Health
Effects
Support
Document
for
Naphthalene
Printed
on
Recycled
Paper
Health
Effects
Support
Document
for
Naphthalene
U.
S.
Environmental
Protection
Agency
Office
of
Water
(
4304T)
Health
and
Ecological
Criteria
Division
Washington,
DC
20460
www.
epa.
gov/
safewater/
ccl/
pdf/
naphthalene.
pdf
EPA
822­
R­
03­
005
February
2003
iii
Naphthalene
 
February
2003
FOREWORD
The
Safe
Drinking
Water
Act
(
SDWA),
as
amended
in
1996,
requires
the
Administrator
of
the
Environmental
Protection
Agency
(
EPA)
to
establish
a
list
of
contaminants
to
aid
the
Agency
in
regulatory
priority
setting
for
the
drinking
water
program.
In
addition,
the
SDWA
requires
EPA
to
make
regulatory
determinations
for
no
fewer
than
five
contaminants
by
August
2001.
The
criteria
used
to
determine
whether
or
not
to
regulate
a
chemical
on
the
Contaminant
Candidate
List
(
CCL)
are
the
following:

The
contaminant
may
have
an
adverse
effect
on
the
health
of
persons.

The
contaminant
is
known
to
occur
or
there
is
a
substantial
likelihood
that
the
contaminant
will
occur
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern.

In
the
sole
judgment
of
the
Administrator,
regulation
of
such
contaminant
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.

The
Agency's
findings
for
all
three
criteria
are
used
in
making
a
determination
to
regulate
a
contaminant.
The
Agency
may
determine
that
there
is
no
need
for
regulation
when
a
contaminant
fails
to
meet
one
of
the
criteria.
The
decision
not
to
regulate
is
considered
a
final
Agency
action
and
is
subject
to
judicial
review.

This
document
provides
the
health
effects
basis
for
the
regulatory
determination
for
naphthalene.
In
arriving
at
the
regulatory
determination,
data
on
toxicokinetics,
human
exposure,
acute
and
chronic
toxicity
to
animals
and
humans,
epidemiology,
and
mechanisms
of
toxicity
were
evaluated.
In
order
to
avoid
wasteful
duplication
of
effort,
information
from
the
following
risk
assessments
by
the
EPA
and
other
government
agencies
were
used
in
development
of
this
document.

U.
S.
EPA
1987.
U.
S.
Environmental
Protection
Agency.
Summary
Review
of
Health
Effects
Associated
with
Naphthalene.
Washington,
D.
C.:
Office
of
Health
and
Environmental
Assessment,
EPA/
600/
8­
87/
005F
U.
S.
EPA.
1990.
U.
S.
Environmental
Protection
Agency.
Naphthalene
Drinking
Water
Health
Advisory.
Office
of
Water.
March.

ATSDR.
1995.
Agency
for
Toxic
Substances
and
Disease
Registry.
Toxicological
Profile
for
Naphthalene
(
update).
Department
of
Health
and
Human
Services.
CRC
Press,
Boca
Raton,
FL
1997.

U.
S.
EPA
1998a.
U.
S.
Environmental
Protection
Agency.
Toxicological
Review
of
Naphthalene
(
CAS
91­
20­
3)
in
support
of
summary
information
on
the
Integrated
Risk
Information
System
(
IRIS).
August
1998.
iv
Naphthalene
 
February
2003
U.
S.
EPA
1998b.
U.
S.
Environmental
Protection
Agency.
Integrated
Risk
Information
System
(
IRIS):
Naphthalene.
Cincinnati,
OH.
September
17,
1998.

Information
from
the
published
risk
assessments
was
supplemented
with
information
from
recent
studies
of
naphthalene
identified
by
literature
searches
conducted
in
1999
and
2000
and
the
primary
references
for
key
studies.

Generally
a
Reference
Dose
(
RfD)
is
provided
as
the
assessment
of
long­
term
toxic
effects
other
than
carcinogenicity.
RfD
determination
assumes
that
thresholds
exist
for
certain
toxic
effects,
such
as
cellular
necrosis.
It
is
expressed
in
terms
of
milligrams
per
kilogram
per
day
(
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.

The
carcinogenicity
assessment
for
naphthalene
includes
a
formal
hazard
identification.
Hazard
identification
is
a
weight­
of­
evidence
judgment
of
the
likelihood
that
the
agent
is
a
human
carcinogen
via
the
oral
route
and
of
the
conditions
under
which
the
carcinogenic
effects
may
be
expressed.

Guidelines
that
were
used
in
the
development
of
this
assessment
may
include
the
following:
the
Guidelines
for
Carcinogen
Risk
Assessment
(
U.
S.
EPA,
1986a),
Guidelines
for
the
Health
Risk
Assessment
of
Chemical
Mixtures
(
U.
S.
EPA,
1986b),
Guidelines
for
Mutagenicity
Risk
Assessment
(
U.
S.
EPA,
1986c),
Guidelines
for
Developmental
Toxicity
Risk
Assessment
(
U.
S.
EPA,
1991a),
Proposed
Guidelines
for
Carcinogen
Risk
Assessment
(
1996a),
Guidelines
for
Reproductive
Toxicity
Risk
Assessment
(
U.
S.
EPA,
1996b),
Guidelines
for
Neurotoxicity
Risk
Assessment
(
U.
S.
EPA,
1998c);
Recommendations
for
and
Documentation
of
Biological
Values
for
Use
in
Risk
Assessment
(
U.
S.
EPA,
1988);
Use
of
the
Benchmark
Dose
Approach
in
Health
Risk
Assessment
(
U.
S.
EPA,
1995);
and
Memorandum
from
EPA
Administrator,
Carol
Browner,
dated
March
21,
1995.

The
chapter
on
occurrence
and
exposure
to
naphthalene
through
potable
water
was
developed
by
the
Office
of
Ground
Water
and
Drinking
Water.
It
is
based
primarily
on
unregulated
contaminant
monitoring
(
UCM)
data
collected
under
SDWA.
The
UCM
data
are
supplemented
with
ambient
water
data,
as
well
as
information
on
production,
use,
and
discharge.
v
Naphthalene
 
February
2003
ACKNOWLEDGMENT
This
document
was
prepared
under
the
U.
S.
EPA
contract
No.
68­
C­
01­
002,
Work
Assignment
No.
B­
02
with
Sciences
International,
Alexandria,
VA.
The
Lead
U.
S.
EPA
Scientist
is
Joyce
Morrissey
Donohue,
Ph.
D.,
Health
and
Ecological
Criteria
Division,
Office
of
Science
and
Technology,
Office
of
Water.
vi
Naphthalene
 
February
2003
TABLE
OF
CONTENTS
FOREWORD
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iii
ACKNOWLEDGMENT
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v
LIST
OF
TABLES
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ix
LIST
OF
FIGURES
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x
1.0
EXECUTIVE
SUMMARY
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1­
1
2.0
IDENTITY:
CHEMICAL
AND
PHYSICAL
PROPERTIES
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2­
1
3.0
USES
AND
ENVIRONMENTAL
FATE
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3­
1
3.1
Production
and
Use
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3­
1
3.2
Environmental
Release
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3­
1
3.3
Environmental
Fate
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3­
3
3.4
Summary
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3­
4
4.0
EXPOSURE
FROM
DRINKING
WATER
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4­
1
4.1
Introduction
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4­
1
4.2
Ambient
Occurrence
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4­
1
4.2.1
Data
Sources
and
Methods
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4­
1
4.2.2
Results
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4­
2
4.3
Drinking
Water
Occurrence
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4­
3
4.3.1
Data
Sources,
Data
Quality,
and
Analytical
Methods
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4­
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4.3.2
Results
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4­
13
4.4
Conclusion
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4­
16
5.0
EXPOSURE
FROM
MEDIA
OTHER
THAN
WATER
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5­
1
5.1
Exposure
from
Food
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5­
1
5.1.1
Concentration
in
Non­
Fish
Food
Items
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5­
1
5.1.2
Concentrations
in
Fish
and
Shellfish
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5­
1
5.1.3
Intake
of
Naphthalene
from
Food
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5­
3
5.2
Exposure
from
Air
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5­
4
5.2.1
Concentration
of
Naphthalene
in
Air
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5­
4
5.2.2
Intake
of
Naphthalene
from
Air
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5­
5
5.3
Exposure
from
Soil
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5­
5
5.3.1
Concentration
of
Naphthalene
in
Soil
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5­
5
5.3.2
Intake
of
Naphthalene
from
Soil
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5­
6
5.4
Other
Residential
Exposures
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5­
7
5.5
Summary
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5­
7
vii
Naphthalene
 
February
2003
6.0
TOXICOKINETICS
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6­
1
6.1
Absorption
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.
6­
1
6.2
Distribution
.
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6­
2
6.3
Metabolism
.
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6­
3
6.4
Excretion
.
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6­
6
7.0
HAZARD
IDENTIFICATION
.
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.
7­
1
7.1
Human
Effects
.
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.
7­
1
7.1.1
Short­
Term
Studies
and
Case
Reports
.
.
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.
7­
1
7.1.2
Long­
Term
and
Epidemiological
Studies
.
.
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.
7­
3
7.2
Animal
Studies
.
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.
7­
4
7.2.1
Acute
Toxicity
.
.
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7­
4
7.2.2
Short­
Term
Studies
.
.
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.
7­
6
7.2.3
Subchronic
Studies
.
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.
7­
7
7.2.4
Neurotoxicity
.
.
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.
7­
10
7.2.5
Developmental/
Reproductive
Toxicity
.
.
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.
7­
10
7.2.6
Chronic
Toxicity
.
.
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.
7­
14
7.2.7
Carcinogenicity
.
.
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.
7­
18
7.3
Other
Key
Data
.
.
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.
7­
23
7.3.1
Mutagenicity
and
Genotoxicity
.
.
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.
7­
23
7.3.2
Ocular
Toxicity
.
.
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.
7­
24
7.3.3
Hematological
Effects
.
.
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.
7­
29
7.3.4
Immunotoxicity
.
.
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.
7­
29
7.3.5
Hormonal
Disruption
.
.
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.
7­
30
7.3.6
Physiological
or
Mechanistic
Studies
.
.
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.
7­
30
7.3.7
Structure­
Activity
Relationship
.
.
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.
7­
34
7.4
Hazard
Characterization
.
.
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.
.
7­
35
7.4.1
Synthesis
and
Evaluation
of
Major
Noncancer
Effects
.
.
.
.
.
.
.
.
.
.
.
.
7­
35
7.4.2
Synthesis
and
Evaluation
of
Carcinogenic
Effects
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
37
7.4.3
Mode
of
Action
and
Implications
in
Cancer
Assessment
.
.
.
.
.
.
.
.
.
.
7­
53
7.4.4
Weight
of
Evidence
Evaluation
for
Carcinogenicity
.
.
.
.
.
.
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.
.
7­
53
7.4.5
Potentially
Sensitive
Populations
.
.
.
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.
7­
56
8.0
DOSE­
RESPONSE
ASSESSMENT
.
.
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.
.
8­
1
8.1
Dose­
Response
for
Noncancer
Effects
.
.
.
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.
.
8­
1
8.1.1
RfD
Determination
.
.
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.
.
8­
1
8.1.2
RfC
Determination
.
.
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.
8­
2
8.2
Dose­
Response
for
Cancer
Effects
.
.
.
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.
.
8­
2
9.0
REGULATORY
DETERMINATION
AND
CHARACTERIZATION
OF
RISK
FROM
DRINKING
WATER
.
.
.
.
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.
.
.
9­
1
9.1
Regulatory
Determination
for
Chemicals
on
the
CCL
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
1
9.1.1
Criteria
for
Regulatory
Determination
.
.
.
.
.
.
.
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.
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.
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.
.
.
.
.
.
.
.
.
.
.
9­
1
9.1.2
National
Drinking
Water
Advisory
Council
Recommendations
.
.
.
.
.
.
9­
2
9.2
Health
Effects
.
.
.
.
.
.
.
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.
.
9­
2
viii
Naphthalene
 
February
2003
9.2.1
Health
Criterion
Conclusion
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
9­
3
9.2.2
Hazard
Characterization
and
Mode
of
Action
Implications
.
.
.
.
.
.
.
.
.
9­
3
9.2.3
Dose­
Response
Characterization
and
Implications
in
Risk
Assessment
.
.
.
.
.
.
.
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.
.
.
.
9­
4
9.3
Occurrence
in
Public
Water
Systems
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
.
.
.
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.
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.
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.
.
.
.
.
.
9­
7
9.3.1
Occurrence
Criterion
Conclusion
.
.
.
.
.
.
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.
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.
.
.
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.
.
.
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.
.
.
.
.
.
.
9­
7
9.3.2
Monitoring
Data
.
.
.
.
.
.
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.
.
.
9­
8
9.3.3
Use
and
Fate
Data
.
.
.
.
.
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.
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.
.
9­
9
9.4
Risk
Reduction
.
.
.
.
.
.
.
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.
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.
.
9­
10
9.4.1
Risk
Criterion
Conclusion
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
9­
10
9.4.2
Exposed
Population
Estimates
.
.
.
.
.
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.
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.
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.
.
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.
.
.
.
9­
11
9.4.3
Relative
Source
Contribution
.
.
.
.
.
.
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.
.
.
.
.
9­
11
9.4.4
Sensitive
Populations
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
.
.
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.
.
.
.
.
.
9­
13
9.5
Regulatory
Determination
Decision
.
.
.
.
.
.
.
.
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.
.
.
.
9­
14
10.0
REFERENCES
.
.
.
.
.
.
.
.
.
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.
.
.
10­
1
APPENDIX
A:
Abbreviations
and
Acronyms
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
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.
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.
.
.
.
.
.
.
.
A­
1
APPENDIX
B:
Naphthalene
Occurrence
Data
for
Public
Water
Systems
(
Round
1
and
Round
2)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
B­
1
ix
Naphthalene
 
February
2003
LIST
OF
TABLES
Table
2­
1.
Chemical
and
Physical
Properties
of
Naphthalene
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
2­
1
Table
3­
1.
Environmental
Releases
(
in
pounds)
for
Naphthalene
in
the
United
States
(
1988
 
1998)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
3­
2
Table
4­
1.
Naphthalene
Detections
and
Concentrations
in
Ground
Water
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
3
Table
4­
2.
Cross­
section
States
for
Round
1
(
24
States)
and
Round
2
(
20
States)
.
.
.
.
.
.
.
4­
7
Table
4­
3.
Summary
Occurrence
Statistics
for
Naphthalene
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
10
Table
5­
1.
Naphthalene
And
Methylnaphthalene
Concentrations
in
Meat
Samples.
.
.
.
.
.
5­
2
Table
5­
2.
Concentrations
of
Naphthalene
in
Vegetables
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
3
Table
5­
3.
Median
Concentrations
of
Naphthalene
and
Methylnaphthalene
in
Harp
Seals
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
3
Table
5­
4.
Concentrations
of
Naphthalene
in
Residential
Dust
(
mg/
g)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
5
Table
5­
5.
Exposure
to
Naphthalene
in
Media
Other
than
Water
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
5­
8
Table
7­
1.
Terminal
Body
Weights
in
Controls
and
in
Fischer
344
Rats
Exposed
to
Naphthalene
by
Gavage
for
13
Weeks
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
8
Table
7­
2.
Summary
of
Developmental
and
Reproductive
Data
on
Naphthalene
.
.
.
.
.
.
7­
11
Table
7­
3.
Survival
and
Incidence
of
Non­
neoplastic
Lesions
in
B6C3F
1
Mice
Exposed
to
Naphthalene
by
Inhalation
for
Their
Lifetime
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
15
Table
7­
4.
Incidence
and
Severity
of
Nonneoplastic
Lesions
in
the
Noses
of
Rats
in
a
Two­
year
Naphthalene
Inhalation
Study
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
17
Table
7­
5.
Incidence
of
Neoplasms
in
Male
and
Female
F344/
N
Rats
in
a
Two­
year
Naphthalene
Inhalation
Exposure
Study
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
7­
21
Table
7­
6.
Summary
of
Studies
of
Naphthalene
Ocular
Toxicity
in
Animals
.
.
.
.
.
.
.
.
.
7­
25
Table
7­
7.
Summary
of
Key
Studies
of
Noncancer
Toxic
Effects
of
Naphthalene
.
.
.
.
.
.
7­
39
Table
9­
1.
Dose­
Response
Information
from
Five
Key
Studies
of
Naphthalene
Toxicity
.
9­
6
Table
9­
2.
National
Population
Estimates
for
Naphthalene
Exposure
via
Drinking
Water
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
11
Table
9­
3.
Comparison
of
Average
Daily
Intakes
from
Drinking
Water
and
Other
Media
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
12
Table
9­
4.
Ratios
of
Exposures
from
Various
Media
to
Exposures
from
Drinking
Water
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
9­
13
x
Naphthalene
 
February
2003
LIST
OF
FIGURES
Figure
2­
1.
Chemical
Structure
of
Naphthalene
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
2­
1
Figure
4­
1.
Geographic
Distribution
of
Cross­
section
States.
Round
1
(
left)
and
Round
2
(
right)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
7
Figure
4­
2.
States
with
PWSs
with
Detections
of
Naphthalene
for
all
States
with
Data
in
URCIS
(
Round
1)
and
SDWIS/
FED
(
Round
2).
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
14
Figure
4­
3.
States
with
PWSs
with
Detections
of
Naphthalene
(
any
PWSs
with
Results
Greater
than
the
Minimum
Reporting
Level
[
MRL])
for
Round
1(
above)

and
Round
2
(
below)
Cross­
section
States.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
17
Figure
4­
4.
Cross­
section
States
(
Round
1
and
Round
2
Combined)
with
PWSs
with
Detections
of
Naphthalene
(
above)
and
Concentrations
Greater
than
the
Health
Reference
Level
(
HRL;
below)
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
4­
18
Figure
6­
1.
Proposed
Pathways
For
Naphthalene
Metabolism
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
.
6­
4
1­
1
Naphthalene
 
February
2003
1.0
EXECUTIVE
SUMMARY
The
U.
S.
Environmental
Protection
Agency
(
EPA)
has
prepared
this
Drinking
Water
Support
Document
to
assist
in
determining
whether
to
establish
a
National
Primary
Drinking
Water
Regulation
(
NPDWR)
for
naphthalene.
Case
study
reports
from
humans
and
laboratory
studies
with
animals
demonstrate
that
naphthalene
can
have
adverse
effects
on
the
oxidation
state
of
hemoglobin
(
methemoglobinemia),
the
structural
integrity
of
the
red
blood
cell
membrane
(
hemolysis),
the
activity
of
selected
hepatic
enzymes,
and
body
weight
gain
following
oral
exposure.
It
also
contributes
to
the
formation
of
cataracts
in
certain
species
and
strains
of
laboratory
animals.
These
effects
tend
to
occur
at
moderate­
to­
high
doses
that
are
unlikely
to
be
found
in
public
water
systems.
Accordingly,
regulation
of
naphthalene
in
public
water
does
not
present
a
meaningful
basis
for
health
risk
reduction.
Prolonged
inhalation
exposure
to
naphthalene,
such
as
can
occur
in
the
workplace,
may
present
risks
to
humans,
but
risk
from
other
exposure
routes
is
minimal.

Naphthalene
(
Chemical
Abstracts
Services
Registry
Number
91­
20­
3)
is
a
bicyclic
aromatic
hydrocarbon
with
the
chemical
formula
C
10
H
8.
In
purified
form,
naphthalene
is
a
white
crystalline
solid
that
is
sparingly
soluble
in
water
(
0.031
g/
L).
Naphthalene
is
a
natural
constituent
of
coal
tar
and
crude
oil.
It
is
obtained
in
purified
form
from
these
raw
materials
by
fractional
distillation.
The
available
historical
data
suggest
that
both
production
and
consumption
of
naphthalene
are
declining
in
the
United
States.
Crystalline
naphthalene
is
used
by
consumers
as
a
moth
repellant
and
as
a
deodorizer
in
toilets
and
diaper
pails.
Approximately
60%
of
the
naphthalene
consumed
in
the
United
States
is
used
commercially
in
the
manufacture
of
phthalate
plasticizers,
resins,
phthaleins,
dyes,
pharmaceuticals,
insect
repellants,
and
other
products.

Direct
releases
to
air
account
for
more
than
90%
of
the
naphthalene
entering
environmental
media.
In
comparison,
about
5%
of
the
naphthalene
entering
the
environment
is
released
to
water
and
about
2.7%
is
discharged
to
land.
Releases
to
water
occur
primarily
from
coal
tar
production
and
distillation
processes.
Other
contributing
sources
include
effluents
from
wood
preserving
facilities
and
oil
spills.
Over
half
of
the
releases
to
water
occur
to
surface
water.

Naphthalene
is
lost
from
surface
water
primarily
by
volatilization.
Estimates
for
half­
life
range
from
4.2
to
7.3
hours.
A
small
fraction
(
less
than
10%)
is
associated
with
organic
material
and
settles
into
sediments.
Naphthalene
remaining
in
the
water
column
is
degraded
by
photolysis
(
half­
life
=
71
hours)
and/
or
biodegradation
processes
(
highly
variable
half­
life
depending
on
naphthalene
concentration,
nutrient
supply,
and
water
temperature).

Naphthalene
has
been
detected
in
untreated
ambient
ground
water
samples
reviewed
and/
or
analyzed
by
the
U.
S.
Geological
Survey
National
Ambient
Water
Quality
Assessment
(
NAWQA)
program.
Detection
frequencies
and
concentrations
for
all
wells
are
relatively
low;
however,
occurrence
is
considerably
higher
for
urban
wells
when
compared
to
rural
wells.
Naphthalene
has
been
detected
at
slightly
higher
frequencies
in
urban
and
highway
runoff.
Concentrations
in
runoff
are
low.
Naphthalene
has
also
been
found
at
Agency
for
Toxic
1­
2
Naphthalene
 
February
2003
Substances
and
Disease
Registry
(
ATSDR)
HazDat
and
Comprehensive
Environmental
Response,
Compensation
and
Liability
Act
(
CERCLA)
National
Priority
List
(
NPL)
sites
across
the
country,
and
releases
have
been
reported
through
the
Toxic
Release
Inventory.

