*>EPA
United States
Environmental Protection
Agency
EPA/690/R-24/00 IF I March 2024 I FINAL
Provisional Peer-Reviewed Toxicity Values for
1-Methylnaphthalene
(CASRN 90-12-0)
PRO1*
SUPERFUND
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A mA United States
Environmental Protection
* ^ ^1 M % Agency
EPA 690 R-24 001F
March 2024
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
1 -Methy lnaphthalene
(CASRN 90-12-0)
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
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
CONTRIBUTOR
Q. Jay Zhao, PhD, MPH, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
M. Margaret Pratt, PhD
Center for Public Health and Environmental Assessment, Washington, DC
J. Andre Weaver, PhD
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
Allison L. Phillips, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
in
1 -Methylnaphthalene
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
2.1. HUMAN STUDIES 11
2.1.1. Oral Exposures 11
2.1.2. Inhalation Exposures 11
2.2. ANIMAL STUDIES 11
2.2.1. Oral Exposures 11
2.2.2. Inhalation Exposures 19
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 21
2.3.1. Genotoxi city 21
2.3.2. Supporting Animal Studies 24
2.3.3. Metabolism/Toxicokinetic Studies 31
2.3.4. Mode-of-Action/Mechanistic Studies 32
3. DERIVATION 01 PROVISIONAL VALUES 34
3.1. DERIVATION OF ORAL REFERENCE DOSES 34
3.1.1. Derivation of a Subchronic Provisional Reference Dose 34
3.1.2. Derivation of a Chronic Provisional Reference Dose 34
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 35
3.2.1. Derivation of a Subchronic Provisional Reference Concentration 37
3.2.2. Derivation of a Chronic Provisional Reference Concentration 38
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 40
3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 41
3.4.1. Mode-of-Action Discussion 41
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 42
3.5.1. Derivation of Provisional Oral Slope Factor (p-OSF) 42
3.5.2. Derivation of Provisional Inhalation Unit Risk (p-IUR) 43
APPENDIX A. SCREENING PROVISIONAL VALUES 44
APPENDIX B. DATA TABLES 52
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 70
APPENDIX D. REFERENCES 91
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1 -Methylnaphthalene
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NOAEL
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
g 1 ut a t h i o nc - V-1 ra n s fc ra sc
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV assessment.
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1 -Methylnaphthalene
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EPA 690 R-24 001F
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1-METHYLNAPHTHALENE (CASRN 90-12-0)
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
toxicologically relevant human-health effects. Questions regarding nomination of chemicals for
update can be sent to the appropriate U.S. EPA eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment
was written with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP),
the QAPP titled Program Quality Assurance Project Plan (POAPP) for the Provisional Peer-
Reviewed Toxicity Values (PPRTVs) and Related Assessments Documents
(L-CPAD-0032718-OP), and the PPRTV assessment development contractor QAPP titled
Quality Assurance Project Plan—Preparation of Provisional Toxicity Value (PIT) Documents
(L-CPAD-0031971-OP). As part of the QA system, a quality product review is done prior to
management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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DISCLAIMERS
The PPRTV document provides toxicity values and information about the toxicologically
relevant effects of the chemical and the evidence on which the value is based, including the
strengths and limitations of the data. All users are advised to review the information provided in
this document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVS
Questions regarding the content of this PPRTV assessment should be directed to the
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
1-Methylnaphthalene, CASRN 90-12-0, is an organic chemical and a member of the
poly cyclic aromatic compounds (PAC) class of chemicals. 1-Methylnapthalene is a component
of petroleum and coal tar (NLM, 2024). It is used as a solvent, an intermediate for pesticides and
drug manufacture (Mason. 2002). a dye carrier (de Guzman and Sutton. 2013). and a flavoring
agent in food (NLM. 2024). 1-Methylnaphthalene is listed as active in commerce on the Toxic
Substances Control Act (TSCA) public inventory (U.S. EPA. 2024c). 1-Methylnaphthalene is no
longer registered with Europe's Registration, Evaluation, Authorization, and Restriction of
Chemicals (REACH) program and is not currently permitted to be manufactured or imported into
the European Economic Area (EEA) (ECHA. 2024).
The U.S. EPA's Chemical Data Reporting (CDR) database reported that the aggregate
production volume was 1,882,047 pounds, domestically manufactured, in 2020 (U.S. EPA.
2022). More recent manufacturing data were not available. 1-Methylnaphthalene is generally
recovered by fractional distillation of coal tar and petroleum (NLM. 2024).
The empirical formula for 1-methylnaphthalene is C11H10; its chemical structure is shown
in Figure 1. Table 1 summarizes the physicochemical properties of 1-methylnapthalene.
Physicochemical properties were collected from the U.S. EPA's CompTox Chemicals Dashboard
(U.S. EPA. 2024a) and the PubChem website (NLM. 2024). except where noted (see Table 1).
1-Methylnaphtalene's high vapor pressure indicates that it will exist primarily in the vapor phase
if released to the atmosphere. 1-Methylnapthalene is moderately volatile from water and moist
soil surfaces based on its reported Henry's law constant. The soil adsorption coefficient indicates
that it may have moderate sorption to soil and moderate to very strong sorption to sediment,
which will reduce its mobility in the environment. Due to its expected sorption, the potential to
leach to groundwater or undergo runoff after precipitation is low.
Figure 1. 1-Methylnaphthalene (CASRN 90-12-0) Structure
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EPA 690 R-24 001F
Table 1. Physicochemical Properties for 1-Methylnaphthalene
(CASRN 90-12-0)
Property (unit)
Value3
Physical state
Liquid
Boiling point (°C)
242
Melting point (°C)
-3.10
Density (g/cm3)
1.01 (predicted average)
Vapor pressure (mm Hg at 25°C)
0.0670
pH (unitless)
NA
Acid dissociation constant (pKa) (unitless)
NA
Solubility in water (mol/L)
0.000195
Octanol-water partition coefficient (log Kow)
3.87
Henry's law constant (atm-m3/mo at 25°C)
5.14 x 10-4
Soil adsorption coefficient (L/kg)
2,290b
Atmospheric OH rate constant (cm3/molecule)
5.30 x 10-" b
Atmospheric half-life (d)
0.20 (calculated based on its measured OH rate
constant)13
Relative vapor density (air = 1)
4.91b
Molecular weight (g/mol)
142.20
Flash point (°C)
91.4 (predicted average)
aUnless otherwise noted, data were extracted from the U.S. EPA CompTox Chemicals Dashboard
(1-methylnaphthalene, CASRN 90-12-0. https://comptox.epa.gov/dashboard/DTXSID9020877. Accessed
January 31, 2024). All values are experimental averages unless otherwise specified.
' NLM (2024): all values are measured unless noted otherwise.
NA = not available.
A summary of available toxicity values for 1-methylnaphthalene from the U.S. EPA and
other agencies/organizations is provided in Table 2.
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EPA 690 R-24 001F
Table 2. Summary of Available Toxicity Values and Qualitative Conclusions
Regarding Carcinogenicity for 1-Methylnaphthalene (CASRN 90-12-0)
Source
(parameter)ab
Value
(applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2024b)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR (MRL, oral,
chronic)
0.07 mg/kg-d
Based on increased incidence of
pulmonary alveolar proteinosis in
female mice.
ATSDR (2024); ATSDR (2005)
WHO
"No safety
concern" when
used as a
flavoring agent
Safety evaluation based on a human
intake threshold value of 90 |ig/d (for
chemicals in WHO structural class III).
WHO (2024); WHO (2006)
CalEPA
NV
NA
CalEPA (2024); CalEPA (2023)
OSHA
NV
NA
OSHA (2022a): OSHA (2022b):
OSHA (2022c)
NIOSH
NV
NA
NIOSH (2018)
ACGIH (TLV-TWA)
0.5 ppm; skin
notation
Based on upper respiratory tract
irritation and lung damage in mice; skin
notation based on alveolar proteinosis in
mice with chronic skin painting.
ACGIH (2007)
Cancer
IRIS
NV
NA
U.S. EPA (2024b)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2021)
IARC
NV
NA
IARC (2024)
CalEPA
NV
NA
CalEPA (2024); CalEPA
(2023)
ACGIH (WOE)
A4, not
classifiable as a
human
carcinogen
Based on limited evidence of lung
adenomas in male mice with
2-methylnaphthalene but not
1 -methylnaphthalene.
ACGIH (2020); ACGIH (2007)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Research; CalEPA = California Enviromnental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OSHA = Occupational Safety and Health Administration; WHO = World Health Organization.
Parameters: MRL = minimum risk level; TLV = threshold limit value; TWA = time-weighted average;
WOE = weight of evidence.
NA = not applicable; NV = not available.
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Non-date limited literature searches were conducted in July 2019 and updated most
recently in November 2023 for studies relevant to the derivation of provisional toxicity values
for 1-methylnaphthalene, CASRN 90-12-0. Search results were conducted using the U.S. EPA's
Health and Environmental Research Online (HERO) database of scientific literature. HERO
searches the following databases: PubMed, TOXLINE (including TSCATS1)1, Scopus, and Web
of Science. The National Technical Reports Library (NTRL) was searched for government
reports from 2018 through November 20232. 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), U.S. EPA's
ChemView, the U.S. EPA Integrated Risk Information System (IRIS), the U.S. EPA Health
Effects Assessment Summary Tables (HEAST), the U.S. EPA Office of Water (OW),
International Agency for Research on Cancer (IARC), the U.S. EPA TSCATS2/TSCATS8e, the
U.S. EPA High Production Volume (HPV), Chemicals via International Programme on Chemical
Safety (IPCS) INCHEM, Japan Existing Chemical Data Base (JECDB), Organisation for
Economic Cooperation and Development (OECD) Screening Information Data Sets (SIDS),
OECD International Uniform Chemical Information Database (IUCLID), OECD HPV, National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP),
Occupational Safety and Health Administration (OSHA), and World Health Organization
(WHO).
TOXLINE was retired in December 2019. Searches of this database were conducted through July 2019.
2NTRL was a subset of TOXLINE until December 2019 when TOXLINE was discontinued. Searches of NTRL
were conducted starting in 2018 to ensure that references were not missed due to delays in importing items into the
database.
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant noncancer and cancer databases,
respectively, for 1-methylnaphthalene, and include all potentially relevant repeated short-term,
subchronic, and chronic studies, as well as reproductive and developmental toxicity studies.
These tables include studies for which no-observed-adverse-effect levels (NOAELs)/lowest-
observed-adverse-effect levels (LOAELs) could be identified (principal studies are identified in
bold). All NOAELs/LOAELs were identified by the U.S. EPA unless noted otherwise. The
phrase "statistical significance" and term "significant," used throughout the document, indicate a
p-walue of <0.05 unless otherwise specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for 1-Methylnaphthalene (CASRN 90-12-0)
Number of Male/Female, Strain Species,
Reference
Category"
Study Type, Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
(comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Subchronic
12 breeding pairs/group, Sprague Dawley
0,10,50,
Increased absolute and relative
50
250
METI (2009b)
PS,
Crl:CD rat, gavage, at least 42 d (from 2 wk
250
liver weights and increased
(study in
NPR
prior to mating, and throughout mating,
relative kidney weights in males
Japanese)
gestation, and lactation until PND 4 in
and increased relative liver
females or for 42 d total in males).
weights in females.
Satellite group: 5 unmated F/per control and
high-dose groups, gavage, 42 d.
Subchronic
10 M/10 F, B6C3F1 gpt delta mouse, diet.
M: 0, 120,
No treatment-related effects at any
220 (M)
NDr
Jinetal. (2012)
PR
13 wk.
220
dose.
280 (F)
Reported treatment: 0, 0.075, or 0.15% in the
F: 0, 170,
diet.
280
Doses reported as ADDs by study authors.
Chronic
50 M/50 F, B6C3F1 mouse, diet, 81 wk
M: 0,71.6,
Pulmonary alveolar proteinosis
NDr
71.6 (M)
Murata et al.
PS, PR
140
(PAP) in males and females.
75.1 (F)
(1993)
Reported treatment: 0,0.075, or 0.15% in
the diet.
F: 0, 75.1,
144
Doses reported as ADDs by study authors.
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Table 3A. Summary of Potentially Relevant Noncancer Data for 1-Methylnaphthalene (CASRN 90-12-0)
Category"
Number of Male/Female, Strain Species,
Study Type, Reported Doses, Study Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Reproductive/
developmental
12 breeding pairs/group, Sprague Dawley
Crl:CD rat, gavage, at least 42 d (from 2 wk
prior to mating, and throughout mating,
gestation, and lactation until PND 4 in females
or for 42 d total in males).
0, 10, 50,
250
Reproductive: No effects
Developmental: No effects
250
NDr
METI (2009b)
(study in Japanese)
NPR
2. Inhalation (mg/m3)
Subchronic
10 M/10 F, F344 rat, whole-body by vapor
inhalation, 6 h/d, 5 d/wk, 13 wk.
Reported analytical concentrations: 0,0.52,
4.08, or 30.83 ppm.
M: 0,0.099,
0.773, 5.833
F: 0.065,
0.510, 3.736
Mucous cell hyperplasia in
nasopharyngeal tissues in males.
Transitional cell hyperplasia in
nasopharyngeal tissues observed
in males and mucous cell
hyperplasia in nasopharyngeal
tissues observed in females at
higher exposure concentrations.
NDr
0.099
(M)
Kim et al. (2020)
PS, PR
"¦Duration categories are defined as follows: acute = exposure for <24 hours; short-term = repeated exposure for 24 hours to <30 days; long-term (subchronic) = repeated
exposure for >30 days to <10% life span (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure for >10%
life span (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002b).
bDosimetry: Doses are presented as ADDs (mg/kg-day) for oral noncancer effects and as HECs (in mg/m3) for inhalation noncancer effects. Because the observed
inhalation effects occurred in nasopharyngeal tissues, HEC values were calculated for the ET region by treating 1 -methylnaphthalene as a Category 1 gas and using the
following equation from U.S. EPA (1994): HEC = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week exposed ^ 7 days) x RGDR. RGDRet values
of 0.184, 0.183, and 0.182 for males and 0.121, 0.120, and 0.117 for females in the low-, mid-, and high-dose groups, respectively, were calculated as per U.S. EPA
(1994) using default values for human VE and human and animal respiratory tissue surface area and animal VE values calculated using study-specific TWA body-weight
values of 0.268, 0.266, and 0.265 kg for low-, mid-, and high-dose males, respectively, and 0.161, 0.160, and 0.154 kg for low-, mid-, and high-dose females,
respectively, determined for this review.
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; ET = extrathoracic; F = female(s); HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; M = male(s);
ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; PND = postnatal day; RGDR = regional gas dose ratio (animal:human);
TWA = time-weighted average; VE = ventilation rate.
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Table 3B. Summary of Potentially Relevant Cancer Data for 1-Methylnaphthalene (CASRN 90-12-0)
Category
Number of Male/Female, Strain, Species, Study
Type, Reported Doses, Study Duration
Dosimetry3
Critical Effects
Reference
(comments)
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
Carcinogenicity
50 M/50 F, B6C3F1 mouse, diet, 81 wk.
Reported treatment: 0,0.075, or 0.15% in the
diet.
Reported ADDs: 0, 71.6, or 140 mg/kg-d (M);
0,75.1, or 144 mg/kg-d (F).
M: 0,10.7,21.1
F: 0,11.1,20.9
Increased adenoma and combined
adenoma or carcinoma in the
lungs of low- and high-dose male
mice.
Murata et al. (1993)
PS, PR
2. Inhalation (mg/m3)
ND
'Dosimetry: Oral exposures are expressed as HEDs (mg/kg-day) for oral cancer effects; HEDs are calculated using DAFs, as recommended by U.S. EPA (2011b):
HED = ADD (mg/kg-day) x DAF. DAFs of 0.149 and 0.150 (males) and 0.147 and 0.145 (females) were calculated as follows: DAF = (BWa ^ BWh)1/4, where
BWa = animal body weight, and BWh = human body weight. Study-specific TWA animal body weights of 0.035 and 0.036 kg for low- and high-dose males,
respectively, and 0.033 and 0.031 kg for low- and high-dose females, respectively, were determined for this review. For humans, the reference value of 70 kg was used
for body weight, as recommended by U.S. EPA (1988).
bPS = principal study; PR = peer reviewed.
ADD = adjusted daily dose; BW = body weight; DAF = dosimetric adjustment factor; F = female(s); HED = human equivalent dose; M = male(s); ND = no data;
TWA = time-weighted average.
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2.1. HUMAN STUDIES
2.1.1. Oral Exposures
No studies were identified.
2.1.2. Inhalation Exposures
No studies were identified.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures
The effects of oral exposure of animals to 1-methylnaphthalene were evaluated in a
combined repeated-dose reproductive/developmental toxicity screening study in rats (METI.
2009b). a subchronic toxicity study in transgenic mice (Jin et al.. 20121 and a chronic/
carcinogenicity toxicity study in mice (Murata et al.. 1993). Supporting acute, short-term, and
subchronic oral studies are described in Section 2.3.2.
Subchronic Studies (Including Combined Reproductive and Developmental Screening)
METI (2009a); METI (2009b); NITE (2009)
METI (2009b) is an unpublished, oral, repeated-dose, reproductive/developmental
toxicity screening study in rats, written in Japanese, with some text, figures, and tables in
English. Additional brief summaries in English are available as separate documents (METI.
2009a; NITE. 2009). The Japanese text was also translated using Google Translate for the
purposes of this review; this was not a comprehensive or certified translation. A combination of
these documents was used to generate the summary of this OECD 422 guideline study below.
Commercially obtained Sprague Dawley Crl:CD rats (12 breeding pairs/group), aged
approximately 9 weeks at the time of treatment, were administered 1-methylnaphthalene (97.2%
purity) in olive oil daily, via gavage, at doses of 0, 10, 50, or 250 mg/kg-day. For the main group
of animals, dosing began 2 weeks prior to mating and continued throughout mating, gestation,
and lactation until postnatal day (PND) 4 (females) or for a total of 42 days (males). An
additional satellite group of females (five per control and high-dose groups) were left unmated
and were dosed for a total of 42 days. Five males/group and all satellite unmated females were
allowed to recover for 14 days prior to sacrifice. The remaining males and mated females were
sacrificed 1 day after the last administered dose. Stability of the test substance was confirmed to
assure accuracy dosing.
Rats were observed twice daily during the administration period and once a day during
the recovery period for mortality and clinical signs of toxicity. More detailed behavioral
observations from an open field test (rises, clonic and tonic involuntary movements, pace,
mobility, wakefulness, behavior, defecations, and urinations) were recorded once per week.
Body weights and food intake were measured at intervals throughout the study. Functional
observational battery [FOB] tests (visual, auditory and pain responses, pupillary reflex aerial
righting reflex, grip strength, and spontaneous locomotor activity) were performed on five males
during the last week of administration and on five selected females on PND 4. Blood was drawn
at terminal necropsy from five parental males and females per group, and from the five recovery
males and unmated females at the end of the recovery period. Hematology (total red blood cell
[RBC] count, hemoglobin [HGB], hematocrit [HCT], mean corpuscular volume [MCV], mean
corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelet
[PLT], total white blood cell [WBC], differential WBC count [neutrophil, stab and segmented],
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lymphocyte, monocyte, eosinophil, and basophil), prothrombin time [PT], and activated partial
thromboplastin time [APTT]), and serum clinical chemistry (alanine aminotransferase [ALT],
aspartate aminotransferase [AST], alkaline phosphatase [ALP], total protein [TP], plasma protein
patterns (albumin [Alb], a-globulin, a-2 globulin, P-globulin, y-globulin, and albumin/globulin
ratio [A/G ratio]), glucose, total cholesterol [TC], triglyceride [TG], total bilirubin [TBIL], blood
urea nitrogen [BUN], creatinine [CRN], inorganic phosphate [IP], calcium [Ca], sodium [Na],
potassium [K] and chloride [CI]) endpoints were measured. Urinalysis was performed on
samples collected from five control and five high-dose males on the last day of dosing or the last
day of recovery (pH, protein, sugar, ketone bodies, bilirubin, occult blood, and urobilinogen).
Measured organ weights (absolute and relative) included brain, thymus, heart, liver, spleen,
kidneys, adrenals, testes, and epididymis. Gross necropsy was performed on all animals;
histopathological examinations were performed on any gross findings and on >25 tissues from
control and high-dose animals (five per group for males and six per group for females). Nasal
tissues were not examined.
Assessment of reproductive endpoints included determinations of the fertility index of
males and females, length of estrous cycle, number of days to copulation, conception rate,
number of pregnant dams, implantation scars and corpora lutea, implantation index, gestation
period, pre- and post-implantation loss, delivery and birth indices, and nursing status. Limited
developmental endpoints included pup survival rate at birth, sex ratio, pup body weight and
number of live/dead pups on PNDs 0 and 4, and examination of pups at sacrifice on PND 4 for
external abnormalities.
Statistical analyses were performed using Williams' multiple comparison, Fisher's exact
test (one-sided), Bartlett's test, Dunnett's multiple comparison, Kruskal-Wallis rank, Student's
Mest and/or Aspin Welch t-test, and a multiple comparison of Steel when appropriate. Each pup
was used as a sample unit for statistical analysis.
No deaths or moribund rats were observed in any group. No general signs of toxicity
were seen in males from any group during normal or detailed clinical observations. In
10-mg/kg-day females, vaginal bleeding on the 23rd day of pregnancy was observed in one
female; this female did not complete delivery by gestation day (GD) 25. Another female from
this group showed signs of yellowish-green mucus from the vagina on PND 3. Behavioral
observations in the open field test showed no consistent differences across dose groups, and there
were no significant differences between treated and control groups in the FOB.
Body weights were similar to controls in the main study group males and females
throughout the study at all dose levels. Body weight was reduced relative to controls starting on
the 8th day of the study in the high-dose unmated satellite female group, with the deficit reaching
approximately 10% at the end of exposure and persisting through the recovery period. Unmated
high-dose satellite females also generally showed somewhat lower food consumption than
controls at times during the exposure and recovery periods; the difference was statistically
significant on Study Day 42, the last day of exposure. No changes in food consumption during
the exposure period were observed in main study group males or females at any dose level.
Hematology and clinical chemistry findings were unremarkable; the few statistically significant
findings were sporadic in occurrence and were slight changes that fell within normal ranges
(see Tables B-l and B-2). Urinary endpoints in treated animals of both sexes were comparable to
controls. At the end of dosing and in the absence of significant changes in body weights in main
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group animals, high-dose males had significantly increased absolute and relative liver weights
(increases of 17 and 26%, respectively) and increased relative (15% increase), but not absolute
(8% increase), kidney weights, compared with controls (see Table B-3). No organ weight
changes were observed in low- or mid-dose males, and none of the organ weight changes in
high-dose males persisted to the end of the recovery period. Compared to control animals, mated
high-dose females showed a significant increase in relative (10% increase), but not absolute (7%
increase), liver weight. No liver weight changes were seen in mated females from the low- or
mid-dose groups. Relative liver weights were also significantly increased (12% increase,
compared to controls) in unmated females on Recovery Day 14.
No gross pathological changes were observed in males. The single female in the
10-mg/kg-day dose group that exhibited yellow-green mucus from the vagina showed slight
atrophy of the thymus and spleen and slight to moderate discoloration of the liver and kidney.
Thymic atrophy also occurred in one other female at 10 mg/kg-day, and single females in both
the 10- and 50-mg/kg-day groups showed unilateral implantation in the uterus. No gross changes
occurred in high-dose females. Histopathological examinations revealed no remarkable changes
or statistically significant increased incidences of lesions in the tissues examined, including the
lungs, liver, or kidney; however, tissues from only five control and high-dose males and six
control and high-dose mated females (in addition to tissues from three females at 10 mg/kg-day
with gross lesions) were examined. No histological data were collected from unmated females
immediately following dosing.
Compared to controls, there were no statistically significant, treatment-related
reproductive or screening-level developmental changes in any of the endpoints examined at any
dose level. Conception rates were 100, 91.7, 100, and 100% in the control, low-, mid-, and high-
dose groups, respectively, reflecting the one infertile female at 10 mg/kg-day. Another female in
the 10-mg/kg-day group failed to deliver by GD 25; due to this single female, the birth rate was
90.9% in the 10-mg/kg-day group, compared with 100% in the other treatment groups and
controls. Single incidences of poor nesting or breastfeeding behaviors, along with low viability
indices from single litters, were reported across all groups, including controls. There were no
treatment-related differences in pup body weights at birth or on PND 4, and no external
abnormalities were found in any group.
A systemic NOAEL of 50 mg/kg-day and a LOAEL of 250 mg/kg-day were determined
based on statistically and biologically significant increases in absolute and relative liver weights
in male rats, relative liver weight in female rats, and relative kidney weight in male rats (METI
2009b). The organ weight changes occurred in the absence of supporting serum chemistry or
histopathological findings but exceed the U.S. EPA criteria for biological significance (a >10%
increase in absolute and relative liver and kidney weight is considered biologically significant by
the U.S. EPA (U.S. EPA 2012)). The high dose of 250 mg/kg-day was a reproductive/
developmental NOAEL, based on the absence of effects on these endpoints at any dose. The
administered doses of 0, 10, 50, and 250 mg/kg-day correspond to human equivalent doses
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(HEDs) of 0, 2.8, 14, and 70.1 mg/kg-day in males and 0, 2.6, 13, and 64.0 mg/kg-day in mated
females. For unmated females administered 250 mg/kg-day, the HED is 62.0 mg/kg-day.3
Jin et al. (2012)
In a peer-reviewed, published study, Jin et al. (2012) investigated in vivo genotoxicity in
combination with systemic toxicity effects in B6C3F1 gpt delta mice4 fed 1-methylnaphthalene
in the diet for 13 weeks (Masumura et al.. 1999; Nohmi et al.. 1996).
Commercially obtained B6C3F1 gpt delta mice (10/sex/group), aged 6 weeks at the start
of treatment, were fed diets containing 0, 0.075, or 0.15% 1-methylnaphthalene for 13 weeks.
