United States
Environmental Protection
1=1 m m Agency
EPA/690/R-08/017F
Final
1-10-2008
Provisional Peer Reviewed Toxicity Values for
1 -Methy lnaphthalene
(CASRN 90-12-0)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and
Liability Act of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
NAAQS	National Ambient Air Quality Standards
NOAEL	no-ob served-adverse-effect level
NOAEL(ADJ)	NOAEL adjusted to continuous exposure duration
NOAEL(HEC)	NOAEL adjusted for dosimetric differences across species to a human
NOEL	no-ob served-effect level
OSF	oral slope factor
p-IUR	provisional inhalation unit risk
p-OSF	provisional oral slope factor
p-RfC	provisional inhalation reference concentration
1

-------
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
11

-------
1-10-2008
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
1-METHYLNAPHTHALENE (CASRN 90-12-0)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
1

-------
1-10-2008
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
Neither a reference dose (RfD), reference concentration (RfC), nor carcinogenicity
assessment are available for 1-methylnaphthalene in the Integrated Risk Information System
(IRIS) database (U.S. EPA, 2007), the Health Effects Assessment Summary Table (HEAST)
(U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2004).
The Chemical Assessments and Related Activities (CARA) database (U.S. EPA, 1991, 1994)
lists no documents for 1-methylnaphthalene. An IRIS Toxicological Review for 2-
Methylnaphthalene (U.S. EPA, 2003) includes a brief summary of results of a chronic toxicity
and carcinogenicity study of mice administered 1-methylnaphthalene in the diet for 81 weeks
(Murata et al., 1993), but does not include a dose response assessment for 1-methylnaphthalene.
An Agency for Toxic Substances and Disease Registry (ATSDR) Toxicological Profile for
Naphthalene, 1-Methylnaphthalene, and 2-Methylnaphthalene (ATSDR, 2005) includes toxicity
data for 1-methylnaphthalene and a chronic-duration oral MRL of 0.07 mg/kg-day for
1-methylnaphthalene based on a LOAEL of 71.6 mg/kg-day for pulmonary alveolar proteinosis
in female mice exposed to 1-methylnaphthalene in the diet for 81 weeks (Murata et al., 1993).
Neither the American Conference of Governmental Industrial Hygienists (ACGIH, 2006), the
National Institute of Occupational Safety and Health (NIOSH, 2006), nor the Occupational
Safety and Health Administration (OSHA, 2006) have adopted exposure limits for
1-methylnaphthalene. Health assessments for 1-methylnaphthalene are not available from other
major sources, including CalEPA (2006), the World Health Organization (WHO, 2006), and the
International Agency for Research on Cancer (IARC, 2006). Available toxicity data for
1-methylnaphthalene from the National Toxicology Program (NTP, 2006) are limited to results
of a single genetic toxicology bacterial assay.
2

-------
1-10-2008
Literature searches covering the time period 1960's to August, 2007 were conducted in
MEDLINE, TOXLINE, TOXCENTER, and DART/ETIC to identify information relevant to
1-methylnaphthalene. Databases searched without date limitations included
TSCATS/TSCATS2, CCRIS, GENETOX, HSDB, and RTECS. Search of Current Contents
encompassed May to August, 2007.
REVIEW OF PERTINENT DATA
Human Studies
Oral Exposure. No data were located regarding the oral toxicity or carcinogenicity of
1-methylnaphthalene in humans.
Inhalation Exposure. No data were located regarding the inhalation toxicity or carcinogenicity
of 1-methylnaphthalene in humans.
Animal Studies
Oral Exposure. The database of repeated oral exposure to 1-methylnaphthalene is limited to an
81-week chronic toxicity and carcinogenicity study in mice and a 13-week pilot study to
determine the concentrations of 1-methylnaphthalene to be added to the diet of the mice of the
chronic study (Murata et al., 1993). In the pilot study, groups of 10 male and 10 female B6C3F1
mice were given diets containing 0, 0.0163, 0.049, 0.147, 0.44, or 1.33% 1-methylnaphthalene
for 13 weeks. According to the study authors, the 0.44 and 1.33% groups of male and female
mice exhibited growth retardation that was probably due to refusal to eat. No histopathological
lesions were detected in any organs, but the extent of histopathological assessment was not
described. In the main (81-week) study, groups of 50 male and 50 female B6C3F1 mice were
given diets containing 0.075 or 0.15% 1-methylnaphthalene for 81 weeks (Murata et al., 1993).
In a simultaneously-conducted study, groups of male and female mice were exposed to 2-
methylnaphthalene under the same experimental conditions and protocols employed in the study
of 1-methylnaphthalene (Murata et al., 1993, 1997). Both studies shared a common group of 50
male and 50 female control mice. Mice in both studies were observed daily for abnormalities,
and body weights were recorded weekly for the first 16 weeks and every two weeks thereafter.
Food consumption was monitored throughout the studies. At the end of the 81-week treatment
period, blood was collected for hematology and serum biochemical analysis. 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. Histopathological examinations were also
performed on all mice found dead or sacrificed moribund prior to scheduled sacrifice.
Based on cumulative intake data provided by the study authors, doses of
1-methylnaphthalene were estimated as 71.6 and 140.2 mg/kg-day for the low- and high-dose
males, and 75.1 and 143.7 mg/kg-day for the low- and high-dose females, respectively. There
3