Naphthalene
has
been
detected
in
public
water
system
(
PWS)
samples
collected
under
the
provisions
of
the
Safe
Drinking
Water
Act
(
SDWA),
although
only
0.43%
and
0.24%
of
total
samples
from
two
rounds
of
sampling
showed
detections.
Significantly,
the
values
for
the
99th
percentile
and
median
concentrations
of
all
samples
are
less
than
the
Minimum
Reporting
Level
(
MRL).
For
Round
1
samples
with
detections,
the
median
concentration
is
1.0
µ
g/
L
and
the
99th
percentile
concentration
is
900
µ
g/
L.
Median
and
99th
percentile
concentrations
for
Round
2
detections
are
0.74
µ
g/
L
and
73
µ
g/
L,
respectively.
Public
water
systems
with
detections
constitute
only
1.2%
of
Round
1
systems
and
0.8%
of
Round
2
systems,
representing
an
estimated
769
systems
(
Round
1)
and
491
systems
(
Round
2)
when
extrapolated
to
the
national
level.
National
estimates
for
the
population
served
by
PWSs
with
detections
are
also
low,
especially
for
detections
greater
than
the
Health
Reference
Level
(
HRL).

Nationally
aggregated
data
for
naphthalene
in
media
other
than
water
are
generally
not
available.
The
available
data
from
localized
studies
suggest
that
naphthalene
levels
in
fish
and
non­
fish
food
items
are
generally
low
unless
they
have
been
smoked
or
grilled.
Estimates
for
daily
intake
of
naphthalene
via
the
diet
ranged
from
40.7
to
237
ng/
kg­
day
for
a
70
kg
adult
and
204
to
940
ng/
kg­
day
for
a
10
kg
child.
Comparison
of
the
available
data
indicates
that,
based
on
rough
estimates
of
average
intakes
for
naphthalene,
most
exposure
occurs
through
inhalation.
Estimated
intakes
from
air
are
approximately
5
to
45­
fold
greater
than
those
from
food
and
water.

Naphthalene
is
absorbed
when
administered
orally,
although
no
studies
were
identified
that
quantified
the
rate
or
extent
of
uptake.
Dermal
absorption
of
naphthalene
has
been
inferred
from
toxicity
observed
in
human
neonates
who
were
reportedly
exposed
by
dermal
contact
with
clothing
that
had
been
stored
with
naphthalene
mothballs
or
naphthalene
flakes.
No
empirical
data
that
describe
the
rate
or
extent
of
naphthalene
absorption
following
inhalation
exposure
were
identified
in
the
materials
reviewed
for
this
report.
Physiologically­
based
pharmacokinetic
modeling
results
suggest
that
inhaled
naphthalene
is
absorbed
rapidly
into
the
blood.

After
distribution,
naphthalene
is
extensively
metabolized.
As
many
as
21
metabolites
(
including
oxidized
derivatives
and
conjugates)
have
been
identified
in
the
urine
of
humans
and
animals
exposed
to
naphthalene.
The
factors
that
influence
the
relative
proportions
of
individual
metabolites
include
species,
tissue
type,
and
tissue
concentration
of
naphthalene.
The
available
evidence
suggests
that
the
naphthalene
metabolites
1,2­
naphthoquinone
and
1,4­
naphthoquinone
are
the
primary
toxic
species.

Information
on
the
human
health
effects
of
naphthalene
have
been
obtained
from
medical
case
reports
of
accidental
or
intentional
ingestion.
These
reports
identify
hemolytic
anemia
as
the
significant
outcome
of
oral
exposure
to
large
doses
of
naphthalene
in
humans.
There
is
one
report
of
cataracts
in
humans,
but
it
was
published
in
the
early
twentieth
century
and,
thus,
has
limited
applicability
because
of
uncertainties
regarding
compound
purity
and
exposure
1­
3
Naphthalene
 
February
2003
conditions.
There
are
no
reliable
human
toxicity
data
for
subchronic
or
chronic
exposure
to
naphthalene.

Studies
of
occupational
exposure
to
naphthalene
are
limited
to
a
single
report
of
possible
naphthalene­
related
cataracts
in
chemical
workers
and
two
limited
epidemiological
studies
that
provide
ambiguous
evidence
of
associations
between
occupational
naphthalene
exposure
and
cancer.
Owing
to
their
numerous
limitations,
none
of
these
studies
is
useful
in
characterizing
the
potential
risks
associated
with
human
exposures
to
naphthalene.

Individuals
deficient
in
the
enzyme
glucose­
6­
phosphate
dehydrogenase
(
G6PD)
have
been
identified
as
a
potentially
sensitive
population
for
naphthalene
exposure.
Individuals
with
this
deficiency
have
low
erythrocyte
levels
of
reduced
glutathione,
a
compound
that
normally
protects
red
blood
cells
against
oxidative
damage.
G6PD­
deficient
neonates,
infants,
and
the
fetus
are
particularly
sensitive
to
naphthalene
toxicity
because
the
metabolic
pathways
responsible
for
conjugation
of
toxic
metabolites
(
a
prerequisite
for
excretion)
are
not
yet
well
developed.
In
addition,
they
have
low
levels
of
methemoglobin
reductase.
This
enzyme
catalyzes
the
reduction
of
methemoglobin,
an
oxidized
form
of
hemoglobin
that
occurs
in
association
with
hemolytic
anemia.

Short­
term
administration
of
an
average
daily
dose
of
262
mg/
kg­
day
to
a
single
dog
resulted
in
signs
of
hemolytic
anemia,
including
decreased
hemoglobin
concentration,
decreased
hematocrit,
presence
of
Heinz
bodies,
extreme
leukocytosis,
and
reticulocytosis.
Other
signs
noted
included
pronounced
lethargy
and
ataxia.
In
mice,
short­
term
oral
exposure
to
naphthalene
at
doses
up
to
53
mg/
kg­
day
had
no
apparent
adverse
effects.
Adverse
effects
observed
in
mice
exposed
to
267
mg/
kg­
day
included
increased
mortality
and
decreased
terminal
body
weights
(
4
 
10%)
in
males
and
females,
decreased
absolute
thymus
weights
(
30%)
in
males,
increased
bilirubin
in
females,
and
increased
spleen
and
lung
weights
(
relative
and
absolute)
in
females.
Neither
red
cell
hemolysis
nor
cataract
formation
was
observed
in
the
naphthalene­
exposed
mice.
Liver
changes
(
increased
liver
weight,
increased
lipid
peroxidation,
moderate
increases
in
serum
enzyme
activity)
have
been
reported
in
rats
exposed
to
relatively
high
doses
of
naphthalene
(
approximately
1,000
mg/
kg­
day
or
more)
when
administered
for
durations
of
10
days
to
9
weeks.
However,
no
effects
on
liver
weight
were
noted
in
a
14­
day
gavage
study
at
doses
up
to
267
mg/
kg­
day.
Naphthalene­
related
cataract
formation
has
been
reported
in
rabbits,
mice
and
rats
following
acute
and
short­
term
oral
exposures.

The
subchronic
oral
toxicity
of
naphthalene
has
been
investigated
in
rats
and
mice.
Male
and
female
rats
administered
400
mg/
kg­
day
by
corn
oil
gavage
for
13
weeks
exhibited
diarrhea,
lethargy,
hunched
posture,
and
rough
coats
during
the
study,
and
one
high­
dose
male
rat
died
during
the
last
week
of
exposure.
Body
weights
were
significantly
decreased
in
males
at
200
mg/
kg­
day
and
in
males
and
females
at
400
mg/
kg­
day.
In
a
similar
study
conducted
in
mice,
transient
signs
of
toxicity
(
lethargy,
rough
coats,
decreased
food
consumption)
were
observed
at
200
mg/
kg­
day
and
above.
Female
mice
exposed
to
naphthalene
exhibited
dose­
related
decreases
in
body
weight
reaching
a
maximum
of
24.5%
in
females
receiving
200­
mg/
kg­
day.
A
second
oral
exposure
study
in
mice
observed
changes
in
organ
weight
and
enzyme
alterations
indicative
of
impacts
on
liver
function
at
133
mg/
kg­
day.
1­
4
Naphthalene
 
February
2003
Relatively
little
information
is
available
regarding
the
neurological
effects
of
naphthalene
exposure
in
experimental
animals.
Two
studies
(
one
each
in
rabbits
and
pregnant
rats)
have
noted
treatment­
related
signs
of
neurotoxicity
(
lethargy,
slow
respiration
including
periods
of
apnea,
body
drop
and
labored
breathing,
and/
or
inability
to
move
after
dosing)
at
doses
of
50
to
450
mg/
kg­
day.
These
effects
were
transient
in
pregnant
rats
at
doses
of
50
to
150
mg/
kg­
day.
However,
the
subchronic
studies
discussed
above
found
no
clinical
signs
of
neurotoxicity
at
similar
doses.

The
reproductive
and
developmental
toxicity
of
naphthalene
has
been
evaluated
in
rats,
mice
and
rabbits.
The
results
of
these
studies
suggest
that
naphthalene
is
a
very
weak
reproductive
and
developmental
toxicant,
with
detectable
effects
occurring
only
at
doses
associated
with
substantial
maternal
toxicity.

The
2­
year
inhalation
National
Toxicology
Program
(
NTP)
bioassays
of
naphthalene
reported
increased
incidences
of
non­
neoplastic
nasal
lesions
in
male
rats
exposed
for
6
hours/
day
to
10
ppm.
In
mice,
there
was
chronic
inflammation
of
the
lungs
and
nasal
epithelium
accompanied
by
hyperplasia
There
are
no
oral
exposure
studies
that
are
considered
adequate
to
fully
assess
the
carcinogenic
potential
of
naphthalene.
No
tumors
were
identified
in
a
study
of
rats
orally
administered
42
mg/
kg­
day
for
over
2
years.
However,
the
published
report
contains
limited
experimental
detail.
NTP
concluded
that
there
was
some
evidence
of
carcinogenic
potential
in
female
mice
exposed
by
inhalation
to
30
ppm
naphthalene
for
2
years.
Clear
evidence
for
carcinogenic
potential
was
observed
in
male
and
female
rats
exposed
to
60
ppm
naphthalene
(
approximately
20
mg/
kg­
day)
by
inhalation
for
2
years.
However,
statistical
significance
was
achieved
only
for
tumors
of
the
respiratory
track
(
lungs
in
mice;
nasal
cavity
in
rats).
Several
studies
have
been
conducted
in
which
naphthalene
was
administered
by
routes
of
exposure
other
than
inhalation
or
diet.
No
carcinogenic
responses
were
observed
in
these
studies
and
each
has
at
least
one
limitation
that
makes
it
inadequate
for
assessing
the
potential
for
lifetime
risk.

The
mutagenic
and
genotoxic
potential
of
naphthalene
has
been
evaluated
in
numerous
in
vitro
and
in
vivo
assays.
The
results
of
most
studies
were
negative,
suggesting
that
the
mutagenic
and
genotoxic
potential
of
naphthalene
and
its
metabolites
are
weak.

When
naphthalene
was
evaluated
for
EPA's
Integrated
Risk
Information
System
(
IRIS),
prior
to
completion
of
the
NTP
bioassay
in
rats,
it
was
classified
in
Group
C:
possible
human
carcinogen.
This
classification
was
based
on
inadequate
human
data
for
exposure
to
naphthalene
via
the
oral
and
inhalation
routes
and
on
limited
evidence
of
carcinogenicity
in
animals
exposed
via
the
inhalation
route.
Using
the
1996
Proposed
Guidelines
for
Carcinogen
Risk
Assessment,
the
human
carcinogenic
potential
of
naphthalene
via
oral
or
inhalation
routes
"
cannot
be
determined."
Following
completion
of
the
IRIS
review,
the
NTP
bioassay
in
rats
showed
clear
evidence
for
carcinogenic
activity
within
the
nasal
cavity,
but
not
in
other
tissues.
The
new
data
strengthen
the
association
of
carcinogenicicty
with
the
inhalation
route
of
exposure
and
weaken
the
tenuous
association
with
the
oral
route.
For
this
reason,
the
carcinogenic
potential
of
naphthalene
via
the
inhalation
route
may
need
to
be
re­
evaluated.
1­
5
Naphthalene
 
February
2003
A
quantitative
cancer
dose­
response
assessment
for
naphthalene
was
not
conducted
for
IRIS.
This
decision
was
made
because
adequate
chronic
oral
animal
data
are
lacking
and
because
the
available
human
data
are
inadequate
to
evaluate
a
plausible
association
with
cancer.
Although
statistically
significant
increases
in
the
incidence
of
respiratory
system
tumors
were
reported
in
female
mice
(
lung)
and
rats
(
nasal
cavity)
exposed
to
naphthalene
via
inhalation
for
2
years,
this
evidence
is
considered
insufficient
to
assess
the
carcinogenic
potential
of
naphthalene
in
humans
exposed
via
the
oral
route.
The
existing
data
on
the
tumorigenic
effects
of
naphthalene
by
the
oral
route
of
exposure
are
inadequate
to
support
a
judgment
and,
therefore,
would
be
categorized
as
Group
D,
"
not
classifiable".
2­
1
Naphthalene
 
February
2003
Naphthalene
2.0
IDENTITY:
CHEMICAL
AND
PHYSICAL
PROPERTIES
Naphthalene
is
a
bicyclic
aromatic
hydrocarbon
with
the
chemical
formula
C
10
H
8
(
Figure
2­
1).
Pure
naphthalene
is
a
white,
water­
insoluble
solid
in
crystalline
or
marble­
like
form
and
has
a
distinct
mothball
odor.
The
chemical
and
physical
properties
of
naphthalene
are
summarized
in
Table
2­
1.

Figure
2­
1.
Chemical
Structure
of
Naphthalene
Table
2­
1.
Chemical
and
Physical
Properties
of
Naphthalene
Property
Information
Chemical
Abstracts
Registry
(
CAS)
No.
91­
20­
3
Registry
of
Toxic
Effects
of
Chemical
Substances
No.
QJ0525000
RCRA
Waste
No.
U165
EPA
Pesticide
Chemical
Code
055801
Synonyms
Tar
Camphor;
Albocarbon;
Naphthene;
Naphthalin;
Naphthaline;
Mothballs;
Mothflakes;
White
Tar;
Dezodorator;
Mighty
150;
Mighty
RD1
Registered
Trade
Name
Caswell
No.
587
®
Chemical
Formula
C
10
H
8
Molecular
Weight
128.19
Boiling
Point
218oC
Melting
Point
80.5oC
Vapor
Pressure
0.087
mm
Hg
Partition
Coefficients
Log
K
ow
3.29
Log
K
oc
2.97
Solubility
in
Water
0.0031
g/
100
mL
Organic
Solvents
Benzene,
Alcohol,
Ether,
Acetone
Source:
ATSDR
(
1995);
ChemIDplus
(
2000)
3­
1
Naphthalene
 
February
2003
3.0
USES
AND
ENVIRONMENTAL
FATE
3.1
Production
and
Use
Naphthalene
is
naturally
present
in
fossil
fuels
such
as
petroleum
and
coal,
and
is
generated
when
wood
or
tobacco
are
burned.
Naphthalene
is
produced
in
commercial
quantities
from
either
coal
tar
or
petroleum.
Most
of
the
naphthalene
produced
in
the
United
States
comes
from
petroleum
by
the
dealkylation
of
methylnaphthalenes
in
the
presence
of
hydrogen
at
high
temperature
and
pressure.
Another
common
production
method
is
the
distillation
and
fractionation
of
coal
tar.

Naphthalene
is
a
natural
constituent
of
coal
tar
and
crude
oil
(
11%
and
1.3%,
respectively)
(
Merck
Index,
1996).
Purified
naphthalene
is
obtained
from
coal
tar
or
petroleum
products
by
fractional
distillation.
Fractional
distillation
is
the
process
of
heating
a
liquid
until
its
more
volatile
constituents
pass
into
the
vapor
phase.
This
vapor
is
then
cooled
to
recover
constituents
by
condensation
(
Encarta,
2000).
Different
constituents
will
vaporize
at
different
boiling
points,
thus
permitting
separation
of
constituents.
Most
naphthalene
is
recovered
in
the
middle
fraction
(
ATSDR,
1995).
This
fraction
is
subsequently
purified
by
treatment
with
sulfuric
acid,
sodium
hydroxide,
and
water,
followed
by
sublimation
or
a
second
fractional
distillation.
U.
S.
manufacturers
produced
1.09
×
105
metric
tons
of
naphthalene
in
1996
(
CEH,
2000).

Naphthalene
production
in
the
United
States
dropped
from
900
million
pounds
per
year
(
lbs/
yr)
in
1968
to
354
million
lbs/
yr
in
1982.
Approximately
7
million
lbs
of
naphthalene
were
imported
and
9
million
lbs
were
exported
in
1978.
By
1989,
imports
had
dropped
to
4
million
lbs,
and
exports
increased
dramatically
to
21
million
lbs
(
ATSDR,
1995).

U.
S.
consumption
of
naphthalene
was
1.08
x
105
metric
tons
in
1996
(
CEH,
2000).
Naphthalene
is
used
in
the
production
of
phthalic
anhydride,
which
is
an
intermediate
in
the
manufacture
of
phthalate
plasticizers,
resins,
phthaleins,
dyes,
pharmaceuticals,
insect
repellants,
and
other
products
(
U.
S.
EPA,
1998a).
These
uses
account
for
approximately
60%
of
naphthalene
consumption
in
the
United
States
(
CEH,
1997).
Crystalline
naphthalene
is
used
as
a
moth
repellant
and
as
a
deodorizer
for
diaper
pails
and
in
toilets
(
U.
S.
EPA,
1998a).
In
the
past,
naphthalene
was
used
medicinally
as
an
antiseptic,
expectorant,
and
anthelminthic,
and
for
treatment
of
gastrointestinal
and
skin
disorders
(
ATSDR,
1995).
Most
naphthalene
consumption
(
60%)
is
through
use
as
an
intermediary
in
the
production
of
phthalate
plasticizers,
resins,
phthaleins,
dyes,
pharmaceuticals,
and
insect
repellents.
Crystalline
naphthalene
is
used
as
a
moth
repellent
and
a
solid
block
deodorizer
for
diaper
pails
and
toilets.
Naphthalene
is
also
used
to
make
the
insecticide
carbaryl,
synthetic
leather
tanning
agents,
and
surface
active
agents
(
ATSDR,
1995).

3.2
Environmental
Release
Naphthalene
is
listed
as
a
toxic
release
inventory
(
TRI)
chemical.
In
1986,
the
Emergency
Planning
and
Community
Right­
to­
Know
Act
(
EPCRA)
established
the
Toxic
3­
2
Naphthalene
 
February
2003
Release
Inventory
(
TRI)
of
hazardous
chemicals.
Created
under
the
Superfund
Amendments
and
Reauthorization
Act
(
SARA)
of
1986,
EPCRA
is
also
sometimes
known
as
SARA
Title
III.
The
EPCRA
mandates
that
larger
facilities
publicly
report
when
TRI
chemicals
are
released
into
the
environment.
This
public
reporting
is
required
for
facilities
with
more
than
10
full­
time
employees
that
annually
manufacture
or
produce
more
than
25,000
pounds,
or
use
more
than
10,000
pounds,
of
TRI
chemical
(
U.
S.
EPA,
1996d,
2000a).

Under
these
conditions,
facilities
are
required
to
report
the
pounds
per
year
of
naphthalene
released
into
the
environment
both
on­
and
off­
site.
The
on­
site
quantity
is
subdivided
into
air
emissions,
surface
water
discharges,
underground
injections,
and
releases
to
land
(
see
Table
3­
1).
For
naphthalene,
air
emissions
constitute
most
of
the
on­
site
releases.
Also,
surface
water
discharges
exhibit
no
obvious
trend
over
the
period
for
which
data
is
available
(
1988
 
1998),
but
discharges
hit
a
low
in
1996
and
1997,
and
increased
again
in
1998.
These
TRI
data
for
naphthalene
were
reported
from
47
States
(
excluding
ID,
NH,
and
VT),
indicating
the
widespread
production
or
use
of
this
chemical
(
U.
S.
EPA,
2000b).

Table
3­
1.
Environmental
Releases
(
in
pounds)
for
Naphthalene
in
the
United
States
(
1988
 
1998).

Year
On­
Site
Releases
Off­
Site
Releases
Total
On­
&
Off­
site
Releases
Air
Emissions
Surface
Water
Discharges
Underground
Injection
Releases
to
Land
1998
3,374,439
34,148
191,677
1,251,040
827,708
5,679,012
1997
2,449,488
13,333
187,927
82,204
491,124
3,224,076
1996
2,863,431
11,836
296,776
301,513
582,717
4,056,273
1995
2,690,669
43,311
44,318
32,085
474,106
3,284,489
1994
2,889,514
28,557
97,186
47,017
496,501
3,558,775
1993
2,744,887
31,179
79,814
49,886
334,985
3,240,751
1992
2,626,986
28,925
78,227
1,667,150
667,556
5,068,844
1991
2,927,511
31,508
39,112
55,278
983,371
4,036,780
1990
3,912,253
36,821
28,130
143,196
919,225
5,039,625
1989
3,523,562
146,983
39,552
118,409
1,054,602
4,883,108
1988
5,165,426
22,518
50,946
123,697
1,359,184
6,721,771
source:
U.
S.
EPA
(
2000b)

Although
the
TRI
information
can
be
useful
in
giving
a
general
idea
of
release
trends,
it
is
far
from
exhaustive
and
has
significant
limitations.
For
example,
only
industries
that
meet
TRI
criteria
(
at
least
10
full­
time
employees
and
manufacture
and
processing
of
quantities
exceeding
25,000
lbs/
yr,
or
use
of
more
than
10,000
lbs/
yr)
are
required
to
report
releases.
These
reporting
criteria
do
not
account
for
releases
from
smaller
industries.
Threshold
manufacture
and
processing
quantities
also
changed
from
1988
 
1990
(
dropping
from
75,000
lbs/
yr
in
1988
to
50,000
lbs/
yr
in
1989
to
25,000
lbs/
yr
in
1990),
creating
possibly
misleading
data
trends.
Finally,
the
TRI
data
are
meant
to
reflect
releases
and
should
not
be
used
to
estimate
general
exposure
to
a
chemical
(
U.
S.
EPA,
2000c,
d).

