*>EPA
EPA/690/R-22/003F | September 2022 | FINAL
United States
Environmental Protection
Agency
Provisional Peer-Reviewed Toxicity Values for
Complex Mixtures of Aliphatic and Aromatic
Hydrocarbons
(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-22/003F
September 2022
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Complex Mixtures of Aliphatic and Aromatic
Hydrocarbons
(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 MANAGER
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
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
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.
in
Complex mixtures of
aliphatic and aromatic hydrocarbons
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
EXECUTIVE SUMMARY 3
1. INTRODUCTION 10
1.1. DEFINITION 01 THE FRACTIONS 11
1.2. OVERVIEW 01 THE APPROACH 13
1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS 18
1.3.1. Indicator Chemical Approach 18
1.3.2. Hazard Index Approach 18
1.3.3. Relative Potency Factor Approach 19
1.3.4. Response-Addition Approach 20
1.3.5. Integrated Addition Approach 20
2. METHODS OF FRACTION-SPECIFIC TOXICITY ASSESSMENT 22
2.1. LITERATURE SEARCHING AND DATA REVIEW 22
2.2. SELECTION OF APPROACH(ES) AND TOXICITY VALUE(S) 23
3. TOXICITY VALUES FOR THE DEFINED TPH FRACTIONS 24
3.1. ALIPHATIC LOW CARBON RANGE FRACTION: C5-C8 (EC5-EC8) 24
3 .2. ALIPHATIC MEDIUM CARBON RANGE FRACTION: C9-C18 (EC > 8-EC16) .. .. 31
3.3. ALIPHATIC HIGH CARBON RANGE FRACTION: C19-C32 (EC > 16-EC35) 35
3.4. AROMATIC LOW CARBON RANGE FRACTION: C6-C8 (EC6-EC < 9) 37
3 .5. AROMATIC MEDIUM CARBON RANGE FRACTION: C9-C10 (EC9-EC < 11).. .. 42
3.6. AROMATIC HIGH CARBON RANGE FRACTION: C10-C32 (EC11-EC35) 54
4. IMPLEMENTATION OI THE APPROACH 65
4.1. FRACTION-BASED NONCANCER RISK ASSESSMENT 65
4.2. FRACTION-BASED CANCER RISK ASSESSMENT 76
4.3. UNCERTAINTY ASSESSMENT 83
APPENDIX A. CHEMICAL SYNONYMS AND ABBREVIATIONS 85
APPENDIX B. REFERENCES 90
aliphatic and aromatic hydrocarbons
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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#
carbon number
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EC
equivalent carbon
SGPT
serum glutamic pyruvic transaminase,
EPA
Environmental Protection Agency
also known as ALT
ER
estrogen receptor
SSD
systemic scleroderma
FDA
Food and Drug Administration
TCA
trichloroacetic acid
FEVi
forced expiratory volume of 1 second
TCE
trichloroethylene
GD
gestation day
TWA
time-weighted average
GDH
glutamate dehydrogenase
UF
uncertainty factor
GGT
y-glutamyl transferase
UFa
interspecies uncertainty factor
GSH
glutathione
UFC
composite uncertainty factor
GST
g 1 ut a t h i o nc - V-1 ra n s fc ra sc
UFd
database uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFh
intraspecies uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFl
LOAEL-to-NOAEL uncertainty factor
HEC
human equivalent concentration
UFS
subchronic-to-chronic uncertainty factor
HED
human equivalent dose
U.S.
United States of America
i.p.
intraperitoneal
WBC
white blood cell
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 COMPLEX MIXTURES
OF ALIPHATIC AND AROMATIC HYDROCARBONS (VARIOUS CASRNS)
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 at
https://ecomments.epa.gov/chemicalsafety/.
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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EXECUTIVE SUMMARY
This Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment document
describes a fraction-based approach to risk assessment for complex mixtures of aliphatic and
aromatic hydrocarbons. This approach is implemented following a chemical analysis of the total
petroleum hydrocarbon (TPH) mixture that is present. The components of TPHs are generally
classified into aliphatics and aromatics, and each of these major fractions are then further
separated into low, medium, and high carbon range fractions based on the number of carbon (C)
atoms in the compounds and/or the compounds' equivalent carbon (EC) number index. In all, the
following six fractions of TPH mixtures are addressed:
• Aliphatic low carbon range TPH fraction
• Aliphatic medium carbon range TPH fraction
• Aliphatic high carbon range TPH fraction
• Aromatic low carbon range TPH fraction
• Aromatic medium carbon range TPH fraction
• Aromatic high carbon range TPH fraction
In this effort, the U.S. EPA is updating the PPRTV assessments for the aliphatic low
carbon range TPH fraction (U.S. EPA. 2022a). the aromatic medium carbon range TPH fraction
(U.S. EPA. 2022d). the aromatic high carbon range TPH fraction cancer assessment (U.S. EPA.
2022b). the aromatic high carbon range TPH fraction noncancer assessment (U.S. EPA. 2022c).
and the TPH mixture assessment (i.e., this document). The U.S. Environmental Protection
Agency (U.S. EPA) published its PPRTV assessments for TPHs in 2009. The primary motivation
for updating this PPRTV assessment was the release of updated toxicity values from the
U.S. EPA's Integrated Risk Information System (IRIS) program and/or PPRTV assessments for
several key constituents of the aliphatic low carbon range fraction and aromatic medium and
high carbon range fractions since 2009. U.S. EPA also revised the fraction boundaries for the
aromatic medium and high carbon range fractions both to align the fraction definitions with the
fractions resulting from current analytical methods and to avoid grouping the generally less toxic
substituted benzenes (now in the aromatic medium carbon fraction) with the polycyclic aromatic
hydrocarbons (PAHs), naphthalenes, and 1,1-biphenyl (in aromatic high carbon range fraction).
The fraction-based approach examines the noncancer hazards or cancer risks associated
with exposure to each of six fractions defined by chemical properties, and then describes the
integration of these fraction hazards and risks to evaluate hazards or risks posed by exposures to
the mixture. This PPRTV assessment presents toxicity values for the aliphatic and aromatic
hydrocarbon fractions, including subchronic and chronic provisional reference doses (p-RfDs)
and provisional reference concentrations (p-RfCs), cancer weight-of-evidence (WOE)
assessments, provisional oral slope factors (p-OSFs), and provisional inhalation unit risks
(p-IURs). This document also presents risk assessment methods for these fractions and chemical
mixtures that are intended to replace current approaches used at TPH-contaminated sites.
The assessment follows a data-driven approach and describes methodological options
according to the available analytical chemistry data. Tables ES-1 and ES-2 summarize the
selected noncancer provisional toxicity values for each fraction under two exposure options
(Options 1 and 2, respectively). Option 1 is utilized when exposure data are available for the
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fraction, rather than individual chemicals in the fraction; Option 2 is utilized when exposure data
include measures of individual chemicals in a fraction. For cancer risk assessment, an indicator
chemical or surrogate mixture approach is generally employed for each fraction; only a single
option generally is utilized, because fewer cancer risk estimates are available for individual
chemicals (see Table ES-3). The exception is the cancer risk assessment for the aromatic high
carbon range fraction that has three options, depending on the available analytic data. For the
cancer assessment for this fraction, Option 1 relies on an indicator chemical approach. Option 2
uses a component approach for selected PAHs (see Table ES-4). Option 3 relies on an integrated
additivity approach that accounts for the contributions to carcinogenic risk from the selected
PAH, but also the contributions of two other carcinogens that can occur in this fraction
(i.e., 1,1-biphenyl and 1-methylnaphthalene).
Depending on the available information about the chemicals present, the toxicity of each
of the six aliphatic or aromatic hydrocarbon fractions is estimated in one or more of the
following ways.
• Indicator Chemical Approach: The toxicity value for an individual compound is selected
to represent the entire fraction.
• Hazard Index (HI) Approach: A hazard quotient (HQ) is calculated as the ratio of human
exposure to a health hazard reference value (RfV) for each mixture component chemical,
and HQs are summed generate an HI. This approach is based on dose addition.
• Relative Potency Factor (RPF) Approach: Using RPFs, chemical component doses are
scaled relative to the potency of an index chemical (IC) and these scaled doses are
summed and expressed as an index chemical equivalent dose (ICED) for the mixture.
This approach is based on dose addition.
• Response-Addition Approach: The response-addition approach assumes simple
independent action for mixture chemicals that cause the same effect, assuming that each
impact is an independent response. The response to the mixture is predicted by summing
the risk estimates for the mixture components under the law of statistical independence.
• Integrated Addition Approach: Mixture components are separated into dose-additive
groups based on similar mode of action (MOA); risks are calculated separately for each
similarity group and summed using response addition. This approach integrates dose and
response addition.
• Surrogate Mixture Approach: Chemical mixtures can be generated in a manner
considered similar to a mixture (or mixture fraction) that might be encountered in the
environment. Health risk values derived from toxicological tests conducted on these
mixtures can be used as surrogates for a mixture that was generated by a similar process
and encountered in the environment. For fractions with multiple methods available,
methodology selection should be driven by the available exposure data.
Section 1 of this document defines the fractions, and provides overviews of the fraction
approach and the various mixtures methods used to evaluate risks and hazards associated with
the fraction. Section 2 details the literature searched and data reviewed as well as the selection of
various mixture approaches. Section 3 reviews the toxicity values defined for the TPH fractions.
An overview of how the presented approaches are applied in this PPRTV assessment is described
in Section 4.
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Table ES-1. Fraction-Specific Noncancer Toxicity Values for Option 1: Exposure Media Analyzed for BTEX and
Fractions
Secondary Fraction
Assessment
Method
Subchronic RfD or p-RfD
(mg/kg-d)a
Chronic RfD or p-RfD
(mg/kg-d)a
Subchronic RfC or
p-RfC (mg/m3)
Chronic RfC or p-RfC
(mg/m3)
Aliphatic
Low carbon range
(C5-C8 [EC5-EC8])b
Indicator chemical
0.05
(cyclohexene)
0.005
(cyclohexene)
2
(«-hexane)
0.4
(//-heptane)
Medium carbon range
(C9-C18 [EC > 8-EC16])
Surrogate mixture
0.1
(mid-range aliphatic
hydrocarbon streams)
0.01
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
High carbon range
(C19-C32
[EC > 16-EC35])
Surrogate mixture
30
(white mineral oil)
3
(white mineral oil)
NA
NA
Aromatic
Low carbon range
(C6-C8 [EC6-EC < 9])
Hazard Index
Benzene: 0.01
Toluene: 0.8
Ethylbenzene: 0.05°
Xylenes: 0.4
Benzene: 0.004
Toluene: 0.08
Ethylbenzene: 0.1°
Xylenes: 0.2
Benzene: 0.08
Toluene: 5
Ethylbenzene: 9
Xylenes: 0.4
Benzene: 0.03
Toluene: 5
Ethylbenzene: 1
Xylenes: 0.1
Medium carbon range
(C9-C10
[EC9-EC < ll])b
Indicator chemical
0.04
(trimethylbenzenes)
0.01
(trimethylbenzenes)
0.2
(trimethylbenzenes)
0.06
(trimethylbenzenes)
High carbon range
(C10-C32
[ECll-EC35])b
Indicator chemical
0.0003
(bcnzo|fl|pyrcnc)
0.0003
(bcnzo|fl|pyrcnc)
0.000002
(bcnzo|fl|pyrcnc)
0.000002
(bcnzo|fl|pyrcnc)
aRisk estimates in italics are PPRTV screening values. Screening values are not assigned confidence statements; however, confidence in these values is presumed to be
low. Screening values are derived when the data do not meet all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review, etc.) as provisional values; however, there is generally
more uncertainty associated with these values.
' Risk estimates(s) updated in 2022 as part of this TPH approach (U.S. EPA. 2022a. c, d).
°The subchronic p-RfD for ethylbenzene is lower than the chronic value because it was derived using data that were not available when the IRIS RfD was derived.
BTEX = benzene, toluene, ethylbenzene, and xylenes; C = carbon; EC = equivalent carbon; IRIS = Integrated Risk Information System; NA = not applicable;
p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfC = reference concentration; RfD = reference dose.
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Table ES-2. Fraction-Specific Noncancer Toxicity Values for Option 2: Analytical Data Available for Individual
Components and Fractions
Fraction and Carbon
Range
Assessment
Method
Subchronic RfD or p-RfD
(mg/kg-d)a
Chronic RfD or p-RfD
(mg/kg-d)a
Subchronic RfC or
p-RfC (mg/m3)"
Chronic RfC or p-RfC
(mg/m3)a
Aliphatic
Low
(C5-C8 [EC5-EC8])b
Hybrid
Components:
Cyclohexene: 0.05
n-Heptane: 0.003
«-Hexane: 0.3
Methylcyclopentane: 0.4
2,4,4-Trimethylpentene: 0.1
Components:
Cyclohexene: 0.005
n-Heptane: 0.0003
2,4,4-Trimethylpentene: 0.01
Components:
Cyclohexane: 18
//-Heptane: 4
«-Hexane: 2
//-Pcntanc: 10
Components:
Cyclohexane: 6
Cyclohexene: 1
n-Heptane: 0.4
«-Hexane: 0.7
//-Pcntanc: 1
Surrogate for balance of
fraction:0
0.05 (cyclohexene)
Surrogate for balance of fraction:0
0.05 (cyclohexene)
Surrogate for balance of
fraction:0
2 («-hexane)
Surrogate for balance of
fraction:0
0.4 (//-heptane)
Medium
(C9-C18 [EC > 8-EC16])
Surrogate
mixture
0.1
(mid-range aliphatic
hydrocarbon streams)
0.01
(mid-range aliphatic hydrocarbon
streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
High
(C19-C32 [EC > 16-EC35])
Surrogate
mixture
30
(white mineral oil)
3
(white mineral oil)
NA
NA
Aromatic
Low
(C6-C8 [EC6-EC < 9])
Hazard Index
Benzene: 0.01
Toluene: 0.8
Ethylbenzene: 0.05
Xylenes: 0.4
Benzene: 0.004
Toluene: 0.08
Ethylbenzene: 0.1
Xylenes: 0.2
Benzene: 0.08
Toluene: 5
Ethylbenzene: 9
Xylenes: 0.4
Benzene: 0.03
Toluene: 5
Ethylbenzene: 1
Xylenes: 0.1
Medium
(C9-C10 [EC9-EC < ll])b
Hybrid
Components
n-Propylbenzene: 0.1
tert-Butylbenzene: 0.1
sec-Butylbenzene: 0.1
//-Butvlbcnzcnc: 0.1
Trimethylbenzenes: 0.04
Components
Isopropylbenzene: 0.1
n-Propylbenzene: 0.1
tert-Butylbenzene: 0.1
sec-Butylbenzene: 0.1
«-Butylbenzene: 0.05
Trimethylbenzenes: 0.01
Components:
n-Propylbenzene: 1
Trimethylbenzenes: 0.2
Components:
Isopropylbenzene: 0.4
n-Propylbenzene: 1
Trimethylbenzenes: 0.06
Surrogate for balance of
fraction:0
0.04 (trimethylbenzenes)
Surrogate for balance of fraction:0
0.01 (trimethylbenzenes)
Surrogate for balance of
fraction:0
0.2 (trimethylbenzenes)
Surrogate for balance of
fraction:0
0.06 (trimethylbenzenes)
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Table ES-2. Fraction-Specific Noncancer Toxicity Values for Option 2: Analytical Data Available for Individual
Components and Fractions
Fraction and Carbon
Assessment
Subchronic RfD or p-RfD
Chronic RfD or p-RfD
Subchronic RfC or
Chronic RfC or p-RfC
Range
Method
(mg/kg-d)a
(mg/kg-d)a
p-RfC (mg/m3)"
(mg/m3)a
High
Hybrid
Components:
Components:
Components:
Components:
(C10-C32 [ECll-EC35])b
Acenaphthene: 0.2
Acenaphthene: 0.06
1,1-Biphenyl: 0.004
1,1-Biphenyl: 0.0004
Anthracene: 1
Anthracene: 0.3
Bcnzo|fl|pyrcnc:
Bcnzo|fl|pyrcnc:
Bcnzo|fl|pyrcnc: 0.0003
Bcnzo|fl|pyrcnc: 0.0003
0.000002;
0.000002;
1,1-Biphenyl: 0.1
1,1-Biphenyl: 0.5
Benzo[e]pyrene: 0.000002
Benzo[e]pyrene:
Fluoranthene: 0.1
Fluoranthene: 0.04
0.000002;
Fluorene: 0.4
Fluorene: 0.04
Naphthalene: 0.003
2-Methylnaphthalene: 0.004
1-Methylnaphthalene: 0.007
Naphthalene: 0.6
2-Methylnaphthalene: 0.004
Pyrene: 0.3
Naphthalene: 0.02
Pyrene: 0.03
Surrogate for balance of
Surrogate for balance of fraction:0
Surrogate for balance of
Surrogate for balance of
fraction:0
0.0003 (bcnzo|fl|pyrcnc)
fraction:0
fraction:0
0.0003 (benzol a | pyrene)
0.000002
0.000002
(bcnzo|fl|pyrcnc)
(bcnzo|fl|pyrcnc)
"Toxicity values in italics are PPRTV screening values. Screening values are not assigned confidence statements; however, confidence in these values is presumed to be
low. Screening values are derived when the data do not meet all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review, etc.) as provisional values; however, there is generally
more uncertainty associated with these values.
' Fraction toxicity value(s) updated in 2022 (U.S. EPA. 2022c).
°Balance of fraction in any given exposure medium equals the total fraction mass concentration minus the sum of the mass concentrations of the individual components
listed.
C = carbon; EC = equivalent carbon; NA = not applicable; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfC = reference
concentration; RfD = reference dose.
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Table ES-3. Fraction-Specific Cancer Toxicity Values
Fraction and Carbon
Range
Assessment
Method
OSF (mg/kg-d)-1 a
IUR (mg/m3)"1 a
Aliphatic
Low
(C5-C8 [EC5-EC8])b
Surrogate
mixture
NA; data do not support cancer
risk assessment
2.0 x 10-4
(icommercial hexane)
Medium
(C9-C18 [EC > 8-EC16])
Surrogate
mixture
NA; data do not support cancer
risk assessment
4.5 x 10-3
(mid-range aliphatic
hydrocarbon streams)
High
(C19-C32 [EC > 16-EC35])
NA; data do not support cancer risk assessment
Aromatic
Low
(C6-C8 [EC6-EC < 9])
Indicator
chemical
Benzene: 1.5 x 10 2-5.5 x 10 2
Benzene: 2.2 x 10 3-7.8 x 10 3
Medium
(C9-C10 [EC9-EC < ll])b
NA; data do not support cancer risk assessment
High
(C10-C32 [ECll-EC35])b
Indicator
Chemical
(Option 1);
Relative
Potency Factor
(Option 2);
Integrated
Addition
(Option 3)
1,1-Biphenyl: 8 xl0~3
1 -Methylnaphthalene: 2.9 x 10"2
Bcnzo|fl|pyrcnc: 1
See relative potency values in
Table 20
Bcnzo|fl|pyrcnc: 6 x 10 1
"Toxicity values in italics PPRTV are screening values. Screening values are not assigned confidence statements;
however, confidence in these values is presumed to be low. Screening values are derived when the data do not meet
all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review,
etc.) as provisional values; however, there is generally more uncertainty associated with these values.
' Toxicity value(s) updated in 2022 (U.S. EPA. 2022a. b, d).
C = carbon; EC = equivalent carbon; IUR = inhalation unit risk; NA = not applicable; OSF = oral slope factor;
PAH = polycyclic aromatic hydrocarbon; RPF = relative potency factor.
8 Complex mixtures of
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Table ES-4. RPFs for PAH Carcinogenicity"
PAH (abbreviation)
RPF
Data Source(s) for RPF Values
Bcn/o |fl|pyrcnc (BaP)
1
NA
Benz[a]anthracene (BaAC)
0.1
Bingham and Falk (1969)
Benz[e]acephenanthrylene (BeAPE)b
0.1
Habs etal. (1980)
Bcn/o |/i | fluoranthcnc (BkFA)
0.01
Habsetal. (1980)
Chrysene (CH)
0.001
Wvnder and Hoffmann (1959)
Dibcn/| A,/? |anthraccnc (DbahAC)
1
Wvnder and Hoffmann (1959)
I ndcno \ 1,2,3-c, d\pyrcnc (I123cdP)
0.1
Habs et al. (1980); Hoffmann and Wvnder (1966)
aU.S. EPA (1993).
bFormerly bcn/o | /> | fl uo ra nthcnc.
NA = not applicable; PAH = poly cyclic aromatic hydrocarbon; RPF = relative potency factor.
9
Complex mixtures of
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EPA/690/R-22/003F
1. INTRODUCTION
This Provisional Peer-Reviewed Toxicity Value (PPRTV) assessment document is the
principal document outlining the methodology for assessing noncancer health hazards and cancer
risks associated with exposures to petroleum hydrocarbons. The methodology uses a
fraction-based approach that examines the noncancer hazards or cancer risks associated with
exposure to each of six fractions defined by chemical properties, and then describes the
integration of these fraction hazards and risks to evaluate hazard or risk posed by exposures to
the mixture. For each petroleum hydrocarbon fraction, the methodology includes the chemical
mixture hazard assessment and risk assessment methods, definition of fractions, selection of
indicator chemicals or specific components for the mixture risk assessment methods, and
selection of toxicity values for the indicator chemicals or the specific components. This PPRTV
assessment is intended to be used in conjunction with fraction-specific PPRTV assessments (U.S.