-------
1-10-2008
were no significant treatment-related effects on food consumption or growth. 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. 1-Methylnaphthalene-treated groups of male mice
exhibited significantly increased (magnitude 6-8%) absolute and relative brain and heart weights,
relative to controls. Statistically significant (p<0.05) findings in 1-methylnaphthalene-treated
groups of female mice included decreased (magnitude 17%) absolute and relative salivary gland
weight, increased (magnitude 7%) absolute (but not relative) heart weight, and decreased
(magnitude 35%) absolute and relative thymus weight. The study authors indicated that thymus
weights in control female mice were abnormally high due to the development of lymphoma in
this group, which may have resulted in the apparent decrease in thymus weights in the
1-methylnaphthalene-treated female mice. No histopathology was detected in these organs. In
addition, the statistical approach appeared to have been simple t tests, apparently without
adjustment for multiple comparisons. These changes may not have been statistically significant if
a procedure that accounts for multiple comparisons would have been used. Given the low
magnitude of the other organ weight changes, uncertainty as to actual statistical significance, and
the lack of histopathological changes, the organ weight changes are discounted for defining a
LOAEL.
Exposure-related lesions were restricted to the lung. Statistically significantly increased
incidences of male and female mice with pulmonary alveolar proteinosis (PAP) were observed
following 81 weeks of 1-methylnaphthalene treatment (Table 1). This lesion was characterized
by an accumulation of phospholipids in the alveolar lumens and 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. Statistically significantly
increased incidences of male, but not female, mice with lung adenoma and combined adenoma or
adenocarcinoma were noted following 81 weeks of 1-methylnaphthalene treatment (Table 1). As
the individual animal data were not presented, the degree of co-occurrence of adenomas and
adenocarcinomas in the same animal could not be determined. The authors stated, however, that
(the) "Number of lung tumors counted on the histological sections per mouse was mostly
single." Accepting this statement at face value would indicate that the degree of double-counting
is minimal, particularly as the total number of tumors was 15, of which only 3 were of a different
type (adenocarcinomas). Results for 2-methylnaphthalene were similar to those for 1-
methylnaphthalene, with PAP occuring in both treatment groups (Murata et al., 1997). Murata et
al. (1993) also reported what appeared to be dose-related significantly elevated monocyte
concentrations in 1-methylnaphthalene-treated males and females. The authors hypothesized
that this change may have been a physiological response to the PAP seen in the exposed animals.
The incidence of PAP in the control animals was 8.2% for males and 10% for females; the
effects in control animals were less pronounced than those in the treatment groups. The authors
stated that this effect had not been observed previously in more than 5000 B6C3F1 mice housed
in the same room and speculated that the control mice may have been exposed to volatilized 1-
methylnaphthalene and 2-methylnaphthalene from the treatment groups housed in the same room
for this experiment.
4

-------
1-10-2008
TABLE 1. Incidences of Male and Female B6C3F1 Mice Exhibiting Neoplastic and
Nonneoplastic Lung Lesions after 81 Weeks of Dietary Exposure to
1-Methylnaphthalene
Sex
Dietary
level
(%)
Dose
(mg/kg-day)
Pulmonary
alveolar
proteinosis
Lung
adenoma
Lung
adenocarcinoma
Combined lung
adenoma or
adenocarcinoma
M
0
0
4/49
2/49
0/49
2/49
M
0.075
71.6
23/503
13/50b
0/50
13/50b
M
0.15
140.2
19/503
12/5 0b
3/50
15/50b
F
0
0
5/50
4/50
1/50
5/50
F
0.075
75.1
23/50a
2/50
0/50
2/50
F
0.15
143.7
17/49*
4/49
1/49
5/49
a Significantly different (p<0.01) from the control value according to the chi-square test
b Significantly different (p<0.05) from the control value according to the chi-square test
Source: Murataetal., 1993
In summary, the 81-week oral toxicity study of 1-methylnaphthalene in male and female
B6C3F1 mice (Murata et al., 1993) identified statistically significantly increased incidences of
pulmonary alveolar proteinosis as the critical nonneoplastic effect. The lowest exposure level
(71.6 mg/kg-day in male mice) represents a LOAEL for the effect. A carcinogenic effect for 1-
methylnaphthalene was indicated by statistically significantly increased incidences of lung
adenoma and combined adenoma or adenocarcinoma in 1-methylnaphthalene-treated male, but
not female, mice.
Inhalation Exposure. Available information in animals following inhalation exposure to
1-methylnaphthalene is restricted to results of a single 4-hour exposure in rats (Korsak et al.,
1998) and a 4-day repeated-exposure study in dogs (Lorber, 1972).
Korsak et al. (1998) exposed male Wistar rats to 1-methylnaphthalene by inhalation for
four hours at exposure concentrations ranging from 152 to 407 mg/m3, after which rats were
assessed for rotarod performance and pain sensitivity. Compared to unexposed control rats,
1-methylnaphthalene-exposed rats exhibited concentration-related decreased pain sensitivity at
exposure concentrations of 352 or 525 mg/m3. Decreased sensitivity to pain was measured as a
decreased time to begin licking of the paws after being placed on a hot plate at 54.5 °C. Under
the conditions of the Korsak et al. (1998) study, 1-methylnaphthalene did not affect rotarod
performance. In similarly-exposed male Balb/C mice, an RD50 (the concentration required to
depress the rate of respiration by 50%) was 129 mg 1-methylnaphthalene/m3 (Korsak et al.,
1998).
Lorber (1972) subjected both intact and splenectomized dogs to mists consisting of 1
liter of refined, deodorized kerosene and quantities of pure or "practical grade"
1-methylnaphthalene that would be expected in 1 liter or 1 gallon of a commercial pesticide
formulation. A pesticide fogger was used to bathe the dogs (2-6 per group) in the generated
5