Naphthalene
is
also
included
in
the
Agency
for
Toxic
Substances
and
Disease
Registry's
(
ATSDR)
Hazardous
Substance
Release
and
Health
Effects
Database
(
HazDat).
This
database
3­
3
Naphthalene
 
February
2003
records
detections
of
listed
chemicals
in
site
samples.
Naphthalene
was
detected
in
44
States;
States
without
detections
are
AK,
AZ,
HI,
NV,
ND,
and
UT
(
ATSDR,
2000).
The
National
Priorities
List
(
NPL)
of
hazardous
waste
sites,
created
in
1980
by
the
Comprehensive
Environmental
Response,
Compensation
and
Liability
Act
(
CERCLA),
is
a
listing
of
some
of
the
most
health­
threatening
waste
sites
in
the
United
States.
Naphthalene
was
again
detected
at
sites
in
all
but
six
States
(
HI,
NE,
NV,
NM,
ND,
and
WV)
(
U.
S.
EPA,
1999a).

3.3
Environmental
Fate
Direct
releases
to
the
air
account
for
more
than
90%
of
the
naphthalene
entering
environmental
media
(
ATSDR,
1995).
The
primary
discharge
source
is
residential
combustion
of
wood
and
fossil
fuels.
Other
residential
sources
of
naphthalene
include
tobacco
smoke
and
the
vaporization
of
moth
repellants.
Naphthalene
may
also
be
released
to
air
during
coal
tar
production
and
distillation,
aeration
processes
in
water
treatment
plants,
and
from
use
of
naphthalene
during
chemical
manufacturing
(
ATSDR,
1995).

About
5%
of
environmental
naphthalene
is
released
into
water,
primarily
from
coal
tar
production
and
distillation
processes
(
ATSDR,
1995).
Other
contributors
to
water
releases
include
effluents
from
wood
preserving
facilities
and
oil
spills.
More
than
half
of
these
releases
are
to
surface
water
(
ATSDR,
1995).
According
to
ATSDR
(
1995),
only
about
2.7%
of
naphthalene
releases
are
discharged
to
land,
but
that
number
increased
to
37%
in
the
most
recent
year
for
which
data
are
available
(
Table
3­
1).
Sources
for
release
to
land
include
coal
tar
production,
naphthalene
production,
publicly
operated
treatment
works
(
POTWs)
sludge
disposal,
and
the
use
of
naphthalene­
containing
organic
chemicals.

The
primary
removal
process
for
naphthalene
in
air
is
through
reactions
with
hydroxyl
radicals.
Naphthalene
will
also
react
with
atmospheric
N
2
O
5,
nitrate
radicals,
and
ozone.
The
major
products
of
these
reactions
are
1­
and
2­
naphthol
and
1­
and
2­
nitronaphthalene.
The
halflife
of
atmospheric
naphthalene
is
less
than
1
day
(
ATSDR,
1995).

Naphthalene
is
lost
from
surface
water
via
several
mechanisms.
Volatilization
into
the
air
is
the
most
important
route
of
loss
from
surface
water
(
ATSDR,
1995).
Mackay
and
Leinonen
(
1975)
estimated
a
half­
life
of
7.2
hours
for
the
volatilization
of
naphthalene
(
quantity
not
stated)
from
an
aqueous
solution
1
meter
deep.
Southworth
(
1979)
estimated
that
a
10­
fold
increase
in
current
velocity
would
accelerate
volatilization
2
to
3
times.
Rodgers
et
al.
(
1983)
estimated
a
volatilization
rate
constant
of
0.16
hour­
1,
which
resulted
in
a
half­
life
of
4.3
hours
(
U.
S.
EPA,
1986d).

A
small
fraction
(
less
than
10%)
of
naphthalene
in
water
will
be
associated
with
particulate
matter
and
will
settle
into
sediments
(
ATSDR,
1995).
Naphthalene
that
remains
in
surface
water
will
be
degraded
through
photolysis
and
biodegradation
processes.
Naphthalene
undergoing
photolysis
has
a
half­
life
of
about
71
hours
(
ATSDR,
1995).
Biodegradation
of
this
chemical
also
occurs
quite
rapidly,
although
degradation
time
will
vary
with
naphthalene
concentration,
water
temperature,
and
the
availability
of
nutrients
(
U.
S.
EPA,
1986d).
In
general,
the
rate
of
biodegradation
increases
as
the
concentration
of
naphthalene
increases.
The
half­
life
3­
4
Naphthalene
 
February
2003
of
naphthalene
in
oil­
polluted
water
versus
unpolluted
water
is
approximately
7
and
1,700
days,
respectively
(
ATSDR,
1995).

Volatilization
from
soil
surfaces
and
biodegradation
are
important
processes
for
the
removal
of
naphthalene
from
soil
(
U.
S.
EPA,
1986d).
The
estimated
volatilization
half­
lives
for
naphthalene
from
soil
containing
1.25%
were
1.1
day
from
soil
1
cm
deep
and
14
days
from
soil
10
cm
deep.
Maximum
biodegradation
is
reported
to
occur
at
a
pH
of
8
and
in
the
presence
of
a
positive
redox
potential
(
U.
S.
EPA,
1986d).
Naphthalene
is
degraded
to
carbon
dioxide
and
salicylate
by
aerobic
microorganisms
(
ATSDR,
1995).
Therefore,
soil
aerobic
conditions
strongly
influence
the
half­
life
of
the
chemical.
In
addition,
soil
organic
matter
is
an
important
factor
in
degradation
time
because
the
adsorption
of
naphthalene
to
organic
matter
significantly
decreases
its
bioavailability
to
microorganisms.

3.4
Summary
In
summary,
most
of
naphthalene's
consumption
is
through
its
use
as
an
intermediary
in
the
production
of
phthalate
plasticizers,
resins,
phthaleins,
dyes,
pharmaceuticals,
and
insect
repellents.
Its
production
in
the
United
States
declined
from
1968
to
1982;
however
its
import
decreased
and
export
increased
from
1978
to
1989.
The
widespread
use
and
production
of
naphthalene
in
the
United
States
is
evidenced
by
its
presence
in
hazardous
waste
sites
in
at
least
44
States
(
at
NPL
sites),
its
presence
in
site
samples
in
at
least
44
States
(
listed
in
ATSDR's
HazDat),
and
its
direct
release
into
the
environment
in
at
least
47
States
(
based
on
TRI
data).
4­
1
Naphthalene
 
February
2003
4.0
EXPOSURE
FROM
DRINKING
WATER
4.1
Introduction
This
section
of
the
report
examines
the
occurrence
of
naphthalene
in
drinking
water.
While
no
complete
national
database
exists
of
unregulated
or
regulated
contaminants
in
drinking
water
from
public
water
systems
(
PWSs)
collected
under
the
Safe
Drinking
Water
Act
(
SDWA),
this
report
aggregates
and
analyzes
existing
state
data
that
have
been
screened
for
quality,
completeness,
and
representativeness.
Populations
served
by
PWSs
exposed
to
naphthalene
are
estimated,
and
the
occurrence
data
are
examined
for
regional
or
other
special
trends.
To
augment
the
incomplete
national
drinking
water
data
and
to
aid
in
the
evaluation
of
occurrence,
information
on
the
ambient
occurrence
of
naphthalene
is
also
reviewed.

4.2
Ambient
Occurrence
To
understand
the
presence
of
a
chemical
in
the
environment,
an
examination
of
ambient
occurrence
is
useful.
In
a
drinking
water
context,
ambient
water
is
source
water
existing
in
surface
waters
and
aquifers
before
treatment.
The
most
comprehensive
and
nationally
representative
data
describing
ambient
water
quality
in
the
United
States
are
being
produced
through
the
United
States
Geological
Survey's
(
USGS)
National
Ambient
Water
Quality
Assessment
(
NAWQA)
program.
However,
as
NAWQA
is
a
relatively
young
program,
complete
national
data
are
not
yet
available
from
their
entire
array
of
sites
across
the
nation.

4.2.1
Data
Sources
and
Methods
The
USGS
instituted
the
NAWQA
program
in
1991
for
the
purpose
of
examining
water
quality
status
and
trends
in
the
United
States.
NAWQA
is
designed
and
implemented
in
such
a
manner
to
allow
consistency
and
comparison
between
representative
study
basins
located
around
the
country,
facilitating
interpretation
of
natural
and
anthropogenic
factors
affecting
water
quality
(
Leahy
and
Thompson,
1994).

The
NAWQA
program
consists
of
59
significant
watersheds
and
aquifers
referred
to
as
"
study
units."
The
study
units
represent
approximately
two­
thirds
of
the
overall
water
usage
in
the
United
States
and
a
similar
proportion
of
the
population
served
by
public
water
systems.
Approximately
one­
half
of
the
nation's
land
area
is
represented
(
Leahy
and
Thompson,
1994).

To
facilitate
management
and
make
the
program
cost­
effective,
approximately
one­
third
of
the
study
units
at
a
time
engage
in
intensive
assessment
for
a
period
of
3
to
5
years.
This
is
followed
by
a
period
of
less
intensive
research
and
monitoring
that
lasts
between
5
and
7
years.
This
way
all
59
study
units
rotate
through
intensive
assessment
over
a
ten­
year
period
(
Leahy
and
Thompson,
1994).
The
first
round
of
intensive
monitoring
(
1991
 
1996)
targeted
20
watersheds.
This
first
group
was
more
heavily
slanted
toward
agricultural
basins.
A
national
synthesis
of
results
from
these
study
units
and
other
research
initiatives
focusing
on
pesticides
and
nutrients
is
being
compiled
and
analyzed
(
Kolpin
et
al.,
1998;
Larson
et
al.,
1999).
4­
2
Naphthalene
 
February
2003
For
volatile
organic
chemicals
(
VOCs),
the
national
synthesis
will
compile
data
from
the
first
and
second
rounds
of
intensive
assessments.
Study
units
assessed
in
the
second
round
represent
conditions
in
more
urbanized
basins,
but
initial
results
are
not
yet
available.
However,
VOCs
were
analyzed
in
the
first
round
of
intensive
monitoring
and
data
are
available
for
these
study
units
(
Squillace
et
al.,
1999).
The
minimum
reporting
level
(
MRL)
for
most
VOCs,
including
naphthalene,
was
0.2
µ
g/
L
(
Squillace
et
al.,
1999).
Additional
information
on
analytical
methods
used
in
the
NAWQA
study
units,
including
method
detection
limits,
are
described
by
Gilliom
and
others
(
in
press).

Furthermore,
the
NAWQA
program
has
compiled,
by
study
unit,
data
collected
from
local,
State,
and
other
Federal
agencies
to
augment
its
own
data.
The
data
set
provides
an
assessment
of
VOCs
in
untreated
ambient
groundwater
of
the
coterminous
United
States
for
the
period
1985
 
1995
(
Squillace
et
al.,
1999).
Data
were
included
in
the
compilation
if
they
met
certain
criteria
for
collection,
analysis,
well
network
design,
and
well
construction
(
Lapham
et
al.,
1997).
They
represent
both
rural
and
urban
areas,
but
should
be
viewed
as
a
progress
report
as
NAWQA
data
continue
to
be
collected
that
may
influence
conclusions
regarding
occurrence
and
distribution
of
VOCs
(
Squillace
et
al.,
1999).

The
National
Highway
Runoff
Data
and
Methodology
Synthesis
has
reviewed
44
highway
and
urban
runoff
studies
implemented
since
1970
(
Lopes
and
Dionne,
1998).
Two
national
studies
were
included
in
this
review:
the
National
Urban
Runoff
Program
(
NURP)
and
studies
associated
with
the
U.
S.
EPA
National
Pollution
Discharge
Elimination
System
(
NPDES)
municipal
stormwater
permits.
NURP,
conducted
in
the
1970s
and
early
1980s,
had
the
most
extensive
geographic
distribution.
The
NPDES
studies
took
place
in
the
early
to
mid­
1990s
(
Lopes
and
Dionne,
1998).
Naphthalene
was
an
analyte
in
both
studies.

4.2.2
Results
Naphthalene
was
detected
in
both
rural
and
urban
wells
of
the
local,
State,
and
Federal
data
set
compiled
by
NAWQA
(
Table
4­
1).
The
data
represent
untreated
ambient
ground
water
of
the
coterminous
United
States
for
the
years
1985
 
1995
(
Squillace
et
al.,
1999).
Detection
frequencies
and
median
concentrations
are
low,
especially
for
rural
areas.
Occurrence
of
naphthalene
in
rural
areas
is
an
order
of
magnitude
lower
than
in
urban
areas,
a
trend
generally
observed
for
VOCs
throughout
the
United
States
(
Miller,
2000).
The
exception
to
this
trend
for
naphthalene
is
the
maximum
concentration,
a
parameter
more
likely
to
be
influenced
by
extreme
values
(
outliers)
that
do
not
well
represent
the
overall
data.

The
NURP
and
NPDES
studies
analyzing
urban
and
highway
runoff
also
found
naphthalene
(
Lopes
and
Dionne,
1998).
Naphthalene
was
detected
in
11%
of
NURP
samples,
making
it
among
the
3
most
detected
VOCs
in
the
study.
Its
detection
frequency
was
7%
in
the
NPDES
studies.
The
maximum
concentration
was
2.3
µ
g/
L
in
NURP
samples
and
5.1
µ
g/
L
in
NPDES
samples.
4­
3
Naphthalene
 
February
2003
Table
4­
1.
Naphthalene
Detections
and
Concentrations
in
Ground
Water.

Location
Detection
frequency
(%
of
sampled
wells
>
MRL*)
Concentration
percentiles
(
of
detections;
µ
g/
L)
Percent
exceeding
HAL**
(
20
µ
g/
L)

median
maximum
all
wells
drinking
water
wells
Urban
3.0
%
3.9
43
0.4
0
Rural
0.2
%
0.4
70
0.1
0
after
Squillace
et
al.(
1999).
*
MRL
for
naphthalene
in
water:
0.001
µ
g/
L
**
U.
S.
EPA
(
1996e);
ATSDR
(
1996)

The
maximum
values
for
urban
and
highway
runoff
are
well
below
the
Health
Advisory
Level
(
HAL)
of
20
µ
g/
L
cited
by
Lopes
and
Dionne
(
1998),
the
HAL
in
effect
at
the
time
(
U.
S.
EPA,
1996e).
The
ground
water
studies
also
reported
few
exceedances
of
the
20
µ
g/
L
HAL
(
Squillace
et
al.,
1999).
The
maximum
values
for
runoff
and
groundwater
are
considerably
less
than
the
current
HAL
of
100
µ
g/
L
(
U.
S.
EPA,
2000e)
and
even
more
so
for
the
Health
Reference
Level
(
HRL)
of
140
µ
g/
L
used
as
a
preliminary
health
effects
level
for
the
drinking
water
data
analysis
presented
below.

4.3
Drinking
Water
Occurrence
The
Safe
Drinking
Water
Act,
as
amended
in
1996,
required
PWSs
to
monitor
for
specified
"
unregulated"
contaminants,
on
a
five­
year
cycle,
and
to
report
the
monitoring
results
to
the
States.
Unregulated
contaminants
do
not
have
an
established
or
proposed
National
Primary
Drinking
Water
Regulation
(
NPDWR),
but
they
are
contaminants
that
were
formally
listed
and
required
for
monitoring
under
federal
regulations.
The
intent
was
to
gather
scientific
information
on
the
occurrence
of
these
contaminants
to
enable
a
decision
as
to
whether
or
not
regulations
were
needed.
All
non­
purchased
community
water
systems
(
CWSs)
and
non­
purchased
nontransient
non­
community
water
systems
(
NTNCWSs),
with
greater
than
150
service
connections,
were
required
to
conduct
this
unregulated
contaminant
monitoring.
Smaller
systems
were
not
required
to
conduct
this
monitoring
under
federal
regulations,
but
were
required
to
be
available
to
monitor
if
the
State
decided
such
monitoring
was
necessary.
Many
States
collected
data
from
smaller
systems.
Additional
contaminants
were
added
to
the
Unregulated
Contaminant
Monitoring
(
UCM)
program
in
1991
[
56
FR
3526]
(
U.
S.
EPA,
1991b)
for
required
monitoring
that
began
in
1993
[
57
FR
31776]
(
U.
S.
EPA,
1992).

Naphthalene
has
been
monitored
under
the
SDWA
UCM
program
since
1987
(
52
FR
25720)
(
U.
S.
EPA,
1987a).
Monitoring
for
naphthalene
under
UCM
continued
throughout
the
1990s,
but
ceased
for
small
public
water
systems
(
PWSs)
under
a
direct
final
rule
published
January
8,
1999
(
64
FR
1494)
(
U.
S.
EPA,
1999b).
Monitoring
ended
for
large
PWSs
with
promulgation
of
the
new
Unregulated
Contaminant
Monitoring
Regulation
(
UCMR)
issued
September
17,
1999
(
64
FR
50556)
(
U.
S.
EPA,
1999c)
and
effective
January
1,
2001.
At
the
time
the
UCMR
lists
were
developed,
the
Agency
concluded
there
were
adequate
monitoring
4­
4
Naphthalene
 
February
2003
data
for
a
regulatory
determination.
This
obviated
the
need
for
continued
monitoring
under
the
new
UCMR
list.

4.3.1
Data
Sources,
Data
Quality,
and
Analytical
Methods
Currently,
there
is
no
complete
national
record
of
unregulated
or
regulated
contaminants
in
drinking
water
from
public
water
systems
collected
under
SDWA.
Many
States
have
submitted
their
unregulated
contaminant
PWS
monitoring
data
to
EPA
databases,
but
there
are
issues
of
data
quality,
completeness,
and
representativeness.
Nonetheless,
a
significant
amount
of
State
data
is
available
for
UCM
contaminants
that
can
provide
estimates
of
national
occurrence.

The
National
Contaminant
Occurrence
Database
(
NCOD)
is
an
interface
to
the
actual
occurrence
data
stored
in
the
Safe
Drinking
Water
Information
System
(
Federal
version;
SDWIS/
FED)
and
can
be
queried
to
provide
a
summary
of
the
data
in
SDWIS/
FED
for
a
particular
contaminant.
The
data
used
in
this
report
were
derived
from
the
data
in
SDWIS/
FED
and
another
database
called
the
Unregulated
Contaminant
Information
System
(
URCIS).

The
data
in
this
report
have
been
reviewed,
edited,
and
filtered
to
meet
various
data
quality
objectives
for
the
purposes
of
this
analysis.
Hence,
only
data
meeting
the
quality
objectives
described
below
were
used,
rather
than
all
available
data
from
a
particular
source.
The
sources
of
these
data,
their
quality
and
national
aggregation,
and
the
analytical
methods
used
to
estimate
a
given
contaminant's
national
occurrence
(
from
these
data)
are
discussed
in
this
section
(
for
further
details
see
Cadmus,
2000a,
b).

UCM
Rounds
1
and
2
The
1987
UCM
contaminants
include
34
volatile
organic
compounds
(
VOCs),
divided
into
two
groups:
one
with
20
VOCs
for
mandatory
monitoring,
and
the
other
with
14
VOCs
for
discretionary
monitoring
[
52
FR
25720].
Naphthalene
was
among
the
14
VOCs
included
for
discretionary
monitoring.
The
UCM
(
1987)
contaminants
were
first
monitored
coincident
with
the
Phase
I
regulated
contaminants,
during
the
1988
 
1992
period.
This
period
is
often
referred
to
as
"
Round
1"
monitoring.
The
monitoring
data
collected
by
the
PWSs
were
reported
to
the
States
(
as
primacy
agents),
but
there
was
no
protocol
in
place
to
report
these
data
to
EPA.
These
data
from
Round
1
were
collected
by
EPA
from
many
States
over
time.

The
Round
1
data
were
put
into
a
database
called
the
Unregulated
Contaminant
Information
System,
or
URCIS.
Most
of
the
Phase
1
regulated
contaminants
were
also
VOCs.
Both
the
unregulated
and
regulated
VOCs
are
analyzed
using
the
same
sample
and
the
same
laboratory
methods.
Hence,
the
URCIS
database
includes
data
on
all
of
these
62
contaminants:
the
34
UCM
(
1987)
VOCs,
the
21
regulated
Phase
1
VOCs,
2
regulated
synthetic
organic
contaminants
(
SOCs),
and
5
miscellaneous
contaminants
that
were
voluntarily
reported
by
some
States
(
e.
g.,
isomers
of
other
organic
contaminants).

The
1993
UCM
contaminants
include
13
SOCs
and
1
inorganic
compound
(
IOC)
[
56
FR
3526].
Monitoring
for
the
UCM
(
1993)
contaminants
began
coincident
with
the
Phase
II/
V
4­
5
Naphthalene
 
February
2003
regulated
contaminants
in
1993
through
1998.
This
is
often
referred
to
as
"
Round
2"
monitoring.
The
UCM
(
1987)
contaminants
were
also
included
in
the
Round
2
monitoring.
As
with
other
monitoring
data,
PWSs
reported
these
results
to
the
States.
During
the
past
several
years,
EPA
has
requested
that
the
States
submit
these
historic
data
to
EPA.

The
details
of
the
actual
individual
monitoring
periods
are
complex.
The
timing
of
required
monitoring
was
staggered
relative
to
different
size
classes
of
PWSs,
and
the
program
was
implemented
somewhat
differently
by
different
States.
While
Round
1
includes
the
period
from
1988
 
1992,
it
also
includes
results
from
samples
analyzed
prior
to
1988
that
were
"
grandfathered"
into
the
database
(
for
further
details
see
Cadmus,
2000a,
b).

Developing
a
Nationally
Representative
Perspective
The
Round
1
and
Round
2
databases
contain
contaminant
occurrence
data
from
a
total
of
40
and
35
primacy
entities
(
largely
States),
respectively.
However,
data
from
some
States
are
incomplete
and
biased.
Furthermore,
the
national
representativeness
of
the
data
is
problematic
because
the
data
were
not
collected
in
a
systematic
or
random
statistical
framework.
These
State
data
could
be
heavily
skewed
to
low­
occurrence
or
high­
occurrence
settings.
Hence,
the
State
data
were
evaluated
based
on
pollution­
potential
indicators
and
the
spatial/
hydrologic
diversity
of
the
nation.
This
evaluation
enabled
the
construction
of
a
cross­
section
from
the
available
State
data
sets
that
provides
a
reasonable
representation
of
national
occurrence.

