vvEPA
United States
Environmental Protection
Agency
EPA/690/R-23/003F | February 2023 | FINAL
Provisional Peer-Reviewed Toxicity Values for
Perylene
(CASRN 198-55-0)
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-23/003F
February 2023
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Perylene
(CASRN 198-55-0)
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
Laura M. Carlson, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Paul G. Reinhart, PhD, DABT
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
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Perylene
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TABLE OF CONTENTS
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
2.3.1. Genotoxicity 10
2.3.2. Supporting Studies in Animals 19
2.3.3. Metabolism/Toxicokinetic Studies 23
3. DERIVATION 01 PROVISIONAL VALUES 25
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES 25
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS 25
3.3. SUMMARY OF NONCANCER SCREENING PROVISIONAL REFERENCE
VALUES 25
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 26
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 27
APPENDIX A. SCREENING NONCANCER PROVISIONAL VALUES 28
APPENDIX B. REFERENCES 57
in
Perylene
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
ACGIH
American Conference of Governmental
Industrial Hygienists
AIC
Akaike's information criterion
ALD
approximate lethal dosage
ALT
alanine aminotransferase
AR
androgen receptor
AST
aspartate aminotransferase
atm
atmosphere
ATSDR
Agency for Toxic Substances and
Disease Registry
BMC
benchmark concentration
BMCL
benchmark concentration lower
confidence limit
BMD
benchmark dose
BMDL
benchmark dose lower confidence limit
BMDS
Benchmark Dose Software
BMR
benchmark response
BUN
blood urea nitrogen
BW
body weight
CA
chromosomal aberration
CAS
Chemical Abstracts Service
CASRN
Chemical Abstracts Service Registry
Number
CBI
covalent binding index
CHO
Chinese hamster ovary (cell line cells)
CL
confidence limit
CNS
central nervous system
CPHEA
Center for Public Health and
Environmental Assessment
CPN
chronic progressive nephropathy
CYP450
cytochrome P450
DAF
dosimetric adjustment factor
DEN
diethylnitrosamine
DMSO
dimethylsulfoxide
DNA
deoxyribonucleic acid
EPA
Environmental Protection Agency
ER
estrogen receptor
FDA
Food and Drug Administration
FEVi
forced expiratory volume of 1 second
GD
gestation day
GDH
glutamate dehydrogenase
GGT
y-glutamyl transferase
GSH
glutathione
GST
glutathione S transferase
Hb/g A
animal blood gas partition coefficient
Hb/gH
human blood gas partition coefficient
HEC
human equivalent concentration
HED
human equivalent dose
i.p.
intraperitoneal
IRIS
Integrated Risk Information System
Abbreviations and acronyms not listed on
PPRTV assessment.
IVF
in vitro fertilization
LC50
median lethal concentration
LD50
median lethal dose
LOAEL
lowest-observed-adverse-effect level
MN
micronuclei
MNPCE
micronucleated polychromatic
erythrocyte
MOA
mode of action
MTD
maximum tolerated dose
NAG
7V-acetyl-P-D-glucosaminidase
NCI
National Cancer Institute
NOAEL
no-observed-adverse-effect level
NTP
National Toxicology Program
NZW
New Zealand White (rabbit breed)
OCT
ornithine carbamoyl transferase
ORD
Office of Research and Development
PBPK
physiologically based pharmacokinetic
PCNA
proliferating cell nuclear antigen
PND
postnatal day
POD
point of departure
PODadj
duration adjusted POD
QSAR
quantitative structure-activity
relationship
RBC
red blood cell
RDS
replicative DNA synthesis
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
regional gas dose ratio
RNA
ribonucleic acid
SAR
structure-activity relationship
SCE
sister chromatid exchange
SD
standard deviation
SDH
sorbitol dehydrogenase
SE
standard error
SGOT
glutamic oxaloacetic transaminase, also
known as AST
SGPT
glutamic pyruvic transaminase, also
known as ALT
SSD
systemic scleroderma
TCA
trichloroacetic acid
TCE
trichloroethylene
TWA
time-weighted average
UF
uncertainty factor
UFa
interspecies uncertainty factor
UFc
composite uncertainty factor
UFd
database uncertainty factor
UFh
intraspecies uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
U.S.
United States of America
WBC
white blood cell
this page are defined upon first use in the
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DRAFT PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
PERYLENE (CASRN 198-55-0)
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 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 development contractor QAPP titled Quality Assurance
Project Plan—Preparation of Provisional Toxicity Value (PTV) Documents
(L-CPAD-0031971-QP). As part of the QA system, a quality product review is done prior to
management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this document
to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the
site in question and the risk management decision that would be supported by the risk
assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
Perylene, CASRN 198-55-0, is a polycyclic aromatic hydrocarbon (PAH) compound that
occurs in coal tar and fossil fuels and is found as a byproduct of incomplete combustion (Nl.M.
2022c). Its structure consists of five fused aromatic rings and can be described as a
dinaphthalene. Perylene is preregistered with Europe's Registration, Evaluation, Authorisation,
and Restriction of Chemicals (REACH) program (HCHA. 2022) and is listed on the U.S. EPA's
Toxic Substances Control Act (TSCA) public inventory (Nl.M. 2022c; U.S. HP A. 2021).
Perylene is used as a fluorescent lipid probe in membrane cytochemistry and in the
production of organic semiconductors (Nl .M. 2022c). Perylene is not produced commercially in
the United Sates; it can be produced by the condensation of naphthalene in the presence of mixed
Lewis acid and protic acid catalysts or by reaction of phenanthrene with acrolein in anhydrous
hydrofluoric acid (Nl.M. 2022c).
The empirical formula for perylene is C20H12; its structure is shown in Figure 1. Table 1
provides physicochemical properties for perylene. Perylene is a yellow to colorless crystalline
solid. Its negligible water solubility and negligible vapor pressure indicate that this substance is
hydrophobic and nonvolatile and will exist predominantly in the particulate phase in air.
Additionally, volatilization from water surfaces or moist soil surfaces is expected to be low
based upon the predicted Henry's law constant of 1.06 x 10 6 atm-m3/mole. In the atmosphere,
perylene has an estimated half-life of 3.7 hours, calculated from a predicted rate constant of
3.45 x 10 " cm3/molecule-second at 25°C for reaction with photochemically-produced hydroxyl
radicals (U.S. HP A. 2012). The estimated soil adsorption coefficient (Koc) for perylene indicates
minimal potential for mobility in soil; therefore, perylene has low potential for migration into
groundwater (U.S. HP A. 2012). Perylene is not expected to undergo hydrolysis due to its lack of
hydrolysable functional groups.
Figure 1. Perylene (CASRN 198-55-0) Structure
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Table 1. Physicochemical Properties of Perylene (CASRN 198-55-0)
Property (unit)
Value3
Molecular weight (g/mol)
252.32
Physical state
Solid
Boiling point (°C)
>350 (estimated, range 443-487);
350-400 (sublimes)b c
Melting point (°C)
274
Density (g/cm3 at 25°C)
1.28 (predicted average)
Vapor pressure (mm Hg at 25°C)
5.25 x 10-9
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mg/L at 25°C)
4.0 x 10~4 (reported as 1.58 x 10~9 mol/L)
Octanol-water partition coefficient (log Kow)
6.04
Henry's law constant (atm-m3/mol at 20°C)
1.06 x 10 6 (predicted average)
Soil adsorption coefficient (Koc) (L/kg)
4.07 x io5 (predicted average)
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
3.45 x 10 11 (predicted average)
Atmospheric half-life (d)
0.31 d (3.7 h)d
Relative vapor density (air =1)
NA
Flash point (open cup in °C)
230 (predicted average)
'Data were extracted from the U.S. EPA CompTox Chemicals Dashboard (pervlene; CASRN 198-55-0) (U.S. EPA.
2022c). Accessed on January 18, 2023. All values are experimental averages unless otherwise specified.
bNLM (2022c).
°NIST (2022): Goldfarb and Suuberg (2008).
Calculated half-life in troposphere; tm = 0.693/kOH [OH] where k0H = 3.45 x 10~n and
[OH] = 1.5 x 106 molecules/cm3
NA = not applicable; U.S. EPA = U.S. Environmental Protection Agency.
A summary of available toxicity values for perylene 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 Perylene
(CASRN 198-55-0)
Source/Par ameterab
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2022e)
HEAST
NV
NA
U.S. EPA (201 lb)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR
NV
NA
ATSDR (2021); ATSDR
(1995)
IPCS
NV
NA
IPCS (2020)
CalFPA
NV
NA
CalEPA (2022); CalEPA
(2020)
OSHA
NV
NA
OSHA (202la): OSHA
(2021b): OSHA (2021c)
NIOSH
NV
NA
NIOSH (2018)
ACGIH
NV
NA
ACGIH (2021)
TCEQ (RfD)
0.02 mg/kg-d
Basis for RfD not specified;
value developed with
TECO's protocol (TCEQ.
2015).
TCEO (2022)
Cancer
IRIS
NV
NA
U.S. EPA (2022e)
HEAST
NV
NA
U.S. EPA (2011b)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2021)
IARC (WOE)
Group 3, not classifiable as
to its carcinogenicity to
humans
Inadequate data to permit
an evaluation of the
carcinogenicity of perylene
in experimental animals
IARC (2010)
CalEPA
NV
NA
CalEPA (2022): CalEPA
(2020)
ACGIH
NV
NA
ACGIH (2021)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; TCEQ = Texas
Commission of Environmental Quality.
Parameters: RfD = reference dose; WOE = weight of evidence.
NA = not applicable; NV = not available.
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Literature searches were conducted in June 2019 and updated in January 2023 for studies
relevant to the derivation of provisional toxicity values for perylene, CASRN 198-55-0. Searches
were conducted using the U.S. EPA's Health and Environmental Research Online (HERO)
database of scientific literature. HERO searches the following databases: PubMed, Web of
Science, TOXLINE1 (including TSCATS1), and Web of Science. The National Technical
Reports Library (NTRL) was searched for government reports from 2018 through September
2020. The following resources were searched outside of HERO for health-related values:
American Conference of Governmental Industrial Hygienists (ACGIH), 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 Co-operation and Development
(OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical
Information Database (IUCLID), OECD HPV, National Institute for Occupational Safety and
Health (NIOSH), National Toxicology Program (NTP), Occupational Safety and Health
Administration (OSHA), and World Health Organization (WHO).
Following the literature search, literature was screened and categorized using systematic
review methods to identify studies pertinent to understanding the potential human health hazard
of perylene. The resulting relevant literature was developed into a systematic evidence map
(SEM) using the methods outlined in Thavcr et al. (2022). A description of how the SEM was
used during assessment development can be found in Appendix A.
'Note that this version of TOXLINE is no longer updated
(https://www.nlm.nih.gov/databases/download/toxlinesubset.html'): therefore, it was not included in the literature
search update from January 2023.
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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 perylene in humans or animals exposed by oral or
inhalation routes adequate for deriving provisional toxicity values have been identified. The
phrase "statistical significance," used throughout the document, indicates ap-value of
< 0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Perylene (CASRN 198-55-0)
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.
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Table 3B. Summary of Potentially Relevant Cancer Data for Perylene (CASRN 198-55-0)
Category
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Study 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.
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2.1. HUMAN STUDIES
Studies directly examining the toxicity or carcinogenicity of perylene in humans were not
located. Perylene is a component of complex PAH-containing combustion product mixtures,
several of which are known or suspected to be carcinogenic in humans (e.g., coal tars, soot, and
tobacco smoke and products) (I ARC. 1998. 1983). However, results from studies of these
mixtures do not provide adequate exposure data for dose-response assessment to derive toxicity
values for perylene or other individual PAH components.
2.2. ANIMAL STUDIES
No studies were located regarding cancer or noncancer effects in animals after oral or
inhalation exposure.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Available toxicity data for perylene are limited to dermal and injection studies in
laboratory animals evaluating immunotoxicity and carcinogenicity. Other available data include
toxicokinetic studies and genotoxicity assays.
2.3.1. Genotoxicity
The genotoxicity of perylene has been examined in numerous in vitro studies and a very
limited number of in vivo studies. Available studies are summarized in Table 4A. The data
indicate that perylene is mutagenic in bacteria in the presence of metabolic activation and is
usually less mutagenic in the absence of metabolic activation. In cultured human cell lines,
perylene was not mutagenic with endogenous or exogenous metabolic activity. In general,
perylene did not cause chromosomal damage in vitro or in host-mediated assays, and there is no
evidence that perylene directly damages or binds deoxyribonucleic acid (DNA). Perylene
induced cell transformation in metabolically competent mouse cells but did not induce cell
transformation in hamster cells in the absence of metabolic activation (see Table 4A).
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Reverse
mutation
Salmonella
typhimurium
TA98, TA100,
TA1535, TA1538
4-2,500 (ig/plate
NDr
+
(TA1535,
TA100)
(TA98,
TA1538)
Plate incorporation method. Perylene was positive in TA1535 and
TA100 in the presence of metabolic activation under conditions in
which background lawn indicated at least 10% survival. The
maximum increase in revertants observed was a 20-fold increase at
100 (ig/plate in TA1535 and a 5-fold increase at 4 (ig/plate in
TA100 (quantitative data not reported at other concentrations).
Perylene was negative in TA98 and TA1538. No details were
provided regarding compound solubility in the test medium.
Anderson and
Stvles (1978)
Reverse
mutation
S. typhimurium
TA98
NS
Plate incorporation method. No increase in revertants was
observed with or without metabolic activation. No details were
provided regarding cytotoxicity or compound solubility in the test
medium.
Anderson et
al. (1987)
Reverse
mutation
S. typhimurium
TA98, TA100
50 (ig/plate
NDr
+
Plate incorporation method. Perylene was positive with metabolic
activation in TA98 and TA100. Mutagenic activity increased with
increasing concentration of rat liver S9 (ranged from 5 to
420 |iL/platc) with a >twofold increase in revertants at S9
concentrations >60 |iL/platc. No cytotoxicity was observed. No
details were provided regarding compound solubility in the test
medium.
Carver et al.
(1985)
Reverse
mutation
S. typhimurium
TA100
5, 10, 15 ng/plate
NDr
+
Plate incorporation method. Perylene was positive with metabolic
activation. Mutagenic activity increased with increasing rat and
hamster liver S9, with a >twofold increase in revertants at all S9
concentrations (ranged from 50 to 400 |iL/platc). Perylene-specific
data on cell survival or compound solubility in the test medium
were not reported, but the study authors indicated that compounds
were tested to limit of solubility, of cytotoxicity, or to
1,000 ng/plate.