HP A. 2022a. b, c, d, 2009p. g, r) and to replace current approaches used at total petroleum
hydrocarbon (TPH)-contaminated sites. The fraction-specific PPRTV assessments assess hazard
and risk using applicable, but different, methods based on available data. Methods used include
the indicator chemical approach, hazard index (HI) approach, relative potency factor (RPF)
approach, response-addition approach, integrated addition approach, and surrogate mixture
approach; these methods are summarized in Section 1.2 and described in the specific fraction
documents. In this data-driven approach, the choice of method depends on the chemical analyses
conducted at a site.
Contamination of the environment by petroleum hydrocarbons is widespread. The initial
contaminating materials range from crude oils to a wide variety of refined fuels and lubricating
oils (IPCS. 1982). These hydrocarbon products are complex mixtures containing perhaps
hundreds of hydrocarbon compounds, including aliphatic compounds (straight-chain,
branched-chain, and cyclic alkanes and alkenes) and aromatic compounds (benzene and
alkylbenzenes, polycyclic aromatic hydrocarbons [PAHs]1) (Potter and Simmons. 1998). In
addition, some of these products contain nonhydrocarbon additives or contaminants [see
discussion in Chapter 5 of ATSDR (1999) and references therein].
Once released into the environment, the composition of a hydrocarbon product will
change due to differential fate and transport of its components (i.e., some of these processes are
sometimes referred to as "weathering") (Kuppusamv et at.. 2020). In general, the more soluble
and/or volatile mixture components will migrate to other locations and environmental media,
while other components may be degraded (e.g., by microorganisms in soils and bodies of water)
(Das and Chandran. 2011). leaving the relatively nonmobile and less readily degraded
compounds (i.e., a weathered product) at the original location of release (Kuppusamv et at..
2019; Truskewvcz et at.. 2019; Batseiro-Romero et al.. 2018; Stellies and Watkin. 1993; Dragun.
1988; Bossert and Bartha. 1986; Coleman et al.. 1984). Thus, the actual aliphatic and aromatic
hydrocarbon mixture at a contaminated site, to which a population could be exposed, will vary
with the quantity of petroleum hydrocarbon initially released, composition of the initial
'In this document, the U.S. Environmental Protection Agency (U.S. EPA) defines PAHs as unsubstituted
compounds with two to six fused aromatic rings made up only of carbon and hydrogen atoms. The definition of the
PAH excludes their alkyl substituted derivatives.
10 Complex mixtures of
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EPA/690/R-22/003F
hydrocarbon mixture, location, time, and environmental medium, among other factors [see
discussion in Chapter 5 of ATSDR (1999)1.
The assessment of human health risks posed by petroleum hydrocarbon-contaminated
sites involves measurement for all chemicals that originated in crude oils or petroleum products,
known as TPHs. TPH is a loosely defined aggregate that depends on the method of analysis as
well as the contaminating material. By definition, TPH is the measurable amount of
petroleum-based hydrocarbon in an environmental medium and represents the total mass of
hydrocarbons present without identifying individual compounds (ATSDR. 1999). As TPH is not
a consistently defined entity, the assessment of health effects and development of toxicity criteria
for the complex mixture as a whole is problematic, although this would be the preferred
approach.
Some toxicity data are available for whole, unweathered hydrocarbon products (Cooper
and Manic. 1996; Bruncr et al.. 1993; Kinkead et al.. 1992; Kancrva et al.. 1987; Gaworski et al..
1985); however, there are limitations to using the whole-product data due to composition
variability caused by differences in the crude oils from which hydrocarbon products are refined,
differences in the refining processes, and differences in formulations of the final products. In
addition, the identity of the released material may not be known, or multiple products may have
been released, potentially at different times. Toxicity data for whole hydrocarbon products that
are relatively heterogeneous are not necessarily applicable to the weathered materials or
petroleum hydrocarbon mixtures in the environment to which exposures occur. These
environmental petroleum hydrocarbon mixtures have been transported through individual
compartments in the environment and subjected to partitioning (i.e., transfer between
environmental compartments) and transformation, mediated by biological, chemical, or physical
agents.
The Total Petroleum Hydrocarbon Criteria Working Group (TPHCWG) estimated there
to be approximately 250 individually identified hydrocarbon components of various
petroleum-derived fuels and crude oil (Potter and Simmons. 1998; Weisman. 1998; Gustafson et
al.. 1997). Toxicity data are available for only a relatively small number of these components.
Thus, any attempt to assess the health effects of TPHs from the individual hydrocarbon
components is inherently uncertain because many of the known components lack appropriate
toxicity data. In addition, the resources needed to analyze for all known TPH constituents are
likely to be prohibitive.
In recognition of the inapplicability of whole-product toxicity data to many
contamination scenarios, the impact of differential fate and transport associated with individual
contaminants, the impracticality of chemically analyzing each constituent separately, and the
need for risk-based assessment of petroleum hydrocarbons, an approach has been developed to
assess aliphatic and aromatic petroleum hydrocarbons on the basis of fractions with similar
physical and chemical properties (MassDEP. 2003; ATSDR. 1999; MassDEP. 1994).
1.1. DEFINITION OF I II I FRACTIONS
Specific petroleum hydrocarbon fractions for risk assessment were initially defined by a
consortium of governmental agencies, professional organizations, academia, and industry more
than 20 years ago on the basis of physicochemical properties, environmental fate, toxicity, and
analytical chemistry considerations (MassDEP. 2003; Gustafson et al.. 1997; MassDEP. 1994).
11 Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
More recent examples of TPH risk assessment using a fraction-based approach include CCME
(20211 BCMoE (2018). ARBCA (20121 and Redman et al. (2014). In brief, the components of
TPHs are generally classified into aliphatics and aromatics, and each of these major fractions are
then further separated into low, medium, and high carbon range fractions based on the number of
carbon (C) atoms in the compounds and/or the compounds' equivalent carbon (EC) number
index.2 The EC index is related to the compounds' potential transport in the environment and is
equivalent to the retention time of the compounds on a boiling-point gas chromatography (GC)
column (nonpolar capillary column), normalized to //-alkanes. For example, benzene, a
C6 aromatic compound, has an EC of 6.5 because its boiling point and GC retention time are
approximately halfway between those of //-hexane (C6 [EC6]) and //-heptane (C7 [EC7]).
Further details regarding the initial fraction definitions are available in previous reports
(MassDEP. 2003; Gustafson et al.. 1997; MassDEP. 1994). In addition, Wang et al. (2012) used
comparative molecular field analysis to assess whether chemical members of the fractions
exhibit similar chemistry and found that this analysis supported the current fraction definitions.
Since the origination of the fraction method, additional toxicity information has become
available for constituents of some fractions, and there have been advances in analytical
characterization of petroleum hydrocarbons. U.S. EPA has reviewed and revised the analytical
methods applicable to petroleum hydrocarbons; the analytical methods match the fractions
developed in this PPRTV assessment.
This document is an update of the PPRTV assessments for TPHs that U.S. EPA published
in 2009 (U.S. EPA. 2009a. b, c, d, e, £ g, h, i, j., k, 1, m, n, o, j), g, r, s, t). The primary motivation
for this update was the release of updated toxicity values from the U.S. EPA's Integrated Risk
Information System (IRIS) program and/or PPRTV assessments for several key constituents of
the aliphatic low carbon range fraction and aromatic medium and high carbon range fractions.
These included toxicity values for benzo[a]pyrene (BaP) (IRIS. U.S. EPA. 2017);
trimethylbenzenes (TMBs) (IRIS. U.S. EPA. 2016b); //-heptane (PPRTV. U.S. EPA. 2016a);
1,1-biphenyl (IRIS. U.S. EPA. 2013b); methylcyclohexane (PPRTV. U.S. EPA. 2013a);
.scc -butylbenzene (PPRTV. U.S. EPA. 2012c); /c/7-butylbenzene (PPRTV. U.S. EPA. 2012d);
fluoranthene (PPRTV. U.S. EPA. 2012b); acenaphthene (PPRTV. U.S. EPA. 2011b);
//-butylbenzene (PPRTV. U.S. EPA. 2010b); cyclohexane (PPRTV. U.S. EPA. 2010a);
1 -methylnaphthalene (PPRTV. U.S. EPA. 2008); and benzo[c]pyrene (BeP) (PPRTV. U.S. EPA.
2021b).
In this update, the fraction boundaries for the aliphatic low, medium, and high carbon
range fractions and the aromatic low carbon range fraction remain unchanged (see Figures 1
and 2 in Section 1.2). Fraction boundaries for the aromatic medium and high carbon range
fractions were revised to accomplish the following goals:
1) Align the fraction definitions with the fractions resulting from current analytical methods
as a practical approach to facilitate application.
2) Avoid grouping the generally less toxic substituted benzenes (C9-C10) with PAHs,
naphthalenes, and 1,1-biphenyl.
2Based on an empirical relationship, the EC index can be calculated 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).
Complex mixtures of
aliphatic and aromatic hydrocarbons
12
-------
EPA/690/R-22/003F
The redefined aromatic fractions are C9-C10 (EC9-EC <11) (medium carbon range)
and C10-C32 (EC11-EC35) (high carbon range). Naphthalene, which is CIO (EC11.57), is
grouped with the high carbon range. Here, the U.S. EPA specifically is updating the PPRTV
assessments for the aliphatic low carbon range TPH fraction (U.S. EPA. 2022a). the aromatic
medium carbon range TPH fraction (U.S. EPA. 2022d). the aromatic high carbon range TPH
fraction cancer assessment (U.S. EPA. 2022b). the aromatic high carbon range TPH fraction
noncancer assessment (U.S. EPA. 2022c). and the TPH mixture assessment (i.e., this document).
1.2. OVERVIEW OF THE APPROACH
The framework for the fractionation approach to risk assessment for complex mixtures of
aliphatic and aromatic petroleum hydrocarbons is derived from, and consistent with, U.S. EPA
mixtures guidelines and supplemental guidance (U.S. EPA. 2000. 1986) and risk assessment
guidance for the U.S. EPA Superfund program (U.S. EPA. 1989). The U.S. EPA mixtures
guidance documents identify a hierarchy of preference for toxicity assessment of mixtures: data
on the mixture of interest are preferred over data on sufficiently similar mixtures, and data on
individual components are preferred least. As discussed above, there are limited toxicity data on
mixtures of weathered petroleum contamination from varying source materials. Likewise, there
are no toxicity data on the petroleum fractions that have been defined for this purpose. However,
toxicity data on mixtures of fraction constituents (i.e., representing subsets of the total fraction)
and on individual constituents are available. For each fraction, toxicity data for mixtures and
individual components that meet the structural requirements (aliphatic or aromatic, carbon
number, and/or EC number) are evaluated to select an approach to toxicity assessment for that
fraction. The evaluation takes into consideration the availability of mixture toxicity data and
whether the mixture is sufficiently representative of the fraction, whether available component
toxicity data are likely to encompass the range of potential toxic effects for members of the
fraction, and the degree to which the component toxicity data suggest that members of the
fraction exert similar effects at similar doses. The analytical data needed for each approach were
also considered in selecting the most appropriate approach.
Based on the results of this analysis, the toxicity of each of the six aliphatic or aromatic
hydrocarbon fractions is estimated in one or more of the following ways:
• Indicator Chemical Approach
• Hazard Index Approach
• Relative Potency Factor Approach
• Response-Addition Approach
• Integrated Addition Approach
• Surrogate Mixture Approach
Additional details of these approaches are described in Section 1.3.
13
Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Figure 1 shows the fraction definitions and the toxicity assessment approaches selected
for each fraction for oral noncancer assessments. Options are presented for risk assessment when
exposure media are analyzed only for the fraction total concentrations (Option 1) and when
exposure media are analyzed both for the fraction total concentrations and for the individual
component concentrations with toxicity values (Option 2).
Figure 2 illustrates the fraction definitions and the toxicity assessment approaches
selected for each fraction for noncancer assessments following inhalation exposures. Options are
presented for risk assessment when exposure media are analyzed only for the fraction total
concentrations (Option 1) and when exposure media are analyzed both for the fraction total
concentrations and for the individual component concentrations with toxicity values (Option 2).
Figure 3 shows the fraction definition and the approaches for both oral and inhalation
cancer risk assessments. For two fractions, the aliphatic high carbon range fraction and the
aromatic medium carbon range fraction, the data do not support a cancer risk assessment. For the
aliphatic low carbon range fraction and the aliphatic medium carbon range fraction, the data do
not support a cancer assessment by the oral route of exposure and only one option is offered for
each fraction to evaluate cancer risks by the inhalation route of exposure. For the aromatic low
carbon range fraction, only one option is offered for oral and inhalation exposure routes. For the
aromatic high carbon range fraction, the following three options are offered: (Option 1) an
indicator chemical approach when exposure media are analyzed only for the fraction total
concentration; (Option 2) an RPF approach when exposure media are analyzed both for the
fraction total concentration and for selected individual PAHs (i.e., components with RPFs); and
(Option 3) an integrated addition approach when exposure media are analyzed for the fraction
total concentration, for concentrations of selected individual PAHs that have RPFs, and for
concentrations of other carcinogens that have cancer risk values but are not PAHs.
14
Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Total Petroleum Hydrocarbon Mixture (TPH)
ALIPHATICS
AROMATICS
Aliphatic Low
(C5-C8
[EC5-EC8])
Aliphatic Medium
(C9-C18
[EC>8-EC16])
Aliphatic High
(C19-C32
[EC > 16-EC35])
Aromatic Low
(C6-C8
[EC6-EC < 9])
Aromatic Medium
(C9-C10
[EC9-EC< 11])
Aromatic High
(C10-C32
[EC11-EC35])
Indicator
Chemical
Approach
{Option 1)
f "N,
Hazard Index
Approach
{Option 2)
^uiToaate
f N
Surrogate
f Hazard j
Mixture
Mixture
Index
Approach
v Approach
Approach
Indicator
Chemical
Approach
, {Option 1)
V '
< N
Hazard Index
Approach
{Option 2) .
Indicator
Chemical
Approach
v
{Option 1)
Hazard Index
Approach
{Option 2) ,
Option 1: environmental media analyzed only for fraction
Option 2: environmental media analyzed for fraction and individual components with toxicity values
Figure 1. Overview of TPH Fractions and Assessment Methods for Oral Noncancer Assessment
15 Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Total Petroleum Hydrocarbon Mixture (TPH)
ALIPHATICS
AROMATICS
Aliphatic Low
(C5-C8
[EC5-EC8])
Indicator
Chemical
Approach
(Option 1)
r
Hazard Index
Approach
{Option 2)
Aliphatic Medium
(C9-C18
[EC>8-EC16])
Surrogate
Mixture
Approach
Aliphatic High
(C19-C32
[EC > 16-EC35])
NA—Data Do
Not Support
Inhalation
Noncancer
Assessment ,
Aromatic Low
(C6-C8
[EC6-EC < 9])
Hazard
Index
Approach
Aromatic Medium
(C9-C10
[EC9-EC< 11])
Indicator
Chemical
Approach
{Option 1)
V ^
* N
Hazard Index
Approach
{Option 2)
Aromatic High
(C10-C32
[EC11-EC35])
Indicator
Chemical
Approach
{Option 1)
^ "N
Hazard Index
Approach
, {Option 2) y
Option 1: enviromnental media analyzed only for fraction
Option 2: environmental media analyzed for fraction and individual components with toxicity values
Figure 2. Overview of TPH Fractions and Assessment Methods for Inhalation Noncancer Assessment
16 Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Total Petroleum Hydrocarbon Mixture (TPH)
ALIPHATICS
AROMATICS
Aliphatic Low
(C5-C8
[EC5-EC8])
Aliphatic Medium
(C9-C18
[EC>8-EC16])
^NA—Data Do
'NA—Data Do
Not Support
Not Support
Oral Cancei-
Oral Cancer
Assessment
Assessment
and
and
Indicator
Surrogate
Chemical
Mixture
Approach for
Approach
Inhalation
for Inhalation
Cancer
Cancer
- Assessment j
v Assessment y
Aliphatic High
(C19-C32
[EC > 16-EC35])
NA—Data Do
Not Support
Cancer
, Assessment
Aromatic Low
Aromatic Medium
Aromatic High
(C6-C8
(C9-C10
(C10-C32
[EC6-EC < 9])
[EC9-EC< 11])
[EC11-EC35])
Indicator
Chemical
Approach
NA—Data Do
Not Support
Cancer
Assessment
Indicator Chemical
Approach for Oral
and Inhalation
Cancer Assessments
y (Option 1)
Relative Potency
Factor Approach for
Oral and Inhalation
Cancer Assessments
^ (Option 2)
Integrated Addition ^
Approach for Oral
Cancer Assessments
(Option 3)
Option 1: environmental media analyzed only for fraction v
Option 2: environmental media analyzed for fraction and PAH components with RPF values
Option 3: environmental media analyzed for fraction and PAH components with RPF values and non-PAH carcinogens with toxicity values
Figure 3. Overview of TPH Fractions and Assessment Methods for Cancer Assessment
17 Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
The methods for assessing toxicity of the fractions are described in Section 1.3, followed
by Sections 1.3.1-1.3.5, which provide details of the assessments for each fraction. Subsequent
sections describe the implementation of the approach in noncancer and cancer risk assessment of
petroleum contamination.
1.3. OVERVIEW OF MIXTURE ASSESSMENT METHODS
This section briefly describes the chemical mixtures risk assessment methods used in the
TPH assessments. These methods are described in the U.S. EPA Supplementary Guidance for
Conducting Health Risk Assessment of Chemical Mixtures (U.S. EPA. 2000. 1986). U.S. EPA
Feasibility of Performing Cumulative Risk Assessments for Mixtures of Disinfection By-Products
in Drinking Water (U.S. EPA. 2003a). and Agency for Toxic Substances and Disease Registry
(ATSDR) Framework for Assessing Health Impacts of Multiple Chemicals and Other Stressors
(ATSDR. 2018).
1.3.1. Indicator Chemical Approach
When the chemical composition of a mixture or a mixture fraction is not known, or
toxicity measures are not available for 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 potent 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. Similarly, for cancer assessments, the indicator chemical needs to have adequate
dose-response data to indicate cancer potential or to develop a dose-response relationship for
cancer outcomes. The health risk value of the indicator chemical is integrated with exposure
estimates for the mixture or mixture fraction to estimate health hazards associated with the
fraction (i.e., calculate fraction-specific HI for a specific exposure pathway or a fraction-specific
cancer risk estimate for a specific exposure pathway). This approach does not scale for potency
of individual constituents; instead, it assumes that the toxicity of all measured members of the
fraction can be adequately estimated by the health reference value of the indicator chemical.
1.3.2. Hazard Index Approach
The HI approach combines estimated population exposures with toxicity information to
characterize the potential for toxicological 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. Instead, the HI is an
indicator of potential hazard. In the HI approach, a hazard quotient (HQ) is calculated as the ratio
of an estimate of exposure (E) to a 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 route
and the reference concentration (RfC) for the inhalation exposure route.
n n F
h/=xhq;.=5; :
,=i
18
Complex mixtures of
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EPA/690/R-22/003F
The HI is based on dose addition (U.S. EPA. 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 have the same units.
1.3.3. Relative Potency Factor Approach
The RPF approach is a component-based approach that assumes components in a mixture
act in a toxicologically similar manner. Such an assumption can be made when the class of
chemicals comprising the mixture shares a known or suspected common mode of action (MOA).
Implementing an RPF approach requires a quantitative dose-response assessment for an index
chemical (IC) and pertinent scientific data that allow the toxic potency of the mixture
components to be meaningfully compared to that of the IC.
Under the assumption of dose addition, the health risk associated with exposure to a
mixture can be estimated as follows: initially, the chemical component doses are scaled relative
to the potency of an IC, and then these scaled doses are summed and expressed as an index
chemical equivalent dose (ICED) for the mixture. For any given mixture, the general equation
below highlights the steps involved in estimating the ICED.
ICED = ^RPFiDi+Die
where:
IC = index chemical
ICED = index chemical equivalent dose of the mixture (e.g., mg/kg-day or mg/m3)
RPF, = relative potency factor of the z'th PAH detected in the mixture (unitless)
Di = dose of the z'th chemical detected in the mixture (mg/kg-day or mg/m3)
D\c = dose of index chemical in the mixture (mg/kg-day or mg/m3), given that
the RPF value for the IC is 1
RPFs for individual components can be estimated using the slope factors of the z'th
components:
RPF, = slope, ^ slopeic
R/BMDr , - R/BMDr ic
= BMDr ic ^ BMDr-i
where:
BMD = benchmark dose
R = response
Next, a plausible upper bound on cancer risk can be estimated by multiplying the ICED
by the cancer risk value for the IC (e.g., oral slope factor [OSF] in [mg/kg-day] or inhalation
unit risk [IUR] in [mg/m3]-1).