Doses were selected as they were previously determined to be carcinogenic in a chronic
carcinogenicity study (Murata et al.. 1993). Corresponding measured intakes provided by the
study authors, based on body weight and food consumption data, were 0, 120, and
220 mg/kg-day for males and 0, 170, and 280 mg/kg-day for females. Diets were prepared fresh
weekly by mixing 1-methylnaphthalene dissolved in corn oil (5% in each diet) with powdered
CFR-1 diet. It is not explicitly stated whether control animals were fed diets containing the corn
oil vehicle alone. Diets were stored in light-shielded containers at 4°C; the study does not
indicate whether the containers were sealed or whether measures were taken to account for
possible volatility. Analytical analysis of 1-methylnaphthalene stability in food during storage or
at the time of feeding was not included in the study.
Animals were observed daily for clinical signs of toxicity; body weight and food
consumption were recorded once per week. Blood was drawn at necropsy for hematology (WBC,
RBC, HGB, HCT, MCV, MCH, MCHC, PLT, and differential leukocyte counts including band
and segmented neutrophils, eosinophils, basophils, lymphocytes, monocytes, and reticulocytes)
and clinical chemistry (AST, ALT, ALP, TP, TBIL, Alb, TG, TC, phospholipid, BUN, CRN, Na,
CI, K, Ca, and IP). Organ weights (brain, heart, lungs, liver, kidneys, spleen, thymus, adrenal
glands, and testes) were recorded and microscopic examinations were performed for all dose
groups on these and other tissues (arteries, bone/marrow, coagulation gland, esophagus,
epididymides, large intestine [cecum, colon, and rectum], lymph node, mammary glands,
pancreas, peripheral nerve, prostate gland, pituitary gland, thyroid glands, salivary gland, skeletal
muscle, skin, small intestine [duodenum, jejunum, and ileum], spinal cord, stomach, urinary
bladder, tongue, trachea, vagina, uterus, and ovaries). Additionally, right lung lobes were fixed
3Adjusted daily doses (ADDs) were converted to HEDs of 2.8, 14, and 70.1 mg/kg-day in low-, mid-, and high-dose
males; 2.6, 13, and 64.0 mg/kg-day in mated low-, mid-, and high-dose females; and 62.0 mg/kg-day inumnated
high-dose females using respective dosimetric adjustment factors (DAFs) of approximately 0.28 (males), and
0.26 (females), where HED = ADD x DAF. The DAFs were calculated as follows: DAF = (BWaI/4 BWh1'4), where
BWa = animal body weight and BWh = human body weight. Individual animal body weights were provided in the
study; group time-weighted average (TWA) body weights determined fortius review were 0.441, 0.442, and
0.433 kg (for low-, mid-, and high-dose males); 0.308, 0.308, and 0.300 kg (for mated low-, mid-, and high-dose
females, respectively); and 0.268 (for umnated high-dose females, respectively). For humans, the reference value of
70 kg was used for body weight, as recommended by U.S. EPA (1988).
4The transgenic gpt delta mouse was developed by Nohmi et al. (1996) for in vivo genotoxicity assays. These mice
have approximately 80 copies of X EG10 DNA at a single site in chromosome 17 of C57 BL/6J mice, allowing for
in vivo detection of point and deletion mutations (Masumura et al„ 1999). B6C3F1 gpt delta mice result from
crossing 57BL/6J gpt delta mice with C3H/He mice. There is uncertainty regarding interpretation of the systemic
toxicity data in Jinet al. (2012) due to the use of transgenic gpt delta mice. Although comparison studies validating
use of gpt delta rats for evaluating general toxicity responses are available (Matsushita et al„ 2021; Akagi et al„
2015). similar validation studies were not located for gpt delta mice.
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for histopathological and immunohistopathological examination; remaining lungs were used for
genomic deoxyribonucleic acid (DNA) extraction for the in vivo mutation assays. Statistical
analysis of continuous data (body weight, food and water consumption, organ weights,
hematology, and serum biochemistry) was performed using analysis of variance (ANOVA)
followed by Dunnett's multiple comparison test. Incidences of histopathological lesions were
evaluated using Fisher's exact probability test.
No mortalities or clinical signs of toxicity were observed. Body weights in treated
animals were statistically indistinguishable from controls throughout the study, including final
body weights. Food consumption was lower in high-dose males and low- and high-dose females
than in controls for much of the study, but overall average food consumption did not differ
significantly from controls in any treated group.
Hematological changes were limited to differential leukocyte counts that either showed
no consistency between sexes or no clear relation to dose (see Table B-4). Compared to control
animals, treated male mice showed a decrease in band form (immature) neutrophils, which was
statistically significant in the low-dose group (51% decrease), and an increase in segmented
(mature) neutrophils, which was statistically significant in the high-dose group (86% increase).
In females, a non-dose-related, but statistically significant, increase in the percentage of
basophils, relative to controls, was observed in both treatment groups; comparison to males,
however, suggests that this apparent increase reflects a low control value rather than a change in
the treated animals. Statistically significant serum chemistry changes in high-dose males
included slight increases in AST and ALT (increases <1.5-fold compared with controls), along
with small decreases in phospholipids (11% less than controls), BUN (14% less than controls),
CRN (18% less than controls), and Ca (3% less than controls) (see Table B-5). Except for a
slight decrease in serum Ca, there were no significant changes in low-dose males. The only
statistically significant serum chemistry changes in females were slight decreases in
phospholipids (9% less than controls) and total cholesterol (7% less than controls) and a slight
(2%) increase in chloride at 280 mg/kg-day. Although increases in serum AST and ALT are
sometimes associated with liver toxicity, that does not appear to be the case in this study
(see discussion of liver lesions below). It is unclear whether any of the other observed serum
chemistry or hematology changes have any toxicological significance.
Organ weight data showed no effect on relative liver weight in male or female mice at
either dose (see Table B-6). Small decreases in absolute liver weights in the high-dose males and
females reflect slightly reduced necropsy body weights in these groups. Absolute and relative
spleen weights were significantly reduced in males of both treated groups, but the magnitude of
change did not increase with dose and no change was seen in treated females. Significant
decreases in absolute and relative heart weights were also reported in males only; however, the
reported heart weights, including those from control animals, were ~6 times greater than mean
absolute heart weights in similarly aged wild-type B6C3F1 males (Marino. 2012). which
suggests caution in using data from these animals. In contrast, heart weight data reported for
females were consistent with historical controls, and no effect of treatment was seen. There was
an increase in thymus weight in females that was attributed by the study authors to one mouse
with lymphoma. No effect on thymus weight was seen in males.
Histopathological examinations revealed liver lesions in treated male and female mice as
well as in untreated (control) female mice. The observed lesions included single cell (necrosis
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involving single hepatocytes) and focal necrosis (necrosis involving small clusters of
hepatocytes), although neither represents extensive injury (Krishna. 2017). Female mice were
more susceptible to these liver lesions than males. In females, incidences of both single cell and
focal necrosis were 50-70% in the control and treated groups (see Table B-7). Vacuolization was
also noted in treated females (1 and 30% in low- and high-dose mice vs. 0% in controls). In
males, the incidence of single cell necrosis was increased relative to controls in the high-dose
group (50 vs. 0% in controls), but focal necrosis was not observed at any dose. The study authors
did not consider the increase in single cell necrosis in high-dose males to be toxicologically
significant. No other statistically significant histopathological changes were observed in any
tissue, including the lungs. Proliferating cell nuclear antigen (PCNA) immunostaining in the
lungs also showed no changes in treated animals, compared to controls, suggesting no increases
in proliferation of type II pneumonocytes, which has been described in other studies (Murata et
al.. 1992). Mutagenicity assays in lung tissue were negative. There were no increases in gpt or
Spi mutation frequencies in lung tissue from any treatment group, although a positive control
for the mutagenicity assay was not used.
This study provided no consistent evidence of toxicologically significant, treatment-
related effects on any endpoint in male or female mice. Slight, statistically significant increases
in serum AST and ALT were seen in high-dose male mice (which showed an increase in
incidence of single cell necrosis, but no focal necrosis, in the liver). However, female mice,
which showed high incidences of both single cell and larger focal necrosis in control and both
dose groups, had AST and ALT levels close to, or lower than, the values in males at all doses.
This suggests a disconnect between the serum chemistry and histopathology results; the slight
increases in AST and ALT in high-dose males cannot reasonably be attributed to the minimal
liver necrosis observed in this group while the females, with a greater degree of necrosis, showed
baseline levels of AST and ALT. The toxicological significance of the slight serum AST and
ALT increases in high-dose males is, therefore, unknown. Similarly, as discussed above, it is
unclear that the increased incidence of single cell necrosis in high-dose male mice represents a
toxicologically significant effect, given the high incidence of necrotic liver lesions in female
mice (including controls) and the absence of the larger, focal necrotic lesions in male mice.
Spleen weights were reduced in both low- and high-dose males, but the magnitude of change did
not increase with dose, and no effect on spleen weight was seen in females. There were no
histopathological findings in the spleen in either sex. None of the observed hematology or serum
chemistry changes are known indicators of damage to the spleen. In the absence of demonstrated
treatment-related toxicologically relevant effects, the high dose (220 mg/kg-day in males and
280 mg/kg-day in females) is identified as a NOAEL for male and female mice fed
1-methylnaphthalene in the diet for 13 weeks in this study. The administered doses of 0, 120, and
220 mg/kg-day in males and 0, 170, and 280 mg/kg-day in females correspond to HEDs of 0,
17.1, and 31.1 mg/kg-day in males and 0, 23.1, and 37.7 mg/kg-day in females, respectively.5
5ADDs were converted to HEDs of 17.1 and 31.1 mg/kg-day for low- and high-dose males, respectively, and
23.1 and 37.7 mg/kg-day for low- and high-dose females, respectively, using DAFs of approximately 0.143 (males)
and 0.135 (females), where HED = daily dose x DAF. The DAFs were calculated as follows:
DAF = (BWa14 ^ BWh1'4), where BWa = animal body weight and BWh = human body weight. Animal body-weight
data reported graphically in the study were extracted using GrabIT™ software. TWA animal body weights of
0.030 and 0.029 kg and 0.024 and 0.023 kg for low- and high-dose males and females, respectively, were
determined. For humans, the reference value of 70 kg was used for body weight, as recommended by U.S. EPA
(1988).
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Chronic/Carcinogenicity Studies
Murata et al. (1993)
In a published, peer-reviewed study, B6C3F1 mice (50/sex/group), aged 6 weeks at study
initiation, were given diets containing 0, 0.075, or 0.15% 1-methylnaphthalene (>97% purity) for
81 weeks. Based on cumulative intake data provided by the study authors, doses of
1-methylnaphthalene were estimated as 71.6 and 140 mg/kg-day for the low- and high-dose
males, respectively, and 75.1 and 144 mg/kg-day for the low- and high-dose females,
respectively. Doses were selected based on results of a subacute toxicity test in which mice given
diets of 0.44 and 1.33% 1-methylnaphthalene for 13 weeks exhibited growth retardation in both
sexes, likely due to refusal of food intake. Food was prepared fresh monthly but the stability of
1-methylnaphthalene in the diet was not monitored and the study authors noted that control
animals may have been exposed to 1-methylnaphthalene vapors. Mice were observed daily for
abnormalities, and body weights were recorded weekly for the first 16 weeks and every 2 weeks
thereafter. Food consumption was monitored throughout the study. At the end of the 81-week
treatment period, blood was collected for hematology (WBC, RBC, HGB, HCT, MCV, MCH,
MCHC, and percentage of different leukocytes [stab cells, segmented, eosinophil, basophil,
lymphocytes, and monocytes]) and serum biochemical analysis (AST, ALT, ALP, lactate
dehydrogenase [LDH], cholinesterase, gamma-glutamyl transpeptidase [y-GTP], TBIL, TP, A/G
ratio, Alb, BUN, uric acid, CRN, Na, K, CI, iron, lipid, phospholipid, nonesterified fatty acid,
neutral fat, cholesterol, esterified cholesterol, high-density lipoprotein [HDL], P-lipoprotein, and
lipid peroxide). Organ weights were recorded for brain, salivary glands, heart, thymus, lung,
liver, pancreas, spleen, kidneys, and testis. These organs and adrenals, trachea, stomach, small
intestine, large intestine, seminal vesicle, ovary, uterus, vagina, mammary gland, skeletal muscle,
eye, Harderian glands, spinal cord, bone (sternal, rib, vertebral), skin, and other tissues with
abnormal appearance were prepared for histopathological examination. Nasal tissues were not
examined. Histopathological examinations were also performed on all mice found dead or
sacrificed moribund prior to scheduled sacrifice. A %2 test was used for analysis of neoplastic and
non-neoplastic incidence data. Body weights, organ weights, and blood and serum endpoints
were analyzed by Student's Mest without adjustment for multiple comparisons.
One control male mouse and one high-dose female mouse died of leukemia at
Weeks 60 and 68, respectively. All other mice survived to scheduled sacrifice. There were no
statistically significant, treatment-related effects on food consumption, growth, or terminal body
weights. The only dose-related, statistically significant hematological changes in treated animals
were increases in the percentages of monocytes in males and females in both the low- and high-
dose groups, compared with controls (see Table B-8). The study authors hypothesized that the
increase in monocytes may have been a physiological response to the pulmonary alveolar
proteinosis (PAP) seen in the exposed animals. Other changes in leukocyte classifications and
RBC parameters either showed no relation to dose or were directionally inconsistent between
sexes or dose groups (see Table B-8). Serum biochemistry changes were generally sporadic and
not related to dosing. The only changes appearing to be dose-related were statistically significant
decreases in LDH and BUN in males (increases are typically expected as indicators of toxicity)
and increased phospholipids and neutral fats in females (see Table B-9). These changes were not
clearly associated with any pathologies, although the study authors previously speculated that the
lipid changes may be related to PAP (Murata et al.. 1992). Statistical analysis of both
hematology and serum chemistry data were performed using simple t-tests, without adjustment
for multiple comparisons, increasing the likelihood of false positive findings.
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As shown in Table B-10, the statistically significant organ weight changes were generally
either small in magnitude (5-9%, relative to controls), did not exhibit a clear relationship with
dose, occurred only in one sex, and/or had questionable toxicological significance. As for the
blood data, the use of simple t-tests by the study authors without adjustment for multiple
comparisons means that there is a likelihood of false positive results. The study authors indicated
that thymus weights in control female mice were abnormally high due to the development of
lymphoma in this group, producing the apparent decrease in thymus weights in the treated mice.
Exposure-related lesions were restricted to the lung. Statistically significant increased
incidences of male and female mice with PAP were observed following 81 weeks of
1-methylnaphthalene treatment in both the low- and high-dose groups (see Table B-l 1). This
lesion was characterized by an accumulation of phospholipids in the alveolar lumens that
appeared grossly as white protuberant nodules approximately 1-5 mm in diameter.
Histologically, there was visible filling of alveolar lumens with cholesterol crystals, foamy cells,
and an amorphous acidophilic material. Alveolar walls and epithelial cells were generally intact
and the interstitium did not exhibit evidence of prominent edema, alveolitis, lipidosis, or fibrosis.
The incidences of PAP lesions in controls, low-dose, and high-dose groups were 4/49, 23/50, and
19/50 in males and 5/50, 23/50, and 17/49 in females, respectively. The study authors stated that
this effect had not been observed previously in >5,000 B6C3F1 mice housed in the same room
and speculated that the incidences in control mice may have been due to exposure to volatilized
1-methylnaphthalene and 2-methylnaphthalene from the treatment groups housed in the same
room for this experiment.
For non-neoplastic effects, a LOAEL of 71.6 mg/kg-day, the lowest dose in male mice
exposed to dietary 1-methylnaphthalene for 81 weeks, was determined based on statistically
significantly increased incidences of PAP. Incidences of PAP were also increased in the
low-dose females (75.1 mg/kg-day). ANOAEL was not identified.
Tumor incidences in the lungs of mice are provided in Table B-12. Statistically
significant increases in incidences of lung adenomas and lung adenomas or adenocarcinomas
(combined) were seen in both low- and high-dose male mice treated with 1-methylnaphthalene in
the diet for 81 weeks. Lung tumors were not increased in the female mice. No tumor increases
were seen in other tissues.
The administered doses of 0, 71.6, and 140 mg/kg-day in males and 0, 75.1, and
144 mg/kg-day in females correspond to HEDs of 0, 10.7, and 21.1 mg/kg-day in males and 0,
11.1, and 20.9 mg/kg-day in females, respectively.6
6ADDs were converted to HEDs of 10.7 and 21.1 mg/kg-day for low- and high-dose males, respectively, and
11.1 and 20.9 mg/kg-day for low- and high-dose females, respectively, using respective DAFs of 0.149 and
0.150 (males) and 0.147 and 0.145 (females). The DAFs were calculated as follows: DAF = (BWaI/4 ^ BWh1'4),
BWa = animal body weight and BWh = human body weight. Animal body-weight data reported graphically in the
study were extracted using GrabIT™ software. TWA animal body weights of 0.035 and 0.036 kg for low- and high-
dose males, respectively, and 0.033 and 0.031 kg for low- and high-dose females, respectively, were determined. For
humans, the reference value of 70 kg was used for body weight, as recommended by U.S. EPA (1988).
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2.2.2. Inhalation Exposures
Relevant studies on the effects of inhalation exposure of animals to 1-methylnaphthalene
were limited to a single subchronic repeated-dose inhalation toxicity study in rats (Kim et al..
2020). Supporting acute and short-term inhalation studies are described in Section 2.3.2.
Subchronic Studies
Kim et al. (2020)
In a published, peer-reviewed study, Kim et al. (2020) reported the effects of repeat
exposure to 1-methylnaphthalene (97.3% pure) in rats. F344 rats (10/sex/group) were
commercially obtained at 6 weeks of age, and exposed, whole-body, to 1-methylnaphthalene
vapors at nominal concentrations of 0, 0.5, 4, and 30 ppm for 6 hours/day, 5 days/week for
13 weeks. Measured analytical concentrations (mean ± standard deviation [SD]) were 0,
0.52 ± 0.05, 4.08 ± 0.25, and 30.83 ± 1.28 ppm for the low-, middle-, and high-exposure groups,
respectively; maintaining significant figures, these concentrations correspond to 0, 3.0, 23.7, and
179.3 mg/m3, respectively7. A low dose of 0.5 ppm was selected to correspond with the
concentration that American Conference of Governmental Industrial Hygienists (ACGIH)
recommended as an 8-hour TWA Threshold Limit Value (TLV) on the basis of respiratory
irritation (ACGIH. 2007).
Animals were observed daily for mortality and clinical signs of toxicity. Body weights
were recorded twice per week for the first 4 weeks then once per week for the remainder of the
study. Monitoring of food consumption was mentioned without details on frequency. At terminal
necropsy, blood was drawn for hematology (RBC, HGB, HCT, MCV, MCH, MCHC, platelets,
WBC, differential WBC count [neutrophil, lymphocyte, monocyte, eosinophil, and basophil],
reticulocyte, PT, and APTT), and serum clinical chemistry (ALT, AST, ALP, BUN, CRN,
creatinine phosphokinase [CPK], TBIL, TP, Alb, TC, TG, and Na). Bronchoalveolar lavage
(BAL) fluid from five rats/sex/group was analyzed for LDH, total cell counts, macrophages,
polymorphonuclear leukocyte (PMN), and lymphocyte counts. Necropsies consisted of external
examinations of body surfaces, orifices, and contents of cranial, thoracic, and abdominal cavities
of all rats. Organs (adrenal glands, brain, heart, kidneys, liver, spleen, testes, thymus,
epididymides, lung, ovaries, and uterus) were weighed (absolute weights only) and select tissues
(adrenal glands, aorta, bone marrow, brain, cecum, colon, duodenum, epididymides, esophagus,
femur, Harderian glands, heart, ileum, jejunum, kidneys, larynx, liver, lung, lymph nodes
[tracheobronchial and mesenteric], mammary gland, nasopharyngeal tissue, nerve [sciatic],
pancreas, parathyroids, pituitary, prostate, rectum, salivary glands [submandibular, sublingual,
and parotid], seminal vesicles, skeletal muscle, skin, spinal cord [cervical, lumbar, and thoracic],
spleen, sternum, stifle joint, stomach, teeth, thymus, thyroids, tongue, trachea, urinary bladder,
ovaries, uterus, eyes/optic nerve, and testes) were preserved. Histological analysis was
performed on fixed tissues from the control and high-exposure animals only, except for
nasopharyngeal tissue, which was examined from animals from all exposure groups.
Depending on tissue type, tissues were preserved in either 10% neutral buffered formalin or
Davidson's solution. Preserved tissues were paraffin-embedded, sectioned, and stained with
'Analytical concentrations of 0.52, 4.08, and 30.83 ppm were converted to mg/m3 using the following formula:
mg/m3 = (ppm x MW)/24.45, where MW = 142.2 g/mol (the molecular weight of 1-methylnaphthalene) and 24.45 is
the volume occupied by 1 g/mol of any compound in a gaseous state at 0°C and 760 mm Hg.
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1 -Methylnaphthalene
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EPA/690/R-24/001F
hematoxylin and eosin. Statistical analysis was performed using the PASW Statistics 18 or
SigmaPlot 12 programs. One-way ANOVA was used to evaluate BAL fluid and organ weight
data; hematological and serum chemistry endpoints were analyzed using Dunnett's test. The
statistical test used for body-weight data was not specified.
No deaths or exposure-related clinical signs were observed (data not shown). Mean body
weights of treated males from all groups were comparable to controls throughout the study. In
females, body weights in the high-exposure group were slightly (<5%) lower than controls
throughout the study (statistically significant only on Day 16), while body weights in the
low- and mid-exposure groups were similar to controls. No significant changes in food
consumption were reported (data not shown). Results from BAL fluid analysis showed no
differences in cell differential counts or in levels of LDH across groups. Observed hematological
and clinical chemistry changes were small in magnitude and fell within normal ranges.
Statistically significant hematological changes were limited to increases in PT in high-exposure
males (10% increase) and females (8% increase) and APTT (8% increase) in high-exposure
males (see Table B-13). Statistically significant serum chemistry changes were limited to a small
(16%) decrease in ALT (increases are considered toxicologically relevant) and small (<5%)
increases in albumin and sodium levels in high-exposure males (see Table B-13). No serum
chemistry changes occurred in low- or mid-exposure males or in any exposed female group.
There were no statistically significant differences in absolute organ weights between exposed
and control groups and magnitudes of change were <5%; relative organ weights were not
reported.
Results from gross examinations were not reported. The incidence of mucous cell
hyperplasia in nasopharyngeal tissues was significantly increased in male rats of all exposed
groups and in high-exposure female rats. Both the incidence (from 40 to 100%) and severity
(from minimal to moderate) of this lesion increased with exposure level in the male rats
(see Table B-14). In females, the incidence and severity increased with exposure, from 30% with
minimal lesions in the mid-exposure group to 100% with minimal-to-moderate lesions in the
high-exposure group. Males in the mid- and high-exposure groups also showed significantly
increased incidences of hyperplasia in transitional epithelial cells of nasopharyngeal tissues (50%
incidence, minimal severity). Aside from nasopharyngeal tissues, all other microscopic findings,
including in the lungs, were reported to be consistent with those normally found in rats of the
same age group, and were considered by the study authors to be spontaneous (data not shown in
study report).
A LOAEL of 3.0 mg/m3 was identified based on statistically significantly increased
incidence of mucous cell hyperplasia in nasopharyngeal tissues in male F344 rats exposed to
1-methylnaphthalene vapors for 6 hours/day, 5 days/week for 13 weeks. A NOAEL was not
determined. Nasal mucous cell hyperplasia increased in incidence and severity with exposure
concentration in both sexes. Nasal transitional epithelial cell hyperplasia was also observed in
males in the higher exposure groups. Analytical concentrations of 0, 3.0, 23.7, and 179.3 mg/m3
correspond to human equivalent concentrations based on extrathoracic effects (HECet) values of
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EPA 690 R-24 001F
0, 0.099, 0.773, and 5.833 mg/m3, respectively, for males and 0, 0.065, 0.510, and 3.736 mg/m3,
respectively, for females for extrathoracic effects (maintaining the stated significant figures).8
Chronic, Reproductive, Developmental, and Carcinogenicity Studies
No inhalation chronic, reproductive, developmental, or carcinogenicity studies on
1-methylnaphthalene in animals were identified.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
2.3.1. Genotoxicity
Table 4 A provides an overview of genotoxicity studies of 1-methylnaphthalene. Limited
genotoxicity data are available for 1-methylnaphthalene but results generally show that
1-methylnaphthalene is non-genotoxic. The chemical produced negative results in the Ames test
with Salmonella typhimurium strains TA98 and TA100 both in the presence and absence of rat
liver S9 metabolic activation (Florin et al.. 1980). These results were consistent with those
obtained in a second Ames test in which S. typhimurium strains TA97, TA98, TA100, and
TA1535 showed negative results both with and without activation (rat and hamster S9) (NTP.
2018). Positive results were reported in a forward mutation assay using S. typhimurium strain
TM677 in the presence of preinduced rat S9, but only at a concentration inducing cytotoxicity
(Kaden et al.. 1979). 1-Methylnaphthalene did not induce chromosomal aberrations (CAs) or
sister chromatid exchanges (SCEs) in human peripheral lymphocytes in the absence or presence
of S9 hepatic microsomal fractions (Kulka et al.. 1988). The micronuclei frequency in V79
hamster fibroblasts exposed to 1-methylnaphthalene did not differ significantly from the
controls, although urine extracts from rats exposed to 1-methylnaphthalene induced a significant
increase in the frequency of micronuclei compared to urine extracts from the group of control
animals (Swiercz et al.. 2022). The study authors concluded that it was likely that
1-methylnaphthalene metabolites present in the rat urine induced increased micronuclei
frequency. In an in vivo transgenic rodent mutation assay, Jin et al. (2012) analyzed mutation
frequencies for gpt and Spi in the lungs of B6C3F1 gpt delta mice administered diets containing
0, 0.075, and 0.15% 1-methylnaphthalene for 13 weeks. There were no significant differences
among groups for either sex, indicating that 1-methylnaphthalene was negative for in vivo
genotoxicity in this test; however, no positive controls were included in the assay.
8HEC values based on extrathoracic effects are calculated by treating 1-methylnaphthalene as a Category 1 gas and
using the following equation from U.S. EPA (1994): HEC = exposure level (mg/m3) x (hours/day exposed
24 hours) x (days/week exposed ^ 7 days) x RGDR, where RGDR is the regional gas dose ratio (animal:human).