Carver et al.
(1986)
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Reverse
mutation
S. typhimurium
TA98, TA100,
TA1535,
TA1537, TA1538
NS (serial twofold
dilution series
starting at a high
concentration of
solubility or
toxicity limit)
NDr
+
(TA98,
TA1537,
TA1538)
±
(TA100)
(TA1535)
Plate incorporation method. Perylene was positive in TA98,
TA1537, and TA1538 (>2-fold increase in revertants) and weakly
positive in TA100 (1.5- to 2-fold increase in revertants) in the
presence of metabolic activation. Perylene was negative in
TA1535. Perylene-specific data on cell survival or compound
solubility in the test medium were not reported, but the study
authors indicated that the highest dose tested was based on
solubility or toxicity limit.
De Flora et al.
(1984)
Reverse
mutation
S. typhimurium
TA97, TA98,
TA100, TA1535,
TA1537, TA1538
40-80 nmol/plate
±
TA100
(TA97,
TA98,
TA1535,
TA1537,
TA1538)
±
(strain[s]
NS)
Plate incorporation method. Perylene was weakly positive
(1.9-fold increase in revertants) in TA100 without metabolic
activation. The addition of metabolic activation was "borderline
activating" (no additional details or strain-specific information
were reported). Perylene-specific data on cell survival or
compound solubility in the test medium were not reported, but the
study authors indicated that the highest dose tested was based on
solubility or toxicity limit.
De Flora
(1981)
Reverse
mutation
S. typhimurium
TA98, TA100
Up to
0.75 nmol/plate
±
(strain NS)
+
(TA98)
(TA100)
Plate incorporation method. Perylene was positive in TA98 and
negative in TA100 with metabolic activation. Perylene was noted
to be "weakly mutagenic" without metabolic activation, but the
magnitude of response and strain were not specified. No details
were provided regarding cytotoxicity or compound solubility in the
test medium.
Florin et al.
(1980)
Reverse
mutation
S. typhimurium
TA97
Up to
400 nmol/plate
NDr
Liquid test and plate incorporation methods. No increase in
revertants was observed with metabolic activation by either
method. No details were provided regarding cytotoxicity or
compound solubility in the test medium.
Hera and
Puevo (1988)
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Reverse
mutation
S. typhimurium
TA98
0.001-
0.020 mg/plate
NDr
+
Plate incorporation method. Revertants were increased two- to
sixfold in TA98 in the presence of metabolic activation. No
cytotoxicity was observed. No details were provided regarding
compound solubility in the test medium.
Ho et al.
(1981)
Reverse
mutation
S. typhimurium
TA100, TA98
10 or 20 (ig/plate
NDr
+
(TA100)
(TA98)
Plate incorporation method. Revertants were increased two- to
threefold in TA100 in the presence of metabolic activation. No
evidence of mutagenicity was observed in TA98 with metabolic
activation. No cytotoxicity was observed. No details were provided
regarding compound solubility in the test medium.
Lavoie et al.
(1979)
Reverse
mutation
S. typhimurium
TA98, TA100
1-40 (ig/plate
+
Plate incorporation method. Perylene was positive in TA98 and
TA100 in the presence of metabolic activation and negative in the
absence of metabolic activation. No details were provided
regarding cytotoxicity or compound solubility in the test medium.
Lofroth et al.
(1984)
Reverse
mutation
S. typhimurium
TA97, TA98,
TA100
1-50 (ig/plate
+
Plate incorporation method. Revertants increased >twofold at all
concentrations in TA97 and at >4 (ig/plate in TA98 and TA100
with metabolic activation. No evidence of mutagenicity was
observed without S9 activation. No cytotoxicity was observed. No
details were provided regarding compound solubility in the test
medium.
Sakai et al.
(1985)
Reverse
mutation
S. typhimurium
TA98, TA100,
TA1535,
TA1537, TA1538
0.1-1,000 (ig/plate
Plate incorporation method. Revertants were increased
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Forward
mutation
S. typhimurium
TM677
1.1 \M
NDr
+
8-Azaguanine resistance assay. Perylene was mutagenic at the
8AGs/8AGr locus. No cytotoxicity was observed. No details were
provided regarding compound solubility in the test medium.
Kaden et al.
(1979)
Forward
mutation
S. typhimurium
TM677
2.6-40 \M
+
8-Azaguanine resistance assay. Perylene increased mutation rates
for 8-azaguanine resistance in the presence of metabolic activation.
Cell survival was >80% at all tested concentrations. No details
were provided regarding compound solubility in the test medium.
Penman et al.
(1980)
Forward
mutation
S. typhimurium
TM677
Up to 80 |iM
NDr
+
8-Azaguanine resistance assay. Perylene increased mutation rates
for 8-azaguanine resistance in the presence of metabolic activation.
No cytotoxicity was observed. No details were provided regarding
compound solubility in the test medium.
Thillv et al.
(1983)
DNA damage
Escherichia coli
PQ37
0.156-10 (ig/assay
SOS chromotest. Perylene was negative for DNA damage with or
without metabolic activation. No cytotoxicity was observed. No
details were provided regarding compound solubility in the test
medium.
Mersch-
Sundermann
et al. (1992)
DNA damage
E. coli PQ37
Three to five
concentrations at
half-log intervals up
to limit of solubility
or 100 mM
NDr
SOS chromotest. Criterion for positive response was not reported.
Perylene was negative for DNA damage without metabolic
activation. Perylene-specific data on cell survival or compound
solubility in the test medium were not reported, but the study
authors indicated that the highest dose tested was based on
solubility limit (up to 100 mM).
von der Hude
et al. (1988)
DNA repair
E. coli WP2,
WP67, CM871
<50 |ig (eight
twofold dilutions)
Liquid micromethod. The minimal inhibitory concentration was
>50 |ig with or without metabolic activation. Perylene-specific
data on cell survival or compound solubility in the test medium
were not reported, but the study authors indicated that the highest
dose tested was based on solubility or toxicity limit.
De Flora et al.
(1984)
DNA repair
E. coli WP2,
WP67, CM871
<50 ng/103 bacteria
±
2-H preincubation assay (treat-and-plate method). Survival did not
differ between repair-deficient and wild-type strains without
metabolic activation. Findings were equivocal with metabolic
activation. No details were provided regarding compound
solubility in the test medium.
De Flora et al.
(1984)
14
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in mammalian cells—in vitro
Mutation
Human
lymphoblast cell
line (AHH-1)
10 or 20 |iM
NA
Forward mutation assay (6-thioguanine-resistance assay). There
was no evidence of mutagenicity without exogenous metabolic
activation (AHH-1 cells have endogenous metabolic capabilities).
No cytotoxicity was observed. Concentrations >20 (iM were not
tested due to solubility issues.
Cresoi and
Thillv (1984)
Mutation
Human
lymphoblast cell
line (hlAlv2)
1-10,000 ng/mL
NA
Forward mutation assay (thymidine kinase locus). There was no
evidence of mutagenicity without exogenous metabolic activation
(hlAlv2 cells constitutively express cytochrome P4501A1). Cell
survival was >75% at all tested concentrations. No details were
provided regarding compound solubility in the test medium.
Durant et al.
(1996)
Mutation
Human diploid
lymphoblast cells
11 or 22 (iM
NDr
Forward mutation assay (6-thioguanine-resistance assay). There
was no evidence of mutagenicity with exogenous metabolic
activation. No details were provided regarding compound
solubility in the test medium.
Penman et al.
(1980)
Mutation
Human diploid
lymphoblast cells
11 or 22 (iM
NDr
Forward mutation assay (thymidine kinase locus). There was no
evidence of mutagenicity with exogenous metabolic activation. No
details were provided regarding compound solubility in the test
medium.
Penman et al.
(1980)
CAs
Human
peripheral
leukocytes
10 (ig/mL
NDr
There was no induction of CAs without metabolic activation. Of
the metaphases scored in cells exposed to perylene, 0/200 showed
chromosomal G bands (no other aberration types were scored). No
cytotoxicity was observed. No details were provided regarding
compound solubility in the test medium.
DiPaolo and
Pooescu
(1974)
CAs
SHE cells
10 (ig/mL
NDr
There was no induction of CAs without metabolic activation. Of
the metaphases scored in cells exposed to perylene, 0/200 showed
chromosomal G bands (no other aberration types were scored). No
cytotoxicity was observed. No details were provided regarding
compound solubility in the test medium.
DiPaolo and
Pone sen
(1974)
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
CAs
Chinese hamster
V79 cells
10 (ig/mL
+
NDr
Perylene increased the frequency of CAs (dicentric chromosomes,
chromatid gaps, chromatid interchanges) without metabolic
activation. The number of cell metaphases showing at least one
aberration was 9/20 for perylene, compared to 0/20 for control. No
details were provided regarding cytotoxicity or compound
solubility in the test medium.
Pooescu et al.
(1977)
SCE
Chinese hamster
V79 cells
10 (ig/mL
NDr
There was no induction of SCE without metabolic activation. No
details were provided regarding cytotoxicity or compound
solubility in the test medium.
Pooescu et al.
(1977)
Unscheduled
DNA synthesis
SHE cells
20 (ig/mL
NDr
There was no induction of unscheduled DNA synthesis without
metabolic activation. No details were provided regarding
cytotoxicity or compound solubility in the test medium.
Casto et al.
(1976)
DNA synthesis
Sprague Dawley
rat primary
hepatocytes
0.01-100 nM
NDr
3H-thymidine incorporation assay. Perylene did not induce DNA
synthesis. Perylene was not tested at concentrations >100 nM due
to cytotoxicity. No details were provided regarding compound
solubility in the test medium.
Zhao and
Ramos (1995)
Cell
transformation
Bhas 42 cells
(v-Ha-rav-
transfected
BALB/c 3T3 cell
line)
0.01-10 (ig/mL
+
NA
Initiation/promotion transformation assay. Perylene significantly
increased the number of transformation foci/well in both the
initiation stage of the assay (2-d treatment of low-density cells;
>1 (ig/mL) and promotion stage of the assay (12-d treatment of
near confluent cells; >0.1 (ig/mL) without exogenous metabolic
activation (Bhas 42 cells have endogenous metabolic capabilities).
No cytotoxicity was observed. No details were provided regarding
compound solubility in the test medium.
Asada et al.
(2005)
Cell
transformation
SHE cells
Up to 20 (ig/mL
NDr
Pretreatment with perylene did not increase transformation
frequency associated with adenovirus infection. No cytotoxicity
was observed. No details were provided regarding compound
solubility in the test medium.
Casto et al.
(1973)
16
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Table 4A. Summary of Perylene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Cell
transformation
SHE cells
20 (ig/mL
NDr
Perylene did not increase transformation frequency. When a
promoter (TPA) was added 48 h after incubation with perylene, the
percentage of transformed colonies was 0.54%. Cloning efficiency
was comparable to control. No details were provided regarding
compound solubility in the test medium.
Pooescu et al.
(1980)
DNA adducts/
binding
Human
peripheral blood
lymphocytes
30 \M
NDr
32P-postlabeling analysis. No DNA adducts were detected in cells
after perylene exposure. No details were provided regarding
cytotoxicity or compound solubility in the test medium.
(junta et al.
(1988)
Genotoxicity studies—mammalian species in vivo
SCE
Chinese hamster
V79 cells
implanted in
mouse (C3H/St)
peritoneal cavity;
mice were
injected with
perylene after
implantation
NS
NA
Host-mediated SCE assay. V79 cells were contained in diffusion
chambers implanted in the peritoneal cavities of mice; V79 cells
were examined for SCE frequencies after perylene injection
(additional treatment details not reported). No increases of SCE
frequency were detected with perylene compared to controls.
Siriatmi and
Huane (1978)
DNA adducts
Female BALB/c
mice exposed via
four topical
applications at 0,
6, 30, and 54 h;
sacrificed 24 h
after last
treatment
1.2 nmol
NA
32P-postlabeling analysis. No adducts were detected in mouse skin.
Reddv et al.
(1984)
a+ = positive; ± = weakly positive/equivocal; - = negative.
CA = chromosomal aberration; DNA = deoxyribonucleic acid; NA = not applicable; NDr = not determined; NS = not specified; SHE = Syrian hamster embryo;
SCE = sister chromatid exchange; TPA = 12-O-tetradecanoylphorbol 13-acetate.
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Mutagenicity
Of the available reverse mutation studies in Salmonella typhimurium, 10/13 reported that
perylene was at least weakly mutagenic in the presence of metabolic activation in one or more
strains (Carver et at., 1986, 1985; Sakai et at., 1985; De Flora et al.. 1984; Lofroth et al.. 1984;
De Flora. 1981; Ho et al.. 1981; Florin et al.. 1980; Lavoie et al.. 1979; Anderson and Styles.
1978) (see Table 4A). In general, perylene induced borderline or low reverse mutation rates in
comparison to other mutagens (e.g., other PAHs) (Hera and Puevo. 1988; Carver et al.. 1986; De
Flora et al.. 1984; Lofroth et al .. 1984; De Flora. 1981; Ho et al.. 1981; Florin et al.. 1980;
Anderson and Styles. 1978). Three studies indicated that perylene was not mutagenic with
metabolic activation (Hera and Puevo. 1988; Anderson et al., 1987; Salamone et al.. 1979).
Two of these studies r Anderson et al. (1987) and Hera and Puevo (1988)1 used low
concentrations of S9 (2-3%), which may have been inadequate to promote metabolic
transformation; however, Salamone et al. (1979) reported negative results with 10% S9. Perylene
also induced forward mutations in S. typhimurium strains in the presence of metabolic activation
(Hera and Puevo. 1988; Thittv et al.. 1983; Penman et al.. 1980; Kaden et al.. 1979). In contrast
to reverse mutations, the forward mutagenic potential of perylene in the 8-azaguanine resistance
assay was similar or more potent compared to other PAHs (e.g., benzo[a]pyrene [BaP]) (Thillv
et al .. 1983; Penman et al .. 1980; Kaden et al.. 1979). In the absence of metabolic activation,
perylene did not induce reverse mutations in S. typhimurium in four of six assays (Anderson et
al.. 1987; Sakai et al.. 1985; Lofroth et al.. 1984; Salamone et al.. 1979) and was weakly
mutagenic in one or more strains in two of six assays (De Flora. 1981; Florin et al .. 1980).
Perylene did not induce forward mutations in S. typhimurium in the absence of metabolic
activation (Penman et al.. 1980).
Perylene was not mutagenic in metabolically competent human cell lines (Durant et al..
1996; Crespi and Thillv. 1984) or in human cell lines with exogenous metabolic activation
(Penman et al.. 1980).