A
national
cross­
section
from
these
State
Round
2
contaminant
databases
was
established
using
the
approach
developed
for
the
EPA
report
A
Review
of
Contaminant
Occurrence
in
Public
Water
Systems
(
U.
S.
EPA,
1999d).
This
approach
was
developed
to
support
occurrence
analyses
for
EPA's
Chemical
Monitoring
Reform
(
CMR)
evaluation.
It
was
supported
by
peer
reviewers
and
stakeholders.
The
approach
cannot
provide
a
"
statistically
representative"
sample
because
the
original
monitoring
data
were
not
collected
or
reported
in
an
appropriate
fashion.
However,
the
resultant
"
national
cross­
section"
of
States
should
provide
a
clear
indication
of
the
central
tendency
of
the
national
data.
The
remainder
of
this
section
provides
a
summary
description
of
how
the
national
cross­
sections
for
the
URCIS
(
Round
1)
and
SDWIS/
FED
(
Round
2)
databases
were
developed.
The
details
of
the
approach
are
presented
in
other
documents
(
Cadmus,
2000a,
b),
to
which
readers
are
referred
for
more
specific
information.

Cross­
Section
Development
As
a
first
step
in
developing
the
cross­
section,
the
State
data
contained
in
the
URCIS
database
(
that
contains
the
Round
1
monitoring
results)
and
SDWIS/
FED
database
(
that
contains
the
Round
2
monitoring
results)
were
evaluated
for
completeness
and
quality.
For
both
the
URCIS
(
Round
1)
and
SDWIS/
FED
(
Round
2)
databases,
some
State
data
were
unusable
for
a
variety
of
reasons.
Some
States
reported
only
detections,
or
their
data
had
incorrect
units.
Datasets
only
including
detections
are
obviously
biased.
Other
problems
included
substantially
incomplete
data
sets
without
all
PWSs
reporting.
Also,
data
from
Washington,
D.
C.
and
the
Virgin
Islands
were
excluded
from
this
analysis
because
it
was
difficult
to
evaluate
them
for
the
current
purposes
in
relation
to
complete
State
data
(
Cadmus,
2000b,
Sections
II
and
III).
4­
6
Naphthalene
 
February
2003
The
balance
of
the
States
remaining
after
the
data
quality
screening
were
then
examined
to
establish
a
national
cross­
section.
This
step
was
based
on
evaluating
the
States'
pollution
potential
and
geographic
coverage
in
relation
to
all
States.
Pollution
potential
is
considered
to
ensure
a
selection
of
States
that
represent
the
range
of
likely
contaminant
occurrence
and
a
balance
with
regard
to
likely
high
and
low
occurrence.
Geographic
consideration
is
included
so
that
the
wide
range
of
climatic
and
hydrogeologic
conditions
across
the
United
States
are
represented,
again
balancing
the
varied
conditions
that
affect
transport
and
fate
of
contaminants,
as
well
as
conditions
that
affect
naturally
occurring
contaminants
(
Cadmus,
2000a,
Sections
III.
A.
and
III.
B.).

The
cross­
section
States
were
selected
to
represent
a
variety
of
pollution
potential
conditions.
Two
primary
pollution
potential
indicators
were
used.
The
first
factor
selected
indicates
pollution
potential
from
manufacturing/
population
density
and
serves
as
an
indicator
of
the
potential
for
VOC
contamination
within
a
State.
Agriculture
was
selected
as
the
second
pollution
potential
indicator
because
the
majority
of
SOCs
of
concern
are
pesticides
(
Cadmus,
2000a,
Section
III.
A.).
The
50
individual
States
were
ranked
from
highest
to
lowest
based
on
the
pollution
potential
indicator
data.
For
example,
the
State
with
the
highest
ranking
for
pollution
potential
from
manufacturing
received
a
ranking
of
1
for
this
factor
and
the
State
with
the
lowest
value
was
ranked
as
number
50.
States
were
ranked
for
their
agricultural
chemical
use
status
in
a
similar
fashion.

The
States'
pollution
potential
rankings
for
each
factor
were
subdivided
into
four
quartiles
(
from
highest
to
lowest
pollution
potential).
The
cross­
section
States
were
chosen
from
all
quartiles
for
both
pollution
potential
factors
to
ensure
representation,
for
example,
from:
States
with
high
agrochemical
pollution
potential
rankings
and
high
manufacturing
pollution
potential
rankings;
States
with
high
agrochemical
pollution
potential
rankings
and
low
manufacturing
pollution
potential
rankings;
States
with
low
agrochemical
pollution
potential
rankings
and
high
manufacturing
pollution
potential
rankings;
and
States
with
low
agrochemical
pollution
potential
rankings
and
low
manufacturing
pollution
potential
rankings
(
Cadmus,
2000a,
Section
III.
B.).
In
addition,
some
secondary
pollution
potential
indicators
were
considered
to
further
ensure
that
the
cross­
section
States
included
the
spectrum
of
pollution
potential
conditions
(
high
to
low).
The
cross­
sections
were
then
reviewed
for
geographic
coverage
throughout
all
sectors
of
the
United
States.

The
data
quality
screening,
pollution
potential
rankings,
and
geographic
coverage
analysis
established
national
cross­
sections
of
24
Round
1
(
URCIS)
States
and
20
Round
2
(
SDWIS/
FED)
States.
In
each
cross­
section,
the
States
provide
good
representation
of
the
nation's
varied
climatic
and
hydrogeologic
regimes
and
the
breadth
of
pollution
potential
for
the
contaminant
groups
(
Table
4­
2
and
Figure
4­
1).
4­
7
Naphthalene
 
February
2003
Table
4­
2.
Cross­
section
States
for
Round
1
(
24
States)
and
Round
2
(
20
States).

Round
1
(
URCIS)
Round
2
(
SDWIS/
FED)

Alabama
Alaska*
Arizona
California
Florida
Georgia
Hawaii
Illinois
Indiana
Iowa
Kentucky*
Maryland*
Minnesota*
Montana
New
Jersey
New
Mexico*
North
Carolina*
Ohio*
South
Dakota
Tennessee
Utah
Washington*
West
Virginia
Wyoming
Alaska*
Arkansas
Colorado
Kentucky*
Maine
Maryland*
Massachusetts
Michigan
Minnesota*
Missouri
New
Hampshire
New
Mexico*
North
Carolina*
North
Dakota
Ohio*
Oklahoma
Oregon
Rhode
Island
Texas
Washington*

*
cross­
section
State
in
both
Round
1
and
Round
2
Figure
4­
1.
Geographic
Distribution
of
Cross­
section
States.
Round
1
(
left)
and
Round
2
(
right).
4­
8
Naphthalene
 
February
2003
Cross­
Section
Evaluation
To
evaluate
and
validate
the
method
for
creating
the
national
cross­
sections,
the
method
was
used
to
create
smaller
State
subsets
from
the
24­
State,
Round
1
cross­
section
and
aggregations.
Again,
States
were
chosen
to
achieve
a
balance
from
the
quartiles
describing
pollution
potential,
as
well
as
a
balanced
geographic
distribution,
to
incrementally
build
subset
cross­
sections
of
various
sizes.
For
example,
the
Round
1
cross­
section
was
tested
with
subsets
of
4,
8
(
the
first
4
State
subset
plus
4
more
States),
and
13
(
8
State
subset
plus
5)
States.
Two
additional
cross­
sections
were
included
in
the
analysis
for
comparison:
a
cross­
section
composed
of
16
biased
States
eliminated
from
the
24­
State
cross­
section
for
data
quality
reasons
and
a
cross­
section
composed
of
all
40
Round
1
States
(
Cadmus,
2000a,
Section
III.
B.
1).

These
Round
1
incremental
cross­
sections
were
then
used
to
evaluate
occurrence
for
an
array
of
both
high­
and
low­
occurrence
contaminants.
The
comparative
results
illustrate
several
points.
The
results
are
quite
stable
and
consistent
for
the
8­,
13­
and
24­
State
cross­
sections.
They
are
much
less
so
for
the
4­
State,
16­
State
(
biased),
and
40­
State
(
all
Round
1
States)
crosssections
The
4­
State
cross­
section
is
apparently
too
small
to
provide
balance
both
geographically
and
with
pollution
potential,
a
finding
that
concurs
with
past
work
(
U.
S.
EPA,
1999d).
The
CMR
analysis
suggested
that
a
minimum
of
6
 
7
States
was
needed
to
provide
balance
both
geographically
and
with
pollution
potential,
and
the
CMR
report
used
8
States
out
of
the
available
data
for
its
nationally
representative
cross­
section.
The
16­
State
and
40­
State
cross­
sections,
both
including
biased
States,
provided
occurrence
results
that
were
unstable
and
inconsistent
for
a
variety
of
reasons
associated
with
their
data
quality
problems
(
Cadmus,
2000a,
Section
III.
B.
1).

The
8­,
13­,
and
24­
State
cross­
sections
provide
very
comparable
results,
are
consistent,
and
are
usable
as
national
cross­
sections
to
provide
estimates
of
contaminant
occurrence.
Including
data
from
more
States
improves
the
national
representation
and
the
confidence
in
the
results,
as
long
as
the
States
are
balanced
relative
to
pollution
potential
and
spatial
coverage.
The
24­
and
20­
State
cross­
sections
provide
the
best
nationally
representative
cross­
sections
for
the
Round
1
and
Round
2
data.

Data
Management
and
Analysis
The
cross­
section
analyses
focused
on
occurrence
at
the
water
system
level;
i.
e.,
the
summary
data
presented
discuss
the
percentage
of
public
water
systems
with
detections,
not
the
percentage
of
samples
with
detections.
By
normalizing
the
analytical
data
to
the
system
level,
skewness
inherent
in
the
sample
data,
particularly
over
the
multi­
year
period
covered
in
the
URCIS
data,
is
avoided.
System
level
analysis
was
used
since
a
PWS
with
a
known
contaminant
problem
usually
has
to
sample
more
frequently
than
a
PWS
that
has
never
detected
the
contaminant.
Obviously,
the
results
of
a
simple
computation
of
the
percentage
of
samples
with
detections
(
or
other
statistics)
can
be
skewed
by
the
more
frequent
sampling
results
reported
by
the
contaminated
site.
This
level
of
analysis
is
conservative.
For
example,
a
system
need
only
have
a
single
sample
with
an
analytical
result
greater
than
the
MRL,
i.
e.,
a
detection,
to
be
counted
as
a
system
with
a
result
"
greater
than
the
MRL."
4­
9
Naphthalene
 
February
2003
Also,
the
data
used
in
the
analyses
were
limited
to
only
those
data
with
confirmed
water
source
and
sampling
type
information.
Only
standard
SDWA
compliance
samples
were
used;
"
special"
samples,
or
"
investigation"
samples
(
investigating
a
contaminant
problem
that
would
bias
results),
or
samples
of
unknown
type
were
not
used
in
the
analyses.
Various
quality
control
and
review
checks
were
made
of
the
results,
including
follow­
up
questions
to
the
States
providing
the
data.
Many
of
the
most
intractable
data
quality
problems
encountered
occurred
with
older
data.
These
problematic
data
were,
in
some
cases,
simply
eliminated
from
the
analysis.
For
example,
when
the
number
of
data
with
problems
was
insignificant
relative
to
the
total
number
of
observations,
they
were
dropped
from
the
analysis
(
for
further
details
see
Cadmus,
2000c).

As
indicated
above,
New
Hampshire
generally
is
included
in
the
20­
State,
Round
2
national
cross­
section.
Naphthalene
occurrence
data
from
the
State
of
New
Hampshire,
however,
are
biased.
New
Hampshire
reported
only
5
samples
from
3
systems
for
naphthalene
with
each
system
showing
a
detection.
Though
these
results
are
simple
detections
not
violating
a
health
effect
standard,
and
inclusion
of
the
data
does
not
significantly
affect
overall
summary
statistics,
to
maintain
a
consistent
method
for
managing
biased
data,
New
Hampshire's
naphthalene
data
were
omitted
from
Round
2
cross­
section
occurrence
analyses
and
summaries
presented
in
this
report.

Occurrence
Analysis
To
evaluate
national
contaminant
occurrence,
a
two­
stage
analytical
approach
has
been
developed.
The
first
stage
of
analysis
provides
a
straight­
forward,
conservative,
broad
evaluation
of
occurrence
of
the
CCL
regulatory
determination
priority
contaminants
as
described
above.
These
descriptive
statistics
are
summarized
here.
Based
on
the
findings
of
the
Stage
1
analysis,
EPA
will
determine
whether
more
intensive
statistical
evaluations,
the
Stage
2
analysis,
may
be
warranted
to
generate
national
probability
estimates
of
contaminant
occurrence
and
exposure
for
priority
contaminants
(
for
details
on
this
two­
stage
analytical
approach,
see
Cadmus,
2000c).

The
summary
descriptive
statistics
presented
in
Table
4­
3
for
naphthalene
are
a
result
of
the
Stage
1
analysis
and
include
data
from
both
Round
1
(
URCIS,
1987
 
1992)
and
Round
2
(
SDWIS/
FED,
1993
 
1997)
cross­
section
States
(
minus
New
Hampshire).
Included
are
the
total
number
of
samples,
the
percent
samples
with
detections,
the
99th
percentile
concentration
of
all
samples,
the
99th
percentile
concentration
of
samples
with
detections,
and
the
median
concentration
of
samples
with
detections.
The
percentages
of
PWSs
and
population
served
indicate
the
proportion
of
PWSs
whose
analytical
results
showed
a
detection(
s)
of
the
contaminant
(
simple
detection,
>
MRL)
at
any
time
during
the
monitoring
period;
or
a
detection(
s)
greater
than
half
the
Health
Reference
Level
(
HRL);
or
a
detection(
s)
greater
than
the
Health
Reference
Level.
The
Health
Reference
Level,
140
µ
g/
L,
is
a
preliminary
estimated
health
effect
level
used
for
this
analysis.

The
HRL
was
derived
as
a
preliminary
estimated
health
effect
level
using
the
Reference
Dose
(
RfD)
for
naphthalene
of
2
×
10­
2
mg/
kg­
day.
The
RfD
is
an
estimate
(
within
an
order
of
magnitude)
of
the
daily
oral
dose
to
the
human
population
that
is
likely
to
be
without
appreciable
4­
10
Naphthalene
 
February
2003
Table
4­
3.
Summary
Occurrence
Statistics
for
Naphthalene.

Frequency
Factors
24­
State
Cross­
Section1
(
Round
1)
20­
State
Cross­
Section2
(
Round
2)
National
System
&
Population
Numbers3
Total
Number
of
Samples
45,567
94,915
­­

Percent
of
Samples
with
Detections
0.43%
0.24%
­­

99th
Percentile
Concentration
(
all
samples)
<
(
Non­
detect)
<
(
Non­
detect)
­­

Health
Reference
Level
140
:
g/
L
140
:
g/
L
­­

Minimum
Reporting
Level
(
MRL)
Variable4
Variable4
­­

99th
Percentile
Concentration
of
Detections
900:
g/
L
73
:
g/
L
­­

Median
Concentration
of
Detections
1.0
:
g/
L
0.74
:
g/
L
­­

Total
Number
of
PWSs
13,452
22,926
65,030
Number
of
GW
PWSs
12,034
20,525
59,440
Number
of
SW
PWSs
1,502
2,401
5,590
Total
Population
77,209,916
67,498,059
213,008,182
Population
of
GW
PWSs
42,218,746
25,185,032
85,681,696
Population
of
SW
PWSs
41,987,010
42,313,027
127,326,486
National
Extrapolation5
Occurrence
by
System
Round
1
Round
2
PWSs
with
detections
(>
MRL)
1.18%
0.75%
769
491
Range
of
Cross­
Section
States
0
 
28.24%
0
 
4.48%
N/
A
N/
A
GW
PWSs
with
detections
1.08%
0.62%
642
368
SW
PWSs
with
detections
1.93%
1.92%
108
107
PWSs
>
1/
2
Health
Reference
Level
(
HRL)
0.01%
0.01%
10
6
Range
of
Cross­
Section
States
0
 
1.53%
0
 
0.06%
N/
A
N/
A
GW
PWSs
>
1/
2
Health
Reference
Level
0.02%
0.01%
10
6
SW
PWSs
>
1/
2
Health
Reference
Level
0.00%
0.00%
0
0
PWSs
>
Health
Reference
Level
0.01%
0.00%
10
0
Range
of
Cross­
Section
States
0
 
1.53%
0.00%
N/
A
N/
A
GW
PWSs
>
Health
Reference
Level
0.02%
0.00%
10
0
SW
PWSs
>
Health
Reference
Level
0.00%
0.00%
0
0
Table
4­
3
(
continued)

Frequency
Factors
24­
State
Cross­
Section1
(
Round
1)
20­
State
Cross­
Section2
(
Round
2)
National
System
&
Population
Numbers3
4­
11
Naphthalene
 
February
2003
Occurrence
by
Population
Served
National
Extrapolation5
Round
1
Round
2
PWS
Population
Served
with
detections
2.910%
4.790%
6,198,000
10,204,000
Range
of
Cross­
Section
States
0
 
37.22%
0
 
31.41%
N/
A
N/
A
GW
PWS
Population
with
detections
4.005%
1.162%
3,431,000
995,000
SW
PWS
Population
with
detections
1.323%
6.950%
1,685,000
8,849,000
PWS
Population
Served
>
1/
2
Health
Ref
Level
0.007%
0.002%
16,000
5,000
Range
of
Cross­
Section
States
0
 
0.23%
0
 
0.01%
N/
A
N/
A
GW
PWS
Population
>
1/
2
Health
Ref
Level
0.013%
0.007%
11,000
6,000
SW
PWS
Population
>
1/
2
Health
Ref
Level
0.000%
0.000%
0
0
PWS
Population
Served
>
Health
Ref
Level
0.007%
0.000%
16,000
0
Range
of
Cross­
Section
States
0
 
0.23%
0.000%
N/
A
N/
A
GW
PWS
Population
>
Health
Ref
Level
0.013%
0.000%
11,000
0
SW
PWS
Population
>
Health
Ref
Level
0.000%
0.000%
0
0
1.
Summary
Results
based
on
data
from
24­
State
Cross­
Section,
from
URCIS,
UCM
(
1987)
Round
1.
2.
Summary
Results
based
on
data
from
20­
State
Cross­
Section
(
minus
New
Hampshire),
from
SDWIS/
FED,
UCM
(
1993)
Round
2.
3.
Total
PWS
and
population
numbers
are
from
EPA
March
2000
Water
Industry
Baseline
Handbook.
4.
See
text
for
discussion
5.
National
extrapolations
are
from
the
24­
State
data
and
20­
State
data
using
the
Baseline
Handbook
system
and
population
numbers.
­
PWS
=
Public
Water
Systems;
GW
=
Ground
Water;
SW
=
Surface
Water;
MRL
=
Minimum
Reporting
Level
(
for
laboratory
analyses);
­
Health
Reference
Level
=
Health
Reference
Level,
an
estimated
health
effect
level
used
for
preliminary
assessment
for
this
review;
N/
A
=
Not
Applicable
­
The
Health
Reference
Level
used
for
naphthalene
is
140
:
g/
L.
This
is
a
draft
value
for
working
review
only.
­
Total
Number
of
Samples
=
the
total
number
of
analytical
records
for
naphthalene.
­
99th
Percentile
Concentration
=
the
concentration
value
of
the
99th
percentile
of
either
all
analytical
results
or
just
the
samples
with
detections
(
in
:
g/
L).
­
Median
Concentration
of
Detections
=
the
median
analytical
value
of
all
the
detections
(
analytical
results
greater
than
the
MRL)
(
in
:
g/
L).
­
Total
Number
of
PWSs
=
the
total
number
of
public
water
systems
with
records
for
naphthalene.
­
Total
Population
Served
=
the
total
population
served
by
public
water
systems
with
records
for
naphthalene.
­
PWS
with
detections,
%
PWS
>
½
Health
Reference
Level,
%
PWS
>
Health
Reference
Level
=
percent
of
the
total
number
of
public
water
systems
with
at
least
one
analytical
result
that
exceeded
the
MRL,
½
Health
Reference
Level,
Health
Reference
Level,
respectively.
­
PWS
Population
Served
with
detections,
%
PWS
Population
Served
>
½
Health
Reference
Level,
%
PWS
Population
Served
>
Health
Reference
Level
=
percent
of
the
total
population
served
by
PWSs
with
at
least
one
analytical
result
exceeding
the
MRL,
½
Health
Reference
Level,
or
the
Health
Reference
Level,
respectively.
4­
12
Naphthalene
 
February
2003
risk
of
adverse
effects
over
a
lifetime
of
exposure.
This
dose
was
converted
to
a
drinking
water
equivalent
concentration
of
700
:
g/
L
by
multiplying
the
RfD
by
the
default
body
weight
for
an
adult
(
70
kg)
and
dividing
the
result
by
the
default
daily
intake
of
drinking
water
for
an
adult
(
2
L).
For
derivation
of
the
HRL,
it
was
assumed
that
about
20%
of
an
individual's
total
exposure
to
naphthalene
was
attributable
to
drinking
water.
Multiplication
of
the
drinking
water
equivalent
concentration
by
0.2
yields
the
HRL
of
140
:
g/
L.
The
HRL
was
derived
as
follows:

HRL
=
RfD
×
BW
×
RSC
DI
Where:

RfD
=
Reference
dose
for
HCBD
in
drinking
water,
2
×
10­
4
mg/
kg­
day
BW
=
Body
weight
of
an
adult,
70
kg
DI
=
Daily
intake
of
water
for
an
adult,
2
L
RSC
=
Relative
Source
Contribution,
default
value
of
20%

Therefore:

HRL
=
(
2
×
10­
2
mg/
kg­
day)
×
(
70
kg)
×
0.20
2
L
=
140
:
g/
L
The
99th
percentile
concentration
is
used
here
as
a
summary
statistic
to
indicate
the
upper
bound
of
occurrence
values
because
maximum
values
can
be
extreme
values
(
outliers)
that
sometimes
result
from
sampling
or
reporting
error.
The
99th
percentile
concentration
is
presented
for
both
the
samples
with
detections
and
for
all
of
the
samples,
because
the
value
for
the
99th
percentile
concentration
of
all
samples
is
below
the
MRL
(
denoted
by
"<"
in
Table
4­
3).
The
95th
percentile
concentration
of
all
samples
and
the
median
(
or
mean)
concentration
of
all
samples
are
omitted
because
these
also
are
below
the
MRL.
Only
0.43%
and
0.24%
of
all
samples
recorded
detections
of
naphthalene
in
Round
1
and
Round
2,
respectively.