19
Complex mixtures of
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1.3.4. Response-Addition Approach
The response-addition approach assumes simple independent action for mixture
chemicals that cause the same effect, assuming that each impact is an independent response. In
this method, the response to the mixture is predicted by summing the risk estimates for the
mixture components under the law of statistical independence. Using n for the z'th component
risk, the formula for predicting the //-chemical response to the mixture probability (rmix) for
simple independent action is then:
1.3.5. Integrated Addition Approach
Many mixture exposures, including the aromatic high carbon range fraction, contain
component chemicals that cause cancer in toxicologically dissimilar ways. This recognition of
the different bioactivities associated with complex mixtures led the U.S. EPA to develop a hybrid
general additivity approach that incorporated both dose addition and response addition, yielding
the probabilistic risk of the adverse endpoint of concern—in this case, carcinogenic risk of the
mixture. While an RPF approach may be most applicable to an assessment of cancer risk posed
by PAHs comprised of the aromatic high carbon TPH fraction, other TPH members of this
fraction (e.g., 1-methylnaphtalene and 1,1-biphenyl) that are not characterized as PAH in this
effort may cause cancer through different MO As. For exposures to mixtures composed of such
components and when required data are available, U.S. EPA recommends the use of an
integrated addition approach.
For chemicals eliciting a common endpoint, the integrated addition approach begins with
separation of the mixture components into dose-additive groups (U.S. EPA. 2007a. 2003 a) based
on similar MO As (i.e., "similarity groups"). Next, the assumptions of similarity within groups,
and then of toxicological independence across groups, are evaluated. If there are interactions,
other mixture assessment methods would be preferred. Otherwise, within each similarity group,
the RPF approach is used to estimate the health risk associated with exposures to the group of
chemicals. The similarity group risks are then combined across all groups using response
addition to estimate the risk posed by the entire mixture (U.S. EPA. 2000). In this assessment,
the MO As of chemicals such as 1,1-biphenyl and 1-methylnaphthalene are assumed to be
independent from the MO As of the PAHs. Specific steps of the integrated addition approach
include:
• Forming toxicological similarity groups based on available information on MO A
(e.g., two similarity groups could cause the same effect through different MO As);
similarity groups can vary in size from a single member to many members.
• Selecting an IC for each similarity group.
n
and for a binary mixture is:
u(v2>=Mi-fi(di>)(i-''2<£y)
= r1(d1)+r2(d2)-r1(d1)p2(d2)
20
Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
• Developing RPFs for each similarity group, reflecting intragroup potency differences,
and exposure estimates.
• Calculating an ICED for each similarity group, based on the RPFs and component
exposure estimates.
• Calculating each similarity group mixture risk (as probability) for the common effect(s)
using the IC dose-response function.
• Estimating the total mixture risk using response addition across the similarity group risk
estimates using the following equation:
Rm = Z^/
where:
Rm = risk posed by the mixture
Rj = the risk posed by the /th subgroup (unitless)
1.3.6. Surrogate Mixture Approach
In some cases, chemical mixtures can be generated in a manner considered similar to a
mixture (or mixture fraction) that might be encountered in the environment. Such mixtures
subsequently can be tested toxicologically. When calculating an RfD, RfC, or slope factor for a
whole mixture (i.e., the tested mixture), the general process is to assume the mixture can be
treated the same as a single chemical and proceed with the established methodology for
generating that estimate. Such RfDs, RfCs, or slope factors calculated for a whole mixture can be
used as a surrogate for a mixture that was generated by a similar process and encountered in the
environment (U.S. EPA. 2000).
The tested mixture needs to have adequate dose-response data to indicate hazard potential
or a dose-response relationship for noncancer outcomes. Similarly, for cancer assessments, the
tested mixture needs to have adequate dose-response data to indicate cancer potential or to
develop a dose-response relationship for cancer outcomes. The health risk value of the tested
mixture 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 or a fraction-specific cancer risk estimate for a specific exposure pathway).
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2. METHODS OF FRACTION-SPECIFIC TOXICITY ASSESSMENT
2.1. LITERATURE SEARCHING AND DATA REVIEW
In 2009, the U.S. EPA compiled a list of individual hydrocarbons as a preliminary step in
identifying potential surrogate compounds or mixtures to represent the toxicity of the fractions or
compounds useful in a component-based method. The list included all individual hydrocarbons
considered previously by the U.S. EPA National Center for Environmental Assessment (NCEA)
Superfund Technical Support Center in the evaluation of hydrocarbons, as well as all those with
toxicity data reviewed by the Massachusetts Department of Environmental Protection
(MassDEP. 2003) or the TPHCWG (Edwards et al .. 1997). Similarly, a list of mixtures, primarily
hydrocarbon streams, was compiled from these sources. Searches were performed in the IRIS
database at the time. Health Effects Assessment Summary Tables (HEAST) (U.S. EPA. 1997a).
ATSDR toxicological profiles, Chemical Assessments and Related Activities (CARA) list (U.S.
EPA. 1994. 1991a). and Drinking Water Standards and Health Advisories (DWSHA) list (U.S.
EPA. 2006). Additionally, the California Environmental Protection Agency (CalEPA), National
Toxicology Program (NTP), World Health Organization (WHO), and International Agency for
Research on Cancer (1ARC) were consulted for information. The U.S. EPA (2007b) High
Production Volume (HPV) Challenge Program, and particularly the Petroleum HPV Testing
Group publications, as well as the Organisation for Economic Co-operation and Development
(OECD) HPV Program Screening Information Data Set (SIDS) documents were searched for
relevant information. Additional pertinent individual compounds and mixtures encountered
during this background search were added to the list for further consideration.
On the basis of the information found during these searches, compounds and mixtures
that appeared to be possible candidates for use as surrogates were subjected to preliminary
searching in PubMed and the Toxic Substances Control Act Test Submissions (TSCATS)
database. If chosen for PPRTV assessment development on the basis of the results of the
background searching or the preliminary searching, compounds and mixtures were then
subjected to full literature searches of the other databases (through 2009). Details of the literature
search methods for the compounds and mixtures selected for PPRTV assessment development
are available in the individual documents (U.S. EPA. 2022a. b, c, d, 2009p. g, r).
For the fraction assessments that were updated in 2022 (aliphatic low carbon range
fraction and aromatic medium and high carbon range fractions), only compounds or mixtures
with existing U.S. EPA or ATSDR toxicity values 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 toxic effects and
potencies across the components and mixtures relevant to the fraction. Hazard identification and
dose-response assessment for the updated fractions entailed the following steps: identifying
mixtures and compounds that met structural criteria specific to each fraction and had available
toxicity values from designated sources; searching published literature to identify other toxicity
data relevant to the fraction; searching the reference list of pertinent reviews, OECD SIDS, and
the Petroleum HPV Testing Group website to identify other mixtures or compounds with toxicity
data that may inform hazard identification for the fraction; and evaluating all collated data to
determine whether effects and/or potencies were consistent across the fraction. Additional details
of the search methods for the updated fractions are available in the fraction-specific PPRTV
assessments (U.S. EPA. 2022a. b, c, d, 2009p. cj, r).
22
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2.2. SELECTION OF APPROACH(ES) AND TOXICITY VALUE(S)
The method for selecting an approach and toxicity value(s) for the fraction was as
follows. First, mixtures were preferred over individual compounds, provided that the mixture
exhibited in vivo toxic effects similar to those exhibited by the individual fraction components. If
suitable mixture data were lacking, but available component data indicated similar toxicity
targets, a representative compound exhibiting in vivo effects and potency similar to those
exhibited by other compounds in the fraction was chosen as an indicator chemical. In the event
that components of the fraction varied widely in toxic effects or potency, the toxicity value for
the most potent component was generally chosen as the 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 sites of aliphatic or aromatic
hydrocarbon contamination, then a component approach would be considered.
23
Complex mixtures of
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3. TOXICITY VALUES FOR THE DEFINED TPH FRACTIONS
3.1. ALIPHATIC LOW CARBON RANGE FRACTION: C5-C8 (EC5-EC8)
The aliphatic low carbon range fraction includes straight-chain, branched, and cyclic
alkanes and alkenes; examples include //-pentane, //-octane, 2-methylpentane, cyclohexane, and
1-hexene. Toxicity assessment and surrogate selection for the aliphatic low carbon range fraction
is detailed in the PPRTV assessment for this fraction (U.S. EPA. 2022a). This section provides a
summary of the approach and results; further detail is available in the PPRTV assessment.
Toxicity values were identified for seven aliphatic low carbon range compounds and one
mixture. Tables 1 and 2 provide summaries of the oral and inhalation noncancer toxicity values,
critical effects, and key studies. In February 2018 and again in August 2021, literature searches
were conducted using a multistep process for the mixtures and individual compounds with
toxicity values and for other mixtures and compounds that are relevant to the fraction. The
primary toxicological endpoints identified for the fraction were neurological, hepatic, body
weight, gastrointestinal [GI], respiratory, and developmental effects. Among members of the
fraction that have undergone in vivo toxicity testing, the data available to assess consistency in
effects are limited for effects on endpoints other than body weight. In addition to the scarcity of
developmental toxicity data for members of the fraction, an important data limitation is the lack
of chronic systemic toxicity information for all but three members of the fraction. Only
cyclohexene, methylcyclohexane, and commercial hexane have been tested in comprehensive
systemic toxicity studies in animals exposed for at least 1 year, all by the inhalation route of
exposure. Furthermore, most of the oral toxicity studies are <13 weeks in duration, and few
examined comprehensive endpoints.
24
Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Table 1. Available RfD Values for Aliphatic Low Carbon Range Fraction (C5-C8 [EC5-EC8])a
Indicator Chemical
or Components
POD
(mg/kg-d)
POD
Type
UFc
UF
Components
RfD or p-RfD
(mg/kg-d)*
Confidence in
RfD or p-RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Subchronic
«-Hexane
(C6 [EC5.80])
785
LOAEL
3,000
UFa, UFd,
UFh, UFl
0.3
Low
Reductions in motor
nerve conduction
velocity (nervous)
Rat, gavage,
8 wk
U.S. EPA (2009a):
Onoetal. (1981)
Methylcyclopentane
(C6 [EC5.89])
357
NOAEL
300
UFa, UFd,
UFh
0.4
Low
Reduced body weight
(body weight)
Rat, gavage,
5 d/wk for 4 wk
U.S. EPA (2009i):
Haider et al.
(1985)
Cyclohexene
(C6 [EC6.24])
4.81
BMDLisd
(HED)
100
UFa, UFd,
UFh
0.05
Low
Increased total serum
bilirubin (hepatic)
Rat, gavage,
one-generation
MHLW (2001) as
cited in U.S. EPA
(2012a)
//-Heptane
(C7 [EC6.71])
3.13
BMDLio
1,000
UFa, UFd,
UFh
0.003b
Low
Based on «-nonane as
analogue; forestomach
histopathology (GI)
Mouse, gavage,
13 wk
Dodd et al. (2003)
as cited in U.S.
EPA (2016a)
2,4,4 -T rimethy lpentene
(C8 [EC6.80-6.90])
41.5
BMDLio
(HED)
300
UFa, UFd,
UFh
o.b
Low
Increased relative liver
weight (hepatic)
Rat, gavage,
one-generation
Huntingdon Life
Sciences (1997a)
as cited in U.S.
EPA (2015)
25
Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Table 1. Available RfD Values for Aliphatic Low Carbon Range Fraction (C5-C8 [EC5-EC8])a
Indicator Chemical
or Components
POD
(mg/kg-d)
POD
Type
UFc
UF
Components
RfD or p-RfD
(mg/kg-d)*
Confidence in
RfD or p-RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Chronic
Cyclohexene
(C6 [EC6.24])
4.81
BMDLisd
(HED)
1,000
UFa, UFd,
UFh, UFs
0.005
Low
Increased total serum
bilirubin
(hepatic)
Rat, gavage,
one-generation
MHLW (2001) as
cited in U.S. EPA
(2012a)
//-Heptane
(C7 [EC6.71])
3.13
BMDLio
10,000
UFa, UFd,
UFh, UFs
0.0003b
Low
Based on «-nonane as
analogue; forestomach
histopathology (GI)
Mouse, gavage,
13 wk
Dodd et al. (2003)
as cited in U.S.
EPA (2016a)
2,4,4 -T rimethy lpentene
(C8 [EC6.80-6.90])
41.5
BMDLio
(HED)
3,000
UFa, UFd,
UFh, UFs
0.01b
Low
Increased relative liver
weight (hepatic)
Rat, gavage,
one-generation
Huntingdon Life
Sciences (1997a)
as cited in U.S.
EPA (2015)
aBolded rows show the compound and toxicity values selected as the indicator chemical for the fraction if analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction.
bToxicity 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; BMDLio = 10% benchmark dose lower confidence limit; C = carbon; EC = equivalent carbon; GI = gastrointestinal;
HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; 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;
UFS = subchronic-to-chronic uncertainty factor.
26
Complex mixtures of aliphatic and aromatic hydrocarbons
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Table 2. Available RfC Values for Aliphatic Low Carbon Range Fraction (C5-C8 [EC5-EC8])a
Indicator
Chemical or
Components
POD
(mg/kg-d)
POD Type
(all are
HECs)
UFc
UF
Components
RfC or p-RfC
(mg/m3)
Confidence in
RfC or p-RfC
Critical Effect(s)
Species,
Mode, and
Duration
Reference
Subchronic
//-Pcntanc
(C5 [EC4.92])
3,658
NOAEL
300
UFa, UFd,
UFh
10
Low
No treatment-related effects
Rat, 6 h/d,
5 d/wk for
13 wk
McK.ee and Frank
(1998) as cited in U.S.
EPA (2009m)
Commercial
hexane
(C6)
804
NOAEL
30
UFa, UFh
27
Medium
Abnormal gait; decreased
body weight; mild atrophy of
sciatic and/or tibial nerve and
skeletal muscle (nervous and
body weight)
Rat, 22 h/d,
7 d/wk for
6 mo
IRDC (1992) as cited
in U.S. EPA (2009e)
w-Hexane
(C6 [EC5.80])
215
BMCLisd
100
UFa, UFd,
UFh
2
Low
Peripheral neuropathy
(nervous)
Rat, 12 h/d,
7 d/wk for
16 wk
Huang (1989) as cited
in U.S. EPA (2009a)
Cyclohexane
(C6 [EC6.16])
1,822
BMCLisd
100
UFa, UFd,
UFh
18
Moderate
Reduced pup weight
(developmental)
Rat, 6 h/d,
5 d/wk,
two-generation
Kreckmann (2000) and
Duootit HLR (1997a).
both as cited in U.S.
EPA (2010a)
//-Heptane
(C7 [EC6.71])
1,170
BMCLisd
300
UFa, UFd,
UFh
4
Low
Loss of hearing sensitivity
(nervous)
Rat, 6 h/d,
7 d/wk for 28 d
Simonsen and Lund
(1995) as cited in U.S.
EPA (2016a)
27
Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Table 2. Available RfC Values for Aliphatic Low Carbon Range Fraction (C5-C8 [EC5-EC8])a
Indicator
Chemical or
Components
POD
(mg/kg-d)
POD Type
(all are
HECs)
UFc
UF
Components
RfC or p-RfC
(mg/m3)
Confidence in
RfC or p-RfC
Critical Effect(s)
Species,
Mode, and
Duration
Reference
Chronic
//-Pcntanc
(C5 [EC4.92])
3,658
NOAEL
3,000
UFa, UFd,
UFh, UFs
1
Low
No treatment-related effects
Rat, 6 h/d,
5 d/wk for
13 wk
McK.ee and Frank
(1998) as cited in U.S.
EPA (2009m)
Commercial
hexane
(C6)
17.59
BMCLio
30
UFa, UFh
0.6
Medium
Nasal epithelial cell
hyperplasia (respiratory)
Rat, 6 h/d,
5 d/wk for 2 yr
Dauehtrev et al. (1999)
and Biodvnamics
(1993). both as cited in
U.S. EPA (2009e)
n-Hexane
(C6 [EC5.80])
215
BMCLisd
300
UFa, UFd,
UFh, UFs
0.7
Medium
Peripheral neuropathy
(nervous)
Rat, 12 h/d,
7 d/wk for
16 wk
Huang et al. (1989) as
cited in U.S. EPA
(2005b)
Cyclohexane
(C6 [EC6.16])
1,822
BMCLisd
300
UFa, UFd,
UFh, UFs
6
Low-moderate
Reduced pup weight
(developmental)
Rat, 6 h/d,
5 d/wk,
2-generatoin
Kreckmann (2000) and
Duootit HLR (1997a).
both as cited in U.S.
EPA (2003e)
Cyclohexene
(C6 [EC6.24])
360
NOAEL
300
UFa, UFd,
UFh
lb
Low
Spongiosis hepatis
(hepatic)
Rat, 6 h/d,
5 d/wk for
104 wk
Mili.W (2003) as cited
in U.S. EPA (2012a)
M-Heptane
(C7 [EC6.71])
1,170
BMCLisd
3,000
UFa, UFd,
UFh, UFs
0.4
Low
Loss of hearing sensitivity
(nervous)
Rat, 6 h/d,
7 d/wk for
28 d
Simonsen and Lund
(1995) as cited in U.S.
EPA (2016a)
aBolded rows show the compounds and toxicity values selected as the indicator chemicals for the fraction if analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction.
bToxicity 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.
BMCL = benchmark concentration lower confidence limit; BMCLio = 10% benchmark concentration lower confidence limit; C = carbon; EC = equivalent carbon;
HEC = human equivalent concentration; NOAEL = no-observed-adverse-effect level; POD = point of departure; PPRTV = Provisional Peer-Reviewed Toxicity Value;
p-RfC = provisional reference concentration; RfC = reference concentration; SD = standard deviation; UF = uncertainty factor; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
28
Complex mixtures of aliphatic and aromatic hydrocarbons
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Available oral and inhalation toxicity data for aliphatic low carbon range compounds did
not show much consistency across fraction members in terms of toxicological effects or
potencies. Thus, there was no basis to identify a surrogate mixture or compound that is
representative of the effects and potency of the fraction as a whole, so the most potent
component compounds and mixtures were considered as the basis for indicator chemical
selection.
Two options are presented for assessment of oral noncancer effects for this fraction. The
first is for use when available analytical chemistry data do not identify concentrations of
individual chemicals composing this fraction. In this case, the subchronic and chronic
provisional reference doses (p-RfDs) (0.05 and 0.005 mg/kg-day, respectively) for cyclohexene
are recommended as the indicator chemical for the aliphatic low carbon range fraction. The
p-RfDs for cyclohexene are based on hepatic toxicity. The available oral toxicity data for
aliphatic low carbon range compounds do not demonstrate significant consistency across fraction
members in terms of toxicological effects or potencies. Therefore, there is no basis to identify an
indicator chemical or mixture that is representative of the effects and potency of the fraction as a
whole. Cyclohexene, among the most potent component compounds and mixtures considered in
this fraction, is the selected indicator chemical (see discussion of method in Section 1.3.1).
Although the RfDs for cyclohexene are not the lowest available, the subchronic and chronic
p-RfD values for w-heptane (0.003 and 0.0003 mg/kg-day, respectively) are not recommended
for the following three reasons. First, the //-heptane p-RfDs are screening values based on an
read-across analysis and therefore carry additional uncertainty associated with the analogue
approach. Second, the analogue upon which the values are based (//-nonane) is outside
(C9 [EC9]) the carbon range of the fraction. Third, the chronic p-RfD for //-heptane is highly
uncertain, derived with a composite uncertainty factor (UFc) of 10,000. Evaluation of available
data [see U.S. EPA (2022a) for further detail] suggests that use of the cyclohexene p-RfD values
is reasonably anticipated to be protective for effects associated with exposure to other
constituents of the fraction. These toxicity values are shown in bold in Table 1 to indicate their
selection as the indicator chemicals for the fraction.
If the available analytical chemistry data quantify the concentrations of //-hexane,
methylcyclopentane, cyclohexene, //-heptane, or 2,4,4-trimethylpentene separately from the
remainder of the low carbon 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 oral exposures, the following subchronic p-RfDs can be used as the
denominator in the HQ equations: //-hexane (0.3 mg/kg-day), methylcyclopentane
(0.4 mg/kg-day), cyclohexene (0.05 mg/kg-day), w-heptane (0.003 mg/kg-day), and
2,4,4-trimethylpentene (0.1 mg/kg-day). In this alternative approach, the subchronic p-RfD
(0.05 mg/kg-day) for cyclohexene is recommended for use with the remainder of the fraction,
including any other fraction members analyzed individually.
For chronic oral exposures, the following chronic p-RfDs can be used in the denominator
of the HQ equations: cyclohexene (0.005 mg/kg-day), w-heptane (0.0003 mg/kg-day), and
2,4,4-trimethylpentene (0.01 mg/kg-day). In this alternative approach, the chronic p-RfD
(0.005 mg/kg-day) for cyclohexene is recommended for use with the remainder of the fraction,
including any other fraction members analyzed individually.
29 Complex mixtures of
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EPA/690/R-22/003F
As with the oral noncancer assessment, two options are presented for inhalation
noncancer assessment of this fraction. If available analytical chemistry data do not identify
concentrations of individual chemicals composing this fraction, the lowest subchronic and
chronic provisional reference concentrations (p-RfCs) among the compounds in this fraction, for
//-hexane and //-heptane, respectively, are recommended for the aliphatic low carbon range
fraction. These toxicity values are shown in bold in Table 2 to indicate their selection as the
indicator chemical for the fraction.