-------
1-10-2008
mist for four 5-minute periods, with pauses lasting 7-10 minutes during which the mist settled.
Strains and gender of dogs were not reported. Based on the information presented, it is not
possible to determine the exposure concentrations. Blood was collected prior to first and last
exposure, and at 7 and 10 days following first exposure. Iliac bone marrow aspirates were
collected under anesthesia before and after exposure. Endpoints measured included mean
levels of leukocytes, reticulocytes, platelets, and red blood cell survival. Post-exposure values
were compared to pre-exposure values. No statistically significant exposure-related effects
were observed for any of the endpoints evaluated.
Other Studies
Limited genotoxicity data are available for 1-methylnaphthalene. 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). Positive
results were reported in a forward mutation assay using Salmonella typhimurium strain TM677
in the presence of preinduced rat liver homogenate (Kaden et al., 1979). 1-Methylnaphthalene
did not induce chromosomal aberrations or sister chromatid exchanges (SCE) in human
peripheral lymphocytes in the absence of S9 hepatic microsomal fractions, but did induce SCE
with S9 present (Kulka et al., 1988).
Rasmussen et al. (1986) administered single intraperitoneal injections of 0, 1, or 2
mmol/kg of 1-methylnaphthalene (0, 142 or 284 mg/kg) in peanut oil to male Swiss-Webster
mice (2/group) with sacrifice at 24 hours, 3 days, 7 days, or 14 days. Lung, liver, and kidney
tissues were examined with light microscopy, and lung cells were analyzed by electron
microscopy. Lung cell proliferation was measured in the control and 284 mg/kg groups only.
Doses of 0.5 or 3 mmol/kg (71 or 427 mg/kg) were also administered, but only electron
microscopy results were reported for these mice. Cytotoxic effects on the epithelium of the lung
airways examined by light microscopy were scored on a 0-5 scale (0 = no effect; 1 = swelling of
Clara cells with occasional sloughed cells in terminal bronchioles; 2 = sloughed cells evident in
bronchioles, but ciliated cells intact and minimal effects in bronchi and trachea; 3 = sloughed
Clara cells throughout airways; 4 = sloughed Clara cells and ciliated cells in bronchioles with
some damage in bronchi and trachea; and 5 = sloughed cells throughout all airways, including
trachea, leaving large areas of bare basement membrane). Maximal average scores for lung
cytotoxic effects (1.0 and 1.5 for 142 and 284 mg/kg mice) were observed between 24 hours and
3 days after injection. Electron microscopy of lung tissue collected from exposed mice at 6, 12,
or 24 hours after injection showed Clara cell flattening, cytoplasmic vacuolization, loss of
smooth endoplasmic reticulum, reduced number of microvilli, prominent ribosomes, and
electron-dense mitochondria. Examination of liver and kidney sections from exposed mice
revealed minimal changes in the liver and no changes in the kidney.
Female Wistar rats given single intraperitoneal injections of 0 or 1 mmol/kg (142 mg/kg)
of 1-methylnaphthalene showed no evidence of pulmonary necrosis (Dinsdale and Verschoyle,
1987).
PAP was also observed in mice following dermal exposure to a mixture of 1-MN and 2-
MN for 30 weeks (Murata et al., 1992). A 100% incidence of PAP was obtained in 15 B6C3F1
6

