decreased estradiol, decreased primordial follicles, and prolonged estrous cycle)
and mice (increased cervical epithelial inflammation and hyperplasia) at doses >2.5 and
0.7 mg/kg-day, respectively.
Ten compounds from across the fraction (C10-C20) have data on reproductive organ
weight and/or histology from subchronic or chronic assays that did not assess reproductive
function or specialized reproductive endpoints (e.g., sperm parameters). One study reported
significant decreases in ovary weight in mice exposed to acenaphthene at doses >175 mg/kg-day
for 13 weeks (U.S. EPA. 201 lb. 1990a). No exposure-related changes in reproductive organ
weight were observed following oral exposure to naphthalene, fluoranthene, anthracene,
1,1-biphenyl, or BaP (U.S. EPA. 2013. 201 la: AT SDR. 2005: U.S. EPA. 1998. 1990b. c). No
effects on reproductive organ histology were reported following subchronic or chronic exposure
to 1-methylnaphthalene, 2-methylnaphthalene, pyrene, naphthalene, 1,1-biphenyl, fluorene,
fluoranthene, acenaphthene, anthracene, or BaP (U.S. EPA. 2013. 2011 a. b, 2008. 2007a. b;
ATS DR. 2005: U.S. EPA. 2003. 1998. 1990a. b, c, d, e).
71
Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
Inhalation data on the potential for altered reproductive function following exposure to
aromatic high carbon range fraction compounds are limited to BaP (U.S. EPA. 2017a. b).
Decreased ovulation rate was observed in female rats exposed to concentrations >0.008 mg/m3
for 2 weeks prior to mating (lowest concentration tested), with decreased ovarian weights
observed at >0.013 mg/m3 and decreased pups/litter and embryo/fetal survival at 0.02 mg/m3. In
another study, various effects were noted in male rats exposed to 0.013 mg/m3 (only
concentration tested), including altered serum hormone levels (increased luteinizing hormone,
decreased testosterone), decreased seminiferous tubule diameter and length, and sperm
alterations (decreased motility and count, and increased percent of abnormal sperm).
Available inhalation data for other compounds in the fraction are limited to naphthalene
and 2-methylnaphthalene (Swiercz et al.. 201 1; ATSDR. 2005). There was no evidence of
histopathological changes in reproductive organs following chronic exposure to naphthalene at
concentrations up to 56 mg/m3 and a lack of exposure-related changes in testes weight following
subchronic exposure to 2-methylnaphthalene or naphthalene at concentrations up to 8.9 or
28 mg/m3, respectively.
Summary of Potentially Relevant Evidence
Human data suggest that PAH mixtures, including compounds from the aromatic high
carbon range fraction, may affect the male and female reproductive systems. Limited data from
two compounds in animals, BaP and 1,1-biphenyl, support that fertility may be reduced
following exposure to some compounds from the aromatic high carbon range fraction. However,
the lack of data from other compounds regarding reproductive function precludes the ability to
assess potential reproductive effects across the fraction in animals following oral or inhalation
exposure.
DEVELOPMENTAL EFFECTS
Developmental toxicity is the critical effect for the subchronic p-RfD for 1,1-biphenyl
(U.S. EPA. 201 la) and the subchronic and chronic RfDs and RfCs for BaP6 (U.S. EPA. 2017a.
b). Observed developmental effects include increased incidence of skeletal anomalies following
oral exposure to 1,1-biphenyl, neurodevelopmental effects following oral exposure to BaP, and
decreased embryo/fetal survival following inhalation exposure to BaP. Several human cohort
studies evaluated potential associations between PAH exposure and altered offspring growth or
neurodevelopment; many of these studies focused on BaP. As shown in Table 5, data on
developmental endpoints in animals were located for five compounds and two mixtures from this
fraction. Endpoints evaluated include standard teratology and offspring growth and survival
studies, as well as special developmental studies (neurological, reproductive, and cardiac
function).
Human Studies
Several cohort studies have evaluated the potential association between exposure to PAH
mixtures and offspring growth (U.S. EPA. 2017a. b). In Chinese women, elevated levels of
benzo[a]pyrene diolepoxide-DNA (BPDE-DNA) adducts in cord blood were associated with
reduced offspring weight at 18, 24, and 30 months of age, but not at birth (U.S. EPA. 2017a. b).
