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Posted Date: 2010-03-26T04:00Z

Naphthalene (CASRN 91-20-3) 

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0436

Naphthalene; CASRN 91-20-3 (09/17/1998)

Health assessment information on a chemical substance is included in
IRIS only after a comprehensive review of chronic toxicity data by U.S.
EPA health scientists from several Program Offices and the Office of
Research and Development. The summaries presented in Sections I and II
represent a consensus reached in the review process. Background
information and explanations of the methods used to derive the values
given in IRIS are provided in the Background Documents. 

STATUS OF DATA FOR Naphthalene

File First On-Line 12/01/1990

Category (section)	Status	Last Revised

Oral RfD Assessment (I.A.)	On-line	09/17/1998 

Inhalation RfC Assessment (I.B.)	On-line	09/17/1998

Carcinogenicity Assessment (II.)	On-line 	09/17/1998 

_I.  Chronic Health Hazard Assessments for Noncarcinogenic Effects

_I.A. Reference Dose for Chronic Oral Exposure (RfD)

Substance Name — Naphthalene

CASRN — 91-20-3

Last Revised — 09/17/1998

The oral Reference Dose (RfD) is based on the assumption that thresholds
exist for certain toxic effects such as cellular necrosis. It is
expressed in units of mg/kg-day. In general, the RfD is an estimate
(with uncertainty spanning perhaps an order of magnitude) of a daily
exposure to the human population (including sensitive subgroups) that is
likely to be without an appreciable risk of deleterious effects during a
lifetime. Please refer to the Background Document for an elaboration of
these concepts. RfDs can also be derived for the noncarcinogenic health
effects of substances that are also carcinogens. Therefore, it is
essential to refer to other sources of information concerning the
carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that
evaluation will be contained in Section II of this file. 

__I.A.1. Oral RfD Summary

Critical Effect	Experimental Doses*	UF	MF	RfD

Decreased mean terminal body weight in males 

Subchronic oral rat study

BCL, 1980a	NOAEL: 100 mg/kg-day;

71 mg/kg-day (adjusted)

LOAEL: 200 mg/kg-day;

142 mg/kg-day (adjusted)	3000  	1  	2E-2

mg/kg-day  

*Conversion Factors and Assumptions — MW = 128.19. Duration adjustment
(5/7) of the doses (100, 200 mg/kg-day) arrived at a critical
NOAEL/LOAEL pair of 71 and 143 mg/kg-day for decreased mean terminal
body weight in male rats. 

__I.A.2. Principal and Supporting Studies (Oral RfD)

Battelle's Columbus Laboratories (BCL). (1980a) Unpublished subchronic
toxicity study: Naphthalene (C52904), Fischer 344 rats. Prepared by
Battelle Laboratories under NTP Subcontract No. 76-34-106002.

Naphthalene (> 99% pure) in corn oil was administered by gavage to
groups of 10 male and 10 female Fischer 344 rats at dose levels of 0,
25, 50, 100, 200, or 400 mg/kg (duration-adjusted 0, 17.9, 35.7, 71.4,
142.9, and 285.7 mg/kg-day), 5 days/week for 13 weeks (BCL, 1980a).
Measured parameters included food consumption and body weight weekly,
twice-daily observation for clinical signs of toxicity, hematological
parameters for blood collected at termination (hemoglobin, hematocrit,
total and differential white blood cell count, red blood cell count,
mean cell volume, mean cell hemoglobin concentration), necropsy of all
rats in the study, and complete histopathological examination of 27
organs and tissues (including the eyes, lungs, stomach, liver, kidney,
reproductive organs, thymus, and kidney) from all control and 400-mg/kg
rats. Male kidneys and female thymuses from the 200-mg/kg group were
also examined histopathologically (according to the histopathology
tables; however, the report text states that the 100-mg/kg group was
examined). Organ weight data were not reported.

At the highest dose level, two males died during the last week of
treatment, and rats of both sexes displayed diarrhea, lethargy, hunched
posture, and rough coats at intermittent intervals throughout the study
(BCL, 1980a). Food consumption was not affected by exposure, but mean
decreases in terminal body weight greater than 10% compared with control
values were found in several groups of exposed rats (over the 13-week
period); namely, 23% depression in females at 400 mg/kg and a 29% and
12% depression in males at 400 and 200 mg/kg-day, respectively.
Differences between mean values of hematological parameters in exposed
groups and control groups were < 10% of control values, except for a 94%
increase in numbers of mature neutrophils and a 25.1% decrease in
numbers of lymphocytes in male 400-mg/kg rats and a 37.2% increase in
mature neutrophils in 400-mg/kg females. Histological examinations
revealed low incidences of lesions in exposed male kidneys and exposed
female thymuses; no lesions were observed in respective control kidneys
or thymuses. Lesions such as focal cortical lymphocytic infiltration or
focal tubular regeneration were observed in kidneys of 2/10 male rats
exposed to 200 mg/kg naphthalene, and diffuse renal tubular degeneration
occurred in 1/10 male rats exposed to 400 mg/kg naphthalene. Other
lesions include lymphoid depletion of the thymus, which occurred in 2/10
females exposed to 400 mg/kg naphthalene, but not in any other females.
No other tissue lesions were detected. Decreased body weight was the
most sensitive effect noted in this study and was identified as the most
appropriate critical effect for the purposes of RfD derivation. Mean
terminal body weight decreases greater than 10% compared with control
values were found in male rats following a 90-day gavage exposure to 200
mg/kg-day (LOAEL). The NOAEL for a > 10% decrease in body weight in this
study was 100 mg/kg-day (71 mg/kg-day duration-adjusted).

Shopp, GM; White, KL, Jr.; Holsapple, MP; et al. (1984) Naphthalene
toxicity in CD-1 mice: general toxicology and immunotoxicology. Fundam
Appl Toxicol 4(3 pt 1):406-419.

Groups of male and female albino CD-1 mice (approximately 6 weeks old at
the start) were administered gavage doses of 0, 5.3, 53, or 133 mg/kg
naphthalene (99.3% pure) in corn oil for 90 consecutive days (Shopp et
al., 1984). A naive control group and the 5.3- and 53-mg/kg dose groups
each contained 76 male mice and 40 female mice. The vehicle control
group contained 112 male mice and 76 female mice. The high-dose group
contained 96 male mice and 60 female mice. Significant chemical-related
decreases in terminal body weights or survival were not observed in
either sex. No significant alterations in absolute or relative organ
weights occurred in exposed male mice. Significant decreases in absolute
weights of brain, liver, and spleen and relative weight of spleen
occurred in high-dose females; however, organ-to-body weight ratios were
significantly different only for the spleen. Histopathological
examination of organs was not conducted, but the authors noted that
cataracts were not formed in exposed mice (methods used to assess the
presence of cataracts were not specified). Examination of hematological
parameters (including numbers of leukocytes, erythrocytes, and platelets
and determination of hematocrit and hemoglobin) at termination revealed
only slight, but statistically significant, increases in hemoglobin in
high-dose females only; however, the hematological data were not shown
in the report. Chemical analysis of serum showed statistically
significant decreased blood urea nitrogen in all exposed female groups,
and increased serum globulin and protein in the two highest female dose
groups. In the same study, no exposure-related responses were found in a
battery of immunological assays (humoral immune response, lymphocyte
responsiveness, delayed-type hypersensitivity response, popliteal lymph
node response, and bone marrow function); immunotoxic responses were
observed in positive controls given intraperitoneal injections of 50
mg/kg cyclophosphamide on days 87, 88, 89, and 90. The study identified
a LOAEL of 133 mg/kg-day and a NOAEL of 53 mg/kg-day with significant
decreases in absolute weight of brain, liver, and spleen and relative
weight of spleen in high-dose females. Therefore, the LOAEL of 133
mg/kg-day is based on the observed organ effects, especially the
decrease in the relative weight of the spleen along with the suggestive
evidence for effects on hepatic enzyme function. The toxicological
significance of the statistically significant alterations in
hematological and serum chemical parameters is not clear.

The use of the BCL (1980a) study in deriving the RfD was based on the
following reasons:

The verification of the chemical dose, animal maintenance, and study
design (10 rats/sex/dose group for 5 dose groups and 1 control group)
are consistent with GLP guidelines submitted for 90-day studies, unlike
the Shopp et al. (1984) study, in which the numbers of animals actually
evaluated compared to those exposed for most endpoints (organ weights,
clinical chemistry, and immunological testing) were small.

The decrease in mean terminal body weight in the BCL (1980a) study was
not a result of decreased food consumption and was accompanied by
clinical signs (diarrhea, lethargy, and rough coats) consistent with
sick animals.

Decreases in mean terminal body weight of at least 10% were observed in
females and males in the case of the BCL (1980a) study, unlike the Shopp
et al. (1984) study, in which no significant changes in body weight were
reported at any dose level.