As
a
simplifying
assumption,
a
value
of
half
the
MRL
is
often
used
as
an
estimate
of
the
concentration
of
a
contaminant
in
samples/
systems
whose
results
are
less
than
the
MRL.
With
a
contaminant
with
relatively
low
occurrence,
such
as
naphthalene
in
drinking
water
occurrence
databases,
the
median
or
mean
value
of
occurrence
using
this
assumption
would
be
half
the
MRL
(
0.5
×
MRL).
However,
for
these
occurrence
data,
this
is
not
straightforward.
For
Round
1
and
Round
2,
States
have
reported
a
wide
range
of
values
for
the
MRLs.
This
is
in
part
related
to
State
data
management
differences
as
well
as
real
differences
in
analytical
methods,
laboratories,
and
other
factors.

The
situation
can
cause
confusion
when
examining
descriptive
statistics
for
occurrence.
For
example,
for
Round
2,
most
States
reported
non­
detections
as
zeros,
resulting
in
a
modal
4­
13
Naphthalene
 
February
2003
MRL
value
of
zero.
By
definition
the
MRL
cannot
be
zero.
This
is
an
artifact
of
State
data
management
systems.
Because
a
simple
meaningful
summary
statistic
is
not
available
to
describe
the
various
reported
MRLs,
and
to
avoid
confusion,
MRLs
are
not
reported
in
the
summary
table
(
Table
4­
3).

In
Table
4­
3,
national
occurrence
is
estimated
by
extrapolating
the
summary
statistics
for
the
24
and
20
State
cross­
sections
(
minus
New
Hampshire)
to
national
numbers
for
systems
and
population
served
by
systems,
using
the
Water
Industry
Baseline
Handbook,
Second
Edition
(
U.
S.
EPA,
2000f).
From
the
handbook,
the
total
number
of
CWSs
plus
NTNCWSs
is
65,030,
and
the
total
population
served
by
CWSs
plus
NTNCWSs
is
213,008,182
persons
(
see
Table
4­
3).
To
arrive
at
the
national
occurrence
estimate
for
a
particular
cross­
section,
the
national
estimate
for
PWSs
(
or
population
served
by
PWSs)
is
simply
multiplied
by
the
percentage
for
the
given
summary
statistic
[
i.
e.,
for
Round
1,
the
national
estimate
for
the
total
number
of
PWSs
with
detections
(
769)
is
the
product
of
the
percentage
of
Round
1
PWSs
with
detections
(
1.18%)
and
the
national
estimate
for
the
total
number
of
PWSs
(
65,030)].

Round
1
(
1987
 
1992)
and
Round
2
(
1993
 
1997)
data
were
not
merged
because
they
represent
different
time
periods
and
different
States
(
only
eight
States
are
represented
in
both
rounds).
Also,
each
round
has
different
data
management
and
data
quality
problems.
The
two
rounds
are
only
merged
for
the
simple
spatial
analysis
overview
presented
in
Section
4.3.2
and
Figures
4­
2
and
4­
4.

4.3.2
Results
Occurrence
Estimates
While
States
with
detections
of
naphthalene
are
widespread
(
Figure
4­
2),
the
percentages
of
PWSs
by
State
with
detections
are
modest
(
Table
4­
3).
In
aggregate,
the
cross­
sections
show
that
approximately
0.8
 
1.2
%
of
PWSs
in
both
rounds
experienced
detections
(>
MRL),
affecting
3.0
 
4.8
%
of
the
population
served
(
approximately
6
 
10
million
people).
Percentages
of
PWSs
with
detections
greater
than
half
the
Health
Reference
Level
(>
½
HRL)
are
much
lower
for
both
rounds:
0.01%.
The
percentage
of
PWSs
exceeding
the
Health
Reference
Level
(>
HRL)
is
also
very
small
(
Table
4­
3).
Detections
>
HRL
were
only
reported
in
Round
1:
0.01%
percent
of
PWSs,
affecting
a
population
of
approximately
16,000.
There
were
no
samples
in
Round
2
with
concentrations
above
the
HRL.

Note
that
for
the
Round
1
cross­
section,
the
total
number
of
PWSs
(
and
the
total
population
served
by
the
PWSs)
is
not
the
sum
of
the
number
of
ground
water
and
surface
water
systems
(
or
the
populations
served
by
those
systems).
Because
some
public
water
systems
are
seasonally
classified
as
either
surface
or
ground
water,
some
systems
may
be
counted
in
both
categories.
The
population
numbers
for
the
Round
1
cross­
section
are
also
incomplete.
Not
all
of
the
PWSs
for
which
occurrence
data
were
submitted
reported
the
populations
they
served.
(
However,
the
population
numbers
4­
14
Naphthalene
 
February
2003
Naphthalene
Detections
in
Round
1
and
Round
2
All
States
States
not
in
Round
1
or
Round
2
No
data
for
Naphthalene
States
with
No
Detections
(
No
PWSs
>
MRL)
States
with
Detections
(
Any
PWS
>
MRL)
Figure
4­
2.
States
with
PWSs
with
Detections
of
Naphthalene
for
all
States
with
Data
in
URCIS
(
Round
1)
and
SDWIS/
FED
(
Round
2).
4­
15
Naphthalene
 
February
2003
presented
in
Table
4­
3
for
the
Round
1
cross­
section
are
reported
from
approximately
95%
of
the
systems.)

The
national
estimates
extrapolated
from
Round
1
and
Round
2
PWS
numbers
and
populations
are
not
additive
either.
In
addition
to
the
Round
1
classification
and
reporting
issues
outlined
above,
the
proportions
of
surface
water
and
ground
water
PWSs,
and
populations
served
by
them,
are
different
between
the
Round
1
and
2
cross­
sections
and
the
national
estimates.
For
example,
approximately
63%
of
the
population
served
by
PWSs
in
the
Round
2
cross­
section
States
are
served
by
surface
water
PWSs
(
Table
4­
3).
Nationally,
however,
that
proportion
changes
to
60%.

Both
Round
1
and
Round
2
national
cross­
sections
show
a
proportionate
balance
in
PWS
source
waters
compared
to
the
national
inventory.
Nationally,
91%
of
PWSs
use
ground
water
(
and
9%
surface
waters):
Round
1
shows
89%
and
Round
2
shows
90%
of
systems
using
ground
water.
The
relative
populations
served
are
not
as
closely
comparable.
Nationally,
about
40%
of
the
population
is
served
by
PWSs
using
groundwater
(
and
60%
by
surface
water).
Round
2
data
is
most
representative
with
37%
of
the
cross­
section
population
served
by
ground
water;
Round
1
shows
about
55%.

There
are
differences
in
the
occurrence
results
between
Round
1
and
Round
2,
as
should
be
expected.
The
differences
are
not
great,
however,
particularly
when
comparing
the
proportions
of
systems
affected.
The
results
range
from
0.8
to
1.2%
of
PWSs
with
detections
of
naphthalene
and
range
from
0.00
to
0.01%
of
PWSs
with
detections
greater
than
the
HRL
of
140
µ
g/
L.
These
are
not
substantively
different,
given
the
data
sources.
The
differences
in
the
population
extrapolations
appear
greater,
but
still
constitute
relatively
small
proportions
of
the
population.
Less
than
5.0%
of
the
population
served
by
PWSs
in
either
round
were
served
by
systems
with
detections
and
only
0.01%
of
the
population
served
by
Round
1
PWSs
were
served
by
systems
with
detections
greater
than
the
HRL.

The
Round
2
cross­
section
provides
a
better
proportional
balance
relative
to
the
national
population
of
PWSs
and
may
have
fewer
reporting
problems
than
Round
1.
The
non­
zero
estimate
of
the
national
population
served
by
PWSs
with
detections
greater
than
the
HRL
using
Round
1
data
can
also
provide
an
upper­
bound
estimate
in
considering
the
data.

Regional
Patterns
Occurrence
results
are
displayed
graphically
by
State
in
Figures
4­
2,
4­
3,
and
4­
4
to
assess
whether
any
distinct
regional
patterns
of
occurrence
are
present.
Combining
Round
1
and
Round
2
data
(
Figure
4­
2),
there
are
47
States
reporting.
Four
of
those
States
have
no
data
for
naphthalene,
while
another
11
have
no
detections
of
the
chemical.
The
remaining
32
States
have
detected
naphthalene
in
drinking
water
and
are
well
distributed
throughout
the
United
States.
In
contrast
to
the
summary
statistical
data
presented
in
the
previous
section,
this
simple
spatial
analysis
includes
the
biased
New
Hampshire
data.
4­
16
Naphthalene
 
February
2003
The
simple
spatial
analysis
presented
in
Figures
4­
2,
4­
3,
and
4­
4
suggests
that
special
regional
analyses
are
not
warranted
because
naphthalene
occurrence
at
concentrations
below
the
HRL
is
widespread.
While
no
clear
geographical
patterns
of
occurrence
are
apparent,
comparisons
with
environmental
use
and
release
information
are
useful
(
see
also
Chapter
3).

The
47
TRI
States
reporting
releases
of
naphthalene
to
the
environment
include
all
of
the
States
that
detected
it
in
drinking
water
except
New
Hampshire.
Also,
four
of
the
six
States
that
have
not
detected
naphthalene
in
site
samples
reported
to
ATSDR's
HazDat
database,
and
three
of
the
six
States
where
it
was
not
detected
at
CERCLA
NPL
sites,
have
detected
it
in
drinking
water.

4.4
Conclusion
Naphthalene
is
naturally
present
in
fossil
fuels,
such
as
petroleum
and
coal,
and
is
generated
when
wood
or
tobacco
are
burned.
Naphthalene
is
produced
in
commercial
quantities
from
either
coal
tar
or
petroleum.
Most
naphthalene
consumption
(
60%)
is
through
use
as
an
intermediary
in
the
production
of
phthalate
plasticizers,
resins,
phthaleins,
dyes,
pharmaceuticals,
and
insect
repellents.
Crystalline
naphthalene
is
used
as
a
moth
repellent
and
a
solid
block
deodorizer
for
diaper
pails
and
toilets.
Naphthalene
is
also
used
to
make
the
insecticide
carbaryl,
synthetic
leather
tanning
agents,
and
surface
active
agents.

Naphthalene
has
been
detected
in
untreated
ambient
ground
water
samples
reviewed
and/
or
analyzed
by
the
USGS
NAWQA
program.
Detection
frequencies
and
concentrations
for
all
wells
are
relatively
low;
however,
occurrence
is
considerably
higher
for
urban
wells
when
compared
to
rural
wells.
Naphthalene
has
been
detected
at
slightly
higher
frequencies
in
urban
and
highway
runoff.
Concentrations
in
runoff
are
low,
with
maximum
concentrations
well
below
the
HRL
of
140
µ
g/
L.
Naphthalene
has
also
been
found
at
ATSDR
HazDat
and
CERCLA
NPL
sites
across
the
country
and
releases
have
been
reported
through
the
Toxic
Release
Inventory.

Naphthalene
has
also
been
detected
in
PWS
samples
collected
under
SDWA.
Occurrence
estimates
are
low
for
Round
1
and
Round
2
monitoring
with
only
0.43%
and
0.24%
of
all
samples
showing
detections,
respectively.
Significantly,
the
values
for
the
99th
percentile
and
median
concentrations
of
all
samples
are
less
than
the
MRL.
For
Round
1
samples
with
detections,
the
median
concentration
is
1.0
µ
g/
L
and
the
99th
percentile
concentration
is
900
µ
g/
L.
Median
and
99th
percentile
concentrations
for
Round
2
detections
are
0.74
µ
g/
L
and
73
µ
g/
L,
respectively.
Systems
with
detections
constitute
only
1.2%
of
Round
1
systems
and
0.8%
of
Round
2
systems
(
an
estimate
of
769
(
Round
1)
and
491
(
Round
2)
systems
nationally).
National
estimates
for
the
population
served
by
PWSs
with
detections
are
also
low,
especially
for
detections
greater
than
the
HRL.
It
is
estimated
that
less
than
0.01%
of
the
national
PWS
population
is
served
by
systems
with
detections
greater
than
the
HRL
(
approximately
16,000
people).
4­
17
Naphthalene
 
February
2003
Naphthalene
Occurrence
in
Round
1
States
not
in
Cross­
Section
No
data
for
Naphthalene
0.00%
PW
Ss
>
MRL
0.01
­
1.00%
PWSs
>
MRL
1.00
­
4.00%
PWSs
>
MRL*
*
Outliers:
S
tate
of
Alabama
a
t
28.3%;
State
of
Florida
at
7.0%

States
not
in
Cross­
Section
No
data
for
Naphthalene
0.00%
PWSs
>
MRL
0.01
­
1.00%
PWSs
>
MRL
1.00
­
4.00%
PWSs
>
MRL*
*
State
o
f
New
Hampshire
is
an
outlier
at
100%
Naphthalene
Occurrence
in
Round
2
Figure
4­
3.
States
with
PWSs
with
Detections
of
Naphthalene
(
any
PWSs
with
Results
Greater
than
the
Minimum
Reporting
Level
[
MRL])
for
Round
1(
above)
and
Round
2
(
below)
Cross­
section
States.
4­
18
Naphthalene
 
February
2003
Naphthalene
Occurrence
in
Round
1
and
Round
2
States
not
in
Cross­
Section
No
data
for
Naphth
alene
0.00%
PW
Ss
>
MRL
0.01
­
1.00%
PWSs
>
M
RL
1.00
­
4.00%
PWSs
>
M
RL*
*
Outliers:
S
tate
of
Alabama
a
t
28.3%;
State
of
Florida
at
7.0%;
State
of
New
Hampshire
at
100%

Naphthalene
Occurrence
in
Round
1
and
Round
2
States
not
in
Cross­
Section
No
data
for
Naphthalene
0.01
­
1.00%
PWSs
>
HRL
1.00
­
4.00%
PWSs
>
HRL
0.00%
PWSs
>
HRL
Figure
4­
4.
Cross­
section
States
(
Round
1
and
Round
2
Combined)
with
PWSs
with
Detections
of
Naphthalene
(
above)
and
Concentrations
Greater
than
the
Health
Reference
Level
(
HRL;
below).
5­
1
Naphthalene
 
February
2003
5.0
EXPOSURE
FROM
MEDIA
OTHER
THAN
WATER
5.1
Exposure
from
Food
5.1.1
Concentration
in
Non­
Fish
Food
Items
Naphthalene
contamination
levels
in
non­
fish
food
items
are
generally
low,
unless
they
have
been
exposed
to
smoke.
Naphthalene
was
detected
in
two
of
13,980
samples
of
foods
analyzed
in
six
U.
S.
states
(
Minyard
and
Roberts,
1991).
Naphthalene
and
methylnaphthalene
levels
in
meat
samples
that
were
not
exposed
to
fire
or
smoke
are
listed
in
Table
5­
1
below.
Naphthalene
and
methylnaphthalene
levels
were
observed
to
be
higher
in
foods
contaminated
by
smoke
during
fire
exposure
(
Johnston
et
al.,
1994;
Snyder
et
al.,
1996).
Naphthalene
levels
in
homogenized
milk
samples
stored
in
low­
density
polyethylene
(
LDPE)
bottles
were
low
(
0.02
:
g/
mL)
at
the
time
of
purchase,
increased
to
0.1
:
g/
mL
30
days
later,
and
averaged
0.25
:
g/
mL
at
the
expiration
date
(
Lau
et
al.,
1994).
Lau
et
al.
(
1994)
hypothesized
that
residual
naphthalene
present
in
the
LDPE
packaging
(
1.5
to
2.0
:
g/
g)
was
the
source
of
the
naphthalene
contamination
in
the
milk
samples.
A
later
study
by
the
same
authors
(
Lau
et
al.,
1995)
observed
that
the
level
of
naphthalene
in
LDPE
milk
bottle
material
had
been
reduced
to
0.1
to
0.4
:
g/
g
due
to
a
new
packaging
method.

Dietary
naphthalene
concentrations
were
evaluated
using
duplicate
diet
food
samples
from
adults
and
children
residing
in
low­
income
housing
in
North
Carolina
(
Chuang
et
al.,
1999).
In
the
adult
diets,
naphthalene
concentrations
were
found
to
average
3.75
±
5.35
:
g/
kg
(
range
=
0.01
to
18.7),
whereas
in
the
child
diets,
naphthalene
concentrations
were
4.08
±
10.9
:
g/
kg
(
range
=
0.01
to
54.9).

Naphthalene
concentrations
from
vegetables
grown
in
an
industrial
area
of
Thessaloniki,
Greece
are
summarized
in
Table
5­
2
(
Kipopoulou
et
al.,
1999).
As
shown
in
the
tabulated
data,
naphthalene
was
detected
in
all
tissue
samples
and
ranged
from
0.37
to
63
:
g/
kg
dry
weight
depending
on
the
vegetable
type.

Naphthalene
and
methylnaphthalene
(
isomer
not
specified)
were
detected
in
five
male
and
five
female
harp
seals
(
Phoca
groenlandica)
caught
in
southern
Labrador
on
the
eastern
coast
of
Canada
in
1994
(
Zitko
et
al.,
1998).
Reported
median
concentrations
of
naphthalene
and
methylnaphthalene
in
harp
seal
tissues
are
presented
in
Table
5­
3.

5.1.2
Concentrations
in
Fish
and
Shellfish
In
the
United
States,
naphthalene
was
not
detected
in
83
biota
samples
(
median
detection
limit
2.5
mg/
kg)
reported
from
1980
to
1982
in
the
STORET
database
(
Staples
et
al.,
1985).
Reported
naphthalene
concentrations
ranged
from
5
to
176
nanograms
per
gram
(
ng/
g)
in
oysters,
from
4
to
10
ng/
g
in
mussels,
and
from
less
than
1
to
10
ng/
g
in
clams
obtained
from
United
States
waters
(
Bender
and
Huggett,
1989).
In
shore
crabs
collected
from
the
San
Francisco
Bay
area,
average
naphthalene
concentrations
were
7.4
ng/
g
(
Miles
and
Roster,
1999).
Naphthalene
was
detected
in
all
samples
of
seven
fish
and
two
shellfish
species
taken
from
Kuwaiti
waters
5­
2
Naphthalene
 
February
2003
Table
5­
1.
Naphthalene
And
Methylnaphthalene
Concentrations
in
Meat
Samples.

SAMPLE
NAPHTHALENE
CONCENTRATION
(
ng/
g)
METHYLNAPHTHALENEa
CONCENTRATION
(
ng/
g)
REFERENCE
Fried
chicken
26
27
Johnston
et
al.,
1994
Beef
26
26
Johnston
et
al.,
1994
Hot
dog
25
5
Johnston
et
al.,
1994
Young
turkey
breast
17
6
Johnston
et
al.,
1994
Smoked
chicken
11.7
Not
evaluated
Snyder
et
al.,
1996
Smoked
chicken
5
13
Johnston
et
al.,
1994
Boneless
beef
5
2
Johnston
et
al.,
1994
Boneless
turkey
breast
4
0
Johnston
et
al.,
1994
Cooked
beef
3
2
Johnston
et
al.,
1994
Corned
beef
3
2
Johnston
et
al.,
1994
Ham
2.5
Not
evaluated
Snyder
et
al.,
1996
Corned
beef
1.7
Not
evaluated
Snyder
et
al.,
1996
Boneless
beef
LOQb
Not
evaluated
Snyder
et
al.,
1996
Turkey
breast
LOQb
Not
evaluated
Snyder
et
al.,
1996
Beef
roast
0
Not
evaluated
Snyder
et
al.,
1996
Boneless
turkey
0
Not
evaluated
Snyder
et
al.,
1996
a
The
isomer
of
methylnaphthalene
was
not
specified.
b
LOQ
=
limit
of
quantitation
(
1
ng/
g
(
1
part
per
billion))
for
the
method
used,
which
involved
supercritical
fluid
extraction
followed
by
gas
chromatograph­
mass
spectrometer
analysis;
the
concentration
was
determined
using
naphthalene­
d8
as
an
internal
standard.
5­
3
Naphthalene
 
February
2003
that
were
polluted
with
crude
oils;
reported
concentrations
of
naphthalene
ranged
from
2.06
to
156.09
ng/
g
dry
weight
(
Saeed
et
al.,
1995).

2­
Methylnaphthalene
was
reported
at
concentrations
ranging
from
0.4
to
320
:
g/
g
in
fish
from
Ohio
waters,
but
neither
isomer
of
methylnaphthalene
was
detected
in
muscle
tissue
of
fish
from
polluted
areas
of
Puget
Sound
(
GDCH,
1992).
Methylnaphthalenes
were
detected
in
oysters
collected
in
Australia
at
less
than
0.3
to
2
:
g/
g.

5.1.3
Intake
of
Naphthalene
from
Food
Factors
that
may
contribute
to
high
dietary
naphthalene
intake
include
consumption
of
grilled
foods.
Assuming
food
ingestion
of
0.76
to
4.43
kg
per
day
for
adults,
(
Chuang
et
al.,
1999)
a
daily
average
intake
of
2.85
to
16.6
:
g
of
naphthalene
can
be
calculated
from
the
dietary
concentration
data
of
Chuang
et
al.
(
1999).
Assuming
food
ingestion
of
approximately
0.5
to
2.3
kg
per
day
for
children
(
Chuang
et
al.,
1999),
an
average
daily
intake
of
2.04
to
9.4
:
g
of
naphthalene
can
be
calculated
from
the
dietary
concentration
data
of
Chuang
et
al.
(
1999).