In cases where the available analytical chemistry data quantify the concentrations of
//-pentane, //-hexane, cyclohexane, or //-heptane separately from the remainder of the low carbon
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 following subchronic p-RfCs can be used as the
denominator in the HQ equations: //-pentane (10 mg/m3), //-hexane (2 mg/m3), cyclohexane
(18 mg/m3), and //-heptane (4 mg/m3). In this alternative approach, the subchronic p-RfC for
//-hexane (2 mg/m3) is recommended for use with the remainder of the fraction, including any
other fraction members analyzed individually.
For chronic inhalation exposures, the following chronic p-RfCs can be used as the
denominator in the HQ equations: //-pentane (1 mg/m3), //-hexane (0.7 mg/m3), cyclohexane
(6 mg/m3), cyclohexene (1 mg/m3), and //-heptane (0.4 mg/m3). In this alternative approach, the
chronic p-RfC for //-heptane (0.4 mg/m3) is recommended for use with the remainder of the
fraction, including any other fraction members analyzed individually.
Few data with which to assess the carcinogenic potential of compounds and mixtures in
the aliphatic low carbon range fraction are available. No human or animal studies examining
carcinogenicity were located for any compound or mixture other than commercial hexane,
//-hexane, cyclohexene, and 2,2,4-trimethylpentane. Only the data for commercial hexane were
considered adequate to assess carcinogenic potential, resulting in a weight-of-evidence (WOE)
descriptor of "Suggestive Evidence for Carcinogenic PotentiaF and a provisional IUR (p-IUR)
of 2 x 10 4 (mg/m3)-1 for combined pituitary adenomas and adenocarcinomas in female mice
(U.S. EPA. 2009e). None of the mixtures or constituents in this fraction had an OSF from the
IRIS database, PPRTVs, HEAST, MassDEP, or TPHCWG. Thus, a provisional OSF (p-OSF)
was not derived for the fraction. The only available IUR for members of the aliphatic low carbon
range fraction is the screening value for commercial hexane (U.S. HP A. 2009e); this p-IUR is
selected to assess inhalation carcinogenicity for this fraction. Table 3 shows the recommended
cancer risk estimate for the aliphatic low carbon range fraction.
30
Complex mixtures of
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EPA/690/R-22/003F
Table 3. Available Cancer Risk Estimates for Aliphatic Low Carbon Range
Fraction (C5-C8 [EC5-EC8])a
Toxicity Type (units);
Indicator Chemical
Species/Sex
Tumor Type
Cancer Risk
Estimate
Reference
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)"1;
commercial hexane
Mouse/F
Pituitary adenomas
or adenocarcinomas
2 x 10~4b
Dautrhtrev et al. (1989) and
Biodvnamics (1993), both as cited
in U.S. EPA (2009e)
aBolded row shows the compound and toxicity value selected as the indicator chemical for the fraction
bToxicity 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.
C = carbon; EC = equivalent carbon; F = female; NDr = not determined; p-IUR = provisional inhalation unit risk;
p-OSF = provisional oral slope factor; PPRTV = Provisional Peer-Reviewed Toxicity Value.
3.2. ALIPHATIC MEDIUM CARBON RANGE FRACTION: C9-C18 (EC > 8-EC16)
The aliphatic medium carbon range fraction includes //-nonane, n-decane, and longer
chain «-alkanes; a few «-alkenes (e.g., tridecene); branched chain alkanes and alkenes; and
alkyl-substituted cycloalkanes. Toxicity values for compounds in this fraction are not available
from the U.S. EPA's IRIS database, or from HEAST, AT SDR, MassDEP, or TPHCWG;
PPRTV assessments for //-nonane and //-decane are available. Limited toxicity data are available
for //-undecane (THRA. 2004). ATSDR toxicological profiles and inhalation Minimal Risk
Levels (MRLs) are available for various jet fuels and kerosene, but these mixtures have a
substantial aromatic content and are therefore not suitable to represent the toxicity of this
fraction. The toxicity of this fraction may be better represented by dearomatized hydrocarbon
streams3 and solvents that fall within this carbon range and have minimal (<1.0%) aromatic
content.
A PPRTV assessment for mid-range aliphatic hydrocarbon streams was prepared (U.S.
EPA. 2009i) to synthesize the findings of these mixture studies and additional supporting toxicity
studies on similar mixtures. Complete descriptions of the studies, as well as details of the
derivation of toxicity values for the mixtures, are provided in the PPRTV assessment.
Tables 4, 5, and 6 list the available RfDs, RfCs, and cancer assessments for compounds
or mixtures in this fraction. The mixture data are considered preferable to single component data,
as previously discussed. The toxicity values for the mid-range aliphatic hydrocarbon stream
mixture are the recommended values for this fraction and include subchronic and chronic
p-RfCs. In addition, Table 4 contains screening oral toxicity values for mixture data that may be
useful in evaluating this fraction, developed in Appendix A of U.S. EPA (2009i). Because the
3"Hydrocarbon streams" is a term used in petroleum production and refers to the specific industrial processing and
refining steps applied to crude material. For example, a typical crude oil refinery may produce as many as
8-15 different streams of hydrocarbons that are eventually mixed into motor fuels; see API (2021a) and API
(2021b).
31
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
toxicity data based on the three unpublished studies (Anonymous. 1990. 1991a. b as cited in U.S.
EPA. 2009a) are not peer reviewed, only screening chronic or sub chronic p-RfDs are available
for the mixture. The surrogate mixture and oral and inhalation noncancer toxicity values selected
to represent the fraction are shown in bold in Tables 4 and 5.
32
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 4. Available RfD Values for Aliphatic Medium Carbon Range Fraction (C9-C18 [EC > 8-EC16)a'b
Surrogate Mixture
or Components
POD
POD Type
UFc
UF Components
RfD or p-RfD
(mg/kg-d)
Confidence
in RfD or
p-RfD
Critical Effect(s)
(system)
Species, Mode,
and Duration
Reference
Subchronic
//-Nonanc
(C9 [EC8.62])
3.13
BMDLio
1,000
UFa, UFd, UFh
0.003°
Low
Proliferative
forestomach lesions
(gastrointestinal)
Mouse, gavage,
7 d/wk for 90 d
Dodd et al. (2003) as
cited in U.S. EPA
(20091)
//-Dccanc
(CIO [EC9.57])
1,000
NOAEL
1,000
UFa, UFd, UFh
1.0c
Low
No effects observed
Rat, gavage,
7 d/wk for
4-8 wk
Sasol (1995) as cited in
U.S. EPA (2009k)
Mid-range aliphatic
hydrocarbon stream
100
NOAEL
1,000
UFa, UFd, UFh
o.r
Low
Liver, kidney, and
hematologic effects
Rat, gavage,
7 d/wk for
13 wk
Anonymous (1990,
1991a) as cited in U.S.
EPA (2009i)
Chronic
//-Nonanc
(C9 [EC8.62])
3.13
BMDLio
10,000
UFa, UFd, UFh,
UFS
0.0003c
Low
Proliferative
forestomach lesions
(gastrointestinal)
Mouse, gavage,
7 d/wk for 90 d
Dodd et al. (2003) as
cited in U.S. EPA
(20091)
Mid-range aliphatic
hydrocarbon stream
100
NOAEL
10,000
UFa, UFd, UFh,
UFs
o.or
Low
Liver, kidney, and
hematologic effects
Rat, gavage,
7 d/wk for
13 wk
Anonymous (1990,
1991a) as cited in U.S.
EPA (2009i)
aU.S. EPA (2009a).
bBolded rows show the mixture and toxicity values selected as the surrogate mixture for the fraction.
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.
BMDLio = 10% benchmark dose lower confidence limit; C = carbon; EC = equivalent carbon; NOAEL = no-observed-adverse-effect level; POD = point of departure;
PPRTV = Provisional Peer-Reviewed Toxicity Value; p-RfD = provisional reference dose; RfD = reference dose; UF = uncertainty factor; UFA = interspecies uncertainty
factor; UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
33
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 5. Available RfC Values for Aliphatic Medium Carbon Range Fraction (C9-C18, EC > 8-EC16)a'b
Surrogate Mixture
or Components
POD
POD Type
(all are
HECs)
UFc
UF
Components
RfC or
p-RfC
(mg/m3)
Confidence
in RfC or
p-RfC
Critical Effect(s)
Species, Mode,
and Duration
Reference
Subchronic
//-Nonanc (C9
[EC8.62])
66.4
NOAEL
300
UFa, UFd,
UFh
0.2°
Low
Salivation, lacrimation,
and marginally
depressed body weight
(whole body effects)
Rat, 6 h/d, 5 d/wk
for 13 wk
Carpenter et al. (1978)
as cited in U.S. EPA
(20091)
Mid-range aliphatic
hydrocarbon stream
12
BMCLio
100
UFa, UFd,
UFh
0.1c
Medium
Nasal goblet cell
hypertrophy
Rat, 6 h/d,
5 d/wk for 13 wk
NTP (2004) as cited in
U.S. EPA (2009i)
Chronic
//-Nonanc (C9
[EC8.62])
66.4
NOAEL
3,000
UFa, UFd,
UFh, UFs
0.02°
Low
Salivation, lacrimation,
and marginally
depressed body weight
(whole body effects)
Rat, 6 h/d, 5 d/wk
for 13 wk
Carpenter et al. (1978)
as cited in U.S. EPA
(20091)
Mid-range aliphatic
hydrocarbon stream
12
BMCLio
100
UFa, UFd,
UFh
0.1c
Medium
Nasal goblet cell
hypertrophy and
adrenal hyperplasia
Rat, 6 h/d,
5 d/wk for 13 wk
NTP (2004) as cited in
U.S. EPA (2009i)
aU.S. EPA (2009a).
bBolded rows show the mixture and toxicity values selected as the surrogate mixture for the fraction.
Toxicity values are provisional values obtained from an existing PPRTV assessment.
BMCLio = 10% benchmark concentration lower confidence limit; C = carbon; EC = equivalent carbon; HEC = human equivalent concentration;
NOAEL = no-observed-adverse-effect level; POD = point of departure; PPRTV = Provisional Peer-Reviewed Toxicity Value; p-RfC = provisional reference
concentration; RfC = reference concentration; UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database
uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
34
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 6. Available Cancer Risk Estimates for Aliphatic Medium Carbon
Range Fraction (C9-C18 [EC > 8-EC16]) of Total Petroleum
Hydrocarbons"'b
Toxicity Type (units);
Surrogate Mixture
Species/Sex
Tumor Type
Cancer Value
Reference
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)"1
Mid-range aliphatic hydrocarbon
stream
Rat/M
Benign or
malignant adrenal
pheochromocytoma
4.5 x 10~3c
NTP (2004) as
cited in U.S. EPA
(2009i)
aU.S. EPA (2009a).
bBolded row shows the mixture and toxicity value selected as the surrogate mixture for the fraction
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.
C = carbon; EC = equivalent carbon; M = male; NDr = not determined; p-IUR = provisional inhalation unit risk;
p-OSF = provisional oral slope factor; PPRTV = Provisional Peer-Reviewed Toxicity Value.
As Table 6 shows, quantitative cancer risk assessments were not available for individual
components of the fraction. The mid-range aliphatic hydrocarbon stream mixture data were
considered adequate to develop a quantitative estimate of cancer risk from inhalation exposure.
However, because the WOE indicates "Suggestive Evidence of Carcinogenic Potential," there is
some uncertainty associated with the quantification. Appendix A of the PPRTV assessment
document on the mid-range aliphatic hydrocarbon streams contains a screening p-IUR
(U.S. EPA. 2009i). The screening p-IUR is listed in Table 6 (U.S. EPA. 2009i).
3.3. ALIPHATIC HIGH CARBON RANGE FRACTION: C19-C32 (EC > 16-EC35)
The aliphatic high carbon range fraction includes longer //-alkanes, such as eicosane, and
branched and cyclic alkanes. Toxicity values are not available for the individual compounds. A
search for toxicity information on eicosane in particular was desirable because MassDEP (1994)
suggested it as a reference compound for this fraction, but data supportive of derivation of
toxicity values were not identified. Food- and medicinal-grade mineral oils are pure
(aromatic-free) mixtures of aliphatic hydrocarbons that correspond to this carbon range fraction
and have data suitable for toxicity value derivation. Literature searches on mineral oils were
performed and the medical literature on mineral oils was consulted. Subchronic and chronic
p-RfDs as well as a cancer assessment, including a WOE of "Inadequate Information to Assess
the Carcinogenic Potential' for white mineral oil, were derived in a PPRTV assessment
(U.S. EPA. 2009s). Table 7 summarizes the resulting oral noncancer values (a quantitative
cancer assessment was not performed). These toxicity values are recommended for assessment of
this fraction using a surrogate mixture approach.
35
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 7. Available RfD Values for Aliphatic High Carbon Range Fraction (C19-C32, EC > 16-EC35)a'b
Surrogate
Mixture
POD
POD Type
UFc
UF Components
RfD or p-RfD
(mg/kg-d)
Confidence
in RfD or
p-RfD
Critical Effect(s)
Species, Mode, and
Duration
Reference
Subchronic
White
mineral oils
870
NOAEL
30
UFd, UFh
30c
Low
Lower end of
human therapeutic
dose range for
laxative effects
Human (<1 yr of
age) daily oral
therapeutic use
(870-2,600 mg/kg-d)
NASPGHN (2006)
as cited in U.S. EPA
(2009s)
Chronic
White
mineral oils
870
NOAEL
300
UFd, UFh, UFs
3C
Low
Lower end of
human therapeutic
dose range for
laxative effects
Human (<1 yr of
age) daily oral
therapeutic use
(870-2,600 mg/kg-d)
NASPGHN (2006)
as cited in U.S. EPA
(2009s)
aU.S. EPA (2009V,).
bBolded rows show the mixture and toxicity values selected as the surrogate mixture for the fraction.
Toxicity values are provisional values obtained from an existing PPRTV assessment.
C = carbon; EC = equivalent carbon; NOAEL = no-observed-adverse-effect level; POD = point of departure; PPRTV = Provisional Peer-Reviewed Toxicity Value;
p-RfD = provisional reference dose; RfD = reference dose; UF = uncertainty factor; UFA = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
36 Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
3.4. AROMATIC LOW CARBON RANGE FRACTION: C6-C8 (EC6-EC < 9)
This fraction contains aromatic hydrocarbons in the C6-C8 range: benzene, toluene,
ethylbenzene, and o-, m-, and ^-xylenes (commonly referred to as BTEX) and styrene. It is
unclear, however, whether styrene is a constituent of petroleum products. For example, styrene is
not reported as a constituent of any of the petroleum mixtures including gasoline, kerosene, jet
fuels, diesel fuel, fuel oils, lubricating and motor oils, and crude oil in Potter and Simmons
(1998). Gustafson et al. (1997) lists styrene as a constituent for only one mixture, diesel, at a
very low percentage of <0.002% (by weight), which may mean that it was detected but was
below the quantitation limit. The reference provided for that information is a personal
communication prepared for British Petroleum; thus, the information cannot readily be
confirmed. Given the uncertainty as to whether styrene is likely to exist in sites of petroleum
contamination, it was not considered in the assessment for this fraction.
Tables 8, 9, and 10 list U.S. EPA RfD assessments, RfC assessments, and a cancer
assessment, respectively, that are available on the IRIS database for the individual compounds
(BTEX) in this fraction. In addition, provisional toxicity values were derived for subchronic oral
and inhalation exposure to BTEX (U.S. EPA. 2009b. d, g, t). Because BTEX components are
routinely analyzed individually at sites of aromatic hydrocarbon contamination and noncancer
toxicity values are available for these components, the recommendation for assessing the
noncancer hazard associated with this fraction is to assess the BTEX components individually
using an HI approach and their compound-specific toxicity values. For cancer assessments,
benzene serves as an indicator chemical, because it is the only chemical in this fraction with IRIS
OSF and IUR estimates. The OSF ([1.5 x 10 2—5.5 x 10~2 mg/kg-day]-1) and the IUR
([2.2 x 10~3-7.8 x 10~3 |ig/m3]-1) for benzene (U.S. EPA. 2003b) are used as indicators to
estimate cancer risks for this fraction from exposures through the oral and inhalation routes,
respectively.
37
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 8. Available RfD Values for Aromatic Low Carbon Range Fraction (C6-C8, EC6-EC < 9)a
Components
POD
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence
in RfD or
p-RfD
Critical Effect(s)
Species, Mode, and
Duration
Reference
Subchronic
Benzene
(C6 [EC6.14])
1.2b
BMCLisd
100
UFh, UFl
0.01c
Medium
Decreased
lymphocyte count
(hematologic)
Human
occupational health
study, 0.7-16 yr
Rothtnan et al. (1996) as
cited in U.S. EPA (2009d)
Ethylbenzene
(C8 [EC8.04])
48
BMDLio
1,000
UFa, UFd,
UFh
0.05°
Medium
Centrilobular
hepatocyte
hypertrophy (hepatic)
Rat, gavage, 7 d/wk
for 13 wk
Mellert et al. (2007) as
cited in U.S. EPA (2009e.)
Toluene
(C7 [EC7.14])
238
BMDLisd
300
UFa, UFd,
UFh
0.8°
Medium
Increased kidney
weight (urinary)
Rat, gavage, 5 d/wk
for 13 wk
NTP (1990) as cited in
U.S. EPA (2009b)
Xylenes
(C8 [EC8.12-8.31])
440
BMDLrdo.i
1,000
UFa, UFd,
UFh
0.4°
Low to
medium
10% decrease in body
weight (whole body
effects)
Rat, gavage, 7 d/wk
for 13 wk
Wolfe et al. (1988a) as
cited in U.S. EPA (2009t)
Chronic
Benzene
(C6 [EC6.14])
1.2b
BMCLisd
300
UFh, UFl,
UFS
0.004
Medium
Decreased
lymphocyte count
(immune)
Human
occupational health
study, 0.7-16 yr
Rothtnan et al. (1996) as
cited in U.S. EPA (2003b)
Ethylbenzene
(C8 [EC8.04])
97.1
NOEL
1,000
UFa, UFh,
UFS
0.1
Low
Liver and kidney
toxicity (hepatic,
urinary)
Rat, gavage 5 d/wk
for 26 wk
Wolf et al. (1956) as cited
in U.S. EPA (1991b)
Toluene
(C7 [EC7.14])
238
BMDLisd
3,000
UFa, UFd,
UFh, UFs
0.08
Medium
Increased kidney
weight (urinary)
Rat, gavage, 5 d/wk
for 13 wk
NTP (1990) as cited in
U.S. EPA (2005a)
38
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 8. Available RfD Values for Aromatic Low Carbon Range Fraction (C6-C8, EC6-EC < 9)a
Components
POD
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence
in RfD or
p-RfD
Critical Effect(s)
Species, Mode, and
Duration
Reference
Xylenes
(C8 [EC8.12-8.31])
179
NOAEL
1,000
UFa, UFd,
UFh
0.2
Medium
Decreased body
weight, increased
mortality (other)
Rat, gavage, 5 d/wk
for 103 wk
NTP (1986) as cited in
U.S. EPA (2003c)
aU.S. EPA (2009r).
bBased on route-to-route extrapolation (inhalation to oral).
Toxicity values are provisional values obtained from an existing PPRTV assessment.
BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; BMDLio = 10% benchmark dose lower confidence limit;
C = carbon; EC = equivalent carbon; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level; POD = point of departure; PPRTV = Provisional
Peer-Reviewed Toxicity Value; p-RfD = provisional reference dose; RD = relative deviation; 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;
UFS = subchronic-to-chronic uncertainty factor.
39
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 9. Available RfC Values for Aromatic Low Carbon Range Fraction (C6-C8, EC6-EC < 9)a
Components
POD
POD Type
UFc
UF
Components
RfC or
p-RfC
(mg/m3)
Confidence
in RfD or
p-RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Subchronic
Benzene
(C6 [EC6.14])
8.2
BMCLisd
100
UFh, UFl
0.08b
Medium
Decreased lymphocyte
count (hematologic)
Human
occupational
health study,
0.7-16 yr
Rothman et al. (1996)
as cited in U.S. EPA
(2009d)
Ethylbenzene
(C8 [EC8.04])
868
LOAEL (HEC)
100
UFa, UFh,
UFl
9b
Medium
Histopathological
evidence of ototoxicity
without functional
changes in audiometric
threshold (other)
Rat, 6 h/d, 6 d/wk
for 13 wk
Gaenaire et al. (2007)
as cited in U.S. EPA
(2009g)
Toluene
(C7 [EC7.14])
46
NOAEL
10
UFh
5b
High
Neurological effects in
occupationally exposed
workers (nervous)
Human
occupational
health studies,
1-36-yr exposure
Multiple human
studies, as cited in
U.S. EPA (2009b)
Xylenes
(C8 [EC8.12-8.31])
39
NOAEL (HEC)
100
UFa, UFd,
UFh
0.4b
Medium
Impaired motor
coordination (whole
body effects)
Rat, 6 h/d, 5 d/wk
for 13 wk
Korsak et al. (1994) as
cited in U.S. EPA
(2009t)
Chronic
Benzene
(C6 [EC6.14])
8.2
BMCLisd
300
UFh, UFl,
UFS
0.03
Medium
Decreased lymphocyte
count (immune)
Human
occupational
health study,
0.7-16-yr
exposure
Rothman et al. (1996)
as cited in U.S. EPA
(2003b)
Ethylbenzene
(C8 [EC8.04])
434
NOAEL (HEC)
1,000
UFa, UFd,
UFh
1
Low
Developmental toxicity
(developmental)
Rat and rabbit,
6-7 h/d, 7 d/wk
on GDs 1-19
(rat) or GDs 1-24
(rabbit)
Andrew et al. (1981).