The statistically significant alterations (p < 0.05) observed in the
absolute (brain, liver, and spleen) and relative weight (spleen) of some
organs in the absence of any decrease in body weight (Shopp et al.,
1984) is not consistent with the absence of lesions and the lack of
significant alterations in the clinical chemistry data, hematology,
mixed-function oxidase activity, or the immunotoxicity assays for either
sex.

Although the gross and histopathological examination was limited to the
control and high-dose group in the BCL (1980a) study, renal lesions of
low incidence were observed in the kidneys (focal cortical lymphocytic
infiltration, focal and diffuse tubular regeneration) and thymus
(lymphoid depletion) in males and females, respectively, at 100 mg/kg
(71 mg/kg-day), unlike the Shopp et al. (1984) study, in which gross
necropsy (no histopathological examination of tissues) on a randomly
selected number of animals revealed no lesions.

__I.A.3. Uncertainty and Modifying Factors (Oral RfD)

UF = 3000.

The duration-adjusted NOAEL for terminal body weight decrease (> 10% of
control) in male rats from the BCL (1980a) 90-day gavage study, 71
mg/kg-day, was divided by an uncertainty factor of 3000 (10 to
extrapolate from rats to humans, 10 to protect sensitive humans, 10 to
extrapolate from subchronic to chronic exposure, and 3 for database
deficiencies including the lack of chronic oral exposure studies and
2-generation reproductive toxicity studies) to arrive at a chronic RfD
for naphthalene of 2E-2 mg/kg-day.

MF = 1.

__I.A.4. Additional Studies/Comments (Oral RfD)

In deriving the RfD additional studies were evaluated for a variety of
critical effects. Nervous system depression in pregnant rats (NTP, 1991)
occurring at a lower dose (50 mg/kg-day), was judged to be nonadverse,
because the effect was considered to be transient in nature. Data from
studies of mice exposed acutely to injections of naphthalene, or 1- or
2-methylnaphthalene (Buckpitt and Franklin, 1989), or chronically to 1-
or 2-methylnaphthalene in the diet (Murata et al., 1993, 1997) provide
suggestive evidence that chronic oral exposure to naphthalene at low
doses may produce lung injury. However, deriving an RfD for naphthalene
based on the methylnaphthalene data was judged to be too uncertain,
because of metabolic differences between naphthalene and
methylnaphthalenes and the absence of lung injury in subchronic oral
studies in rats (BCL, 1980a) and mice with naphthalene (BCL, 1980b;
Shopp et al., 1984).

A benchmark dose (BMD) approach to modeling the male rat body weight
data fits mathematical models for a continuous variable to the data
using maximum likelihood methods (see Appendix B to the Toxicological
Review of Naphthalene, "Benchmark Dose Calculations"). In this approach,
maximum likelihood estimates (MLEs) of dose (with no duration
adjustment) associated with a 10% decrease in mean body weight compared
with nonexposure conditions were 171 and 172 mg/kg-day using a
polynomial and power model, respectively; respective 95% confidence
lower limits on these doses, taken as BMDs, were 130 and 135 mg/kg-day.
Assuming that either of these BMDs are surrogates for NOAELs, as
suggested by the analysis of developmental toxicity data by Allen et al.
(1994a,b) and Kavlock et al. (1995), making duration adjustments (BMD x
5/7) and applying the same 3000 uncertainty factor used for the
NOAEL/LOAEL approach arrives at a prospective RfD for naphthalene, 3E-2
mg/kg-day, that is comparable to the RfD derived with the NOAEL/LOAEL
approach.

Benchmark dose approaches to deriving a chronic RfD for naphthalene were
also examined using data for maternal body weight decreases in the NTP
(1991) rat developmental toxicity study and data for lung proteinosis in
mice exposed for 81 weeks to 1-methylnaphthalene in the diet (Murata et
al., 1993). Decreased maternal body weight was not selected as the basis
of chronic RfD derivation because the pregnant rats were exposed for
only a small percentage of their lives. As discussed earlier, deriving
the naphthalene RfD based on 1-methylnaphthalene data was judged to be
too uncertain because of metabolic differences between naphthalene and
methylnaphthalenes and the absence of lung injury in rats and mice
orally exposed to naphthalene for subchronic periods.

The benchmark methodology for naphthalene is contained within an
appendix of the Toxicological Review for the readers' information,
however it was decided to use the LOAEL/NOAEL approach rather than the
benchmark approach in the derivation of the RfD/RfC.

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l "page=42"  the
toxicological review, Section 4.7  (PDF). 

__I.A.5. Confidence in the Oral RfD

Study — High

Database — Low

RfD — Low

The principal study was given a high confidence rating because adequate
numbers of animals were included and experimental protocols were
adequately designed, conducted, and reported. Confidence in the database
was rated low because of the lack of adequate chronic oral data for
naphthalene; the lack of any dose-response data for naphthalene-induced
hemolytic anemia, probably one of the most well-known health Hazards to
humans exposed to naphthalene; and the lack of two-generation
reproductive toxicity studies. Humans exposed via inhalation, combined
inhalation and dermal exposure, and combined inhalation and oral
exposure have developed hemolytic anemia. Hemolytic anemia is
characterized by findings of lowered hemoglobin, hematocrit, and
erythrocyte values, elevated reticulocyte counts, Heinz bodies, elevated
serum bilirubin, and fragmentation of erythrocytes. In severe cases, the
hemolytic anemia was accompanied by jaundice, high serum levels of
bilirubin, cyanosis, and kernicterus with pronounced neurological signs.
Neither oral nor inhalation exposure levels were available in human
studies reporting anemia (Melzer-Lange and Walsh-Kelly, 1989; Owa, 1989;
Owa et al., 1993). Infants deficient in G6PDH are thought to be
especially sensitive to naphthalene-induced hemolytic anemia. Resulting
confidence in the RfD is low. A quantitative comparison of the acute dog
study (7 days at 262 mg/kg-day; free-standing LOAEL of 262 mg/kg-day
based hemolytic anemia) with the RfD (chronic oral rat study based on
decrease in mean terminal body weight) to determine whether the RfD is
protective of hemolytic anemia in humans is not possible since adequate
dose-response data in a subchronic or chronic dog study are lacking.
Therefore, because of the absence of an appropriate animal model one
cannot extrapolate either qualitatively or quantitatively to humans with
respects to hemolytic anemia.

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=48"  the toxicological review, Section 6  (PDF). 

__I.A.6. EPA Documentation and Review of the Oral RfD

Source Document — U.S. EPA, 1998

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included in an appendix to
the Toxicological Review of Naphthalene in support of Summary
Information on the Integrated Risk Information System (IRIS) (U.S. EPA,
1998).   HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=62"  To review this appendix, exit to the toxicological review,
Appendix A, Summary of and Response to External Peer Review Comments
(PDF) . 

Other EPA Documentation — U.S. EPA, 1980, 1986, 1987a, 1988

Agency Consensus Date - 07/01/98

__I.A.7. EPA Contacts (Oral RfD)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(fax), or   HYPERLINK "mailto:rih.iris@epa.gov"  hotline.iris@epa.gov 
(Internet address).

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_I.B. Reference Concentration for Chronic Inhalation Exposure (RfC)

Naphthalene

CASRN — 91-20-3

Last Revised — 09/17/1998

The inhalation Reference Concentration (RfC) is analogous to the oral
RfD and is likewise based on the assumption that thresholds exist for
certain toxic effects such as cellular necrosis. The inhalation RfC
considers toxic effects for both the respiratory system
(portal-of-entry) and for effects peripheral to the respiratory system
(extrarespiratory effects). It is generally expressed in units of mg/m3.
In general, the RfC is an estimate (with uncertainty spanning perhaps an
order of magnitude) of a daily inhalation exposure of the human
population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation
RfCs were derived according to the Interim Methods for Development of
Inhalation Reference Doses (EPA/600/8-88/066F, August 1989), and
subsequently according to Methods for Derivation of Inhalation Reference
Concentrations and Application of Inhalation Dosimetry
(EPA/600/8-90/066F, October 1994). RfCs can also be derived for the
noncarcinogenic health effects of substances that are carcinogens.
Therefore, it is essential to refer to other sources of information
concerning the carcinogenicity of this substance. If the U.S. EPA has
evaluated this substance for potential human carcinogenicity, a summary
of that evaluation will be contained in Section II of this file.

__I.B.1. Inhalation RfC Summary

Critical Effect	Experimental Doses*	UF	MF	RfC

Nasal effects: hyperplasia 

and metaplasia in respiratory 

and olfactory epithelium,

respectively

Chronic mouse inhalation 

study

NTP, 1992a	NOAEL: None

LOAEL(HEC): 9.3 mg/m3  	3000

 

 	1

 

 	3E-3 

mg/m3 

 

 

*Conversion Factors and Assumptions — Following the Category 3
guidance (U.S. EPA, 1994), experimental exposure concentrations of 0,
10, and 30 ppm were converted to 0, 52, and 157 mg/m3, respectively;
adjusted to a continuous exposure basis in mg/m3 (6/24 hr x 5/7 days)
equals mg/m3 x 0.1786: 0, 9.3, and 28 mg/m3. Because the blood:gas (air)
coefficients for naphthalene were not available, the default ratio of 1
was used and the values for the LOAEL(HEC) were 0, 9.3, and 28 mg/m3.
Scenario -- The LOAEL human equivalent concentration (HEC) was
calculated for an extrarespiratory effect for a category 3 gas. Since
the b:a lambda for humans (h) is unknown, a default value of 1.0 is used
for this ratio. LOAEL(HEC) x [b:a lambda(animal)/b:a lambda(human)] =
9.3 mg/m3. 