-------
1-10-2008
female mice dermally treated with 119 mg MN/kg twice a week. No lesions were observed in
the control animals (acetone vehicle only).
Toxicokinetics and Mode of Action
No studies evaluating the metabolism or mode of action (MOA) of 1-methylnaphthalene
in humans or animals are available. There are, however, several studies evaluating metabolism
and MOA for the structurally-related compounds, 2-methylnaphthalene and naphthalene.
Exposure to methylnaphthalenes or naphthalene by non-inhalation routes appears to produce
lung damage in rodents, especially mice. Several laboratories have found that single
intraperitoneal injections of naphthalene or certain other chemicals that are metabolically
activated, including methylnaphthalenes, bromobenzene, and carbon tetrachloride, produce
bronchiolar epithelial cell injury in rodent species with mice being the most sensitive species (see
U.S. EPA, 2003).
Studies of the mode of action by which acute intraperitoneal injections of 2-
methylnaphthalene cause bronchiolar necrosis in mice indicate the possible involvement of
reactive metabolites produced via CYP enzymes, but the mode of action at the molecular level
has not been elucidated and the ultimate toxicant has not been identified. The mode of action of
acute Clara cell toxicity of 2-methylnaphthalene may be similar to that of naphthalene. The mode
of action of naphthalene toxicity is hypothesized to involve metabolism by CYPIA1 and other
enzymes via ring epoxidation to reactive species such as 1,2-epoxides and 1,2-quinones (see U.S.
EPA, 1998). The reactive species then interact with cellular components. The observation that 2-
methylnaphthalene is less acutely toxic than naphthalene supports this hypothesis, since only a
small fraction of 2-methylnaphthalene (15-20%) undergoes ring epoxidation (see U.S. EPA,
2003).
Naphthalene toxicity and carcinogenicity have been hypothesized to be due to, at least in
part, metabolism via CYP-mediated ring epoxidation to reactive metabolites such as the 1,2-
epoxide or 1,2-quinone derivatives (see U.S. EPA, 1998). However, for 2-methylnaphthalene,
the metabolic formation of ring epoxides is a relatively minor pathway (NTP 2000; U.S. EPA,
2003). Metabolism of 1-methylnaphthalene may follow a similar pathway (i.e., side chain
oxidation) as these chemicals are structurally similar, although the position of the side chain may
affect the metabolic pathway.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfDs FOR
1-METHYLNAPHTHALENE
The pilot subchronic study reported by Murata et al (1993) lacked sufficient detail for the
derivation of a subchronic pRfD. No other applicable data were found. The lack of adequate
subchronic data for humans or animals precludes the derivation of a provisional subchronic RfD
for 1-methylnaphthalene.
The only study applicable for derivation of a chronic p-RfD (Murata et al., 1997) has
several limitations. Although well-conducted in many respects, there was probable confounding
7

-------
1-10-2008
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
was not quantified. Therefore, the exact dosage of 1-methylnaphthalene and the fraction of the
response attributable to oral ingestion are difficult to estimate with accuracy. These factors add
uncertainty to the dose-response relationship between oral exposure to 1-methylnaphthalene and
pulmonary alveolar proteinosis assessed from the Murata et al. (1997) study. As the toxicity of
1-methylnaphthalene and 2-methylnaphthalene is similar, 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. In spite of the uncertainties associated with the
Murata et al. (1993) chronic study the data could be used to determine a point of departure with
pulmonary alveolar proteinosis as the critical effect, but the additional multiple areas of
uncertainty associated with the application of uncertainty factors (e.g., animal to human
extrapolation, LOAEL to NOAEL extrapolation) preclude the derivation of a p-RfD . However,
Appendix A of this document contains a Screening Value that may be useful in certain instances.
Please see the attached Appendix A for details.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC RfCs FOR
1-METHYLNAPHTHALENE
No human or animal data are available regarding the toxicity of 1-methylnaphthalene
following repeated inhalation exposure, thus precluding the derivation of provisional subchronic
or chronic RfC values for 1-methylnaphthalene.
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
1-METHYLNAPHTHALENE
Weight-of-Evidence Descriptor
No information was located regarding the carcinogenicity of 1-methylnaphthalene in
humans. 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 140.2 mg/kg-day (males) or 0, 75.1, or 143.7 mg/kg-day
(females) (Murata et al., 1993). Under the conditions of the study, statistically significantly
increased incidences were observed for male, but not female, mice with lung adenoma and
combined lung adenoma and adenocarcinoma (see Table 1 on p. 6 for tumor incidence data).
However, incidences of male or female mice exhibiting lung carcinoma were not significantly
increased relative to controls. The results of the Murata et al. (1993) study provide evidence for
1-methylnaphthalene-induced carcinogenicity in male, but not female, mice. No information
was located regarding the potential carcinogenicity of orally-administered 1-methylnaphthalene
in a second animal species. Limited genotoxicity data are available for 1-methylnaphthalene.
The chemical was mutagenic in a forward mutation assay using Salmonella typhimurium strain
TM677 in the presence of preinduced rat liver homogenate (Kaden et al., 1979), but not
8