RGDRet values of 0.184, 0.183, and 0.182 for males and 0.121, 0.120, and 0.117 for females in the low-, mid-, and
high-dose groups, respectively, were calculated as per U.S. EPA (1994) using default values for human VE
(ventilation rate) and human and animal respiratory tissue surface area and animal VE values calculated using study-
specific TWA body-weight values of 0.268, 0.266, and 0.265 kg for low-, mid-, and high-dose males and 0.161,
0.160, and 0.154 kg for low, mid-, and high-dose females determined for this review.
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Table 4A. Summary of 1-Methylnaphthalene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested3
Results
Without
Activationb
Results
With
Activationb
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella tvphimurium
TA98 and TA100; bacteria
were tested with and without
metabolic activation by S9 rat
liver fraction (0 or
0.03-30 |imol/platc)
30 |imol/platc
(4,300 |ig/platcc).
Ames assay. No evidence of
mutagenicity in any of the strains
tested with or without S9 activation.
Toxic to bacteria at >3 |imol/platc.
Florin et al. (1980)
Mutation
S. tvphimurium strains TA97,
TA98, TA100, and TA1535;
bacteria were tested with and
without metabolic activation
by rat or hamster S9 (0 or
0.3-100.0 ng/plate)
100.0 ng/plate.
Ames assay. No evidence of
mutagenicity in any of the strains
tested with or without S9 activation.
NTP (2018)
Mutation
S. tvphimurium TM677;
bacteria were tested in the
presence of preinduced rat
liver homogenate (0 or
0.7-7 mM)
7 mM
(1,000 ng/mL°).
NDr
+ (T)
Forward mutation assay. Positive for
mutations at 7mM. Cytotoxicity at
>3.5 mM.
Kaden et al. (1979)
Genotoxicity studies in mammalian cells—in vitro
Clastogenicity
(CA)
Human peripheral
lymphocytes; cells were tested
with or without activation by
S9 hepatic microsomal
fraction (without S9: 0, 1.0, or
2.0 mM; with S9: 0 or
0.25-2.0 mM)
Without activation:
2.0 mM
(280 |ig/mLc).
With activation:
2.0 mM
(280 |ig/mLc).
No increase in chromatid breaks, gaps,
or number of S-cells with or without
S9 activation.
Kulkaetal. (1988)
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Table 4A. Summary of 1-Methylnaphthalene Genotoxicity
Endpoint
Test System
Doses/
Concentrations
Tested3
Results
Without
Activationb
Results
With
Activationb
Comments
References
Clastogenicity
(SCE)
Human peripheral
lymphocytes; cells were tested
with and without activation by
S9 hepatic microsomal
fraction (without S9: 0, 1.0, or
2.0 inM; with S9: 0 or
0.25-2.0 mM)
Without activation:
2.0 mM (280 |ig/mLc)
With activation:
2.0 mM (280 |ig/mLc)
No increase in SCEs without
activation. Slight increase in SCEs
with activation did not meet criteria for
a positive test (
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EPA 690 R-24 001F
2.3.2. Supporting Animal Studies
A limited number of supporting acute, short-term, subchronic, and chronic studies are
summarized in Table 4B. These include inadequately reported studies, studies that evaluate only
one endpoint, studies with short exposure durations, studies conducted via routes of exposure
other than oral or inhalation (e.g., dermal, injection), and select mixture studies. Supporting oral
studies include a poorly described acute oral toxicity study in rats (DuPont. 1992). a 14-day
study in rats reporting transient weight loss and no histopathological findings (DuPont. 1992).
and a preliminary 13-week study in B6C3F1 mice, briefly mentioned in another study report
(Murata et al.. 1993). that reported growth retardation at >624.4 mg/kg-day and no abnormal
histopathology (doses up to 1,887 mg/kg-day). Acute and short-term inhalation studies provide
limited support that 1-methylnaphthalene may have mild neurotoxic effects, such as decreasing
pain sensitivity and reducing corticosterone stress responses (Swiercz and Stepnik. 2020; Korsak
et al.. 1998). and possibly produce immune and/or hematological effects (Lorber. 1972) or
induce changes in liver function (Swiercz et al.. 2022). The chemical was shown to be an acute
respiratory irritant (Korsak et al.. 1998). Intraperitoneal (i.p.) injection studies found minimal
lung lesions (swollen Clara cells) in the bronchiolar epithelium of treated mice (Rasmussen et al..
1986). but not in rats (Dinsdale and Verschoyle. 1987). A series of chronic dermal studies in
mice performed using a mixture of 1- and 2-methylnaphthalene found lung lesions described in
the earlier studies as lipid pneumonia or proliferation of type II pneumocytes (Taki et al.. 1986;
Emi and Konishi. 1985) and in the later study as PAP (Murata et al.. 1992). as observed in the
chronic dietary study of Murata et al. (1993) described above.
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence-noncancer effects in animals following oral exposure
Acute (oral)
Rats (strain, sex, and number not
specified) were dosed orally with
1-methylnaphthalene at up to
7,500 mg/kg.
Marked incoordination and muscle weakness
lasting 24-48 h were observed in rats at doses
>3,375 mg/kg. A rat given 7,500 mg/kg died.
Congestion of internal organs and kidney damage
were observed in the animal that died.
A single dose was lethal to a
rat at 7,500 mg/kg.
DuPont (1992)
Short-term (oral)
Rats (six rats, strain, and sex not
specified) were orally administered
10 treatments of 1,500 mg/kg
1-methylnaphthalene over 14 d.
No deaths were observed. Transient weight loss
was reported, but animals regained weight and
were in "good condition" 14 d after the last
treatment. No gross or histopathological changes
were observed in animals 14 d after the last
treatment.
There was limited evidence
of transient weight loss in
rats treated at 1,500 mg/kg.
DuPont (1992)
Subchronic (oral)
B6C3F1 mice (10/sex/group) were
administered diets containing 0, 0.0163,
0.049,0.147,0.44, or 1.33%
1-methylnaphthalene for 13 wk
(approximately 0, 23.13, 69.54, 208.6,
624.4, or 1,887 mg/kg-d, respectively, as
determined for this review)3. Endpoints
evaluated were not clearly specified but
included growth and histopathology.
Growth retardation was observed at >0.44%
(624.4 mg/kg-d), likely due to refusal to eat. No
histopathological lesions were observed in any
group (data not shown).
There was limited evidence
of growth retardation in mice
at >624.4 mg/kg-d.
This was a preliminary
study, which was poorly
described in the main study
report.
Murata et al.
(1993)
Supporting evidence-noncancer effects in animals following inhalation exposure
Acute (inhalation)
Wistar rats (10 males/group) were
exposed, whole-body, to
1-methylnapthalene vapor concentrations
of 0, 152, 253, or 407 mg/m3 for 4 h.
Endpoints evaluated included mortality,
rotarod performance (measured before and
immediately after exposure), and a hot
plate test.
No deaths occurred. Increased latency of the
paw-lick response was seen (increases of 143 and
254% at 253 and 405 mg/m3, respectively),
compared with controls. There was no effect on
rotarod performance.
There was evidence of a
concentration-related
decrease in pain sensitivity
in rats exposed to
>253 mg/m3 for 4 h.
Korsak et al.
(1998)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute (inhalation)
Balb/C mice (8-10 males/group) were
exposed, whole-body, to
1-methylnapthalene vapor concentrations
of 54, 103, 203, 310, or 416 mg/m3 for
6 min. Respiratory rates were recorded
continuously before exposure, during
6 min of exposure, and for 12 min after
exposure and used to determine an RD50
value.
Concentration-dependent decreases in respiratory
rates were seen in mice, with maximum decreases
in the first 2 min of exposure.
Mouse RD50 (95%
CI) = 129 (61-228) mg/m3.
Korsak et al.
(1998)
Acute (inhalation)
Wistar rats (four males per group) were
exposed to 1-methylnaphthalene vapors
(nose-only) for 6 h (single exposure) at
analytical concentrations of 0, 50.3, and
194.5 mg/m3. Tissue and blood samples
were collected at the end of the exposure
and urine samples were collected at 0, 24,
48, and 72 h following exposure.
Endpoints evaluated included body
weight, organ weight (lung, liver, spleen,
and kidney), and tissue metabolite
distribution.
Significant increases in absolute but not relative
liver weight (22-43% higher than controls) were
observed in both dose groups; a significant
reduction in relative, but not absolute, spleen
weight (30-36% lower than controls) was
observed in the low-dose group only; a significant
increase in absolute, but not relative, kidney
weight (18-19% higher than controls) was
observed in the high-dose group only.
There was limited evidence
of renal and hematological
changes in rats.
Swiercz et al.
(2022)
Short-term (inhalation)
Dogs (intact, recently splenectomized, or
chronically splenectomized; at least
2-6 group; sex and strain not specified)
were exposed to mists containing pure or
practical-grade 1-methynaphthalene for
5-min periods, with 7-10 min pauses in
between, over a period of 4 consecutive
days. Animals were observed for up to
10 d. Endpoints evaluated included
differential WBC, reticulocyte and platelet
counts, and RBC survival. Blood and bone
marrow were collected pre- and post-
exposure.
Pure 1-methylnaphthalene increased the percent
of reticulocytes in six of six chronic
splenectomized dogs and in one of four intact
dogs and decreased platelets in one of six chronic
splenectomized dogs.
Practical-grade 1-methylnaphthalene increased the
mean leucocyte counts in both intact and recently
splenectomized dogs (four per group) and
increased the mature and mean immature
neutrophil counts in intact dogs.
There was limited evidence
of hematological changes in
dogs.
Based on the information
provided, exposure
concentrations could not be
determined.
Lorber (1972)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term (inhalation)
Wistar rats (three males/group) were
exposed to 1-methylnaphthalene vapors
(nose-only in glass restrainer tubes)
6 h/day for 5 d at analytical concentrations
of 0, 53.7, or 195.5 mg/m3. A second
unrestrained control group was included.
Endpoints evaluated included body
weights, food and water intake, and
measurements of serum corticosterone (as
a biomarker for stress). A 3-h time course
analysis of serum corticosterone levels
was performed during the first 3 h after
termination of the 6-h exposure on
Study Day 5.
Restrained control rats had significantly higher
serum corticosterone levels than unrestrained
controls. Exposing restrained rats to
1-methylnaphthalene significantly reduced serum
corticosterone levels (more so in the 57.3 mg/m3
group than in the 195.5 mg/m3 group) measured
immediately after exposure ended. The 3-h time
course after the end of exposure showed an initial
increase in serum corticosterone levels in rats that
had been exposed to 1-methylnaphthalene,
followed by a decline to levels similar to
unrestrained controls.
The study presents some
evidence that
1 -methylnaphthalene
reduced the corticosterone
stress response in rats, but
the results are questionable,
as the observed effect was
stronger at the lower
exposure level.
Swiercz and
Steonik (2020)
Short-term (inhalation)
Wistar rats (four males per group) were
exposed to 1-methylnaphthalene vapors
(nose-only) 6 h/day for 5 d at analytical
concentrations of 0, 53.7, and
198.1 mg/m3. Tissue and blood samples
were collected at the end of the exposure
and urine samples were collected at 0, 24,
48, and 72 h following exposure.
Endpoints evaluated included body
weights, organ weights (lung, liver,
spleen, and kidney), serum ALT and AST
activity, liver CYP1A1 and CYP1A2
activity, and tissue metabolite distribution
and urinary excretion.
Significant reductions in absolute and relative
spleen weights (19-39% lower than controls)
were observed in both dose groups; significantly
higher ALT activity (40% higher than controls)
was observed in serum of rats exposed to the high
dose only; liver CYP1A1 activity was increased
(32% higher than controls) at the high dose only;
and liver CYP1A2 activity was increased
(54-71% higher than controls) in both dose
groups.
Inhalation exposure to
1-methylnaphthalene may
induce changes in liver
function at >53.7 mg/m3.
Swiercz et al.
(2022)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Supporting evidence-noncancer effects in animals following other exposure routes
Acute (i.p.)
Male Swiss-Webster mice (two per group)
were given single doses of 0, 1, or
2 mmol/kg (equivalent to 0, 142, or
284 mg/kg) of 1-methylnaphthalene in
peanut oil via i.p. injection. Animals were
sacrificed 1, 3, 7, or 14 d post-treatment.
Endpoints evaluated included light
microscopic examination of lung, liver,
and kidney tissues and electron
microscopic examination of lung tissue.
Minimal morphology changes were observed in
bronchiolar epithelium, consisting of swelling of
Clara cells with occasional sloughed cells in
terminal bronchioles at >142 mg/kg. No effects on
liver or kidneys were observed.
There was evidence for
minimal lesions in the lungs
of male mice at >142 mg/kg
i.p.
Rasmussen et al.
(1986)
Acute (i.p.)
Female Wistar-derived rats (number not
reported) were given single doses of 0 or
1.0 mmol/kg (equivalent to 142 mg/kg) of
1-methylnaphthalene via i.p. injection.
Use of vehicle was not reported. Animals
were sacrificed 24 h post-dosing and lung
tissues were examined microscopically.
No lesions in the lungs were detected.
There was no evidence of
lung lesions in female rats at
142 mg/kg i.p.
Dinsdale and
Verschovle
(1987)
Acute (dermal)
Rabbits (strain, sex, and number treated
not reported).
A rabbit exposed to 3,750 mg/kg on the skin was
inactive and refused food for 24 h after treatment.
A rabbit exposed to 7,500 mg/kg on the skin
refused food and was almost completely inactive
until it died 48 h after treatment. Possible kidney
damage was reported. Skin irritation was
observed.
Acute dermal exposure to
7,500 mg/kg was lethal to a
rabbit.
DuPont (1992)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Chronic (dermal)
Mixture (composition not
reported)
Female B6C3F1 mice (4, 11, and
32/group, respectively) were dennally
exposed to 0, 29.7, or 118.8 mg/kg of a
mixture containing 1-methylnaphthalene
and 2-methylnaphthalene in acetone
2 times/wk for 61 wk. Mortality was
recorded, and histology was performed on
skin, lungs, and unspecified organs.
Mortality was observed as early as 10 wk and
peaked at 38 wk; deaths were attributed to lipid
pneumonia. Lipid pneumonia was observed in 0/4,
3/11, and 31/32 animals at 0, 29.7, and
118.8 mg/kg, respectively. White spots with
demarcated nodules were grossly visible.
Histological observations included hypertrophy
and hyperplasia of type II pneumocytes, alveolar
wall thickening, and multinucleated giant cells,
foamy cells, and cholesterol crystals in the
alveolar lumen.
Dermal exposure to a
mixture of 1- and
2-methylnaphthalene for
61 weeks produced lung
lesions described as lipid
pneumonia in mice.
Emi and Konishi
(1985)
Chronic (dermal)
Mixture (composition not
reported)
Female B6C3F1 mice (three, eight, or
seven per group, respectively) were
dennally administered 0, 118.8, or
237.6 mg/kg of a mixture containing
1-methylnaphthalene and
2-methylnaphthalene dissolved in acetone
2 times/wk for 50 wk. Lipids were
extracted from lung tissues for lipid
profiling.
Increased levels of triglyceride, cholesterol,
cholesteryl ester, and phospholipids were seen in
the lungs of exposed mice at >118.8 mg/kg,
compared to control.
The study authors
considered the observed
pulmonary lipid changes to
be indicative of proliferation
of Type II pneumocytes,
because these cells are
known to produce some of
the increased lipids.
Taki et al.
(1986)
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Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Chronic (dermal)
Mixture (approximate
2:1 2-methylnaphthalane:
1 -methylnaphthalene
ratio)
Female B6C3F1 mice (15/group) were
dennally exposed to 0 or 119 mg/kg of a
mixture containing 1-methylnaphthalene
and 2-methylnaphthalene in acetone
2 times/wk for 30 wk. Lungs were fixed
for light and electron microscopy.
Final body weight was reduced 14% in exposed
animals, compared with control. PAP occurred in
100% of the exposed animals and was
characterized by grey-white nodules on lung
surfaces, alveoli filled with eosinophilic material,
mononucleated giant cells with foamy cytoplasm,
and myelinoid structures present in areas of
proteinosis. The study also reported 100% PAP in
animals similarly exposed dennally to 238 mg/kg
2 times/wk for 20 wk (data not shown).
Dermal exposure to a
mixture of 1- and
2-methylnaphthalene for
30 wk produced lung lesions
described as PAP in 100% of
exposed mice.
Murata et al.
(1992)
"Reported dietary intakes (% 1-methylnaphthalene in food) were converted to ADDs using the following equation: ADD = [1-methylnaphthalene (% in diet) x food
intake (kg food/day)]/average body weight (kg) x 106 (mg/kg), where reference values for body weight and food intake were used as recommended by U.S. EPA (1988).
An average value of food intake for males and females of 0.003555 kg/day was used (average of female B6C3F1 84-93-day intake [0.00344 kg/day] and male B6C3F1
84-91-day intake [0.00367 kg/day]) and an average body weight for males and females of 0.02505 kg was used (average of female B6C3F1 84-93-day body weight
[0.0214 kg] and male B6C3F1 84-91-day body weight [0.0287 kg]).
1-NA = 1-naphtholic acid; ADD = adjusted daily dose; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CI = confidence interval; CYP = cytochrome
P450; i.p. = intraperitoneal; PAP = pulmonary alveolar proteinosis; RBC = red blood cell; RD50 = concentration depressing respiratory rate to 50%; WBC = white blood
cell.
30
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2.3.3. Metabolism/Toxicokinetic Studies
No studies are available that quantify the rate or extent of 1-methylnaphthalene uptake
following oral exposure; however, oral toxicity studies, such as those discussed in Section 2.2.1,
show that 1-methylnaphthalene is absorbed via the gastrointestinal tract. Inhalation and dermal
toxicokinetic studies indicate that 1-methylnaphthalene is rapidly absorbed through the lungs
(Swiercz et al.. 2022; Swiercz and Wasowicz. 2018) and the skin (Mcdougal et al.. 2000).
1-Methylnaphthalene was detected in blood samples taken immediately after exposure from male
Wister rats exposed, nose-only, to vapor concentrations of 50 or 200 mg/m3 for 6 hours (Swiercz
and Wasowicz. 2018) and for 6 hours/day for 5 days (Swiercz et al.. 2022). Examination of the
absorption and penetration examination of methylnaphthalene (assumed mixture) using excised
rodent skin, exposed for 4 hours in static diffusion cells, demonstrated a flux of
1.55 |ig/cm2/hour and a skin permeability coefficient of 1.6 x 10 4 (Mcdougal et al.. 2000).
No data on distribution following oral or dermal exposure were identified. After
inhalation exposure in rats, elimination from blood was rapid and followed a two-compartment
model (Swiercz et al.. 2022; Swiercz and Wasowicz. 2018). Half-lives for phase I were similar
following single or repeat exposures (1.08 and 2.46 minutes, respectively). Half-lives and areas
under the curve (AUCs) during phase II were concentration-dependent; after a single 6-hour
exposure, the half-lives in blood during phase II were 39.1 minutes at an exposure concentration
of 50 mg/m3 and 104 minutes at an exposure concentration of 200 mg/m3. 1-Methylnaphthalene
concentration in rat tissues was also dependent on the concentration of exposure. After
inhalation, 1-methylnaphthalene immediately distributed primarily to kidney and fat, with greater
distribution to fat at increasing exposure concentrations (Swiercz and Wasowicz. 2018). Lower
concentrations of 1-methylnaphthalene were found in the lungs, spleen, liver, and brain.
Twenty-four hours post-exposure, the parent compound was only detected in fat (single and
repeat exposures) and kidney (single exposure only). No 1-methylnaphthalene was detected in
any tissues at 72 hours following termination of exposure. In general, 1-methylnaphthalene
concentrations in tissues were lower in animals repeatedly exposed to 1-methylnaphthalene for
5 days, compared with those exposed for a single 6-hour period, suggesting increased
metabolism following repeated exposure (Swiercz and Wasowicz. 2018). Swiercz et al. (2022)
monitored levels of 1-naphtholic acid (1-NA), a metabolite of 1-methylnaphthalene, following
single (6-hour) or repeated (6 hours/day for 5 days) exposure to 1-methylnapthalene via nose-
only inhalation in rats (see Table 4B). The highest 1-NA concentrations were observed in kidney
tissue following exposure, although no 1-NA was detected 72 hours after the end of the exposure
in any analyzed tissues. In collected urine samples (3 days, 24 hours/day), 95% of total measured
1-NA was detected in the first 0-24 hours, suggesting rapid metabolism of 1-methylnaphthalene
at the administered doses (up to 200 mg/m3).
No in vivo animal studies on 1-methylnaphthalene metabolism are available. Based on
similarities to the 2-methylnaphthalene isomer, 1-methylnaphthalene is expected to be oxidized
by cytochrome P450 (CYP450) monooxygenases to dihydrodiols or alcohols that are further
modified to glucuronides and sulfates, which are then excreted (Lin et al.. 2009). Metabolism is
expected to occur in the nose and respiratory tract, which contain CYP450 monooxygenases and
are known targets of 1-methylnaphthalene toxicity (Kim et al.. 2020; Murata et al.. 1993).
However, no studies directly linking metabolic activation with toxic effects are available (Lin et
al.. 2009). Based on in vitro studies in human and rat liver microsomes, 1-methylnaphthalene can
also be metabolized in the liver. Using inhibition studies, (Wang et al.. 2020) showed that the
CYP450 enzyme, CYP1 A, was involved in aromatic ring and alkyl chain oxidation of
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1-methylnaphthalene in human microsomes but may not play an important role in oxidation of
1-methylnaphthalene in the liver of rats. Incubations with human and rat liver microsomes
identified l-(hydroxymethyl)naphthalene, resulting from side-chain oxidation, as the primary
metabolite of 1-methylnaphthalene (Wang et al.. 2020). Minor metabolites included
dihydro-l-methylnaphthalenediol and 1-methylnapthol. Apparent Km, Vmax values, and intrinsic
clearance Clint (Vmax/Km) were calculated for each metabolite. The metabolic rate for formation
of dihydro-l-methylnaphthalenediol was significantly higher in humans compared with rats
(Vmax of 163 vs. 56 pmol/minute/mg microsomal protein, respectively), whereas Vmax values for
1-methylnaphthol were higher in rat microsomes (Wang et al.. 2020). A human biomarker study
(Li et al.. 2014) identified five purported metabolites of 1-methylnaphthalene
[8-methyl-2-naphthol, 4-methyl-l-napthol, 5-methyl-l-napthol, 4-methyl-2-napthol, and
5-methyl-2-napthol] at higher levels in the urine of smokers compared with nonsmokers.
No data on elimination following oral exposures in animals are available. After
termination of inhalation exposure in rats, Swiercz and Wasowicz (2018) measured levels of the
1-methylnaphthalane parent compound in urine over a 72-hour period. Approximately 85% of
the total amount of parent 1-methylnaphthalene detected in urine was eliminated during the first
24 hours of collection and urinary parent levels showed dependence on the concentration but not
duration of exposure. Daily elimination in repeat-exposure animals showed a reduction in
1-methylnaphthalene removal over consecutive days in the 50 mg/m3 group, but not in the
200 mg/m3 group. In humans, Li et al. (2014) suggested that metabolites of 1-methylnaphthalene
are excreted in urine, predominantly as conjugates (data not shown).
2.3.4. Mode-of-Action/Mechanistic Studies
Available data on 1-methylnaphthalene indicate the lung as one of the primary target
organs. In a mouse chronic dietary study, 1-methylnaphthalene caused an increase in incidences
of PAP in both male and female mice (Murata et al.. 1993). The same study authors reported a
similar effect in 100% of treated female mice in a 30-week skin painting study (see Table 4B)
using a methylnaphthalene mixture that contained both 1- and 2-methylnaphthalene isomers
(Murata et al.. 1992). Earlier dermal studies in female mice reported similar lung changes, which
were described as endogenous lipid pneumonia or proliferation of type II pnuemocytes in
response to the methylnaphthalene mixture (Taki et al.. 1986; Emi andKonishi. 1985).
1-Methylnaphthalene induced minimal changes (swelling of Clara cells) in the lungs of male
mice given a single intraperitoneal (i.p.) injection (Rasmussen et al.. 1986). No lung toxicity has
been observed in rats (Kim et al.. 2020; METI. 2009b; Dinsdale and Verschoyle. 1987).
indicating that similar to naphthalene (U.S. EPA. 1998). 1-methylnaphthalene-induced lung
injury may be species-specific, with mice being the more sensitive species.
The mechanism underlying 1-methylnaphthalene-induced PAP was proposed by Murata
et al. (1992). Murata et al. (1992) hypothesized that 1-methylnaphthalene first induces injury to
type I pneumocytes, leading to compensatory hyperplasia and hypertrophy of type II
pneumocytes, along with intercellular structural changes to lamellar bodies and myelinoid
structures (Murata et al.. 1993; Murata et al.. 1992). Swollen type II pneumocytes are then
thought to detach from the alveolar wall, becoming mononucleated balloon cells that eventually
accumulate lipid droplets and ascicular crystals in the cytoplasm. Rupture of these cells is then
thought to release proteinaceous materials into the surrounding tissue, thus causing PAP (Murata
et al.. 1992).
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EPA 690 R-24 001F
It is not clear whether this proposed sequence of events is compatible with the current
understanding of PAP pathogenesis in humans (reviewed in Kumar and Cummings. 2021;
Trapnell et al.. 2019). PAP, which can be classified into primary, secondary, or congenital PAP,
each with distinct etiologies, is characterized by excessive accumulation of surfactants, which are
composed of primarily phospholipids, such as phosphatidylcholine, as well as neutral lipids, in
the lung alveoli. This can occur from disruptions in granulocyte-macrophage colony-stimulating
factor (GM-CF), dysfunctional changes or reductions in the numbers of alveolar macrophages, or
changes in neutrophils that lead to the disruption of surfactant homeostasis (Salvaterra and
Campo. 2020; Trapnell et al.. 2019). Taki et al. (1986) showed an accumulation of surfactant
phospholipids in the lungs of female mice exposed dermally to 1-methylnaphthalene that the
study authors presumed to be due to proliferation of type II pneumocytes. Alterations in
percentages of neutrophil and or monocyte (macrophage precursor) cells in animals exposed to
1-methylnaphthalene were also reported in two studies in mice, although no functional tests were
performed (Jin et al.. 2012; Murata et al.. 1993). These observations could be in line with the
current understanding of PAP pathogenesis, but more mechanistic studies are needed.