__I.B.2. Principal and Supporting Studies (Inhalation RfC)

National Toxicology Program (NTP). (1992a) Toxicology and carcinogenesis
studies of naphthalene in B6C3F1 mice (inhalation studies). Technical
Report Series No. 410. NIH Publication No. 92-3141.

B6C3F1 mice (75/sex/group) were exposed to naphthalene (scintillation
grade, > 99% pure) at target concentrations of 0, 10, and 30 ppm (0, 52,
157 mg/m3) for 6 hr/day, 5 days/week, for 103 weeks (NTP, 1992a). The
duration-adjusted levels were 0, 9.3, and 28 mg/m3, respectively.
Additional groups of 75 male and 75 female replacement animals were
exposed to 30 ppm to ensure that a sufficient number of mice lived to
study termination. Naphthalene vapor was generated by direct sublimation
and monitored by a software feedback arrangement. Average weekly
concentrations were within 20% of target concentrations, except one week
when the mean concentration in the low-concentration chamber was 5.5
ppm. Supplemental hematology studies were scheduled with 25
animals/sex/group, but only the first sacrifice (at 14 days) was
conducted because of high mortality in the male control group from
fighting. Serial slit-lamp biomicroscopy and indirect ophthalmoscopic
examinations were conducted on 5 animals/sex/group at 6-mo intervals.
Gross necropsies were conducted on all animals. Complete histopathologic
examinations of major tissues were conducted on all animals, except that
the only tissues examined from low-concentration animals dying or killed
after 21 mo of exposure were the lungs and nasal cavities.

Survival of the male controls was significantly lower than in the
exposed males. Reduced survival was related to wound trauma and lesions
from increased fighting in this group. Similar effects were not seen in
the exposed males, because they tended to huddle in cage corners during
exposure periods and so fought less. There was no significant difference
in survival between the treatment and control females. There were no
treatment-related ocular lesions in the selected mice that underwent
ophthalmologic examinations at 6-mo intervals. There were no
biologically significant changes in hematology parameters at day 14 of
the study. Final mean body weights of the treated animals were within
10% of the corresponding controls.

Inflammation, metaplasia of the olfactory epithelium, and hyperplasia of
the respiratory epithelium were noted in the noses of virtually all
exposed mice of both sexes, but in only one control female mouse. These
effects were slightly more severe in the high-concentration group. See
Table 1 for incidence data. The lesions were focal or multifocal,
occurred mainly in the posterior nasal cavity, and were minimal to mild
in severity. Inflammatory lesions included substantia propria edema,
congestion, mixed inflammatory cell infiltrates, necrotic debris, and
intraluminal serous to fibrinopurulent exudate. Respiratory epithelial
hyperplasia resulted in a thickened, folded, irregular mucosal surface.
Olfactory epithelial metaplasia often involved ciliated columnar or
pseudocolumnar respiratory-like epithelial cells replacing the usual
olfactory cell layer. The lesions were collectively considered features
of a generalized inflammatory and regenerative process.

Table 1. Incidence of nonneoplastic respiratory lesions in B6C3F1 mice
exposed by inhalation to naphthalene, 6 hr/day, 5 days/week for 2 years

Exposure

level/sex

(ppm)	Respiratory lesion

	Inflammation, lung	Hyperplasia, nasal

respiratory

epithelium	Metaplasia, nasal

olfactory epithelium

0/male

0/female	0/70

3/69	0/70

0/69	0/70

0/69

10/male

10/female	21/69

13/65	66/69

65/65	66/69

65/65

30/male

30/female	56/135

52/135	134/135

135/135	134/135

135/135

Source: NTP, 1992a.

Minimal to mild lung lesions, including infiltration of histiocytes or
lymphocytes, inflammation, hyperplasia of the alveolar epithelium, and
bronchial submucosal gland distension, were observed in both controls
and treated mice. The incidence and severity were generally higher in
the treated groups of both sexes, but there was no clear
concentration-response relationship.

Females in the high-exposure group had elevated incidences of
alveolar/bronchiolar adenomas and carcinomas (combined incidence 22%,
compared with 7% in the control group and 3% in the low-exposure group).
The incidence was also above that of historical controls and was
considered compound-related. The incidences of alveolar/bronchiolar
adenomas and carcinomas in treated males were marginally increased (10%,
25%, and 23%, in the control, low-concentration, and high-concentration
groups, respectively). However, because the increase was not
statistically significant and was within the range of historical
controls, it was not considered exposure related. Instead, it was
attributed to the longer life span of the treated animals. Nasal
adenomas occurred in the anterior nasal cavities of two females in the
low-concentration group. They were not considered compound related
because the increase was not concentration related or statistically
significant. Therefore, the nasal lesions discussed above should not be
considered preneoplastic.

Calculation of the Human Equivalent Concentration (HEC)

Dose conversion: Because of its low water solubility and low reactivity,
naphthalene-related effects on the nasal epithelium are expected to
result following absorption of naphthalene and metabolism to reactive
oxygenated metabolites, rather than being a result of direct contact.
This hypothesis is supported by data on naphthalene metabolism
indicating that toxic effects on the respiratory tract are due to a
naphthalene metabolite that may be formed either in the liver or in the
respiratory tract. For example, necrosis of bronchial epithelial (Clara)
cells in mice (O'Brien et al., 1985, 1989; Tong et al., 1981) and
necrosis of olfactory epithelium in mice, rats, and hamsters (Plopper et
al., 1992) occur following intraperitoneal injection of naphthalene. The
nasal effects from inhalation exposure to naphthalene were considered to
be extra-respiratory 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 exposure concentrations were adjusted to a mg/m3
basis (0, 52, and 157 mg/m3), adjusted to a continuous exposure basis
(mg/m3 x 6h/24h x 5d/7d = mg/m3 x 0.1786: 0, 9.3, and 28 mg/m3), and
converted to human equivalent concentrations (HECs) by multiplying the
adjusted concentrations by the ratio of mouse:human blood/gas partition
coefficients. Because the blood/gas coefficients for naphthalene were
not available, the default ratio of 1 was used.

Dose-response modeling: Whereas the data from the NTP (1992a) study show
nasal effects to be the most sensitive effects from chronic inhalation
exposure to naphthalene, they provide no indication of the shape of the
dose-response curve because the incidence of nasal lesions at the lowest
exposure level was 100% in females and nearly 100% in males (see Table
1). In this case, application of a BMD approach, in which quantal
mathematical models are fit to the incidence data for nasal effects,
does not sensibly assist in extrapolating to a NOAEL, and a NOAEL/LOAEL
approach was taken for deriving an RfC for naphthalene.

__I.B.3. Uncertainty and Modifying Factors (Inhalation RfC)

UF = 3000.

The adjusted LOAEL(HEC) of 9.3 mg/m3 for nasal effects (hyperplasia in
respiratory epithelium and metaplasia in olfactory epithelium) was
divided by an uncertainty factor of 3000 (10 to extrapolate from mice to
humans, 10 to protect sensitive humans, 10 to extrapolate from a LOAEL
to a NOAEL, and 3 for database deficiencies including the lack of a
2-generation reproductive toxicity study and chronic inhalation data for
other animal species) to arrive at a chronic RfC for naphthalene of 3E-3
mg/m3.

MF = 1.

__I.B.4. Additional Studies/Comments (Inhalation RfC)

SUPPORTING STUDIES

Human experience with acute accidental exposures to naphthalene
identifies the development of hemolytic anemia and cataracts as health
Hazards of concern. However, information is not available regarding
dose-response relationships for these effects in humans with acute,
subchronic, or chronic exposure by any route. Animal inhalation studies
are restricted to three studies of mice: a 2-year study (NTP, 1992), a
6-mo study (Adkins et al., 1986), and a 4-hr study (Buckpitt, 1982).
Results from the chronic study, supported by the subchronic and acute
studies, identify nasal and pulmonary injuries as critical effects from
chronic inhalation exposure to naphthalene; effects in other organs or
tissues were not found. Incidence data for male and female mice with
hyperplasia of the nasal respiratory epithelium, metaplasia of the nasal
olfactory epithelium, and chronic pulmonary inflammation clearly show
that the nose is more sensitive than the lung to chronic inhalation
exposure to naphthalene. At both exposure levels (10 and 30 ppm, 6
hr/day, 5 days/week), > 95% of mice of either sex showed nasal lesions,
whereas pulmonary lesions were found in < 1/3 and < 1/2 of mice exposed
at 10 and 30 ppm, respectively (Table 1). Nasal lesions in the
respiratory and olfactory epithelium in mice found in the NTP (1992a)
study were therefore selected as the critical effects for the purpose of
RfC derivation.

