EPA/690/R-23/005F | September 2023 | FINAL
United States
Environmental Protection
Agency
xvEPA
Provisional Peer-Reviewed Toxicity Values for
l-Phenyl-l-(2,4-dimethylphenyl)-ethane (PXE)
(CASRN 6165-52-2)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United States
Environmental Protection
%#UI JTT,Agency
EPA/690/R-23/005F
September 2023
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane (PXE)
(CASRN 6165-52-2)
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
Kyoungju Choi, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
SCIENTIFIC TECHNICAL LEAD
Lucina E. Lizarraga, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
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
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
2.1. HUMAN STUDIES 10
2.2. ANIMAL STUDIES 10
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10
3. DERIVATION 01 PROVISIONAL VALUES 15
3.1. DERIVATION OF ORAL REFERENCE DOSES 15
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 15
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 15
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 15
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 16
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES 17
APPENDIX B. REFERENCES 27
iv 1-Phenyl-1-(2,4-dimethylphenyl)-ethane
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NO A F.I.
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
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
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
glutathione-S'-transfcrase
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV assessment.
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EPA/690/R-23/005F
DRAFT PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1 -PHENYL-1 -(2,4-DIMETHYLPHENYL)-ETHANE (PXE; CASRN 6165-52-2)
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
toxicologically relevant human-health effects. Questions regarding nomination of chemicals for
update can be sent to the appropriate U.S. EPA eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment
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 assessment 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 toxicologically
relevant 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.
2 1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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1. INTRODUCTION
1-Phenyl-1-(2,4-dimethylphenyl)-ethane (PXE), CASRN 6165-52-2, is a discrete organic
chemical; it is a hydrocarbon containing both aromatic and aliphatic carbons (Figure 1). PXE is
listed with the U.S. EPA Substance Registry Services and the Toxic Substances Control Act's
public inventory (U.S. EPA. 2022c. d). It is listed on the European Chemicals (EC) inventory
and is preregistered with Europe's Registration, Evaluation, Authorization, and Restriction of
Chemicals (REACH) program (ECHA. 2022). There are no data available on the production of
PXE in the United States or commercial uses reported for PXE (NLM. 2022b; U.S. EPA. 2022d).
Synonyms of 1-phenyl-1-(2,4-dimethylphenyl)-ethane appearing in these databases and other
sources include 2,4-dimethy-l-(l-phenylethyl)benzene, 1 -phenyl- 1-metaxylyl-ethane,
1-phenyl-1-(2,4-xylyl)ethane and 4-(l-phenylethyl)-w-xylene.
The empirical formula for PXE is Ci6Hi8. The physicochemical properties for PXE are
provided in Table 1. There are no experimental physicochemical property data available for
PXE; therefore, all property data presented are estimates from the U.S. EPA CompTox
Chemicals Dashboard version 2.2.1 and EPI Suite™. PXE is slightly soluble in water and has
moderate vapor pressure (U.S. EPA. 2012). Its moderate vapor pressure indicates that it may
volatilize from dry soil surfaces and will exist in the vapor phase in air. In the atmosphere,
vapor-phase PXE has an estimated half-life of 0.5 days, based on its estimated rate of reaction
with photochemically-produced hydroxyl radicals (U.S. EPA. 2012). At ambient temperatures,
the potential for volatilization from water surfaces or moist soil surfaces is expected to be
moderate, based on its estimated Henry's law constant. The estimated soil adsorption coefficient
(K oc) values for PXE indicate the potential for sorption to soil is high. Based on its Log Koc
value, PXE is classified to be slightly mobile in soils by the Food & Agriculture Organization of
the United Nations (FAO) (U.S. EPA. 2012). Hydrolysis is not expected to be an important fate
process due to the lack of hydrolysable functional groups in this chemical.
Figure 1. l-Phenyl-l-(2,4-dimethylphenyl)-ethane (PXE) (CASRN 6165-52-2) Structure
3 1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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Table 1. Physicochemical Properties of PXE (CASRN 6165-52-2)
Property (unit)
Value3
Molecular formula
Cl6Hl8
Molecular weight (g/mol)
210.32
Physical state
NA
Boiling point (°C)
301
Melting point (°C)
29°C
Density (g/cm3 at 25°C)
0.962
Vapor pressure (mm Hg at 25°C)
2.7 x 10-3
Vapor density
NA
Water solubility (mol/L)
1.46 x 10-6
Log octanol-water partition coefficient (log Kow)
5.29
pKa (unitless)
NA
Henry's law constant (atm-m3/mol at 25°C)
5.25 x 10-4
Soil adsorption coefficient Koc (L/kg)
2.29 x 103
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
2.14 x 10-11
Atmospheric half-life (d)
0.5 (calculated using a 12-hday; 1.5 x 106OH/cm3)b
Flash point (°C)
142
aUnless otherwise noted, data were extracted from the U.S. EPA CompTox Chemicals Dashboard (2,4-dimethyl-
1 -(1 -phehvlet hy 1 )ben/ene. CASRN 6165-52-2. https://comptox.epa.gov/dashboard/DTXSID50884231: accessed
July 31, 2023). All values are predicted averages unless otherwise specified.
bU.S. EPA (2012) (EPI Suite™ estimates using SMILES CC(C1 =CC=CC=C 1 )C 1 =CC=C(C)C=C 1C.
EPI = Estimation Programs Interface; NA = not applicable; PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane;
SMILES = Simplified Molecular Input Line Entry System; U.S. EPA = U.S. Environmental Protection Agency.