6The chronic RfD for BaP is based on a developmental exposure; therefore, it is also applicable to subchronic
exposures. Subchronic and chronic screening p-RfD values for BeP were also based on developmental effects
because BaP was used as an analogue.
72 Aromatic high carbon range
TPH fraction (noncancer)
-------
EPA/690/R-22/005F
In a U.S. cohort, reduced birth weight was associated with a doubling of cord blood
BPDE-adducts combined with exposure to environmental tobacco smoke (no effect of either
parameter alone) (U.S. EPA. 2017a. b). In a Spanish study, dietary BaP intake, determined by
questionnaire, was associated with reduced birth weight, birth length, and small for gestational
age (SGA) infants born to mothers with low vitamin C intake only (U.S. EPA. 2017a. b). Similar
findings were reported in a larger cohort from Norway, which demonstrated an association
between reported dietary BaP intake and reduced birth weight and birth length of offspring from
all women, regardless of vitamin C intake. The magnitude of the association was increased for
women consuming less than the recommended intake of vitamin C (U.S. EPA. 2017a. b). A
case-control study of fetal death prior to 14 weeks of gestation in China showed a significant
association between the level of maternal blood BPDE-DNA adducts and increased risk of fetal
death; however, no association was observed between fetal tissue BPDE-DNA adduct levels and
risk of fetal death (U.S. EPA. 2017a. b).
Several cohort studies have also evaluated the potential relationships between PAH
exposure and neurodevelopmental effects occurring at birth and during childhood (U.S. EPA.
2017a. b). A birth cohort study from China showed evidence of associations between cord blood
BPDE-adducts and reduced head circumference at birth, altered motor behavior and coordination
at age 2 years, and reduced intelligence quotient scores at age 5 years (U.S. EPA. 2017a. b).
Interactions with the effects of environmental tobacco smoke were noted. A birth cohort study
conducted in New York City showed a similar association between cord blood BPDE-adducts
and reduced head circumference at birth and also symptoms of anxiety/depression and attention
problems at ages 6-7 years (U.S. EPA. 2017a. b). An magnetic resonance imaging (MRI) study
of 8-12-year-old children in Spain showed an association between indoor and outdoor air levels
of BaP and a decrease in the caudate nucleus volume of the basal ganglia (Mortamais et at..
2017). Neurobehavioral testing did not reveal significant changes in attention-deficit/
hyperactivity disorder (ADHD) symptoms in this study.
Animal Studies
Figures C-13 and C-14 show the effects of orally-administered aromatic high carbon
range compounds on standard developmental endpoints (teratology and growth) and specialized
developmental endpoints (neurodevelopment, reproductive development, cardiac function),
respectively. Data for these endpoints are available for four compounds, including compounds
with carbon numbers C10-C20. Developmental effects were reported for all tested compounds.
Effects associated with gestational exposure to benzo[A]fluoranthene included impaired male
reproductive development at >0.002 mg/kg-day (lowest dose tested) and decreased pup weight at
0.02 mg/kg-day (Kim et at.. 2011). Effects associated with exposure to BaP included
neurodevelopmental effects (altered behavior, impaired learning, altered cortical activity)
following gestational exposure to doses >0.2 mg/kg-day, altered cardiovascular function in
offspring following gestational exposure to doses >0.6 mg/kg-day, decreased pup body weight
following early postnatal exposure to doses >2 mg/kg-day or gestational doses >10 mg/kg-day,
and altered reproductive development and decreased Fi fertility in males and females at
>10 mg/kg-day (U.S. EPA. 2017a. b).
73
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however, no special developmental studies (e.g., neurodevelopmental) were identified. A
decrease in the number of live pups was observed in mice following gestational exposure to
naphthalene at 300 mg/kg-day; similar effects were not seen in similarly exposed rats or rabbits
(U.S. EPA. 1998). For 1,1-biphenyl, effects included increased incidence of missing or
unossified sternebrae after gestational exposure to doses >500 mg/kg-day and decreased Fi, F2,
and F3 pup weights in a multigenerational study with exposure to 1,006 mg/kg-day (U.S. HP A.