1-Methylnaphthalene has been shown to produce nasal lesions by inhalation exposure in
male and female rats (Kim et al.. 2020). but no known mechanisms have been proposed. The
olfactory and respiratory epithelia of the nose are known targets of naphthalene, a structurally
related compound (U.S. EPA. 1998). The mode of action (MOA) of naphthalene toxicity is
hypothesized to involve metabolism by CYP1 Al and other enzymes via ring epoxidation to
reactive species such as 1,2-epoxides and 1,2-quinones (Lin et al.. 2009; U.S. EPA. 1998). The
reactive species then interact with cellular components. It is currently unknown whether reactive
metabolites generated via CYP450-mediated oxidation are responsible for 1-methylnaphthalene-
induced toxicities. Based on in vitro metabolism studies with human liver microsomes,
1-methylnaphthalene undergoes ring epoxidation mediated, in part, by CYP1A (Wang et al..
2020). which is similar to naphthalene, although to a lesser extent.
Increased absolute and/or relative liver weight was found in rats of both sexes treated
orally with 1-methylnaphthalene (METI. 2009b). The liver is a site of 1-methylnaphthalene
metabolism (Wang et al.. 2020). and stimulation of metabolism is a known cause of increased
liver weight for many chemicals (U.S. EPA. 2002a). There are, however, no specific data
available relating metabolic activity to liver weight following 1-methylnaphthalene exposure.
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EPA 690 R-24 001F
3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF ORAL REFERENCE DOSES
3.1.1. Derivation of a Subchronic Provisional Reference Dose
The database of relevant studies for derivation of a subchronic provisional reference dose
(p-RfD) for 1-methylnaphthelene is limited. No data in humans were located. Animal studies
available via the oral route include an unpublished, non-peer-reviewed OECD 422 guideline
study written in Japanese (METI. 2009b) and a published study performed in transgenic mice,
which presents interpretation challenges for use in a toxicity assessment (Jin et al.. 2012). The
Jin et al. (2012) study also had some notable study limitations.
There is uncertainty regarding interpretation of the systemic toxicity data in Jin et al.
(2012) due to the use of transgenic gpt delta mice. Although comparison studies validating use of
gpt delta rats for evaluating general toxicity responses are available (Matsushita et al.. 2021;
Akagi et al.. 2015). similar validation studies were not located for gpt delta mice. The current
OECD test guideline for transgenic rodent gene mutation assays (Test Guideline 488) anticipates
that these assays could be combined with OECD Test Guideline 407 (28-day repeated-dose
toxicity studies), but an official guideline for this integration is not yet available. It is unclear
whether the transgene would make mice susceptible to potential systemic effects compared with
wild-type counterparts. Other limitations of the Jin et al. (2012) 13-week feeding study include
the lack of stability measurements of 1-methylnaphthalene in food preparations and analytical
measurements of 1-methylnaphthalene concentrations in food at the time of feeding. Although
the study specified that food preparations were stored in light-shielded containers, it was not
indicated whether other precautions were taken to prevent loss from volatilization. The lack of
these evaluations in the Jin et al. (2012) feeding study is especially significant, because no
treatment-related effects were seen in any group to indicate that the 1-methylnaphthalene added
to the diet was received by the test animals. Due to the limitations of this study, Jin et al. (2012)
was not considered further for RfD derivation.
Although unpublished, METI (2009b) is a well-conducted guideline study that reported
adequate information with which to derive a screening subchronic level p-RfD value for
1-methylnaphthalene (see Appendix A).
3.1.2. Derivation of a Chronic Provisional Reference Dose
The only study applicable for derivation of a chronic p-RfD (Murata et al.. 1993) has
several limitations. Although well-conducted in many respects, there was probable confounding
from possible inhalation and dermal exposure of all animals (controls and treated) to volatilized
1-methylnaphthalene and 2-methylnaphthalene. In addition, the resulting loss from the feedstock,
which was prepared monthly and stored at room temperature, was not quantified. Therefore, the
exact dosage of 1-methylnaphthalene and the fraction of the response attributable to oral
ingestion cannot be estimated with accuracy. These factors add uncertainty to the dose-response
relationship between oral exposure to 1-methylnaphthalene and PAP assessed from the Murata et
al. (1993) study. As the toxicity of 1-methylnaphthalene and 2-methylnaphthalene is similar
(both methylnaphthalene isomers are associated with PAP following oral exposure), additional
insight into the uncertainty in the use of these data can be obtained from the Toxicological
Review of 2-Methylnaphthalene (U.S. EPA. 2003). with particular reference to Chapters 5 and 6,
where a more extensive discussion of the uncertainties is presented. Due to the uncertainties
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EPA 690 R-24 001F
associated with the Murata et al. (1993) study, a chronic p-RfD cannot be confidently derived.
However, the study provides sufficient data to develop a screening value that may be useful in
certain instances (see Appendix A).
3.2. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
No human data are available regarding the toxicity of 1-methylnaphthalene following
repeated inhalation exposure. The database on repeat-exposure inhalation toxicity of
1-methylnaphthalene is limited to a single published, peer-reviewed, subchronic study in rats
exposed to 1-methylnaphthalene vapors for 13 weeks (Kim et al.. 2020). Although the study did
not follow any guidelines, it was conducted in a manner similar to OECD Test
Guideline 413 (90-day subchronic inhalation toxicity study). According to the study authors, "the
test material was generated in the form of vapor by a liquid vapor generator and gas
chromatography was used for the analysis of concentrations in the inhalation chambers
sequentially, approximately every 40 minutes." Nominal concentrations (0.5, 4, and 30 ppm)
were confirmed to be 0.52 ± 0.05, 4.08 ± 0.25, and 30.83 ± 1.28 ppm, respectively. Although
potential exposure from coat cleaning cannot be discounted with the whole-body exposure
paradigm used by Kim et al. (2020). whole-body exposures introduce less stress to test animals
compared to nose-only exposures (Ovabu et al.. 2015). Whole-body exposure chambers also
simulate environmental or work-places exposures (Wong. 2007). The critical effects identified in
this study were increased incidence of mucous cell hyperplasia in nasopharyngeal tissues in
males at >3.0 mg/m3 and females at 179.3 mg/m3 and increased incidence of transitional
epithelial cell hyperplasia in nasopharyngeal tissues in males at >23.7 mg/m3 (see Table 5).
There is additional support for 1-methylnaphthalene as a respiratory irritant; an acute study of
sensory irritation in mice found concentration-dependent decreases in respiratory rates during
acute inhalation exposure and calculated an RD50 (concentration depressing respiratory rate to
50% of control) of 129 mg/m3 (Korsak et al.. 1998).
35
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table 5. Data for Sensitive Endpoints in F344 Rats Exposed to
1-Methylnaphthalene Vapors for 6 Hours/Day, 5 Days/week for 13 Weeks3
Lesion
Analytical Concentration [HECet] in (mg/m3)b
0
3.0 [0.099]
23.7 [0.773]
179.3 [5.833]
Males
Hyperplasia, mucous cell in
nasopharyngeal tissues (total)
0/10 (0%)c
4/10 (40%)*
10/10 (100%)*
10/10 (100%)*
Hyperplasia, transitional epithelial
cell in nasopharyngeal tissues (total)
0/10 (0%)
0/10 (0%)
5/10 (50%)*
5/10 (50%)*
Lesion
Analytical Concentration [HECet] in (mg/m3)
0
3.0 [0.065]
23.7 [0.510]
179.3 [3.736]
Females
Hyperplasia, mucous cell in
nasopharyngeal tissues (total)
0/10 (0%)
0/10 (0%)
3/10 (30%)
10/10 (100%)*
aKim et al (2020V
bHECET values are calculated by treating 1-methylnaphthalene as a Category 1 gas and using the following
equation from U.S. EPA (1994): HEC = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x RGDR. RGDRet values of 0.184, 0.183, and 0.182 for males and 0.121, 0.120, and 0.117 for
females in the low-, mid-, and high-dose groups, respectively, were calculated as per U.S. EPA (1994) using
default values for human VE and human and animal respiratory tissue surface area and animal VE values
calculated using study-specific TWA body-weight values of 0.268, 0.266, and 0.265 kg for low-, mid-, and high-
dose males, respectively, and 0.161, 0.160, and 0.154 kg for low, mid-, and high-dose females, respectively,
determined for this review.
0Values denote number of animals showing changes/total number of animals examined (% incidence).
* Significantly different from control by Fisher's exact test (one-sided p < 0.05), conducted for this review.
HECet = human equivalent concentration based on extrathoracic effects; RGDR = regional gas dose ratio
(animal:human); TWA = time-weighted average; VE = ventilation rate.
The Kim et al. (2020) hyperplasia data were modeled using the available dichotomous
models in the U.S. EPA's Benchmark Dose Software (BMDS; Version 3.2). Human equivalent
concentration based on extrathoracic effects (HECet) values were used as the dose metric, and a
reporting benchmark response (BMR) of 10% extra risk for incidence data was used. Table 6
summarizes the benchmark concentration (BMC) modeling results and provides candidate points
of departure (PODs) for the modeled endpoints. Details of model fit for each data set are
presented in Appendix C.
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EPA 690 R-24 001F
Table 6. BMC and BMCL Values from Best Fitting Models for Mucous Cell
and Transitional Epithelial Hyperplasia in Male and Female F344 Rats
Exposed to 1-Methylnaphthalene Vapors for 6 Hours/Day, 5 Days/week for
13 Weeks3
Endpoint
Best Fitting
Model
BMR
BMCio (HECet)
(mg/m3)
BMCLio (HECet)
(mg/m3)
Mucous cell hyperplasia in
nasopharyngeal tissues in males
Multistage
1-degree
10% extra risk
0.018
0.009
Transitional epithelial cell
hyperplasia in nasopharyngeal tissues
in males
Log-logistic
10% extra risk
0.26
0.12
Mucous cell hyperplasia in
nasopharyngeal tissues in females
Multistage
1-degree
10% extra risk
0.12
0.066
aKim et al (2020V
BMC = benclimark concentration; BMCio = 10% benchmark concentration; BMCL = benchmark concentration
lower confidence limit; BMCLio = 10% benclimark concentration lower confidence limit; BMR = benclimark
response; HECet = human equivalent concentration based on extrathoracic effects.
3.2.1. Derivation of a Subchronic Provisional Reference Concentration
The 10% benchmark concentration lower confidence limit (BMCLio) (HECet) of
0.009 mg/m3 for increased incidence of mucous cell hyperplasia in nasopharyngeal tissues in
male F344 rats in the 13-week inhalation study by Kim et al. (2020) is selected as the most
health-protective POD for derivation of the subchronic p-RfC.
The subchronic provisional reference concentration (p-RfC) of 3 x 10 5 mg/m3 is derived
by applying a composite uncertainty factor (UFc) of 300 (reflecting an interspecies uncertainty
factor [UFa] of 3, a database uncertainty factor [UFd] of 10, and an intraspecies uncertainty
factor [UFh] of 10) to the selected POD of 0.009 mg/m3, as follows:
Subchronic p-RfC = POD (HECet) - UFc
= 0.009 mg/m3 ^ 300
= 3 x 10"5 mg/m3
Table 7 summarizes the uncertainty factors for the subchronic p-RfC for
1 -methylnaphthalene.
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EPA 690 R-24 001F
Table 7. Uncertainty Factors for the Subchronic p-RfC for
1-Methylnaphthalene (CASRN 90-12-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HEC calculation) is performed.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The repeat-
exposure inhalation database is limited to a single published, peer-reviewed, 13-wk inhalation study
in rats. Reproductive and developmental endpoints were studied in rats following oral exposure and
no effects were found, but only a limited screening-level assessment was performed.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility, in the absence of
information to assess toxicokinetics and toxicodynamic variability of 1-methylnaphthalene in
humans.
UFl
1
A UFl of 1 is applied because the POD is a BMCL.
UFS
1
A UFS of 1 is applied because the subchronic POD was derived from subchronic data.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; 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.
Confidence in the subchronic p-RfC for 1-methylnaphthalene is low, as described in
Table 8.
Table 8. Confidence Descriptors for the Subchronic p-RfC for
1-Methylnaphthalene
Confidence in study
M
Confidence in the Drincioal studv bv Kim et al. (2020) is medium. The
study was conducted in a manner similar to OECD Test Guideline 413 but
there were some deficiencies in reporting (e.g., organ weights were
reported only as absolute, and not relative, values).
Confidence in database
L
Confidence in the database is low. The database comprises a single
repeat-exposure inhalation study. Some supporting information for the
critical effect in this study (nasal irritation in rats) was provided by an
acute inhalation study in mice. Reproductive and developmental endpoints
were studied in rats following oral exposure and no effects were found, but
only a limited screening-level assessment was performed.
Confidence in subchronic p-RfC
L
Overall, the confidence in the subchronic p-RfC is low.
L = low; M = medium; OECD = Organisation for Economic Co-operation and Development; p-RfC = provisional
reference concentration.
3.2.2. Derivation of a Chronic Provisional Reference Concentration
No chronic inhalation studies were identified for 1-methylnaphthalene. In the absence of
available chronic inhalation studies, the POD from the subchronic study by Kim et al. (2020)
was selected as a suitable basis for the chronic p-RfC. As discussed above, the POD from this
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EPA/690/R-24/001F
study is a BMCLio (HECet) of 0.009 mg/m3 for increased incidence of mucous cell hyperplasia
in nasopharyngeal tissues in male rats.
The chronic p-RfC of 3 x 10~6 mg/m3 is derived by applying a UFc of 3,000 (reflecting a
UFa of 3, UFd of 10, UFh of 10, and a subchronic to chronic uncertainty factor [UFs] of 10) to
the selected POD of 0.009 mg/m3.
Chronic p-RfC = POD (HECet) - UFc
= 0.009 mg/m3 ^ 3,000
= 3 x 10"6 mg/m3
Table 9 summarizes the uncertainty factors for the chronic p-RfC for
1 -methylnaphthalene.
Table 9. Uncertainty Factors for the Chronic p-RfC for
1-Methylnaphthalene (CASRN 90-12-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HEC calculation) is performed.
UFd
10
A UFd of 10 is applied to account for deficiencies and uncertainties in the database. The
repeat-exposure inhalation database is limited to a single published, peer-reviewed, 13-wk inhalation
study in rats. Reproductive and developmental endpoints were studied in rats following oral exposure
and no effects were found, but only a limited screening-level assessment was performed.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility, in the absence of
information to assess toxicokinetics and toxicodynamic variability of 1-methylnaphthalene in
humans.
UFl
1
A UFl of 1 is applied because the POD is a BMCL
UFS
10
A UFS of 10 is applied because the chronic POD was derived from subchronic data.
UFC
3,000
Composite UF = UFA x UFD x UFH x UFL x UFS
BMCL = benchmark concentration lower confidence limit; 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.
Confidence in the chronic p-RfC for 1-methylnaphthalene is low, as described in
Table 10.
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EPA 690 R-24 001F
Table 10. Confidence Descriptors for the Chronic p-RfC for
1-Methylnaphthalene
Confidence in study
M
Confidence in the ori ncioal studv bv Kim et al. (2020) is medium.
The study was conducted in a manner similar to OECD Test
Guideline 413 but there were some deficiencies in reporting
(e.g., organ weights were reported only as absolute and not relative
values).
Confidence in database
L
Confidence in the database is low. The database comprises a single
repeat-exposure inhalation study that was subchronic, not chronic, in
duration. Some supporting information for the critical effect in this
study (nasal irritation in rats) was provided by an acute inhalation
study in mice. Reproductive and developmental endpoints were
studied in rats following oral exposure and no effects were found, but
only a limited screening-level assessment was performed.
Confidence in Chronic RfC
L
Overall, the confidence in the chronic p-RfC is low
L = low; M = medium; OECD = Organisation for Economic Co-operation and Development; p-RfC = provisional
reference concentration.
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
Table 11 presents a summary of noncancer references values.
Table 11. Summary of Noncancer Reference Values for
1-Methylnaphthalene (CASRN 90-12-0)
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)
(see Appendix A)
Rat/M
Increased relative
liver weight
2 x KT1
BMDLo.ird
24.12
100
METI
(2009b)
Screening chronic
p-RfD (mg/kg-d)
(see Appendix A)
Mouse/M
PAP
1 x 1(T2
LOAEL
10.7
1,000
Murata et al.
(1993)
Subchronic p-RfC
(mg/m3)
Rat/M
Mucous cell
hyperplasia in
nasopharyngeal
tissues
3 x 10"5
BMCLio
0.009
300
Kim et al.
(2020)
Chronic p-RfC
(mg/m3)
Rat/M
Mucous cell
hyperplasia in
nasopharyngeal
tissues
3 x 1(T6
BMCLio
0.009
3,000
Kim et al.
(2020)
BMDL = benchmark dose lower confidence limit; BMDLio = 10% benchmark dose lower confidence limit;
HEC = human equivalent concentration; HED = human equivalent dose; LOAEL = lowest-observed-adverse-effect
level; M = male; PAP = pulmonary alveolar proteinosis; POD = point of departure; p-RfC = provisional reference
concentration; p-RfD = provisional reference dose; RD = relative deviation; UFC = composite uncertainty factor.
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3.4. CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Following the U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment,
1-methylnaphthalene has "Suggestive Evidence of Carcinogenic PotenticiF by oral exposure and
"Inadequate Information to Assess Carcinogenic Potential' by inhalation exposure
(see Table 12). There are no human studies to indicate cancer risk. The database of information
regarding the carcinogenicity of 1-methylnaphthalene in animals is limited to a single
carcinogenicity study in which male and female B6C3F1 mice (50/sex/group) were given
1-methylnaphthalene in the diet for 81 weeks at concentrations resulting in doses of 0, 71.6, or
140 mg/kg-day (males) or 0, 75.1, or 144 mg/kg-day (females) (Murata et al.. 1993). Under the
conditions of the study, significantly increased incidences of lung adenoma and combined lung
adenoma or adenocarcinoma were observed in male mice of both dose groups, but not in female
mice (see Table B-12 for tumor incidence data). No information was located regarding the
potential carcinogenicity of 1-methylnaphthalene by oral exposure in a second animal species or
via inhalation or other routes of exposure. Genotoxicity studies were largely negative, including
two Ames tests for mutation in bacteria (NTP. 2018; Florin et al.. 1980). assays for CAs and
SCEs in human peripheral lymphocytes (Kulka et al.. 1988). a subchronic in vivo assay for gpt
and Spi mutations in the lungs of mice (Jin et al.. 2012). and a micronucleus test in Chinese
hamster fibroblasts (Swiercz et al.. 2022). One of the only positive responses reported, in a
forward mutation assay in bacteria (Kaden et al.. 1979). was confounded by high cytotoxicity at
the same dose level. The other positive response was observed when urine extracts from rats
exposed to 1-methylnaphthalene were used in a micronucleus test in Chinese hamster fibroblasts
(Swiercz et al.. 2022).
Table 12. Cancer WOE Descriptor for 1-Methylnaphthalene
(CASRN 90-12-0)
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
The available data do not support this
descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
Selected
Oral
Lung tumors were significantly increased
in male, but not female, mice in an 81-wk
feeding study of 1-methylnaphthalene. No
other oral cancer bioassays were located.
"Inadequate Information to
Assess Carcinogenic Potential"
Selected
Inhalation
No information is available on the
carcinogenicity of 1-methylnaphthalene
by inhalation exposure.
"Not Likely to Be Carcinogenic
to Humans"
NS
NA
The available data do not support this
descriptor.
NA = not applicable; NS = not selected; WOE = weight-of-evidence.
3.4.1. Mode-of-Action Discussion
The Guidelines for Carcinogen Risk Assessment (U.S. EPA. 2005) define MO A ".. .as a
sequence of key events and processes, starting with interaction of an agent with a cell,
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proceeding through operational and anatomical changes, and resulting in cancer formation."
Examples of possible modes of carcinogenic action for any given chemical include
"mutagenicity, mitogenesis, programmed cell death, cytotoxicity with reparative cell
proliferation, and immune suppression."
The MOA for tumor formation in male mice in the Murata et al. (1993) study is not
known. The available data do not support the hypothesis that PAP might be a precursor to lung
tumor formation (Murata et al.. 1997; Murata et al.. 1993). For example, compared with
2-methylnaphthalene, 1-methylnaphthalene induced equal or slightly lower incidences of PAP,
but higher incidences of lung tumors. In addition, Murata et al. (1993) reported that the numbers
of mice developing PAP and lung tumors following exposure to 1-methylnaphthalene were not
statistically correlated, and the sites of development of alveolar proteinosis and lung tumors were
not always clearly linked. Furthermore, lung tumors were increased only in male mice, while
PAP was increased in both male and female mice. Genotoxicity data for 1-methylnaphthalene are
limited but are mostly consistent in finding that 1-methylnaphthalene is not genotoxic or
mutagenic. A mutagenic MOA has also not been established for either of the structurally related
compounds, 2-methylnaphthalene (U.S. EPA. 2007) and naphthalene (U.S. EPA. 1998).
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Table 13 presents a summary of cancer risk estimates values.
Table 13. Summary of Cancer Risk Estimates for 1-Methylnaphthalene
(CASRN 90-12-0)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
Screening p-OSF
(mg/kg-dr1
(see Appendix A)
Mouse/M
Combined lung
adenoma or
adenocarcinoma
0.051
Murata et al. (1993)
p-IUR (lng/in3) 1
NDr
M = male; NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
3.5.1. Derivation of Provisional Oral Slope Factor (p-OSF)
Murata et al. (1993) is the only available cancer bioassay for 1-methylnaphthalene. As
noted in Section 3.1.2, this study has several limitations. The exposure of all animals (including
treated and controls), to volatilized 1- and 2-methylnaphthalene originating from the diets
introduces considerable uncertainty into the quantitative analysis. Some of the lung tumors in
these animals may have arisen (at least in part) with contributions from inhalation exposure, and
some of these with contributions from 2-methylnaphthalene exposure. It is possible that the two
lung adenomas in the control animals were a result of unintentional inhalation exposure to
methylnaphthalene vapors, although historical control data are lacking to verify that conjecture.
Although solubilization in corn oil used in the preparation of animal diets was anticipated to
minimize 1-methylnaphthalene loss due to volatilization, loss from the feedstock, which was
prepared monthly and stored at room temperature, was not quantified. Therefore, the exact
dosage of 1-methylnaphthalene and the fraction of the response attributable to oral ingestion
cannot be estimated with accuracy. It could be assumed that inhalation exposure was the same
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for all animals, and the control incidence could still serve as an approximate measure of
background incidence, with respect to secondary inhalation exposure; however, the assumption
of equal exposure for all animals is somewhat tenuous since proximity to the possible emission
source was not the same for all animals, with treated animals being closer. As such, a modeled
p-OSF based on these data might reflect a health-protective bias, resulting from potential
differences in unintentional inhalation exposure across treatment groups. Due to the limitations
described, Murata et al. (1993) was considered inadequate for derivation of a p-OSF. However,
the study provided sufficient data to develop a screening value that may be useful in certain
instances (see Appendix A).
3.5.2. Derivation of Provisional Inhalation Unit Risk (p-IUR)
There is inadequate information to assess the carcinogenic potential of
1-methylnaphthalene by inhalation exposure. There are no suitable human or animal inhalation
data available.
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APPENDIX A. SCREENING PROVISIONAL VALUES
Due to the lack of evidence described in the main Provisional Peer-Reviewed Toxicity
Value (PPRTV) assessment, it is inappropriate to derive a provisional toxicity value for
1-methylnaphthalene. However, some information is available for this chemical, which although
insufficient to support derivation of a provisional toxicity value under current guidelines, may be
of limited use to risk assessors. In such cases, the Center for Public Health and Environmental
Assessment (CPHEA) summarizes available information in an appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the provisional reference values to ensure their appropriateness within the limitations
detailed in the document. Users of screening toxicity values in an appendix to a PPRTV
assessment should understand that there could be more uncertainty associated with deriving an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
CPHEA.
Screening subchronic and chronic provisional reference doses (p-RfDs) and a screening
provisional oral slope factor (p-OSF) were derived for 1-methylnaphthalene, as described in the
sections below.
DERIVATION OF SCREENING PROVISIONAL REFERENCES DOSES
As discussed in the main body of the report, the 42-day gavage rat study (METI 2009b)
and the chronic dietary mouse study (Murata et al.. 1993) provide sufficient information for
derivation of screening subchronic and chronic p-RfD values, respectively, for
1-methylnaphthalene. Due to several limitations of these studies, they were only considered
suitable to support the derivation of screening values. Although a well-conducted guideline
study, (METI 2009b) is unpublished, not peer-reviewed, and written primarily in Japanese.
Although well-conducted in many respects, data presented in Murata et al. (1993) were likely
confounded by possible inhalation and dermal exposure of all animals (controls and treated) to
volatilized 1-methylnaphthalene and 2-methylnaphthalene. Resulting loss from the feedstock was
not quantified, making the administered dose of 1-methylnaphthalene and the fraction of the
response attributable to oral ingestion difficult to estimate with accuracy.
Derivation of Screening Subchronic p-RfD
METI (2009b) exposed 12 breeding pairs of Sprague Dawley Crl:CD rats to
1-methylnaphthalene doses of 0, 10, 50, or 250 mg/kg-day by gavage beginning 2 weeks prior to
mating, and continuing through mating, gestation, and lactation until postnatal day (PND) 4
(females) or for a total of 42 days (males). The most sensitive effects in this study were increased
absolute and relative liver weights and increased relative kidney weights in males and increased
relative liver weights in females at 250 mg/kg-day (see Table A-l). When amenable, these data
were used for benchmark dose (BMD) modeling. Modeling of these endpoints was performed
using all available dichotomous models in the U.S. Environmental Protection Agency
(U.S. EPA) Benchmark Dose Software (BMDS) (Version 3.2). Human equivalent dose (HED)
values in mg/kg-day were used as the dose metric (see Table A-l). A benchmark response
(BMR) of 10% relative deviation (RD) was used, because a 10% change in liver and/or kidney
weight was considered biologically significant.