-------
1-10-2008
mutagenic in an Ames test using Salmonella typhimurium strains TA98 and TA100 either with or
without metabolic activation (Florin et al., 1980). 1-Methylnaphthalene induced SCE in human
peripheral lymphocytes with S9 present, but otherwise did not induce chromosomal aberrations
or SCE (Kulka et al., 1988).
The finding of significantly increased incidences of male B6C3F1 mice with lung
adenoma and combined adenoma and adenocarcinoma following 81 weeks of oral exposure to 1-
methynaphthalene provides "Suggestive Evidence of Carcinogenicity" in accordance with
current U.S. EPA (2005) carcinogen risk assessment guidelines. Mode of action data for 1-
methylnaphthalene-induced lung tumors in the male mice are limited to results of a few
genotoxicity tests that provide equivocal evidence of a mutagenic mode of action.
Mode of Action Discussion
The mode of action (MOA) for tumor formation in mice in the Murata et al. (1997) study
is not known. No evidence of bronchiolar necrosis or Clara cell damage was seen in the mice
exhibiting lung tumors after 81 weeks of dietary exposure to 1-MN (Murata et al., 1997). In
addition, the available data do not support the hypothesis that pulmonary alveolar proteinosis
might be a precursor to lung tumor formation (Murata et al., 1993, 1997). For example,
compared with 2-MN, 1-MN induced equal or slightly lower incidences of pulmonary alveolar
proteinosis, but higher incidences of lung tumors. In addition, Murata et al. (1993) reported that
the numbers of mice developing pulmonary alveolar proteinosis and lung tumors following
exposure to 1-MN were not statistically correlated and the sites of development of alveolar
proteinosis and lung tumors were not always clearly linked. The potential mutagenicity of 1-
methylnaphthalene has not been adequately assessed. Results of the few available assays of 1-
methylnaphthalene provide equivocal evidence of 1-methylnaphthalene genotoxicity or
mutagenicity. A mutagenic MO A, thus cannot be unequivocally established for 1-MN. In
addition, a mutagenic MOA has not been established for either of the structurally related
compounds, 2-MN (U.S. EPA, 2005) or naphthalene (U.S. EPA, 1998).
Quantitative Estimates of Carcinogenic Risk
Oral Exposure. Oral data are available from which to derive a quantitative estimate of cancer
risk from 1-methylnaphthalene. Although a dose-response assessment is generally not
performed with suggestive evidence, quantitative analyses is of use in assessing the general
magnitude of risk at Superfund sites and the tumorigenicity data in the Murata et al. (1993) study
show a clear dose-response relationship. The Murata et al. (1993) 81-week oral study of
B6C3F1 male and female mice provided the only available carcinogenicity assay for 1-
methylnaphthalene and was selected as the principal study for carcinogenic risk assessment,
based on significantly increased incidences of lung adenomas or carcinomas (combined) in 1-
methylnaphthalene-treated male mice. Limited genotoxicity data provide equivocal evidence of
a mutagenic mode of action; thus, a mutagenic mode of action cannot be ruled out and a low-
dose linear extrapolation was conducted.
To obtain a point of departure (POD) for a quantitative assessment of cancer risk,
benchmark dose analysis was performed on the lung adenoma or carcinoma (combined)
9

-------
1-10-2008
incidence data for the male mice (see Table 1 on p. 6). 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. Appendix B provides details of the modeling results and
the selection of the best-fitting model based on goodness-of fit criteria. The log-logistic model
provided the best fit as assessed by Akaike's Information Criterion (AIC), and predicted a
BMDio of 35.29 mg/kg-day and a BMDLio of 22.91 mg/kg-day for lung adenoma or carcinoma
(combined). The BMDLio of 22.91 mg/kg-day was used as the POD for the provisional oral
slope factor.
The BMDLio of 22.91 mg/kg-day for lung adenoma or carcinoma (combined) in the male
mice was converted to a human equivalent dose (HED) using a cross-species scaling factor of
body weight raised to the 3/4 power (or body weight ratio raised to the Vi power; U.S. EPA,
2005) as follows:
BMDLiohed = BMDLio x (mouse average body weight/human reference body weight)174
BMDLiohed = 22.91 mg/kg-day x (0.0325 kg / 70 kg)1/4
BMDLiohed = 3.4 mg/kg-day
A linear extrapolation to the origin (0.1/3.4 mg/kg-day) results in a provisional human
oral slope factor of 2.9E-2 (mg/kg-day)"1 for 1-methylnaphthalene. Available data for 1-
methylnaphthalene are not sufficient to establish a mutagenic mode of action (MOA) for the
observed carcinogenicity. Consequently, the application of age-dependent adjustment factors
for early-life exposure should not be applied when conducting a risk assessment (U.S. EPA,
2005). Doses of 1-methylnaphthalene associated with some specific risk levels are shown in
Table 2.
TABLE 2. Dose of 1-Methylnaphthalene Associated With Some
Specific Levels of Cancer Risk
Risk Level
Dose (mg/kg-day)
10"4
0.003
10"5
0.0003
10"6
0.00003
The exposure of all animals, control and treated alike, to fugitive vapor emissions of both
1-MN and 2-MN introduces considerable uncertainty into the quantitative analysis. Some of the
lung tumors in these animals may have arisen from inhalation exposure and some of the latter
from 2-MN exposure. Most likely, the 2 lung adenomas in the control animals were a result of
inhalation exposure to fugitive vapors, although historical control data are lacking to verify that
conjecture. However, assuming that inhalation exposure was the same for all animals, the
control incidence still serves as an approximate measure of background incidence, with respect
to secondary inhalation exposure, and is accounted for in the Benchmark Dose modeling. The
assumption of equal exposure for all animals is somewhat tenuous, however, in that the treated
animals, in closer proximity to the source of the fugitive emissions, probably experienced a
higher exposure to 1-MN vapors. The degree to which the treated-animal inhalation exposure
was greater than the controls correspondingly increases the uncertainty in the modeled slope
10