A summary of available toxicity values for PXE from the U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for PXE
(CASRN 6165-52-2)
Source (parameter)3
Value (applicability)
Notes
Reference0
Noncancer
IRIS
NV
NA
U.S. EPA (2022b)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR
NV
NA
ATSDR (2022)
WHO
NV
NA
WHO (2022); IPCS (2021)
CalFPA
NV
NA
CalEPA (2022. 2020)
OSHA
NV
NA
OSHA (2020. 2017a.
2017b)
NIOSH
NV
NA
NIOSH (2018)
ACGIH
NV
NA
ACGIH (2022)
DOE (PAC)
NV
NA
DOE (2018)
Cancer
IRIS
NV
NA
U.S. EPA (2022b)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2021)
IARC
NV
NA
IARC (2022)
CalEPA
NV
NA
CalEPA (2022. 2020)
ACGIH
NV
NA
ACGIH (2022)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DOE = U.S. Department
of Energy; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment
Summary Tables; IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information
System; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; WHO = World Health Organization.
Parameters: PAC = protective action criteria.
°Reference date is the publication date for the database and not the date the source was accessed.
NA = not applicable; NY = not available; PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane.
Literature searches were conducted in November 2018 and October 2022, and updated
mostly recently in July 2023 for studies relevant to the derivation of provisional toxicity values
for PXE. Searches were conducted using the U.S. EPA's Health and Environmental Research
Online (HERO) database of scientific literature. HERO searches for the following databases:
PubMed, TOXLINE1 (including TSCATS1), Scopus, and Web of Science. The National
Technical Reports Library (NTRL) was searched for government reports from 2018 through
'Note that this version of TOXLINE is no longer updated
(https://www.nlm.nib.gov/databases/download/toxlinesubset.html): therefore, it was not included in the literature
search update from October 2022 or July 2023.
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September 20202. The following resources were searched outside of HERO for health-related
values: American Conference of Governmental Industrial Hygienists (ACGIH), U.S. Agency for
Toxic Substances and Disease Registry (ATSDR), California Environmental Protection Agency
(CalEPA), Defense Technical Information Center (DTIC), European Centre for Ecotoxicology
and Toxicology of Chemicals (ECETOC), European Chemicals Agency (ECHA), the U.S. EPA
Chemical Data Access Tool (CDAT), the U.S. EPA ChemView, the U.S. EPA Integrated Risk
Information System (IRIS), the U.S. EPA Health Effects Assessment Summary Tables
(HEAST), the U.S. EPA Office of Water (OW), International Agency for Research on Cancer
(IARC), the U.S. EPA TSCATS2/TSCATS8e, the U.S. EPA High Production Volume (HPV)
Chemicals via International Programme on Chemical Safety (IPCS) INCHEM, Japan Existing
Chemical Data Base (JECDB), Organisation for Economic Cooperation and Development
(OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical
Information Database (IUCLID), OECD HPV, U.S. National Institute for Occupational Safety
and Health (NIOSH), U.S. National Toxicology Program (NTP), the U.S. EPA Office of Water
(OW) Drinking Water Standards and Health Advisories, U.S. Occupational Safety and Health
Administration (OSHA), and World Health Organization (WHO).
2NTRL was a subset of TOXLINE until December 2019 when TOXLINE was discontinued. Searches of NTRL
were conducted starting in 2018 to ensure that references were not missed due to delays in importing items into the
database.
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
As summarized in Tables 3A and 3B, no short-term, subchronic, chronic, or
reproductive/developmental toxicity studies of PXE in humans or animals exposed by oral or
inhalation routes adequate for deriving provisional toxicity values were identified. The phrase
"statistical significance" and term "significant," used throughout the document, indicate a
p-value of < 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for PXE (CASRN 6165-52-2)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
(comments)
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level; PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane.
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Table 3B. Summary of Potentially Relevant Cancer Data for PXE (CASRN 6165-52-2)
Category
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Duration
Dosimetry
Critical Effects
Reference
(comments)
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
ND = no data; PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane.
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2.1. HUMAN STUDIES
No studies were located regarding the toxicity or carcinogenicity of PXE in humans after
oral or inhalation exposure.
2.2. ANIMAL STUDIES
No studies were located regarding the toxicity or carcinogenicity of PXE in animals after
oral or inhalation exposure.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
No genotoxicity or other supporting studies were identified for PXE. However, some
limited data were located for mixtures containing PXE (see Table 4). Male rats treated with
100 mg/kg-day of SAS-296, a commercial preparation containing 7% PXE and 93%
1-phenyl-1-orthoxylyl-ethane, daily for 1 month showed increases in relative liver weights.
Statistically significant decreases in lipid profiles (free cholesterol, total cholesterol, and/or
phospholipids) in serum and the liver were observed, as were other significant increases in liver
enzyme (alkaline phosphatase), and free fatty acids in serum (Hasegawa et al.. 1982a). A
companion toxicokinetics study performed in rats using a single oral dose showed that SAS-296
(a mixture of PXE and 1-phenyl-1-orthoxylyl-ethane) was absorbed through the gastrointestinal
tract, rapidly cleared from the blood and widely distributed throughout the body, with large
amounts initially found in the liver and slight accumulation in fat (Hasegawa et al.. 1982b). The
percent dissipation of SAS-296, enzyme kinetics, and Km value determined by toxicokinetic
experiments from the same group using rat liver microsomes supported the rapid disappearance
and altered composition of SAS-296 observed in vivo. However, PXE dissipation rates were not
accurately measured due to the lack of the saturation of substrate to enzymatic reaction
(Hasegawa et al.. 1982b).