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Table A-l. Data for Increased Liver and Kidney Weights in Sprague Dawley
Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage During
Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days3
Endpoint
Males: ADD [HED] (mg/kg-d)b
0
10 [2.8]
50 [14]
250 [70.1]
Number of animals (n)
7
12
12
7
Liver weight
Absolute (g)
12.94 ± 1.905c
12.895 ± 1.604 (-0%)d
13.043 ± 1.272 (±1%)
15.159 ± 1.934 (+17%)*
Relative (g%)
2.628 ±0.233
2.678 ± 0.223 (±2%)
2.685 ±0.17 (±2%)
3.309 ± 0.416 (+26%)**
Kidney weight
Absolute (g)
2.905 ±0.299
3.006 ±0.298 (±3%)
3.006 ±0.285 (±3%)
3.127 ±0.287 (+8%)
Relative (g%)
0.593 ±0.057
0.626 ± 0.053 (±6%)
0.62 ± 0.053 (±5%)
0.683 ± 0.06 (+15%)*
Endpoint
Mated Females: ADD [HED] (mg/kg-d)
0
10 [2.6]
50 [13]
250 [64.0]
Number of animals (n)
11
8
12
11
Liver weight
Absolute (g)
9.859 ±0.808c
9.563 ± 0.599 (-3%)d
9.929 ± 0.63 (±1%)
10.588 ± 0.988 (+7%)
Relative (g%)
3.193 ±0.227
3.148 ±0.275 (-1%)
3.188 ±0.169 (-0%)
3.521 ± 0.373 (+10%)*
aMETI (2009b).
bADDs were converted to HEDs of 2.8, 14, and 70.1 mg/kg-day in low-, mid-, and high-dose males, respectively,
and 2.6, 13, and 64.0 mg/kg-day in low-, mid-, and high-dose females, respectively, using DAFs of approximately
0.28 (males), and 0.26 (females), where HED = ADD x DAF. The DAFs were calculated as follows:
DAF = (BWa14 + BWh1'4), where BWa = animal body weight and BWh = human body weight. Individual animal
body weights were provided in the study; group TWA body weights determined for this review were 0.441, 0.442,
and 0.433 kg for low-, mid-, and high-dose males, respectively, and 0.308, 0.308, and 0.300 kg for low-, mid-, and
high-dose females, respectively. For humans, the reference value of 70 kg was used for body weight, as
recommended by U.S. EPA (1988).
Data are mean ± SD.
dValue in parentheses is percent change relative to control = ([treatment mean - control mean] + control
mean) x 100.
* Significantly different from control (p < 0.05), by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01), by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; DAF = dosimetric adjustment factor; HED = human equivalent dose; PND = postnatal
day; SD = standard deviation; TWA = time-weighted average.
Table A-2 summarizes the BMD modeling results and provides candidate points of
departure (PODs) for the organ weight data from METI (2009b). Details of model fit for each
data set are presented in Appendix C.
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Table A-2. BMD and BMDL Values from Best Fitting Models for Increased
Organ Weights in Male and Female Sprague Dawley Crl:CD Rats Exposed
to 1-Methylnaphthalene via Gavage During Premating, Mating, Gestation,
and Lactation Until PND 4 or for 42 Days3
Endpoints
Best Fitting Model
BMR
BMD (HED)
(mg/kg-d)
BMDL (HED)
(mg/kg-d)
Increased absolute liver
weight (males)
No selected modelb
10% RD from control
(0.1RD)
NA
NA
Increased relative liver
weight (males)
Polynomial 2-degree
(nonconstant variance)
10% RD from control
(0.1RD)
44.79
24.12
Increased relative
kidney weight (males)
No selected modelb
10% RD from control
(0.1RD)
NA
NA
Increased relative liver
weight (females)
Polynomial 3-degree
(nonconstant variance)
10% RD from control
(0.1RD)
62.40
42.30
aMETI (2009b).
bData were not amenable to BMD modeling.
BMD = benclunark dose; BMDL = benchmark dose lower confidence limit; BMR = benchmark response;
HED = human equivalent dose; NA = not applicable; PND = postnatal day; RD = relative deviation.
The benchmark dose lower confidence limit with 10% relative deviation (BMDLo.ird )
(HED) of 24.12 mg/kg-day based on increased relative liver weight in male rats in the 42-day
gavage study (METI. 2009b) is the most health-protective POD identified and is selected as the
POD for derivation of the screening subchronic p-RfD.
The screening subchronic p-RfD of 2 x 10 1 mg/kg-day is derived by applying a
composite uncertainty factor (UFc) of 100 (reflecting an interspecies uncertainty factor [UFa] of
3, a database uncertainty factor [UFd] of 3, and an intraspecies uncertainty factor [UFh] of 10) to
the selected POD of 24.12 mg/kg-day, as follows:
Screening Subchronic p-RfD = POD (HED) UFc
= 24.12 mg/kg-day -M00
= 2 x 10"1 mg/kg-day
Table A-3 summarizes the uncertainty factors for the screening subchronic p-RfD for
1 -methylnaphthalene.
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Table A-3. Uncertainty Factors for the Screening Subchronic p-RfD for
1-Methylnaphthalene (CASRN 90-12-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFd
3
A UFd of 3 is applied to account for deficiencies and uncertainties in the database. Subchronic oral
studies include an unpublished, Japanese-language, 42-d gavage study in rats that collected
comprehensive svstemic data (METI. 2009b) and a published 13-wk dietary studv in transgenic mice
that had significant limitations (Jin et al.. 2012). Reproductive and developmental endpoints were
studied in rats following 42-d savage exposure and no effects were found (METI. 2009a): although a
wide variety of reproductive endpoints were collected, only a limited screening-level assessment for
developmental endpoints was performed.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility in the absence of
information to assess the toxicokinetic and toxicodynamic variability of 1-methylnaphthalene in
humans.
UFl
1
A UFl of 1 is applied because the POD is a BMDL.
UFS
1
A UFS of 1 is applied because the POD was derived from a study of suitable duration (42 days) for a
subchronic value.
UFC
100
Composite UF = UFA x UFD x UFH x UFL x UFS.
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 Screening Chronic p-RfD
Murata et al. (1993). the only available oral chronic study on 1-methylnaphthalene, was
identified as the principal study for derivation of a screening chronic p-RfD. Pulmonary alveolar
proteinosis (PAP) observed in both male and female rats at the lowest doses tested was selected
as the critical effect (see Table A-4). Although this lesion was not seen in other oral or inhalation
studies of 1-methylnapthalene, there is some supporting evidence for the observed effect. An
isomer of 1-methylnaphthalene, 2-methylnaphthalene has also been associated with PAP
following chronic dietary exposure in mice, and derivation of an Integrated Risk Information
System (IRIS) oral reference dose (RfD) value for 2-methylnaphthalane was based on this effect
(U.S. EPA 2003; Murata et al.. 1997). The same study authors reported PAP in 100% of treated
female mice in a 30-week skin painting study using a mixture of 1- and 2-methylnaphthalene
(Murata et al.. 1992). Earlier dermal studies in female mice reported similar lung changes, which
were described as endogenous lipid pneumonia, in response to a methylnaphthalene mixture
(Taki et al.. 1986; Emi and Konishi. 1985). Lipid pneumonia and PAP are distinct conditions but
share similar features and can coexist (Salvaterra and Campo. 2020). and although rare, lipid
pneumonia may precede development of PAP in some cases in humans (Trapnell et al.. 2019;
Antoon et al.. 2016). The absence of supporting data by oral or inhalation exposure could reflect
the relatively short duration of the available studies. A 13-week preliminary study briefly
described in Murata et al. (1993) using the same mouse strain did not report any incidences of
PAP, suggesting that development of PAP may require longer durations of oral exposure.
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Table A-4. Incidence of Pulmonary Alveolar Proteinosis in B6C3F1 Mice
Fed 1-Methylnaphthalene in the Diet for 81 Weeks3
Males: ADD [HED] (mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
4/49 (8.2%)b
23/50 (46.0%)*
19/50 (38.0%)*
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
5/50 (10.0%)
23/50 (46.0%)*
17/49 (34.7%)*
aMurata et al. (1993).
bThe ADDs were converted to HEDs of 10.7 and 21.1 mg/kg-day for low- and high-dose males and 11.1 and
20.9 mg/kg-day for low- and high-dose females using respective DAFs of 0.149 and 0.150 (males) and 0.147 and
0.145 (females). The DAFs were calculated as follows: DAF = (Bwa14 ^ Bwh1/4), where DAF = dosimetric
adjustment factor, BWa = animal body weight and BWh = human body weight. Animal body weight data reported
graphically in the study were extracted using GRAB IT™ software. TWA animal body weights of 0.035 and
0.036 kg for low- and high-dose males, respectively, and 0.033 and 0.031 kg for low- and high-dose females,
respectively, were determined. For humans, the reference value of 70 kg was used for body weight, as
recommended by U.S. EPA (1988).
°Values denote number of animals showing changes / total number of animals examined (% incidence).
* Significantly different from control (p < 0.01) value by y; test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose
The PAP data from Murata et al. (1993) were modeled using the available
dichotomous models in the U.S. EPA's BMDS (Version 3.2). HED values were used as the
dose metric, and the standard reporting BMR of 10% extra risk for incidence data was used.
None of the available models provided adequate fit to either data set. Therefore, the lowest
lowest-observed-adverse-effect level (LOAEL) of 71.6 mg/kg-day in males, corresponding to an
HED of 10.7 mg/kg-day, is selected as the POD for the screening chronic p-RfD value.
The screening chronic p-RfD of 1 x 1CT2 mg/kg-day is derived by applying a UFc of
1,000 (reflecting a UFa of 3, UFd of 3, UFh of 10, and LOAEL-to-no-observed-adverse-effect
level [NOAEL] uncertainty factor [UFl] of 10) to the selected POD of 10.7 mg/kg-day, as
follows:
Screening Chronic p-RfD = LOAEL (HED) UFc
= 10.7 mg/kg-day ^ 1,000
= 1 x 10"2 mg/kg-day
Table A-5 summarizes the uncertainty factors for the screening chronic p-RfD for
1 -methylnaphthalene.
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Table A-5. Uncertainty Factors for the Screening Chronic p-RfD for
1-Methylnaphthalene (CASRN 90-12-0)
UF
Value
Justification
UFa
3
A UFa of 3 (10"5) is applied to account for uncertainty associated with extrapolating from animals to
humans when cross-species dosimetric adjustment (HED calculation) is performed.
UFd
3
A UFd of 3 is applied to account for deficiencies and uncertainties in the database. The animal oral
database for chronic studies consists of a single chronic dietary study in mice that investigated
comprehensive svstemic endooints (Murata et al.. 1993). Reproductive and developmental endooints
were studied in rats following 42-d savase c\do sure and no effects were found (METI. 2009b)
although a wide variety of reproductive endpoints were collected only a limited screening-level
assessment for developmental endpoints was performed.
UFh
10
A UFh of 10 is applied to account for human variability and susceptibility in the absence of
information to assess toxicokinetic and toxicodynamic variability of 1-methylnaphthalene in humans.
UFl
10
A UFl of 10 is applied because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because the POD was derived from chronic data.
UFC
1,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
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 Provisional Oral Slope Factor (p-OSF)
The Murata et al. (1993) 81-week oral cancer bioassay in mice provides sufficient data to
derive a screening p-OSF for 1-methylnaphthalene, based on significantly increased incidence of
lung tumors (combined adenomas or adenocarcinomas) in treated male mice (see Table A-6).
Due to several limitations of the study, it was only considered suitable to support the derivation
of a screening value. Limitations include potential exposure of all animals to volatilized 1- and
2-methylnaphthalene and the lack of monitoring 1-methylnaphthalene loss from the feedstock.
These limitations introduce uncertainty to the exact dosage of 1-methylnaphthalene administered
and the fraction of the response attributable to oral ingestion.
Table A-6. Incidence Data for Lung Tumors in Male B6C3F1 Mice Fed
1-Methylnaphthalene in the Diet for 81 Weeks3
Males: ADD [HED] (mg/kg-d)
Endpoint
0
71.6 [10.7]
140 [21.1]
Lung adenoma or adenocarcinoma (combined)
2/49 (4.1%)b
13/50 (26.0%)*
15/50 (30.0%)*
aMurata et al. (1993).
bValues denote number of animals showing changes / total number of animals examined (% incidence).
* Significantly different from control (p < 0.01) value by y; test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose.
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To obtain a POD for a quantitative assessment of cancer risk, BMD analysis was
performed on the incidence data for lung adenoma or carcinoma (combined) in the male mice.
The POD is an estimated dose (expressed in human-equivalent terms) near the lower end of the
observed range that marks the starting point for extrapolation to lower doses. Multistage cancer
models in the U.S. EPA BMDS (Version 3.2) were fit to the incidence data shown above
(see Table A-6). The BMR used was 10% extra risk, and the HED in mg/kg-day was used as the
dose metric. The modeling results are summarized in Table A-7 (see additional BMD details in
Appendix C).
Table A-7. Modeling Results Based on the Incidence of Lung Tumors in
Male B6C3F1 Mice Fed 1-Methylnaphthalene in the Diet for 81 Weeks3
Tumor Endpoint
Selected Model
BMDio (HED)
(mg/kg-d)
BMDLio (HED)
(mg/kg-d)
Lung adenoma or adenocarcinoma (combined)
Multistage (1-degree)
6.01
4.16
aMurata et al. (1993).
BMDio = 10% benchmark dose; BMDLio = 10% benchmark dose lower confidence limit; HED = human
equivalent dose
The Multistage 1-degree model provided adequate fit to the data for combined lung
adenoma or carcinoma in male mice (see Table A-7). The Multistage 2-degree model took the
form of the 1-degree model. Higher-degree models were not applied to the data set because only
three dose groups were available. The predicted 10% benchmark dose (BMDio) (HED)
associated with 10% extra risk is 6.01 mg/kg-day and the 95% lower confidence limit, the 10%
benchmark dose lower confidence limit (BMDLio) (HED), is 4.16 mg/kg-day for lung adenoma
or carcinoma (combined). The BMDLio (HED) of 4.16 mg/kg-day is used as the POD for
derivation of the p-OSF.
In the absence of data for the MOA of 1-methylnaphthalene induced tumorigenesis, the
screening p-OSF for 1-methylnaphthalene, based on the BMDLio (HED) of 4.16 mg/kg-day, is
derived using a linear approach, as follows:
Screening p-OSF (unadjusted) = BMR ^ BMDLio (HED)
= 0.1^-4.16 mg/kg-day
= 0.024 (mg/kg-day)"1
An adjustment was applied to account for the less-than-lifetime observation period (U.S.
EPA 1980). The (Murata et al.. 1993) bioassay exposed mice to 1-methylnaphthalene for only
81 weeks. Thus, due to the short duration of the study, it cannot be known how an increased
duration (i.e., 2-year lifetime exposure) might have influenced tumor incidence. Therefore, an
adjustment factor of (L Le)3 was applied to the unadjusted screening p-OSF, where L = the
lifetime of the animal and Le = duration of the experimental dosing (U.S. EPA 1980). Using this
adjustment, an adjusted screening p-OSF is derived as follows:
50
1 -Methylnaphthalene
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EPA 690 R-24 001F
Screening p-OSF (adjusted) = p-OSF (unadjusted) x (L Le)3
= 0.024 (mg/kg-day)-1 x (104 weeks -^81 weeks)3
= 0.051 (mg/kg-day)"1
It is important to note that the (Murata et al.. 1993) bioassay raises concern for exposures
of longer duration. Although there is uncertainty associated with the degree of adjustment, the
adjusted estimate is more health-protective than the estimate without the (L Le)3 adjustment,
which is likely to be underestimated. Because 1-methylnaphthalene shows "Suggestive Evidence
of Carcinogenic Potentiar by oral exposure (see Table 12), derivation of a screening p-OSF for
this chemical is warranted despite the aforementioned uncertainty arising from the application of
the less-than-lifetime adjustment factor.
51
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EPA/690/R-24/001F
APPENDIX B. DATA TABLES
Table B-l. Select Hematology Findings in Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage
During Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days"
Endpoint
Males (main group): ADD [HED] (mg/kg-d)b
Males (recovery): ADD [HED] (mg/kg-d)
0
10 [2.8]
50 [14]
250 [70.1]
0
250 [70.1]
RBC (x 104/|iL)
902 ± 47°
932 ± 72 (+3%)d
892 ± 23 (-1%)
900 ± 34 (-0%)
922 ± 65
882 ± 35 (-4%)
HGB (g/dL)
16.8 ±0.6
16.9 ± 1.2 (+1%)
16.7 ± 0.9 (-1%)
16 ± 0.6 (-5%)
17 ±0.7
15.9 ± 0.2 (-6%)*
HCT (%)
49 ±2.6
49 ± 4.5 (+0%)
50.1 ±3.9 (+2%)
48.5 ± 1.4 (-1%)
50.5 ±2
46.5 ±0.6 (-8%)**
MCV (fL)
54.3 ± 1.3
52.5 ± 1 (-3%)
56.1 ±3.2 (+3%)
53.9 ±2.1 (-1%)
55 ±3.2
52.8 ± 1.8 (-4%)
MCH (pg)
18.6 ±0.8
18.1 ±0.4 (-3%)
18.7 ± 0.6 (+1%)
17.8 ± 0.6 (-4%)
18.5 ± 1
18.1 ±0.8 (-2%)
MCHC (g/dL)
34.3 ± 1.1
34.5 ± 0.9 (+1%)
33.3 ± 1.5 (-3%)
33.1 ±1.6 (-3%)
33.6 ± 1
34.2 ± 0.8 (+2%)
WBC (x 102/(iL)
91 ± 21
78 ± 23 (-14%)
117 ± 117 (+29%)
117 ±29 (+29%)
110 ± 10
100 ± 15 (-9%)
Leukocyte classification
Basophil (%)
0±0
0±0
0±0
0±0
0±0
0±0
Eosinophil (%)
1.4 ±0.5
1.4 ± 0.9 (+0%)
1 ± 0.7 (-29%)
1.8 ± 1.8 (+29%)
1.2 ± 1.3
1.4 ±0.5 (+17%)
Stab neutrophil (%)
0±0
0±0
0±0
0±0
0±0
0±0
Segmented neutrophil (%)
18.4 ±2.9
20.6 ± 10.3 (+12%)
17.2 ± 7.3 (-7%)
22.2 ± 5.6 (+21%)
11.8 ± 4.1
16.4 ± 4.4 (+39%)
Lymphocyte (%)
80.2 ±2.9
78 ± 10.3 (-3%)
81.8 ±7.8 (+2%)
76 ± 6.4 (-5%)
87 ± 4.7
82.2 ± 4.1 (-6%)
Monocyte (%)
0±0
0±0
0±0
0±0
0±0
0±0
Other (%)
0±0
0±0
0±0
0±0
0±0
0±0
52
1 -Methylnaphthalene
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EPA 690 R-24 00IF
Table B-l. Select Hematology Findings in Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage
During Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days3
Endpoint
Mated Females: ADD [HED] (mg/kg-d)
Unmated Females (recovery): ADD [HED] (mg/kg-d)
0
10 [2.6]
50 [13]
250 [64.0]
0
250 [62.0]
RBC (x 104/(iL)
696 ± 80
699 ± 90 (±0%)
700 ± 34 (±1%)
723 ± 24 (±4%)
817 ±28
838 ±31 (±3%)
HGB (g/dL)
14 ± 1.2
14.2 ± 1.5 (±1%)
14.5 ± 0.8 (±4%)
14.8 ± 0.5 (±6%)
15.7 ±0.2
16.3 ± 0.6 (±4%)
HCT (%)
42 ±3.2
42.9 ±3.2 (±2%)
40.4 ±2.1 (-4%)
42.3 ± 1.9 (±1%)
44.9 ± 1.2
46.7 ±3.1 (±4%)
MCV (fL)
60.6 ± 3
61.9 ±4.5 (±2%)
57.6 ± 1.1 (-5%)
58.5 ± 2.5 (-3%)
55 ± 1.6
55.7 ± 2.7 (±1%)
MCH (pg)
20.1 ± 1.4
20.4 ± 1 (±1%)
20.7 ± 0.4 (±3%)
20.4 ± 0.5 (±1%)
19.3 ±0.6
19.5 ± 0.7 (±1%)
MCHC (g/dL)
33.2 ±0.09
33.1 ±1.7 (-0%)
35.9 ± 1.1 (+8%)*
35 ± 1.7 (±5%)
35 ±0.5
34.9 ± 1.2 (-0%)
WBC (x 102/(iL)
101 ±7
121 ± 47 (±20%)
101 ±23 (±23%)
117 ± 18 (±16%)
49 ±7
54 ± 15 (±10%)
Leukocyte classification
Basophil (%)
0±0
0±0
0±0
0.2 ±0.4 (100%)
0±0
0±0
Eosinophil (%)
0.3 ±0.5
0.4 ± 0.9 (±33%)
0.2 ± 0.4 (-33%)
0.6 ± 0.9 (±100%)
2.0 ± 1.4
0.8 ± 0.8 (-60%)
Stab neutrophil (%)
0±0
0±0
0±0
0±0
0±0
0±0
Segmented neutrophil (%)
29 ± 11.7
30.6 ± 18.9 (±6%)
27.6 ± 6.6 (-5%)
25 ±5.1 (-14%)
17.8 ±8
10.4 ± 4.6 (-42%)
Lymphocyte (%)
70.3 ± 12.3
69 ± 18.6 (-2%)
72.2 ± 6.4 (±3%)
74.2 ± 5.8 (-6%)
80.2 ±8.6
88.8 ±4.2 (±11%)
Monocyte (%)
0.5 ± 1
0±0
0±0
0±0
0±0
0±0
Other (%)
0±0
0±0
0±0
0±0
0±0
0±0
aMETI (2009b).
bADDs (mg/kg-day) were reported by the study authors; calculated HEDs appear in brackets.
Data are mean ± SD (g) for five animals/group with the following exceptions: one mated and one unmated control female were excluded due to death during anesthesia.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05) by Student's /-test. Aspin-Welch's test, orDunnett's test as reported by the study authors.
**Significantly different from control (p < 0.01) by Student's /-test. Aspin-Welch's test, orDunnett's test as reported by the study authors.
ADD = adjusted daily dose; HCT = hematocrit; HED = human equivalent dose; HGB = hemoglobin; MCH = mean corpuscular hemoglobin; MCHC = mean corpuscular
hemoglobin concentration; MCV = mean corpuscular volume; PND = postnatal day; RBC = red blood cell; SD = standard deviation; WBC = white blood cell.
53
1 -Methylnaphthalene
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EPA 690 R-24 00IF
Table B-2. Select Serum Chemistry Findings in Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via
Gavage During Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days3
Endpoint
Males (main group): ADD [HED] (mg/kg-d)b
Males (recovery): ADD [HED] (mg/kg-d)
0
10 [2.8]
50 [14]
250 [70.1]
0
250 [70.1]
AST (IU/L)
70 ± 7°
70 ± 9 (±0%)d
76 ± 8 (±9%)
83 ± 27 (±19%)
70 ±7
62 ±8 (-11%)
ALT (IU/L)
30 ±4
31 ±7 (±3%)
31 ±6 (±3%)
42 ± 18 (±40%)
36 ±4
30 ± 7 (-17%)
ALP (IU/L)
259 ±52
253 ± 50 (-2%)
238 ± 18 (-8%)
253 ± 36 (-2%)
241 ±53
207 ± 18 (-14%)
TP (g/dL)
6.3 ±0.3
6.4 ± 0.2 (±2%)
6.4 ± 0.3 (±2%)
6.5 ± 0.4 (±3%)
6.4 ±0.1
6.4 ± 0.3 (+0%)
a 1-globulin (%)
21.4 ± 1.6
21.5 ± 1.3 (±0%)
22.2 ± 0.9 (±4%)
22 ± 1.2 (±3%)
22.8 ±2.3
22.7 ± 1.1 (-0%)
K (mEq/L)
4.42 ±0.28
4.47 ± 0.33 (±1%)
4.27 ± 0.26 (-3%)
4.37 ± 0.22 (-1%)
4.49 ±0.13
5.01 ± 0.4 (+12%)*
IP (mg/dL)
6.2 ±0.8
6.1 ±0.8 (-2%)
6.5 ± 0.7 (±5%)
6.3 ± 0.3 (±2%)
5.4 ±0.4
5.6 ± 0.6 (+4%)
Endpoint
Mated Females: ADD [HED] (mg/kg-d)
Unmated Females (recovery): ADD [HED] (mg/kg-d)
0
10 [2.6]
50 [13]
250 [64.0]
0
250 [62.0]
AST (IU/L)
93 ±22
95 ± 40 (±2%)
75 ± 9 (-19%)
76 ± 7 (-18%)
62 ±4
70 ± 34 (+13%)
ALT (IU/L)
53 ±9
45 ± 19 (-15%)
40 ± 7 (-25%)
44 ± 11 (-17%)
20 ±3
31 ±20 (+55%)
ALP (IU/L)
123 ±25
127 ± 56 (±3%)
114 ±26 (-7%)
123 ± 48 (±0%)
103 ± 10
79 ± 9 (-23%)"
TP (g/dL)
5.9 ±0.2
6.3 ± 0.2 (+7%)*
6.3 ± 0.2 (±7%)
6.4 ±0.3 (+8%)**
6.8 ±0.4
7.5 ± 0.3 (+10%)*
a 1-globulin (%)
18.6 ±0.8
19.1 ± 1.8 (±3%)
21.2 ± 1.2 (+14%)*
20.3 ± 1.2 (±9%)
17.3 ± 1.3
17.7 ± 0.9 (+2%)
K (mEq/L)
4.09 ±0.32
4.05 ±0.41 (-1%)
4.39 ± 0.26 (±7%)
4.52 ±0.16 (±11%)
3.79 ±0.37
3.7 ±0.13 (-2%)
IP (mg/dL)
6.8 ± 1.4
6.5 ± 1 (-4%)
7.1 ±0.4 (±4%)
8.5 ± 0.9 (+25%)*
5.2 ±1.1
5.1 ± 1.4 (-2%)
aMETI (2009b).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
Data are mean ± SD (g) for five animals/group with the following exceptions: one mated and one umnated control female were excluded due to death during anesthesia.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05) by Student's /-test. Asprin-Welch's test, or Dunnett's test as reported by the study authors.
**Significantly different from control (p < 0.01) by Student's /-test. Asprin-Welch's test, or Dunnett's test as reported by the study authors.
ADD = adjusted daily dose; ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; HED = human equivalent dose;
IP = inorganic phosphate; K = potassium; PND = postnatal day; SD = standard deviation; TP = total protein.