2013).
Neurodevelopmental data are also available in rats following exposure to a mixture of
16 PAHs during gestation or gestation and lactation, which contained 2.5% BaP (Crepeaux et al..
2014. 2013. 2012); this study is not included in Figure C-14. Complete mixture composition is
presented in Appendix B, Table B-2. Adverse effects (delayed eye or ear opening, impaired
neuromuscular coordination, increased activity, increased anxiety-like behavior) were observed
at mixture doses >0.002 mg/kg-day, which delivered a BaP dose of 0.00005 mg/kg-day.
The potential effects of inhalation exposure to aromatic high carbon range compounds on
the developing organism were only evaluated for BaP and a 9-PAH mixture (predominantly
pyrene, composition shown in Appendix B, Table B-3); therefore, an exposure-response graph
comparing potencies across compounds was not included. Adverse developmental effects were
noted in all three available BaP gestational studies, including decreased embryo survival,
decreased number of implantations, and decreased pups/litter at concentrations >0.0042 mg/m3
(U.S. EPA. 2017a. b). Electrophysiological changes in the hippocampus were also observed in
offspring following maternal exposure to BaP at 0.02 mg/m3 during gestation (only tested
concentration). Standard developmental endpoints were not evaluated for the 9-PAH mixture;
instead, endpoints in offspring included adiposity and immune function in offspring (Yan et al..
2014; Chu et al.. 2013). Observed findings included increased airway reactivity in
ovalbumin-sensitized mice following early postnatal exposure (Chu et al.. 2013) and elevated
body weight and fat mass in Fi and F: offspring (Yan et al.. 2014). The study authors reported a
nominal exposure concentration of 7.29 ng/m3 (7.29 x 10 6 mg/m3) for the mixture exposure
level. However, the measured concentration of pyrene (as a marker of mixture exposure) in the
exposure chamber averaged 23 ng/m3 (range 7.38-40 ng/m3); the control exposure chamber
averaged 3 ng/m3 pyrene, with a range of 0-9 ng/m3. Based on the reported proportion of pyrene
in the mixture (52.59%), the 23 ng/m3 average for pyrene corresponds to an approximate average
mixture concentration of 44 ng/m3 (4.4 x 10 5 mg/m3). This exposure concentration is well
below the developmental LOAEL for BaP (0.0042 mg/m3).
Summary of Potentially Relevant Evidence
Human data suggest that PAH mixtures, including compounds from the aromatic high
carbon range fraction, may adversely affect offspring growth and neurodevelopment. Limited
data from three compounds in animals, benzo[A]fluoranthene, BaP, and 1,1-biphenyl, show that
offspring growth may be affected following exposure to some compounds from the aromatic
high carbon range fraction. Data on neurodevelopment in animals are limited to BaP (and
mixtures containing BaP) but indicate that adverse neurological effects can occur following early
life exposure at low doses. Limited animal data from benzo[A]fluoranthene, BaP, and mixtures
also indicate that the developing reproductive, immune, and cardiovascular systems may be
targets of toxicity for this fraction. However, the lack of developmental data from other
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compounds, particularly specialized developmental data, precludes a comparison of
developmental effects and potencies across the fraction.
OTHER EFFECTS
Human Studies
Cataract formation was reported in 8 of 21 workers exposed to naphthalene for >5 years
in a dye-producing plant. Bilateral cataracts were also reported in a case study of a pharmacist
who ingested 5 g of naphthalene (ATSDR. 2005; U.S. EPA. 1998).
Studies in coke oven workers have suggested that PAHs may impair the immune system
(U.S. EPA. 2017a. b). Affected immune parameters include reductions in serum immunoglobulin
M (IgM) and/or immunoglobulin A (IgA) titers, elevated immunoglobulin G (IgG) and
immunoglobulin E (IgE) levels, and reduced T-cell mitogenic and proliferative responses (U.S.
EPA. 2017a. b). Elevated levels of the urinary metabolites of naphthalene, phenanthrene, and
pyrene were associated with hypersensitivity in 5- and 9-year-old children, as measured by
serum levels of cockroach-specific IgE (an indicator of hypersensitivity) (U.S. EPA. 2017a. b).