Clastogenicity
Evidence from in vitro studies in mammalian cells regarding clastogenicity is mostly
negative. Sister chromatid exchanges (SCEs) were not observed in Chinese hamster V79 cells in
the absence of metabolic activation (Popescu et al.. 1977). Similarly, chromosomal aberrations
(CAs), specifically chromosomal G bands, were not observed during metaphase in human
peripheral lymphocytes or Syrian hamster embryonic (SHE) cells in the absence of metabolic
activation (Popescu et al.. 1977; Pi Paolo and Popescu. 1974). However, the frequency of CAs
was increased in Chinese hamster V79 cells without metabolic activation, including dicentric
chromosomes, chromatid gaps, and chromatid interchanges (Popescu et al .. 1977). None of the
in vitro clastogenicity studies were conducted in the presence of metabolic activation. In a
host-mediated assay, SCEs were not observed in Chinese hamster V79 cells implanted into the
peritoneal cavity of mice prior to perylene injection (Sirianni and Huang, 1978).
DNA Damage and Repair
Findings were generally negative in in vitro assays of DNA damage and repair. In
Escherichia coli, perylene did not induce DNA damage or repair without metabolic activation;
with activation, findings were negative or equivocal/borderline (Mersch-Sundermann et al..
1992; von der I hide et al.. 1988; De Flora et al.. 1984). In mammalian cells, perylene did not
induce DNA synthesis in Sprague Dawley rat primary hepatocytes or unscheduled DNA
synthesis in SHE cells in the absence of metabolic activation; assays were not conducted in the
presence of metabolic activation (Zhao and Ramos, 1995; Casto et al.. 1976).
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Perylene did not form DNA adducts in cultured human peripheral blood lymphocytes
(Gupta et al.. 1988). Similarly, no DNA adducts were identified in mouse skin following
repeated topical application of perylene to shaved skin of mice (four exposures over 54 hours)
(Reddv et al.. 1984).
Cell Transformation
Perylene did not induce cell transformation in SHE cells in the absence of metabolic
activation (Popescu et al.. 1977; Casto et al.. 1973). In an assay specifically designed to evaluate
tumor initiation and promotion potentials of compounds, perylene induced transformation foci in
metabolically competent Bhas 42 cells (derived from BALB/c mouse 3T3 cells) in both initiation
and promotion stages (Asada et al.. 2005).
2.3.2. Supporting Studies in Animals
Immunotoxicity
Humoral immunity in mice was not suppressed following subcutaneous (s.c.) injection of
perylene for 1 or 14 days (see Table 4B), as measured by antibody responses to an antigen (sheep
red blood cells [sRBCs]) in a plaque-forming cell (PFC) assay (White et al.. 1985). The study
also evaluated spleen weight, spleen cellularity, and thymus weight, and observed no statistically
significant changes. A statistically significant increase in body weight was reported following a
14-day exposure to perylene. This study compared the response of perylene to the robust
immunosuppressive response of BaP administered at the same dose level (40 mg/kg-day). It is
unclear whether perylene would have elicited an immunosuppressive response if given at higher
doses, for a longer duration, or via a different route of exposure. No additional in vivo studies
evaluating immunotoxicity were identified. In an in vitro assay in human skin keratinocytes,
perylene induced dose-dependent inflammatory cytokine secretion (interleukin-la, interleukin-6)
(Bahri et al.. 2010).
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Table 4B. Other Supporting Studies of Perylene
Test
Materials and Methods
Results
Conclusions
References
Immunotoxicity in vivo studies
T-cell-dependent
antibody response
study by s.c. injection
Female B6C3F1 mice (n = 8); daily s.c.
injections containing 0 (corn oil vehicle) or
40 mg/kg-d (160 |imol/kg-d) for 1 or 14 d;
spleen IgM response was evaluated 4 d after
injection with sRBCs (body weight, spleen
weight, thymus weight, cellularity, and
number of PFCs).
No change in the spleen IgM
response to sRBCs. No change in
spleen or thymus weight or spleen
cellularity. A statistically significant
increase (-34%) in body weight was
reported after the 14-d exposure.
Perylene did not impair humoral
immunity in mice under the
conditions of this study.
White etal. (1985)
Immunotoxicity in vitro studies
Cytokine release and
cytotoxicity in human
keratinocytes
Keratinocytes (Clonetics) were dosed at
various concentrations (1, 2, 5, 10, or 15 |iIVI)
with perylene, methylpyrene, or both
dissolved in sodium dodecyl sulfate for
24 h-9 d (depending on endpoint). Cells were
assessed for viability, colony forming
efficiency, scrape-wound healing assay,
apoptosis/necrosis, and cytokine secretion.
At the lowest tested concentration
(1 nM), perylene decreased
keratinocyte adhesion and viability in
a concentration-dependent manner.
Perylene reduced keratinocyte colony
formation, and increased apoptosis.
Interleukin-la and interleukin-6
levels were significantly increased
with increasing exposure to perylene
(>2 nM). Toxicity was enhanced
when perylene and methylpyrene
were assessed as a mixture.
Perylene induced dose-
dependent increases in
inflammatory cytokine secretion
and exerted a cytotoxic effect on
human keratinocytes.
Baltri et al. (2010)
Carcinogenicity in vivo studies
Dermal complete
carcinogenicity study
Male C3H mice (n = 20); 60 of a 0.15%
perylene solution in decalin per application;
2 times/wk for up to 82 wk. An appropriate
negative control group was not included. BaP
(0.14%) was used as a positive control.
Skin tumors
Perylene: 0/16 (0%)
Positive control (BaP): 15/21 (71%)
(10 papillomas, 5 carcinomas)
Note: Incidence is based on the
number of mice alive at least 52 wk.
Perylene was not carcinogenic
under the conditions of this
study.
Morton and Christian
(1974)
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Table 4B. Other Supporting Studies of Perylene
Test
Materials and Methods
Results
Conclusions
References
Dermal complete
carcinogenicity study
Male Swiss mice (n = 20); 0.3% perylene in
benzene every 4 d for up to 24 wk; a
benzene-only vehicle control group was not
included. BaP (0.3%) was used as a positive
control.
Skin tumors (unspecified)
Perylene was not carcinogenic
under the conditions of this
study.
Finzi et al. (1968)
Perylene: 0/20 (0%)
Positive control (BaP): 36/40 (90%)
Dermal complete
carcinogenicity and
initiation-promotion
studies
Female CD-I mice (number/group not
specified); dermal application of 0 or 1%
perylene 3 times/wk for 1 yr (vehicle not
reported); a separate group of mice were
initiated with a single 300 |ig dermal dose of
BaP followed by dermal application of 1%
perylene 3 times/wk for 1 yr.
No increase in skin tumors in
perylene or BaP + perylene treated
mice, compared to vehicle control
(incidence data not reported).
Perylene was not a complete
carcinogen or tumor promotor
under the conditions of this
study. Data reporting is too
limited for independent review
(abstract only).
Anderson and
Anderson (1987)
Dermal initiation-
promotion study
Female Crl/CD-1(ICR)BR mice (n = 20);
dermal application of 1 mg perylene in
acetone applied in 10 doses (every other day),
followed by 2.5 (ig TP A in 0.1 mL acetone
3 times/wk for 25 wk; the vehicle control
group was acetone with TPA promotion. BaP
(0.05 mg) was used as a positive control.
Skin tumors ("Drcdominantlv"
Perylene was not a tumor
initiator under the conditions of
this study.
Hl-Bavoutnv et al.
papillomas)
(1982)
Acetone + TPA: 1/20 (5%)
Perylene + TPA: 1/20 (5%)
Positive control (BaP + TPA):
18/20 (90%)
Dermal initiation-
promotion study
Female ICR/Ha Swiss mice (n = 20); single
dermal application of 800 |ig perylene in
benzene followed by 2.5 |ig TPA in 0.1 mL
acetone 3 times/wk for 58-60 wk; four control
groups were used: untreated, acetone, perylene
initiating dose only, and TPA-only (with no
initiator). A benzene vehicle control was not
included. DMBA (20 |ig in acetone) was used
as a positive control.
Skin tumors
Perylene was not a tumor
initiator under the conditions of
this study. Perylene may be a
weak tumor initiator; papilloma
incidence was slightly increased
compared to controls but did not
reach statistical significance.
Van Dmiren et al.
Untreated control: 0/20 (0%)
Acetone control: 0/20 (0%)
Perylene only: 0/20 (0%)
TPA only: 1/20 (5%)
(1 papilloma)
Perylene + TPA: 3/20 (15%)
(3 papillomas)
Positive control (DMBA + TPA):
19/20 (95%)
(13 carcinomas, 6 papillomas)
(1970)
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Table 4B. Other Supporting Studies of Perylene
Test
Materials and Methods
Results
Conclusions
References
Dermal
cocarcinogenicity
study
Male C3H mice (n = 20); 60 of a 0 or
0.15% perylene solution in a
50:50 decalin:dodecane (De:Do) vehicle per
application; 2 times/wk for up to 82 wk. BaP
(0.14%) was used as a positive control using
100:0, 80:20, or 60:40 De:Do vehicle.
Dodecane was selected as the cocarcinogen
because it had previously been shown to be a
skin cocarcinogen with benz[a]anthracene but
is not a skin carcinogen when administered
alone.
Skin tumors
Perylene was not cocarcinogenic
(with dodecane) under the
conditions of this study.
Morton and Christian
Vehicle control: 2/13 (15%)
(2 papillomas)
Perylene: 1/15 (7%)
(1 papilloma)
Positive control (BaP):
100% decalin: 15/21 (71%)
(5 carcinomas, 10 papillomas)
80:20 De:Do: 13/15 (87%)
(6 carcinomas; 7 papillomas)
60:40 De:Do: 15/15 (100%)
(15 carcinomas)
Note: Incidence is based on the
number of mice alive at least 52 wk.
(1974)
Dermal tumor
inhibition study
Male Swiss mice (n = 40); 0.3% BaP in
benzene or 0.3% perylene and 0.3% BaP in
benzene every 4 d for up to 24 wk.
Skin Daoillomas
Perylene inhibited the
tumorigenic response of BaP
under the conditions of this
study. Statistical analysis of
results was not performed by the
study authors.
Finzi et al. (1968)
BaP: 36/40 (90%)
BaP + perylene: 13/40 (30%)
Lung tumor study by
i.p. injection
Strain A mice (sensitive model for lung tumor
induction); i.p. injection of 0, 200, 500, or
1,000 mg/kg perylene 3 times/wk for 8 wk
followed by a 16-wk observation period.
No increase in lung adenomas
compared to control (vehicle not
reported; incidence data not reported).
Perylene did not induce lung
tumors under the conditions of
this study. Data reporting is too
limited for independent review
(abstract only).
Anderson and
Anderson (1987)
BaP = bcnzo|fl|pyrcnc: DMBA = 7,12-dimethylbenz[a]anthracene; IgM = immunoglobulinM; i.p. = intraperitoneal; n = number; s.c. = subcutaneous; sRBC = sheep red
blood cell; PFC = plaque forming colony; TPA = 12-O-tetradecanoylphorbol acetate.
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Cancer
Available skin painting studies (see Table 4B), while limited by design flaws (lack of
negative controls, potentially inadequate dose levels, small group sizes) and/or limited reporting
(abstract only), do not indicate that perylene is a complete dermal carcinogen or cocarcinogen.
No skin tumors were observed in 16 mice following exposure to 0.15% perylene twice weekly in
a decalin vehicle for up to 82 weeks; in contrast, the same protocol with 0.14% BaP induced skin
tumors (1 tort on and Christian. 1974). Similarly, no skin tumors were observed in 20 mice
exposed to 0.3% perylene in benzene every 4 days for up to 24 weeks, while exposure to 0.3%
BaP induced skin tumors using the same protocol (Finzi et al.. 1968). In a study only available as
an abstract, dermal application of 1% perylene (vehicle not reported) 3 times weekly for 1 year
did not increase the number of skin tumors, compared to vehicle control (incidence data not
reported) (Anderson and Anderson. 1987).
Skin tumor initiation-promotion studies do not indicate that perylene is a strong tumor
initiator or promotor. Perylene was not a mouse skin tumor initiator following single exposure
(800 jug in benzene) or 10 repeated exposures (total dose 1 g in acetone) with
12-0-tetradecanoylphorbol-13 acetate (TPA) as a promotor (Hl-Bavoumv et al.. 1982; Van
Duurcn et al.. 1970). In both studies, the positive control group (BaP or
7,12-dimethylbenz[a]anthracene) showed expected tumor-initiating activity. In a study only
available as an abstract, perylene was not a tumor promotor when applied as a 1% solution
(vehicle not reported) 3 times weekly for 1 year following a single initiating dose of 300 |ig BaP
(Anderson and Anderson. 1987).
Two dermal studies also evaluated carcinogenic potential of perylene in the presence of
other chemicals. Horton and Christian (1974) evaluated cocarcinogenic potential of 0.15%
perylene twice weekly in a decalin/dodecane vehicle (50:50 ratio). Dodecane had previously
been shown to be a skin cocarcinogen with benz[a]anthracene, but is not a skin carcinogen when
administered alone (Horton and Christian, 1974). Animals coexposed to perylene did not have
significantly increased skin papillomas (1/15) compared with animals exposed only to
decalin/dodecane (2/13). In contrast, BaP and dodecane showed evidence of cocarcinogenicity
following a similar protocol (Horton and Christian. 1974). In a study by Finzi et al. (1968).
perylene coexposure decreased the number of skin tumors induced by BaP (13/40) compared to
BaP alone (36/40); however, statistical analysis of the data was not performed. The study authors
proposed that perylene prevented BaP-induced tumor formation via competitive binding to
epidermal proteins.
In a study only available as an abstract, intraperitoneal (i.p.) injections of perylene at
doses of 200-1,000 mg/kg 3 times/week for 8 weeks did not induce lung tumors in Strain A
mice, a sensitive model for detecting lung tumor induction, following a 16-week postexposure
observation period (Anderson and Anderson. 1987). Due to the limitations of these available
injection and dermal cancer studies, it is not possible to thoroughly assess perylene's
carcinogenic potential following oral and inhalation exposures.