Adkins et al. (1986) exposed female A/J mice (30/group) to 0, 10, or 30
ppm (0, 52, or 157 mg/m3) naphthalene for 6 hr/day, 5 days/week for 6
mo, and counted the number of adenomas in each lung. The
duration-adjusted concentrations were 0, 9.2, and 28 mg/m3,
respectively. Exposure to naphthalene caused increases in the total
number of adenomas and the percentage of animals with adenomas, but the
differences were not significant. The number of tumors per tumor-bearing
mouse lung was significantly increased at both exposure levels.

Buckpitt (1982) subjected groups of five male mice (Swiss Webster) plus
control group to 1-hr exposures to naphthalene concentrations of 0,
52.4, 95.8, 204, or 380 mg/m3. Adverse effects were seen only at the
highest concentration, and included swelling of cells and sloughing into
the airway lumen of cells from either the major and/or terminal airways.
The effects were milder in the presence of cytochrome P450 inhibitor and
stronger in the presence of a glutathione depletor, suggesting that
cytotoxicity is due to a naphthalene metabolite produced by P450 and
that glutathione plays a protective role. Naphthalene reduced
glutathione levels in the lung, liver, and kidney, but the
concentration-response curve was flat.

Following a single 4-hr exposure of five male and five female Wistar
Albino rats to 77.7 ppm (407 mg/m3), closed eyes, lacrimation, and mouth
breathing were observed (Bushy Run Research Center, 1986). No signs of
toxicity were observed postexposure or during the 14-day observation
period, and gross necropsy revealed no exposure-related lesions.

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l "page=42"  the
toxicological review, Section 4.7  (PDF). 

__I.B.5. Confidence in the Inhalation RfC

Study — Medium

Database — Low to Medium

RfC -- Low to Medium

The principal study was given medium confidence because adequate numbers
of animals were used, and the severity of nasal effects increased at the
higher exposure concentration. However, the study produced high
mortality, (< 40% survival in the male control group due to wound trauma
and secondary lesions resulting from increased fighting). Also,
hematological evaluation was not conducted beyond 14 days. The database
was given a low-to-medium confidence rating because there are no chronic
or subchronic inhalation studies in other animal species, and there are
no reproductive or developmental studies for inhalation exposure. In the
absence of human or primate toxicity data, the assumption is made that
nasal responses in mice to inhaled naphthalene are relevant to humans;
however, it cannot be said with certainty that this RfC for naphthalene
based on nasal effects will be protective for hemolytic anemia and
cataracts, the more well-known human effects from naphthalene exposure.
Medium confidence in the RfC follows. 

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=48"  the toxicological review, Section 6  (PDF). 

__I.B.6. EPA Documentation and Review of the Inhalation RfC

Source Document — U.S. EPA, 1998

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included in an appendix to
the Toxicological Review of Naphthalene in support of Summary
Information on the Integrated Risk Information System (IRIS) (U.S. EPA,
1998).   HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=62"  To review this appendix, exit to the toxicological review,
Appendix A, Summary of and Response to External Peer Review Comments
(PDF) . 

Other EPA Documentation — U.S. EPA, 1980, 1986, 1987a, 1988

Agency Consensus Date - 7/1/98

__I.B.7. EPA Contacts (Inhalation RfC)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(fax), or   HYPERLINK "mailto:hotline.iris@epa.gov" 
hotline.iris@epa.gov  (Internet address).

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_II.  Carcinogenicity Assessment for Lifetime Exposure

Naphthalene

CASRN — 91-20-3

Last Revised — 09/17/1998

Section II provides information on three aspects of the carcinogenic
assessment for the substance in question, the weight-of-evidence
judgment of the likelihood that the substance is a human carcinogen, and
quantitative estimates of risk from oral exposure and from inhalation
exposure. The quantitative risk estimates are presented in three ways.
The slope factor is the result of application of a low-dose
extrapolation procedure and is presented as the risk per (mg/kg)/day.
The unit risk is the quantitative estimate in terms of either risk per
µg/L drinking water or risk per µg/m3 air breathed. The third form in
which risk is presented is a concentration of the chemical in drinking
water or air associated with cancer risks of 1 in 10,000, 1 in 100,000,
or 1 in 1,000,000. The rationale and methods used to develop the
carcinogenicity information in IRIS are described in the Risk Assessment
Guidelines of 1986 (EPA/600/8-87/045) and in the IRIS Background
Document. IRIS summaries developed since the publication of EPA's more
recent Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA,
1996) also utilize those Guidelines where indicated. Users are referred
to Section I of this IRIS file for information on long-term effects
other than carcinogenicity.

_II.A. Evidence for Human Carcinogenicity

__II.A.1. Weight-of-Evidence Characterization

Using criteria of the 1986 Guidelines for Carcinogen Risk Assessment,
naphthalene is classified in Group C, a possible human carcinogen. This
is based on the inadequate data of carcinogenicity in humans exposed to
naphthalene via the oral and inhalation routes, and the limited evidence
of carcinogenicity in animals via the inhalation route.

Using the 1996 Proposed Guidelines for Carcinogen Risk Assessment, the
human carcinogenic potential of naphthalene via the oral or inhalation
routes "cannot be determined" at this time based on human and animal
data; however, there is suggestive evidence (observations of benign
respiratory tumors and one carcinoma in female mice only exposed to
naphthalene by inhalation [NTP, 1992a]). Additional support includes
increase in respiratory tumors associated with exposure to
1-methylnaphthalene.

At the present time the mechanism whereby naphthalene produces benign
respiratory tract tumors are not fully understood, but are hypothesized
to involve oxygenated reactive metabolites produced via the cytochrome
P-450 monooxygenase system. However, based on the many negative results
obtained in genotoxicty tests, a genotoxic mechanism appears unlikely.

For more detail on Characterization of Hazard and Dose Response, exit to
  HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=48"  the toxicological review, Section 6  (PDF).

For more detail on Susceptible Populations, exit to   HYPERLINK
"http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l "page=42"  the
toxicological review, Section 4.7  (PDF). 

__II.A.2. Human Carcinogenicity Data

Available data are inadequate to establish a causal association between
exposure to naphthalene and cancer in humans. Adequately scaled
epidemiological studies designed to examine a possible association
between naphthalene exposure and cancer were not located. Overall, no
data are available to evaluate the carcinogenic potential in exposed
human populations.

__II.A.3. Animal Carcinogenicity Data

Inhalation: In an NTP (1992a) cancer bioassay, groups of male and female
B6C3F1 mice were exposed (whole-body) to naphthalene (> 99% pure) vapors
at concentrations of 0 (75 mice/sex), 10 (75 mice/sex), or 30 ppm (150
mice/sex) 6 hr/day, 5 days/week for 2 years. Mice were housed five to a
cage. There were 150 mice housed in each of 4 inhalation chambers; 2
chambers were used for the high-exposure level. A comprehensive
histological examination was performed on all control and high-dose mice
and on low-dose mice that died or were sacrificed before 21 months of
exposure. After 21 months of exposure, only the nasal cavity and lung
were examined in the low-dose group. In each chamber, 50 animals per sex
were designated for the 2-year studies; 5 animals per sex were
designated for hematological evaluations at 14 days and 3, 6, 12, and 18
mo. However, because of high mortality in the male control group (see
next paragraph), only the 14-day hematological evaluation was conducted.
The other surviving interim mice were incorporated into the 2-year
study.

Statistically significant decreases in survival were observed in the
control male mice compared with the exposed groups. Exposed male mice
were observed to huddle in corners of the cages during exposure and were
less inclined to fight. Survival percentages at the end of the study
were 37% (26/70), 75% (52/69), and 89% (118/133) for the 0, 10, and 30
ppm male groups, respectively. Survival percentages did not include mice
sacrificed at 14 days, mice that died before the study began, mice that
were accidentally killed, or mice that were lost during the study.
Survival at 2 years in the control female mice (86%; 59/69) was
comparable to survival in the exposed groups; survival percentages were
88% (57/65) and 76% (102/135) for low- and high-dose females. Body
weights were not affected by exposure in either sex.

Statistically significant increases in incidences of nonneoplastic
lesions were found in the lung and nose of males and females at both
exposure levels. Observed nonneoplastic effects included the following
(with respective incidences listed in the order of control, low-, and
high-exposure groups): chronic inflammation of the lung (0/70, 21/69,
and 56/135 for males; 3/69, 13/65, and 52/135 for females); chronic
inflammation (0/70, 67/69, and 133/135 for males and 1/69, 65/65, and
135/135 for females); metaplasia of the olfactory epithelium (0/70,
66/69, and 134/135 for males; 0/69, 65/65, and 135/135 for females); and
hyperplasia of the respiratory epithelium in the nose (0/70, 66/69, and
134/135 for males; 0/69, 65/65, and 135/135 for females).