In skin painting experiments, the test material, described only as a diaryl-alkane
phenyl-xylyl-ethane synthetic fluid (and presumed to be a mixture of PXE, PXE isomers, and
other structurally related compounds) was negative for tumorigenicity and carcinogenicity in two
strains of SENCAR mice or hr/hr Oslo mice treated twice per week with 100% of diaryl-alkane
phenyl-xylyl-ethane for 18 months (Iversen. 1990). Lower concentrations of diaryl-alkane
phenyl-xylyl-ethane in acetone (20 or 40%) did not initiate or promote tumors in studies with
dimethylbenz[a]anthracene or 12-O-tetradecanoylphorbol 13-acetate (Iversen. 1990).
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Table 4. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting studies in animals following oral exposure
Short-term
Mixture: SAS-296
(contains 7% PXE and
93% 1-phenyl-
1 -ortho xy ly 1-ethane)
Male JCL:SD rats (5-6/group) were administered
SAS-296, via gavage (no vehicle specified) at a dose of
100 mg/kg-day for 1 mo. Body-weight change during the
experiment was recorded. Rats were sacrificed ~2 h after
the final dose. Blood and liver were collected for limited
serum and liver biochemistry measurements (unfasted).
Select organs (liver, kidney, heart, spleen, and brain) were
weighed. Gross and microscopic examinations were not
performed.
Reported changes included decreased body
weight gain, increased relative liver weight,
increased serum ALP, and lipid profile
changes in serum (increased fatty acids;
decreased cholesterol and phospholipids) and
liver (increased phospholipids and pyruvate;
decreased cholesterol, triglycerides, glycogen
and glycolipids).
Repeated exposure to
SAS-296 produced
effects on the liver in
treated rats; the
potential contribution
of PXE to the observed
toxicologically
relevant effects is
unclear.
Haseeawa
et al.
(1982a)
Supporting studies in animals following dermal exposure
Carcinogenicity
Mixture: diary 1-alkane
phenyl-xylyl-ethane
(presumed to be a
mixture of PXE, PXE
isomers, and other
structurally related
compounds; mixture
composition
uncharacterized in the
study)
In a skin painting study, hr/hr Oslo mice and SENCAR
mice (16/sex/group; 24/sex for controls) were dermally
exposed to 0% (vehicle), 20 or 40% (SENCAR mice), or
100% (Oslo mice) diary 1-alkane phenyl-xylyl-ethane in an
acetone vehicle, 2 times/wk for 18 mo. A positive control
group was administered 51.2 |ig or 25.6 |ig of DMBA.
100 |iL of the test solutions were applied to the backs of
mice and the applications sites were left uncovered. Mice
were observed to lick each other after painting and an "oil
smell" was apparent for up to 4 h; therefore, oral and
inhalation exposures were also likely. Body and organ
weights were not recorded. Signs of skin and general
toxicity were noted but not actively monitored. Animals
were monitored 1 time/wk for skin tumors. Necropsies
were performed "whenever possible." Tumors in other
organs were examined histologically along with areas
showing skin toxicity (eczematous changes, pigmentation,
or ulcerations).
No increases in incidences of skin tumors or
differences in tumor rates or in overall tumor
yields were observed in either hr/hr Oslo or
SENCAR mice, compared to controls.
Death rates were reported to increase in hr/hr
mice, but data were not provided. Signs of
toxicity (hyperplasia, ulcers, mast cell
collections) were reported as "scant" (data
were not provided).
Diaryl-alkane
phenyl-xylyl ethane
was nontumorigenic in
hr/hr Oslo or
SENCAR mice; the
potential contribution
of PXE to the lack of
observed effects is
unclear.
Iversen
(1990)
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Table 4. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Tumor initiation and
promotion
Mixture: diary 1-alkane
phenyl-xylyl-ethane
(presumed to be a
mixture of PXE, PXE
isomers, and
structurally related
compounds; mixture
composition
uncharacterized in the
study)
Tumor promotion tests were conducted in hr/hr Oslo and
SENCAR mice (16/sex/strain/group; 24/sex for controls).
hr/hr Oslo mice were dermally treated: once with 51.2 |ig
DMBA and then with 40% diaryl-alkane phenyl-
xylyl-ethane in acetone 2 times/wk for 18 mo; with 2.6 |ig
DMBA 2 times/wk for 10 wk followed by applications of
40% diaryl-alkane phenyl-xylyl-ethane 2 times/wk for
18 mo; with 2.6 |ig DMBA alternating with 20% diaryl-
alkane phenyl-xylyl-ethane in acetone 2 times/wk for
20 wk; or 100% PXE 2 times/wk for 18 mo. Negative
control mice were administered acetone 2 times/wk for the
duration of the experiment. Other groups of control mice
received single applications of 51.2 or 25.6 |ig DMBA
only, 2.6 |ig of DMBA 2 times/wk for 5 wk, or 2.6 |ig
DMBA alternating with acetone 2 times/wk for 10 wk.
SENCAR mice were dermally treated: once with 51.2 |ig
DMBA and followed by 20% diaryl-alkane phenyl-
xylyl-ethane in acetone 2 times/wk for 18 mo; once with
20% diaryl-alkane phenyl-xylyl-ethane in acetone and with
10 nmol TPA 2 times/wk for 18 mo; 2.6 ng DMBA
alternating with 20% diaryl-alkane phenyl-xylyl-ethane in
acetone 2 times/wk for lOwk; or 20 and 40% diaryl-alkane
phenyl-xylyl-ethane in acetone 2 times/wk for 18 mo.