2.3.3. Metabolism/Toxicokinetic Studies
There is limited information available on in vivo toxicokinetics or metabolism of
perylene. A single study evaluated metabolism in rat subcutaneous tissue following s.c. injection
of various PAHs (Flesher and Myers. 1990). In this study, perylene did not show any evidence of
bioalkylation or metabolism within subcutaneous tissue. In contrast, a weakly carcinogenic PAH,
benz[a]anthracene, showed evidence of bioalkylation substitution reactions in rat subcutaneous
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tissue. Other tissues in the body were not evaluated for parent compound or metabolite levels in
this study. No other studies were identified to evaluate in vivo toxicokinetics or metabolism of
perylene. Because absorption and distribution of a chemical in the body are determined largely
by physical and chemical properties related to chemical size and general structure (e.g.,
lipophilicity, vapor pressure, etc.), it is reasonable to assume that perylene will be absorbed and
distributed similarly to other PAHs of similar size and structure with similar physical and
chemical properties (e.g., BaP). PAHs, in general, are metabolized in multiple tissues in the body
into more soluble metabolites, including dihydrodiols, phenols, quinones, and epoxides, that
form conjugates with glucuronide, glutathione (GSH), or sulfate (U.S. EPA. 2017b; I ARC. 2010;
AT SDR. 1995).
Several studies have evaluated the potential for perylene to induce metabolic enzymes.
Most studies have focused on aryl hydrocarbon hydroxylase (AHH), an enzyme induced by
many PAHs (Neubert and Tapken. 1988; Asokan et at.. 1986; Mukhtar et at.. 1982; Neubert and
Tapken. 1978). Findings for AHH induction by perylene are mixed. In dermal studies with
neonatal rats, Asokan et at. (1986) reported a significant 1.6-fold induction of AHH in neonatal
rat skin, but not neonatal liver, while Mukhtar et at. (1982) observed the opposite (a significant
1.6-fold increase in AHH in neonatal liver, but not the skin). In both studies, the induction by
perylene was approximately an order of magnitude lower than known inducers
(e.g., 3-methyl-cholanthrene, 7,12-demethylbenzanthracene). During gestational exposures, both
AHH activity and overall "BaP hydrolase" activity were elevated in maternal livers, but not in
fetal livers (Neubert and Tapken. 1988. 1978). "BaP hydrolase" activity was measured as total
BaP breakdown, as opposed to activities of specific hydrolase enzymes. In these studies, the
magnitude of perylene enzyme induction was -25% lower than induction by BaP. In male rats,
i.p. injections of perylene did not induce AHH in the liver (Harris et at., 1988). In vitro, perylene
is a weak inducer of AHH and a weak binder of aryl hydrocarbon receptors (AhRs) in rat
hepatocytes (Piskorska-Ptiszczvnska et at.. 1986).
In general, exposure to perylene did not lead to induction of other metabolic enzymes
measured in skin and/or liver, including 7-ethoxyresorufin O-deethylase (EROD),
7-ethoxycoumarin O-deethylase (ECOD), benzphetamine //-demethylase (BPD), nicotinamide
adenine dinucleotide phosphate (NADPH)-cytochrome c, nicotinamide adenine dinucleotide
hydrogen (NADH)-ferricyanide reductase, or cytochrome P450 (CYP450) (Harris et at.. 1988;
Asokan et at., 1986; Mukhtar et at., 1982). Following i.p. exposure to perylene, there was no
evidence of induction of glycolytic enzymes, pyruvate kinase, or lactate dehydrogenase in the
mouse lung (Radv et at.. 1981; Radv et at.. 1980).
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES
No studies were located regarding toxicity of perylene to humans or animals via oral
exposure. Due to the lack of oral toxicity data for perylene, subchronic and chronic provisional
reference doses (p-RfDs) were not derived directly. Instead, screening subchronic and chronic
p-RfDs are derived in Appendix A using an alternative analogue approach. Based on the overall
analogue approach presented in Appendix A, BaP was selected as the most appropriate analogue
for perylene for deriving screening subchronic and chronic p-RfDs (see Table 5).
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS
No studies were located regarding toxicity of perylene to humans or animals via
inhalation exposure. Due to the lack of inhalation toxicity data for perylene, subchronic and
chronic provisional reference concentrations (p-RfCs) were not derived directly. Instead,
screening subchronic and chronic p-RfCs are derived in Appendix A using an alternative
analogue approach. Based on the overall analogue approach presented in Appendix A, BaP was
selected as the most appropriate analogue for perylene for deriving screening subchronic and
chronic p-RfCs (see Table 5).
3.3. SUMMARY OF NONCANCER SCREENING PROVISIONAL REFERENCE
VALUES
The noncancer screening provisional reference values for perylene are summarized in
Table 5.
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Table 5. Summary of Noncancer Reference Values for
Perylene (CASRN 198-55-0)
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
(HED/HEC)
UFc
Principal
Study
Screening
subchronic
p-RfD (mg/kg-d)
Rat/
M, F
Neurobehavioral
effects following
early postnatal
exposure
9 x 1(T5
BMDLisd
0.092a
(based on
analogue POD)
1,000
Chen et al.
(2012): U.S.
EPA (2017a)
Screening
chronic p-RfD
(mg/kg-d)
Rat/
M, F
Neurobehavioral
effects following
early postnatal
exposure
9 x 1(T5
BMDLisd
0.092a
(based on
analogue POD)
1,000
Chen et al.
(2012): U.S.
EPA (2017a)
Screening
subchronic p-RfC
(mg/m3)
Rat/F
Decreased
embryo/fetal
survival
2 x 1(T6
LOAEL
0.0046 (based
on analogue
POD)
3,000
Archibong et
al. (2002);
U.S. EPA
(2017a)
Screening
chronic p-RfC
(mg/m3)
Rat/F
Decreased
embryo/fetal
survival
2 x 1(T6
LOAEL
0.0046 (based
on analogue
POD)
3,000
Archibong et
al. (2002):
U.S. EPA
(2017a)
aThe POD was not converted into a HED using BW3'4 because it is unknown whether allometric scaling is
appropriate for exposure in early postnatal animals (see Appendix A for more details).
BMDL = benchmark dose lower confidence limit; BW = body weight; F = female(s); HEC = human equivalent
concentration; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect level; M = male(s);
POD = point of departure p-RfC = provisional inhalation reference concentration; p-RfD = provisional oral
reference dose; SD = standard deviation; UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Although the scientific literature provides limited information on the mutagenicity and
genotoxicity of perylene, no oral or inhalation studies have been conducted to assess its
carcinogenicity. Available dermal studies and a single i.p. carcinogenicity study provide limited
evidence of carcinogenic potential; the relevance of these findings to oral or inhalation exposure
is unclear. Under the U.S. EPA Cancer Guidelines (U.S. EPA. 2005). there is "Inadequate
Information to Assess Carcinogenic Potential' of perylene by oral or inhalation exposure
(see Table 6).
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Table 6. Cancer WOE Descriptor for Perylene (CASRN 198-55-0)
Possible WOE Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to Humans"
NS
NA
No human data are available.
"Likely to be Carcinogenic
to Humans "
NS
NA
No adequate chronic animal cancer bioassays
are available.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
No adequate chronic animal cancer bioassays
are available.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No adequate chronic animal cancer
bioassays are available. Dermal and i.p.
studies in animals provide limited evidence
of carcinogenic potential.
"Not Likely to be
Carcinogenic to Humans"
NS
NA
No evidence of noncarcinogenicity following
oral or inhalation exposure is available. No
adequate chronic animal cancer bioassays are
available.
i.p. = intraperitoneal; NA = not applicable; NS = not selected; WOE = weight of evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Due to inadequate information to assess carcinogenic potential, quantitative cancer risk
estimates could not be derived for perylene (see Table 7).
Table 7. Summary of Cancer Risk Estimates for
Perylene (CASRN 198-55-0)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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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 perylene.
However, some information is available for this chemical, which although insufficient to support
derivation of provisional toxicity values under current guidelines, may be of 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 assessment. Users of
screening toxicity values in an appendix to a PPRTV assessment should understand that there
could be more uncertainty associated with the derivation of 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). 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 Wang et al. (2012) was developed to
collect a more 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 ChemlDplus (Nl.M. 2022a). the CompTox Chemicals Dashboard
(U.S. EPA, 2022c). and the Organisation for Economic Co-operation and Development (OECD)
Quantitative Structure-Activity Relationship (QSAR) Toolbox (OECD. 2022). 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 Beta version, 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
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
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[ATSDR], California Environmental Protection Agency [CalEPA], 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. EPA. 2011a). 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.
During the development of a systematic evidence map (SEM), toxicokinetic studies were
identified and tagged as potentially relevant supplemental material. These studies were used to
identify metabolic analogues (metabolites and metabolic precursors). Metabolites were also
identified from the two OECD QSAR Toolbox 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, CalEPA,
U.S. EPA IRIS, PPRTV assessments).
In vivo toxicity data for the target chemical (if available from the SEM) are evaluated to
determine whether specific or characteristic toxicity was observed (e.g., cholinesterase
inhibition, inhibition of oxidative phosphorylation). In addition, in vitro mechanistic data tagged
as potentially relevant supplemental material from the SEM or obtained from tools including
GenRA, ToxCast/Tox21, and Comparative Toxicogenomics Database (CTD) (("I'D. 2022; Davis
et at.. 2021) were evaluated for this purpose. Data from CompTox Chemicals Dashboard
ToxCast/Tox21 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 at.. 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, CalEPA, U.S. EPA IRIS, PPRTV assessments).
The tools used for the expanded analogue searches were selected because they are
publicly available, which allows for transparency and reproducibility of the results, and because
they are supported by U.S. and OECD agencies, updated regularly, and widely used. 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.
Analogue Search Results for Perylene
Candidate analogues for perylene were identified based on metabolic relationships,
structural relationships, and toxicodynamic relationships. For candidates identified through these
approaches, the U.S. EPA (IRIS and PPRTV assessments), ATSDR, and CalEPA sources were
29
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searched for subchronic, intermediate, and chronic oral and inhalation toxicity values. Details are
provided below (see "Identification of Structural Analogues with Established Toxicity Values").
Identification of Structural Analogues with Established Toxicity Values
Perylene is not a member of an existing OECD or New Chemical category. Candidate
structural analogues for perylene were identified using similarity searches in the OECD Toolbox,
the U.S. EPA CompTox Chemicals Dashboard, and ChemlDplus tools (MM. 2022a; OECD,
2022; U.S. EPA. 2022a). A total of 521 unique structural analogues were identified for perylene
in the Dashboard, OECD QSAR Toolbox, and ChemlDplus (80% similarity threshold).
The list of potential analogues was reviewed by a chemist with expertise in read-across.
Criteria for including/excluding candidates were as follows:
1. Exclude compounds with elements other than carbon and hydrogen.
2. Include compounds with four, five, or six fused six-carbon aromatic rings.
3. Exclude compounds with smaller or larger rings (greater than six or less than six carbon
rings).
4. Include only compact, condensed compounds:
a. compounds containing the pyrene fragment (17 compounds); or
b. at least one ring shares bonds with three or more other rings (12 compounds).
Using these criteria, a total of 29 candidate structural analogues for perylene were
identified, as shown in Table A-l. Two of the candidate structural analogues had relevant
toxicity values: benzo[a]pyrene (BaP) and pyrene.
Table A-l. Candidate Structural Analogues Identified for Perylene based on
Tools and Expert Judgment
\y\j
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dashboard
(Tanimoto
method), OECD
Toolbox (Dice
method), and
ChemlDplus
(method not
described)
Benzo [a] pyrene (CASRN 50-32-8)
Benzo[e]pyrene (CASRN 192-97-2)
f^YYl
Dibenzo(a,e)pyrene (CASRN 192-65-4)
Dibcnzo|fl,/?|pyrcnc (CASRN 189-64-0)
oSpo
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Table A-l. Candidate Structural Analogues Identified for Perylene based on
Tools and Expert Judgment
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dibenzo[a,/]pyrene (CASRN 189-55-9)
Dibcnzo|fl,/|pyrcnc (CASRN 191-30-0)
(iijpo
XzrJ
Naphtho(2.1.8-f/ra)naplitliaccnc (CASRN 196-42-9)
d^3
Dashboard
(Tanimoto
method) and
ChemlDplus
(method not
described)
Anthanthrene (CASRN 191-26-4)
Benzo(g)chrysene (CASRN 196-78-1)
cSp
Bcnzo(/?)pcntaphcnc (CASRN 214-91-5)
wU.
Benzo(a)perylene (CASRN 191-85-5)
Ben/o|/> | perylene (CASRN 197-70-6)
B c n/o (»,/?,/) pc ry 1 c lie (CASRN 191-24-2)
Bcnzo(/?r//')piccnc (CASRN 189-96-8)
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Table A-l. Candidate Structural Analogues Identified for Perylene based on
Tools and Expert Judgment
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Dibcn/1a,c|anthraccnc (CASRN 215-58-1)
Dibenzo[c,g]chrysene (CASRN 53156-66-4)
Dibenzo(c,w;;?o)chrysene (CASRN 196-28-1)
Dibenzo(c,/?)chrysene (CASRN 196-52-1)
Dibenzo(g,/?)chrysene (CASRN 191-68-4)
Dibenzo(o,c)naphthacene (CASRN 216-00-2)
Dibenzo(fife,gr)naphthacene (CASRN 193-09-9)
Dibcn/o(/w r;/?)naphthaccnc (CASRN 192-51-8)
Naphtho(2,3-g)chrysene (CASRN 196-64-5)
cc^
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Table A-l. Candidate Structural Analogues Identified for Perylene based on
Tools and Expert Judgment
Tool (method)3
Analogue (CASRNs) Selected for Toxicity Value Searchesb
Structure
Pyrene (CASRN 129-00-0)
Tribenz(a,c,/z)anthracene (8CI)(9CI) (CASRN 215-26-9)
1°
Triphenylene (CASRN 217-59-4)
Dashboard
(Tanimoto)
Dibcnzolc/e./w?|tctraccnc (CASRN 214-63-1)
Dibenzo[/)',«o]tetraphene (CASRN 143214-92-0)
Naphtho[1,2-g]chrysene (CASRN 112772-15-3)
<5$
a80% similarity threshold was applied.
bBold shows compounds with oral or inhalation toxicity values.
Identification of Toxicokinetic Precursors or Metabolites with Established Toxicity
Values
Experimental studies identifying metabolites of perylene were not identified in the
scientific literature. Metabolism of other polycyclic aromatic hydrocarbons (PAHs) has been
investigated extensively in both in vitro and in vivo studies (U.S. EPA. 2017a. b; ATSDR. 1995).
Metabolites resulting from oxidation of PAHs include epoxides, dihydrodiols, phenols, and
quinones (U.S. EPA, 2017a, b; ATSDR, 1995). Oxidized forms of perylene are candidate
metabolites based on known metabolic pathways involving cytochrome P450 (CYP450)
oxidation of other PAHs such as naphthalene, pyrene, and BaP (Shimada and Fuiii-Kurivama.