54
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Table B-3. Select Organ Weights in Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage During
Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days"
Endpoint
Males (main group): ADD [HED] (mg/kg-d)b
Males (recovery): ADD [HED] (mg/kg-d)
0
10 [2.8]
50 [14]
250 [70.1]
0
250 [70.1]
Number of animals (n)
7
12
12
7
5
5
Necropsy body weight
491.4 ±46.8C
480.7 ± 34.5 (-2%)d
485.5 ± 30 (-1%)
458.9 ± 27.3 (-7%)
523.5 ±54.8
520.2 ± 19 (-1%)
Liver weight
Absolute (g)
Relative (g%)
12.94 ± 1.905
2.628 ±0.233
12.895 ± 1.604 (-0%)
2.678 ± 0.223 (+2%)
13.043 ± 1.272 (+1%)
2.685 ±0.17 (+2%)
15.159 ± 1.934 (+17%)*
3.309 ± 0.416 (+26%)**
14.219 ± 1.381
2.726 ± 0.248
14.131 ±0.78 (-1%)
2.723 ± 0.241 (-0%)
Kidney weight
Absolute (g)
Relative (g%)
2.905 ± 0.299
0.593 ±0.057
3.006 ±0.298 (+3%)
0.626 ± 0.053 (+6%)
3.006 ±0.285 (+3%)
0.62 ± 0.053 (+5%)
3.127 ±0.287 (+8%)
0.683 ± 0.06 (+15%)*
2.944 ± 0.223
0.565 ± 0.049
2.939 ± 0.249 (-0%)
0.566 ± 0.053 (+0%)
Spleen weight
Absolute (g)
Relative (g%)
0.759 ±0.114
0.155 ±0.023
0.768 ±0.128 (+1%)
0.159 ±0.022 (+3%)
0.775 ± 0.072 (+2%)
0.16 ±0.016 (+3%)
0.794 ±0.116 (+5%)
0.173 ±0.026 (+12%)
0.875 ±0.135
0.167 ±0.012
0.759 ±0.1 (-13%)
0.146 ±0.016 (-13%)*
55
1 -Methylnaphthalene
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EPA 690 R-24 00IF
Table B-3. Select Organ Weights in Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage During
Premating, Mating, Gestation, and Lactation Until PND 4 or for 42 Days3
Endpoint
Mated Females: ADD [HED] (mg/kg-d)
Unmated Females (recovery):
ADD [HED] (mg/kg-d)
0
10 [2.6]
50 [13]
250 [64.0]
0
250 [62.0]
Number of animals (n)
11
8
12
11
5
5
Necropsy body weight
308.9 ± 14.9
304.7 ± 16.8 (-1%)
311.6 ± 14.3 (±1%)
302 ± 24.5 (-2%)
322.7 ±34.1
288.9 ±21.2 (-10%)
Liver weight
Absolute (g)
Relative (g%)
9.859 ±0.808
3.193 ±0.227
9.563 ± 0.599 (-3%)
3.148 ±0.275 (-1%)
9.929 ± 0.63 (±1%)
3.188 ±0.169 (-0%)
10.588 ± 0.988 (±7%)
3.521 ± 0.373 (+10%)*
7.626 ±0.714
2.368 ±0.138
7.69 ± 0.606 (±1%)
2.663 ± 0.106 (+12%)**
Kidney weight
Absolute (g)
Relative (%)
1.956 ±0.109
0.634 ±0.04
1.852 ±0.122 (-5%)
0.609 ± 0.048 (-4%)
1.935 ±0.128 (-1%)
0.622 ± 0.04 (-2%)
1.957 ±0.209 (±0%)
0.65 ± 0.072 (±3%)
1.845 ±0.194
0.574 ±0.06
1.762 ±0.125 (-4%)
0.612 ±0.044 (+7%)
Spleen weight
Absolute (g)
Relative (%)
0.693 ±0.095
0.225 ±0.033
0.652 ± 0.096 (-6%)
0.214 ±0.028 (-5%)
0.655 ± 0.041 (-5%)
0.211 ±0.014 (-6%)
0.601 ±0.066 (-13%)
0.199 ±0.021 (-12%)
0.574 ±0.15
0.179 ±0.046
0.472 ± 0.038 (-18%)
0.164 ±0.015 (-8%)
aMETI (2009b).
bADD (mg/kg-day) values were reported by the study author; calculated HEDs appear in brackets.
Data are mean ± SD (g).
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05), by Student's /-test, or Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01), by Student's /-test, or Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; PND = postnatal day; SD = standard deviation.
56
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-4. Select Hematological Results of Male and Female B6C3F1 gpt
Delta Mice Treated with 1-Methylnaphthalene in the Diet for 13 Weeks3
Endpoint
Males: ADD [HED] in (mg/kg-d)b
0
120 [17.11
220 [31.11
WBC (x 102/|iL)
24.2 ± 15c
22 ± 9 (-9%)d
15 ± 7 (-38%)
Leukocyte classification
Band form neutrophils (%)
5.3 ± 1.8
2.6 ±0.9 (-51%)*
3.9 ±2.4 (-26%)
Segmented neutrophils (%)
14.8 ±3.2
16.8 ±3.9 (±14%)
27.5 ± 13.5 (+86%)*
Eosinophils
1.3 ±0.9
0.6 ± 0.4 (-54%)
1.1 ±0.4 (-15%)
Basophils (%)
0.3 ±0.5
0.4 ± 0.2 (±33%)
0.3 ± 0.3 (+0%)
Lymphocytes (%)
77 ±7.5
79 ± 3.7 (±3%)
66.4 ± 16 (-14%)
Monocytes (%)
0.9 ±0.3
0.6 ± 0.3 (-33%)
0.6 ± 0.3 (-33%)
Endpoint
Females: ADD [HED] in (mg/kg-d)
0
170 [23.1]
280 [37.7]
WBC (x 102/(iL)
16 ±8
17 ± 11 (±6%)
17 ± 8 (+6%)
Leukocyte classification
Band form neutrophils (%)
3.1 ± 1.7
2.2 ±1.1 (-29%)
2.6 ± 1.5 (-16%)
Segmented neutrophils (%)
10.7 ±3.9
10.4 ±3.2 (-3%)
10.9 ±3.4 (+2%)
Eosinophils
1 ±0.6
1.1 ±0.7 (±10%)
1.1 ±0.6 (+10%)
Basophils (%)
0.1 ±0.2
0.4 ± 0.2 (+300%)*
0.4 ± 0.2 (+300%.)*
Lymphocytes (%)
84.7 ±5.1
85.3 ±3.8 (±1%)
84.4 ± 4.2 (-0%)
Monocytes (%)
0.5 ±0.3
0.5 ± 0.3 (±0%)
0.4 ± 0.3 (-20%)
aJin et al. (2012).
bDoses equivalent to 0, 0.075, and 0.15% 1-methylnaphthalene in the diet; calculated HEDs appear in brackets.
Data are mean ± SD; n = 10 animals per group.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation; WBC = white blood cell.
57
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-5. Select Serum Biochemistry Results of Male and Female B6C3F1
gpt Delta Mice Treated with 1-Methylnaphthalene in the Diet for 13 Weeks3
Endpoint
Males: ADD [HED] in (mg/kg-d)b
0
120 [17.11
220 [31.11
AST (IU/L)
37.1 ± 2.8°
37.3 ±3.2 (±l%)d
50.6 ± 15.6 (+36%)*
ALT (IU/L)
20.3 ±2.1
20.9 ± 4.5 (±3%)
30.1 ± 10.4 (+48%)*
Phospholipid (mg/dL)
232.3 ±22.8
218.9 ± 15.2 (-6%)
207.4 ± 5.6 (-11%.)*
TC (mg/dL)
119.6 ± 12.5
121.3 ±8.1 (±1%)
113.9 ±5.8 (-5%)
CRN (mg/dL)
0.11±0.01
0.1 ±0.01 (-9%)
0.09 + 0.01 (-18%.)**
Ca (mg/dL)
9.2 ±0.3
8.9 ± 0.2 (-3%)*
8.9 ± 0.3 (-3%.)*
CI (mEO/L)
115.4 ± 1.4
115.4 ± 1.3 (±0%)
116.9 ±3 (±1%)
BUN (mg/dL)
31.1 ± 3.8
28.6 ± 20 (-8.0)
26.6 ± 3.7 (-14%.)*
Endpoint
Females: ADD [HED] in (mg/kg-d)
0
170 [23.1]
280 [37.7]
AST (IU/L)
39.6 ±2.4
38.6 ±3.4 (-3%)
40.3 ± 4.1 (±2%)
ALT (IU/L)
18 ± 2.1
16.7 ± 1.2 (-7%)
18.4 ± 2.5 (±2%)
Phospholipid (mg/dL)
189.2 ±8.1
181 ± 7.9 (-4%)
172.3 ± 16.6 (-9%.)*
TC (mg/dL)
104.6 ±4.8
98.6 ±7.1 (-6%)
97.1 ± 7.1 (-7%.)*
CRN (mg/dL)
0.09 ±0.01
0.11 ±0.02 (±22%)
0.09 ± 0.02 (±0%)
Ca (mg/dL)
8.9 ±0.2
9 ± 0.3 (±1%)
8.7 ± 0.2 (-2%)
CI (mEQ/L)
115.6 ± 1.5
115.9 ± 1.4 (±0%)
117.6 + 2.1 (+2%.)*
BUN (mg/dL)
20.9 ±4.1
24.4 ± 10.4 (±16%)
25.3 ±5.4 (±21%)
aJin et al. (2012).
bDoses equivalent to 0, 0.075, and 0.15% 1-methylnaphthalene in the diet; calculated HEDs appear in brackets.
Data are mean ± SD; n = 10 animals per group.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood
urea nitrogen; Ca = calcium; CI = chloride; CRN = creatinine; HED = human equivalent dose; SD = standard
deviation; TC = total cholesterol.
58
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-6. Select Organ Weights of Male and Female B6C3F1 gpt Delta
Mice Treated with 1-Methylnaphthalene in the Diet for 13 Weeks3
Endpoint
Males: ADD [HED] in (mg/kg-d)b
0
120 [17.1]
220 [31.1]
Necropsy body weight (g)
33.1 ± 1.8°
33.1 ±3.7 (±0%)d
30.7 ± 2 (-7%)
Liver weight
Absolute (g)
Relative (%)
1.35 ±0.1
4.09 ±0.27
1.32 ±0.18 (-2%)
3.99 ±0.19 (-2%)
1.21 ±0.11 (-10%)
3.93 ±0.23 (-4%)
Kidney weight
Absolute (g)
Relative (%)
0.46 ±0.08
1.38 ±0.24
0.45 ± 0.03 (-2%)
1.38 ±0.11 (±0%)
0.45 ± 0.04 (-2%)
1.47 ±0.12 (±7%)
Spleen
Absolute (g)
Relative (%)
0.09 ±0.01
0.27 ±0.04
0.07 ± 0.02* (-22%)*
0.21 ± 0.04 (-22%.)*
0.06 ± 0.01 (-33%.)**
0.21 ± 0.05 (-22%.)*
Heart weight
Absolute (g)
Relative (%)
0.97 ±0.06
2.94 ±0.21
0.81 ± 0.24 (-16%.)*
2.48 ± 0.77 (-16%)
0.72 ± 0.03 (-26%.)**
2.35 ± 0.19 (-20%.)**
Thymus weight
Absolute (g)
Relative (%)
0.03 ±0.01
0.09 ±0.02
0.03 ±0.01 (±0%)
0.08 ±0.04 (-11%)
0.03 ±0.01 (±0%)
0.08 ±0.01 (-11%)
Endpoint
Females: ADD [HED] in (mg/kg-d)
0
170 [23.1]
280 [37.7]
Necropsy body weight (g)
25.6 ± 1.4
25.5 ± 2.6 (-0%)
24.8 ± 1.3 (-3%)
Liver weight
Absolute (g)
Relative (%)
1.08 ±0.06
4.28 ±0.43
1.04 ± 0.06 (-4%)
4.12 ±0.29 (-4%)
1.00 ± 0.07 (-7%.)*
4.05 ± 0.27 (-5%)
Kidney weight
Absolute (g)
Relative (%)
0.34 ±0.02
1.33 ± 0.13
0.33 ± 0.02 (-3%)
1.29 ±0.11 (-3%)
0.33 ± 0.02 (-3%)
1.32 ±0.1 (-1%)
Spleen weight
Absolute (g)
Relative (%)
0.08 ±0.01
0.32 ±0.03
0.08 ±0.01 (±0%)
0.3 ± 0.04 (-6%)
0.07 ±0.01 (-13%)
0.3 ± 0.04 (-6%)
Heart weight
Absolute (g)
Relative (%)
0.13 ±0.01
0.51 ±0.02
0.12 ±0.01 (-8%)
0.49 ± 0.04 (-4%)
0.12 ±0.01 (-8%)
0.47 ± 0.04 (-8%)
Thymus weight
Absolute (g)
Relative (%)
0.04 ±0.01
0.14 ±0.02
0.04 ±0.01 (±0%)
0.15 ±0.02 (±7%)
0.08 ±0.10 (+100%.)**-e
0.35 ± 0.44 (±150%)
aJin et al. (2012).
bDoses equivalent to 0, 0.075, and 0.15% 1-methylnaphthalene in the diet; calculated HEDs appear in brackets.
Data are mean ± SD; n = 10 animals per group.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
eLymphoma was observed in one mouse.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Significantly different from control (p < 0.01) by Dunnett's test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation.
59
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Table B-7. Histopathological Changes in Male and Female B6C3F1 gpt Delta
Mice Treated with 1-Methylnaphthalene in the Diet for 13 Weeks3
Males
Endpoints
ADD [HED] in (mg/kg-d)b
0
120 [17.1]
220 [31.1]
Liver
Single cell necrosis
Focal necrosis
Vacuolization
0/10 (0%)c
0/10 (0%)
0/10 (0%)
3/10 (30%)
0/10 (0%)
0/10 (0%)
5/10 (50%)*
0/10 (0%)
0/10 (0%)
Females
Endpoints
ADD [HED] in (mg/kg-d)
0
170 [23.1]
280 [37.7]
Liver
Single cell necrosis
Focal necrosis
Vacuolization
7/10 (70%)
5/10 (50%)
0/10 (0%)
5/10 (50%)
5/10 (50%)
1/10 (1%)
5/10 (50%)
7/10 (70%)
3/10 (30%)
aJin et al. (2012).
bDoses equivalent to 0, 0.075, and 0.15% 1-methylnaphthalene in the diet; calculated HEDs appear in brackets.
°Values denote number of animals showing changes / total number of animals examined (% incidence).
* Significantly different from control (p < 0.01) by Fisher's exact test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose.
60
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Table B-8. Select Hematological Results in Male and Female B6C3F1 Mice
Fed 1-Methylnaphthalene in the Diet for 81 Weeks"
Endpoint
Males: ADD [HED] (mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
RBC (x 1CT3/|iL)c
8.42 ± 0.84d
8.13 ± 0.39 (-3%)e
8.49 ± 0.66 (+1%)
HGB (g/dL)°
14.1 ± 1.98
13.3 ±0.57 (-6%)
14 ± 1.23 (-1%)
HCT (%)c
40.5 ± 5.26
36.8 ± 1.8 (-9%)*
41 ±3.51 (+1%)
MCV (fL)°
48 ±2.7
45 ± 2.1 (-6%)*
48 ± 0.6 (+0%)
MCH (pg)c
16.7 ± 1.85
16.4 ± 0.8 (-2%)
16.5 ± 0.6 (-1%)
MCHC (%)c
35 ± 3.31
36.3 ± 1.68 (+4%)
34.2 ± 1.04 (-2%)
WBC (x 10_3/(iL)°
2.8 ± 1.22b
2.2 ±0.71 (-21%)°
2.9 ± 0.99 (+4%)
Leukocyte classification
Stab cell (%)f
0.42 ± 0.44
2.57 ± 1.5 (+512%)*
1.5 ± 0.98 (+257%)*
Segmented (%)f
13.77 ± 16
20.94 ± 13.63 (+52%)*
13.98 ± 8.42 (+2%)
Eosinophil (%)f
0.05 ± 0.28
0.13 ±0.36 (+160%)
0.04 ± 0.2 (-20%)
Basophil (%)f
0±0
0±0
0±0
Lymphocyte (%)e
85.61 ± 16.54
75.54 ± 14.51 (-12%)*
81.3 ± 8.91 (-5%)*
Monocyte (%)e
0.17 ±0.41
0.81 ± 0.9 (+376%)*
1.18 ±0.97 (+594%)*
Endpoint
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
RBC (x 1CT3/|iL)c
8.19 ±0.36
8.43 ± 0.23 (+3%)
8.31 ± 0.35 (+1%)
HGB (g/dL)°
12.8 ±0.87
14.4 ± 0.57 (+13%)*
14.2 ± 0.41 (+11%)*
HCT (%)c
38.3 ± 1.97
40.6 ± 3.89 (+6%)
39.2 ± 1.33 (+2%)
MCV (fL)°
47 ±0.6
47 ± 3.9 (+0%)
46 ± 1 (-2%)
MCH (pg)c
15.6 ±0.49
17.1 ± 0.21 (+10%)*
17 ± 0.69 (+9%)*
MCHC (%)c
33.2 ± 1.27
35.8 ± 2.08 (+8%)*
36.1 ± 0.75 (+9%)*
WBC (x lCT3/|iL)c
2.8 ±0.78
1.8 ±0.79 (-36%)
2.2 ± 0.42 (-21%)
Leukocyte classification
Stab cell (%)f
1.55 ±0.8
2.46 ± 1.49 (+59%)*
1.22 ± 1.01 (-21%)
Segmented (%)f
15.55 ±9.01
15.21 ± 8.32 (-2%)
10.86 ± 7.48 (-30%)*
Eosinophil (%)f
0.11 ±0.33
0.07 ± 0.26 (-36%)
0.14 ±0.42 (+27%)
Basophil (%)f
0±0
0±0
0±0
61
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-8. Select Hematological Results in Male and Female B6C3F1 Mice
Fed 1-Methylnaphthalene in the Diet for 81 Weeks3
Endpoint
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
Lymphocyte (%)f
82.35 ±9.35
81.37 ±8.52 (-1%)
86.69 ± 8.6 (+5%)*
Monocyte (%)f
0.42 ±0.51
0.91 ±0.95 (+117%)*
1.1 ± 1.15 (+162%)*
aMurata et al. (1993).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
°Number of animals = 4-15 per group.
dData are mean ± SD.
eValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
fNumber of animals = 49-50 per group.
* Significantly different from control (p < 0.05) by Student's /-test, as reported by the study authors.
ADD = adjusted daily dose; HCT = hematocrit; HED = human equivalent dose; HGB = hemoglobin; MCH = mean
corpuscular hemoglobin; MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular
volume; RBC = red blood cell; SD = standard deviation; WBC = white blood cell.
62
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Table B-9. Select Serum Chemistry Results in Male and Female
B6C3F1 Mice Fed 1-Methylnaphthalene in the Diet for 81 Weeks"
Endpoint
Males: ADD [HED] (mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
AST (U/L)
101 ±28cd
127 ± 66 (+26%)e
117 ± 136 (+16%)
ALT (U/L)
46 ±34
73 ± 86 (+59%)
74 ± 115 (+61%)
ALP (K-AU)
5.3 ± 1.68
5.2 ± 1.11 (-2%)
9.6 ± 14 (+81%)
LDH (U/L)
815 ±329
579 ±511 (-29%)
397 ± 246 (-51%)*
y-GTP (U/L)
5± 1.4
3 ± 2 (-40%)*
7 ± 7.1 (+40%)
TBIL (mg/dL)
0.4 ±0.259
0.2 ± 0.091 (-50%)*
0.2 ± 0.077 (-50%)
A/G ratio
0.37 ±0.025
0.32 ± 0.05 (-14%)*
0.4 ± 0.037 (+8%)*
Alb (g/dL)
1.6 ± 0.13
1.4 ± 0.25 (-13%)*
1.6 ± 0.14 (+0%)
BUN (mg/dL)
22 ±4.5
20 ± 6.5 (-9%)
18 ± 4.6 (-18%)*
Uric acid (mg/dL)
4 ±0.82
3.8 ±0.87 (-5%)
4.4 ± 1.53 (+10%)
Na (mEQ/L)
154 ±3
148 ± 4 (-4%)*
151 ± 4 (-2%)*
K (mEQ/L)
4.9 ±0.39
4.3 ± 0.3 (-12%)*
4.6 ± 0.34 (-6%)*
CI (mEQ/L)
119 ± 8
111 ±5 (-7%)*
116 ±5 (-3%)
Fe (|ig/dL)
151 ±32
107 ± 16 (-29%)*
145 ± 34 (-4%)
Lipid (mg/dL)
436 ± 85
512 ± 105 (+17%)*
441 ± 50 (+1%)
Phospholipid (mg/dL)
165 ± 40
190 ± 36 (+15%)
233 ± 200 (+41%)
Neutral fat (mg/dL)
81 ±22
101 ± 20 (+25%)*
83 ± 22 (+2%)
Cholesterol (mg/dL)
122 ±41
153 ± 53 (+25%)
128 ± 22 (+5%)
Esterified cholesterol ratio (%)f
90 ±4
91 ±3 (+1%)
88 ± 3 (-2%)
HDL cholesterol (mg/dL)
97 ±3
93 ± 5 (-4%)*
90 ± 13 (-7%)
(^-Lipoprotein (mg/dL)
260 ± 75
316 ± 104 (+22%)
263 ± 44 (+1%)
Lipid peroxide (nmol/dL)
4.1 ±0.97
3.7 ± 1 (-10%)
3.7 ±0.78 (-10%)
Endpoint
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
AST (U/L)
113 ±158
67 ± 6 (-41%)
182 ± 269 (+61%)
ALT (U/L)
38 ±20
33 ± 4 (-13%)
87 ± 164 (+129%)
ALP (K-AU)
9.6 ± 1.71
9 ± 1.96 (-6%)
10 ± 2.61 (+4%)
LDH (U/L)
435 ±386
457 ± 170 (+5%)
338 ± 190 (-22%)
y-GTP (U/L)
4 ±2.4
3 ± 0.9 (-25%)
6 ± 7.2 (+50%)
TBIL (mg/dL)
0.2 ±0.043
0.2 ± 0.033 (+0%)
0.2 ± 0.046 (+0%)
A/G ratio
0.35 ±0.07
0.45 ± 0.05 (+29%)*
0.39 ±0.037 (+11%)*
Alb (g/dL)
1.4 ±0.21
1.7 ±0.13 (+21%)*
1.6 ±0.13 (+14%)*
BUN (mg/dL)
19 ± 15
15 ±2.2 (-21%)
16 ±3.1 (-16%)
Uric acid (mg/dL)
3.8 ± 1.22
4.7 ± 1.31 (+24%)*
3.9 ± 1.15 (+3%)
Na (mEQ/L)
153 ±4
152 ± 1 (-1%)
152 ± 2 (-1%)
63
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-9. Select Serum Chemistry Results in Male and Female
B6C3F1 Mice Fed 1-Methylnaphthalene in the Diet for 81 Weeks3
Endpoint
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
K (mEQ/L)
4.2 ±0.43
4.2 ± 0.38 (±0%)
3.8 + 0.69 (-10%)
CI (mEQ/L)
115 ± 4
115 ± 2 (±0%)
115 ± 4 (+0%)
Fe (|ig/dL)
138 ±32
160 ± 28 (+16%)*
157 ± 26 (+14%)
Lipid (mg/dL)
430 ±48
473 ± 49 (+10%)*
467 ± 65 (+9%)
Phospholipid (mg/dL)
147 ±29
154 ± 22 (+5%)
171 +19 (+16%)*
Neutral fat (mg/dL)
111 ±22
130 ±31 (+17%)
138 + 44 (+24%)*
TC (mg/dL)
109 ± 20
121 ± 13 (+11%)*
114 ± 16 (+5%)
Esterified cholesterol ratio (%)
89 ±3
87 + 2 (-2%)*
86 + 3 (-3%)*
HDL cholesterol (mg/dL)
88 ± 19
92 ± 3 (+5%)
91 ± 16 (+3%)
(3-Lipoprotein (mg/dL)
229 ± 40
254 + 28 (+11%)*
242 ± 34 (+6%)
Lipid peroxide (mnol/dL)
3.4 ±0.57
3.9 + 0.7 (+15%)*
3.4 ± 0.62 (+0%)
aMurata et al. (1993).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
Data are mean ± SD.
dNumber of samples = 11-16, pooled sera from 3 or 4 mice.
eValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
* Significantly different from control (p < 0.05) by Student's /-test, as reported by the study authors.
ADD = adjusted daily dose; A/G = albumin to globulin ratio; Alb = albumin; ALP = alkaline phosphatase;
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CI = chloride;
Fe = iron; HED = human equivalent dose; y-GTP = gamma-glutamyl transpeptidase; HDL = high-density
lipoprotein; K = potassium; LDH = lactate dehydrogenase; Na = sodium; SD = standard deviation; TBIL = total
bilirubin; TC = total cholesterol.