Negative control mice were administered acetone
2 times/wk for the duration of the experiment. Other
groups of control mice received single application of
51.2 |ig DMBA; 2.6 |ig of DMBA 2 times/wk for 10 wk;
or 2.6 |ig of DMBA alternating with acetone 2 times/wk
for 10 wk. Body and organ weights were not recorded.
Signs of skin and general toxicity were noted but not
actively monitored. Animals were monitored 1 time/wk for
skin tumors. Necropsies were performed "whenever
possible." Tumors in other organs were examined
histologically along with areas showing skin toxicity
(eczematous changes, pigmentation, or ulcerations).
Treatment with diaryl-alkane phenyl-xylyl-
ethane did not enhance or diminish
DMBA-induced tumorigenesis in either
mouse strain in any experiment. There were
no significant tumorigenic responses after
initiation with 20% diaryl-alkane phenyl-
xylyl-ethane in acetone and promotion with
TPA in SENCAR mice.
Diaryl-alkane
phenyl-xylyl ethane
was not a tumor
promoter or a tumor
initiator; the potential
contribution of PXE to
the lack of observed
effects is unclear.
Iversen
(1990)
12
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EPA/690/R-23/005F
Table 4. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Metabolism and Toxicokinetics
In vivo
Distribution
Mixture: SAS-296
(contains PXE and
1 -phenyl-1 -orthoxy ly 1-
ethane; administered
mixture composition
uncharacterized in the
study)
Groups of 8-wk-old male JCL-SD rats (number per group
not specified) were administered SAS-296 orally either by
a single dose of 100 mg/kg or daily doses of
100 mg/kg-day for 1 mo (performed simultaneously with
the 1-mo toxicity study described above). Rats were
sacrificed at 0, 2, 4, 24, and 48 h after the single dose, and
at 2, 4, 24 h, and 7 d after the final dose in the repeated
dose experiment. Multiple organs and tissues were excised
at each sacrifice and analyzed by GC for SAS-296
components.
Sinsle dose:
SAS-296 was absorbed
through the
gastrointestinal tract
and was rapidly
cleared from the blood
and widely distributed
throughout the body.
After a single dose of
SAS-296, large
amounts were initially
found in the liver,
followed by fat. After
continuous
administration,
SAS-296 showed some
potential for
accumulation in fat.
Haseeawa
• At 2 h: SAS-296 peaked and was primarily
observed in the liver followed by fat, with
smaller amounts in other organs.
• At 4 h: SAS-296 was nearly absent in the
liver and continued to increase in total body
fat and in subcutaneous fat for 24 h.
• At 48 h: SAS-296 was only present in
subcutaneous fat and body fat, although at
lower levels than at 24 h.
• Composition of each SAS-296 component
in varying in organs changed over time in
comparison to material administered, which
the study authors attributed to different rates
of metabolism for the two components
(see in vitro study, below).
Reoeat dose:
• At 2 h: SAS-296 was primarily distributed
to body fat, followed by subcutaneous fat,
and to a lesser extent in the liver, heart,
kidney, and brain.
• SAS-296 continued to accumulate in body
and subcutaneous fat and concentrations
peaked at 24 h postdosing and then
declined. SAS-296 was still present in fat
after 7 d. Concentrations in all other organs
and blood were near zero at 7 d.
• SAS-296 concentrations in liver declined
rapidly over time.
et al.
(1982b)
13
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EPA/690/R-23/005F
Table 4. Other Studies
Test
Materials and Methods
Results
Conclusions
References
In vitro
Rat liver microsomes
Mixture: SAS-296
(contains PXE and
1 -phenyl-1 -ortho xylyl-
ethane; mixture
composition
uncharacterized in the
study)
In a reaction mixture, 2.5 mL of freshly prepared rat liver
homogenates were incubated with SAS-296 (final
concentrations of PXE at 2.6, 3.6, or 4.6 ng/mL and
1-phenyl-l-orthoxylyl-ethane at 1.1, 1.6, or 2.0 |ig/mL)
for 2 h at 37°C. Concentrations of PXE and
1-phenyl-1-orthoxylyl-ethane were analyzed at time zero
and after 2 h and chemical dissipation rates, Michaelis
constants (KM) and maximum reaction velocities (Vmax)
were determined.
• After 2 h, PXE concentrations were reduced
by 23-32%, and concentrations of
1-phenyl-1-orthoxylyl-ethane were reduced
by 58-60%.
• Km and Vmax values were 11.2 ng/mL and
3.6 ng/mL/g/h for PXE and 16.2 ng/mL and
10 iig/mL/g/h for 1-phenyl-1-orthoxylyl-
ethane, reflecting the higher enzyme affinity
and lower maximal velocity of enzyme-
catalyzed reaction for PXE.
The percent dissipation
of SAS-296 and KM
and Vmax values are
supportive of the rapid
disappearance and
altered isomer
composition of
SAS-296 in rats.
However, PXE
dissipation rates were
not accurately
measured due to the
lack of the saturation
of substrate to
enzymatic reaction.
Haseeawa
et al.
(1982b)
ALP = alkaline phosphatase; DMBA = dimethylbenz[a]anthracene; GC = gas chromatography; PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane;
TPA = 12-O-tetradecanoylphorbol 13-acetate.