2004; ATSDR, 1995). Predicted metabolites of perylene were collected from the OECD QSAR
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Toolbox (OHCD. 2022). Pub Med searches (searching "perylene" or "198-55-0" and
"metabolite") were conducted to identify metabolic precursors to perylene. No metabolic
precursors were identified. PubMed was also searched to identify other compounds that are
metabolized to any of the observed or predicted metabolites of perylene (searching the
metabolite name or [CASRN if available] and "metabolite"). No compounds that share at least
one metabolite with perylene were identified in these searches.
Table A-2 summarizes the candidate metabolic analogues for perylene. The predicted
metabolites of perylene are a result of CYP450 oxidation occurring at the 1- (bay) or 3- (peri)
positions of the aromatic rings. Searches for relevant toxicity values for the candidate metabolic
analogues of perylene did not identify oral or inhalation toxicity values for any of the observed
or predicted metabolites.
Table A-2. Candidate Metabolic Analogues of Perylene
Relationship to Perylene
Compound
Metabolic precursor
None identified
Predicted metabolites3
3 -Hydro xy-peryleneb
1 -Hydro xy-peryleneb
Shares common metabolite(s)
None identified
'Predicted metabolites of pervlene were collected from the OECD QSAR Toolbox (OECD. 20221.
bCASRN not available for this metabolite.
OECD = Organisation for Economic Co-operation and Development; QSAR = quantitative structure-activity
relationship.
Identification of Analogues on the Basis of ToxicityZMechanistic/MOA Information
and Established Toxicity Values
The toxicological data for perylene, described in the main PPRTV assessment above, do
not suggest any specific, characteristic toxicity (e.g., cholinesterase inhibition, inhibition of
oxidative phosphorylation) that could be used to identify candidate analogues. One study
examining immunosuppression after short-term subcutaneous administration of perylene in mice
(White et al.. 1985) showed no evidence of immunosuppression. No other relevant toxicity or
mechanistic studies on perylene were identified.
Perylene was active in 1 1 PubChem bioactivity assays reported in the Dashboard (U.S.
EPA, 2020b) but was not active in the three available ToxCast/Tox21 assays (U.S. EPA, 2020a).
The GenRA option within the Dashboard offers an option to search for analogues based on
similarities in activity in ToxCast/Tox21 in vitro assays; however, because perylene was not
active in any ToxCast assays, there were no results (U.S. EPA, 2020c).
The CTD (2022) identified several compounds with gene interactions similar to
interactions induced by perylene. In the CTD, similarity is measured by the Jaccard index,
calculated as the size of the intersection of interacting genes for chemical A and chemical B
divided by the size of the union of those genes (range from 0 [no similarity] to 1 [complete
similarity]). Among the compounds with gene interactions similar to perylene, the numbers of
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common gene interactions ranged from 1 to 2 and similarity indices ranged from 0.33 to 0.67.
Although there was one compound with a similarity index over 0.5 (1-methylfluorene,
CASRN 1730-37-6, similarity index of 0.67), the similarity was based on only two gene
interactions and there were no relevant toxicity values available for this chemical, so it was not
considered a candidate analogue.
Summary
Searches for structural, metabolic, and toxicity/mechanistic analogues for perylene
yielded a total of 31 unique candidate analogues: 2 metabolites and 29 structural analogues.
Neither of the identified metabolic analogues had oral or inhalation noncancer toxicity values. Of
the 29 structural candidates, 1 had relevant oral and inhalation noncancer toxicity values (BaP)
and 1 had relevant oral noncancer toxicity values (pyrene).
Structural Analogues
BaP and pyrene were identified as candidate analogues of perylene based on structural
similarity. Table A-3 illustrates the chemical structures and summarizes the physicochemical
properties for perylene and the two candidate analogues. All three compounds are members of
the PAH class of chemicals and are nonsubstituted PAHs. Perylene and BaP consist of five
benzene rings, while pyrene contains only four benzene rings. Due to the aromatic ring number,
perylene and BaP share the same molecular weight, while the molecular weight of pyrene is
lower. Some physicochemical properties are similar for the target compound and both analogues.
For example, melting points show that all the compounds are solids at room temperature. In
addition, perylene and both candidate analogues have the potential for moderate volatilization
from water to air based on their Henry's law constant values. Considering vapor pressure, water
solubility and, octanol-water partition coefficient (log Kow) values presented in Table A-3, BaP
appears to be more similar to perylene than pyrene. Although all three compounds are expected
to have low volatility from dry surfaces and will exist as particulates in the atmosphere, perylene
and BaP, with vapor pressures of > 5 x 10 9 mm Hg, have lower potential for inhalation
exposure as gases or vapors than does pyrene. Water solubility is considerably lower for
perylene and BaP, compared to pyrene, and the log Kow values for perylene and BaP are higher
than that of pyrene. In general, compounds with log Kow values >4 are considered hydrophobic
chemicals, which are likely to partition to fat compartments in the body following absorption
(Schwarzenbach et al.. 2016). Consequently, partitioning to fat will be greater for perylene and
BaP, compared to pyrene. Based on structural characteristics (i.e., five- vs. four-ring PAHs) and
some physicochemical properties (vapor pressure, water solubility, log Kow), BaP is a more
similar candidate structural analogue to perylene than is pyrene.
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Table A-3. Physical-Chemical Properties of Perylene and Candidate
Structural Analogues
Chemical
Perylene3
BaPb
Pyrene0
Structure
m
<&
CASRN
198-55-0
50-32-8
129-00-0
Molecular weight (g/mol)
252.32
252.32
202.26
Melting point (°C)
274
177
150
Boiling point (°C)
>350 (estimated range
443-487)
495
399
Vapor pressure (mm Hg at
25°C)
5.25 x 10-9
5.49 x 10-9
4.5 x 10-6
Henry's law constant
(atm-m3/mole)
1.06 x 10-«
(predicted average)
4.57 x 10-7
1.19 x 10-5
Water solubility (mg/L)
1.58 x 10-9
8.40 x 10-9
6.65 x 10-'
Octanol-water partition
coefficient (log Kow)
6.04
6.13
4.88
"The U.S. EPA CompTox Chemicals Dashboard (perylene CASRN 198-55-0) (U.S. EPA. 2022c). Accessed on
January 18, 2023.
'The U.S. EPA CompTox Chemicals Dashboard (benzo[a]pyrene CASRN 50-32-8) (U.S. EPA. 2022b). Accessed
on January 18, 2023.
The U.S. EPA CompTox Chemicals Dashboard (pyrene CASRN 129-00-0) (U.S. EPA. 2022d). Accessed on
January 18, 2023.
All values are experimental averages unless otherwise specified.
Structural alerts and predictions for genotoxicity and carcinogenicity were identified
using computational tools as follows. Relevant structural alerts and toxicity predictions for
noncancer health effects were identified using computational tools from the OECD (2022)
QSAR Toolbox profilers, OCHEM (2022) ToxAlerts, and IDHAconsult (2018) Toxtree. The
model results for perylene and its candidate analogue compounds are shown in Figure A-l.
Concerns for protein binding, hepatotoxicity, renal toxicity, developmental/reproductive toxicity,
metabolism/reactivity, and endocrine receptor binding are indicated for perylene and its
candidate analogues. Based on structural alerts, BaP is a more similar candidate analogue to
perylene than is pyrene.
36
Perylene
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EPA 690 R-23 003F
February 2023
Structural Category
Compounds (CASRN)
Perylene
(198-55-0)
Benzofalpyrene
(50-32-8)
Pyrene
(129-00-0)
Source
Protein Binding
Protein binding (based on a Michael Acceptor alert for a
predicted hydroxylated metabolite)
Toxtree
Hepatotoxicity
Hepatotoxicity (based on alerts for
3-methylcholanthrene)—Hazard Evaluation Support
System (HESS)
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for tamoxifen)—HESS
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for
a-naphthylisothiocyanate)—HESS
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for carbamazepine)—HESS
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for
(3-naphthy lisothiocy anate)—HE S S
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for oxyphenisatin—HESS
OECD QSAR
Toolbox
Hepatotoxicity (based on alerts for methylclofenapate)—
HESS
OECD QSAR
Toolbox
Renal Toxicity
Renal toxicity (based on alerts for 2-amino-4,5-diphenyl
thiazole) —HESS
OECD QSAR
Toolbox
Renal toxicity (based on alerts for anthraquinone)—HESS
OECD QSAR
Toolbox
Renal toxicity (based on alerts for carbamazepine)—HESS
OECD QSAR
Toolbox
Developmental/Reproductive Toxicity
Aryl hydrocarbon receptor (AliR) binders and prostaglandin
receptor agonists (based on polycyclic aromatic
hydrocarbons [PAHs]); potential for reproductive/
developmental toxicity (Developmental and Reproductive
Toxicity [DART] scheme)—DART
OECD QSAR
Toolbox
Metabolism/Reactivity
Liver enzyme induction (based on aromatic hydrocarbons
alert. Rank C)—HESS
OECD QSAR
Toolbox
Endocrine Receptor Binding
Estrogen receptor binding affinity potential (based on
multicyclic hydrocarbons)—Estrogen Receptor Expert
System (rtER Expert System)
OECD QSAR
Toolbox
~ Model results or structural alerts indicating concern for toxicity.
~ Model results or structural alert indicating no concern for toxicity.
Models with results are presented in the heat map (models without results were omitted).
OECD = Organisation for Economic Co-operation and Development; QSAR = quantitative structure-activity
relationship.
Figure A-l. Structural Alerts for Perylene and Candidate Analogues
37
Perylene
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EPA/690/R-23/003F
February 2023
Toxtree indicated the potential for protein binding based on predicted hydroxylated
metabolites for perylene and both candidate analogues. PAHs, in general, are metabolized in
multiple tissues in the body into more soluble metabolites, including dihydrodiols, phenols,
quinones, and epoxides, that form conjugates with glucuronide, glutathione (GSH), or sulfate
(U.S. EPA. 2017b; IARC. 2010; ATS DR. 1995). There is also limited experimental evidence of
perylene metabolism (see Section 2.3.3)
The OECD QSAR Toolbox Hazard Evaluation Support System (HESS) model showed a
concern for hepatotoxicity for perylene and both analogues based on structural similarity to
3-methylcholanthrene (inducer of hepatic enzymes) and tamoxifen (hepatic steatosis). There is
supportive evidence for hepatic enzyme induction for both analogues and limited experimental
evidence of perylene inducing various hepatic enzymes including AHH, "BaP hydrolase,"
7-ethoxyresorufin O-deethylase (EROD), 7-ethoxycoumarin O-deethylase (ECOD),
benzphetamine «-demethylase (BPD), and other CYP450 enzymes (see Section 2.3.3). The
HESS model also showed a concern for hepatotoxicity for perylene and BaP based on structural
similarity to a-naphthylisothiocyanate, which induces cholestasis, hyper-bilirubinemia, and
necrotic injury in biliary epithelial cells. Concerns for perylene were also predicted based on a
structural alert for carbamazepine, which is associated with vanishing bile duct syndrome;
neither candidate analogue showed this alert. Other structural alerts showing concern for
hepatotoxicity for BaP and/or pyrene (based on structural similarity to P-naphthylisothiocyanate,
oxyphenisatin, or methylclofenapate) were not alerts for perylene.
The OECD QSAR Toolbox HESS model showed a concern for renal toxicity for
perylene and both analogues based on structural similarity to 2-amino-4,5-diphenyl thiazole
(renal polycystic disease). The HESS model also showed a concern for renal toxicity for
perylene and BaP based on structural similarity to anthraquinone (renal degeneration). Concerns
for perylene were also predicted based on a structural alert for carbamazepine, which is
associated with acute renal failure, hyponatremia, and immunologically mediated acute
interstitial nephritis without nephrotic syndrome; neither candidate analogue showed this alert.
The OECD QSAR Toolbox Developmental and Reproductive Toxicity (DART) model
showed a concern for developmental and/or reproductive toxicity for perylene and BaP, but not
pyrene, based on aryl hydrocarbon receptor (AhR) binders and prostaglandin receptor agonists.
The structural alert applies to PAH compounds containing three to five fused aromatic rings
aligned in line, such as BaP and benz[a]anthracene. Pyrene's aromatic rings are grouped
together, which made it inactive for this particular model alert. There is also limited experimental
evidence of perylene binding AhR (see Section 2.3.3 for additional context).
Other alerts from the OECD QSAR Toolbox include an alert from the HESS model for
potential for liver enzyme induction for perylene and both candidate analogues based on the
aromatic hydrocarbon structure and an alert from the Estrogen Receptor Expert System (rtER
Expert System) for potential estrogen receptor binding affinity based on a multicyclic
hydrocarbons structure. Although there are some inconsistencies that varied by model system,
some predictive structure-activity relationship (SAR) tools support concern for mutagenicity/
carcinogenicity.
Metabolic Analogues
Table A-4 summarizes available toxicokinetic data for perylene and the structurally
similar compounds identified as potential analogues.
38
Perylene
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EPA/690/R-23/003F
February 2023
Table A-4. Comparison of ADME Data for Perylene (CASRN 198-55-0) and Candidate Analogues
Chemical
Perylene
BaP
Pyrene
Structure
CASRN
198-55-0
50-32-8
129-00-0
Absorption
Rate and extent
of absorption
• No experimental data.
Laboratory animals (all routes):
• Absorbed by oral, inhalation, and dermal
exposure.
• Rate and extent of absorption is variable,
depending on exposure medium (e.g., oral and
dermal absorption enhanced in presence of oils
and fats; dermal absorption decreased in presence
of soils with high organic carbon content).
• Significant mucociliary clearance of inhaled
particulate to gut.
• Absorption from gut depends on presence of bile
in intestinal lumen.
Laboratory animals (oral, i.t., dermal):
• Peak blood level achieved ~1 h after oral dosing.
• Extensive oral absorption (68-92% in one study).
• Absorbed through tracheal epithelium more rapidly
than BaP following i.t. exposure.
• Rapid and extensive dermal absorption in acetone
(disappearance half-time of radiolabel from skin of
0.5-0.8 d; -50% of applied radiolabel recovered in
urine and feces within 6 d of application).
• Dermal absorption of 94% in guinea pigs.
Distribution
Extent of
distribution
• No experimental data.
• Based on log Kow value >4, perylene is
hydrophobic and is more likely to
partition to fat compartments.
Laboratory animals (all routes):
• Widely distributed throughout the body.