Hardin et al. (1981) as
cited in U.S. EPA
(1991b)
40
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 9. Available RfC Values for Aromatic Low Carbon Range Fraction (C6-C8, EC6-EC < 9)a
Components
POD
POD Type
UFc
UF
Components
RfC or
p-RfC
(mg/m3)
Confidence
in RfD or
p-RfD
Critical Effect(s)
Species, Mode,
and Duration
Reference
Toluene
(C7 [EC7.14])
46
NOAEL
10
UFh
5
High
Neurological effects in
occupationally exposed
workers
(nervous)
Human
occupational
health studies,
1-36-yr exposure
Multiple human
studies, as cited in
U.S. EPA (2005a)
Xylenes
(C8 [EC8.12-8.31])
39
NOAEL (HEC)
300
UFa, UFd,
UFh, UFl
0.1
Medium
Impaired motor
coordination (decreased
rotarod performance)
(nervous)
Rat, 6 h/d, 5 d/wk
for 13 wk
Korsak et al. (1994) as
cited in U.S. EPA
(2003c)
aU.S. EPA (2009r).
bToxicity values are provisional values obtained from an existing PPRTV assessment.
BMCL = benchmark concentration lower confidence limit; C = carbon; EC = equivalent carbon; GD = gestation day; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; 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; UFS = subchronic-to-chronic uncertainty factor.
41
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 10. Available Cancer Risk Estimates for Aromatic Low Carbon
Range Fraction (C6-C8 [EC6-EC < 9])a
Toxicity
Type
(units);
Indicator
Chemical
Species/Sex
Tumor Type
Cancer Value
Reference
OSF (mg/kg-d)1
Benzene
(C6
[EC6.14])
Human/M, F
Leukemia
1.5 x lCT2-5.5 x to-2
Ritiskv et al. (1981. 1987). Paustenbach et al.
(1993). Crutitn and Allen (1984). Cranio (1992.
1994). and U.S. EPA (1998) as cited in U.S.
EPA (2003b)
IUR (mg/m3) 1
Benzene
(C6
[EC6.14])
Human/M, F
Leukemia
2.2 x lCT3-7.8 x 10-3
Ritiskv et al. (1981. 1987). Paustenbach et al.
(1993). Cranio and Allen (1984). Cranio (1992.
1994). and U.S. EPA (1998) as cited in U.S.
EPA (2003b)
aU.S. EPA (2009r).
C = carbon; EC = equivalent carbon; F = female; IUR = inhalation unit risk; M = male; OSF = oral slope factor.
3.5. AROMATIC MEDIUM CARBON RANGE FRACTION: C9-C10 (EC9-EC <11)
Constituents of the aromatic medium carbon range fraction include longer chain and
multi-substituted benzenes (e.g., cumene [isopropylbenzene], //-propylbenzene,
methylethylbenzenes, and TMBs). Toxicity assessment and surrogate selection for the aromatic
medium carbon range fraction is detailed in the PPRTV assessment for this fraction (U.S. HP A.
2022d). This section provides a summary of the approach and results; further detail is available
in the PPRTV assessment.
Toxicity values were identified for eight aromatic medium carbon range compounds and
one mixture. Tables 11 and 12 provide a summary of the noncancer toxicity values, critical
effects, and key studies. Literature searches, OECD SIDS, and the Petroleum HPV Testing
Group website yielded relevant toxicity data for four additional compounds and one additional
mixture4 for use in hazard identification for the fraction. The primary toxicological endpoints
identified for the fraction were neurological, hepatic, renal, body weight, hematological,
endocrine, and developmental effects. The data available to assess consistency in effects across
members of the fraction are limited for effects on endpoints other than body weight. There are no
reliable human or animal data for three members of the fraction (//-propylbenzene, and tert- and
.sec-butylbenzene).5 There are body-weight data for 11 members, and there are neurotoxicity data
for 9 members. For all other primary toxicological endpoints, there are oral or inhalation data for
5-7 members of the fraction. Most of the animal data are from inhalation toxicity studies.
4The four additional aromatic medium carbon range compounds identified in the literature searches and
tree-searching of reviews, OECD SIDS, and the Petroleum HPV Testing Group website are
l-methyl-4-ethylbenzene; 1,3-diethylbenzene; 1,4-diethylbenzene, and 1,2-diethylbenzene; the additional mixture is
a mixture of diethylbenzenes.
5In the absence of human or animal data, screening toxicity values were derived using appropriate analogue
chemicals (ethylbenzene and isopropylbenzene) in the PPRTV assessments of these compounds.
42
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Comprehensive systematic toxicity was evaluated in rats and mice in subchronic and chronic
inhalation studies for one member of the fraction (isopropylbenzene). In general, studies for
other members of the fraction ranged in duration from 4 to 18 weeks; several of these studies
(e.g., diethylbenzenes and TMBs) evaluated only neurological endpoints. Developmental
inhalation toxicity studies were available for four members of the fraction (isopropylbenzene,
1,3,5- and 1,2,4-trimethylbenzene, and high flash aromatic naphtha [HFAN]).
43
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 11. Available RfD Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical,
Components or Mixture
POD
(mg/kg-d)
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence in
p-RfD or RfD
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference (source)
Subchronic
//-Propylbcnzcnc
(C9 [EC8.94])
97.1
NOELadj
1,000
UFa, UFh,
UFS
0.1b
Low
Based on ethylbenzene
as an analogue;
increased liver and
kidney weights
(hepatic, urinary);
histopathologic
changes in kidney
Rat, gavage,
5 d/wk for
182 d
Wolf (1956) as
cited in U.S. EPA
(2009n)
1,3,5-T rimethylbenzene
(C9 [EC9.15])
3.5
BMDL
(HED)
100
UFa, UFd,
UFh
0.04
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvd/vnski (1996)
as cited in
U.S. EPA (2016b)
1,2,4-T rimethylbenzene
(C9 [EC9.36])
3.5
BMDL
(HED)
100
UFa, UFd,
UFh
0.04
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvd/vnski (1996)
as cited in
U.S. EPA (2016b)
fer/-Butylbenzene
(CIO [EC9.36])
110
NOAELadj
1,000
UFa, UFd,
UFh, UFs
0.1b
Low
Based on
isopropylbenzene as an
analogue; increased
kidney weight
(urinary)
Rat, 5 d/wk for
194 d
Wolf (1956) as
cited in U.S. EPA
(2012d)
vc'c-Butylbcn/cnc
(CIO [EC9.57])
110
NOAELadj
1,000
UFa, UFd,
UFh, UFs
0.1b
Low
Based on
isopropylbenzene as an
analogue; increased
kidney weight
(urinary)
Rat, 5 d/wk for
194 d
Wolf (1956) as
cited in U.S. EPA
(2012c)
1,2,3-T rimethylbenzene
(C9 [EC9.65])
3.5
BMDL
(HED)
100
UFa, UFd,
UFh
0.04
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvd/vnski (1996)
as cited in
U.S. EPA (2016b)
44
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 11. Available RfD Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical,
Components or Mixture
POD
(mg/kg-d)
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence in
p-RfD or RfD
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference (source)
//-Butylbcnzcnc
(CIO [EC9.96])
137
BMDLio
1,000
UFa, UFd,
UFh
0.1b
Low
Increased incidence of
hepatocellular
hypertrophy in F0 and
Fi parent male rats
(hepatic)
Rat, gavage,
2-genearation
Izumi et al. (2005)
as cited in
U.S. EPA (2010b)
HFAN
(C9-10)
85
BMDLisd
300
UFa, UFd,
UFh
0.3b
Low
Mild anemia,
evidenced by a
decrease in RBC count
(hematological)
Dog, gelatin
capsules,
13 wk
Bio l)vnatnics Inc.
(1990b) as cited in
U.S. EPA (2009h)
Chronic
Isopropylbenzene
(C9 [EC8.66])
110
NOAELadj
1,000
UFa, UFd,
UFh, UFs
0.1
Low-medium
Increased average
kidney weight in
female Wistar rats
(urinary)
Rat, 5 d/wk for
194 d
Wolf (1956) as
cited in U.S. EPA
(1997b)
«-Propylbenzene
(C9 [EC8.94])
97.1
NOELadj
1,000
UFa, UFh,
UFS
0.1b
Low
Based on ethylbenzene
as an analogue;
increased liver and
kidney weights
(hepatic, urinary)
Rat; gavage;
5 d/wk for
182 d
Wolf (1956) as
cited in U.S. EPA
(2009n)
1,3,5-T rimethylbenzene
(C9 [EC9.15])
3.5
BMDL
(HED)
300
UFa, UFd,
UFh, UFs
0.01
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvd/vnski (1996)
as cited in
U.S. EPA (2016b)
1,2,4-T rimethylbenzene
(C9 [EC9.36])
3.5
BMDL
(HED)
300
UFa, UFd,
UFh, UFs
0.01
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvd/vnski (1996)
as cited in
U.S. EPA (2016b)
45
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 11. Available RfD Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical,
Components or Mixture
POD
(mg/kg-d)
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence in
p-RfD or RfD
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference (source)
fer/-Butylbenzene
(CIO [EC9.36])
110
NOAELadj
1,000
UFa, UFd,
UFh, UFs
0.1b
Low
Based on
isopropylbenzene as an
analogue; increased
kidney weight
(urinary)
Rat, 5 d/wk for
194 d
Wolf (1956) as
cited in U.S. EPA
(2012d)
sec-Butylbenzene
(CIO [EC9.57])
110
NOAELadj
1,000
UFa, UFd,
UFh, UFs
0.1b
Low
Based on
isopropylbenzene as an
analogue; increased
kidney weight
(urinary)
Rat, 5 d/wk for
194 d
Wolf (1956) as
cited in U.S. EPA
(2012c)
1,2,3-T rimethylbenzene
(C9 [EC9.65])
3.5
BMDL
(HED)
300
UFa, UFd,
UFh, UFs
0.01
Low
Decreased pain
sensitivity in male
Wistar ratsc (nervous)
Rat, 6 h/d,
5 d/wk for
13 wk
Korsak and
Rvdzvnski (1996)
as cited in U.S.
EPA (2016b)
«-Butylbenzene
(CIO [EC9.96])
137
BMDL io
3,000
UFa, UFd,
UFh, UFs
0.05b
Low
Increased incidence of
hepatocellular
hypertrophy in F0 and
Fi parent male Cij:CD
(SD) IGS rats (hepatic)
Rat, gavage,
two-generation
Izumi et al. (2005)
as cited in U.S.
EPA (2010b)
46
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 11. Available RfD Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical,
Components or Mixture
POD
(mg/kg-d)
POD Type
UFc
UF
Components
RfD or
p-RfD
(mg/kg-d)
Confidence in
p-RfD or RfD
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference (source)
HFAN
(C9-10)
85
BMDLisd
3,000
UFa, UFd,
UFh, UFs
0.03b
Low
Mild anemia,
evidenced by a
decrease in RBC count
(hematological)
Dog, gelatin
capsules,
13 wk
Bio Dvnatnics Inc.
(1990b) as cited in
U.S. EPA (2009h)
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.
bToxicity 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.
Toxicity values based on route-to-route extrapolation (inhalation to oral) using a modified PBPK model.
ADJ = adjusted; BMDL = benchmark dose lower confidence limit; BMDLio = 10% benchmark dose lower confidence limit; C = carbon; EC = equivalent carbon;
HED = human equivalent dose; HFAN = high-flash aromatic naphtha; NOAEL = no-observed-adverse-effect level; NOEL = no-observed-effect level;
PBPK = physiologically based pharmacokinetic; POD = point of departure; PPRTV = Provisional Peer-Reviewed Toxicity Value; p-RfD = provisional reference dose;
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; UFS = subchronic-to-chronic uncertainty factor.
47
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 12. Available RfC Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical
Components, or
Mixture
POD
POD Type
(all are
HECs)
UFc
UF
Components
RfC or p-RfC
(mg/m3)
Confidence in
p-RfC or RfC
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference
(source)
Subchronic
//-Propylbcnzcnc
(C9 [EC8.94])
434
NOAEL
300
UFa, UFd,
UFh
lb
Low
Based on ethylbenzene
as an analogue;
developmental toxicity
(developmental)
Rat, 6-7 h/d,
7 d/wk for 3 wk
prior to mating
and GDs 1-19;
rabbit, 6-7 h/d,
7 d/wk on
GDs1-24
Andrews (1981)
and Hardin (1981).
as cited in U.S.
EPA (2009n)
1,3,5-T rimethylbenzene
(C9 [EC9.15])
18.15
BMCL
100
UFa, UFd,
UFh
0.2
Low-medium
Decreased pain
sensitivity in male
Wistar rats
(nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
1,2,4-T rimethylbenzene
(C9 [EC9.36])
18.15
BMCL
100
UFa, UFd,
UFh
0.2
Low-medium
Decreased pain
sensitivity in male
Wistar rats
(nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
1,2,3-T rimethylbenzene
(C9 [EC9.65])
18.15
BMCL
100
UFa, UFd,
UFh
0.2
Low-medium
Decreased pain
sensitivity in male
Wistar rats
(nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
HFAN
(C9-10)
125
LOAEL
300
UFa, UFh,
UFl
lb
Moderate
Decreased maternal
body weight vs. controls
(reproductive) in CD-I
mice
Mouse, 6 h/d,
7 d/wk on
GDs 6-15
McK.ee et al.
(1990) as cited in
U.S. EPA (2009h)
48
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 12. Available RfC Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical
Components, or
Mixture
POD
POD Type
(all are
HECs)
UFc
UF
Components
RfC or p-RfC
(mg/m3)
Confidence in
p-RfC or RfC
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference
(source)
Chronic
Isopropylbenzene
(C9 [EC8.66])
435
NOAEL
1,000
UFa, UFd,
UFh, UFs
04
Medium
Increased kidney
weights in female rats
and adrenal weights in
male and female F344
rats (endocrine, urinary)
Rat, 6 h/d, 5 d/wk
for 13 wk
Cushman (1995)
as cited in U.S.
EPA ( 1997b)
«-Propylbenzene
(C9 [EC8.94])
434
NOAEL
300
UFa, UFd,
UFh
lb
Low
Based on ethylbenzene
as an analogue;
developmental toxicity
(developmental)
Rat, 6-7 h/d,
7 d/wk for 3 wk
prior to mating
and GDs 1-19;
rabbit, 6-7 h/d,
7 d/wk on
GDs1-24
Andrews (1981)
and Hardin (1981).
as cited in U.S.
EPA (2009n)
1,3,5-T rimethylbenzene
(C9 [EC9.15])
18.15
BMCL
300
UFa, UFd,
UFh, UFs
0.06
Low-medium
Decreased pain
sensitivity in male
Wistar rats (nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
1,2,4-T rimethylbenzene
(C9 [EC9.36])
18.15
BMCL
300
UFa, UFd,
UFh, UFs
0.06
Low-medium
Decreased pain
sensitivity in male
Wistar rats (nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
1,2,3-T rimethylbenzene
(C9 [EC9.65])
18.15
BMCL
300
UFa, UFd,
UFh, UFs
0.06
Low-medium
Decreased pain
sensitivity in male
Wistar rats (nervous)
Rat, 6 h/d,
5 d/wk for 13 wk
Korsak and
Rvd/vnski (1996)
as cited in U.S.
EPA (2016b)
49
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 12. Available RfC Values for Aromatic Medium Carbon Range Fraction (C9-C10 [EC9-EC < ll])a
Indicator Chemical
Components, or
Mixture
POD
POD Type
(all are
HECs)
UFc
UF
Components
RfC or p-RfC
(mg/m3)
Confidence in
p-RfC or RfC
Critical Effect(s)
Species, Mode,
and Duration
Primary
Reference
(source)
HFAN
(C9-10)
125
LOAEL
1,000
UFa, UFh,
UFl, UFs
0.1b
Moderate
Decreased maternal
body weight vs. controls
(reproductive) on GD 15
in CD-I mice
Mouse, 6 h/d,
7 d/wk on
GDs 6-15
McK.ee et al.
(1990) as cited in
U.S. EPA (2009h)
aBolded row shows the compounds 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.
bToxicity 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.
BMCL = benchmark concentration lower confidence limit; C = carbon; EC = equivalent carbon; GD = gestation day; HEC = human equivalent concentration;
HFAN = high-flash aromatic naphtha; LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of departure;;
PPRTV = Provisional Peer-Reviewed Toxicity Value; p-RfC = provisional reference concentration; RfC = reference concentration; UF = uncertainty factor;
UFa = interspecies uncertainty factor; UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFS = subchronic-to-chronic uncertainty factor.
50
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
The data available to assess consistency in critical effects across members of the fraction
are limited for effects on endpoints other than body weight. The potencies are comparable with
RfDs being within 1 order of magnitude of one another. Given the limited data, the compounds
that resulted in the lowest RfDs for these effects and target tissues were considered as the basis
for indicator chemical selection. The subchronic and chronic p-RfDs (0.04 and 0.01 mg/kg-day,
respectively) for TMBs are recommended as indicator chemicals for the aromatic medium
carbon range fraction. The RfDs for TMBs are based on neurological effects (decreased pain
sensitivity). While toxicological data from mixtures such as HFAN might be preferred in some
cases, the p-RfD for HFAN is based on a screening value, and the Agency has more confidence
in EPA's IRIS TMB oral assessments as the indicator chemical.
Options for oral noncancer assessment of this fraction are presented based on available
analytical chemistry information.
If available analytical chemistry data do not identify concentrations of individual
chemicals composing this fraction, the subchronic and chronic p-RfDs (0.04 and
0.01 mg/kg-day, respectively) for TMBs are recommended for the aromatic medium carbon
range fraction (U.S. EPA. 2016b). Evaluation of available data suggests that use of the p-RfDs
for TMBs is reasonably anticipated to be protective for effects associated with exposure to other
constituents of the fraction. The indicator chemical and oral noncancer toxicity values selected to
represent the fraction are shown in bold in Table 11.
If the available analytical chemistry data quantify the concentrations of TMBs,
//-propylbenzene, //-butylbenzene, sec-butylbenzene, /e/7-butylbenzene, or isopropylbenzene
separately from the remainder of the aromatic medium 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 oral exposures, the following subchronic RfDs or p-RfDs can be used as
the denominator in the HQ equations: TMBs (0.04 mg/kg-day), //-propylbenzene
(0.1 mg/kg-day), //-butylbenzene (0.1 mg/kg-day), sec-butylbenzene (0.1 mg/kg-day), and
/e/7-butylbenzene (0.1 mg/kg-day). In this alternative approach, the subchronic RfD for TMBs
(0.04 mg/kg-day) is recommended for use with the remainder of the fraction, including any other
fraction members analyzed individually.
For chronic oral exposures, the following chronic RfDs or p-RfDs can be used as the
denominator in the HQ equations: TMBs (0.01 mg/kg-day), isopropylbenzene (0.1 mg/kg-day),
//-propylbenzene (0.1 mg/kg-day), //-butylbenzene (0.05 mg/kg-day), sec-butylbenzene
(0.1 mg/kg-day), and /^/'/-butylbenzene (0.1 mg/kg-day). In this alternative approach, the chronic
RfD for TMBs (0.01 mg/kg-day) is recommended for use with the remainder of the fraction,
including any other fraction members analyzed individually.
In some cases, toxicological data from mixtures such as HFAN might be preferred;
however, the p-RfD for HFAN is based on a screening value. The Agency has more confidence
in an HI approach as an alternative to the indicator chemical approach than for the surrogate
mixture approach for this fraction.
51
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Critical effects and values of RfCs for fraction members show consistency across the
fraction with respect to the toxicological effects exerted (most frequently, neurological and
developmental effects). The data show that an indicator chemical identifying effects on these
targets would be reasonably anticipated to be representative of the effects of the fraction as a
whole. Therefore, the compounds that resulted in the lowest RfCs for these effects were
considered as the basis for surrogate selection.
As with oral noncancer assessment, two options for inhalation noncancer assessment are
presented. If available analytical chemistry data do not identify concentrations of individual
chemicals in this fraction, the subchronic and chronic p-RfCs (0.2 mg/m3 and 0.06 mg/m3,
respectively) for TMBs (U.S. EPA. 2016b) are recommended as an indicator chemical for the
aromatic medium carbon range fraction. The RfCs for TMBs are based on neurological effects
(decreased pain sensitivity), and available data generally support the nervous system as a target
of the aromatic medium carbon compounds. Use of these values is anticipated to be protective
for exposure to other constituents based on available information. The indicator chemical and
inhalation noncancer toxicity values selected to represent the fraction are shown in bold in
Table 12.