-------
1-10-2008
factor, which would bias the estimate high. As the degree of co-occurrence of adenomas and
adenocarcinomas in the same animal could not be determined, combining the incidence the two
tumor types could result in double-counting of incidence. However, as the authors stated that the
tumor occurrence per mouse was mostly single, the degree of double-counting is anticipated to
be minimal. Also, as the double-counting could only occur at the highest dose, at which the three
adenocarcinomas were observed, the slope factor, in this case, would tend to be biased low, as a
lower incidence at the highest dose would generally result in a lower POD.
Inhalation Exposure. There are no appropriate human or animal data from which to derive an
inhalation unit risk for 1-methylnaphthalene.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2006. 2006 Threshold
Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices.
Cincinnati, OH.
ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for
Naphthalene, 1-methylnaphthalene, and 2-Methylnaphthalene. Available at
http://www.atsdr.cdc.gov/toxpro2.html
CalEPA (California Environmental Protection Agency). 2006. Air - Chronic RELs. California
Office of Environmental Health Hazard Assessment. Available at:
http://www.oehha.ca.gov/air/chronic rels/Al lChrels.html
Dinsdale, D. and R. Verschoyle. 1987. Pulmonary toxicity of naphthalene derivatives in the rat.
Arch. Toxicol. 11:288-291.
Florin, I., L. Rutberg, M. Curvall and C. Enzell. 1980. Screening of tobacco smoke constituents
for mutagenicity using the Ames'test. Toxicology. 18:219-232.
IARC (International Agency for Research on Cancer). 2006. http://www.iarc,fr/index.html
Kaden, D.A., R.A. Hites and W.G. Thilly. 1979. Mutagenicity of soot and associated polycyclic
aromatic hydrocarbons to Salmonella typhimurium. Cancer Res. 39:4152-4159.
Korsak, Z., W. Majcherek and K. Rydzynski. 1998. Toxic effects of acute inhalation exposure
to 1-methylnaphthalene and 2-methylnaphthalene in experimental animals. Int. J. Occup. Med.
Environ. Health. 11(4):335-342.
Kulka, U., E. Schmid, R. Huber and M. Bauchinger. 1988. Analysis of the cytogenetic effect in
human lymphocytes induced by metabolically activated 1- and 2-methylnaphthalene. Mutat.
Res. 208:155-158.
11

-------
1-10-2008
Lorber, M. 1972. Hematotoxicity of synergized pyrethrin insecticides and related chemicals in
intact, totally and subtotally splenectomized dogs. Acta Hepato-Gasteroenterol. 19:66-78.
Mazzone, P., M.J. Thomassen and M. Kavuru. 2001. Our new understanding of pulmonary
alveolar proteinosis: what an internist needs to know. Cleve. Clin. J. Med. 68:977-985.
Murata, Y., Y. Emi, A. Denda and Y. Konishi. 1992. Ultrastructural analysis of pulmonary
alveolar proteinosis induced by methylnaphthalene in mice. Exp. Toxicol. Pathol. 44:47-54.
Murata, Y., A. Denda, H. Maruyama and Y. Konishi. 1993. Chronic toxicity and
carcinogenicity studies of 1-methylnaphthalene in B6C3F1 mice. Fund. Appl. Toxicol. 21:44-
51.
Murata, T., A. Denda, H. Maruyama, D. Nakae, M. Tsutsumi, T. Tsujiuchi and Y. Konishi.
1997. Chronic toxicity and carcinogenicity studies of 2-methylnaphthalene in B6C3F1 mice.
Fund. Appl. Toxicol. 36:90-93.
NIOSH (National Institute for Occupational Safety and Health). 2006. Online NIOSH Pocket
Guide to Chemical Hazards. Index by CASRN. Available at: http://www.cdc.gov/niosh/npg
NTP (National Toxicology Program). 2006. http://ntp-server.niehs.nih.gov/
NTP (National Toxicology Program). 2000. Toxicology and carcinogenesis studies of
naphthalene (CAS No. 91-20-3) in F344/N rats (inhalation studies). National Toxicology
Program. NTP TR 500, NIH Publ. No. 01-4434.
OSHA (Occupational Safety and Health Administration). 2006. OSHA Standard 1910.1000
TableZ-1. Part Z, Toxic and Hazardous Substances. Available at:
http://www.osha.gov/pls/oshaweb/owadisp.show docuinent'.'p table=STANDARDS&p id=9992
Rasmussen, R.E., D.H. Do, T.S. Kim and L. Dearden. 1986. Comparative cytotoxicity of
naphthalene and its monomethyl- and mononitro-derivatives in the mouse lung. J. Appl.
Toxicol. 6(1): 13-20.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Office of
Research and Development, Office of Solid Waste and Emergency Response, Washington, DC.
OSWERDir. 9200-6-303 (97-1).
U.S. EPA. 1998. Integrated Risk Information System (IRIS). Toxicological review for
naphthalene. Online. Office of Research and Development, National Center for Environmental
Assessment, Washington, DC. http://www.epa.gov/iris/
12