• Initial rapid uptake into well-perfused tissues
(e.g., lung, kidney, liver).
• Subsequent accumulation, retention, and slow
release from fat (consistent with log Kow value >4).
• High levels in gut (from any route) due to
mucociliary clearance from respiratory tract and
hepatobiliary excretion of metabolites.
• Limited placental transfer.
Laboratory animals (all routes):
• Widely distributed throughout the body.
• Initial rapid uptake into well-perfused tissues
(e.g., lung, kidney, liver).
• Subsequent accumulation, retention, and slow
release from fat (consistent with log Kow value >4).
• High levels in gut (from any route) due to
mucociliary clearance from respiratory tract and
hepatobiliary excretion of metabolites.
• Limited placental transfer.
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Perylene
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February 2023
Table A-4. Comparison of ADME Data for Perylene (CASRN 198-55-0) and Candidate Analogues
Chemical
Perylene
BaP
Pyrene
Metabolism
Rate;
Primary reactive
metabolites
• No experimental data.
• By analogy to other PAHs, expected to
be metabolized via CYP450 oxidation.
• Metabolites predicted by both the in
vivo rat metabolism simulator and rat
liver S9 metabolism simulator (OECD
QSAR Toolbox): 3-hydroxy-perylene,
1 -hydroxy-perylene.
Laboratory animals (all routes), in vitro:
• Metabolism is rapid and occurs in many tissues
throughout the body.
• Oxidized via CYP450; primary metabolites are 9-,
10-, 7,8-, 4,5-, and 2,3-dihydrodiols and epoxides,
as well as various phenols, quinones, and
derivatives.
• Oxidative metabolism can be induced by CYP450
inducers.
• Oxidative metabolites conjugated with GSH,
glucuronic acid, and sulfate esters.
Laboratory animals (i.p.)
• Oxidized to 1-and 4-hydroxypyrene, 1,6-and
1,8-dihydroxypyrene, 1,6- and 1,8-pyrenequinone,
and /ra«.Y-4.5-dihydro-4.5-dihydro\ypyrcnc in rats
and rabbits.
• Oxidative metabolites conjugated with GSH,
glucuronic acid, and sulfate esters.
• By analogy to other PAHs, metabolism is
expected to be mediated via CYP450 oxidation.
Enzyme
induction
• Mixed evidence for weak induction of
AHH in vivo; no evidence for
induction of other monooxygenase
enzymes.
• Weak inducer of AHH in vitro; weak
affinity for AhR binding.
• Induces monooxygenase enzymes in vivo and in
vitro (AHH, EROD, etc.).
• Strong affinity for AhR binding.
• Mixed evidence for weak induction of AHH and
EROD in vivo; no evidence for induction of other
monooxygenase enzymes.
• Weak inducer of AHH in vitro; weak affinity for
AhR binding.
Excretion
Elimination
half-time; route
of excretion
• No experimental data.
Laboratory animals (all routes):
• Elimination is rapid, with half-times of 22-30 h.
• Primary route is biliary excretion to feces; urine is
secondary route.
• Excreted mainly as conjugated metabolites.
• Small amounts excreted in breast milk.
Laboratory animals (oral, dermal):
• Elimination is rapid (half-time not specified).
• Eliminated in urine and feces in similar amounts.
References
OECD (2022): Harris et al. (1988):
Asokan et al. (1986); Piskorska-
U.S. EPA (2017a): IARC (2010): ATSDR (1995):
Harris et al. (1988); Piskorska-Pl is/czv ttska et al.
OECD (2022): IARC (2010): ATSDR (1995):
Lintiiak and Brandvs (1993); Asokan et al. (1986);
Pliszczvnska et al. (1986): Mukhtar et al.
(1982): Neubert and Tanken (1978)
(1986); Mukhtar et al. (1982); Neubert and Tanken
(1978)
Piskorska-Pliszczvnska et al. (1986); Mukhtar et al.
(1982); Bon land and Sims (1964)
ADME = absorption, distribution, metabolism, excretion; AhR = aryl hydrocarbon receptor; AHH = aryl hydrocarbon hydroxylase; BaP = benzo[a]pyrene;
CYP450 = cytochrome P450; EROD = 7-ethoxyresorufin O-deethylase; GSH = glutathione; i.t. = intratracheal; Kow = octanol-water partition coefficient;
PAH = polycyclic aromatic hydrocarbon; OECD = Organisation for Economic Cooperation and Development; QSAR = quantitative structure-activity relationship.
40
Perylene
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EPA/690/R-23/003F
February 2023
No data on absorption or distribution are available for perylene. Both candidate
analogues are absorbed via oral, inhalation, and dermal routes and show initial widespread
distribution followed by accumulation and retention in fat (U.S. EPA. 2017a; IARC. 2010;
ATS DR. 1995; Lipniak and Brandys, 1993). Rate and extent of absorption vary depending on
exposure medium (i.e., enhanced in the presence of oils and fats), and oral absorption is
dependent on presence of bile in the small intestines. Pyrene is absorbed more readily and
completely than BaP. The candidate analogues are widely distributed in the body with
preferential accumulation in fat as suggested by the log Kow values >4. High levels are also
observed in the gut (following exposure via any route) due to mucociliary clearance from the
respiratory tract and hepatobiliary excretion of metabolites. Because absorption and distribution
of a chemical in the body are determined largely by physical and chemical properties related to
chemical size and general structure (e.g., lipophilicity [log Kow values >4], vapor pressure,
molecular weight, etc.) (Schwarzenbach et al.. 2016). it is reasonable to assume that perylene
will be absorbed and distributed similarly to the candidate analogues based on similar size,
structure, and physicochemical properties.
No in vivo or in vitro metabolism data are available for perylene. In silico predictions
from the OECD QSAR Toolbox predict metabolism of perylene via oxidation to 1- and
3-hydroxy-perylene. The metabolism of BaP has been extensively reviewed by the U.S. EPA
(2017a). IARC (2010). and ATS PR (1995). BaP is oxidized by CYP450 in multiple tissues
in the body to more soluble metabolites, including dihydrodiols, phenols, quinones, and
epoxides, which then form conjugates with glucuronide, glutathione (GSH), or sulfate.
Limited in vivo evidence also indicates that pyrene undergoes oxidative metabolism to
1- and 4-hydroxypyrene, 1,6- and 1,8-dihydroxypyrene, 1,6- and 1,8-pyrenequinone, and
/ra//.v-4,5-dihydro-4,5-dihydroxypyrene (Bovland and Sims, 1964). Based on analogy to other
PAHs (ATSDR. 1995). oxidative metabolism of pyrene is expected to be mediated by CYP450s.
As discussed in the main PPRTV assessment, some studies reported weak induction of
the monooxygenase enzyme, aryl hydrocarbon hydroxylase (AHH), following in vivo exposure
to perylene (Asokan et al .. 1986; Mukhtar et al .. 1982; Neubert and Tapken. 1978). Of the
candidate analogues, BaP is a known inducer of monooxygenase enzymes, particularly AHH
(ATSDR. 1995; Neubert and Tapken. 1978). Like perylene, evidence for AHH induction in vivo
is mixed for pyrene (Asokan et al.. 1986; Mukhtar et al.. 1982; Neubert and Tapken. 1978). In
vitro, perylene and pyrene are weak AhR binders and BaP is a strong AhR binder (Pi skor ska-
Pi iszczvn ska ct al.. 1986).
No elimination data are available for perylene. Elimination is rapid via all routes in
laboratory animals (22-30 hours, see Table A-4) for BaP and via oral and dermal routes for
pyrene (there are no data on elimination following inhalation exposure to pyrene) (U.S. EPA.
2017a. b; IARC. 2010; ATSDR. 1995; Lipniak and Brandvs. 1993). For BaP, the primary route
of elimination is via feces, with lesser amounts excreted via urine and small amounts excreted in
breast milk. For all routes, BaP is excreted mainly as conjugated metabolites. Data for pyrene are
less robust but indicate that similar amounts are eliminated via feces and urine.
41
Perylene
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EPA/690/R-23/003F
February 2023
In summary, there are no experimental toxicokinetic data for the target chemical,
perylene. Absorption and distribution are similar for the candidate analogues. Similarities in
log Kow values suggest a similar potential accumulation in fat tissues for the target and analogue
compounds. Experimental metabolism data are available for both candidate analogues, and
metabolic pathways (CYP450 oxidation) are expected to be similar for the target compound
based on in silico predictions from the OECD QSAR Toolbox. There is evidence of enzyme
induction by perylene and both candidate analogues, although the magnitude of induction varies
across compounds. Elimination rate is similar for both candidate analogues, with a higher portion
of elimination occurring via feces for BaP. Based on the limited data available, both candidate
analogues appear to be suitable metabolic analogues for perylene.
Toxicity-Like Analogues
Oral Exposure
No repeat-dose oral toxicity studies evaluating noncancer effects or acute oral lethality
studies are available for perylene. The available oral toxicity values for candidate analogues are
summarized in Table A-5. Critical effects for candidate analogues include neurodevelopmental
effects (BaP) (U.S. EPA. 2017a) and kidney effects (pyrene) (U.S. EPA. 2007. 1990). Numerous
additional toxicity targets have been identified for BaP at doses higher than the lowest
lowest-observed-adverse-effect level (LOAEL) associated with neurodevelopmental effects
(0.2 mg/kg-day), which corresponds to the BMDLisd of 0.092 mg/kg-day presented in
Table A-5. The lowest LOAELs for additional toxicity targets of BaP include: reproductive
system (1 mg/kg-day), adult nervous system (2 mg/kg-day), cardiovascular system
(12.5 mg/kg-day), immunological system (15 mg/kg-day), and the kidney and liver
(30 mg/kg-day) (U.S. EPA. 2017a. b). Repeat-dose oral exposure data for pyrene are limited, and
do not identify additional toxicity targets other than the kidney, for which effects were observed
at >125 mg/kg-day (U.S. EPA. 2007). Reproductive and/or developmental toxicity have not been
evaluated following oral exposure to pyrene.
Table A-5. Comparison of Available Oral Toxicity Values for Perylene
(CASRN 198-55-0) and Candidate Structural Analogues
Chemical
Perylene
BaP
Pyrene
Structure
oo
CASRN
198-55-0
50-32-8
129-00-0
Subchronic oral toxicity values
POD (mg/kg-d)
ND
The POD for the chronic RfD
(0.092 mg/kg-d) is also applicable to
subchronic exposure because it is
based on a developmental study (see
further details below)
75
POD type
ND
ND
NOAEL
Subchronic UFC
ND
ND
300 (UFh, UFa, UFd)
Subchronic p-RfD
(mg/kg-d)
ND
ND
3 x 10-1
42
Perylene
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EPA/690/R-23/003F
February 2023
Table A-5. Comparison of Available Oral Toxicity Values for Perylene
(CASRN 198-55-0) and Candidate Structural Analogues
Chemical
Perylene
BaP
Pyrene
Critical effects
ND
ND
Kidney effects (renal tubular
pathology, decreased kidney
weights) at >125 mg/kg-d
Species
ND
ND
Mouse
Duration
ND
ND
13 wk
Route (method)
ND
ND
Oral (gavage)
Source
NA
NA
U.S. EPA (2007) (PPRTV)
Chronic oral toxicity values
POD (mg/kg-d)
ND
0.092
75
POD type
ND
BMDLi sd
NOAEL
Chronic UFC
ND
300 (UFh, UFa, UFd)
3,000 (UFh, UFa, UFs, UFd)
Chronic RfD/
p-RfD (mg/kg-d)
ND
3 x 10-4
3 x 10-2
Critical effects
ND
Neurodevelopmental effects (open
field crossed squares at PND 69;
elevated plus maze open arm entries at
PND 70; Morris water maze hidden
platform trial escape latency at
PNDs 71-74)
Kidney effects (renal tubular
pathology, decreased kidney
weights) at >125 mg/kg-d
Species
ND
Rat
Mouse
Duration
ND
PNDs 5-11
13 wk
Route (method)
ND
Oral (gavage)
Oral (gavage)
Source
NA
U.S. EPA (2017a. 2017b) (IRIS)
U.S. EPA (1990) (IRIS)
Acute oral lethality data
Oral LD50 (mg/kg)
ND
ND
ND
Toxicity at LD50
ND
ND
ND
Source
NLM (2022c)
NLM (2022b): U.S. EPA (2017a)
NLM (2022d): U.S. EPA
(2007)
BaP = bcnzo|fl|pyrcnc: BMDL = benchmark dose lower confidence limit; IRIS = Integrated Risk Information
System; LD5o = median lethal dose; NA = not applicable; ND = no data; NOAEL = no-observed-adverse-effect
level; PND = postnatal day; POD = point of departure; p-RfD = provisional reference dose; RfD = reference dose;
SD = standard deviation; UFa = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFS = subchronic-to-chronic uncertainty
factor.
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Perylene
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EPA/690/R-23/003F
February 2023
Of the candidate analogues, BaP provides the lowest candidate point of departure (POD)
based on neurodevelopment (0.092 mg/kg-day, which is nearly 3 orders of magnitude lower than
the POD of 75 mg/kg-day for pyrene based on kidney effects). Additionally, the lowest LOAEL
identified for kidney effects following repeat-dose oral exposure to BaP is 30 mg/kg-day (U.S.
EPA. 2017a). which is lower than the POD for pyrene based on kidney effects. In the absence of
repeated exposure oral toxicity data for perylene, there is no information with which to clearly
identify the most suitable candidate analogue based on toxicity comparisons. From available
toxicity data, BaP provides the most conservative candidate POD, which is based on
neurodevelopmental effects. In development of the reference dose (RfD) for BaP, the U.S. EPA
compared candidate values for developmental, reproductive, and immunological effects (U.S.
EPA. 2017a. b). The overall RfD, based on neurobehavioral effects in rats exposed during the
early postnatal period, was supported by numerous human and animal studies and was
considered protective of all types of health effects. The MOA for neurodevelopmental effects of
BaP is not fully understood; however, possible mechanisms may involve oxidative stress in the
brain or disrupted gene and/or protein expression levels of neurotransmitters or receptors,
resulting in altered neurotransmitter signaling in the brain (U.S. EPA, 2017a). Available data are
inadequate to determine whether these possible mechanistic events might occur following
exposure to perylene.
Inhalation Exposure
No repeat-exposure inhalation toxicity studies or acute inhalation lethality studies are
available for perylene. Inhalation toxicity values for candidate analogues are presented in
Table A-6. Of the candidate analogues, only BaP has an inhalation toxicity value, which is based
on developmental effects (decreased embryo/fetal survival) (U.S. EPA. 2017a). No inhalation
toxicity values were developed for pyrene due to lack of adequate data (U.S. EPA, 2007).