The lung inflammation in the exposed mice was described as consisting of
"focal intra-alveolar mixed inflammatory cell exudates and interstitial
fibrosis" that in more advanced lesions consisted "primarily of large
foamy macrophages, sometimes accompanied by multinucleated giant cells."
Foci of alveolar epithelial hyperplasia were noted to occur generally in
regions distant to inflammation.

A statistically significant increase in the incidence of
alveolar/bronchiolar adenomas was observed in the 30 ppm group of
females (28/135), but not in the 10 ppm group (2/65), relative to the
control female group (5/69). Among females, an additional mouse in the
30-ppm group displayed an alveolar/bronchiolar carcinoma. The historical
combined incidence of alveolar/bronchiolar adenomas and carcinomas in
control B6C3F1 female mice from NTP inhalation studies was cited as
39/466 (8.4%, range 0-12%). The authors commented that
alveolar/bronchiolar adenomas and carcinomas constitute a morphologic
continuum. The incidences of male mice with alveolar/bronchiolar
adenomas were 7/70, 15/69, and 27/135 for the control, 10 ppm, and 30
ppm groups, respectively; for combined adenomas and carcinomas of the
alveolar/bronchiolar region, the respective incidences were 7/70, 17/69,
and 31/135. A statistical analysis that adjusted for intercurrent
mortality (logistics regression analysis) determined that the tumor
incidences for control and exposed groups of male mice were not
significantly different (NTP, 1992a). Historical incidence for combined
alveolar/bronchiolar adenomas and carcinomas in control male B6C3F1 mice
from NTP inhalation studies was cited as 94/478 (19.7%, range 10%-30%).
The adenomas were described as "locally compressive nodular masses
consisting of cords of well-differentiated epithelial cells," whereas
the carcinoma was "composed of ribbons and/or coalescing sheets of
smaller, more anaplastic, cells which sometimes extended into adjacent
parenchyma."

Hemangiosarcomas occurred at various sites within the vascular
endothelium in five high-dose female mice (5/135), but not within the
other groups of female mice (0/69 and 0/65 for control and 10 ppm
females, respectively). The high-dose female incidence (3.7%) was not
significantly different from the concurrent control incidence and was
within the range of historical control incidences from NTP inhalation
studies (range: 0-8%; overall incidence: 17/467 or 3.6%). No
significantly elevated incidences of tumors were found at other tissue
sites in exposed male or female mice (NTP, 1992a).

Adkins et al. (1986) exposed groups of 30 female A/J strain mice (6 to 8
weeks old) to 0, 10, or 30 ppm naphthalene (98%-99% pure) vapors, 6
hr/day, 5 days/week for 6 mo. After the 6-mo exposure period, excised
lungs were examined for tumors. Tumors were examined histologically. The
authors did not describe any noncancer histopathological effects that
their examinations may have revealed. Survival was not different between
the exposed and control groups. Lung tumors were found in all 20
positive control mice given single intraperitoneal injections of 1 g
urethane/kg; the mean number of tumors per mouse in the positive control
was 28.9. Increased numbers of lung tumors were found in the
naphthalene-exposed groups compared with the control group, but the
differences were not statistically significant (6, 10, and 11 for the 0,
10, and 30 ppm groups). Tumors were described as alveolar adenomas
consisting of "large cuboidal or columnar pithelial cells supported by a
sparse fibroblastic stroma and arranged in poorly defined acinar
structures with papillary formations." No carcinomas were found.
Naphthalene exposure did not significantly increase the percentage of
animals with tumors (21%, 29%, and 30% for 0, 10, and 30 ppm mice,
respectively). Statistically significant increases in the number of
adenomas per tumor-bearing lung were observed in the exposed mice, but
there was no increase in response with increasing dose. Mean numbers of
tumors per tumor-bearing lung (sd noted in parentheses) were: 1.00
(0.00), 1.25 (0.07), and 1.25 (0.07) for 0, 10, and 30 ppm mice,
respectively. Applicability of this study to the assessment of risk for
lifetime exposure is limited due to the less-than-lifetime exposure and
observation periods, and the limited tissue evaluation examining only
the lung. Nevertheless, the finding that only 6 months of exposure
caused statistically significant increased numbers of lung tumors per
tumor-bearing lung in the exposed groups, coupled with the results of
the NTP (1992a) mouse bioassay, provides further suggestive evidence
that naphthalene produces a tumorigenic response in the mouse lung. 

Oral: Schmahl (1955) reported that naphthalene administered in food did
not cause cancer in a group of 28 rats (in-house strains BDI and BDII).
Naphthalene (purchased from Merck Co. and described as "Naphthalene
puriss. cryst. alcoh. depur. [54935]") was dissolved in oil and given 6
times/week in food. The absorption spectrum of the test material
displayed no atypical peaks compared with published data for
naphthalene, suggesting high purity. The daily dose was reported to vary
between 10 and 20 mg, but further details regarding dose variation were
not provided. After reaching a total dose of 10 g/rat (food intake and
body weights were not reported), treatment was stopped on the 700th
experimental day, and animals were observed until spontaneous death,
between 700 and 800 days of age. Assuming an average daily dose of 15
mg/rat and a body weight of 0.36 kg (U.S. EPA, 1987b, reference body
weight for male Fischer 344 rats), an estimated average daily dose of 42
mg/kg is calculated. Autopsies were performed on dead animals, and
organs that appeared unusual were examined histologically (the report
did not specify which organs were histologically examined). The number
of rats in the control group was not reported; survival for control and
exposed rats was reported to be similar. Reported results from the
autopsy and histological examinations were restricted to the statement
that no toxic effects were seen, including eye damage and tumors.
Inadequacies in experimental design (e.g., only one dose level was
administered, the histopathological examination was not complete,
hematological endpoints were not evaluated, and some rats lived as long
as 300 days beyond exposure before being examined) and inadequacies in
reporting of experimental details and results limit the conclusions that
can be drawn from this study regarding either the carcinogenicity or
noncarcinogenic toxicity of naphthalene. This study is considered
inadequate as a cancer bioassay because of reporting and design
inadequacies and the likelihood that the maximum tolerated dose may not
have been approached.

Other Routes of Administration: Schmähl (1955) reported that
naphthalene repeatedly administered by subcutaneous or intraperitoneal
injection did not produce tumors in rats (in-house strains BDI and
BDIII). Groups of 10 rats were given either subcutaneous or
intraperitoneal weekly injections of naphthalene in oil (20 mg/rat per
injection) starting at 100 days of age and continuing for 40 weeks (the
total doses were 820 mg/rat). Rats were maintained until spontaneous
death occurred. Life spans were reported to be 700 or 900 days for rats
with subcutaneous or intraperitoneal doses, respectively. Autopsies were
performed on dead animals, and organs which appeared unusual were
examined histologically (the report did not specify which organs were
examined, if any). The author reported that no toxic effects were found
with parenteral administration of naphthalene. No tumors developed in
either group. Reported information on control rats was restricted to the
statement that lifespan for exposed rats was similar to lifespan for
control rats (700 days with subcutaneous doses and 900 days with
intraperitoneal doses).

Boyland et al. (1964) implanted naphthalene into the bladder of stock
Chester Beatty mice and examined them after 30 weeks in an effort to
determine the suitability of naphthalene as a potential vehicle for
carcinogenicity testing. The original number of mice implanted with
naphthalene was not reported, but 23 mice were reported to have survived
30 weeks. One mouse developed a bladder carcinoma (1/23; 4%); no
adenomas or papillomas were found. Tumor incidence was as low as when
paraffin wax was used (2-4%), and lower than with the implantation of
cholesterol (12%). There are limitations of this study that make it an
inadequate lifetime cancer bioassay including the short exposure and
observation periods, and the lack of untreated controls.

Coal tar-derived naphthalene that contained approximately 10%
unidentified impurities was tested for carcinogenicity by Knake (1956).
White rats (40, sex unspecified) were given seven subcutaneous
injections of 0 or 500 mg/kg naphthalene in sesame oil at 2-week
intervals over an approximate 3.5-month period. Thirty-four of 38
naphthalene rats and 32/38 control rats survived the injection period.
Survival was somewhat reduced in the naphthalene-exposed rats compared
with the vehicle-control rats during the following 18-month period.
Survival incidences at 6, 11, and 17 months after the injection period
were 21/34, 6/34, and 0/34 for the naphthalene-exposed rats and 17/32,
12/32, and 4/32 for the control rats. Lymphosarcomas were found in 5/34
(14.7%) exposed rats during the 18-month observation period; one exposed
rat showed a mammary fibrosarcoma. Vehicle controls showed a 6% (2/32)
incidence of tumors (one with lymphosarcoma and one with mammary
fibrosarcoma). Mice (25, inbred black) were painted with 0.5%
naphthalene in benzene 5 days/week for life; 21 control mice were
painted with benzene alone. Four treated mice developed lymphomatic
leukemia, three had lung adenomas, one had lymphosarcoma, and one had a
non-specified tumor (9/25 with tumors). In the benzene controls, one had
lymphosarcoma, one had lung adenoma, and one had a non-specified tumor
(3/21 with tumors). These studies are limited for the assessment of
carcinogenicity due to the presence of unknown impurities that may have
carcinogenic properties. Moreover, the vehicle (benzene) in the mouse
study has been shown to cause leukemia in humans and rodents, and the
site of injection in the rat study was painted, prior to injection, with
carbolfuchsin, a known carcinogen.