14
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EPA/690/R-23/005F
3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF ORAL REFERENCE DOSES
No studies were located regarding toxicity of PXE to humans or animals via oral
exposure. Due to the lack of oral toxicity data for PXE, subchronic and chronic provisional
reference doses (p-RfDs) could not be derived directly. Instead, the derivation of oral toxicity
values was attempted using an alternative analogue approach, but a suitable analogue with
available toxicity values was not identified (see Appendix A).
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No studies were located regarding toxicity of PXE to humans or animals via inhalation
exposure. Due to the lack of inhalation toxicity data for PXE, subchronic and chronic provisional
reference concentrations (p-RfCs) could not be derived directly. Instead, the derivation of
inhalation toxicity values was attempted using an alternative analogue approach, but a suitable
analogue with available toxicity values was not identified (see Appendix A).
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
Table 5 presents a summary of noncancer provisional reference values.
Table 5. Summary of Noncancer Reference Values for PXE
(CASRN 6165-52-2)
Toxicity Type
(units)
Species/ Critical p-Reference POD POD Principal
Sex Effect Value Method (HED/HEC) UFc Study
Subchronic p-RfD
(mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
NDr
Subchronic p-RfC
(mg/m3)
NDr
Chronic p-RfC
(mg/m3)
NDr
HEC = human equivalent concentration; HED = human equivalent dose; NDr = not determined; POD = point of
departure; p-RfC = provisional reference concentration; p-RfD = provisional reference dose;
PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane; UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No oral or inhalation studies have been conducted to assess the carcinogenicity of PXE.
Under the U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate Information to
Assess the Carcinogenic Potential' of PXE by oral or inhalation exposure (see Table 6).
15
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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EPA/690/R-23/005F
Table 6. Cancer WOE Descriptor for PXE (CASRN 6165-52-2)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans"
NS
NA
The available data do not support this
descriptor.
"Likely to be Carcinogenic
to Humans "
NS
NA
The available data do not support this
descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
The available data do not support this
descriptor.
"Inadequate Information
to Assess Carcinogenic
Potential"
Selected
Both
No adequate information is available to
assess the carcinogenic potential of PXE by
the inhalation or oral routes of exposure.
"Not Likely to be
Carcinogenic to Humans"
NS
NA
The available data do not support this
descriptor.
NA = not applicable; NS = not selected; PXE = 1-phenyl-1-(2,4-dimethylphenyl)-ethane; WOE = weight of
evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Due to a lack of carcinogenicity data, derivation of cancer risk estimates is precluded
(see Table 7).
Table 7 Summary of Cancer Risk Estimates for PXE (CASRN 6165-52-2)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Risk Estimate
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (lng/in3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor;
PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane.
16
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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EPA/690/R-23/005F
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES
Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity
Value (PPRTV) assessment, it is inappropriate to derive provisional toxicity values for PXE.
However, some information is available for this chemical, which although insufficient to support
derivation of a provisional toxicity value under current guidelines, may be of limited use to risk
assessors. In such cases, the Center for Public Health and Environmental Assessment (CPHEA)
summarizes available information in an appendix and develops a "screening value." Appendices
receive the same level of internal and external scientific peer review as the provisional reference
values to ensure their appropriateness within the limitations detailed in the document. Users of
screening toxicity values in an appendix to a PPRTV assessment should understand that there
could be more uncertainty associated with deriving an appendix screening toxicity value than for
a value presented in the body of the assessment. Questions or concerns about the appropriate use
of screening values should be directed to the CPHEA.
APPLICATION OF AN ALTERNATIVE ANALOGUE APPROACH (METHODS)
The analogue approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for analogue analysis are presented in Wang et al. (2012) and
Lizarraga et al. (2023). Three types of potential analogues (structural, metabolic, and toxicity-
like) are identified to facilitate the final analogue chemical selection. The analogue approach
may or may not be route specific or applicable to multiple routes of exposure. All information is
considered together as part of the final weight-of-evidence (WOE) approach to select the most
suitable analogue both toxicologically and chemically.
An expanded analogue identification approach was developed to collect a comprehensive
set of candidate analogues for the compounds undergoing U.S. Environmental Protection
Agency (U.S. EPA) PPRTV screening-level assessment. As described below, this method
includes application of a variety of tools and methods for identifying candidate analogues that
are similar to the target chemical based on chemical structure and key features; metabolic
relationships; or related toxic effects and mechanisms of action.
To identify structurally-related compounds, an initial pool of analogues is identified using
automated tools, including ChemlDplus3 (Nl.M. 2022a). the CompTox Chemicals Dashboard
(U.S. EPA, 2022a). and the Organisation for Economic Co-operation and Development (OECD)
Quantitative Structure-Activity Relationship (QSAR) Toolbox (OECD. 2021). to conduct
structural similarity searches. Additional analogues identified as ChemlDplus-related substances,
parent, salts, and mixtures, and CompTox-related substances are considered. CompTox
Generalized Read-Across (GenRA) analogues are collected using the methods available on the
publicly available GenRA version 3.2, which may include Morgan fingerprints, Torsion
fingerprints, ToxPrints and ToxCast, Tox21, and ToxRef data. For compounds that have very
few analogues identified by structure similarity using a similarity threshold of 0.8 or 80%,
substructure searches in the QSAR Toolbox may be performed, or similarity searches may be
rerun using a reduced similarity threshold (e.g., 70 or 60%). The compiled list of candidate
analogues is batch run through the CompTox Chemicals Dashboard where QSAR-ready
3The National Library of Medicine (NLM) retired ChemlDplus in December 2022.