Previously, in the PPRTV TPH mixtures document (U.S. EPA. 2009f). the HFAN
subchronic and chronic p-RfCs were recommended for assessing noncancer hazards associated
with inhalation route exposures to this fraction, based on a 2009 PPRTV assessment (U.S. EPA.
200%). In 2016, the U.S. EPA IRIS Program published TMB subchronic and chronic p-RfCs of
0.2 and 0.06 mg/m3, respectively (U.S. EPA. 2016b) that are lower than the respective HFAN
values of 1 and 0.1 mg/m3 (U.S. EPA. 2009h) (see Table 12). Because these are IRIS values
rather than PPRTVs, these IRIS single chemical values should be used in the indicator chemical
approach rather than HFAN-based surrogate mixture approach. The 2009 TPH mixture
assessment indicates that the HFAN toxicity values are similar to values for other individual
compounds in the fraction, which supports using HFAN as a surrogate for the fraction; however,
the 2016 TMB values are much lower than the HFAN values and that logic is not applicable.
If the available analytical chemistry data quantify the concentrations of TMBs,
//-propylbenzene, or isopropylbenzene separately from the remainder of the aromatic medium
carbon range fraction, it is recommended that HQs for the individual chemicals with analytical
data be calculated and a HI for the mixture be developed using the calculated HQs.
For subchronic inhalation exposures, the subchronic RfCs or p-RfCs for TMBs
(0.2 mg/m3) or w-propylbenzene (1.0 mg/m3) can be used as the denominator in the HQ
equations. In this alternative approach, the subchronic RfC for TMBs (0.2 mg/m3) is
recommended for use with the remainder of the fraction, including any other fraction members
analyzed individually.
For chronic inhalation exposures, the following chronic RfCs or p-RfCs can be used in
the denominator of the HQ equations: TMBs (0.06 mg/m3), isopropylbenzene (0.4 mg/m3), and
//-propylbenzene (1 mg/m3). In this alternative approach, the chronic RfC for TMBs
(0.06 mg/m3) is recommended for use with the remainder of the fraction, including any other
fraction members analyzed individually.
52
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Previously, in the PPRTV TPH mixtures document (U.S. EPA. 2009f). the HFAN
subchronic and chronic p-RfCs were recommended for assessing noncancer hazards associated
with inhalation route exposures to this fraction, based on a 2009 PPRTV assessment (U.S. HP A.
200%). By definition, HFAN mixtures must contain a combined total of 75% TMB and
ethyltoluene isomers (of which at least 22% is ethyltoluene and at least 15% is TMB) (U.S. HP A.
200%). As noted previously, in 2016, the U.S. EPA IRIS Program published TMB subchronic
and chronic p-RfCs of 0.2 and 0.06 mg/m3, respectively (U.S. HP A. 2016b) that are lower than
the HFAN values of 1 and 0.1 mg/m3, respectively (U.S. HP A. 2009fa) (see Table 12). Because
these are IRIS values rather than PPRTVs, the U.S. EPA has more confidence in using these
IRIS single chemical values in a hazard index approach rather than the HFAN values in
surrogate mixture approach. The 2009 TPH mixture assessment indicates that the HFAN toxicity
values are similar to values for other individual compounds in the fraction, which supports using
HFAN as a surrogate for the fraction; however, the 2016 TMB values are much lower than the
HFAN values and that logic is not applicable.
Few data are available to assess the carcinogenic potential of compounds and mixtures in
the aromatic medium carbon range fraction. No human data were identified. Animal data are
limited to studies of 1,2,4-trimethylbenzene and isopropylbenzene. Several limitations were
identified in the only carcinogenicity study of 1,2,4-trimethylbenzene reported in U.S. HP A
(2016b); these limitations included the use of one rodent species, treatment at a single dose level,
and lack of quantitative mortality data. Only data from a newly identified study for
isopropylbenzene (N I P. 2009) are considered adequate to sufficiently assess carcinogenic
potential. This recently identified study was a 105-week chronic toxicity/carcinogenicity study of
isopropylbenzene in rats and mice (NTP. 2009). Statistically significant increases in the
incidence of respiratory epithelial adenomas of the nose in both sexes and renal adenoma or
carcinoma (combined) in males were observed in rats. Increased interstitial cell adenomas were
also reported in the male testis; however, the NTP report stated that these are possibly related to
isopropylbenzene exposure. While the incidence of interstitial cell adenomas reported in the
highest dose group in the male rats was significantly increased compared to the control group
and there was a positive trend in the incidences reported among all exposed groups, the incidence
in the high-dose group was within the range for historical chamber controls when studies with all
exposure routes were considered. Interstitial cell hyperplasia and adenoma are common
proliferative lesions in F344/N rats (i.e., the test species) and reportedly will develop in nearly all
male rats of this strain that are allowed to complete their natural life span (NTP. 2009). In mice,
the incidences of alveolar/bronchiolar adenomas were significantly increased in both sexes;
increased incidences of hemangiosarcomas and follicular cell adenomas in males (possibly
related to exposure) and hepatocellular adenomas or carcinomas in females were also noted.
Based on these data, the study authors indicated that there was clear evidence of carcinogenicity
in male rats and male and female mice, and some evidence of carcinogenic activity in female
rats.
None of the mixtures or constituents in this fraction had an OSF or IUR from the IRIS
database, PPRTVs, HEAST, MassDEP, or TPHCWG. At this time, the U.S. EPA has not
formally evaluated the NTP (2009) study and has not estimated the cancer potency associated
with the study results. Thus, a p-OSF or p-IUR was not derived for the fraction.
53
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
3.6. AROMATIC HIGH CARBON RANGE FRACTION: C10-C32 (EC11-EC35)
The aromatic high carbon range fraction contains PAHs (e.g., naphthalene, anthracene,
BaP, BeP, dibenzo[de/p]chrysene) and benzenes with larger aliphatic substituents
(e.g., //-hexylbenzene, phenylcyclohexane). This fraction is further subdivided for the purposes
of this document. Unsubstituted PAHs consist of aromatic hydrocarbons comprised of two to six
fused aromatic hydrocarbon rings and exclude all compounds with alkyl or other substituents on
the ring as well as compounds with anything other than carbon and hydrogen in their
composition (i.e., exclude heterocyclic compounds). Substituted PAHs (subPAHs) include alkyl-
substituted PAH derivatives such as 1,4-dimethylphenanthrene, 1-methylnaphthalene, and
5-methylchrysene. Carcinogenic fraction members that cannot be classified as either PAH or
subPAH include all other aromatic hydrocarbons within the C10-C32 and EC11-EC35 ranges
that occur in petroleum contamination, such as 1,1-biphenyl. Noncancer toxicity assessment and
surrogate selection for the aromatic high carbon range fraction is detailed in the PPRTV
assessment for this fraction (U.S. EPA. 2022c). This section provides a summary of the approach
and results; further detail is available in the PPRTV assessment.
Noncancer toxicity values were identified for 10 aromatic high carbon range compounds.
Tables 13, 14, and 15 provide summaries of the toxicity values, critical effects, and key studies.
Literature searches and searches of reviews, OECD SIDS and the Petroleum HPV Testing Group
website yielded relevant toxicity data for five additional compounds and three defined mixtures6
for use in hazard identification for the fraction. In addition, limited toxicity data that were not
sufficient to derive a toxicity value are available in the PPRTV assessment for phenanthrene
(U.S. HP A. 2009o). Critical effects identified with existing toxicity values were 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 GI system.
6The five additional aromatic medium carbon range compounds identified in the literature searches and
tree-searching of reviews, OECD SIDS, and the Petroleum HPV Testing Group website are benzo[/>]fluoranthene,
benzo[c]fluorene, dibenzo[fife//>]chrysene, 1,2,4-triethylbenzene, and 1,3,5-triethylbenzene; the additional mixtures
are PAH mixtures containing 21, 16, or 9 PAHs.
54 Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 13. 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] py reneb
(C20 [EC29.95])
0.092
BMDLisd
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 (2017)
Benzo [e]pyrene (C20
[EC27.80])
0.092
BMDLisd
1,000
UFa, UFh, UFd
0.00009c
NA
Based on
benzo|c/|pyrenc 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
NIP (1991) as
cited in ATSDR
(2005)
2-Methylnaphthalene
(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 (2007c)
1,1-Biphenyl
(C12 [EC13.45])
9.59
BMDLo5
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
BMDLio
1,000
UFa, UFd, UFh
0.2°
Low
Increased relative
liver weight in
females (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
(2009c)
55
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 13. 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 (2007d)
Fluoranthene
(C16 [EC21.11])
124
BMDL10
1,000
UFa, UFd, UFh
0.1c
Low
Nephropathy
(urinary)
Mouse, gavage,
13 wk
U.S. EPA (1989)
as cited in U.S.
EPA (2012b)
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.
56
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 14. 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
BMDLisd
300
UFac, UFd,
UFh
0.0003
Medium
Neurobehavioral
changes
(developmental)
Rat, gavage,
PNDs 5-11
Chen et al. (2012) as
cited in U.S. EPA
(2017)
Benzo [e]pyrene
(C20 [EC27.80])
0.092
BMDLisd
1,000
UFA, UFH,
UFD
0.00009d
NA
Based on
benzo [a]pyrene as an
analogue;
neurodevelopmental
changes
(developmental)
Rat, gavage,
PNDs 5-11
U.S. EPA (2021b)
Naphthalene
(CIO [EC11.57])
71
NOAELadj
3,000
UFa, UFd,
UFh, UFs
0.02
Low
Decreased mean
terminal body weight
in males (other)
Rat, gavage,
5 d/wk, 13 wk
BCL (1980) as cited
in U.S. EPA (1998)
2-Methylnaphthalene
(Cll [EC12.72])
3.5
BMDL05
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
(2003d)
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
Murata et al. (1993)
as cited in U.S. EPA
(2008)
1,1-Biphenyl
(C12 [EC13.45])
13.9
BMDLio
(HED)
30
UFa, UFh
0.5
Medium-high
Renal papillary
mineralization in male
F344 rats (urinary)
Rat, diet,
104 wk
Utneda et al. (2002)
as cited in U.S. EPA
(2013b)
Acenaphthene
(C12 [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)
57
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 14. 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
Wolfe (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. 20171.
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; PND = postnatal day; POD = point of departure; PPRTV = Provisional Peer-Reviewed Toxicity Value; p-RfD = provisional
reference dose; 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.
58
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 15. Available RfC Values for Aromatic High Carbon Range Fraction (C10-C32 [ECll-EC35])a
Indicator
Chemical or
Components
POD
(mg/m3)
POD Type
(all are
HECs)
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
Camion Laboratories
Inc. (1977) as cited in
U.S. EPA (2011a)
Benzo [a] pyrened
(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
Archibong et al.
(2002) as cited in
U.S. EPA (2017)
Benzo [e]pyrene
(C20 [EC27.80])
0.0046
LOAEL
3,000
UFa, UFh,
UFd, UFl
0.000002°
Low
Based on benzo [a]pyrene
as an analogue; decreased
embryo/fetal survival
(developmental)
Rat, 4 h/d on
GDs11-20
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
Medium
Nasal effects: hyperplasia
and metaplasia in
respiratory and olfactory
epithelium, respectively
(nervous, respiratory)
Mouse, 6 h/d,
5 d/wk for
2 yr
NTP (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
Archibong et al.
(2002) as cited in
U.S. EPA (2017)
59
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 15. Available RfC Values for Aromatic High Carbon Range Fraction (C10-C32 [ECll-EC35])a
Indicator
Chemical or
Components
POD
(mg/m3)
POD Type
(all are
HECs)
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, UFh,
UFd, UFl
0.000002°
NA
Based on benzo[a]pyrene
as an analogue; decreased
embryo/fetal survival
(developmental)
Rat, 4 h/d on
GDs11-20
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 assessment 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.
60 Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
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.
Based on review of the available data [see (U.S. EPA. 2022c) for further details], 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).
The lowest oral subchronic and chronic RfD among the compounds in this fraction that is
not a screening value is the chronic RfD for BaP (see Table 14); 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. In addition,
extensive chronic toxicity information has been reported for BaP and the developmental endpoint
is the most sensitive. Subchronic and chronic toxicity values for several other PAHs, except for
those of BeP, which is a screening value, 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 in this fraction may induce
altered reproductive tract development (Kim et al.. 2011). neurodevelopmental effects (Crepeaux
et at.. 2014; Crepeaux et al.. 2013. 2012). transgenerational changes in immune function (Chu et
al.. 2013) or 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 toxicologically relevant for
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
61
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
aromatic high carbon range fraction than for its applications in assessments of BaP as an
individual chemical in U.S. EPA (2017).
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 analytical data be
calculated and an HI for the mixture be developed using the calculated HQs.
For subchronic oral exposures, the following subchronic RfDs or p-RfDs can be used as
the denominator in the HQ equations: naphthalene (0.6 mg/kg-day), 2-methylnaphthalene
(0.004 mg/kg-day), 1,1-biphenyl (0.1 mg/kg-day), acenaphthene (0.2 mg/kg-day), fluorene
(0.4 mg/kg-day), anthracene (1 mg/kg-day), pyrene (0.3 mg/kg-day), BeP (9 x 10~5 mg/kg-day),
and fluoranthene (0.1 mg/kg-day). 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.
For chronic oral exposures, the following chronic RfDs or p-RfDs can be used as the
denominator in the HQ equations: naphthalene (0.02 mg/kg-day), 2-methylnaphthalene
(0.004 mg/kg-day), 1-methylnaphthalene (0.007 mg/kg-day), 1,1-biphenyl (0.5 mg/kg-day),
acenaphthene (0.06 mg/kg-day), fluorene (0.04 mg/kg-day), anthracene (0.3 mg/kg-day), pyrene
(0.03 mg/kg-day), fluoranthene (0.04 mg/kg-day), BeP (9 x 10~5 mg/kg-day), and BaP
(0.0003 mg/kg-day). 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.
The lowest RfC among the compounds in this fraction is the chronic RfC for BaP
(see Table 15)7; this value is recommended as the indicator chemical 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 IRIS program did not develop subchronic values), the chronic
RfC is based on a developmental exposure, so the RfC value is applicable to subchronic
exposures as well. In addition, extensive chronic toxicity information has been reported for BaP
and the developmental endpoint is the most sensitive. Several 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, emerging information (Crepeaux et al.. 2014: Yan et al.. 2014:
Chu et al.. 2013: Crepeaux et al.. 2013. 2012) on mixtures shows neurodevelopmental effects at
exposures 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.
7Both the subchronic and chronic p-RfCs for BeP are the same as those for BaP. The U.S. EPA's BeP p-RfCs were
developed using a read-across approach where BaP was the selected analogue.
Complex mixtures of
aliphatic and aromatic hydrocarbons
62
-------
EPA/690/R-22/003F
If the available analytical chemistry data quantify the concentrations of 1,1-biphenyl,
naphthalene, BeP or BaP 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-RfCs for 1,1-biphenyl
(0.004 mg/m3) and 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 following chronic RfCs or p-RfCs can be used in
the denominator of the HQ equations: naphthalene (0.003 mg/m3), 1,1-biphenyl (0.0004 mg/m3),
BeP (2 x 10 6 mg/m3), and BaP (2 x 10 6 mg/m3). 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.
Table 16 shows the available cancer risk estimates for components of the fraction. If
analytical chemistry data do not identify concentrations of individual chemicals composing this
fraction, an indicator chemical approach should be used. In this case, the BaP OSF should be
integrated with an estimate of the oral exposure rates for the aromatic high carbon range fraction
to estimate the oral cancer risk. The IUR should be estimated with the concentration of the
fraction in the air to estimate the inhalation cancer risk. Table 17 shows the available RPF values
for seven PAHs, with BaP serving as the IC. If analytical chemistry data identify individual
concentrations of any of these seven PAH composing this fraction, an RPF approach should be
used. In this case, the BaP OSF and IUR estimates can be integrated with estimates of the
individual PAH exposure rates to estimate the oral or inhalation cancer risk associated with
exposure to the fraction. If analytical chemistry data identify concentrations of individual of
PAHs, subPAHs, and other carcinogenic fraction members with cancer risk values, an integrated
addition approach should be used. The integrated addition approach assumes that the
carcinogenic MO As of the PAHs are independent of those of subPAH, 1-methylnaphthalene, and
the other carcinogenic fraction member, 1,1-biphenyl. In this case, the RPF approach can be used
to estimate cancer risk associated with the PAH portion of the fraction, and p-OSF values for
1-methylnaphthalene and 1,1-biphenyl can be integrated individually with their corresponding
exposure rates. Response addition can then be used to sum risks across the three similarity
groups (i.e., PAH, 1-methylnaphthalene, and 1,1-biphenyl) to estimate the oral cancer risk
associated with exposure to the fraction. Because IURs (or p-IURs) were not identified for either
1-methylnaphthalene or 1,1-biphenyl, the integrated addition approach is only applicable to
estimating oral cancer risks at this time.
63
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 16. Available Cancer Risk Estimates for Aromatic High Carbon
Range Fraction (C10-C32 [ECll-EC35])a b
Toxicity Type
(units);
Indicator Chemical
or Component
Species/Sex
Tumor Type
Cancer
Value
Reference
OSF or p-OSF (mg/kg-d)1
1 -Methy lnaphthalene
(Cll [EC12.77])
Mouse/M
Lung adenomas or carcinomas
2.9 x KT2c
Murata et al. (1997) as
cited in U.S. EPA (2008)
1,1-Biphenyl
(C12 [EC13.45])
Mouse/F
Liver
8 x 10-3
Unieda et al. (2005) as
cited in U.S. EPA (2013b)
Benzo[a]pyrene
(C20 [EC29.95])
Rat/M, F;
mouse/F
Forestomach, esophagus, tongue,
and larynx tumors
1
Kroese et al. (2001),
Beland and Culo (1998)
as cited in U.S. EPA
(2017)
IUR (mg/m3) 1
Benzo[a]pyrene
(C20 [EC29.95])
Hamster/M
Squamous cell neoplasia in the
larynx, pharynx, trachea, nasal
cavity, esophagus, and forestomach
6 x 101
Thvssen et al. (1981) as
cited in U.S. EPA (2017)
aInthe 2007 PPRTV assessment, a screening p-OSF of 0.7 (mg/kg-day) 1 was derived for benz[a]anthracene using
the RPF and OSF for benzo[a]pyrene at the time. Both the RPF for benz[a]anthracene (see Table 17) and the OSF
for bcnzo|fl|pyrcnc have since been updated, so this value is no longer relevant and is not presented herein.
bBolded rows show the compound and toxicity values selected as the indicator chemical for the fraction if
analytical chemistry data do not identify concentrations of individual chemicals composing this fraction.
Toxicity value is a provisional value obtained from an existing PPRTV assessment.
C = carbon; EC = equivalent carbon; F = female; IUR = inhalation unit risk; M = male; NDr = not determined;
OSF = oral slope factor; PPRTV = Provisional Peer-Reviewed Toxicity Value; p-OSF = provisional oral slope
factor.
Table 17. RPFs in the U.S. EPA's 1993 Provisional Guidance
PAH (abbreviation)
RPF
Source(s)
Bcnzo|fl|pyrcnc (BaP)
1
NA
Benz[a]anthracene (BaAC)
0.1
Bingham and Fa Ik (1969)
Benz[e]acephenanthrylene (BeAPE)3
0.1
Habs et al. (1980)
Bcn/o |/i | flnoranthene (BkFA)
0.01
Habs et al. (1980)
Chrysene (CH)
0.001
Wvnder and Hoffmann (1959)
Dibcnz|o,/? |anthraccnc (DbahAC)
1
Wvnder and Hoffmann (1959)
I ndcno \ 1,2,3-c, d\pyrenc (I123cdP)
0.1
Habs et al. (1980); Hoffmann and Wvnder (1966)
aFormerly benzo[/>]fluoranthene.
NA = not applicable; PAH = poly cyclic aromatic hydrocarbon; RPF = relative potency factor;
U.S. EPA = U.S. Environmental Protection Agency.
64
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
4. IMPLEMENTATION OF THE APPROACH
To estimate health risk or hazard for the entire hydrocarbon mixture, the estimates for all
six of the aromatic and aliphatic fractions are summed using an appropriate additivity method,
following relevant U.S. EPA guidance for risk assessment of mixtures (U.S. EPA. 2000. 1989.
1986). U.S. EPA (2000) recommends use of dose-addition methods for characterization of
potential risk from exposure to a mixture of chemicals that are toxicologically similar.8
Dose-addition methods are commonly used in noncancer risk assessment using the HI approach,
and in cancer risk assessment using RPFs or toxic equivalency factors. Response-addition is
recommended for mixture components that act on different systems or produce effects that do
not influence each other, and, thus, can be assumed to act independently. Response-addition
methods are commonly used in cancer risk assessment, wherein risks are estimated for individual
compounds using corresponding dose-response curves and summed to yield an estimate of risk
for the mixture.
Sections 4.1 and 4.2 briefly describe the methods for noncancer hazard assessment and
cancer risk assessment, respectively, using the fraction approach for petroleum hydrocarbon
mixtures.