La Voie et al. (1988) gave intraperitoneal naphthalene doses (in
dimethylsulfoxide) of 0.25, 0.50, and 1.0 µmole to male and female
newborn CD-1 mice on days 1, 8, and 15 of life (total dose = 1.75 µmole
naphthalene). The report did not specify the purity of the naphthalene
tested. Forty-nine pups were treated with naphthalene and 46 control
pups were treated with dimethylsulfoxide alone. Mice were maintained (10
mice/cage) until moribund or until 52 weeks when survivors were killed.
All gross lesions as well as liver sections from all mice were examined
histologically. No statistically significant increased incidence of
liver tumors (adenomas or hepatomas) was found in the exposed mice.
Reported incidences for the number of mice with liver tumors were
(denominators are for the number of mice that lived at least 6 months):
0/16 and 2/31 for exposed females and males, and 0/21 and 4/21 for
vehicle-control females and males. This assay is inadequate to assess
the carcinogenicity of lifetime exposure to naphthalene because the
exposure period (2 weeks) and observation period (52 weeks) were
significantly less than the lifetime for mice (approximately 2 years),
and complete histological examinations were not conducted.

__II.A.4. Supporting Data for Carcinogenicity 

The genotoxic potential of naphthalene has been evaluated in many test
systems. Most studies provided negative results. Naphthalene was not
mutagenic in Salmonella typhimurium assays in the presence or absence of
liver metabolic preparations (Bos et al., 1988; Connor et al., 1985;
Florin et al., 1980; Godek et al., 1985; McCann et al., 1975; Nakamura
et al., 1987; Narbonne et al., 1987; NTP, 1992a; Sakai et al., 1985).
Naphthalene did not damage DNA (as assayed by the induction of the
SOS-repair system) in E. coli PQ37 (Mersch-Sundermann et al., 1993).

NTP (1992a) found that naphthalene induced, in cultured Chinese hamster
ovary cells, sister chromatid exchanges within a concentration range of
27 to 90 µg/mL in the presence or absence of metabolic activation, and
chromosomal aberrations within a range of 30 to 67.5 µg/mL only in the
presence of metabolic activation.

Naphthalene was mutagenic in the marine bacterium Vibrio fischeri
(Arfsten et al., 1994) and in the Drosophila melanogaster wing somatic
mutation and recombination test (Delgado-Rodriguez et al., 1995).
Culture of mouse embryos in medium containing 0.16 mM naphthalene
produced a 10-fold increase in chromosomal damage compared to untreated
controls; the genotoxic response to naphthalene was amplified by the
inclusion of a hepatic metabolic activation system in the medium
(Gollahon et al., 1990).

Incubation of human peripheral lymphocytes in medium containing
naphthalene and a human liver metabolic activation system did not
produce increased frequency of sister chromatid exchanges compared with
controls (Tingle et al., 1993; Wilson et al., 1995). Naphthalene did not
induce unscheduled DNA synthesis in cultured rat hepatocytes (Barfknecht
et al., 1985) or increased numbers of micronuclei in bone marrow cells
of mice following intraperitoneal injection of single 250-mg/kg doses
(Sorg et al., 1985). Single oral doses of naphthalene as high as 500
mg/kg did not increase the frequency of micronucleated erythrocytes in
exposed mice compared with untreated control mice (Harper et al., 1984).
Naphthalene did not induce in vitro transformations of Fischer rat
embryo cells (Freeman et al., 1973) or Swiss mouse embryo cells (Rhim et
al., 1974). Sina et al. (1983) reported that naphthalene did not induce
single-strand DNA breaks in cultured rat hepatocytes as detected by
alkaline dilution.

Naphthalene metabolites 1-naphthol and 2-naphthol were not mutagenic in
S. typhimurium, with or without metabolic activation (Florin et al.,
1980; McCann et al., 1975; Narbonne et al., 1987). Another proposed
naphthalene metabolite, naphthoquinone, was not mutagenic in several
strains of S. typhimurium with or without metabolic activation (Sakai et
al., 1985), but Flowers-Geary et al. (1994) reported that
naphthalene-1,2-dione was mutagenic in strains of S. typhimurium without
metabolic activation. The naphthalene metabolite, 1-naphthol, failed to
produce positive results in several other genotoxicity assays including
tests for sex- linked recessive lethal mutations in Drosophila
melanogaster (Gocke et al., 1981), mutations in mouse L5178Y cells
(Amacher and Turner, 1982), unscheduled DNA synthesis in cultured rat
hepatocytes (Probst and Hill, 1980), and induction of micronuclei in
bone marrow cells of mice (Gocke et al., 1981) and rats (Hossack and
Richardson, 1977) after acute in vivo exposure.

Tsuda et al. (1980) found no evidence for neoplastic transformation of
liver cells in a group of 10 young adult F344 rats (sex not specified)
treated with single gavage doses of 100 mg/kg naphthalene in corn oil
compared with a group of 10 vehicle control rats. Rats were given gavage
doses of naphthalene or vehicle following partial hepatectomy, but
before dietary treatment with an anti-cell proliferation agent
(2-acetylaminofluorene) and a necrotizing agent (carbon tetrachloride).
Gamma-glutamyl transpeptidase foci (observed following the dietary
treatments of exposed and control rats) were used as an indicator of
neoplastic transformation. In contrast to naphthalene, a single gavage
dose of 200 mg/kg benzo[a]pyrene induced significant increases in the
number, area, and size of gamma-glutamyl transpeptidase foci. 

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_II.B. Quantitative Estimate of Carcinogenic Risk from Oral Exposure

An oral slope factor for naphthalene was not derived because of a lack
of chronic oral naphthalene studies.

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_II.C. Quantitative Estimate of Carcinogenic Risk from Inhalation
Exposure

An inhalation unit risk estimate for naphthalene was not derived because
of the weakness of the evidence (observations of predominant benign
respiratory tumors in mice at high dose only) that naphthalene may be
carcinogenic in humans.

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_II.D. EPA Documentation, Review, and Contacts (Carcinogenicity
Assessment)

__II.D.1. EPA Documentation

Source Document — U.S. EPA, 1998

This assessment was peer reviewed by external scientists. Their comments
have been evaluated carefully and incorporated in finalization of this
IRIS Summary. A record of these comments is included in an appendix to
the Toxicological Review of Naphthalene in support of Summary
Information on the Integrated Risk Information System (IRIS) (U.S. EPA,
1998).   HYPERLINK "http://www.epa.gov/iris/toxreviews/0436-tr.pdf" \l
"page=62"  To review this appendix, exit to the toxicological review,
Appendix A, Summary of and Response to External Peer Review Comments
(PDF) . 

__II.D.2. EPA Review (Carcinogenicity Assessment)

Agency Consensus Date - 07/01/1998

__II.D.3. EPA Contacts (Carcinogenicity Assessment)

Please contact the IRIS Hotline for all questions concerning this
assessment or IRIS, in general, at (202)566-1676 (phone), (202)566-1749
(fax), or   HYPERLINK "mailto:hotline.iris@epa.gov" 
hotline.iris@epa.gov  (Internet address).

  HYPERLINK "http://www.epa.gov/iris/subst/0436.htm" \l
"content#content"  Top of page 

_III.  [reserved]

_IV.  [reserved] 

_V.  [reserved]

_VI.  Bibliography 

Naphthalene

CASRN — 91-20-3

Last Revised — 09/17/1998

_VI.A. Oral RfD References

Allen, BC; Kavlock, RJ; Kimmel, CA; et al. (1994a) Dose response
assessments for developmental toxicity: II. Comparison of generic
benchmark dose estimates with NOAELs. Fundam Appl Toxicol 23:487-495.

Allen, BC; Kavlock, RJ; Kimmel, CA; et al. (1994b) Dose response
assessments for developmental toxicity: III. Statistical models. Fundam
Appl Toxicol 23:496-509.

Battelle's Columbus Laboratories (BCL). (1980a) Unpublished subchronic
toxicity study: Naphthalene (C52904), Fischer 344 rats. Prepared by
Battelle Laboratories under NTP Subcontract No. 76-34-106002. Available
from the Center for Environmental Research Information, (202)566-1676.