-------
1-10-2008
U.S. EPA. 2000. Benchmark Dose Technical Guidance Document. [External Review Draft],
EPA/63 0/R-00/001.
U.S. EPA. 2003. Integrated Risk Information System (IRIS). Toxicological Review of 2-
Methylnaphthalene (CAS No. 91-57-6). Online. Office of Research and Development, National
Center for Environmental Assessment, Washington, DC. EPA635R03010.
http://www.epa.gov/iris/
U.S. EPA. 2004. 2004 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA/822/R-02/038. Available at:
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum,
Washington, DC. EPA/630/P-03/00IB. Available at: www.epa.gov/cancerguidelines
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa.gov/iris/
Wang, B.M., E.J. Stern, R.A. Schmidt and D.J. Pierson. 1997. Diagnosing pulmonary alveolar
proteinosis. A review and an update. Chest. Ill :460-466.
WHO (World Health Organization). 2006. Online Catalogs for the Environmental Criteria
Series. Available at: http://www.inchem.org/pages/ehc.html
13

-------
1-10-2008
APPENDIX A
Derivation of a Screening Value for 1-Methylnaphthalene
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for 1-methylnaphthalene, RfD. However, 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 Superfund Health
Risk Technical Support Center summarizes available information in an Appendix and develops a
"Screening Value." Material provided in appendices receive the same level of internal and
external scientific peer review as the PPRTV documents to ensure their appropriateness within
the limitations detailed in the document. In some cases, as for 1-methylnaphthalene, a Screening
Value was developed and included in an Appendix as a result of comments received during
external review. In the OSRTI hierarchy, Screening Values are considered to be below Tier 3,
"Other (Peer-Reviewed) Toxicity Values."
Screening Values are intended for use in limited circumstances when no Tier 1, 2, or 3
values are available. Screening Values may be used, for example, to rank relative risks of
individual chemicals present at a site to determine if the risk developed from the associated
exposure at the specific site is likely to be a significant concern in the overall cleanup decision.
Screening Values are not defensible as the primary drivers in making cleanup decisions because
they are based on limited information. Questions or concerns about the appropriate use of
Screening Values should be directed to the Superfund Health Risk Technical Support Center.
Results of the only available chronic oral study of 1-methylnaphthalene (Murata et al.,
1993) provide sufficient information from which a screening-value chronic RfD for
1-methylnaphthalene can be derived. This study identified significantly increased incidences of
mice with pulmonary alveolar proteinosis as the critical effect following 81 weeks of oral
exposure to 1-methylnaphthalene. The study appears to be well designed and conducted, except
for the poor controls on ventilation in the exposure facility. As a result, there is some uncertainty
as to the contribution of inhalation of fugitive 1-methylnaphthalene and 2-methylnaphthalene
vapors to the observed effects, given the unusually high incidence of PAP in the control animals.
The incidence of this effect in the treated animals is also quite high and did not show a dose-
response relationship, although the effect may exhibit a plateau. This observation also could be a
result of exposure to fugitive vapors masking the systemic exposure response. The incidence of
pulmonary alveolar proteinosis in the treament groups attributable to inhalation exposure is thus
impossible to estimate, but could be substantial. The 10% incidence in the control animals, if
attributable to fugitive vapors, would be a lower bound estimate, as the animals in closer
proximity to the source of the vapors would have been exposed to a higher concentration. The
lack of lung lesions in the subchronic study at dose levels up to 2000 mg/kg-day could suggest
that the lung lesions observed in the chronic study could have resulted primarily from inhalation
exposure or could be an indication of the impact of continued exposure duration for this
endpoint. The acute injection and longer-term dermal exposure studies clearly indicate, however,
that lung lesions can arise from systemic exposure to methylnaphthalenes. It seems likely that at
least part of the observed response is a result of ingestion of 1-methylnaphthalene. Additional
support for the selection of pulmonary alveolar proteinosis as the critical effect is provided by a
14

-------
1-10-2008
similar finding in other mice receiving 2-methylnaphthalene in the diet for 81 weeks (Murata et
al., 1997). The Toxicological Review for 2-methylnaphthalene (U.S. EPA, 2007) contains
additional detail on this issue.
The lowest dose of 1-methylnaphthalene associated with pulmonary alveolar proteinosis
is 71.6 mg/kg-day in the male mice of the principal study (Murata et al., 1993). Pulmonary
alveolar proteinosis in humans is a disease characterized by the accumulation of surfactant
material in the alveolar lumen that has been associated with decreased functional lung volume,
reduced diffusing capacity, and symptoms such as dyspnea and cough (Mazzone et al., 2001;
Wang et al., 1997). In mice given repeated dermal doses (twice weekly for 30 weeks) of a
mixture of 1- and 2-methylnaphthalene, pulmonary hyperplasia and hypertrophy of type II
pneumocytes in alveolar regions with proteinosis were observed by light microscopy (Murata et
al., 1992). Therefore, dermal absorption may have contributed to the incidence of lung lesions in
mice, as well. The pulmonary alveolar proteinosis observed in the mice exposed to
1-methylnaphthalene in the diet for 81 weeks consisted of cholesterol crystals, foamy cells, and
an amorphous acidophilic material in alveolar lumen, with no notable edema, alveolitis, lipidosis,
or fibrosis at either dose level. Therefore, the dose of 71.6 mg/kg-day in the male mice of the
principal study is considered a LOAEL for RfD derivation.
A benchmark dose (BMD) analysis of the Murata et al. (1993) data is not appropriate
because of the confounding inhalation exposure from fugitive vapors, which was likely not
constant across dose groups. In addition, the incidence of alveolar proteinosis (46%) at the
lowest exposure level would lend uncertainty to the estimation of a point of departure at lower
incidences of the effect. . Therefore, the LOAEL of 71.6 mg/kg-day for significantly increased
incidences of male mice exhibiting pulmonary alveolar proteinosis is selected as the point of
departure for the chronic RfD screening value.
A chronic screening-value RfD of 7E-3 mg/kg-day based on pulmonary alveolar
proteinosis in mice (Murata et al., 1993) is derived by dividing the LOAEL of 71.6 mg/kg-day
by a composite uncertainty factor (UF) of 10,000, which includes factors of 10 for extrapolating
from a LOAEL to a NOAEL, 10 for interspecies extrapolation, 10 for interindividual variability,
and 10 for database deficiencies.
The standard 10-fold UF is used to extrapolate from a LOAEL to a NOAEL. A 10-fold
UF is used to account for uncertainty in extrapolating from laboratory animals to humans (i.e.,
interspecies variability). No information is available regarding the toxicity of
1-methylnaphthalene in orally-exposed humans. No comparative information is available
regarding the toxicokinetics or toxicodynamics of 1-methylnaphthalene in animals and humans.
A 10-fold UF is used to account for variation in sensitivity among members of the human
population (i.e., interindividual variability), as there is no human oral exposure data. A 10-fold
UF is used to account for uncertainty associated with database deficiencies. One chronic-
duration oral toxicity study in one animal species (mouse) is available (Murata et al., 1993). The
database lacks adequate studies of oral neurotoxicity, developmental toxicity, and reproductive
toxicity (including 2-generation reproductive toxicity).
15