Blood phenanthrene levels were elevated in children (1-14 years old) diagnosed with bronchial
asthma in a hospital-based, case-control study in India (Surcsh et at.. 2009).
Occupational exposure to PAH mixtures and cigarette smoke have been associated with
cardiovascular effects including atherosclerosis and ischemic heart disease (U.S. EPA. 2017a. b).
Mortality from cardiovascular disease and risk of ischemic heart disease were elevated in
workers at a coke oven plant and an aluminum smelter, respectively (U.S. EPA. 2017a. b).
Urinary metabolites of phenanthrene, BaP, and benzo[a]anthracene were positively correlated
with diastolic blood pressure in chimney sweeps in Sweden (Alhamdow et at.. 2017). Serum
markers of cardiovascular disease risk were also elevated in these workers (increased
homocysteine, cholesterol, and high-density lipoproteins). Two cross-sectional studies of the
U.S. population used National Health and Nutrition Examination Survey (NHANES) data to
evaluate potential associations between urinary PAH metabolites and risk factors of
cardiovascular disease (Ranibar et at.. 2015; Clark et at.. 2012). Clark et at. (2012) did not
demonstrate a relationship between urinary concentrations of naphthalene, fluorene,
phenanthrene, or pyrene metabolites (NHANES 2001-2004 data set) and serum biomarkers of
cardiovascular disease (fibrinogen, homocysteine, and WBC count) (Clark et at.. 2012). Ranibar
et at. (2015) showed positive associations between the urinary concentrations of some PAH
metabolites (NHANES 2001-2008 data set) and hypertension (naphthalene and phenanthrene),
obesity (phenanthrene), metabolic syndrome risk factors including cholesterol, triglycerides,
blood pressure, and glucose abnormalities (naphthalene, fluorene, and phenanthrene), and
type 2 diabetes (naphthalene, phenanthrene, and pyrene).
Animal Studies
As observed in human studies, cataract formation is a well-documented effect in
laboratory animals following exposure to high oral doses of naphthalene, generally at doses
>1,000 mg/kg-day (U.S. EPA. 1998).
The immune system has been identified as a potential target of BaP toxicity in animals
exposed by multiple routes (U.S. EPA. 2017a. b). Changes in thymus weight and histology and
alterations in the spleen (e.g., decreased B cell percentages) have been reported at oral doses
>7.1 mg/kg-day, with decreased immune responses in a modified local lymph node assay at
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13 mg/kg-day. Immune function was also impaired following subcutaneous doses >5 mg/kg-day.
Developmental immunotoxicity studies reported impaired immune responses following in utero
exposure via intraperitoneal (i.p.) injection. Inhalation data for immune endpoints were not
available for BaP. Data regarding immune function for other members of the fraction are limited
to naphthalene, which did not show any exposure-related changes in a battery of immunological
assays following oral exposure to doses up to 133 mg/kg-day for 90 days (U.S. HP A. 1998).
Several studies have reported oral transplacental carcinogenesis following gestational
exposure to dibenzo[c/t;/,/?] chry sene in mice (Madeen et al.. 2016; Benninghoff and Williams.
2013; Shorev et al.. 2013; Shorev et al.. 2012; Castro et al.. 2009; Castro et al.. 2008c; Castro et
al.. 2008a; Castro et al.. 2008b). In these studies, dibenzo[de//>]chrysene was administered
during gestation, resulting in the induction of fatal T-cell acute lymphoblastic leukemia/
lymphoma in offspring; pups typically died from this or other tumors within a year. Those that
survived frequently developed lung, liver, or ovarian tumors. Because of the fatal nature of the
neoplasia in offspring, and the fact that they result from gestational exposure, these studies can
be considered to straddle the line between cancer and developmental toxicity outcomes. None of
the studies identified a dose that did not influence offspring tumor incidence, with doses
>1 mg/kg administered once yielding increased lung tumor incidences. Pup mortality due to
T-cell acute lymphoblastic leukemia/lymphoma was increased at doses >6.5 mg/kg.
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