Battelle's Columbus Laboratories (BCL). (1980b) Unpublished subchronic
toxicity study: Naphthalene (C52904), B6C3F1 mice. Prepared by Battelle
Laboratories under NTP Subcontract No. 76-34-106002.

Buckpitt, AR; Franklin, RB. (1989) Relationship of naphthalene and
2-methylnaphthalene metabolism to pulmonary bronchiolar epithelial cell
necrosis. Pharm Ther 41:393-410.

Kavlock, RJ; Allen, BC; Faustman, EM; et al. (1995) Dose response
assessments for developmental toxicity: IV. Benchmark doses for fetal
weight changes. Fundam Appl Toxicol 26:211-222.

Melzer-Lange, M; Walsh-Kelly, C. (1989) Naphthalene-induced hemolysis in
a black female toddler deficient in glucose-6-phosphate dehydrogenase.
Pediatr Emerg Care 5(1):24-26.

Murata, T; Denda, A; Maruyama, H; et al. (1993) Chronic toxicity and
carcinogenicity studies of 1-methylnaphthalene in B6C3F1 mice. Fundam
Appl Toxicol 21:44-51.

Murata, Y; Denda, A; Maruyama, H; et al. (1997) Chronic toxicity and
carcinogenicity studies of 2-methylnaphthalene in B6C3F1 mice. Fundam
Appl Toxicol 36:90-93.

National Toxicology Program (NTP). (1991) Final report on the
developmental toxicity of naphthalene (CAS no. 91-20-3) in Sprague
Dawley (CD) rats. #TER91006. NTIS Technical Report (NTIS/PB92-135623).

Owa, JA. (1989) Relationship between exposure to icterogenic agents,
glucose-6-phosphate dehydrogenase deficiency and neonatal jaundice in
Nigeria. Acta Paediatr Scand

78(6):848-852.

Owa, JA; Izedonmwen, OE; Ogundaini, AO; et al. (1993) Quantitative
analysis of 1-naphthol in urine of neonates exposed to mothballs: the
value in infants with unexplained anaemia. Afr J Med Sci 22:71-76.

Shopp, GM; White, KL, Jr.; Holsapple, MP; et al. (1984) Naphthalene
toxicity in CD-1 mice: general toxicology and immunotoxicology. Fundam
Appl Toxicol 4(3 pt 1):406-419.

U.S. Environmental Protection Agency (U.S. EPA). (1980) Ambient water
quality criteria for naphthalene. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH, for the Office of Water Regulations and Standards,
Washington, DC. EPA/440/5-80-059. NTIS PB81-117707.

U.S. EPA. (1986) Health and environmental effects profile for
naphthalene. Environmental Criteria and Assessment Office, Office of
Health and Environmental Assessment, Office of Research and Development,
U.S. Environmental Protection Agency, Cincinnati, OH 45268.
EPA/600/X-86/241. NTIS/PB88-24238.

U.S. EPA. (1987a) Summary review of health effects associated with
naphthalene: health issue assessment. Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Research
Triangle Park, NC. EPA/600/8-87/055F.

U.S. EPA. (1988) Health effects assessment for naphthalene.
Environmental Criteria and Assessment Office, Office of Health and
Environmental Assessment, Office of Research and Development, U.S.
Environmental Protection Agency, Cincinnati, OH 45268. EPA/600/8-89/094.
NTIS/PB90-142464.

U.S. EPA. (1998) Toxicological review for naphthalene. Available online
at   HYPERLINK "http://www.epa.gov/ncea/iris" 
http://www.epa.gov/ncea/iris . 

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_VI.B. Inhalation RfC References

ACGIH. (1986) Documentation of the threshold limit values and biological
exposure indices. 5th ed. Cincinnati, OH: American Conference of
Governmental Industrial Hygienists.

Adkins, B, Jr.; Van Stee, EW; Simmons, JE; et al. (1986) Oncogenic
response of strain A/J mice to inhaled chemicals. J Toxicol Environ
Health 17(2-3):311-322.

Buckpitt, AR. (1982) Comparative biochemistry and metabolism. Part II:
naphthalene lung toxicity. Prepared for Air Force Aerospace Medical
Research Laboratory, Wright-Patterson Air Force Base, OH.
AFAMRL-TR-82-52. p. 25-30.

Bushy Run Research Center. (1986) Naphthalene acute inhalation toxicity
study. TSCATS/303984, EPA/OTS Doc no. 86-870000558.

National Toxicology Program (NTP). (1992a) Toxicology and carcinogenesis
studies of naphthalene in B6C3F1 mice (inhalation studies). Technical
Report Series No. 410. NIH Publication No. 92-3141.

O'Brien, KAF; Smith, LL; Cohen, GM. (1985) Differences in
naphthalene-induced toxicity in the mouse and rat. Chem Biol Interact
55(1-2):109-122.

O'Brien, KAF; Suverkropp, C; Kanekal, S; et al. (1989) Tolerance to
multiple doses of the pulmonary toxicant, naphthalene. Toxicol Appl
Pharmacol 99(3):487-500.

Plopper, CG; Suverkropp, C; Morin, D; et al. (1992) Relationship of
cytochrome P-450 activity to Clara cell cytotoxicity. I. Histopathologic
comparison of the respiratory tract of mice, rats and hamsters after
parenteral administration of naphthalene. J Pharmacol Exp Ther
261(1):353-363.

Tong, SS; Hirokata, Y; Trush, MA; et al. (1981) Clara cell damage and
inhibition of pulmonary mixed-function oxidase activity by naphthalene.
Biochem Biophys Res Commun 100(3):944-950.

U.S. Environmental Protection Agency (U.S. EPA). (1980) Ambient water
quality criteria for naphthalene. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH, for the Office of Water Regulations and Standards,
Washington, DC. EPA/440/5-80-059. NTIS PB81-117707.

U.S. EPA. (1986) Health and environmental effects profile for
naphthalene. Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
EPA/600/X-86/241. NTIS/PB88-24238.

U.S. EPA. (1987a) Summary review of health effects associated with
naphthalene: health issue assessment. Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Research
Triangle Park, NC. EPA/600/8-87/055F.

U.S. EPA. (1988) Health effects assessment for naphthalene.
Environmental Criteria and Assessment Office, Office of Health and
Environmental Assessment, Office of Research and Development, U.S.
Environmental Protection Agency, Cincinnati, OH 45268. EPA/600/8-89/094.
NTIS/PB90-142464.

U.S. EPA. (1994) Methods for derivation of inhalation reference
concentrations and application of inhalation dosimetry. Office of Health
and Environmental Assessment, U.S. Environmental Protection Agency,
Washington, DC. EPA/600/8-90/066F.

U.S. EPA. (1998) Toxicological review for naphthalene. Available online
at   HYPERLINK "http://www.epa.gov/ncea/iris" 
http://www.epa.gov/ncea/iris . 

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_VI.C. Carcinogenicity Assessment References

Adkins, B; Van Stee, EW; Simmons, JE; et al. (1986) Oncogenic response
of strain A/J mice to inhaled chemicals. J Toxicol Environ Health
17:311-322.

Amacher, DE; Turner, GN. (1982) Mutagenic evaluation of carcinogens and
non-carcinogens in the L5178Y/TK assay utilizing postmitochondrial
fractions (S9) from normal rat liver. Mutat Res 97:49-65.

Arfsten, DP; Davenport, R; Schaeffer DJ. (1994) Reversion of
bioluminescent bacteria (MutatoxTM) to their luminescent state upon
exposure to organic compounds, munitions, and metal salts. Biomed
Environ Sci 7:144-149.

Barfknecht, TR; Naismith, RW; Matthews RJ. (1985) Rat hepatocyte primary
culture/DNA repair test. PH 311-TX-008-85. 5601-56-1 (unpublished
material). Pharmakon Research International, Inc., Waverly, PA.
Submitted to Texaco, Inc., Beacon, NY. Submitted to U.S. EPA by Texaco,
Inc. Office of Toxic Substances Microfiche No. 0TS0513638.

Bos, RP; Theuws, JL; Jongeneelen, FJ; et al. (1988) Mutagenicity of bi-,
tri- and tetracyclic aromatic hydrocarbons in the taped-plate assay and
in the conventional Salmonella mutagenicity assay. Mutat Res
204:2033-206.

Boyland, E; Busby, ER; Dukes, CE; et al. (1964) Further experiments on
implantation of materials into the urinary bladder of mice. Br J Cancer
18:575-581.

Buckpitt, AR. (1982) Comparative biochemistry and metabolism. Part II:
naphthalene lung toxicity. Prepared for Air Force Aerospace Medical
Research Laboratory, Wright-Patterson Air Force Base, OH.
AFAMRL-TR-82-52. p. 25-30.

Connor, TH; Theiss, JC; Hanna, HA; et al. (1985) Genotoxicity of organic
chemicals frequently found in the air of mobile homes. Toxicol Lett
25:33-40.