17 1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
-------
EPA/690/R-23/005F
simplified molecular-input line-entry system (SMILES) notations are collected and toxicity data
availability is determined (e.g., from the Agency for Toxic Substances and Disease Registry
[ATSDR], Office of Environmental Health Hazard Assessment [OEHHA], California
Environmental Protection Agency [CalEPA], the U.S. EPA Integrated Risk Information System
[IRIS], PPRTV assessments). The batch output information is then uploaded into the Chemical
Assessment Clustering Engine (C hem ACE) (U.S. HP A. 201 la), which clusters the chemicals
based on chemical fragments and displays the toxicity data availability for each candidate. The
ChemACE output is reviewed by an experienced chemist, who narrows the list of structural
analogues based on known or expected structure-toxicity relationships, reactivity, and known or
expected metabolic pathways.
Toxicokinetic studies tagged as potentially relevant supplemental material during
screening were used to identify metabolic analogues (metabolites and metabolic precursors).
Metabolites were also identified from the two OECD QSAR Toolbox version 4.4 metabolism
simulators (in vivo rat metabolism simulator and rat liver S9 metabolism simulator). Targeted
PubMed searches were conducted to identify metabolic precursors and other compounds that
share any of the observed or predicted metabolites identified for the target chemical. Metabolic
analogues are then added to the pool of candidate analogues and toxicity data availability is
determined (e.g., from ATSDR, OEHHA, CalEPA, U.S. EPA IRIS, PPRTV assessments).
In vivo toxicity data for the target chemical (if available) are evaluated to determine
whether characteristic toxicity associated with a particular mechanism of toxicity was observed
(e.g., cholinesterase inhibition, inhibition of oxidative phosphorylation). In addition, in vitro
mechanistic data tagged as potentially relevant supplemental material during screening or
obtained from tools including GenRA version 3.2, ToxCast/Tox21, and Comparative
Toxicogenomics Database (CTD) (CTD. 2022; Davis et al.. 2021) were evaluated for this
purpose. Data from CompTox Chemicals Dashboard ToxCast/Tox 21 are collected to determine
bioactivity of the target chemical in in vitro assays that may indicate potential mechanism(s) of
action. The GenRA option within the Dashboard also offers an option to search for analogues
based on similarities in activity in ToxCast/Tox21 in vitro assays. Using the ToxCast/Tox21
bioactivity data, nearest neighbors identified with similarity indices of >0.5 may be considered
potential candidate analogues. The CTD (CTD. 2022; Davis et al.. 2021) is searched to identify
compounds with gene interactions similar to interactions induced by the target chemical;
compounds with gene interactions similar to the target chemical (with a similarity index >0.5)
may be considered potential candidate analogues. These compounds are then added to the pool
of candidate analogues, and toxicity data availability is determined (e.g., from ATSDR, OEHHA,
CalEPA, the U.S. EPA IRIS, PPRTV assessments).
The application of a variety of different tools and methods to identify candidate
analogues serves to minimize the limitations of any individual tool with respect to the pool of
chemicals included, chemical fragments considered, and methods for assessing similarity.
Further, the inclusion of techniques to identify analogues based on metabolism and toxicity or
bioactivity expands the pool of candidates beyond those based exclusively on structural
similarity. The specific tools described above used for the expanded analogue approach searches
were selected because they are publicly available, supported by U.S. and OECD agencies,
updated regularly, and widely used.
18
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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EPA/690/R-23/005F
Analogue Search Results for PXE
Candidate analogues for PXE were identified based on structural, metabolic, and
toxicity/mechanisms/mode-of-action (MOA) relationships. For candidates identified through
these approaches, the U.S. EPA (IRIS and PPRTV), ATSDR, and CalEPA sources were searched
for subchronic, intermediate, and chronic oral and inhalation toxicity values. Details are provided
below.
Identification of Structural Analogues with Established Toxicity Values
Table A-l summarizes the candidate structural analogues for PXE. PXE is not a member
of an existing OECD or New Chemical category. Candidate structural analogues for PXE were
identified using the U.S. EPA CompTox Chemistry Dashboard, OECD QSAR Toolbox, and
ChemlDplus tools. Using similarity searches, 411unique structural analogues were identified in
the Dashboard version 2.2.1, GenRA version 3.2, OECD QSAR Toolbox version 4.4, and
ChemlDplus.
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
J v J
HjC
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto) AND
OECD QSAR
Toolbox (Dice)
AND ChemlDplus
1,4-dimethyl-2-( 1 -phenylethyl)benzene (6165-5 l-l)b
Y ^CH3
Dashboard
(Tanimoto) AND
OECD QSAR
Toolbox (Dice)
l-methyl-2-(l-phenylethyl)benzene (40766-30-1)
CH,
Dashboard
(Tanimoto) AND
OECD QSAR
Toolbox (Dice)
l,2-Dimethyl-3-(l-phenylethyl)benzene (40766-3l-2)b
ch3
H,C.
III |j
ch3
19
1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
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EPA/690/R-23/005F
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto) AND
OECD QSAR
Toolbox (Dice)
l,2-Dimethyl-4-(l-phenylethyl)benzene (6196-95-8)
CHS
ch3
Dashboard
(Tanimoto) only
l-Methyl-2-[l-(4-methylphenyl)ethyl]benzene (5080-10-4)
Dashboard
(Tanimoto) only
4-Benzyl-1,2-dimethylbenzene (13 540-56-2)
ch3
Dashboard
(Tanimoto) only
1 -Methyl-2-[(3-methylphenyl)methyl]benzene (21895-13-6)
Dashboard
(Tanimoto) only
l-Benzyl-2,4-dimethylbenzene (28122-28-3)
Dashboard
(Tanimoto) only
2-Benzyl-l,3-dimethylbenzene (28122-29-4)
H3C.