-------
1-10-2008
The principal study for the RfD (Murata et al., 1997) examined a comprehensive number
of endpoints, including extensive histopathology, and tested two dietary dose levels using
sufficient numbers (50/sex/group) of B6C3F1 mice. Confidence in the study however, is low
because 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 was not quantified. Therefore, the exact dosage of
1-methylnaphthalene and the fraction of the response attributable to oral ingestion are difficult to
estimate with accuracy. These factors add considerable uncertainty to the dose-response
relationship between oral exposure to 1-methylnaphthalene and pulmonary alveolar proteinosis
assessed from the Murata et al. (1997) study. As the toxicity of 1-methylnaphthalene and 2-
methylnaphthalene is similar, 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. Confidence in the oral toxicity database is also low. No epidemiology studies or case
reports were located which examined the potential effects of human exposure to 1-
methylnaphthalene. Only mice have been examined in adequate animal studies on toxicity from
repeated exposure to 1-methylnaphthalene. No assays of developmental toxicity, reproductive
toxicity, or neurotoxicity following oral exposure to 1-methylnaphthalene are available.
Confidence in the oral RfD is low, as it is likely to change with acquisition of new data.
16

-------
1-10-2008
APPENDIX B
BENCHMARK DOSE ANALYSIS OF LUNG ADENOMAS OR CARCINOMAS
(COMBINED) IN MALE MICE RECEIVING 1-METHYL-NAPHTHALENE IN THE
DIET FOR 81 WEEKS (MURATA ET AL. 1993)
All available dichotomous models in the EPA Benchmark Dose Software (Version 1.3.2)
were fit to the incidence data for male mice exhibiting lung adenoma or carcinoma (combined)
(see Table 1 on p. 5). As assessed by the % goodness-of-fit test, several models provided
adequate fits to the data p value > 0.1) (Table B-l). Comparing across models, the best-
fitting model is the log-logistic model, as indicated by the lowest AIC value (U.S. EPA, 2000).
In accordance with U.S. EPA (2000, 2005) guidance, benchmark doses (BMDs) and
corresponding lower 95% confidence intervals (BMDLs) associated with an extra risk of 10%
were calculated.
TABLE B-l. BMD Modeling Results
Model
Degrees of
Freedom
X2
X2 Goodness-
of-Fit
p-Value
AIC
BMDio
(mg/kg-d)
BMDL10
(mg/kg-d)
Log-logistic (slope>l)
1
0.78
0.3760
139.875
35.29
22.91
Multistage (degree=l)a
1
1.15
0.2837
140.225
39.95
27.67
Quantal Linear
1
1.15
0.2837
140.225
39.95
27.67
Weibull (power>l)
1
1.15
0.2837
140.225
39.95
27.67
Gamma (power>l)
1
1.15
0.2837
140.225
39.95
27.67
Log-probit (slope>l)
1
3.24
0.0719
142.215
59.26
44.69
Probit
1
3.33
0.0682
142.401
64.27
50.74
Logistic
1
3.68
0.0551
142.801
68.34
54.19
Quantal Quadratic
1
5.32
0.0211
144.147
75.50
59.70
aDegree of polynomial initially set to (n-1) where n = number of dose groups including control;
model selected is lowest degree model providing adequate fit. Betas restricted to >0.
17

-------
1-10-2008
Probit Model with 0.95 Confidence Level
Probit
0	20	40	60
100	120	140
12:55 09/21 2006
dose
Figure A-l. Fit of Log-Logistic Model to Male Mouse Lung Adenoma or Carcinoma (Combined)
Data (Murata et al., 1993)
18

-------