4.1. FRACTION-BASED NONCANCER RISK ASSESSMENT
Noncancer health hazard assessment for the entire hydrocarbon mixture using the fraction
approach is performed at a screening level using the HI approach. The quantitative exposure
information for these individual chemicals or fractions is based on analytical data from the
hazardous waste sites. Figure 4-Figure 7 provide graphic illustrations of how noncancer risk
assessments are carried out using the toxicity values for the total petroleum hydrocarbon
fractions under two scenarios: Option 1 (see Figures 4 and 5), where environmental media have
been analyzed for the total fraction concentration only; and Option 2 (see Figures 6 and 7),
where environmental media have been analyzed for the total fraction concentration as well as
individual fraction components. For the sake of completeness, Figure 4-Figure 7 show
summation across all six fractions, but, depending on the source of the mixture and weathering
and transport, exposure may not include all fractions.
8U.S. EPA (2000) defines "similar components" as single chemicals that cause the same biologic activity or are
expected to cause a type of biologic activity based on chemical structure. Evidence of similarity may include
similarly shaped dose-response curves, or parallel log dose-probit-response curves for quantal data on the number of
animals (people) responding, and the same mechanism of action or toxic endpoint. These components may also be
expected to have comparable characteristics for fate, transport, physiologic processes, and toxicity.
65 Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
OPTION 1 - ORAL NONCANCER
Aliphatic Fractions HI,-
HI m =
ZHl>
;=1
/ = AtiphMed. AjighHi,
Aromatic Fractions HI =
c*
^ AliphLow
Rf^Cycloh €
' AliphMed
RfV
MRAHS
Hazard Index
AliphLow
Hazard Index
AromLow
Hazard Index
AliphMed
Hazard Index
AromMed
1
Et
. , RfVi
i=i
i = Jwisene, toluene,
ethylbenzene, or xylene
P
AromMed
RfV
TMBs
EAliphHigh
Hazard Index
Hazard Index
F
^AromHigh
White Mineral Oils
AliphHigh
AromHigh
RfVBaP
Sum fraction-specific hazard indices
assuming dose addition
I
Examine uncertainties: identify
percent of hazard index associated
with screening values and indicator
chemical or surrogate mixture
Figure 4. Fraction-Based Oral Noncancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons:
Option 1
66
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
OPTION 1 - INHALATION NONCANCER
Aliphatic Fractions HI,-
Et
' AliphLow
^f^nHexane or
nHeptane
' AliphMed
RfV
MRAHS
Data do not support
inhalation noncancer
risk assessment
HI m=
u
z
HI
j
7=1
J = AjjphLQWj AliphMed, AfiphHi,
AromLow. AromMed. AromHi
-Vy^
Sum fraction-specific hazard indices
assuming dose addition
1
Aromatic Fractions HI-
i
Hazard Index
AliphLow
Hazard Index
AromLow
Hazard Index
AliphMed
Hazard Index
AromMed
Hazard Index
AliphHigh
Hazard Index
AromHigh
I
Et
. 1 RfV I
i = benzene, toluene,
ethylbenzene, or xylene
' AromMed
RfVrMBs
F
c AromHigh
RfV
BaP
Examine uncertainties: identify
percent of hazard index associated
with screening values and indicator
chemical or surrogate mixture
Figure 5. Fraction-Based Inhalation Noncancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons:
Option 1
67
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
OPTION 2 - ORAL NONCANCER
Aliphatic Fractions HI-
5
I
E,
' Balarice
[}fVj ^f^Cycloh e
i=1
i = nhexane,
me thy Icy clop enta n e,
cyclohexene.nkeptane,or
2,4,4 trxmetftvipentene th
AliphMed
RfV
MRAHS
E AliphHi
^ White Mineral Oils
HI m =
o
i
HI,
> = 1
j = AliphLowJ AliphMed, AliphHi,
V
Sum fraction-specific hazard indices
assuming dose addition
1
Aromatic Fractions HI-
Hazard Index
AliphLow
Hazard Index
AromLow
Hazard Index
AliphMed
Hazard Index
AromMed
Hazard Index
AliphHigh
Hazard Index
AromHigh
I
E
i = benzene, toluene,
ethylbenzene, or xylene
6
E:
' Balance
i=1
RfVt RfV.
TMBs
i = TMBs,npropylbenzne,nbuty Ibenzene
secbutylbenzene, tertbutylbenzene, or isopropylbenzene
10
I
E;
_l_ Bala?ice
i=1 mi WZp
= NPT, 2 MeNPT, lMeNPT. BH,
AN,FE,AC,Pyr,FA,or BaP
Examine uncertainties: identify
percent of hazard index associated
with screening values and indicator
chemical or surrogate mixture
Figure 6. Fraction-Based Oral Noncancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons:
Option 2
68
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
OPTION 2 - INHALATION NONCANCER
Aliphatic Fractions HI -
4 T7 E
C i , Balance
I
« R?v'
i = npentane.nhexane,
cyclohexene or nhaptane
^fV n H exane
or nHeptane
^ AliphMed
RfV
MRAHS
Data do not support
inhalation noncancer
risk assessment
HI m =
o
z
HI,
;=i
j—AiipHLowr AjiphMed, AiiphHi,
AromLow, AromMedj Aromlji
Hazard Index
AliphLow
Hazard Index
AN oh Med
Hazard Index
AromLow
Hazard Index
AromMed
Sum fraction-specific hazard indices
assuming dose addition
1
Aromatic Fractions HJL=
4
y—
Z^RfV
„ RfV I
i=l
i = benzene, toluene,
ethylbenzene, or xyleiie
3
E,
y—
LRfX
' Balance
RfV { RfV
TMBs
i = TMBs.npropylbenzne, or isopropylbenzene
Hazard Index
Hazard Index
AliphHigh
AromHigh
I
Ei
' Balance
i = NPT, BH or BaP
RfV
BaP
Examine uncertainties: identify
percent of hazard index associated
with screening values and indicator
chemical or surrogate mixture
Figure 7. Fraction-Based Inhalation Noncancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons:
Option 2
69
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Screening Hazard Index for the whole mixture
Hazard Index calculated for the /th fraction (j = AliphLow [aliphatic low], AliphMed [aliphatic medium], AliphHi
[Aliphatic High], AromLow [aromatic low], AromMed [Aromatic Medium], and AromHi [aromatic high])
Daily oral dose (mg/kg-day) or inhalation exposure concentration (mg/m3) for the /th fraction
Daily oral dose (mg/kg-day) or inhalation exposure concentration (mg/m3) for the /th component
Daily oral dose (mg/kg-day) or inhalation exposure concentration (mg/m3) for portion of fraction not evaluated as
individual components
Reference value: reference dose (RfD, mg/kg-day) or reference concentration (RfC, mg/m3) for indicator chemical
or surrogate mixture
Mid-range aliphatic hydrocarbon streams
70
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
The steps involved in noncancer risk assessment of the hydrocarbon mixture using
Option 1 are as follows:
Oral
1) Aliphatic low, medium, and high carbon range fractions and aromatic medium and
high carbon range fractions:
a. Combine exposure estimate (mg/kg-day) for the fraction with the appropriate
duration (subchronic or chronic) RfD from Table 18 to estimate HI for each
fraction.
2) Aromatic low carbon range fraction:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 18 to calculate His for each component; sum His across
the components.
3) Sum His across all fractions assessed at the site.
Inhalation
1) Aliphatic low and medium carbon range fractions and aromatic medium and high
carbon range fractions:
a. Combine exposure estimate (mg/m3) for the fraction with the appropriate duration
(subchronic or chronic) RfC from Table 18 to estimate HI for each fraction.
2) Aromatic low carbon range fraction:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 18 to calculate His for each component; sum His across
the components.
3) Sum His across all fractions assessed at the site. Note: data do not support inhalation
noncancer assessment for the aliphatic high carbon range fraction.
71
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 18. Fraction-Specific Noncancer Toxicity Values for Option 1: Exposure Media Analyzed for BTEX and
Fractions
Secondary Fraction
Assessment
Method
Subchronic RfD or p-RfD
(mg/kg-d)a
Chronic RfD or p-RfD
(mg/kg-d)a
Subchronic RfC or
p-RfC (mg/m3)
Chronic RfC or p-RfC
(mg/m3)
Aliphatic
Low carbon range
(C5-C8 [EC5-EC8])b
Indicator chemical
0.05
(cyclohexene)
0.005
(cyclohexene)
2
(«-hexane)
0.4
(//-heptane)
Medium carbon range
(C9-C18 [EC > 8-EC16])
Surrogate mixture
0.1
(mid-range aliphatic
hydrocarbon streams)
0.01
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
High carbon range
(C19-C32
[EC > 16-EC35])
Surrogate mixture
30
(white mineral oil)
3
(white mineral oil)
NA
NA
Aromatic
Low carbon range
(C6-C8 [EC6-EC < 9])
Hazard Index
Benzene: 0.01
Toluene: 0.8
Ethylbenzene: 0.05°
Xylenes: 0.4
Benzene: 0.004
Toluene: 0.08
Ethylbenzene: 0.1°
Xylenes: 0.2
Benzene: 0.08
Toluene: 5
Ethylbenzene: 9
Xylenes: 0.4
Benzene: 0.03
Toluene: 5
Ethylbenzene: 1
Xylenes: 0.1
Medium carbon range
(C9-C10
[EC9-EC < ll])b
Indicator chemical
0.04
(trimethylbenzenes)
0.01
(trimethylbenzenes)
0.2
(trimethylbenzenes)
0.06
(trimethylbenzenes)
High carbon range
(C10-C32
[ECll-EC35])b
Indicator chemical
0.0003
(bcnzo|fl|pyrcnc)
0.0003
(bcnzo|fl|pyrcnc)
0.000002
(bcnzo|fl|pyrcnc)
0.000002
(bcnzo|fl|pyrcnc)
aRisk estimates in italics are PPRTV screening values. Screening values are not assigned confidence statements; however, confidence in these values is presumed to be
low. Screening values are derived when the data do not meet all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review, etc.) as provisional values; however, there is generally
more uncertainty associated with these values.
' Risk estimates(s) updated in 2022 as part of this TPH approach (U.S. EPA. 2022a. c, d).
°The subchronic p-RfD for ethylbenzene is lower than the chronic value because it was derived using data that were not available when the IRIS RfD was derived.
BTEX = benzene, toluene, ethylbenzene, and xylenes; C = carbon; EC = equivalent carbon; IRIS = Integrated Risk Information System; NA = not applicable;
p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfC = reference concentration; RfD = reference dose.
72
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
The steps involved in noncancer risk assessment of the hydrocarbon mixture using
Option 2 are as follows:
Oral
1) Aliphatic medium and high carbon range fractions:
a. Combine exposure estimate (mg/kg-day) for the fraction with the appropriate
duration (subchronic or chronic) RfD from Table 19 to estimate HI for each
fraction.
2) Aromatic low carbon range fraction:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 19 to calculate His for each component; sum His across
the components.
3) Aliphatic low and aromatic medium and high carbon range fractions:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 19 to calculate component-specific His.
b. Subtract doses or concentrations (mg/kg-day) of all components assessed
individually (by route and exposure duration) from the estimated dose or
concentration of the total fraction to estimate the exposure concentration for the
balance of the fraction.
c. Combine the exposure estimate (mg/kg-day) for the balance of the fraction with
the appropriate duration (subchronic or chronic) RfD for the surrogate shown in
Table 19.
d. Sum the His for the components with the HI calculated for the remaining fraction
mass to estimate the HI for the fraction.
4) Sum His across all fractions assessed at the site.
Inhalation
1) Aliphatic medium range fraction:
a. Combine exposure estimate (mg/m3) for the fraction with the appropriate duration
(subchronic or chronic) RfC from Table 19 to estimate HI for each fraction.
2) Aromatic low carbon range fraction:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 19 to calculate His for each component; sum His across
the components.
3) Aliphatic low and aromatic medium and high carbon range fractions:
a. Combine individual exposure estimates for components with their corresponding
toxicity values in Table 19 to calculate component-specific His.
b. Subtract doses or concentrations (mg/m3) of all components assessed individually
(by route and exposure duration) from the estimated dose or concentration of the
total fraction to estimate the exposure concentration for the balance of the
fraction.
c. Combine the exposure estimate (mg/m3) for the balance of the fraction with the
appropriate duration (subchronic or chronic) RfC for the surrogate shown in
Table 19.
d. Sum the His for the components with the HI calculated for the remaining fraction
mass to estimate the HI for the fraction.
4) Sum His across all fractions assessed at the site. Note: data do not support inhalation
noncancer assessment for the aliphatic high carbon range fraction.
73 Complex mixtures of aliphatic and aromatic
hydrocarbons
-------
EPA/690/R-22/003F
Table 19. Fraction-Specific Noncancer Toxicity Values for Option 2: Analytical Data Available for Individual
Components and Fractions
Fraction and Carbon
Range
Assessment
Method
Subchronic RfD or p-RfD
(mg/kg-d)a
Chronic RfD or p-RfD
(mg/kg-d)a
Subchronic RfC or
p-RfC (mg/m3)"
Chronic RfC or p-RfC
(mg/m3)a
Aliphatic
Low
(C5-C8 [EC5-EC8])b
Hybrid
Components:
Cyclohexene: 0.05
n-Heptane: 0.003
«-Hexane: 0.3
Methylcyclopentane: 0.4
2,4,4-Trimethylpentene: 0.1
Components:
Cyclohexene: 0.005
n-Heptane: 0.0003
2,4,4-Trimethylpentene: 0.01
Components:
Cyclohexane: 18
//-Heptane: 4
«-Hexane: 2
//-Pcntanc: 10
Components:
Cyclohexane: 6
Cyclohexene: 1
n-Heptane: 0.4
«-Hexane: 0.7
//-Pcntanc: 1
Surrogate for balance of
fraction:0
0.05 (cyclohexene)
Surrogate for balance of fraction:0
0.05 (cyclohexene)
Surrogate for balance of
fraction:0
2 («-hexane)
Surrogate for balance of
fraction:0
0.4 (//-heptane)
Medium
(C9-C18 [EC > 8-EC16])
Surrogate
mixture
0.1
(mid-range aliphatic
hydrocarbon streams)
0.01
(mid-range aliphatic hydrocarbon
streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
0.1
(mid-range aliphatic
hydrocarbon streams)
High
(C19-C32 [EC > 16-EC35])
Surrogate
mixture
30
(white mineral oil)
3
(white mineral oil)
NA
NA
Aromatic
Low
(C6-C8 [EC6-EC < 9])
Hazard Index
Benzene: 0.01
Toluene: 0.8
Ethylbenzene: 0.05
Xylenes: 0.4
Benzene: 0.004
Toluene: 0.08
Ethylbenzene: 0.1
Xylenes: 0.2
Benzene: 0.08
Toluene: 5
Ethylbenzene: 9
Xylenes: 0.4
Benzene: 0.03
Toluene: 5
Ethylbenzene: 1
Xylenes: 0.1
Medium
(C9-C10 [EC9-EC < ll])b
Hybrid
Components
n-Propylbenzene: 0.1
tert-Butylbenzene: 0.1
sec-Butylbenzene: 0.1
//-Butvlbcnzcnc: 0.1
Trimethylbenzenes: 0.04
Components
Isopropylbenzene: 0.1
n-Propylbenzene: 0.1
tert-Butylbenzene: 0.1
sec-Butylbenzene: 0.1
«-Butylbenzene: 0.05
Trimethylbenzenes: 0.01
Components:
n-Propylbenzene: 1
Trimethylbenzenes: 0.2
Components:
Isopropylbenzene: 0.4
n-Propylbenzene: 1
Trimethylbenzenes: 0.06
Surrogate for balance of
fraction:0
0.04 (trimethylbenzenes)
Surrogate for balance of fraction:0
0.01 (trimethylbenzenes)
Surrogate for balance of
fraction:0
0.2 (trimethylbenzenes)
Surrogate for balance of
fraction:0
0.06 (trimethylbenzenes)
74
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table 19. Fraction-Specific Noncancer Toxicity Values for Option 2: Analytical Data Available for Individual
Components and Fractions
Fraction and Carbon
Assessment
Subchronic RfD or p-RfD
Chronic RfD or p-RfD
Subchronic RfC or
Chronic RfC or p-RfC
Range
Method
(mg/kg-d)a
(mg/kg-d)a
p-RfC (mg/m3)"
(mg/m3)a
High
Hybrid
Components:
Components:
Components:
Components:
(C10-C32 [ECll-EC35])b
Acenaphthene: 0.2
Acenaphthene: 0.06
1,1-Biphenyl: 0.004
1,1-Biphenyl: 0.0004
Anthracene: 1
Anthracene: 0.3
Bcnzo|fl|pyrcnc:
Bcnzo|fl|pyrcnc:
Bcnzo|fl|pyrcnc: 0.0003
Benzo[a]pyrene: 0.0003
0.000002;
0.000002;
1,1-Biphenyl: 0.1
1,1-Biphenyl: 0.5
Benzo[e]pyrene: 0.000002
Benzo[e]pyrene:
Fluoranthene: 0.1
Fluoranthene: 0.04
0.000002;
Fluorene: 0.4
Fluorene: 0.04
Naphthalene: 0.003
2-Methylnaphthalene: 0.004
1-Methylnaphthalene: 0.007
Naphthalene: 0.6
2-Methylnaphthalene: 0.004
Pyrene: 0.3
Naphthalene: 0.02
Pyrene: 0.03
Surrogate for balance of
Surrogate for balance of fraction:0
Surrogate for balance of
Surrogate for balance of
fraction:0
0.0003 (bcnzo|fl|pyrcnc)
fraction:0
fraction:0
0.0003 (benzol a | pyrene)
0.000002
0.000002
(bcnzo|fl|pyrcnc)
(bcnzo|fl|pyrcnc)
"Toxicity values in italics are PPRTV screening values. Screening values are not assigned confidence statements; however, confidence in these values is presumed to be
low. Screening values are derived when the data do not meet all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review, etc.) as provisional values; however, there is generally
more uncertainty associated with these values.
' Fraction toxicity value(s) updated in 2022 (U.S. EPA. 2022a. c, d).
°Balance of fraction in any given exposure medium equals the total fraction mass concentration minus the sum of the mass concentrations of the individual components
listed.
C = carbon; EC = equivalent carbon; NA = not applicable; p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfC = reference
concentration; RfD = reference dose.
75
Complex mixtures of aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
There may be circumstances in which a combination of Options 1 and 2 are used. For
example, if there are analytical data for individual components of the aromatic medium carbon
range fraction, but not the aromatic high carbon range fraction, Option 2 would be used for the
medium fraction, while Option 1 would be used for the high fraction.
4.2. FRACTION-BASED CANCER RISK ASSESSMENT
Cancer health risk assessment for the entire hydrocarbon mixture using the fraction
approach is performed using a combination of dose- and response-addition methods.
Dose-addition methods are used in application of the RPFs to cancer risk assessment of PAHs
that lack cancer risk values. Response addition is used for the components with corresponding
OSFs or IURs. Figures 8 and 9 provide graphic illustrations of how oral and inhalation cancer
risk assessments are carried out using the toxicity values for petroleum fractions. For the sake of
completeness, Figures 8 and 9 show summation of all fractions, but exposure at some sites may
be limited to fewer fractions. Figure 10 details three options for estimating oral cancer risk for
exposure to the aromatic high carbon range fraction.
76
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
ORAL CANCER
Aliphatic Fractions R;=
Rrn =
£
R
7
;=i
/ =>Jroni!lgwr AromM
Aromatic Fractions R;=
Data do not support
cancer risk assessment
Data do not support
cancer risk assessment
Cancer Risk
AliphLow
Cancer Risk
AromLow
Cancer Risk
AliphMed
Cancer Risk
AromMed
(LE
AromLow
, X OSF
Benzene)
Data do not support
cancer risk assessment
Data do not support
cancer risk assessment
Cancer Risk
AliphHigh
Cancer Risk
AromHigh
3 Options (see Figure 10)
Sum fraction-specific risk estimates
assuming response addition
Examine uncertainties: identify
percent of risk associated with
screening values and indicator
chemical or surrogate mixture
Figure 8. Fraction-Based Oral Cancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons
77 Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA 690 11-22,003$
INHALATION CANCER
Aliphatic Fractions R~
Rm =
J
M-
j = AliphLow, AliphMed,
Aromatic Fractions R,=
(LEAliphLow X IURComHex)
(.LE.AliphMed X ^^MRAHs)
Data do not support
cancer risk assessment
Cancer Risk
AliphLow
Cancer Risk
AromLow
Cancer Risk
AliphMed
Cancer Risk
AromMed
Cancer Risk
AliphHigh
Cancer Risk
AromHigh
Sum fraction-specific risk estimates
assuming response addition
I
Examine uncertainties: identify
percent of risk associated with
screening values and indicator
chemical or surrogate mixture
(L EAyomLow X ^ U^Benzene)
Data do not support
cancer risk assessment
2 Options (see Figure 10)
Figure 9. Fraction-Based Inhalation Cancer Risk Assessment for Complex Mixtures of Aliphatic and Aromatic Hydrocarbons
78
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA 690 R-22 003F
Cancer Risk
AromHigh
Option 1
(LEAromHigh xOSF or IURBclP)
7 Option 2
^ (LEi x RPFt x OSF or WRBaP)
i=1
i = BaP, BaAC, BeAPE, BkFA,
CH, DbahAC, or Il23cdP
Option 3a
"Only applicable to oral cancer
assessments
I
(LEt x
i=l
i = lMeNPT or BH
1
(LEi x RPFi x OSFBaP)
i=l
i = BaP,BaAC.BeAPE.BkFA,
CH, DbahAC. or llZZcdP
Figure 10. Options for Oral Cancer Risk Assessment for the Aromatic High Carbon Range Fraction
79
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
where:
Rm =
Risk associated with the mixture
Rj =
Risk associated with the /th fraction (j = AliphLow [aliphatic low], AliphMed [aliphatic medium],
AromLow [aromatic low], AromHi [aromatic high])
LEj =
Lifetime oral dose (mg/kg-day) or inhalation exposure concentration (mg/m3) for the /th fraction
LEi
Lifetime oral dose (mg/kg-day) or inhalation exposure concentration (mg/m3) for the /th component
OSFi
Cancer oral slope factor (OSF [mg/kg-day]1) for indicator chemical or surrogate mixture
IURi
Inhalation unit risk (IUR [mg/m3]-1) for indicator chemical or surrogate mixture
Comhex =
Commercial hexane
MRAHS
Mid-range aliphatic hydrocarbon streams
RPFi
Relative potency factor for the /th PAH
80
Complex mixtures of aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
The steps involved in cancer risk assessment of the hydrocarbon mixture are shown
below for oral and inhalation exposures.