Table
5­
2.
Concentrations
of
Naphthalene
in
Vegetables
VEGETABLE
TYPE
CONCENTRATION
(:
g/
kg
dry
weight)

Range
Median
Cabbage
(
n=
8)
0.37
 
15
5.0
Carrot
(
n=
6)
8.9
 
30
21
Leek
(
n=
5)
6.3
 
35
18
Lettuce
(
n=
8)
4.9
 
53
42
Endive
(
n=
3)
27
 
63
29
Source:
Kipopoulou
et
al.
(
1999)

Table
5­
3.
Median
Concentrations
of
Naphthalene
and
Methylnaphthalene
in
Harp
Seals
Compound
Tissue
Concentration
(
ng/
g
wet
weight)

Muscle
Kidney
Liver
Blubber
Female
Male
Female
Male
Female
Male
Female
Male
Naphthalene
3.10
2.90
4.30
4.15
4.70
4.15
21.00
23.50
Methylnaphthalene
1.50
1.55
1.70
1.40
1.70
1.40
8.30
8.85
Source:
Zitko
et
al.
(
1998)
5­
4
Naphthalene
 
February
2003
Using
the
average
ranges
of
naphthalene
intake
determined
above,
an
estimated
daily
intake
of
40.7
to
237
ng/
kg­
day
can
be
calculated
for
a
70­
kg
adult,
and
an
average
daily
intake
of
204
to
940
ng/
kg­
day
can
be
calculated
for
a
10­
kg
child.
Values
for
individuals
will
vary
depending
upon
dietary
composition.

5.2
Exposure
from
Air
5.2.1
Concentration
of
Naphthalene
in
Air
The
average
reported
concentration
for
67
ambient
air
samples
in
the
United
States
was
0.991
parts
per
billion
(
ppb)
(
5.19
:
g/
m3),
and
the
majority
(
60)
of
these
samples
and
the
highest
concentrations
were
collected
at
source­
dominated
locations
(
Shah
and
Heyerdahl,
1988).
Howard
(
1989)
reported
a
median
naphthalene
level
in
urban
air
in
11
U.
S.
cities
of
0.18
ppb
(
0.94
:
g/
m3).
Chuang
et
al.
(
1991)
reported
an
average
naphthalene
concentration
of
170
:
g/
m3
in
outdoor
air
in
a
residential
area
of
Columbus,
Ohio.
Naphthalene
was
detected
in
ambient
air
in
Torrance,
California,
at
a
concentration
of
3.3
:
g/
m3
(
Propper,
1988).
Patton
et
al.
(
1997)
reported
a
naphthalene
concentration
of
1.50
×
10­
4
:
g/
m3
in
an
air
sample
collected
from
the
Department
of
Energy's
Hanford
site
in
Washington
State.
Average
naphthalene
concentrations
detected
in
ambient
air
at
five
hazardous
waste
sites
and
one
landfill
in
New
Jersey
ranged
from
0.08
to
0.88
ppb
(
0.42
to
4.6
:
g/
m3)
(
La
Regina
et
al.,
1986).
Atmospheric
concentrations
of
naphthalene
in
total
suspended
particles
were
reported
to
range
from
0.003
to
0.095
:
g/
m3
(
median
=
0.017)
in
the
city
of
Ionia,
Greece
and
from
0.002
to
0.179
:
g/
m3
(
median
=
0.030)
in
the
city
of
Sindos,
Greece
(
Kipopoulou
et
al.,
1999).

1­
Methylnaphthalene
and
2­
methylnaphthalene
have
also
been
detected
in
ambient
air.
Shah
and
Heyerdahl
(
1988)
reported
average
concentrations
of
0.086
and
0.011
ppb
(
0.51
and
0.065
:
g/
m3)
for
1­
methylnaphthalene
and
2­
methylnaphthalene,
respectively.
ATSDR
(
1995)
indicated
that
these
data
were
obtained
from
source­
dominated
areas
where
the
highest
concentrations
were
detected.
Methylnaphthalene
(
isomer
not
specified)
was
detected
in
ambient
air
at
a
hazardous
waste
site
in
New
Jersey;
however
the
concentration
was
not
reported
(
La
Regina
et
al.,
1986).
A
mean
concentration
of
0.252
ppb
(
1.5
:
g/
m3)
2­
methylnaphthalene
was
reported
for
indoor
air
(
Shah
and
Heyerdahl,
1988).

Naphthalene
has
been
detected
in
indoor
air
samples,
and
residential
indoor
concentrations
are
sometimes
higher
than
outdoor
air
levels.
Published
average
indoor
concentrations
of
naphthalene
in
various
locations
within
homes
range
from
0.860
to
1,600
:
g/
m3
(
Chuang
et
al.,
1991;
Hung
et
al.,
1992;
Wilson
et
al.,
1989;
Lau
et
al.,
1995).
However,
ATSDR
(
1995)
suggested
that
the
upper
range
value
reported
in
Chuang
et
al.
(
1991)
might
be
erroneous
and
indicated
that
a
more
representative
upper
limit
concentration
for
indoor
air
might
be
32
:
g/
m3,
recorded
in
buildings
in
heavily
trafficked
urban
areas
of
Taiwan
(
Hung
et
al.,
1992).
Lau
et
al.
(
1995)
reported
mean
naphthalene
vapor
concentrations
of
5
to
41
:
g/
m3
and
less
than
3
to
100
:
g/
m3
in
office
and
laboratory
air,
respectively.
Concentrations
of
naphthalene
vapor
were
found
to
be
high
(
350
:
g/
m3)
in
a
flat
that
had
been
freshly
painted
with
lacquer
paint
(
Lau
et
al.,
1995).
Measurements
of
naphthalene
concentrations
in
both
indoor
and
outdoor
air
were
obtained
from
24
low­
income
homes
in
North
Carolina
in
1995
(
Chuang
et
al.,
1999).
5­
5
Naphthalene
 
February
2003
Indoor
air
concentrations
ranged
from
0.33
to
9.7
:
g/
m3
(
mean
±
Std
Dev
=
2.2
±
1.9),
whereas
outdoor
air
concentrations
were
lower
and
ranged
from
0.057
to
1.82
:
g/
m3
(
mean
±
Std
Dev
=
0.
43
±
0.51).

In
homes
with
residents
who
smoke,
indoor
and
outdoor
air
concentrations
of
naphthalene
were
reported
to
be
2.2
:
g/
m3
and
0.3
:
g/
m3,
respectively
(
Gold
et
al.,
1991;
IARC,
1993).
A
similar
analysis
of
air
in
homes
without
smokers
detected
indoor
and
outdoor
air
concentrations
of
1.0
:
g/
m3
and
0.1
:
g/
m3,
respectively.
Lofgren
et
al.
(
1991)
reported
an
average
concentration
of
naphthalene
inside
automobiles
in
commuter
traffic
of
about
4.5
:
g
/
m3.

5.2.2
Intake
of
Naphthalene
from
Air
Assuming
an
average
ambient
concentration
level
of
5.19
:
g
naphthalene/
m3
and
an
average
inhalation
rate
of
15.2
m3/
day
(
U.
S.
EPA,
1996c),
an
average
daily
dose
of
1,127
ng/
kgday
can
be
calculated
for
a
70­
kg
adult.
An
estimated
average
daily
dose
of
4,515
ng/
kg­
day
can
be
calculated
for
a
10­
kg
child
assuming
an
inhalation
rate
of
8.7
m3/
day
(
U.
S.
EPA,
1996c).
Individual
intake
will
vary
depending
on
factors
including
activity,
geographic
location,
and
inhalation
rate.

5.3
Exposure
from
Soil
5.3.1
Concentration
of
Naphthalene
in
Soil
Chuang
et
al.
(
1995)
analyzed
house
dust
samples
obtained
from
carpet
in
homes
in
Columbus,
Ohio.
They
reported
mean
naphthalene
levels
of
530
:
g/
kg
(
measured
following
Soxhlet
extraction)
and
350
:
g/
kg
(
measured
using
sonication
extraction).
Measurements
of
naphthalene
concentrations
in
household
dust
were
obtained
from
24
low­
income
homes
in
North
Carolina
in
1995
(
Chuang
et
al.,
1999).
Concentrations
ranged
from
<
10
to
4,300
:
g/
kg,
depending
on
the
location
of
sampling
(
Table
5­
4).

Table
5­
4.
Concentrations
of
Naphthalene
in
Residential
Dust
(
mg/
g)

LOCATION
CONCENTRATION
(:
g/
kg)

Range
Mean
±
Std
Dev
House
Dust
20
­
4,300
330
±
850
Entryway
Dust
10
­
1,310
110
±
260
Pathway
Soil
<
10
­
40
10
±
10
Source:
Chuang
et
al.
(
1999)
5­
6
Naphthalene
 
February
2003
Low
levels
of
naphthalene
and
methylnaphthalenes
have
been
found
in
uncontaminated
soils
and
sediments,
while
higher
levels
have
been
reported
for
samples
taken
near
sources
of
contamination.
Wild
et
al.
(
1990)
reported
that
naphthalene
levels
in
untreated
agricultural
soils
ranged
from
0
to
3
:
g/
kg.
Published
naphthalene
concentrations
in
contaminated
soils
included
up
to
66
:
g/
kg
in
sludge­
treated
soils
(
Wild
et
al.,
1990),
6,100
:
g/
kg
in
coal
tar­
contaminated
soil
(
Yu
et
al.,
1990)
and
16,700
:
g/
kg
in
soil
from
a
former
tar­
oil
refinery
(
Weissenfels
et
al.,
1992).
Kipopoulou
et
al.
(
1999)
reported
naphthalene
concentrations
in
agricultural
soil
from
Thessaloniki,
Greece
ranging
from
3.1
to
78
:
g/
kg
dry
weight
(
median
=
17).
For
methylnaphthalene
(
isomer
not
specified),
Yu
et
al.
(
1990)
reported
a
concentration
of
2,900
:
g/
kg
in
coal
tar­
contaminated
soil.

For
sediments,
naphthalene
was
detected
in
7
percent
of
267
sediment
samples
entered
into
the
STORET
database
(
1980
to
1982);
the
median
concentration
for
all
samples
was
reported
to
be
less
than
500
:
g/
kg
(
Staples
et
al.,
1985).
Coons
et
al.
(
1982)
performed
a
separate
analysis
of
the
STORET
data
and
reported
that
concentrations
in
positive
sediment
samples
ranged
from
0.02
to
496
:
g/
kg.

Naphthalene
and
methylnaphthalene
have
been
detected
in
marine
and
estuarine
sediments
near
petroleum
production
and
transport
facilities.
Brooks
et
al.
(
1990)
reported
average
concentrations
of
54.7
and
61.9
:
g/
kg
naphthalene
and
50.4
and
55.3
:
g/
kg
methylnaphthalenes
at
10
and
25
miles,
respectively,
from
an
offshore
multi­
well
drilling
platform.
The
study
also
reported
that
naphthalene
and
methylnaphthalene
concentrations
in
nearby
noncontaminated
estuarine
sediments
were
2.1
and
1.9
:
g/
kg,
respectively.
Sharma
et
al.
(
1997)
analyzed
sediments
from
52
sites
in
the
upper
part
of
the
Laguna
Madre
system,
a
large
coastal
basin
located
south
of
Corpus
Christi,
Texas,
that
supports
the
Gulf
Coast
Intracoastal
Waterway
and
petroleum
production
wells
and
pipelines.
They
detected
methylnaphthalene
at
four
sites,
and
the
mean
concentrations
identified
at
these
four
sites
ranged
from
9,400
to
81,000
:
g/
kg
dry
weight.
The
Laguna
Madre
site
with
the
highest
concentration
of
methylnaphthalene
receives
dredged
material
from
the
waterway
and
other
canals.

5.3.2
Intake
of
Naphthalene
from
Soil
Humans
may
be
exposed
to
soil
naphthalene
by
inhalation
of
airborne
soil
particles,
by
ingestion
of
food­
borne
soil
residues,
by
ingestion
of
household
dust,
or
by
direct
ingestion
of
soil.
Exposure
by
inhalation
of
airborne
soil
particles
is
accounted
for
in
Section
5.4.
Infants
and
toddlers
ingest
soil
and
household
dust
by
hand­
to­
mouth
transfer
during
everyday
activities,
and
may
therefore
be
exposed
to
higher
levels
of
soil
naphthalene
than
the
general
population.

Assuming
average
ingestion
of
50
milligram
(
mg)
of
soil
per
day
by
adults
(
U.
S.
EPA,
1996c),
and
house
dust
concentrations
from
0.02
to
4.3
milligram
per
kilogram
(
mg/
kg)
(
average
=
0.33),
the
estimated
average
daily
intake
for
a
70­
kg
adult
is
calculated
to
be
0.00001
to
0.003
mg/
kg­
day
(
average
=
0.00002).
An
estimated
intake
range
of
0.0002
to
0.043
mg/
kg­
day
(
average
=
0.0033)
was
calculated
for
a
10­
kg
child,
assuming
ingestion
of
100
mg
of
soil
per
day
(
U.
S.
EPA,
1996c).
For
comparison
with
intake
from
other
media,
these
ranges
have
been
5­
7
Naphthalene
 
February
2003
converted
to
units
of
10
to
3,000
ng/
kg­
day
(
average
=
20)
for
adults,
and
200
to
43,000
ng/
kgday
(
average
=
3,300)
for
a
10­
kg
child
(
Table
5­
5).

5.4
Other
Residential
Exposures
Naphthalene,
1­
methylnaphthalene,
and
2­
methylnaphthalene
have
been
identified
in
cigarette
smoke
(
HSDB,
1999).
Schmeltz
et
al.
(
1978)
reported
levels
of
3
:
g
napthalene,
1
:
g
1­
methylnaphthalene,
and
1
:
g
2­
methylnaphthalene
in
the
smoke
from
one
commercial
U.
S.
unfiltered
cigarette.
Sidestream
smoke
levels
of
46
:
g,
30
:
g,
and
32
:
g
per
cigarette
were
reported
for
these
three
compounds,
respectively
(
Schmeltz
et
al.,
1976).

Use
of
naphthalene­
containing
moth
repellents
also
contributes
to
naphthalene
in
indoor
air.
Lau
et
al.
(
1995)
measured
350
:
g/
m3
naphthalene
in
the
air
inside
a
cupboard
containing
approximately
36
grams
of
mothballs.
Unvented
kerosene
space
heaters,
gas
cooking
and
heating
appliances,
as
well
as
wood­
burning
fireplaces,
might
also
contribute
to
indoor
air
concentrations
of
naphthalene
(
HSDB,
1999;
Chuang
et
al.,
1995).

In
Taiwan,
mosquito
coils
are
frequently
burned
despite
being
categorized
as
a
source
of
indoor
air
pollution.
Lin
and
Lee
(
1997)
identified
naphthalene
in
smoke
resulting
from
the
burning
of
two
prevalent
brands
of
mosquito
coils.
Burning
one
gram
of
the
mosquito
coils
yielded
20.98
or
30.45
:
g
of
naphthalene
vapor
and
7.35
or
9.23
:
g
of
particulate­
bound
naphthalene,
depending
on
the
brand.
The
study
authors
estimated
that
the
concentration
of
naphthalene
in
the
air
would
be
up
to
3.35
:
g/
m3
after
burning
a
mosquito
coil
for
6
hours
in
a
40
cubic
meter
(
m3)
room.

5.5
Summary
Estimated
concentration
and
intake
values
for
naphthalene
in
media
other
than
water
are
summarized
in
Table
5­
5.
Inspection
of
the
data
reveals
that,
based
on
average
intakes,
most
exposure
occurs
through
inhalation,
with
average
intakes
being
approximately
5­
to
27­
fold
greater
than
those
from
food
and
up
to
about
5­
fold
greater
than
those
from
soil.
However,
soil
may
be
a
significant
route
of
exposure
for
children
living
in
areas
with
soils
containing
high
levels
of
naphthalene.
5­
8
Naphthalene
 
February
2003
Table
5­
5.
Exposure
to
Naphthalene
in
Media
Other
than
Water
PARAMETER
MEDIUM
Food
Air
Soil*

Adult
Child
Adult
Child
Adult
Child
Concentration
in
medium
[
average]
[
3.75]
:
g/
kg
[
4.08]
:
g/
kg
[
5.19]
:
g/
m3
0.02
 
4.3
[
0.33]
mg/
kg
Estimated
daily
intake
(
ng/
kg­
day)
[
average]
[
40.7
 
237]
**
[
204
 
940]
**
[
1,127]
[
4,515]
10
 
3,000
[
235]
200
 
43,000
[
3,300]

*
based
on
household
dust
concentrations
**
range
based
on
different
total
food
intakes
(
0.076
to
4.43
kg/
day
adults;
0.5
to
2.3
kg/
day
child)
(
Chuang
et
al.,
1999)
6­
1
Naphthalene
 
February
2003
6.0
TOXICOKINETICS
6.1
Absorption
Oral
Exposure
Naphthalene
is
readily
absorbed
when
administered
orally
as
inferred
from
the
occurrence
of
adverse
effects
after
exposure.
Toxic
effects
have
been
reported
in
humans,
dogs,
mice,
rats,
and
rabbits
following
oral
exposures
to
naphthalene,
although
the
extent
of
absorption
was
not
quantified
(
ATSDR,
1995).

Bock
et
al.
(
1979)
instilled
14C­
naphthalene
into
isolated
rat
intestinal
loops.
When
assayed
30
minutes
after
instillation,
84%
of
the
administered
dose
was
recovered
unmetabolized
in
the
portal
blood,
while
only
1%
remained
in
the
luminal
contents.
Absorption
is
believed
to
occur
by
passive
diffusion
across
the
intestinal
membranes,
with
the
rate
of
absorption
determined
by
the
partition
coefficient
between
the
contents
of
the
intestinal
lumen
and
the
lipids
of
the
intestinal
membranes
(
ATSDR,
1995).

No
studies
were
identified
that
quantified
the
rate
and
extent
of
naphthalene
absorption
in
humans
following
ingestion.
However,
the
results
of
case
reports
confirm
that
significant
amounts
of
naphthalene
ingested
by
humans
may
be
absorbed
and
that
adverse
effects
may
result
(
Zuelzer
and
Apt,
1949;
Mackell
et
al.,
1951;
Bregman,
1954;
MacGregor,
1954;
Chusid
and
Fried,
1955;
Gidron
and
Leurer,
1956;
Haggerty,
1956;
Santhanakrishnan
et
al.,
1973;
Gupta
et
al.,
1979;
Shannon
and
Buchanan,
1982;
Ojwang
et
al.,
1985;
Kurz,
1987).

Dermal
Exposure
Evidence
of
naphthalene
toxicity
has
been
described
in
human
neonates
who
reportedly
were
exposed
by
dermal
contact
with
diapers
that
had
been
stored
with
naphthalene
mothballs
or
naphthalene
flakes
(
Schafer,
1951;
Dawson
et
al.,
1958).
However,
inhalation
of
naphthalene
vapors
could
not
be
excluded
as
a
contributing
route
of
exposure
(
ATSDR,
1995;
U.
S.
EPA,
1998a).

Turkall
et
al.
(
1994)
applied
3.3
:
g/
cm2
of
naphthalene
to
the
shaved
skin
of
male
rats
and
sealed
the
area
of
application
under
a
glass
cap
for
48
hours.
Dermal
absorption
occurred
rapidly,
with
approximately
50%
of
the
dose
being
absorbed
in
2.1
hours.

Inhalation
Exposure
No
empirical
data
that
describe
the
rate
or
extent
of
naphthalene
absorption
following
inhalation
exposure
were
identified
in
the
materials
reviewed
for
this
report.
NTP
(
2000)
developed
a
physiologically­
based
pharmacokinetic
model
to
describe
the
uptake
of
naphthalene
in
rats
and
mice
following
inhalation
exposure.
The
model
was
calibrated
using
blood
time
course
data
for
naphthalene
(
parent
compound).
Results
from
this
model
suggest
that
inhaled
naphthalene
is
absorbed
rapidly
into
the
blood
(
Blood:
air
partition
coefficient
of
571).
On
the
6­
2
Naphthalene
 
February
2003
basis
of
estimates
of
naphthalene
metabolism
generated
by
the
model,
approximately
22%
to
31%
of
inhaled
naphthalene
is
absorbed
by
rats
and
65%
to
73%
of
inhaled
naphthalene
is
absorbed
by
mice.

6.2
Distribution
Oral
Exposure
Absorbed
naphthalene
is
expected
to
be
distributed
throughout
the
body
(
U.
S.
EPA,
1998a).
Eisele
(
1985)
evaluated
the
distribution
of
naphthalene
following
oral
administration
to
pigs,
to
chickens,
or
to
a
single
cow.
A
single
0.123
mg
dose
of
radiolabeled
naphthalene/
kg
(
4.8
Ci/
kg)
was
administered
to
young
pigs,
and
distribution
was
monitored
at
24
and
72
hours.
Adipose
tissue
had
the
highest
percentage
of
the
label
(
3.48
±
2.16%
dose/
mg
tissue)
at
24
hours
post­
administration.
Lower
percentages
were
reported
in
the
kidney
(
0.96%
dose/
mg
tissue),
liver
(
0.26
±
0.06%
dose/
mg
tissue),
lungs
(
0.16%
dose/
mg
tissue),
heart
(
0.09
±
0.04%
dose/
mg
tissue)
and
spleen
(
0.07
±
0.01%
dose/
mg
tissue).
At
72
hours,
the
percentage
of
the
label
in
adipose
tissue
had
decreased
to
2.18
±
1.16%
dose/
mg
tissue,
while
the
activity
in
the
liver
was
0.34
±
0.24%
dose/
mg
tissue.
Activities
of
0.96%
dose/
mg
tissue
were
determined
in
the
kidneys
and
lung.