64
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EPA/690/R-24/001F
Table B-10. Select Organ Weights of Male and Female B6C3F1 Mice Fed
1-Methylnaphthalene in the Diet for 81 Weeks"
Endpoint
Males: ADD [HED] (mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
Necropsy body weight (g)
41 ±3.6C
40 ± 3.7 (-2%)d
42 ± 3.4 (+2%)
Liver weight
Absolute (mg)
Relative6
1,667 ± 760
41.4 ± 21
1,664 ± 656 (-0%)
41.9 ±21.3 (+1%)
1,732 ± 484 (+4%)
41.5 ± 10.6 (+0%)
Kidney weight (right)
Absolute (mg)
Relative
310 ±32
7.7 ±0.8
303 ± 32 (-2%)
7.5 ± 0.9 (-3%)
295 ± 31 (-5%)*
7.1 ± 0.8 (-8%)*
Kidney weight (left)
Absolute (mg)
Relative
300 ±31
7.4 ±0.8
299 ± 37 (-0%)
7.4 ± 0.9 (+0%)
290 ±31 (-3%)
7 ± 0.6 (-5%)*
Brain weight
Absolute (mg)
Relative
425 ± 42
10.5 ± 1.5
455 ± 25 (+7%)*
11.3 ± 1.1 (+8%)*
457 ± 25 (+8%)*
11 ± 1 (+5%)*
Salivary gland weight
Absolute (mg)
Relative
316 ±48
7.8 ± 1.2
307 ± 42 (-3%)
7.6 ± 1 (-3%)
313 ±53 (-1%)
7.5 ± 1.3 (-4%)
Thymus weight
Absolute (mg)
Relative
48 ±22
1.2 ±0.6
49 ± 33 (+2%)
1.2 ± 0.8 (+0%)
51 ± 22 (+6%)
1.2 ±0.5 (+0%)
Heart weight
Absolute (mg)
Relative
177 ± 23
4.4 ±0.6
167 ± 20 (-6%)*
4.1 ±0.7 (-7%)*
162 ± 20 (-8%)*
3.9 ±0.4 (-11%)*
Lung weight
Absolute (mg)
Relative
292 ± 43
7.2 ±1.1
293 ± 45 (+0%)
7.3 ± 1.2 (+1%)
289 ± 60 (-1%)
6.9 ± 1.3 (-4%)
Spleen weight
Absolute (mg)
Relative
115±124
2.8 ±2.9
101 ± 40 (-12%)*
2.5 ± 1.1 (-11%)
112 ± 107 (-3%)
2.7 ± 2.6 (-4%)
Pancreas weight
Absolute (mg)
Relative
386±194
9.5 ±4.6
381 ± 97 (-1%)
9.5 ± 2.4 (+0%)
412 ± 183 (+7%)
9.9 ± 4.3 (+4%)
Testis weight (right)
Absolute (mg)
Relative
98 ± 12
2.4 ±0.3
99 ± 17 (+1%)
2.5 ± 0.4 (+4%)
103 ± 10 (+5%)*
2.5 ± 0.3 (+4%)
65
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-10. Select Organ Weights of Male and Female B6C3F1 Mice Fed
1-Methylnaphthalene in the Diet for 81 Weeks3
Endpoint
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
Testis weight (left)
Absolute (mg)
Relative
100 ± 13
2.5 ±0.5
103 ± 18 (±3%)
2.6 ± 0.5 (±4%)
102 ± 13 (±2%)
2.5 ± 0.3 (±0%)
Necropsy body weight (g)
45 ±7.5
46 ± 7.7 (±2%)
46 ± 6.6 (±2%)
Liver weight
Absolute (mg)
Relative
1,428 ±458
32.6 ± 16.3
1,348 ± 183 (-6%)
29.9 ±3.8 (-8%)
1,450 ± 192 (±2%)
32.3 ± 5.6 (-1%)
Kidney weight (right)
Absolute (mg)
Relative
224 ± 28
5 ± 1
205 ± 26 (-8%)*
4.6 ± 0.9 (-8%)*
213 ±28 (-5%)
4.8 ± 1.2 (-4%)
Kidney weight (left)
Absolute (mg)
Relative
219 ±30
5 ± 1.2
199 ± 27 (-9%)*
4.5 ± 0.9 (-10%)*
212 ±22 (-3%)
4.8 ± 1.1 (-4%)
Brain weight
Absolute (mg)
Relative
468 ± 27
10.6 ±2.2
469 ± 22 (±0%)
10.6 ± 2.2 (±0%)
460 ±31 (-2%)
10.3 ± 1.9 (-3%)
Salivary gland weight
Absolute (mg)
Relative
235 ± 74
5.2 ± 1.5
192 ± 34 (-18%)*
4.3 ± 1.1 (-17%)*
190 ± 44 (-19%)*
4.2 ± 0.9 (-19%)*
Thymus weight0 ,1
Absolute (mg)
Relative
82 ±58
1.8 ±1.1
53 ± 25 (-35%)*
1.2 ± 0.6 (-33%)*
54 ± 29 (-34%)*
1.2 ± 0.6 (-33%)*
Heart weight
Absolute (mg)
Relative
131 ±20
2.9 ±0.8
122 ± 22 (-7%)*
2.7 ± 0.8 (-7%)
123 ± 18 (-6%)*
2.7 ± 0.7 (-7%)
Lung weight
Absolute (mg)
Relative
309 ±67
6.9 ± 1.6
279 ± 64 (-10%)*
6.3 ±2.1 (-9%)*
293 ± 129 (-5%)
6.9 ± 5.9 (±0%)
Spleen weight
Absolute (mg)
Relative
153 ±222
3.7 ±7.2
118 ±36 (-23%)
2.7 ± 1 (-27%)
134 ± 77 (-12%)
3.1 ±2.2 (-16%)
Pancreas weight
Absolute (mg)
Relative
366±175
8.2 ±3.6
330 ± 63 (-10%)
7.3 ±1.7 (-11%)
306 ± 81 (-16%)*
6.8 ± 2 (-17%)*
aMurata et al. (1993).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
Data are mean ± SD; n = 49-50 animals per group.
dValue in parentheses is % change relative to control = ([treatment mean - control mean] control mean) x 100.
eReported as ratio to body weight x 103.
* Significantly different from control (p < 0.05) by Student's /-test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose; SD = standard deviation.
66
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EPA 690 R-24 001F
Table B-ll. Incidence of Nonneoplastic Lung Lesions in B6C3F1 Mice Fed
1-Methylnaphthalene in the Diet for 81 Weeks3
Observation
Males: ADD [HED]
(mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
Pulmonary alveolar proteinosis
4/49 (8.2%)°
23/50 (46.0%)*
19/50 (38.0%.)*
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
Pulmonary alveolar proteinosis
5/50 (10.0%)
23/50 (46.0%.)*
17/49 (34.7%.)*
aMurata et al. (1993).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
°Values denote number of animals showing changes / total number of animals examined (% incidence).
* Significantly different from control (p < 0.01) value by x2 test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose.
Table B-12. Tumor Incidences in the Lungs of B6C3F1 Mice Fed
1-Methylnaphthalene in the Diet for 81 Weeks3
Observation
Males: ADD [HED] (mg/kg-d)b
0
71.6 [10.7]
140 [21.1]
Lung adenoma
2/49 (4.1%)°
13/50 (26.0%.)*
12/50 (24.0%.)*
Lung adenocarcinoma
0/49 (0%)
0/50 (0%)
3/50 (6.0%)
Combined lung adenoma or adenocarcinoma
2/49 (4.1%)
13/50 (26.0%.)*
15/50 (30.0%.)*
Females: ADD [HED] (mg/kg-d)
0
75.1 [11.1]
144 [20.9]
Lung adenoma
4/50 (8.0%)
2/50 (4.0%)
4/49 (8.2%)
Lung adenocarcinoma
1/50 (2.0%)
0/50
1/49 (2.0%)
Combined lung adenoma or adenocarcinoma
5/50 (10.0%)
2/50 (4.0%)
5/50 (10.2%)
aMurata et al. (1993).
bADD (mg/kg-day) values were reported by the study authors; calculated HEDs appear in brackets.
°Values denote number of animals showing changes / total number of animals examined (% incidence).
* Significantly different from control (p < 0.01) value by y; test, as reported by the study authors.
ADD = adjusted daily dose; HED = human equivalent dose.
67
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table B-13. Select Hematological and Serum Biochemistry Results in Male
and Female F344 Rats Exposed to 1-Methylnaphthalene Vapors for
6 Hours/Day, 5 Days/week for 13 Weeks3
Endpoint
Analytical Concentration [HECer]1" in mg/m3
0
3.0 [0.540]
23.7 [4.237]
179.3 [31.552]
Males
APTT (s)
17.5 ± 1.7°
18 ± 0.8 (±3%)d
18.6 ± 0.8 (±6%)
18.9 ± 0.5 (+8%)*
PT (s)
10.2 ±0.3
10.5 ± 0.4 (±3%)
10.6 ± 0.3 (±4%)
11.2 ±0.6 (+10%)**
ALT (IU/L)
50.8 ±5.6
51.2 ±8.8 (±1%)
45.2 ±4.6 (-11%)
42.9 ± 5.8 (-16%)*
AST (IU/L)
91.5 ± 13.1
95.7 ± 12.8 (±5%)
88.7 ± 10.6 (-3%)
89.5 ± 36 (-2%)
ALP (IU/L)
456 ±27.5
445.6 ± 35.2 (-2%)
455.9 ± 43 (-0%)
443 ± 44.9 (-3%)
Alb (g/dL)
4.1 ± 0.1
4.2 ±0.1 (±2%)
4.1 ±0.1 (±0%)
4.3 ±0.2 (+5%)**
Na (mmol/L)
144.3 ±0.8
144.6 ± 0.8 (±0%)
145.1 ± 1 (±1%)
145.7 ±1.8 (+1%)*
Endpoint
Analytical Concentration [HECer] in mg/m3
0
3.0 [0.540]
23.7 [4.237]
179.3 [31.552]
Females
APTT (s)
17.9 ±0.8
18.5 ± 1.4 (±3%)
18.2 ± 1 (±2%)
19.1 ±0.6 (±7%)
PT (s)
9.9 ±0.4
10 ± 0.6 (±1%)
10.1 ±0.2 (±2%)
10.7 ±0.7 (+8%)**
ALT (IU/L)
38.4 ±7.2
44.7 ± 11.3 (±16%)
40.9 ± 11 (±7%)
38.8 ± 5.2 (±1%)
AST (IU/L)
81.6 ± 14.6
94.5 ± 18.4 (±16%)
86.5 ± 12.6 (±6%)
81.9 ±7.3 (±0%)
ALP (IU/L)
362.5 ±33.3
365.6 ± 50.9 (±1%)
367 ± 32 (±1%)
365.3 ± 51.8 (±1%)
Alb (g/dL)
4.3 ±0.2
4.4 ± 0.2 (±2%)
4.3 ± 0.2 (±0%)
4.2 ± 0.2 (-2%)
Na (mmol/L)
146.3 ± 1.3
147.2 ± 2.4 (±1%)
146.1 ± 0.6 (-0%)
146.4 ± 0.9 (±0%)
aKim et al (2020V
bReported concentrations; calculated HECer values appear in brackets. Systemic effects from inhalation exposure
to 1-methylnaphthalene were considered to be extrarespiratory effects of a Category 3 gas, as defined in the
U.S. EPA guidance for deriving RfCs (U.S. EPA. 1994). Following this guidance, experimental exposures were
adjusted to a mg/m3 basis (3.0, 23.7, and 179.3 mg/m3), adjusted to a continuous exposure basis
(mg/m3 x 6 hours/24 hours x 5 days/7 days = mg/m3 x 0.1786: 0, 0.540, 4.237 and 31.552 mg/m3), and converted
to HECs by multiplying the adjusted concentrations by the ratio of rat :human blood/gas partition coefficients.
Because the blood/gas coefficients for 1-methylnaphthalene were not available, the default ratio of 1 was used.
Data are mean ± SD; n = 10/group.
dValue in parentheses is percent change relative to control = ([treatment mean - control mean] + control
mean) x 100.
* Significantly different from control (p < 0.05) by Dunnett's test, as reported by the study authors.
**Statistically different from control (p < 0.01) by Dunnett's test, as reported by the study authors.
Alb = albumin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; APTT = activated partial
thromboplastin time; AST = aspartate aminotransferase; HEC = human equivalent concentration; HECer = human
equivalent concentration based on extrarespiratory effects; Na = sodium; PT = prothrombin time; RfC = oral
reference concentration; SD = standard deviation; U.S. EPA = U.S. Enviromnental Protection Agency.
68
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EPA 690 R-24 001F
Table B-14. Incidence and Severity of Histopathological Lesions in
Nasopharyngeal Tissues in F344 Rats Exposed to 1-Methylnaphthalene
Vapors for 6 Hours/Day, 5 Days/week for 13 Weeks3
Lesion and Severity
Analytical Concentration [HECet]1" in mg/m3
0
3.0 [0.099]
23.7 [0.773]
179.3 [5.833]
Males
Hyperplasia, mucous cell in
nasopharyngeal tissues
Minimal
0/10 (0%)c
4/10 (40%)*
4/10 (40%)*
0/10 (0%)
Mild
0/10 (0%)
0/10 (0%)
6/10 (60%)*
0/10 (0%)
Moderate
0/10 (0%)
0/10 (0%)
0/10 (0%)
10/10 (100%)*
Total
0/10 (0%)
4/10 (40%)*
10/10 (100%)*
10/10 (100%)*
Hyperplasia, transitional epithelial cell
in nasopharyngeal tissues
Minimal
0/10 (0%)
0/10 (0%)
5/10 (50%)*
5/10 (50%)*
Mild
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
Moderate
0/10 (0%)
0/10 (0%)
0/10 (0%)
0/10 (0%)
Total
0/10 (0%)
0/10 (0%)
5/10 (50%)*
5/10 (50%)*
Lesion and Severity
Analytical Concentration [HECet] in mg/m3
0
3.0 [0.065]
23.7 [0.510]
179.3 [3.736]
Females
Hyperplasia, mucous cell in
nasopharyngeal tissues
Minimal
0/10 (0%)
0/10 (0%)
3/10 (30%)
2/10 (20%)
Mild
0/10 (0%)
0/10 (0%)
0/10 (0%)
6/10 (60%)*
Moderate
0/10 (0%)
0/10 (0%)
0/10 (0%)
2/10 (20%)
Total
0/10 (0%)
0/10 (0%)
3/10 (30%)
10/10 (100%)*
aKim et al. (2020).
bReported concentrations; calculated HECet values appear in brackets.
0Values denote number of animals showing changes/total number of animals examined (% incidence).
* Significantly different from control by Fisher's exact test (one-sided p < 0.05) conducted for this review.
HECet = human equivalent concentration based on extrathoracic effects.
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EPA 690 R-24 001F
APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODELING PROCEDURE
Dichotomous Noncancer Data
The benchmark dose (BMD) modeling of dichotomous data is conducted with the
U.S. Environmental Protection Agency (U.S. EPA) Benchmark Dose Software (BMDS)
(Version 3.2 was used for this document). For these data, the Gamma, Logistic, Log-Logistic,
Log-Probit, Multistage, Probit, and Weibull dichotomous models available within the software
are fit using a benchmark response (BMR) of 10% extra risk. The Dichotomous Hill model was
not considered for the derivation of a point of departure (POD) because it has four parameters
and requires a data set with a minimum of five data points (including control). Alternative BMRs
may also be used where appropriate, as outlined in the Benchmark Dose Technical Guidance
(U.S. EPA 2012). In general, the BMR should be near the low end of the observable range of
increased risk in the study. BMRs that are too low can result in widely disparate benchmark dose
lower confidence limit (BMDL) estimates from different models (high model-dependence).
Adequacy of model fit is judged based on the %2 goodness-of-fit /rvalue (p > 0.1), magnitude of
scaled residuals for the dose group nearest to the BMD (absolute value < 2.0), and visual
inspection of the model fit. Among all models providing adequate fit, the BMDL from the model
with the lowest Akaike's information criterion (AIC) is selected as a potential POD if the
BMDLs are sufficiently close (less than threefold); if the BMDLs are not sufficiently close
(greater than threefold), model-dependence is indicated, and the model with the lowest reliable
BMDL is selected.
Cancer Data
The model-fitting procedure for dichotomous cancer incidence is as follows. The
Multistage cancer model in the U.S. EPA's BMDS (Version 3.2) is fit to the incidence data using
the extra risk option. The Multistage cancer model is run for all polynomial degrees up to n-1
(where n is the number of dose groups including control). An adequate model fit is judged by
three criteria: (1) goodness-of-fit /rvalue (p < 0.1); (2) visual inspection of the dose-response
curve; and (3) scaled residual at the data point (except the control) for the dose group nearest to
the BMD (absolute value <2.0). Among all of the models providing adequate fit to the data, the
BMDL for the model with the lowest AIC is selected as the POD. In accordance with the U.S.
EPA (2012) and U.S. EPA (2005) guidance, BMD and BMDL values associated with an extra
risk of 10% are calculated, which should be within the observable range of increased risk in a
cancer bioassay. Modeling is performed for each individual tumor type with at least a
statistically significant trend. Where applicable, the MS Combo model is used to evaluate the
combined cancer risk of multiple tumor types. MS Combo is run using the incidence data for the
individual tumor types and the polydegrees identified in the model runs for the individual tumor
types.
Continuous Data
The BMD modeling of continuous data is conducted with the U.S. EPA's BMDS
(Version 3.2) as well. For these data, the Exponential, Linear, Polynomial, and Power continuous
models were fit using a standard reporting BMR of 1 standard deviation (SD) relative risk or
10% relative deviation as outlined in the Benchmark Dose Technical Guidance (U.S. EPA.
2012). The continuous Hill model was not considered for the derivation of a POD because it has
five parameters and requires a data set with a minimum of six data points (including control). An
70
1 -Methylnaphthalene
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EPA 690 R-24 001F
adequate fit is judged based on the %2 goodness-of-fit p value (p > 0.1), magnitude of the scaled
residuals for the dose group nearest to the BMD (absolute value <2.0), and visual inspection of
the model fit. In addition to these three criteria forjudging adequacy of model fit, a
determination was made as to whether the variance across dose groups was constant. If a
constant variance model was deemed appropriate based on the statistical test provided in BMDS
(i.e., Test 2; />-value > 0.1), the final BMD results were estimated from a constant variance
model. If the test for homogeneity of variance was rejected (p-value <0.1), the model was run
again while modeling the variance as a power function of the mean to account for this
nonconstant variance. If this nonconstant variance model did not adequately fit the data
(i.e., Test 3; />-value <0.1), the data set was considered unsuitable for BMD modeling. Among
all models providing adequate fit, the lowest BMDL has been selected if the BMDLs estimated
from different models varied by greater than threefold; otherwise, the BMDL from the model
with the lowest AIC has been selected as a potential POD from which to derive the proposed
reference value.
BMD MODELING TO IDENTIFY POTENTIAL PODS FOR DERIVATION OF A
SCREENING SUBCHRONIC PROVISIONAL REFERENCE DOSE (p-RfD)
Increased Relative Liver Weight in Male Sprague Dawley Crl:CD Rats Exposed to
1-Methylnaphthalene by Gavage for 42 Days (METI, 2009b)
The procedure outlined above for continuous data was applied to the data for increased
relative liver weight in male Sprague Dawley Crl:CD rats orally exposed to 1-methylnaphthalene
for 42 days (METI. 2009b). The constant variance model did not provide adequate fit to the
variance data (test 2 /;-value <0.1), but the nonconstant variance model did. With the
nonconstant variance model applied, all available models provided adequate fit to the means,
except for the Exponential 5 model. Visual inspection of the dose-response curves suggested
adequate fit, and scaled residuals did not exceed ±2 units at the data point closest to the BMD.
BMDLs for models providing adequate fit were sufficiently close (differed by less than
threefold), so the model with the lowest AIC was selected (Polynomial 2-degree). The
Polynomial 2-degree model estimated human equivalent benchmark dose with 10% relative
deviation (BMDo.ird) and benchmark dose lower confidence limit with 10% relative deviation
(BMDLo.ird) values of 44.79 and 24.12 mg/kg-day, respectively. The results of the BMD
modeling are summarized in Table C-l and plotted in Figure C-l.
Table C-l. BMD Modeling Results (Nonconstant Variance) for Increased
Relative Liver Weight in Male Sprague Dawley Crl:CD Rats Exposed to
1-Methylnaphthalene by Gavage for 42 Days3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual
at Dose Nearest
BMD
AIC
BMDo.ird
(mg/kg-d)
HED
BMDLo.ird
(mg/kg-d)
HED
Exponential (model 2)°
0.54
0.35
-0.86
3.69
30.08
22.32
Exponential (model 3)°
0.54
0.62
-0.00017
3.85
61.29
25.20
Exponential (model 4)°
0.54
0.12
-0.95
6.05
28.46
17.82
Exponential (model 5)°
0.54
NA
-0.00036
5.85
61.32
14.69
Polynomial (3-degree)d
0.54
0.62
-0.0062
3.84
51.81
24.46
Polynomial (2-degree)d*
0.54
0.84
0.0071
1.94
44.79
24.12
71
1 -Methylnaphthalene
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EPA 690 R-24 001F
Table C-l. BMD Modeling Results (Nonconstant Variance) for Increased
Relative Liver Weight in Male Sprague Dawley Crl:CD Rats Exposed to
1-Methylnaphthalene by Gavage for 42 Days3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual
at Dose Nearest
BMD
AIC
BMDo.ird
(mg/kg-d)
HED
BMDLo.ird
(mg/kg-d)
HED
Power0
0.54
0.62
-0.0026
3.85
54.58
24.45
Linear"1
0.54
0.30
-0.95
4.05
28.62
20.37
aMETI (2009b).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be positive.
* Selected model. The constant variance model did not provide adequate fit to the variance data, but the nonconstant
variance model did. With the nonconstant variance model applied, all models except the Exponential 5 model
provided adequate fit to the means. BMDLs for models providing adequate fit were sufficiently close (differed by
-------
EPA/690/R-24/001F
BMD Model Output of Polynomial 2-Degree Model for Increased Relative Liver Weight in
Male Sprague Dawley Crl:CD Rats Exposed to 1-Methvlnaphthalene by Gavage for
42 Days TMETL 2009b)
Frequentist Polynomial Degree 2 Restricted
User Input
Info
Model
frequentist Polynomial degree 2 vi.l
Dataset Name
Relative Liver Weights in Males
User notes
[Add user notes here]
Dose-Response Model
M[dose] =g + bl*dose + b2*doseA2 + ...
Variance Model
Var[i] = alpha * mean[i] A rho
Model Options
BMR Type
Rel. Dev.
BMRF
0.1
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Non-Constant
Model Data
Dependent Variable
HED
Independent Variable
mean
Total # of Observations
4
Adverse Direction
Upward
73
1 -Methylnaphthalene
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EPA/690/R-24/001F
Model Results
Benchmark Dose
BMD
44.79469795
BMDL
24.12204139
BMDU
5B.7608522B
AIC
1.943404034
Test 4 P-value
0.844416786
D.O.F.
2
Model Parameters
# of Parameters
5
Variable
Estimate
a
2.65BB6B348
betal
Bounded
beta 2
0.000132509
rho
6 009127996
alpha
-9.135257856
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Observed
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
7
2.65886834S
2.628
2.628
0.196D3462
0.233
0.233
-0.41660994
2.6
12
2.659907215
2.678
2.678
0.19626484
0.223
0.223
0.319340154
14
12
2.6B4840031
2.685
2.685
0.20184444
0.17
0.17
0.002745434
70.1
7
3.3i::i6!62
3.309
3.309
0.3785 8821
0.416
0.416
-0.00710631
Likelihoods of Interest
# of
Model
Log Likelihood"
Parameters
AIC
A1
-0.034941499
5
ID.069883
A2
3.810519056
8
8.37896189
A3
3.19740706B
6
5.60518586
fitted
3,028297983
4
1.94340403
R
-13.72096852
2
31.441937
Includes addi
ve constant of -34.91966. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of Interest
Test
2*Log(Likelihoo
d Ratio)
Test df
p-value
1
35.06297515
6
<0.0001
2
7.69092111
3
0.052B5056
3
1.226223977
2
0.5416626
4
0.338218169
2
0.B4441679
Increased Relative Liver Weights in Female Sprague Dawley Crl:CD Rats Exposed to
1-Methylnaphthalene via Gavage for 42 Days (METI, 2009b)
The procedure outlined above for continuous data was applied to the data for increased
relative liver weight in female Sprague Dawley Crl:CD rats orally exposed to
1-methylnaphthalene for 42 days (METI. 2009b). The constant variance model did not provide
adequate fit to the variance data (test 2 p-value < 0.1), but the nonconstant variance model did.
With the nonconstant variance model applied, all available models provided adequate fit to the
means, except for the Exponential 5 model. Visual inspection of the dose-response curves
suggested adequate fit and scaled residuals did not exceed ±2 units at the data point closest to the
BMD. BMDLs for models providing adequate fit were sufficiently close (differed by less than
threefold), so the model with the lowest AIC was selected (Polynomial 3-degree). The
Polynomial 3-degree model estimated human equivalent BMDo.ird and BMDLo.ird values of
74
1 -Methylnaphthalene
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EPA 690 R-24 001F
62.40 and 42.30 mg/kg-day, respectively. The results of the BMD modeling are summarized in
Table C-2 and plotted in Figure C-2.
Table C-2. BMD Modeling Results (Nonconstant Variance) for Increased
Relative Liver Weight in Female Sprague Dawley Crl:CD Rats Exposed to
1-Methylnaphthalene by Gavage for 42 Days3
Model
Variance
/>-Valucb
Means
/>-Valucb
Scaled Residual
at Dose Nearest
BMD
AIC
BMDo.ird
(mg/kg-d)
HED
BMDLo.ird
(mg/kg-d)
HED
Exponential (model 2)°
0.33
0.44
0.16
9.21
58.03
39.35
Exponential (model 3)°
0.33
0.68
-0.00022
9.74
63.54
42.79
Exponential (model 4)°
0.33
0.19
0.19
11.31
58.11
33.29
Exponential (model 5)°
0.33
NA
-0.00032
11.74
63.14
14.23
Polynomial (3-degree)d*
0.33
0.90
-0.0013
7.78
62.40
42.30
Polynomial (2-degree)d
0.33
0.83
-0.042
7.95
60.73
41.52
Power0
0.33
0.68
0.00032
9.74
63.80
42.42
Linear"1
0.33
0.42
0.19
9.31
58.07
36.85
aMETI (2009b).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
Coefficients restricted to be positive.
* Selected model. The constant variance model did not provide adequate fit to the variance data, but the nonconstant
variance model did. With the nonconstant variance model applied, all models except the Exponential 5 model
provided adequate fit to the means. BMDLs for models providing adequate fit were sufficiently close (differed by
-------
EPA/690/R-24/001F
Frequentist Polynomial Degree 3 Model with BMR of 0.1 Rel.
Dev. for the BMD and 0.95 Lower Confidence Limit for the
BiMDL
4
3.5
(D$ 0 —
£ 2.5
C
0 2
Q.
1 1.5
1
0.5
0
0 10 20 30 40
Dose
Figure C-2. Fit of Polynomial 3-Degree Model to the Data for Increased Relative Liver
Weight in Female Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene by
Gavage for 42 Days (METI, 2009b)
BMD Model Output of Polynomial 3-Degree Model for Increased Relative Liver Weight in
Female Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene by Gavage for
42 Days (METL 2009b)
Frequentist Polynomial Degree 3 Restricted
User Input
Info
Model
frequentist Polynomial degree 3 vl.l
Dataset Name
Relative Liver Weights in Females
User notes
[Add user notes here]
Dose-Response Model
M[dose] = g + bl'dose + b2*doseA2 +...