Oral:
1) Aliphatic low, medium, and high carbon range fractions and aromatic medium carbon
range fraction:
a. Data do not currently support direct cancer assessment.
2) Aromatic low carbon range fraction:
a. Combine individual lifetime oral exposure estimate (mg/kg-day) for aromatic low
carbon range fraction with the OSF for benzene in Table 20 to estimate risk for
the fraction.
3) Aromatic high carbon range fraction:
Option 1:
a. Combine oral exposure estimate (mg/kg-day) for fraction with the OSF for
benzo[a]pyrene in Table 20 to estimate risk for the fraction.
Option 2:
a. For PAHs with RPFs, multiply each individual exposure estimate by its
corresponding RPFs from Table 21 and the OSF for benzo[a]pyrene to estimate risks.
b. Sum risks across the PAHs.
Option 3:
a. Combine individual exposure estimates (mg/kg-day) for components with OSFs in
Table 20 to estimate risks.
b. For PAHs9 with RPFs, multiply each individual exposure estimate by its
corresponding RPF from Table 21 and the OSF for benzo[a]pyrene to estimate risks.
c. Sum risks across the PAHs, subPAH, and other carcinogenic fraction member with
OSFs.
4) Sum risks across aromatic low and high carbon range fractions (if assessed at the
site).
Inhalation:
1) Aliphatic low and medium carbon range fractions:
a. Combine inhalation exposure estimate (mg/m3) for each fraction with its
corresponding IUR from Table 20 to estimate risk for each fraction.
2) Aromatic low carbon range fraction:
a. Combine individual exposure estimate (mg/m3) for the aromatic low carbon range
fraction with the IUR for benzene in Table 20 to estimate risk for the fraction.
9Recall that, in this document, U.S. EPA defined PAHs as unsubstituted compounds with two to six fused aromatic
rings made up only of carbon and hydrogen atoms. The definition of the PAH excludes their alkyl substituted
derivatives.
Complex mixtures of
aliphatic and aromatic hydrocarbons
81
-------
EPA/690/R-22/003F
3) Aromatic high carbon range fraction:
Option 1:
a. Combine inhalation exposure estimate (mg/m3) for fraction with the IUR for
benzo[a]pyrene in Table 20 to estimate risk for the fraction.
Option 2:
a. For PAHs with RPFs, multiply each individual exposure estimate by its
corresponding RPFs from Table 21 and the IUR for benzo[a]pyrene to estimate risks.
b. Sum risks across the PAHs.
5) Sum risks across all fractions assessed at the site.
Table 20. Fraction-Specific Cancer Toxicity Values
Fraction and Carbon
Range
Assessment Method
OSF (mg/kg-d)-1 a
IUR (mg/m3) la
Aliphatic
Low
(C5-C8 [EC5-EC8])b
Surrogate mixture
NA; data do not support
cancer risk assessment
2.0 x 10T4
(icommercial hexane)
Medium
(C9-C18 [EC > 8-EC16])
Surrogate mixture
NA; data do not support
cancer risk assessment
4.5 x 10-3
(mid-range aliphatic
hydrocarbon streams)
High
(C19-C32 [EC > 16-EC35])
NA; data do not support cancer risk assessment
Aromatic
Low
(C6-C8 [EC6-EC < 9])
Indicator chemical
Benzene:
1.5 x 10-2-5.5 x lO-2
Benzene: 2.2 x 10 3-7.8 x 10 3
Medium
(C9-C10 [EC9-EC < ll])b
NA; data do not support cancer risk assessment
High
(C10-C32 [ECll-EC35])b
Indicator Chemical
(Option 1); Relative
Potency Factor
(Option 2);
Integrated Addition
(Option 3)
1,1-Biphenyl: 8 xio 3
1-Methylnaphthalene:
2.9 x 10-2
Bcnzo|fl|pyrcnc: 1
See relative potency values
in Table 20
Bcnzo|fl|pyrcnc: 6 x 10 1
"Toxicity values in italics PPRTV are screening values. Screening values are not assigned confidence statements;
however, confidence in these values is presumed to be low. Screening values are derived when the data do not meet
all requirements for deriving a provisional toxicity value. Screening values are derived using the same
methodologies and undergo the same development and review processes (i.e., internal and external peer review,
etc.) as provisional values; however, there is generally more uncertainty associated with these values.
'Toxicity value(s) updated in 2022 (U.S. EPA. 2022a. b, d).
C = carbon; EC = equivalent carbon; IUR = inhalation unit risk; NA = not applicable; OSF = oral slope factor;
PAH = polycyclic aromatic hydrocarbon; RPF = relative potency factor.
82
Complex mixtures of
aliphatic and aromatic hydrocarbons
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EPA/690/R-22/003F
Table 21. RPFs for PAH Carcinogenicity
PAH (abbreviation)
RPF
Data Source(s) for RPF Values
Bcnzo|fl|pyrcnc (BaP)
1
Benz[a]anthracene (BaAC)
0.1
Bingham and Falk (19691
Benz[e]acephenanthrylene (BcAPE)1'
0.1
Habsetal. (1980)
Bcnzo|A| fluoranthcnc (BkFA)
0.01
Habsetal. (1980)
Chrysene (CH)
0.001
Wvnder and Hoffmann (1959)
Dibcnz|o,/? |anthraccnc (DbahAC)
1
Wvnder and Hoffmann (1959)
I ndcno \ 1,2,3-c, d\pyrcnc (I123cdP)
0.1
Habs et al. (1980); Hoffmann and Wvnder (1966)
aFormerly bcnzo|/> | fluoranthcnc.
PAH = polycyclic aromatic hydrocarbon; RPF = relative potency factor.
4.3. UNCERTAINTY ASSESSMENT
Mixture risk assessment with dose- or response-addition is a default approach that is used
to evaluate potential health risks when whole mixture toxicity data are not available. Application
of the petroleum fraction method, using both dose- and response-addition approaches, involves
assumptions that may be difficult to substantiate for complex mixtures of petroleum
contaminants, including:
1) The surrogate mixture or component(s) represents the toxicity of the entire fraction.
2) Synergistic or potentiating toxicological interactions among chemicals are less likely to
happen at low environmental contamination levels.
3) Compounds act through independent modes of toxic action when compounds are
evaluated using response addition, OR there is a common mode of toxic action for
compounds evaluated using dose-addition.
Whenever possible, these assumptions should be evaluated and verified as part of the risk
assessment process, and the results should be articulated as part of the final risk characterization.
This PPRTV assessment, and the companion documents on individual compounds, mixtures, or
fractions, can provide information pertaining to the first assumption. The second assumption can
be evaluated through literature review. If two or more chemicals at a site are detected at high
exposure concentrations, the toxicology literature should be consulted for information on
toxicological interactions among these chemicals. If interactions are demonstrated, especially if
synergism or potentiation is shown, this information should be described in the risk
characterization along with the quantitative risk or hazard estimates. The assumptions regarding
modes of toxic action may be informed by review of the toxicity assessments (IRIS toxicological
reviews, PPRTV assessment documents, or ATSDR toxicological profiles) for the most
important contaminants. For further guidance, details, and discussion, see U.S. EPA (2000) and
the other references cited above.
83
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
An important source of uncertainty is the use of an indicator compound or surrogate
mixture to represent the toxicity of an untested mixture or portion of a mixture. Therefore, the
U.S. EPA suggests that risk assessors characterize the percentage of the estimated risk or of the
HI that is calculated using an indicator chemical or surrogate mixture approach. To that end, the
U.S. EPA suggests that when a hybrid approach (as described above) is used, risk assessors
estimate the risk associated with the measured amount of the surrogate compound (e.g., TMBs
for the aromatic medium carbon range or BaP for the aromatic high carbon range) separately
from the balance of the fraction, as a means of explicitly characterizing the more uncertain
portion associated with the balance of the fraction. For example, when a hybrid approach is used
for the chronic inhalation toxicity of the aromatic medium carbon range fraction, risks or His
would be calculated separately for isopropylbenzene, //-propylbenzene, and TMBs, before using
the toxicity value of TMBs to estimate the risk or HI associated with the balance of the fraction.
The quality of the underlying toxicity data used to develop either a provisional or
screening RfD, a provisional or screening RfC, or a provisional or screening OSF or IUR is an
additional source of uncertainty. To convey the difference in quality in the mixture risk
assessment, the U.S. EPA suggests that risk assessors identify the percentage of the estimated
risk or of the HI that is associated with screening toxicity estimates (i.e., screening OSFs,
screening p-RfDs, or screening p-RfCs) and the percentage based on provisional estimates
(i.e., p-OSFs, p-IURs, or p-RfDs). Such examinations of mixture risk estimates are consistent
with mixture risk assessment practices (Rice et al.. 2005; U.S. EPA. 2000).
84
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
APPENDIX A. CHEMICAL SYNONYMS AND ABBREVIATIONS
Table A-l. Chemical Synonyms and Abbreviations
Chemical Name
(common synonyms3)
CASRN
Abbreviation
Structure
Molecular
Weight
(g/mol)
Aromatic High Carbon Range
1,1-Biphenyl
(biphenyl;
l,l'-biphenyl;
1,1-biphenyl)
92-52-4
BH
C^-O
154.212
1-Methylnaphthalene
(naphthalene, 1-methyl-)
90-12-0
lMeNPT
CHj
142.201
2-Methylnaphthalene
(naphthalene, 2-methyl-)
91-57-6
2MeNPT
xh3
142.201
Acenaphthene
(acenaphthylene, 1,2-dihydro-;
1,2-dihydroacenaphthylene;
1,8-ethy lenenaphthalene)
83-32-9
ANL
154.212
Anthracene
(anthracin;
paranaphthalene)
120-12-7
AC
178.234
Benz [e] acephenanthrylene
(bcnzo| /> | riuoranthcnc:
benzo [e]fluoranthene;
benzo [e] acephenanthrylene;
3,4-benz[e]acephenanthrylene;
2.3-benzofluoranthene;
3.4-benzofluoranthene)
205-99-2
BeAPE
252.316
Benz [a] anthracene
(tetraphene;
benzo [b ] phenanthrene;
1.2-benzanthracene;
2.3-benzophenanthrene;
1,2-benzanthrene;
naphthanthracene)
56-55-3
BaAC
228.294
Benzo [A]tluoranthene
(dibenzo [b jl]fluorene;
8,9-benzofluoranthene;
11,12-benzofluoranthene;
2,3:1 ',8'-biaphthylene)
207-08-9
BkFA
coS
252.316
85
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA 690 R-22 003F
Table A-l. Chemical Synonyms and Abbreviations
Chemical Name
(common synonyms3)
CASRN
Abbreviation
Structure
Molecular
Weight
(g/mol)
Benzo[a]pyrene
(benzo [pqr\tetraphene;
bcnzo|tfe/lclmscnc:
1,2-benzpyrene;benzene
3.4-benzopyren;
4.5-benzpyrene;
6,7-benzopy rene)
50-32-8
BaP
V_y
J>\^)
252.316
Benzo [e]pyrene
192-97-2
BeP
T^if
Jf
252.316
Chrysene
(benzo |«|phcnanthrcnc;
1,2-benzophenanthrene)
218-01-9
CH
O1
-4
228.294
Dibenz [a,A] anthracene
(benzo[A]tetraphene;
l,2:5,6-dibenzoanthracene;
1,2:5,6 -benzantliracene;
1.2:5.6-bcnz|fl|anthraccnc)
53-70-3
DBaliAC
/
_J~
\
278.354
Fluoranthene
(clustercarbon;
idryl;
benzo [/'A]fluorene;
l,2-[l,8-naphthalenediyl]benzene;
bcnz|«| acenaphthy lene;
1,2-benzoacenaphyhylene)
206-44-0
FA
jl
202.256
5^/
Fluorene
(9H-fluorene;
2,3-benzidene;
o-biphenylenemethane;
diphenylenemethane;
2,2' -methylenebiphenyl;
o-biphenylmethane)
86-73-7
FE
^1
166.223
Indeno [l,2,3cd\ py rene
(o-phenylenepyrene;
1,10-[o-phenylene]pyrene;
1,10-[l,2-phenylene]pyrene;
2,3 - [o -pheny lene] py rene;
2,3 -pheny lenepy rene)
193-39-5
I123cdP
-------
EPA/690/R-22/003F
Table A-l. Chemical Synonyms and Abbreviations
Chemical Name
(common synonyms3)
CASRN
Abbreviation
Structure
Molecular
Weight
(g/mol)
Naphthalene
(naphthalin)
91-20-3
NPT
CO
128.174
Pyrene
(benzo |cfe/|phcnanthrcne;
pyren)
129-00-0
Pyr
(2?
202.256
Aromatic Medium Carbon Range
1,2,3-T rimethylbenzene
(benzene, 1,2,3-trimethyl-)
526-73-8
1,2,3-TMB
h3c.
ch3
/CH3
120.195
1,2,4-T rimethylbenzene
(benzene, 1,2,4-trimethyl-)
95-63-6
1,2,4-TMB
h3c
0
ch3
120.195
1,3,5-T rimethylbenzene
(benzene, 1,3,5-trimethyl-)
108-67-8
1,3,5-TMB
H3cr
CH,
X
t.h.
120.195
Isopropylbenzene
(cumene;
[propan-2-yl]benzene;
benzene, [1-methylethyl]-)
98-82-8
vo
h3c n '
120.195
87
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table A-l. Chemical Synonyms and Abbreviations
Chemical Name
(common synonyms3)
CASRN
Abbreviation
Structure
Molecular
Weight
(g/mol)
HFAN
(light aromatic solvent naphtha
[petroleum];
solvent naphtha, petroleum, light
aromatic;
super high flash naphtha;
aromatic solvent;
solvent, aromatic petroleum;
solvent naphtha;
light aromatic solvent naphtha;
low boiling point naphtha-
unspecified;
solvent naphtha [petroleum], light
aromatic)
64742-95-6
Various
Various
M-Butylbenzene
(benzene, butyl-)
104-51-8
134.222
M-Propylbenzene
(propylbenzene;
benzene, propyl-)
103-65-1
120.195
sec-Butylbenzene
([butan-2-y l]benzene;
benzene, [1-methylpropyl]-)
135-98-8
if^l
/CH3
h3c
134.222
tert- Bu ty 1 be n zcn c
(benzene, [1,1-dimethylethyl]-)
98-06-6
(
h3c—
-If
ch3
4?
134.222
Aliphatic Low Carbon Range
2,4,4-Trimethylpentene
2516-77-08
(mixture of
two isomers,
107-39-1 and
107-40-4)
w„n,r. pHj
M V yC
"CM,
*/ 3
H^C
IS-
and
H,C CHj CH,
XX
H3C CH,
112.22
88
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
Table A-l. Chemical Synonyms and Abbreviations
Chemical Name
(common synonyms3)
CASRN
Abbreviation
Structure
Molecular
Weight
(g/mol)
Commercial hexane
(NOCAS 872521)
Various
Various
Various
Cyclohexane
110-82-7
0
84.162
Cyclohexene
110-83-8
o
82.146
M-Heptane
(heptane)
142-82-5
100.205
w-Hexane
(hexane)
110-54-3
/CH3
86.178
M-Pentane
(pentane;
norpar 55)
109-66-0
72.151
Methylcyclopentane
(cyclopentane, methyl-)
96-37-7
hjc-0
84.162
'Synonyms arc listed according to National Institute of Standards and Technology (NIST. 2020) and include valid
synonyms from U.S. EPA CompTox Chemicals Dashboard; accessed 03-30-2020 (U.S. EPA. 2021a).
U.S. EPA = U.S. Environmental Protection Agency.
89
Complex mixtures of
aliphatic and aromatic hydrocarbons
-------
EPA/690/R-22/003F
APPENDIX B. REFERENCES
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https://www.api.org/oii-and-naturai-gas/weiis-to-consumer/fueis-and-
reti n i n g/rcfi n cri es. li o\v-rcti n cry - works re ti n cry -processes
API (American Petroleum Institute). (2021b). Petroleum substances and categories. Available
online at https://www.petroleumhpv.org/petroleum-substances-and-categories
ARBCA (Atlantic KBCA). (2012). Atlantic RBCA (risk-based corrective action) for petroleum
impacted sites in Atlantic Canada version 3. http://www.atlanticrbca.com/wp-
content files mf/1398705926ATLANTIC RBCA User Guidance v3 July 2012doc fin
al.pdf
ATSDR (Agency for Toxic Substances and Disease Registry). (1995). Toxicological profile for
polycyclic aromatic hydrocarbons - Update [ATSDR Tox Profile], (CIS/97/00215).
Atlanta, GA: U.S. Department of Health and Human Services, Public Health Service.
https://www.atsdr.cdc. gov/substances/toxsubstance.asp?toxid=25
ATSDR (Agency for Toxic Substances and Disease Registry). (1999). Toxicol ogical profile for
Total Petroleum Hydrocarbons (TPH). In Govt Reports Announcements and Index (GRA
and I), Issue 04, 2000. (NTIS/02921054_a). U.S. Department Of Health And Human
Services, Public Health Service, https://www.atsdr.cdc.gov/toxprofiles/tpl23.pdf
ATSDR (Agency for Toxic Substances and Disease Registry). (2005). Toxicological profile for
naphthalene, 1-methylnaphthalene, and 2-methylnaphthalene. (PB2006100004). Atlanta,
GA.
https:/ntrl.ntis.gov/NTRI. dashboard/searchResults.xhtml'.'searchQuervPB2006100004
ATSDR (Agency for Toxic Substances and Disease Registry). (2018). Framework for assessing
health impacts of multiple chemicals and other stressors (update). Washington, DC: U.S.
Department of Health and Human Services.
https://www.atsdr.cdc.gov/interactionprofiles/ip-ga/ipga.pdf
Balsciro-Romcro. M; Monterroso. C; Casares. JJ. (2018). Environmental fate of petroleum
hydrocarbons in soil: review of multiphase transport, mass transfer, and natural
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0160(18)60046-3
BCMoE (British Columbia Ministry of Environment). (2018). Contaminated sites regulation.
July. B.C. Reg. 375/96.
Benninghoff AD; Williams. DE. (2013). The role of estrogen receptor P in transplacental cancer
prevention by indole-3-carbinol. Cancer Prev Res 6: 339-348.
http://dx.doi. org/10.115 8/1940-6207. C APR-12-0311
Bingham. E; Falk. HL. (1969). Environmental carcinogens. The modifying effect of
cocarcinogens on the threshold response. Arch Environ Health 19: 779-783.
http://dx.doi.org/10.1080/00039896.1969.1066693Q
Bossert. ID; Bartha. R. (1986). Structure-biodegradabilitv relationships of polycyclic aromatic
hydrocarbons in soil (pp. 490-496). Bossert, ID; Bartha, R.
http://link.springer.com/10.1007/BF01607793
Bruner. RH; Kinkead. ER; O'Neill. TP; Flemming C. D; Mattie. PR; Russell. CA; Wall. HG.
(1993). The toxicologic and oncogenic potential of JP-4 jet fuel vapors in rats and mice:
12-month intermittent inhalation exposures. Fundam Appl Toxicol 20: 97-110.
90
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aliphatic and aromatic hydrocarbons
-------
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Castro. DJ; Baird. WM; Pereira. CB; Giovanini. J; Lohr. CV; Fischer. KA; Yu. Z; Gonzalez. FJ;
Krueger. SK; Williams. DE. (2008a). Fetal mouse CYP1B1 and transplacental
carcinogenesis from maternal exposure to dibenzo(a,l)pyrene. Cancer Prev Res 1: 128-
134. http://dx.doi.org/10.1158/1940-6207.CAPR-07-00Q4
Castro. DJ; Lohr. CV; Fischer. KA; Pereira. CB; Williams. DE. (2008b). Lymphoma and lung
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