CH3
fl ^
20 1-Phenyl-1-(2,4-dimethylphenyl)-ethane
-------
EPA/690/R-23/005F
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto) only
1 -Methy 1-3 -(1 -phenylethyl)benzene (32341-91-6)
Dashboard
(Tanimoto) only
1 -Benzy 1-2,3-dimethylbenzene (32518-97-1)
H,C
Dashboard
(Tanimoto) only
1,2-Dimethy 1-3 -[(2-methylphenyl)methyljbenzene (41888-01-1)
H,c. A. CH,
^11
Dashboard
(Tanimoto) only
l-Methyl-4-[l-(4-methylphenyl)ethyl]benzene (530-45-0)
CH3
Dashboard
(Tanimoto) only
l,4-Dimethyl-2-[(3-methylphenyl)methyl]benzene (61819-81-6)
Dashboard
(Tanimoto) only
1,3 -Dimethyl-2-[(3 -methylphenyl)methyljbenzene (721 -34-6)
21 1 -Phenyl-1 -(2,4-dimethylphenyl)-ethane
-------
EPA/690/R-23/005F
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto) only
l,4-Dimethyl-2-[(4-methylphenyl)methyl]benzene (721-45-9)
Dashboard
(Tanimoto) only
2,4-Dimethyl-1 -[(3 -methylphenyl)methyl]benzene (721 -54-0)
[ ch3
H3C.
ch3
Dashboard
(Tanimoto) only
l,2-Dimethyl-4-[(2-methylphenyl)methyl]benzene (721-80-2)
CH3
CHj
Dashboard
(Tanimoto) only
l,2-Dimethyl-4-[l-(3-methylphenyl)ethyl]benzene (874811-05-9)
H3Cs> Jl
ch3
ch3
Dashboard
(Tanimoto) only
l-Methyl-2-[(2-methylphenyl)methyl]benzene (1335-47-3)
22 1-Phenyl-1-(2,4-dimethylphenyl)-ethane
-------
EPA/690/R-23/005F
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto) only
2-Benzyl-1,4-dimethylbenzene (13 540-50-6)
^ H:
Dashboard
(Tanimoto) only
l-Benzyl-2-methylbenzene (713-36-0)
Dashboard
(Tanimoto) only
1 -Ethyl-2-( 1 -phenylethyl)benzene (18908-70-8)
^-CH3
H3C
Dashboard
(Tanimoto) only
1 -Ethy 1-3-(1 -phenylethyl)benzene (18908-71-9)
Dashboard
(Tanimoto) only
l-Benzyl-2-ethylbenzene (28122-25-0)
H^C
23 1-Phenyl-1-(2,4-dimethylphenyl)-ethane
-------
EPA/690/R-23/005F
Table A-l. Candidate Structural Analogues Identified for PXE
ch3 ch3
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
ChemlDplus0 only
l,3-Dimethyl-2-(l-phenylethyl)benzene (81749-29-3)
CH3
aAll software tools set to 80% similarity threshold for analogue identification.
bOECD QSAR Toolbox reported that repeated dose toxicity data are available in the Japanese NITE database.
°ChemIDplus structural similarity search algorithms embedded in the software.
NITE = National Institute of Technology and Evaluation; OECD = Organisation for Economic Co-Operation and
Development; PXE = 1-phenyl-1-(2,4-dimethylphenyl)-ethane; QSAR = quantitative structure-activity relationship.
After eliminating analogues containing metals or deuterated compounds, the remaining
list of analogues was reviewed by a chemist with expertise in read-across. The following criteria
for determining PXE analogues were applied as part of the expert review: (1) the presence of a
methylene or 1,1-ethylidene bridge connecting the two aromatic rings (compounds with other
hydrocarbon moieties connecting the two aromatic rings were excluded because additional
substitutions would impact the steric rotation of the molecule and would block the bridge atom
from metabolism ([or reactivity in general]); (2) compounds with any other atom (such as
oxygen or sulfur) at the bridge or substituted on the structure were excluded because this could
change the activation/reactivity of the aromatic rings; (3) consistent with the structure of PXE,
methyl groups and/or ethyl/ethynyl group on the rings were limited to no more than two per ring
or one per ring, respectively, because more or larger substitutions would result in steric
hinderance, decrease the solubility, and increase the log Kow of the compound; and (4) the
presence of methyl or ethyl/ethynyl groups, as they are potential sites for metabolism. Of the
411 unique structural analogues identified by similarity searches, only 26 met the criteria above
and were carried forward as candidate structural analogues (see Table A-l). No toxicity values
were identified for any of the 26 candidate structural analogues.
Identification of Toxicokinetic Precursors or Metabolites with Established Toxicity
Values
PubMed searches (searching "1-phenyl-1-(2,4-dimethylphenyl)-ethane" or "6165-52-2"
and "metabolite") were conducted to identify metabolic precursors to PXE. No metabolic
precursors were identified. No metabolites were identified for PXE in the scientific literature.