Additional adverse toxicological effects have been identified for BaP at concentrations higher
than the lowest LOAEL associated with developmental effects (0.025 mg/m3), including
reproductive toxicity at >0.075 mg/m3 and neurodevelopmental effects at 0.1 mg/m3 (only
concentration evaluated for neurodevelopmental effects) (U.S. EPA. 2017a. b).
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February 2023
Table A-6. Comparison of Available Inhalation Toxicity Values for Perylene
(CASRN 198-55-0) and Candidate Structural Analogues
Chemical
Perylene
BaP
Pyrene
Structure
CASRN
198-55-0
50-32-8
129-00-0
Subchronic inhalation toxicity values
POD (mg/m3)
ND
The POD for the chronic RfC
(0.0046 mg/m3) is also applicable
to subchronic exposure because it
is based on a developmental
study (see further details below)
ND
POD type
ND
ND
ND
Subchronic UFC
ND
ND
ND
Subchronic p-RfC (mg/m3)
ND
ND
ND
Critical effects
ND
ND
ND
Species
ND
ND
ND
Duration
ND
ND
ND
Route (method)
ND
ND
ND
Source
NA
NA
U.S. EPA (2007) (PPRTV)
Chronic inhalation toxicity values
POD (mg/m3)
ND
0.0046
ND
POD type
ND
LOAEL
ND
Chronic UFC
ND
3,000 (UFh, UFa, UFl, UFd)
ND
Chronic p-RfC/RfC
(mg/m3)
ND
2 x 10-6
ND
Critical effects
ND
Decreased embryo/fetal survival
ND
Species
ND
Rat
ND
Duration
ND
GDs 11-20
ND
Route (method)
ND
Inhalation (nose-only)
ND
Source
NA
U.S. EPA (2017a) (IRIS)
U.S. EPA (2007) (PPRTV)
Acute inhalation lethality data
Oral LC50 (mg/m3)
ND
ND
ND
Toxicity at LC50
ND
ND
ND
Source
NLM (2022c)
NLM (2022b): U.S. EPA (2017a)
NLM (2022d): U.S. EPA (2007)
BaP = bcnzo|fl|pyrcnc: GD = gestation day; IRIS = Integrated Risk Information System; LC50 = median lethal
concentration; LOAEL = lowest-observed-adverse-effect level; NA = not applicable; ND = no data; POD = point
of departure; NOAEL = no-observed-adverse-effect level; PPRTV = Provisional Peer-Revised Toxicity Value;
p-RfC = provisional reference concentration; RfC = reference concentration; UFA = interspecies uncertainty factor;
UFC = composite uncertainty factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor;
UFl = LOAEL-to-NOAEL uncertainty factor.
45
Perylene
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EPA/690/R-23/003F
February 2023
As described in U.S. EPA (2017a. 2017b). the U.S. EPA IRIS assessment derived
candidate reference concentration (RfC) values for BaP for both reproductive and developmental
effects. The overall RfC, based on decreased embryo/fetal survival following prenatal inhalation
exposure, was considered protective of all types of health effects. The MOA for BaP-mediated
developmental effects is unknown. Possible mechanisms may include covalent protein binding of
oxidative metabolites, oxidative stress, and formation of reactive oxygen species; AhR-mediated
effects on cell growth and differentiation; stimulation of apoptosis; disrupted development of
fetal vascular system (resulting in impaired fetal nutrition); developmental immune dysfunction;
and alterations in maternal hormones/hormone receptors following exposure during gestation
(U.S. EPA. 2017a; IARC. 2010; Archibong et at.. 2002; ATSDR. 1995). Based on structural
alerts only, perylene would also be expected to show covalent protein binding of oxidative
metabolites, AhR-mediated effects, and alterations in progesterone and estrogen binding.
However, in vitro data suggest that perylene is a weak AhR inducer, whereas BaP is a strong
AhR inducer (see Section 2.3). In the absence of repeated-exposure inhalation toxicity data for
perylene, there is no information with which to clearly identify or rule out BaP as an appropriate
analogue based on toxicity comparisons.
Weight-of-Evidence Approach
A tiered WOE approach as described in Wang et al. (2012) was used to select the overall
best analogue chemical. The approach focuses on identifying a preferred candidate for
three types of analogues: structural analogues, toxicokinetic or metabolic analogues, and
toxicity-like analogues. Selection of the overall best analogue chemical is then based on all of the
information from the three analogue types, and the following considerations used in a WOE
approach: (1) lines of evidence from the U.S. EPA assessments are preferred; (2) biological and
toxicokinetic data are preferred over the structural similarity comparisons; (3) lines of evidence
that indicate pertinence to humans are preferred; (4) chronic studies are preferred over
subchronic studies when selecting an analogue for a chronic value; (5) chemicals with more
conservative/health-protective toxicity values may be favored; and (6) if there are no clear
indications as to the best analogue chemical based on the other considerations, then the candidate
analogue with the most structural similarity may be preferred.
BaP is the closest analogue based on structural characteristics and physicochemical
properties. Perylene and BaP both contain five benzene rings, whereas pyrene contains only
four benzene rings. Physicochemical properties (see Table A-3) suggest that pyrene is more
volatile and water soluble than perylene or BaP. In addition, log Kow values suggest that
partitioning to fat is greater for perylene and BaP compared to pyrene. Perylene and BaP also
share more common structural alerts from models than perylene and pyrene. There are no
toxicokinetic data available for perylene, but in general, PAHs as a class show similar
toxicokinetic profiles (e.g., CYP450 oxidation). Therefore, both BaP and pyrene are suitable
toxicokinetic analogues. There are no oral or inhalation data available for perylene. Therefore,
toxicity comparisons provide little basis for assessment of candidate analogues. For oral
exposure, critical targets of toxicity were neurodevelopmental effects for BaP and kidney effects
for pyrene. The neurodevelopmental effects of BaP provide the most sensitive measure of
toxicity among the candidate analogue compounds, making BaP a health-protective analogue.
For inhalation exposure, BaP is the only candidate analogue compound with an inhalation
toxicity value, which is based on developmental effects.
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In summary, both BaP and pyrene are considered suitable analogues. However, BaP is
the closest analogue based on structural and physicochemical properties and provides the most
health-protective oral toxicity value and the only inhalation toxicity value. Therefore, BaP is
selected as the analogue compound for both oral and inhalation screening toxicity values.
ORAL NONCANCER TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Dose
Based on the overall analogue approach presented in this PPRTV assessment, BaP is
selected as the analogue for perylene for derivation of screening subchronic and chronic
provisional reference doses (p-RfDs). The study used for the U.S. EPA screening subchronic and
chronic p-RfD values for perylene is an early postnatal gavage study of BaP in rats (U.S. HP A.
2017a; Chen et at.. 2012). The ToxicologicalReview of Benzo/a/pyretic (CASRN50-32-8):
Supplemental Information (U.S. EPA, 2017b) provided the following summary:
Chen et al. (2012) treated male andfemale neonatal Spr ague-Daw ley rats
(10/sex/group) with benzo[a]pyrene (unspecifiedpurity) dissolved in peanut oil
by gavage daily on PNDs 5 11, at doses of 0.02, 0.2, or 2 mg/kg in 3 mL
vehicle/kg body weight, determined individually based upon daily measurements.
This time period was described as representing the brain growth spurt in rodents,
analogous to brain developmental occurring from the third trimester to 2 years of
age in human infants. Breeding was performed by pairs of 9-week-old rats, with
delivery designated as PND 0. Litters were culled to eight pups/dam (four males
andfour females, when possible) and randomly redistributed at PND 1 among the
nursing dams; dams themselves were rotated every 2-3 days to control for
caretaking differences, and cage-side observations of maternal behavior were
made daily. One male andfemale from each litter were assigned per treatment
group, and the following physical maturation landmarks were assessed daily in
all treatment groups until weaning at PND 21: incisor eruption, eye opening,
development of fur, testis decent, and vaginal opening.
Neonatal sensory and motor developmental tests were administered to
pups during the preweaningperiod at PNDs 12, 14, 16, and 18, and were
behavioral tests administered to rats as adolescents (PNDs 35 and 36) or as
adults (PNDs 70 and 71): each rat was only tested during one developmental
period. All dosing was performed from 1,300 to 1,600 hours, and behavioral
testing was during the "dark" periodfrom 1,900 to 2,300 hours, although tests
were performed in a lighted environment. Pups were observed individually and
weighed daily, the order of testing litters was randomized each day, and all
observations were recorded by investigators blinded to group treatment.
Sensory and motor developmental tests, including the surface righting
reflex test, negative geotaxis test, and cliff aversion test, were performed only
once, while the forelimb grip strength test was assessed during three 60-second
trials on PND 12. Rat movements during the open-field test were recorded by
camera, and two blinded investigators scored movement and rearing separately
during a 5-minute evaluation period. Blinded investigators directly observed
video monitoring of rat movements during the elevated plus maze, and after a
5-minute free exploration period, recorded number of entries into the closed and
open arms, time spent in the open arms, and latency to the first arm entry.
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Assessment of the Morris water maze was slightly different, in that the rats were
habituated to the testing pool by a 60-second swim without a platform on the day
prior to testing. The rats were then tested during a 60-second swim with a hidden
platform present at a constant position each day for 4 days; on the 5th day, the
rats were evaluated during a 60-second probe swim without a platform. The
number of times each animal crossed the original platform location and the
duration of time spent in the platform quadrant were recorded during this final
evaluation. One pup/sex/litter were assignedfor behavioral testing to each of four
tracks: Track 1, surface righting reflex test, cliff aversion test, and open-field test
(PNDs 12-18); Track 2, negative geotaxis test, forelimb grip strength test, and
open-field test (PNDs 12-20); Track 3, elevated plus maze, Morris water maze,
and open-field test (PNDs 34-36); and Track 4, elevated plus maze, Morris water
maze, and open-field test (PNDs 69-71). All results were presented in graphic
form only.
No significant effects on pup body weight were observed during the 7-day
treatment period (PNDs 5-11). Three-way ANOVA (time x benzo[a]pyrene
treatment x sex) indicated that effects of benzo[a]pyrene were not sex-dependent
throughout the 71-day experiment, so both sexes were pooled together. From this
pooled analysis, pups in the 2 mg/kg-day treatment group gained significantly less
weight at both PND 36 and 71. There were no differences among treatment
groups in incisor eruption, eye opening, development of fur, testis decent, or
vaginal opening.
For all measurements of neonatal sensory and motor development, results
from both sexes were analyzed together since benzo[a]pyrene was reported to
have no significant interaction with sex by 3-way ANOVA. No significant
differences were observed in either the cliff aversion or forelimb grip strength
tests. In the surface righting reflex test, latency was increased in the
0.2 mg/kg-day group at PND 12, in the 0.02 and 2 mg/kg-day groups at PND 14,
and in only the high-dose group at PND 16; latency was not significantly different
in any group at PND 18. At PND 12, there was a dose-related increase in
negative geotaxis latency associated with 0.02, 2, and 2 mg/kg-day
benzo[a]pyrene, which was also present in the 2 mg/kg-day group at PND 14, but
returned to control levels at PND 16 and 18. In the open field test, there were no
significant differences in either locomotion or rearing activity at PND 18 or 20.
At PND 34, the 2 mg/kg-day group exhibited significantly increased movement,
but increases in rearing were not significant. At PND 69, increased locomotion
was observed in both the 0.2 and 2 mg/kg-day groups, while rearing was
significantly increased in only the 2 mg/kg-day treatment group.
The elevated plus maze performance was only evaluated in adolescent and
adult rats. Unlike the previous tests, 3-way ANOVA revealed a statistically
significant interaction between neonatal benzo[a]pyrene treatment and sex, so
male andfemale performance was analyzed independently. No significant
differences in PND 35 males were observed, and the only significant observation
in PND 35 females was increased time spent in the open maze arms by the
2 mg/kg-day treatment group. Significantly decreased latency time to first open
arm entry was observed in PND 70 males andfemales in both 0.2 and
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2 mg/kg-day treatment groups; these groups also spent significantly more time in
open maze arms, along with the 0.02 mg/kg-day female group. AtPND 70, the
2 mg/kg-day males, along with the 0.2 and 2 mg/kg-day females, entered more
frequently into open arms and less frequently into closed arms than the vehicle
controls. In the Morris water maze, escape latency (time to reach the platform
during each of the four testing days) was consistently increased in the
2 mg/kg-day treatment group of both sexes, in both adolescent and adult animals.
These increases were statistically significant in both males andfemales treated
with 2 mg/kg-day benzo[a]pyrene at both PNDs 39 and 74, and were also
significantly elevated in 0.2 mg/kg-day animals of both sexes at PND 74.
Likewise, performance during the 5th test day, in the absence of the escape
platform, was significantly adversely affected by both metrics (decreased time
spent in the target quadrant and decreased number of attempts to cross the
platform location) in 2 mg/kg-day rats of both sexes at both PNDs 40 and 75.
PND 75 females treated with 0.2 mg/kg-day benzo[a]pyrene also showed
significant decreases in both performance metrics, while PND 75 0.2 mg/kg-day
males only demonstrated significant differences in "time spent in target
quadrant. " Swim speed was also assessed, but there were no differences among
any treatment group at either age evaluated.
The benchmark dose lower confidence limit with one standard deviation (BMDLisd) of
0.092 mg/kg-day was identified as the POD for BaP based on neurobehavioral effects during a
susceptible life stage (U.S. EPA. 2017a). This POD is selected from among a suite of available
endpoints because it represents multiple neurobehavioral endpoints from several behavioral
tests (i.e., Morris water maze, elevated plus maze, and open field test). Similar effects were
replicated among numerous additional studies. As described in U.S. EPA (2017a): "modeling
for each of the three endpoints resulted in BMDLisd values that clustered in the range
0.092-0.16 mg/kg-day. The lower end of this range ofBMDLs, 0.092 mg/kg-day, was selected to
represent the point of departure (POD) from these three endpoints for RfD derivation. " Thus,
the BMDLs representing different behavioral manifestations of neurotoxicity were considered
together to define the POD for neurobehavioral changes. The U.S. EPA (2017a) did not convert
the POD into a human equivalent dose (HED) using BW3 4 because the critical study evaluated
developmental toxicity in early postnatal animals directly exposed to BaP. BW3/4 scaling was
determined to be inappropriate because: (1) it is unknown if allometric scaling derived from
adult animals is appropriate for extrapolating doses in neonates in the absence of quantitative
toxicokinetic and toxicodynamic differences; and (2) differences in temporal patterns of
development across species result in complications for interspecies dose extrapolation.