Eisele
(
1985)
also
administered
oral
doses
of
0.006
mg
radiolabeled
naphthalene/
kg­
day
(
0.22
Ci/
kg­
day)
to
pigs
daily
for
31
days.
Repeated
administration
resulted
in
a
pattern
of
distribution
that
differed
from
the
pattern
observed
following
a
single
oral
dose.
Following
repeated
doses,
the
highest
tissue
concentration
of
naphthalene
occurred
in
the
lung
(
0.15%
dose/
mg
tissue).
The
heart
and
liver
each
contained
0.11%
dose/
mg
tissue,
and
0.03%
dose/
mg
tissue
was
reported
in
adipose
tissue.
The
spleen
and
the
kidney
had
0.09
±
0.05%
and
0.09%
dose/
mg
tissue,
respectively.

Following
single
or
repeated
administration
to
one
dairy
cow,
naphthalene
was
reported
to
distribute
to
milk,
with
the
highest
concentration
in
the
lipid
fraction
(
Eisele,
1985).
After
31
days,
the
highest
tissue
concentration
was
reported
in
the
liver,
and
the
lowest
concentration
was
reported
in
adipose
tissue.

Data
for
distribution
of
naphthalene
or
its
metabolites
in
humans
are
unavailable.
However,
there
is
evidence
that
naphthalene
can
cross
the
placenta
in
humans.
Erythrocyte
hemolysis
of
sufficient
magnitude
to
cause
anemia
was
reported
in
infants
born
to
mothers
that
had
consumed
naphthalene
while
pregnant
(
Zinkham
and
Childs,
1957,
1958;
Anziulewicz
et
al.,
1959).
The
glucose­
6­
phosphate
dehydrogenase
status
(
see
Section
7.4.5)
of
the
infants
was
not
indicated
in
the
materials
reviewed
for
this
document.

Dermal
Exposure
No
data
describing
the
distribution
of
naphthalene
following
dermal
exposures
in
humans
were
identified
in
the
materials
reviewed
for
this
document.
6­
3
Naphthalene
 
February
2003
Turkall
et
al.
(
1994)
applied
14C­
radiolabeled
naphthalene
(
3.3
:
g/
cm2)
to
the
skin
of
rats.
At
48
hours
post­
application,
the
highest
concentration
(
0.56%
of
the
initial
dose)
was
observed
at
the
application
site.
Approximately
0.01%­
0.02%
of
the
initial
dose
was
recovered
in
the
ileum,
duodenum,
and
kidney.
Presence
of
the
radiolabel
in
the
ileum
and
duodenum
was
considered
by
the
authors
as
evidence
for
biliary
excretion
of
naphthalene
metabolites.

Inhalation
Exposure
A
recent
case
report
of
hemolytic
anemia
in
a
neonate
whose
mother
inhaled
naphthalene
during
the
28th
week
of
gestation
suggests
that
inhaled
naphthalene
can
cross
the
placenta
(
Athanasiou
et
al.,
1997).
No
other
data
describing
the
distribution
of
naphthalene
in
humans
or
animals
following
inhalation
exposure
were
identified
in
the
materials
reviewed
for
this
document.

6.3
Metabolism
Overview
of
Metabolic
Pathways
The
in
vivo
and
in
vitro
metabolism
of
naphthalene
in
mammalian
systems
has
been
extensively
studied
(
U.
S.
EPA
1998a).
As
many
as
21
metabolites,
including
oxidized
derivatives
and
conjugates,
have
been
identified
in
the
urine
of
animals
exposed
to
naphthalene
(
Horning
et
al.,
1980;
Wells
et
al.,
1989;
Kanekal
et
al.,
1990).
Factors
that
potentially
influence
the
relative
proportions
of
individual
metabolites
include
species,
tissue
type,
and
tissue
concentration
of
naphthalene
(
U.
S.
EPA,
1998a).
The
initial
step
in
naphthalene
metabolism
is
catalyzed
by
cytochrome
P­
450
monooxygenases,
and
results
in
the
formation
of
the
arene
epoxide
intermediate
1,2­
naphthalene
oxide
(
Figure
6­
1).
1,2­
Naphthalene
oxide
can
undergo
spontaneous
rearrangement
to
form
naphthols
(
predominately
1­
naphthol).
The
resulting
intermediates
may
be
further
metabolized
by
oxidation
reactions,
resulting
in
the
formation
of
di­,
tri­,
and
tetrahydroxylated
intermediates
(
Horning
et
al.,
1980).
Some
metabolites
may
undergo
conjugation
with
glutathione,
glucuronic
acid,
or
sulfate
(
ATSDR,
1995;
U.
S.
EPA,
1998a).
Glutathione
conjugates
undergo
additional
reactions
to
form
cysteine
derivatives
(
thioethers).
These
cysteine
derivatives
may
be
further
metabolized
to
mercapturic
acids
and
may
be
excreted
in
the
bile
(
U.
S.
EPA,
1998a).

An
alternative
pathway
of
naphthol
metabolism
involves
enzymatic
hydration
by
epoxide
hydrolase.
This
reaction
results
in
the
formation
of
trans­
1,2­
dihydro­
dihydroxynaphthalene,
also
referred
to
as
naphthalene­
1,2­
dihydrodiol
(
U.
S.
EPA,
1998a).
Trans­
1,2­
dihydrodihydroxynaphthalene
can
be
converted
to
1,2­
naphthalenediol
by
catechol
reductase,
and
with
subsequent
oxidation
to
1,2­
naphthoquinone
and
hydrogen
peroxide.
In
addition,
1,2­
naphthoquinone
may
rearrange
to
form
1,4­
naphthoquinone
and
vice
versa
(
U.
S.
EPA,
1998a).
The
1,2­
naphthoquinone
and
1,4­
naphthoquinone
metabolites
may
be
the
primary
toxic
metabolites,
rather
than
the
1,2­
naphthalene­
epoxide
intermediate.
This
conclusion
is
based
on
observations
that
1,2­
naphthoquinone
and
1,4­
naphthoquinone
were
cytotoxic
and
genotoxic
to
human
lymphocytes,
and
that
6­
4
Naphthalene
 
February
2003
OH
OH
OH
OH
O
O
O
OH
OH
OH
OH
O
O
OH
GSH
GSH
GSH
OH
Naphthalene
2­
Naphthol
1­
Naphthol
1,4­
Naphthalenediol
1,4­
Naphthoquinone
Naphthalene
1,2
oxide
1,2­
Dihydro­
1,2­
naphthalenediol
1,2­
Naphthalenediol
1,2­
Naphthoquinone
Glutathione
Conjugates
Cysteine
Conjugates
Derivatives
(
Thioethers)
Glutathione­
S­
transferase
Epoxide
hydrolase
Catechol
reductase
Figure
6­
1.
Proposed
Pathways
For
Naphthalene
Metabolism
Source:
U.
S.
EPA
(
1998a)
6­
5
Naphthalene
 
February
2003
they
depleted
glutathione.
In
contrast,
the
epoxide
was
not
cytotoxic
or
genotoxic,
and
did
not
deplete
glutathione
(
Wilson
et
al.,
1996).

Studies
of
Naphthalene
Metabolism
in
Humans
Data
describing
the
metabolism
of
naphthalene
in
humans
are
limited.
Human
lung
microsome
preparations
from
three
individuals
aged
60
to
77
years
metabolized
naphthalene
to
dihydro­
1,2­
naphthalenediol
and
three
glutathione
adducts
(
Buckpitt
and
Richieri,
1984;
Buckpitt
and
Bahnson,
1986).
There
was
considerable
variation
in
the
amount
of
each
metabolite
formed
by
each
of
the
three
individuals.
Buonarati
et
al.
(
1990)
subsequently
identified
these
adducts
as
trans­
1­(
S)­
hydroxy­
2­(
S)­
glutathionyl­
1,2­
dihydronaphthalene;
trans­
1­(
R)­
glutathionyl­
2­(
R)­
hydroxy­
1,2­
dihydronaphthalene;
and
trans­
1­(
S)­
hydroxy­
2­
S­
glutathionyl­
1,2­
dihydronaphthalene.

Tingle
et
al.
(
1993)
investigated
naphthalene
metabolism
using
microsomes
prepared
from
six
histologically
normal
human
livers.
The
primary
stable
metabolite
was
1,2­
dihydro­
1,2­
naphthalenediol,
generated
by
the
action
of
epoxide
hydrolase
on
1,2­
naphthalene
oxide,
whereas,
1­
naphthol
was
a
minor
metabolite.
Inhibition
of
epoxide
hydrolase
increased
the
amount
of
1­
naphthol
formed.

Analysis
of
urine
indicates
that
naphthols
(
specifically
1­
and
2­
naphthol),
1,2­
naphthoquinone,
and
1,4­
naphthoquinone
are
formed
in
humans
exposed
to
naphthalene
(
Zuelzer
and
Apt,
1949;
Mackell
et
al.,
1951).

Animal
Studies
of
Naphthalene
Metabolism
There
is
some
evidence
that
metabolism
of
naphthalene
may
vary
among
species.
Urinary
mercapturic
acid
excretion
increased
in
a
dose­
dependent
manner
following
the
administration
of
naphthalene
to
rats
via
gavage
(
Summer
et
al.,
1979).
In
comparison,
glucuronic
acid
and
sulfate
conjugates
were
the
primary
conjugates
excreted
in
the
urine
of
chimpanzees,
based
on
limited
data
collected
from
two
animals
(
Summer
et
al.,
1979).

Urinary
metabolites
identified
in
rats
and
rabbits
following
the
oral
administration
of
naphthalene
included
1­
and
2­
naphthol,
1,2­
dihydro­
1,2­
naphthalenediol,
1­
naphthyl
sulfate,
and
1­
naphthylglucuronic
acid
(
Corner
and
Young,
1954).
With
the
exception
of
1­
naphthylglucuronic
acid
in
the
urine
of
guinea
pigs,
the
same
metabolites
were
also
identified
in
the
urine
of
mice,
rats
and
guinea
pigs
following
intraperitoneal
injection.
A
glucuronic
acid
conjugate
of
1,2­
naphthalenediol
was
also
likely
present
in
all
species;
however,
the
presence
of
this
metabolite
was
not
confirmed.
In
addition,
the
urine
of
rats
and
rabbits
contained
1,2­
dihydro­
2­
hydroxy­
1­
naphthyl
glucuronic
acid,
while
in
guinea
pigs,
unconjugated
1,2­
naphthalenediol
was
excreted.

Horning
et
al.
(
1980)
administered
a
100
mg/
kg
intraperitoneal
dose
of
naphthalene
to
male
Sprague­
Dawley
rats.
The
majority
of
the
administered
dose
(
80­
95%)
was
excreted
in
the
urine
as
conjugated
glucuronide,
sulfate,
and
thioether
metabolites;
the
major
metabolites
6­
6
Naphthalene
 
February
2003
identified
were:
1­
naphthol,
2­
naphthol,
1,2­
naphthalenediol,
cis­
and
trans­
1,2­
dihydro­
1,2­
naphthalenediol,
cis­
and
trans­
1,4­
dihydro­
1,4­
naphthalenediol,
and
1,1­,
2,7­
and
2,6­
naphthalenediol.

Stillwell
et
al.
(
1982)
identified
1­
naphthol,
trans­
1­
hydroxy­
2­
methylthio­
1,2­
dihydroxynaphthalene,
trans­
1,2­
dihydro­
1,2­
naphthalenediol,
methylthionaphthalene,
and
2­
naphthol
as
the
major
metabolites
in
the
urine
of
male
mice
that
received
naphthalene
by
intraperitoneal
injection.
Seven
sulfur­
containing
metabolites
were
identified,
with
the
N­
acetyl­
S­(
1­
hydroxy­
1,2­
dihydro­
2­
naphthenyl)
cysteine
being
the
primary
sulfur
metabolite
identified.

Bakke
et
al.
(
1990)
identified
the
glucuronic
acid
conjugate
and
the
dihydro­
1­
hydroxy­
2­
cysteine
derivative
of
dihydronaphthalenediol
in
the
urine
of
calves.
The
cysteine
derivative
was
excreted
in
slightly
larger
amounts.
The
two
metabolites
accounted
for
approximately
81%
of
the
administered
dose.

6.4
Excretion
Oral
Exposure
Limited
information
exists
on
the
excretion
of
orally
ingested
naphthalene
by
humans.
The
results
of
a
case­
study
indicated
that
naphthol
was
present
in
human
urine
four
days
postingestion
(
Zuelzer
and
Apt,
1949).
Smaller
amounts
were
found
at
five
days
post­
ingestion.
Naphthol
was
not
present
in
subsequent
specimens.
Mackell
et
al.
(
1951)
reported
that
1­
and
2­
naphthol,
1,
2­
naphthoquinone,
and
1,4­
naphthoquinone
were
present
in
the
urine
of
an
18­
month­
old
infant
9
days
after
ingestion.
At
13
days
post­
ingestion,
all
metabolites
except
1,4­
naphthoquinone
were
still
detectable.
These
results
suggest
that
urinary
excretion
may
be
extended
following
the
ingestion
of
naphthalene.
In
some
exposure
scenarios,
delayed
dissolution
and
absorption
from
the
gastrointestinal
tract
may
also
contribute
to
an
extended
pattern
of
excretion.
Zuelzer
and
Apt
(
1949)
noted
that
naphthalene
was
visible
in
fecal
matter
after
the
ingestion
of
naphthalene
flakes
or
mothballs
in
several
individuals.

Boyland
and
Sims
(
1958)
reported
that
only
trace
amounts
of
mercapturic
acids
were
detected
in
the
urine
of
a
man
who
ingested
a
500
mg
dose
of
naphthalene,
an
observation
that
is
consistent
with
the
findings
in
non­
human
primates
described
below.

Animal
studies
indicate
that
the
majority
of
ingested
naphthalene
is
eliminated
as
metabolites
in
the
urine,
with
a
small
fraction
eliminated
in
the
feces
(
U.
S.
EPA,
1998a).
Bakke
et
al.
(
1985)
administered
oral
doses
of
radiolabeled
naphthalene
to
rats.
At
24
hours
postadministration
the
majority
of
the
label
(
77­
93%)
was
recovered
in
the
urine,
while
6­
7%
was
recovered
in
the
feces.

Urinary
excretion
of
premercapturic
acids
and
mercapturic
acids
represents
a
major
excretory
pathway
(
accounting
for
approximately
80%
of
urinary
metabolites)
in
rodents
(
Stillwell
et
al.,
1978;
Chen
and
Dorough,
1979).
However,
thioethers
were
not
detected
in
the
6­
7
Naphthalene
 
February
2003
urine
of
chimpanzees
(
Summer
et
al.,
1979)
or
rhesus
monkeys
(
Rozman
et
al.,
1982)
administered
oral
doses
of
up
to
200
mg
naphthalene/
kg.
This
result
suggests
that
minimal
glutathione
conjugation
occurs
in
these
species
(
ATSDR,
1995).
Urinary
metabolite
data
collected
from
two
chimpanzees
suggests
that
naphthalene
is
excreted
primarily
as
glucuronide
and
sulfate
conjugates
in
this
species
(
Summer
et
al.,
1979).

Animal
evidence
exists
for
enterohepatic
recirculation
of
naphthalene
metabolites.
Experiments
with
normal
bile­
duct­
cannulated
and
germ­
free
rats
(
Bakke
et
al.,
1985)
suggest
that
premercapturic
acid
metabolites
of
naphthalene
are
excreted
in
the
bile
and
subsequently
converted
by
the
intestinal
microflora
to
1­
naphthol.
The
newly
formed
1­
naphthol
is
then
subject
to
absorption
and
re­
circulation.

Dose­
dependent
increases
in
urinary
thioether
levels
were
reported
in
rats
that
received
gavage
doses
of
30,
75,
or
200
mg
naphthalene/
kg
(
Summer
et
al.,
1979).
The
levels
of
thioethers
excreted
accounted
for
approximately
39%,
32%,
and
26%,
respectively,
of
the
dose
levels
tested.

Dermal
Exposure
No
studies
were
located
that
documented
the
excretion
of
naphthalene
in
humans
following
dermal
exposures.

Turkall
et
al.
(
1994)
evaluated
the
excretion
of
dermally
applied
14C­
labeled
naphthalene
by
rats
over
a
48­
hour
period.
A
dose
of
3.3
:
g/
cm2
of
neat
naphthalene
or
naphthalene
adsorbed
to
clay
or
sandy
soils
was
applied
to
the
shaved
skin
of
rats
under
a
sealed
plastic
cap.
In
all
cases,
excretion
was
primarily
through
the
urine
(
70­
87%).
Exhaled
air
accounted
for
6­
14%
of
the
administered
dose,
and
2­
4%
was
recovered
in
feces.
Less
than
0.02%
of
the
label
was
exhaled
as
carbon
dioxide.

Inhalation
Exposure
Bieniek
(
1994)
analyzed
the
excretion
patterns
of
1­
naphthol
in
three
groups
of
workers
occupationally
exposed
to
naphthalene.
The
mean
excretion
rate
for
these
workers
was
0.57
mg/
hour,
with
a
calculated
excretion
half­
life
of
approximately
4
hours.
The
highest
urinary
levels
of
1­
naphthol
were
reported
for
workers
in
a
naphthalene
oil
distribution
plant.
Peak
1­
naphthol
levels
were
detected
in
urine
collected
one
hour
after
finishing
the
shift.
7­
1
Naphthalene
 
February
2003
7.0
HAZARD
IDENTIFICATION
7.1
Human
Effects
7.1.1
Short­
Term
Studies
and
Case
Reports
General
Population
Intentional
and
Accidental
Acute
Ingestion
The
earliest
account
of
acute
oral
exposure
to
naphthalene
(
Lezenius,
1902)
describes
the
ingestion
of
impure
naphthalene
by
a
man
over
the
course
of
13
hours
in
an
attempt
to
cure
an
abdominal
ailment
(
ATSDR,
1995).
The
dose
of
naphthalene
was
not
known
precisely,
but
was
estimated
to
be
approximately
5
grams.
Assuming
a
body
weight
of
70
kg
for
an
adult,
this
amount
corresponds
to
a
dose
of
approximately
71
mg/
kg.
Within
8
to
9
hours,
vision
became
severely
impaired.
No
evidence
of
hematological
impacts
was
reported,
but
painful
urination
and
urethral
swelling
were
noted.
Upon
examination
1
month
later,
bilateral
zonular
cataracts
were
seen,
visual
fields
were
constricted,
and
the
subject
could
count
fingers
up
to
a
distance
of
only
1.5
meters.
The
contribution
of
impurities
in
the
naphthalene
to
the
observed
toxic
effects
is
unknown.

Several
reports
describe
cases
in
which
accidental
or
intentional
ingestion
of
naphthalene
resulted
in
death.
Gupta
(
1979)
reported
a
case
of
a
17­
year­
old
male
who
had
ingested
an
unknown
quantity
of
mothballs.
He
died
after
exhibiting
symptoms
that
included
vomiting,
gastrointestinal
bleeding,
blood­
tinged
urine,
jaundice,
and
coma.
Additional
observations
included
liver
enlargement,
elevated
creatine
and
blood
urea
nitrogen,
and
reduction
in
urine
output.
Death
occurred
5
days
after
ingestion.
Proximal
tubular
damage
and
general
tubular
necrosis
were
recorded
at
autopsy.

Kurz
(
1987)
reported
the
death
of
a
30­
year­
old
woman
after
she
ingested
a
large
number
of
moth
balls.
The
patient
reported
consuming
at
least
40
mothballs,
25
of
which
were
recovered
at
autopsy.
The
patient
exhibited
abdominal
pain,
blood
in
the
urine,
and
vomiting
of
blood.
Neurological
signs
included
malaise,
loss
of
response
to
painful
stimuli,
and
muscular
twitching
or
convulsions.
Hemolytic
anemia
was
diagnosed
prior
to
death,
and
the
increased
plasma
level
of
liver
enzymes
indicated
potential
hepatic
injury.
Death
occurred
5
days
after
ingestion.
Limited
areas
of
mucosal
hemorrhage
in
the
small
bowel
and
colon
were
seen
at
autopsy.

Two
cases
describe
the
death
of
a
child
following
the
ingestion
of
naphthalene.
In
the
first
case,
a
Japanese
child
died
after
ingesting
approximately
5
grams
of
mothballs
(
Ijiri
et
al.,
1987).
Assuming
a
body
weight
of
10
kg
(
the
age
of
the
child
is
unknown),
this
amount
corresponds
to
a
dose
of
approximately
500
mg/
kg.
The
blood
level
of
naphthalene
was
reported
to
be
0.55
mg/
L.
Pulmonary
edema,
congestion,
and
hemorrhage
of
the
lungs
were
found
to
be
present
at
autopsy.
Liver
pathology
included
fatty
changes,
and
leucocyte
and
lymphocyte
infiltration.
In
the
second
case,
a
6­
year­
old
child
died
after
ingesting
an
estimated
2
grams
of
7­
2
Naphthalene
 
February
2003
naphthalene
over
approximately
2
days
(
Gerarde,
1960).
Assuming
a
body
weight
of
21
kg
(
U.
S.
EPA,
1996c),
this
amount
corresponds
to
an
estimated
dose
of
95
mg/
kg.

Gidron
and
Leurer
(
1956)
reported
sublethal
acute
effects
in
the
case
of
a
16­
year­
old
girl
who
consumed
6
g
of
naphthalene
in
a
suicide
attempt.
Assuming
a
body
weight
of
55
kg,
this
dose
corresponds
to
109
mg/
kg.
Symptoms
and
treatment
were
recorded
during
18
days
of
hospitalization.
Indications
of
hemolytic
anemia
(
low
hemoglobin
concentration,
low
erythrocyte
count,
discolored
urine),
fever,
and
pain
in
the
kidney
region
were
observed.

Dreisbach
and
Robertson
(
1987)
reported
a
fatal
dose
from
oral
exposure
to
be
approximately
2
grams,
although
this
information
was
not
well
documented.
This
dose
is
equivalent
to
about
28
mg/
kg
for
a
70­
kg
reference
human.

Additional
reports
of
sublethal
acute
naphthalene
poisoning
have
been
summarized
in
ATSDR
(
1995)
and
U.
S.
EPA
(
1998a).
Most
of
these
cases
involved
naphthalene
ingestion
by
children.
Case
reports
document
hemolytic
anemia
characterized
by
methemoglobinemia,
the
occurrence
of
Heinz
bodies,
reduced
hemoglobin
levels,
reduced
hematocrit,
increased
reticulocyte
counts,
and
increased
serum
bilirubin
levels.
None
of
these
cases
provides
estimates
of
the
dose
levels
associated
with
the
development
of
hemolytic
anemia.