Variance Model
Var[i] = alpha *mean[i] Arho
Model Options
BMR Type
Rel. Dev.
BMRF
0.1
Tail Probability
-
Confidence Level
0.95
Distribution Type
Normal
Variance Type
Non-Constant
Model Data
Dependent Variable
[Custom]
Independent Variable
[Custom]
Total # of Observations
4
Adverse Direction
Upward
^—Estimated Probability
^—Response at BMD
O Data
—.BMD
BMDL
50 60
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EPA/690/R-24/001F
Model Results
Benchmark Dose
BMD
62.40411377
BMDL
42.29521502
BMDU
91.70616072
AIC
7.77746S742
Test 4 P-value
0.901815633
D.O.F.
2
Model Parameters
#of Parameters
6
Variable
Estimate
£
3.178293321
betal
Bounded
beta2
Bounded
beta 3
1.30784E-06
rho
10.24-003463
alpha
-14.96157255
Goodness of Fit
Dose
Size
Estimated
Median
Calc'd
Median
Obse rved
Mean
Estimated
SD
Calc'd SD
Observed
SD
Scaled
Residual
0
11
3.173293321
3.193
3.193
0.21-007 66
0.227
0.227
0.23213455
2.6
S
3.178316307
3.143
3.148
0.2100844
0.275
0.275
-0.4-0815728
13
12
3.131166642
3.133
3.133
0.2110508
0.169
0.169
0.11215996
&4
11
3.521135321
3.521
3.521
0.3549448
0.373
0.373
-0.00126445
Li kel i hoods of 1 nterest
1
#of
Model
Log Likelihood*
Parameters
AIC
A1 ^
-2.343937716
5
14.697375
A2
1.330142963
8
13.339714
A3
0.214610302
6
11.570778
fitted
0.111265629
4
7.7774637
R
-3.625073633
2
21.250147
* Includes additive constant of-3 S. 59542. This constant was not included in the LL derivation prior to BMDS 3.0.
Tests of 1 nterest
-2*Logl Likelihood
Test
Ratio)
T est df
p-value
i ^
19.9104332
6
0.0023729
2
7.353161357
3
0.0613171
3 1
2.231064321
2
0.32774-03
4
0.206690346
2
0.9013156
Increased Absolute Liver Weights and Increased Relative Kidney Weights in Male
Sprague Dawley Crl:CD Rats Exposed to 1-Methylnaphthalene via Gavage for 42 Days
(MKTL 2009b)
BMD modeling results of the data for increased absolute liver weights in male rats or
increased relative kidney weights in male rats (MET! 2009b) indicated that there was no
significant dose-response (test 1 p-value > 0.05); therefore, BMD modeling of these data sets
was not pursued.
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BENCHMARK CONCENTRATION (BMC) MODELING TO IDENTIFY POTENTIAL
PODS FOR DERIVATION OF A SUBCHRONIC PROVISIONAL REFERENCE
CONCENTRATION
Increased Incidence of Mucous Cell Hyperplasia in Nasopharyngeal Tissues in Male F344
Rats Exposed to 1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day,
5 Days/Week) (Kim et al., 2020)
The procedure outlined above for dichotomous noncancer data was applied to the
incidence data for mucous cell hyperplasia in nasopharyngeal tissues in male F344 rats exposed
to 1-methylnaphthalene via inhalation (vapor) for 13 weeks (6 hours/day, 5 days/week) (Kim et
al.. 2020). All the models provided an adequate fit according to the %2 goodness-of-fit p-value
(p > 0.1), and scaled residuals did not exceed ± 2 units at the data point closest to the BMC
(see Table C-3). However, the benchmark concentration lower confidence limit (BMCL)
computation for the Weibull model failed so it was not considered for POD derivation. The
BMCLs for the remaining models were not sufficiently close (differed by greater than
approximately threefold), so the model with the lowest BMCL was selected (Multistage
[degree = 1]). Figure C-3 shows the fit of the Multistage (degree =1) model to the data. Based
on human equivalent concentrations (HECs), the 10% benchmark concentration (BMCio) and
10% benchmark concentration lower confidence limit (BMCLio) for increased incidence of
mucous cell hyperplasia in nasopharyngeal tissues in male F344 rats were 0.018 and
0.009 mg/m3, respectively.
Table C-3. BMC Modeling Results for Increased Incidence of Mucous Cell
Hyperplasia in Nasopharyngeal Tissues in Male F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day,
5 Days/Week)3
Model
X2 Goodness-
of-fit />-valueb
AIC
Scaled Residual at
Dose Nearest BMC
BMCio
(mg/m3)
HEC
BMCLio
(mg/m3)
HEC
Gamma0
1.00
17.46
-0.000755448
0.042
0.010
Log-logisticd
1.00
17.46
-0.000457297
0.067
0.011
Multistage (degree = 3)e
1.00
19.46
-0.000390256
0.030
0.010
Multistage (degree = 2)e
1.00
17.46
-0.000390256
0.028
0.010
Multistage (degree = l)e *
0.98
15.74
-0.000390256
0.018
0.009
78
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Table C-3. BMC Modeling Results for Increased Incidence of Mucous Cell
Hyperplasia in Nasopharyngeal Tissues in Male F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day,
5 Days/Week)3
Model
X2 Goodness-
of-fit />-valucb
AIC
Scaled Residual at
Dose Nearest BMC
BMCio
(mg/m3)
HEC
BMCLio
(mg/m3)
HEC
Weibull0
1.00
17.47
-0.001761315
0.029
0f
Logistic
0.76
17.40
0.538780371
0.051
0.029
Log-probitd
1.00
17.46
-0.000303782
0.060
0.010
Probit
0.29
21.66
0.825377764
0.087
0.057
aKim et al. (2020).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
dSlope restricted to be >1.
eBetas restricted to be >0.
fBMCL computation failed.
* Selected model. All models provided adequate fit to the data, but the Gamma, Multistage, Log-probit, and
Weibull models were not considered for POD derivation due to issues with the BMCLs. BMCLs for the remaining
models were not sufficiently close (differed by >threefold), so the one of these with the lowest BMCL
(Log-logistic) was selected.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = 10% benchmark concentration;
BMCL = benclunark concentration lower confidence limit; BMCLio = 10% benclunark concentration lower
confidence limit; HEC = human equivalent concentration; POD = point of departure.
Frequentist Multistage Degree 1 Model with BMR of 10%
Extra Risk for the BMC and 0.95 Lower Confidence Limit
for the BMCL
Estimated Probability
^—Response at BMC
— — Linear Extrapolation
O Data
BMC
BMCL
Dose
Figure C-3. Fit of Multistage (degree = 1) Model to the Data for Increased Incidence of
Mucous in Nasopharyngeal Tissues Cell Hyperplasia in Male F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)
(Kim et al., 2020)
79
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
BMD Model Output of Multistage (degree = 1) Model for Increased Incidence of Mucous
Cell Hyperplasia in Nasopharyngeal Tissues in Male F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)
(Kim et al., 2020)
Frequentist Multistage Degree 1 Restricted
User Input
Info
Model
frequentist Multistage degree lvl.l
Dataset Name
Total mucous cell hyperplasia Male rats
User notes
[Add user notes here]
Dose-Response Model
P[dose] =g + (l-g)*[l-exp(-bl*doseAl-b2*doseA2-...)
Model Options
RiskType
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
[Custom]
Independent Variable
[Custom]
Total # of Observations
4
80
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Model Results
Benchmark Dose
BMC
0.018083913
BMCL
0.009475298
BMCU
0.034878884
AIC
15.74287758
P-value
0.982050735
D.O.F.
3
.-.1.2 T
Chi
0.171518085
Slope Factor
10.5537579
Model Parameters
# of Parameters
2
Variable
Estimate
g
Bounded
bl
5.826201507
The value of this parameter, 1.52299795127603E-08,
is within the tolerance of the bound
(see user guide for tolerance limits)
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.523E-08
1.523E-07
0
10
-0.0003903
0.099
0.438303699
4.383036988
4
10
-0.2441194
0.773
0.988931519
9.889315192
10
10
0.3345499
5.833
1
10
10
10
1.333E-07
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-6.73011667
4
-
-
NA
Fitted Model
-6.871438792
1
0.28264424
3
0.9632589
Reduced Model
-26.92046668
1
40.3807
3
<0.0001
Increased Incidence of Transitional Cell Hyperplasia in Male F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)
(Kim et al., 2020)
The procedure outlined above for dichotomous noncancer data was applied to the
incidence data for transitional cell hyperplasia in male F344 rats exposed to 1-methylnaphthalene
via inhalation (vapor) for 13 weeks (6 hours/day, 5 days/week) (Kim et al.. 2020). Only the
Log4ogistic and Log-probit models provided an adequate fit according to the %2 goodness-of-fit
/rvalue (p > 0.1) and scaled residuals (see Table C-4). However, the BMC/BMCL ratio for the
Log-probit model was >20; therefore, this model was not considered for derivation of a POD,
leaving only the Log-logistic model as a viable alternative. Figure C-4 shows the fit of the
Log-logistic model to the data. Based on HECs, the BMCio and BMCLio for increased incidence
of transitional cell hyperplasia in male F344 rats were 0.26 and 0.12 mg/m3, respectively.
81
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Table C-4. BMC Modeling Results for Increased Incidence of Transitional
Cell Hyperplasia in Male F344 Rats Exposed to 1-Methylnaphthalene via
Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)3
Model
x2
Goodness-
of-fit
/>-valucb
AIC
Scaled Residual at
Dose Nearest BMC
BMCio
(mg/m3)
HEC
BMCLio
(mg/m3)
HEC
Gamma0
0.003
40.75
3.06
0.51
0.30
Log-logisticd*
0.109
35.49
-0.65
0.26
0.12
Multistage (degree = 3)e
0.003
40.75
3.06
0.51
0.30
Multistage (degree = 2)e
0.003
40.75
3.06
0.51
0.30
Multistage (degree = l)e
0.003
40.75
3.06
0.51
0.30
Weibull0
0.003
40.75
3.06
0.51
0.30
Logistic
0.005
43.43
2.71
1.72
1.05
Log-probitd
0.177
35.84
-0.96
0.12
0.001f
Probit
0.005
43.29
2.72
1.61
1.01
aKim et al. (2020).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
dSlope restricted to be >1.
eBetas restricted to be >0.
fBMC/BMCL ratio is >20.
* Selected model. Only the Log-logistic and Log-probit models provided an adequate fit to the data. The Log-probit
model was not considered for POD derivation because the BMC/BMCL ratio was >20, so the Log-logistic was
selected.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = 10% benchmark concentration;
BMCL = benclunark concentration lower confidence limit; BMCLio = 10% benclunark concentration lower
confidence limit; HEC = human equivalent concentration; POD = point of departure.
82
1 -Methylnaphthalene
-------
EPA/690/R-24/001F
Frequentist Log-Logistic Model with BMR of 10% Extra Risk for
the BMC arid 0.95 Lower Confidence Limit for the BMCL
^—Estimated Probability
^—Response at BMC
0 Data
—BMC
BMCL
Dose
Figure C-4. Fit of Log-Logistic Model to the Data for Increased Incidence of Transitional
Cell Hyperplasia in Male F344 Rats Exposed to 1-Metliylnaphthalene via Inhalation
(Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week) (Kim et al., 2020)
BMD Model Output of Log-Logistic Model for Increased Incidence of Transitional Cell
Hyperplasia in Male F344 Rats Exposed to 1-Methylnaphthalene via Inhalation (Vapor)
for 13 Weeks (6 Hours/Day, 5 Days/Week) (Kim et al., 2020)
Frequentist Log-Logistic Restricted Option Set #1
User Input
Info
Model
f re q u e nti st Log- Logi sti c vl. 1
Dataset Name
Transitional cell hyperplasia male rats
User notes
[Add user notes here]
Dose-Response Model
P[dose] =g+(l-g)/[l+exp(-a-b*Log(dose})]
Model Options
RiskType
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
[Custom]
Independent Variable
[Custom]
Total # of Observations
4
83
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Model Results
Benchmark Dose
BMC
0.261574763
BMCL
0.119303974
BMCU
0.590187836
AIC
35.49347532
P-value
0.108799645
D.O.F.
3
.-.1.2 T
Chi
6.058475938
Model Parameters
# of Parameters
Variable
g
Estimate
Bounded
-0.856189441
Bounded
The value of this parameter, 1.52299795127603E-08,
is within the tolerance of the bound
(see user guide for tolerance limits)
-A
The value of this parameter, 1,
is within the tolerance of the bound
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.523E-08
1.523E-07
0
10
-0.0003903
0.099
0.040355915
0.403559151
0
10
-0.6484829
0.773
0.247188137
2.471881373
5
10
1.8532773
5.833
0.712455952
7.124559517
5
10
-1.4843547
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-13.86294361
4
-
-
NA
Fitted Model
-16.74673766
1
5.7675881
3
0.1234816
Reduced Model
-22.49340578
1
17.2609243
3
0.0006246
Increased Incidence of Mucous Cell Hyperplasia in Nasopharyngeal Tissues in Female
F344 Rats Exposed to 1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks
(6 Hours/Day, 5 Days/Week) (Kim et al., 2020)
The procedure outlined above for dichotomous noncancer data was applied to the
incidence data for mucous cell hyperplasia in nasopharyngeal tissues in female F344 rats
exposed to 1-methylnaphthalene via inhalation (vapor) for 13 weeks (6 hours/day, 5 days/week)
(Kim et al.. 2020). All of the models provided adequate fit according to the %2 goodness-of-fit
/rvalue (p > 0.1) and scaled residuals (see Table C-5). The BMCLs for the models were not
sufficiently close (differed by greater than approximately threefold), so the model with the
lowest BMCL was selected (Multistage 1-degree). Figure C-5 shows the fit of the Multistage
1-degree model to the data. Based on HECs, the BMCio and BMCLio for increased incidence of
mucous cell hyperplasia in nasopharyngeal tissues in female F344 rats were 0.12 and
0.066 mg/m3, respectively.
84
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Table C-5. BMC Modeling Results for Increased Incidence of Mucous Cell
Hyperplasia in Nasopharyngeal Tissues in Female F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day,
5 Days/Week)3
Model
X2 Goodness-
of-fit
/>-valucb
AIC
Scaled Residual at
Dose Nearest BMC
BMCio
(mg/m3)
HEC
BMCLio
(mg/m3)
HEC
Gamma0
1.00
16.22
0.0003
0.40
0.090
Log-logisticd
1.00
14.22
3.32 x 10-8
0.44
0.140
Multistage (degree = 3)e
1.00
14.23
0.004
0.34
0.087
Multistage (degree = 2)e
1.00
14.33
-0.24
0.28
0.087
Multistage (degree = l)e *
0.57
18.29
-0.76
0.12
0.066
Weibull0
0.99
16.24
0.01
0.33
0.090
Logistic
1.00
14.22
4.23 x 10"5
0.46
0.23
Log-probitd
1.00
16.22
-8.2 x 10-9
0.40
0.13
Probit
1.00
14.32
0.06
0.36
0.21
aKim et al (2020V
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
Tower restricted to be >1.
dSlope restricted to be >1.
eBetas restricted to be >0.
* Selected model. All models provided adequate fit to the data. BMCLs for models providing adequate fit were not
sufficiently close (differed by >threefold), so the model with the lowest BMCL (Multistage 1 -degree) was selected.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = 10% benchmark concentration;
BMCLio = 10% benclunark concentration lower confidence limit; HEC = human equivalent concentration.
85
1 -Methylnaphthalene
-------
EPA/690/R-24/001F
Frequentist Multistage Degree 1 Model withBMRof 10% Extra Risk for the BMC and 0.95
Lower Confidence Limit for the BMCL
Resets? uvu
I iiiwMi Fxiufii'Jjiiii'Ki
O Data
BMCt
Figure C-5. Fit of Multistage 1-Degree Model to the Data for Increased Incidence of
Mucous Cell Hyperplasia in Nasopharyngeal Tissues in Female F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)
(Kim et al., 2020)
BMC Model Output of Multistage 1-Degree Model for Increased Incidence of Mucous Cell
Hyperplasia in Nasopharyngeal Tissues in Female F344 Rats Exposed to
1-Methylnaphthalene via Inhalation (Vapor) for 13 Weeks (6 Hours/Day, 5 Days/Week)
(Kim et al., 2020)
Frequentist Multistage Degree 1 Restricted
User Input
Info
Model
frequentist Multistage degree 1 vl.l
Dataset Name
Total mucous cell hyperplasia female rats
User notes
[Add user notes here]
Dose-Response Model
P[dose] =g + (l-g)*[l-exp(-bl*doseAl-b2*doseA2 - ...)
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
[Custom]
Independent Variable
[Custom]
Total # of Observations
4
86
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Model Results
Benchmark Dose
BMC
0.120729623
BMCL
0.066284393
BMCU
0.223184123
AIC
18.29099358
P-value
0.566919696
D.O.F.
2
/~u-2 1
Chi
1.135075228
Slope Factor
1.508650756
Model Parameters
# of Parameters
2
Variable
Estimate
g
1.52361E-08
bl
0.872698106
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
1.52361E-08
1.52361E-07
0
10
-0.0003903
0.065
0.055146502
0.55146502
0
10
-0.7639708
0.51
0.359224456
3.592244563
3
10
-0.3903599
3.736
0.96162696
9.616269596
10
10
0.6316984
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-6.108643021
4
-
-
NA
Fitted Model
-7.14549679
2
2.07370754
2
0.3545685
Reduced Model
-25.22324114
1
38.2291962
3
<0.0001
BMD MODELING TO IDENTIFY POTENTIAL PODS FOR DERIVATION OF A
PROVISIONAL CANCER RISK ESTIMATE FOR ORAL EXPOSURE
Increased Incidence of Combined Lung Adenoma or Adenocarcinoma in Male
B6C3F1 Mice Exposed to 1-Methylnaphthalene via Diet for 81 Weeks (Murata et al., 1993)
The procedure outlined above for cancer data was applied to the data for combined lung
adenoma or adenocarcinoma in male B6C3F1 mice exposed to 1-methylnaphthalene via diet for
81 weeks (Murata et al.. 1993). The Multistage 1-degree model provided adequate fit to the data,
as shown by the %2 goodness-of-fit/rvalue (p > 0.1) and scaled residuals (see Table C-6). The
Multistage 2-degree model took the form of the 1-degree model. Higher-degree models were not
applied to the data set because only three dose groups were present. Figure C-6 shows the fit of
the Multistage 1-degree model to the data. Based on HEDs, the BMDio and BMDLio values for
increased incidence of combined lung adenoma or adenocarcinoma in male B6C3F1 mice were
6.01 and 4.16 mg/kg-day, respectively.
87
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Table C-6. BMD Modeling Results for Increased Incidence of Combined
Lung Adenoma or Adenocarcinoma in Male B6C3F1 Mice Exposed to
1-Methylnaphthalene via Diet for 81 Weeks3
Model
X2 Goodness-
of-fit
/>-valucb
AIC
Scaled Residual at
Dose Nearest BMD
BMDio
(mg/kg-d)
HED
BMDLio
(mg/kg-d)
HED
Multistage (degree = 2)c
0.28
140.26
0.87
6.01
4.16
Multistage (degree = 1 )'•'
0.28
140.26
0.87
6.01
4.16
aMurata et al. (1993).
bValues <0.10 fail to meet conventional goodness-of-fit criteria.
°Betas restricted to >0.
* Selected model. The Multistage 1-degree model provided adequate fit to the data. The Multistage 2-degree model
took the form of the 1-degree model.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCio = 10% benchmark concentration;
BMCLio = 10% benclunark concentration lower confidence limit; HED = human equivalent dose.
Frequentist Multistage Degree 1 Model with BMR of 10% Extra
Risk for the BMD and 0.95 Lower Confidence Limit for the BMDL
i
O.B
Estimated Probataiity
Response at BMD
Linear Extrapolation
Data
BMD
BMDL
Dose
Figure C-6. Fit of Multistage 1-Degree Model to the Data for Increased Incidence of
Combined Lung Adenoma or Adenocarcinoma in Male B6C3F1 Mice Exposed to
1-Methylnaphthalene via Diet for 81 Weeks (Murata et al., 1993)
88
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
BMD Model Output of Multistage 1-Degree Model for Increased Incidence of Combined
Lung Adenoma or Adenocarcinoma in Male B6C3F1 Mice Exposed to 1-Methyl-
naphthalene via Diet for 81 Weeks (Murata et al., 1993)
Frequentist Multistage Degree 1 Restricted
User Input
Info
Model
frequentist Multistage degree 1 vl.l
Dataset Name
CombLungAdenoAdenocarcMMice
User notes
[Add user notes here]
Dose-Response Model
P[dose] -g + (l-g)*[l-exp(-bl*doseAl-b2*doseA2-...}]
Model Options
Risk Type
Extra Risk
BMR
0.1
Confidence Level
0.95
Background
Estimated
Model Data
Dependent Variable
HED
Independent Variable
Incidence
Total # of Observations
3
89
1 -Methylnaphthalene
-------
EPA/690/R-24/001F
Model Results
Benchmark Dose
BMD
6.005170966
BMDL
4.156604153
BMDU
10.3SS6S25S
AIC
140.2583 658
P-value
0.276456526
D.O.F.
1
Chi2
1.184427297
Slope Factor
0.0240581
Model Parameters
# of Parameters
2
Variable
Estimate
g
0.046432018
bl
0.017544966
Goodness of Fit
Dose
Estimated
Probability
Expected
Observed
Size
Scaled
Residual
0
0.046432018
2.275168878
2
49
-0.1868171
10.7
0.209647076
10.4823538
13
50
0.8746912
21.11
0.341584303
17.07921516
15
50
-0.6200338
Analysis of Deviance
Model
Log Likelihood
# of Parameters
Deviance
Test d.f.
P Value
Full Model
-67.55202394
3
-
-
NA
Fitted Model
-68.12918292
2
1.154317958
1
0.28264707
Reduced Model
-74.83638246
1
14.56871703
2
0.00068619
90
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
APPENDIX D. REFERENCES
ACGIH. (2007). 1-Methylnaphthalene and 2-methylnaphthalene. In Documentation of the
threshold limit values and biological exposure indices (7th ed.). Cincinnati, OH.
ACGIH. (2020). 2020 TLVs and BEIs: Based on the documentation of the threshold limit values
for chemical substances and physical agents & biological exposure indices. Cincinnati,
OH.
Akagi. JI; Tovoda. T; Cho. YM; Mizuta. Y; Nohmi. T; Nishikawa. A; Ogawa. K. (2015).
Validation study of the combined repeated-dose toxicity and genotoxicity assay using gpt
delta rats. Cancer Sci 106: 529-541. http://dx.doi.org/10. Ill 1/cas. 12634
Antoon. JW: Hernandez. ML: Roehrs. PA: Noah. TL; Leigh. MW; Byerlev. JS. (2016).
Endogenous lipoid pneumonia preceding diagnosis of pulmonary alveolar proteinosis.
Clin Respir J 10: 246-249. http://dx.doi.org/10.1111/cri.12197
ATSDR. (2005). Toxicological profile for naphthalene, 1-methylnaphthalene, and 2-
methylnaphthalene [ATSDR Tox Profile], (PB2006100004). Atlanta, GA: Department of
Health and Human Services.
https://ntrl.ntis. gov/NTRL/dashboard/searchResults.xhtml?searchOuerv=PB20061000Q4
ATSDR. (2024). Toxic substances portal: Toxicological profiles [Database], Atlanta, GA.
Retrieved from https://www.atsdr.cdc.gov/toxprofiledocs/index.html
CalEPA. (2023). Consolidated table of OEHHA/CARB approved risk assessment health values.
Sacramento, California, https://ww2.arb.ca.gov/resources/documents/consolidated-table-
oehha-carb-approved-risk-assessment-health-values
CalEPA. (2024). Oehha chemical database [Database], Sacramento, CA: Office of
Environmental Health Hazard Assessment. Retrieved from
http s://oehha.ca. gov/chemi cal s
de Guzman. E; Sutton. B. Jr. (2013). Dye carriers. In Kirk-Othmer encyclopedia of chemical
technology. Hoboken, NJ: John Wiley & Sons.
http://dx.doi.org/10.1002/0471238961.04250503Q7212613.a01.pub2
Dinsdale. D; Verschoyle. RD. (1987). Pulmonary toxicity of naphthalene derivatives in the rat.
Arch Toxicol Suppl 11: 288-291. http://dx.doi.org/10.1007/978-3-642-72558-6 54
DuPont. (1992). Initial submission: preliminary toxicity investigation of alpha-
methylnaphthalene and diisobutyl carbinol with cover letter dated 101892 [TSCA
Submission], (MR-183. OTS0556357. 88-920010961. 8EHQ-1192-13158.
TSCATS/441533). Haskell Laboratory.
ECHA. (2024). Substance infocard: 1-methylnaphthalene. Available online at
https://echa.europa.eu/bg/substance-information/-/substanceinfo/100.001.788
Emi. Y; Konishi. Y. (1985). Endogenous lipid pneumonia in female B6C3F1 mice. In TC Jones;
U Mohr; RD Hunt (Eds.), Respiratory system (pp. 166-168). Berlin, Germany: Springer.
http://dx.doi.org/10.1007/978-3-642-96846-4 25
Florin. I: Rutberg. L; Curvall. M; Enzell. CR. (1980). Screening of tobacco smoke constituents
for mutagenicity using the Ames' test. Toxicology 15: 219-232.
http://dx.doi.org/10.1016/0300-483X(80)90055-4
IARC. (2024). Agents classified by the IARC monographs. Lyon, France.
http://monographs.iarc.fr/ENG/Classification/List of Classifications.pdf
Jin. M; Kijima. A: Suzuki. Y; Hibi. D; Ishii. Y; Nohmi. T; Nishikawa. A: Ogawa. K; Umemura.
T. (2012). In vivo genotoxicity of 1-methylnaphthalene from comprehensive toxicity
studies with B6C3F1 gpt delta mice. J Toxicol Sci 37: 711-721.
91
1 -Methylnaphthalene
-------
EPA 690 R-24 001F
Kaden. DA; Hites. RA; Thilly. WG. (1979). Mutagenicity of soot and associated polycyclic
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