The RfD for BaP is derived using a composite uncertainty factor (UFc) of 300, reflecting
10-fold uncertainty factors for interspecies extrapolation and intraspecies variability (UFa and
UFh, respectively) and a 3-fold uncertainty factor for database uncertainties (UFd) (U.S. HP A.
2017a). Wang et al. (2012) indicated that the uncertainty factors typically applied in deriving a
toxicity value for the chemical of concern are the same as those applied to the analogue unless
additional information is available. To derive the screening subchronic p-RfD for perylene from
the BaP data, the UFd of 3 is increased to 10 to account for the absence of repeat-dose oral
toxicity data for perylene.
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Screening Subchronic p-RfD = Analogue POD (HED) ^ UFc
= 0.092 mg/kg day ^ 1,000
= 9 x 10"5 mg/kg day
Table A-7 summarizes the uncertainty factors for the screening subchronic p-RfD for
perylene.
Table A-7. Uncertainty Factors for the Screening Subchronic p-RfD for
Perylene (CASRN 198-55-0)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans when no cross-species dosimetric adjustment (HED calculation) is performed.
UFd
10
A UFd of 10 is applied to reflect database limitations for the BaP analogue and the absence of
repeat-dose and reproductive/developmental toxicity data for perylene.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of perylene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study. The
developmental period is recognized as a susceptible life stage when exposure during a time window
of development is more relevant to the induction of developmental effects than lifetime exposure
ru.s. EPA. 19911.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BaP = bcnzo|fl|pyrcnc: BMDL = benchmark dose lower confidence limit; HED = human equivalent dose;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional reference dose; 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.
Derivation of a Screening Chronic Provisional Reference Dose
BaP is also selected as the analogue for perylene for derivation of a screening chronic
p-RfD. The key study and calculation of the POD are described above for the subchronic p-RfD.
In deriving the screening chronic p-RfD for perylene, the same uncertainty factors used for the
screening subchronic p-RfD (UFa of 10, UFh of 10, and UFd of 10) are applied. An additional
uncertainty factor for study duration is not applied because a developmental study is used as the
principal study.
Screening Chronic p-RfD = Analogue POD UFc
= 0.092 mg/kg day ^ 1,000
= 9 x 10"5 mg/kg day
Table A-8 summarizes the uncertainty factors for the screening chronic p-RfD for
perylene.
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Table A-8. Uncertainty Factors for the Screening Chronic p-RfD for
Perylene (CASRN 198-55-0)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty associated with extrapolating from animals to
humans when no cross-species dosimetric adjustment (HED calculation) is performed.
UFd
10
A UFd of 10 was applied to reflect database limitations for the BaP analogue and the absence of
repeat-dose and reproductive/developmental toxicity data for perylene.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of perylene in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study. The
developmental period is recognized as a susceptible life stage when exposure during a time window
of development is more relevant to the induction of developmental effects than lifetime exposure
ru.s. EPA. 19911.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BaP = bcnzo|fl|pyrcnc: BMDL = benchmark dose lower confidence limit; HED = human equivalent dose;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional reference dose; 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.
INHALATION NONCANCER TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Concentration
Based on the overall analogue approach presented in this PPRTV assessment, BaP is
selected as the analogue for perylene for deriving the screening subchronic and chronic
provisional reference concentrations (p-RfCs). The study used for the U.S. EPA screening
subchronic and chronic p-RfC values for perylene is a prenatal inhalation study of BaP in rats
(U.S. EPA. 2017a; Archibong et al.. 2002). The ToxicologicalReview o/Benzo/a/pyrene
(CASRN 50-32-8): Supplemental Information (U.S. EPA. 2017b) provided the following
summary:
Archibong et al. (2002) evaluated the effect of exposure to inhaled
benzo[a]pyrene on fetal survival and luteal maintenance in timed-pregnant
F344 rats. Prior to exposure on GD 8, laparotomy was performed to determine
the number of implantation sites, and confirmed pregnant rats were divided into
three groups, consisting of rats that hadfour to six, seven to nine, or more than
nine conceptuses in utero. Rats in these groups were then assigned randomly to
the treatment groups or control groups to ensure a similar distribution of litter
sizes. Animals (10/group) were exposed to benzo[a]pyrene:carbon black aerosols
at concentrations of25, 75, or 100 /jg/m3 via nose-only inhalation, 4 hours/day on
GDs 11-20. Control animals were either sham-exposed to carbon black or
remained entirely unexposed. Results ofparticle size analysis of generated
aerosols were reported by several other reports from this laboratory (Inyang et
al., 2003; Ramesh et al., 2001a; Hood et al., 2000). Aerosols showed a trimodal
distribution (average of cumulative mass, diameter) <95%, 15.85 urn; 89%,
<10 fim; 55%, <2.5 urn; and 38%, <1 urn (Inyang et al., 2003). Ramesh et al.
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(2001a) reported that the MMAD (± geometric SD) for the 55% mass fraction
with diameters <2.5 urn was 1.7 ± 0.085. Progesterone, estradiol-17ft, and
prolactin concentrations were determined in plasma collected on GDs 15 and 17.
Fetal survival was calculated as the total number of pups divided by the number
of all implantation sites determined on GD 8. Individual pup weights and crown-
rump length per litter per treatment were determined on PND 4 (PND 0 = day of
parturition).
Archibong et al. (2002) reported that exposure of rats to benzo[a]pyrene
caused biologically and statistically significant (p <0.05) reductions in fetal
survival compared with the two control groups; fetal survival rates were 78.3,
38.0, and 33.8%per litter at 25, 75, and 100 /Jg/m3, respectively, and 96.7% with
carbon black or 98.8% per litter in untreated controls (see Table D-30).
Consequently, the number of pups per litter was also decreased in a
concentration-dependent manner. The decrease was -50% at 75 /jg/m3 and -65%
at 100 /Jg/m3, compared with sham-exposed and unexposed control groups. No
effects on hormone levels were observed on GDs 15 or 17 at the low dose.
Biologically significant decreases in mean pup weights (expressed as gper litter)
of >5% relative to the untreated control group were observed at doses >75 /jg/m3
(14 and 16% decreases at 75 and 100 /Jg/m3, respectively, p < 0.05). There were
no statistically significant differences from the control groups in crown-rump
length (see Table D-30).
Benzo[a]pyrene exposure at 75 /jg/m3 caused a statistically significant
decrease in plasma progesterone, estradiol, and prolactin on GD 17; these levels
were not determined in the rats exposed to 100 /jg/m3 (Archibong et al., 2002).
Plasma prolactin is an indirect measure of the activity of decidual luteotropin, a
prolactin-like hormone whose activity is necessary for luteal maintenance during
pregnancy in rats. Control levels of prolactin increasedfrom GD 15 to 17, but
this increase did not occur in the rats exposed to 75 /jg/m3. Although the
progesterone concentration at 75 /jg/m3 was significantly lower than in controls
on GD 17, the authors thought that the circulating levels should have been
sufficient to maintain pregnancy; thus, the increased loss of fetuses was thought
to be caused by the lower prolactin levels rather than progesterone deficiency.
The reduced circulating levels of progesterone and estradiol-17fi among
benzo[a]pyrene-treated rats were thought to be a result of limited decidual
luteotropic support for the corpora lutea. The authors proposed the following
mechanism for the effects of benzo [a]pyrene on fertility: benzo[a]pyrene or its
metabolites decreased prolactin and decidual luteotropin levels, compromising
the luteotropic support for the corpora lutea and thereby decreasing the plasma
levels of progesterone and estradiol-17p. The low estradiol-17fi may decrease
uterine levels ofprogesterone receptors, thereby resulting in fetal mortality.
Based on biologically and statistically significant decreases in pups/litter and
percent fetal survival/per litter, the LOAEL was 25 /Jg/m3; no NOAEL was
identified.
The LOAEL of 25 ng/m3 for decreased embryo/fetal survival was selected
as the POD for BaP (U.S. EPA, 2017a). The POD was converted into a
LOAELhec of 4.6 ng/m3 (0.0046 mg/m3) by the U.S. EPA (2017a):
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By definition, the RfC is intended to apply to continuous lifetime exposures
for humans (U.S. EPA, 1994a). EPA recommends that adjusted continuous
exposures be usedfor developmental toxicity studies by the inhalation route as
well as for inhalation studies of longer durations (U.S. EPA, 2002). The PODs
were adjusted to account for the discontinuous daily exposure as follows:
PODadj = POD x hours exposed per day/24 hours
= LOAEL x (duration of exposure/24 hours)
= PODadj
Next, the human equivalent concentration (HEC) was calculatedfrom the
PODadj by multiplying by a DAF, which, in this case, was the regional deposited
dose ratio (RDDRer) for extrarespiratory (i.e., systemic) effects as described in
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (U.S. EPA, 1994a). The observed developmental effects
are considered systemic in nature (i.e., extrarespiratory) and the normalizing
factor for extrarespiratory effects ofparticles is body weight (i.e., the equivalent
dose across species is mass deposited in the entire respiratory tract per unit body
weight). The RDDRer was calculated as follows:
RDDRer = (BWh/BWa) x ((Ve)a/(Ve)h) x ((Ftot)a/(Ftot)h)
where:
BW = body weight (kg);
VE = ventilation rate (L/minute); and
Ftot = total fractional deposition.
The total fractional deposition includes particle deposition in the nasal-
pharyngeal, tracheobronchial, and pulmonary regions. Ftot for both animals and
humans was calculated using the Multi-Path Particle Dosimetry (MPPD) model,
a computational model used for estimating human and rat airway particle
deposition (MPPD; Version 2.0 © 2006, as accessed through the former Hamner
Institute; now publicly available through Applied Research Associates). Ftot was
based on the average particle size of 1.7 ± 0.085 urn (mass median aerodynamic
diameter [MMAD] ± geometric SD) as reported in Wu et al. (2003a) for the
exposure range 25-100 urn3. For the model runs, the Yeh-Schum 5-lobe model
was usedfor the human and the asymmetric multiple path model was usedfor the
rat (see Appendix E for MPPD model output). Both models were run under nasal
breathing scenarios after adjusting for inhalability. A geometric SD of 1 was used
as the default by the model because the reported geometric SD of0.085 was
<1.05.
The human parameters used in the model for calculating Ftot and in the
subsequent calculation of the PODnECwere as follows: human body weight,
70 kg; VE, 13.8 L/minute; breathing frequency, 16 per minute; tidal volume,
860 mL; functional residual capacity, 3,300 mL; and upper respiratory tract
volume, 50 mL. Although the most sensitive population in Archibong et al. (2002)
is the developing fetus, the adult rat dams were directly exposed. Thus, adult rat
parameters were used in the calculation of the HEC. The parameters usedfor the
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rat were body weight, 0.25 kg (a generic weight for male andfemale rats); VE,
0.18 L/minute; breathing frequency, 102 per minute; tidal volume, 1.8 mL;
functional residual capacity, 4 mL; and upper respiratory tract volume, 0.42 mL.
All other parameters were set to default values (see Appendix E).
Under these conditions, the MPPD model calculated Ftot values of
0.621 for the human and 0.181 for the rat. Using the above equation, the RDDRer
was calculated to be 1.1.
From this, the PODhec was calculated as follows:
PODhec = PODadj x RDDRer
The RfC for BaP is derived from the LOAELhec of 0.0046 mg/m3 using a UFc of 3,000,
reflecting a 10-fold LOAEL-to-no-observed-adverse-effect level (NOAEL) uncertainty factor
(UFl), UFh, and UFd and a 3-fold UFaQJ.S. EPA, 2017a). Wang et al. (2012) indicated that the
uncertainty factors typically applied in deriving a toxicity value for the chemical of concern are
the same as those applied to the analogue unless additional information is available. Given the
limitations of the current database, the uncertainty factors for BaP were adopted for perylene.
Screening Subchronic p-RfC = Analogue POD ^ UFc
= 0.0046 mg/m3 3,000
= 2 x 10"6 mg/m3
Table A-9 summarizes the uncertainty factors for the screening subchronic p-RfC for
perylene.
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Table A-9. Uncertainty Factors for the Screening Subchronic p-RfC for
Perylene (CASRN 198-55-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans, using toxicokinetic cross-species dosimetric adjustment (HEC calculation) as specified in
the U.S. EPA (1994) guidelines.
UFd
10
A UFd of 10 is applied to reflect the database limitations for the BaP analogue and the absence of
repeat-dose and reproductive/developmental toxicity data for perylene.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of perylene in humans.
UFl
10
A UFl of 10 is applied for LOAEL-to-NOAEL extrapolation because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study. The
developmental period is recognized as a susceptible life stage when exposure during a time window
of development is more relevant to the induction of developmental effects than lifetime exposure
ru.s. EPA. 1991).
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BaP = bcnzo|fl|pyrcnc: HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; 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.
Derivation of a Screening Chronic Provisional Reference Concentration
BaP is also selected as the analogue for perylene for derivation of a screening chronic
p-RfC. The key study and calculation of the POD are described above for the subchronic p-RfC.
In deriving the screening chronic p-RfC for perylene, the same uncertainty factors used for the
screening subchronic p-RfC (UFa of 3, UFh of 10, UFd of 10, UFl of 10) are applied. An
additional uncertainty factor for study duration is not applied because a developmental study is
used as the principal study.
Screening Chronic p-RfC = Analogue POD ^ UFc
= 0.0046 mg/m3 3,000
= 2 x 10"6 mg/m3
Table A-10 summarizes the uncertainty factors for the screening chronic p-RfC for
perylene.
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Table A-10. Uncertainty Factors for the Screening Chronic p-RfC for
Perylene (CASRN 198-55-0)
UF
Value
Justification
UFa
3
A UFa of 3 is applied to account for uncertainty associated with extrapolating from animals to
humans when a cross-soecies dosimetric adjustment (HEC calculation) as specified in the U.S. EPA
(1994) guidelines.
UFd
10
A UFd of 10 is applied to reflect the database limitations for the BaP analogue and the absence of
repeat-dose and reproductive/developmental toxicity data for perylene.
UFh
10
A UFh of 10 is applied for interindividual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of perylene in humans.
UFl
10
A UFl of 10 is applied for LOAEL-to-NOAEL extrapolation because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because a developmental study was selected as the principal study. The
developmental period is recognized as a susceptible life stage when exposure during a time window
of development is more relevant to the induction of developmental effects than lifetime exposure
ru.s. EPA. 19911.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BaP = bcnzo|fl|pyrcnc: HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level;
NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; 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.
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