Predicted metabolites were queried with the OECD QSAR Toolbox version 4.4 using the in vivo
rat metabolism simulator and the rat liver S9 metabolism simulator. PubMed was also searched
to identify other compounds that are metabolized to one of the 33 predicted metabolites of PXE
(searching the metabolite name [none of the metabolites had CASRNs] and "metabolite"); no
24
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EPA/690/R-23/005F
compounds that share at least one metabolite with PXE were identified. Table A-2 summarizes
the 33 candidate metabolic analogues for PXE identified by the OECD QSAR Toolbox. Searches
for relevant toxicity values available from the U.S. EPA, ATSDR, or CalEPA for the candidate
metabolic analogues of PXE did not identify toxicity values for any of the predicted metabolites.
Table A-2. Candidate Metabolic Analogues of PXE
Relationship to PXE
Compound3
Metabolic precursor
None identified
[3 -methy l-4-( 1 -methyl-1 -pheny lethy l)pheny 1] methanol
[5 -methy l-2-( 1 -pheny lethy l)pheny 1] methanol
2-(2,4-dimethyl-phenyl)-2-phenyl)ethanol
5-[ 1 -(4-hydroxyphenyl)ethyl] -2,4-dimethylphenol
3 -[ 1 -(2,4-dimethylphenyl)ethyl]phenol
2,4-dimethyl-5-(l-phenylethyl)phenol
2,6-dimethyl-3-(lphenylethyl)phenol
4-[ 1 -(2,4-dimethylphenyl)ethyl]phenol
4-[ 1 -(2,hydroxymethyl-4-methylphenyl)-ethyl] -phenol
4- [ 1 - [2-methy l-4-(hy droxy methy l)pheny 1] ethy lphenol
4-[l-(2,4-dimethylphenyl)-2-hydroxy]ethylphenol
3 -methyl-4-( 1 -phenylethyl)benzoic acid
3 -methy l-4-( 1 -pheny lethy l)benzaldehyde
5 -methyl-2-( 1 -phenylethyl)benzoic acid
5 -methy l-2-( 1 -pheny lethy l)benzaldehyde
2-(2,4-dimethylphenyl)-2-phenylacetic acid
Predicted metabolite
2-(2,4-dimethyl-phenyl)-2-pheny lacetaldehyde
4-(2-hydroxy-1 -pheny lethy l)-3 -methy lbenzaldehyde
2-(4-hydroxymethyl-2-methy lphenyl)-2-pheny lacetaldehyde
2-(4-hydroxymethyl-2-methy lphenyl)-2-phenylethanol
(2-hydroxymethyl-4-methylphenyl)-2-pheny lacetaldehyde
2-(2-hydroxy-l-phenylethyl)-5-methy lbenzaldehyde
2-(2-hydroxymethyl-4-methylphenyl)-2-phenylethanol
4-hydroxy-5-methyl-2-(l-phenylethyl)benzaldehyde
4-hydroxymethyl-2-methyl-5-( 1 -pheny lethy l)phenol
2-hydroxy-5-methyl-4-(l-phenylethyl)benzaldehyde
2-hydroxymethyl-4-methyl-5-( 1 -pheny l-ethyl)-phenol
5-(2-hydroxy-l-phenylethyl)-2,4-dimethy lphenol
2-hydroxymethyl-5-(2-hydroxy-l-phenyl-ethyl)-4-methyl-phenol
4-hydroxymethyl-5-(2-hydroxy-l-phenylethyl)-2-methylphenol
4-[ 1 -(2,4-dimethylphenyl)ethyl] -benzene-1,2-diol
2-( 1 -pheny lethy l)-3,5-dimethy lphenol
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Table A-2. Candidate Metabolic Analogues of PXE
Relationship to PXE
Compound3
2-(5-hydroxy-2,4-dimethylphenyl)-2-phenylacetaldehyde
1 -(2,4-dimethylphenyl)-1 -phenylethane- l-hydroperoxideb
2-( 1 -phenylethyl)-2,5-dimethylphenol
Shares common metabolite(s)
None identified
aNo CASRNs are available for these metabolites.
bChemical structure is unstable or otherwise unsuitable for use as PXE analogue.
PXE = l-phenyl-l-(2,4-dimethylphenyl)-ethane.
Identification of Analogues on the Basis of Toxicity/Mechanistic/MOA) Information
and Established Toxicity Values
No toxicity or mechanistic/MOA data relevant for identifying candidate analogues for
PXE were identified in the scientific literature. The GenRA option version 3.2 within the
Dashboard version 2.2.1 offers the ability to search for analogues based on similarities in activity
in ToxCast/Tox21 in vitro assays; however, there were no bioactivity data for PXE, so this was
not further investigated. The CTD did not have an entry for PXE.
Summary
Searches for metabolic, structural, and toxicity/mechanistic analogues for PXE yielded a
total of 59 unique candidate analogues: 33 metabolism-related analogues and 26 structural
analogues. No candidate analogues were identified on the basis of having similar characteristic
toxicity or mechanisms/MOAs.
None of the candidate analogues have oral or inhalation toxicity values from the
U.S. EPA, ATSDR, or CalEPA. Therefore, no suitable candidate analogues were identified to
calculate screening oral or inhalation toxicity values.
ORAL NONCANCER TOXICITY VALUES
Derivation of Subchronic and Chronic Screening Provisional Reference Doses
Subchronic and chronic provisional reference doses could not be derived due to the lack
of an appropriate analogue having oral toxicity values.
INHALATION NONCANCER TOXICITY VALUES
Derivation of Subchronic and Chronic Screening Provisional Reference Concentrations
Subchronic and chronic provisional reference concentrations could not be derived due to
the lack of an appropriate analogue having inhalation toxicity values.
26
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EPA/690/R-23/005F
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