Delgado-Rodriguez, A; Ortiz-Marttelo, R; Graf, U; et al. (1995)
Genotoxic activity of environmentally important polycyclic aromatic
hydrocarbons and their nitro derivatives in the wing spot test of
Drosophila melanogaster. Mutat Res 341:235-247.

Florin, I., Rutberg, L; Curvall, M; et al. (1980) Screening of tobacco
smoke constituents for mutagenicity using the Ames test. Toxicology
18:219-232.

Flowers-Geary, L; Bleczinski, W; Harvey, RG; et al. (1994) Cytotoxicity
and mutagenicity of polycyclic aromatic hydrocarbons (PAH) o-quinones
produced by dihydrodiol dehydrogenase. Proc Ann Meet Am Assoc Cancer Res
35:A965.

Freeman, AE; Weisburger, EK; Weisburger, JH; et al. (1973)
Transformation of cell cultures as an indication of the carcinogenic
potential of chemicals. J Natl Cancer Inst 51:799-808.

Gocke, E; King, M-T; Eckhardt, K; et al. (1981) Mutagenicity of
cosmetics ingredients licensed by the European communities. Mutat Res
90:91-109.

Godek, EG; Naismith, RW; Matthews, RJ. (1985) Ames Salmonella/microsome
plate test (EPA/OECD) (unpublished material). Pharmakon Research
International Inc, Waverly, PA. Submitted to Texaco, Inc, Beacon, NY.
Submitted to U.S. EPA by Texaco, Inc. Office of Toxic Substances
Microfiche No. OTS0513637.

Gollahon, LS; Iyer, P; Martin, JE; et al. (1990) Chromosomal damage to
preimplantation embryos in vitro by naphthalene. Toxicologist 10:274.

Harper, BL; Ramanujam, VMS; Gad-El-Karim, MM; et al. (1984) The
influence of simple aromatics on benzene clastogenicity. Mutat Res
128:105-114.

Hossack, DJN; Richardson, JC. (1977) Examination of the potential
mutagenicity of hair dye constituents using the micronucleus test.
Experientia 33:377-378.

Ijiri, I; Shimosato, K; Ohmae, M; et al. (1987) A case report of death
from naphthalene poisoning. Jpn J Legal Med 41(1):52-55.

Knake, E. (1956) Weak tumor producing effect of naphthalene and benzene.
Virchows Arch Pathol Anat Physiol 329:141-176. (Ger.)

La Voie, EJ; Dolan, S; Little, P; et al. (1988) Carcinogenicity of
quinoline, 4- and 8-methylquinoline and benzoquinolines in newborn mice
and rats. Food Chem Toxicol 26:625-629.

McCann, J; Choi, E; Yamasaki, E; et al. (1975) Detection of carcinogens
as mutagens in the Salmonella/microsome test: assay of 300 chemicals.
Proc Natl Acad Sci 72:5135-5139.

Mersch-Sundermann, V; Mochayedi, S; Kevekordes, S; et al. (1993) The
genotoxicity of unsubstituted and nitrated polycyclic aromatic
hydrocarbons. Anticancer Res 13:2037-2044.

Murata, T; Denda, A; Maruyama, H; et al. (1993) Chronic toxicity and
carcinogenicity studies of 1-methylnaphthalene in B6C3F1 mice. Fundam
Appl Toxicol 21:44-51.

Murata, Y; Denda, A; Maruyama, H; et al. (1997) Chronic toxicity and
carcinogenicity studies of 2-methylnaphthalene in B6C3F1 mice. 36:90-93
(1997).

Nakamura, S; Oda, Y; Shimada, T; et al. (1987) SOS-inducing activity of
chemical carcinogens and mutagens in Salmonella typhimurium TA1535/pSK
1002: examination with 151 chemicals. Mutat Res 192:239-246.

Narbonne, JF; Cassand, P; Alzieu, P; et al. (1987) Structure-activity
relationships of the N-methylcarbamate series in Salmonella typhimurium.
Mutat Res 191:21-27.

National Toxicology Program (NTP). (1992a) Technical Report on the
Toxicology and Carcinogenesis Studies of Naphthalene (CAS No. 91-20-3)
in B6C3F1 Mice. (Inhalation Studies). DHHS, PHS, NIH, Rockville, MD.

Probst, GS; Hill, LE. (1980) Chemically-induced DNA repair synthesis in
primary rat hepatocytes: A correlation with bacterial mutagenicity. Ann
NY Acad Sci 349:405-406.

Rhim, JS; Parks, DK; Weisburger, EK. (1974) Evaluation of an in vitro
assay system for carcinogens based on prior infection of rodent cells
with nontransforming RNA tumor virus. J Natl Cancer Inst 52:1167-1173.

Sakai, M; Yoshida, D; Mizusdki, S. (1985) Mutagenicity of polycyclic
aromatic hydrocarbons and quinones on Salmonella typhimurium TA97. Mutat
Res 156:61-67.

Schmähl, D. (1955) Examination of the carcinogenic action of
naphthalene and anthracene in rats. Z Krebsforsch 60:697-710.

Sina, JF; Bean, CL; Dysart, GR; et al. (1983) Evaluation of the alkaline
elution/rat hepatocyte assay as a predictor of carcinogenic/mutagenic
potential. Mutat Res 113:357-391.

Sorg, RM; Naismith, RW; Matthews, RJ. (1985) Micronucleus test (MNT)
OECD (unpublished material). Pharmakon Research International Inc.,
Waverly PA. Submitted to U.S. EPA by Texaco, Inc. Office of Toxic
Substances Microfiche No. OTS0513639.

Tingle, MD; Pirmohamed, M; Templeton, E; et al. (1993) An investigation
of the formation of cytotoxic, genotoxic, protein-reactive and stable
metabolites from naphthalene by human liver microsomes. Biochem
Pharmacol 46:1529-1538.

Tsuda, H; Lee, G; Farber, E. (1980) Induction of resistant hepatocytes
as a new principle for a possible short-term in vivo test for
carcinogens. Cancer Res 40:1157-1164.

U.S. EPA. (1987b) Recommendations for and documentation of biological
values for use in risk assessment. Environmental Criteria and Assessment
Office, Office of Health and Environmental Assessment, Cincinnati, OH.
EPA/600/6-87-008.

U.S. EPA. (1996, April 23) Proposed guidelines for carcinogen risk
assessment. Federal Register 61(79):17960-18011.

U.S. EPA. (1998) Toxicological review for naphthalene. Available online
at   HYPERLINK "http://www.epa.gov/ncea/iris" 
http://www.epa.gov/ncea/iris .

Wilson, AS; Tingle, MD; Kelly, MD; et al. (1995) Evaluation of the
generation of genotoxic and cytotoxic metabolites of benzo[a]pyrene,
aflatoxin B, naphthalene and tamoxifen using human liver microsomes and
human lymphocytes. Human Exp Toxicol 14:507-515. 

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_VII.  Revision History

Naphthalene

CASRN — 91-20-3

Last Revised — 09/17/1998 

Date	Section	Description

12/01/1990	II.	Carcinogen assessment on-line

12/01/1990	VI.	Bibliography on-line

01/01/1992	IV.	Regulatory Action section on-line

09/01/1992	II.	Classification noted as pending change

09/01/1992	II.D.2.	Work group review date added

11/01/1993	I.A.	Work group review date added

09/01/1994	I.A.	Work group review date added

05/01/1995	II.	Pending change note replaced

05/01/1995	II.D.2.	Work group review date added

07/01/1995	II.	Pending change note replaced; see new note

08/01/1995	I.A., II., II.D.2 	EPA's RfD/RfC and CRAVE workgroups were
discontinued in May, 1995. Chemical substance reviews that were not
completed by September 1995 were taken out of IRIS review. The IRIS
Pilot Program replaced the workgroup functions beginning in September,
1995.

08/01/1995	II.	Note revised

08/01/1995	II.A.3.	Paragraph 1 revised

04/01/1997	III., IV., V.	Drinking Water Health Advisories, EPA
Regulatory Actions, and Supplementary Data were removed from IRIS on or
before April 1997. IRIS users were directed to the appropriate EPA
Program Offices for this information.

09/17/1998	I., II., VI.	Revised RfD, RfC, carcinogenicity assessments

01/09/2002	II.	This chemical is being reassessed under the IRIS Program.

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_VIII.  Synonyms

Naphthalene

CASRN — 91-20-3

Last Revised — 12/01/1990

91-20-3 

Naphthalene 

Albocarbon 

Caswell No. 587 

Dezodorator 

EPA Pesticide Chemical Code 055801 

HSDB 184 

MOTH BALLS 

MOTH FLAKES 

Naftalen [Polish] 

Naftaleno [Spanish] 

Naphtalene [French] 

Naphthalene 

Naphthalin 

Naphthaline 

Naphthene 

NAPTHALENE, molten 

NCI-C52904 

NSC 37565 

RCRA WASTE NUMBER U165 

TAR CAMPHOR 

UN 1334 

UN 2304 

WHITE TAR