Acute
and
Short­
Term
Inhalation
Exposure
Household
inhalation
exposures
to
naphthalene
have
also
been
associated
with
adverse
effects.
Eight
adults
and
one
child
reported
gastrointestinal
(
nausea,
vomiting,
abdominal
pain)
and
neurological
(
headache,
malaise,
confusion)
symptoms
after
exposure
to
large
numbers
of
mothballs
in
their
homes
(
Linick,
1983).
The
duration
of
exposure
was
not
specified,
and
a
single
measurement
of
the
level
of
naphthalene
in
indoor
air
(
20
ppb)
was
taken
at
a
time
when
exposures
were
thought
to
be
lower
because
the
mothballs
were
not
"
fresh."
Symptoms
were
relieved
when
the
mothballs
were
removed
(
U.
S.
EPA,
1998a).

Short­
Term
Exposure
by
Other
Pathways
Dermal
exposure
to
naphthalene
has
occasionally
been
associated
with
adverse
effects
in
humans.
Valaes
et
al.
(
1963)
reported
adverse
health
effects
in
an
infant
exposed
to
naphthalene
by
wearing
diapers
that
had
been
stored
with
mothballs.
The
infant
developed
severe
hemolytic
anemia
accompanied
by
jaundice,
enlarged
liver,
methemoglobinemia,
and
cyanosis.
A
similar
case
was
reported
by
Schafer
(
1951).
In
the
latter
case,
symptoms
persisted
after
cessation
of
exposure,
and
death
resulted.
Levels
of
exposure
were
not
estimated
in
either
case.

Three
reports
(
Zinkham
and
Childs,
1958;
Anziulewicz
et
al.,
1959;
Athanasiou
et
al.,
1997)
describe
apparent
transplacental
exposure
of
a
fetus
during
pregnancy,
which
resulted
in
neonatal
hemolysis.
In
the
two
older
cases,
unspecified
amounts
of
naphthalene
had
been
ingested
by
the
mother
during
pregnancy.
The
more
recent
report
by
Athanasiou
et
al.
(
1997)
documented
the
occurrence
of
hemolytic
anemia
in
a
neonate
whose
mother
had
inhaled
naphthalene
during
the
28th
week
of
pregnancy.
7­
3
Naphthalene
 
February
2003
Sensitive
Populations
Short­
term
inhalation
exposures
to
naphthalene
have
been
associated
with
hemolytic
anemia,
and
occasionally,
death.
Valaes
et
al.
(
1963)
reported
adverse
effects
in
21
Greek
infants
exposed
to
naphthalene
from
clothing,
diapers,
blankets,
and
other
items
that
had
been
stored
in
contact
with
mothballs.
Durations
of
exposure
ranged
from
1
to
7
days.
Inhalation
was
identified
as
the
primary
route
of
exposure
because
19
of
the
21
infants
did
not
have
dermal
contact
with
the
naphthalene­
contaminated
materials.
A
total
of
21
infants
developed
hemolytic
anemia
and
two
infants
died
from
kernicterus,
a
severe
neurological
condition
that
was
thought
to
be
a
consequence
of
massive
hemolysis.
Ten
of
the
21
anemic
children
and
1
of
the
2
infants
that
died
from
naphthalene
exposure
had
a
genetic
polymorphism
that
resulted
in
a
deficiency
in
glucose­
6­
phosphate
dehydrogenase
(
G6PD).
This
enzyme
helps
to
protect
red
blood
cells
from
oxidative
damage,
and
G6PD
deficiency
makes
the
cells
more
sensitive
to
a
wide
variety
of
toxicants,
including
naphthalene.

7.1.2
Long­
Term
and
Epidemiological
Studies
General
Populations
Ghetti
and
Mariani
(
1956)
reported
the
development
of
pin­
point
lens
opacities
in
8
of
21
individuals
employed
for
five
years
at
a
dye
manufacturing
plant.
The
individuals
were
involved
in
the
heating
of
large
amounts
of
naphthalene
in
open
vats.
Exposure
of
these
workers
likely
occurred
primarily
via
inhalation
and
dermal
contact,
but
exposure
levels
were
not
estimated.
Although
cataracts
may
develop
spontaneously
with
age,
seven
of
the
affected
individuals
were
younger
than
50
years
old.
The
probability
of
spontaneous
cataract
development
in
these
individuals
was
therefore
considered
to
be
low.
The
lesions,
which
did
not
affect
visual
acuity,
were
attributed
to
naphthalene
exposure
because
no
correlation
existed
between
incidence
and
age,
and
because
they
occurred
in
the
crystalline
lens
(
ATSDR,
1995).

Two
epidemiological
studies
addressed
a
potential
relationship
between
occupational
exposure
to
naphthalene
and
cancer
in
German
workers.
An
abstract
of
a
case­
control
study
by
Kup
(
1978)
described
12
cases
of
laryngeal
carcinomas,
2
cases
of
epipharyngeal
cancer,
and
one
case
of
nasal
carcinoma.
All
but
three
workers
were
smokers.
Four
of
the
patients
with
laryngeal
cancer
also
had
a
history
of
occupational
exposure
to
naphthalene.
Limitations
to
this
study
include
the
small
number
of
patients
studied,
uncertainty
about
how
naphthalene
exposures
were
identified,
and
known
exposures
to
other
potential
carcinogens.
Consequently,
this
study
does
not
provide
strong
evidence
for
an
association
between
naphthalene
exposure
and
pharyngeal
cancer.
The
author
suggested
that
most
of
the
observed
cancers
were
probably
due
to
nonoccupational
causes
(
U.
S.
EPA,
1998a).

The
second
epidemiological
study
reported
the
finding
of
6
cases
of
cancer
among
15
workers
exposed
to
naphthalene
vapors
at
a
coal
tar
and
naphthalene
production
facility
(
Wolf,
1976).
The
duration
of
exposure
ranged
from
7
to
32
years.
Four
workers
developed
carcinomas
of
the
larynx.
Two
workers
developed
cancer
of
the
stomach
and
cecum.
All
of
the
subjects
were
smokers.
Limitations
to
this
study
include
lack
of
a
control
population,
the
small
numbers
7­
4
Naphthalene
 
February
2003
of
workers
involved,
lack
of
quantitative
exposure
data,
and
the
presence
of
both
occupational
and
nonoccupational
exposures
to
other
potential
carcinogens.
Therefore,
this
study
does
not
provide
strong
evidence
for
a
relationship
between
naphthalene
exposure
and
cancer
incidence
(
U.
S.
EPA,
1998a).

Sensitive
Populations
No
long­
term
studies
conducted
in
sensitive
populations
were
identified
in
the
materials
reviewed
for
this
document.

7.2
Animal
Studies
This
section
presents
the
results
of
toxicity
studies
of
naphthalene
in
animals.
The
first
four
subsections
provide
study
results
by
duration
of
exposure.
Acute
studies
are
those
which
address
exposure
durations
of
24
hours
or
less.
Short­
term
studies
are
those
in
which
the
exposure
duration
is
greater
than
24
hours
but
less
than
approximately
90
days.
The
exposure
duration
of
subchronic
studies
is
typically
90
days,
and
chronic
studies
are
those
in
which
exposure
lasts
one
year
or
more.
Some
studies
fall
into
more
than
one
category
because
they
measure
impacts
over
several
exposure
periods.
The
discussion
of
acute,
short­
term,
subchronic,
and
chronic
studies
summarizes
observed
toxicological
effects
on
all
body
systems.

The
last
four
subsections
of
Section
7.2
provide
toxicological
data
related
to
specific
organ
systems
and
types
of
endpoints:
ocular
toxicity,
neurotoxicity,
developmental/
reproductive
toxicity,
and
carcinogenicity.

7.2.1
Acute
Toxicity
Oral
Exposure
Acute
lethality
data
have
been
reported
for
rats
and
mice.
LD
50
values
in
various
strains
of
rats
typically
range
between
1,780
mg/
kg
and
2,800
mg/
kg
(
Gaines,
1969;
NIOSH,
1977;
Papciak
and
Mallory,
1990),
although
LD
50
values
as
high
as
9,430
mg/
kg
have
been
reported
in
one
study
(
Union
Carbide
Corp.,
1968).
Shopp
et
al.
(
1984)
reported
LD
50
values
of
533
mg/
kg
for
male
mice
and
710
mg/
kg
for
female
mice.

Zuelzer
and
Apt
(
1949)
administered
single
dietary
doses
of
410
mg/
kg
or
1,530
mg/
kg
naphthalene
to
two
dogs.
Both
dogs
developed
signs
of
hemolytic
anemia
including
a
29
 
33%
reduction
in
hemoglobin
concentrations,
decreased
hematocrit,
presence
of
Heinz
bodies,
and
reticulocytosis.

Shopp
et
al.
(
1984)
administered
0,
200,
400,
600,
800,
or
1,000
mg/
kg
naphthalene
via
oral
gavage
(
in
a
corn
oil
vehicle)
to
CD­
1
mice
(
8
animals/
sex/
dose).
Mice
displayed
ptosis
(
drooping
of
eyelids)
and
red
discharge
soon
after
receiving
doses
of
400
mg/
kg
or
higher
(
males)
or
600
mg/
kg
or
higher
(
females).
These
findings
suggest
NOAEL
and
LOAEL
values
7­
5
Naphthalene
 
February
2003
for
this
study
of
200
and
400
mg/
kg,
respectively,
based
on
the
occurrence
of
ptosis
(
drooping
of
the
eyelids)
in
male
mice.

Naphthalene­
related
cataract
formation
has
been
reported
in
animals
following
acute
oral
exposure.
Van
Heyningen
and
Pirie
(
1976)
administered
naphthalene
by
gavage
at
1,000
mg/
kgday
to
rabbits
and
observed
cataract
formation
in
some
animals
after
a
single
dose.
Ikemoto
and
Iwata
(
1978)
observed
that
oral
administration
of
1,000
mg/
kg
to
albino
rabbits
of
both
sexes
for
two
consecutive
days
resulted
in
cataract
formation.
The
ocular
toxicity
of
naphthalene
is
further
discussed
in
Section
7.3.2.

Dermal
Exposure
Acute
toxicity
testing
in
rabbits
revealed
that
2,000
mg/
kg
of
naphthalene
causes
moderate
dermal
irritation
(
erythema,
edema,
and/
or
fissuring
that
resolved
within
7
days)
when
applied
directly
to
intact
or
abraded
skin
(
Papciak
and
Mallory,
1990).
Application
of
500
mg/
kg
to
intact
or
abraded
skin
resulted
in
slight
irritation
(
some
reversible
erythema
at
24
and
72
hours
after
application)
(
Papciak
and
Mallory,
1990).
In
a
separate
study,
application
of
500
mg
to
intact
shaved
skin
(
area
not
specified)
resulted
in
mild
to
well­
defined
erythema
and
some
fissuring
(
PRI,
1985).
Mild
ocular
irritation
occurred
following
the
instillation
of
100
mg
of
naphthalene
into
the
eye
(
PRI,
1985;
Papciak
and
Mallory,
1990).
These
effects
were
reversed
within
7
days,
and
they
occurred
only
when
naphthalene
was
left
on
the
eye
surface
rather
than
rinsed
off
after
application
(
ATSDR,
1995).

Inhalation
Exposure
U.
S.
EPA
(
1987b)
has
previously
summarized
acute
inhalation
data
for
naphthalene.
Union
Carbide
(
1968)
reported
that
the
8­
hour
LC
50
value
for
naphthalene
was
100
ppm.
Buckpitt
(
1985)
suggested
that
this
value
may
be
too
low,
on
the
basis
of
calculated
body
burdens.
Buckpitt
(
1985)
calculated
that
following
8
hours
of
inhalation
exposure
at
100
ppm,
the
body
burden
would
be
less
than
30
mg/
rat,
or
approximately
150
to
200
mg/
kg.
This
value
is
considerably
less
than
the
oral
or
intraperitoneal
LD
50
values
for
rats.
Fait
and
Nachreiner
(
1985)
reported
that
exposure
of
male
and
female
Wistar
rats
to
78
ppm
naphthalene
for
4
hours
did
not
result
in
mortalities
or
any
abnormalities
in
the
lung,
liver,
kidney,
or
nasal
passages.
Buckpitt
(
1985)
conducted
an
inhalation
study
with
male
Swiss­
Webster
mice.
No
deaths
were
observed
after
exposure
to
90
ppm
naphthalene
for
4
hours,
but
lung
lesions
were
reported
to
be
prominent.

No
new
data
for
acute
inhalation
toxicity
were
identified
in
the
materials
reviewed
for
this
document.
7­
6
Naphthalene
 
February
2003
7.2.2
Short­
Term
Studies
Oral
Exposure
Zuelzer
and
Apt
(
1949)
administered
seven
consecutive
daily
doses
of
naphthalene
in
the
diet
to
a
single
dog.
The
daily
doses
ranged
from
74
to
441
mg/
kg,
with
an
average
daily
dose
of
262
mg/
kg­
day.
The
dog
developed
signs
of
hemolytic
anemia,
including
decreased
hemoglobin
concentration,
decreased
hematocrit,
presence
of
Heinz
bodies,
extreme
leukocytosis,
and
reticulocytosis.
Other
signs
noted
included
pronounced
lethargy
and
ataxia.

Shopp
et
al.
(
1984)
administered
0,
27,
53,
or
267
mg/
kg­
day
naphthalene
in
corn
oil
via
oral
gavage
to
CD­
1
mice
(
76
 
112
males/
dose,
40
 
76
females/
dose)
for
14
days.
Gross
pathology
was
performed,
but
a
histopathological
examination
was
not
conducted.
No
adverse
effects
were
noted
at
doses
of
53
mg/
kg­
day
or
less.
Adverse
effects
observed
in
animals
exposed
to
267
mg/
kg­
day
included
increased
mortality
and
decreased
terminal
body
weights
(
4
 
10%)
in
males
and
females,
decreased
absolute
thymus
weights
(
30%)
in
males,
increased
bilirubin
in
females,
and
increased
spleen
and
lung
weights
(
relative
and
absolute)
in
females.
Serum
enzyme
activities
(
lactic
dehydrogenase
and
serum
glutamic­
oxaloacetic
transamidase)
and
electrolyte
levels
were
not
altered
in
a
dose­
dependent
pattern.
There
were
no
effects
on
hexobarbital
sleeping
time
or
on
various
immunological
screening
parameters
(
with
the
exception
of
decreased
lymphocyte
response
to
concanavalin
A
in
high­
dose
females).
Values
for
hematological
and
coagulation
parameters
were
similar
to
controls,
with
the
exception
of
decreased
prothrombin
time
in
high­
dose
females,
and
a
small
but
significant
increase
in
eosinophils
in
high­
dose
males.
Neither
red
cell
hemolysis
nor
cataract
formation
was
observed
in
the
naphthalene­
exposed
mice,
and
the
authors
suggested
that
this
mouse
strain
appears
to
be
resistant
to
these
toxic
effects.
This
study
identified
a
NOAEL
of
53
mg/
kg­
day
and
a
LOAEL
of
267
mg/
kg­
day.

Plasterer
et
al.
(
1985)
administered
doses
of
0,
125,
250,
500,
1,200,
and
2,000
mg/
kgday
to
non­
pregnant
female
CD­
1
mice
(
10
per
dose
group)
by
gavage
in
corn
oil.
A
steep
doseresponse
relationship
was
observed
for
lethality
in
naphthalene­
exposed
mice.
After
8
daily
gavage
doses,
an
LD
50
value
of
354
mg/
kg
was
determined
for
male
and
female
mice.
This
value
is
based
on
100%
mortality
at
500
mg/
kg­
day
and
no
deaths
at
250
mg/
kg­
day.
In
pregnant
mice,
15%
mortality
was
observed
in
the
300­
mg/
kg­
day
group.
In
contrast,
no
mortality
was
reported
in
2
strains
of
rabbits
that
received
1,000
mg/
kg
naphthalene
via
gavage,
twice
a
week
for
12
weeks
(
Rossa
and
Pau,
1988),
suggesting
that
there
are
species
differences
in
response
to
naphthalene
exposure.

Liver
changes
have
been
reported
in
rats
exposed
to
relatively
high
doses
of
naphthalene
(
approximately
1,000
mg/
kg­
day
or
more)
when
administered
for
durations
of
10
days
to
9
weeks
(
ATSDR,
1995).
Rao
and
Pandya
(
1981)
reported
hepatic
toxicity
in
rats
administered
1,000
mg/
kg­
day
naphthalene
(
LOAEL)
for
10
days.
Observed
effects
included
a
39%
increase
in
liver
weight,
increased
lipid
peroxidation,
and
a
modest
increase
in
aniline
hydroxylase
activity
(
ATSDR,
1995).
Increased
lipid
peroxidation
was
also
reported
in
rats
that
received
1,000
mg/
kg­
day
naphthalene
for
18
days
(
Yamauchi
et
al.,
1986),
and
in
rats
that
received
escalating
7­
7
Naphthalene
 
February
2003
doses
of
naphthalene
up
to
750
mg/
kg­
day
over
a
9­
week
period
(
Germansky
and
Jamall,
1988).
No
effects
on
liver
weight
were
noted
in
the
14­
day
gavage
study
reported
by
Shopp
et
al.
(
1984)
at
tested
doses
as
high
as
267
mg/
kg­
day.

Dermal
Exposure
No
short­
term
animal
studies
evaluating
the
dermal
route
of
exposure
were
identified
in
the
materials
reviewed
for
this
document.

Inhalation
Exposure
No
short­
term
inhalation
studies
of
naphthalene
exposure
were
identified
in
the
materials
reviewed
for
this
document.

7.2.3
Subchronic
Studies
Oral
Exposure
Naphthalene
(>
99%
in
corn
oil)
was
administered
to
Fischer
344
rats
(
10/
sex/
dose),
5
days
per
week
for
13
weeks
(
BCL,
1980a).
Unadjusted
daily
dose
levels
were
0,
25,
50,
100,
200,
and
400
mg/
kg­
day.
Weekly
food
consumption
and
body
weights
were
measured,
and
rats
were
examined
twice
daily
for
clinical
signs
of
adverse
effects.
Hematological
parameters
(
hemoglobin,
hematocrit,
total
and
differential
white
cell
count,
red
blood
cell
count,
mean
cell
volume
and
mean
cell
hemoglobin)
were
measured
in
all
animals
at
the
end
of
the
study.
All
rats
were
necropsied,
and
detailed
histopathological
examinations
on
27
tissues
were
performed
on
all
rats
in
the
control
and
400
mg/
kg­
day
groups.
The
tissues
examined
included
eyes,
stomach,
liver,
reproductive
organs,
thymus,
and
kidneys.
In
the
100­
mg/
kg­
day
group,
male
kidneys
and
female
thymus
tissues
were
subject
to
detailed
histopathological
examinations.

Male
and
female
rats
in
the
400
mg/
kg­
day
dose
group
exhibited
diarrhea,
lethargy,
hunched
posture,
and
rough
coats
during
the
study,
and
one
high­
dose
male
rat
died
during
the
last
week
of
exposure.
Food
consumption
was
not
affected
in
any
dose
group,
but
body
weights
were
significantly
decreased
in
several
of
the
groups
(
Table
7­
1).
Males
in
the
high­
dose
group
experienced
a
94%
increase
in
the
number
of
mature
neutrophils
and
a
25.1%
decrease
in
circulating
lymphocytes,
as
compared
to
control
group
rats.
No
other
differences
were
observed
in
hematological
parameters.
Histopathological
examination
of
kidney
and
thymus
tissues
revealed
the
following
changes:
focal
cortical
lymphocyte
infiltration
was
observed
in
1
of
10
males
in
the
200­
mg/
kg­
day
group;
focal
tubular
degeneration
was
observed
in
1
of
10
males
in
the
200­
mg/
kg­
day
group;
diffuse
renal
tubular
degeneration
was
observed
in
1
male
in
the
400­
mg/
kg­
day
group;
and
lymphoid
depletion
of
the
thymus
was
seen
in
2
of
10
females
in
the
high­
dose
group.
No
other
tissue
abnormalities
were
seen
in
any
group.
The
NOAEL
and
LOAEL
values
derived
from
this
study
were
100
and
200
mg/
kg­
day,
respectively,
on
the
basis
of
reduced
body
weight
(>
10%)
in
males
(
U.
S.
EPA,
1998a).
These
NOAEL
and
LOAEL
values
correspond
to
duration­
adjusted
doses
of
71
and
143
mg/
kg­
day,
respectively.
7­
8
Naphthalene
 
February
2003
Table
7­
1.
Terminal
Body
Weights
in
Controls
and
in
Fischer
344
Rats
Exposed
to
Naphthalene
by
Gavage
for
13
Weeks
Dose
(
mg/
kg­
day
)
Average
Terminal
Body
Weight
Males
(
g)
Average
Terminal
Body
Weight
Females
(
g)
Unadjusted
Durationadjusted
0
0
348.9
203.4
25
17.9
353.4
197.8
50
35.7
351.2
203.5
100
71.4
333.4
197.2
200
142.9
306.7*
190.5
400
285.7
250.6*
156.7*

*
Decrease
>
10%
relative
to
controls
Source:
U.
S.
EPA
(
1998a)

In
a
second
study
(
BCL,
1980b),
the
same
investigators
exposed
B6C3F
1
mice
to
naphthalene
in
corn
oil
by
gavage.
The
administered
doses
were
0,
12.5,
25,
50,
100,
and
200
mg/
kg­
day,
5
days
per
week
for
13
weeks.
Seven
mice
died
during
the
exposure
period,
all
from
gavage
trauma
unrelated
to
naphthalene
dose.
In
weeks
3
and
5
of
the
exposure
period,
transient
signs
of
toxicity
(
lethargy,
rough
coats,
decreased
food
consumption)
occurred
in
the
highestdose
groups.
The
average
weight
gain
during
the
study
was
higher
for
all
of
the
exposed
male
groups
than
for
the
control
group.
Female
mice
exposed
to
naphthalene,
in
contrast,
gained
less
weight
than
the
control
group.
The
reduction
in
weight
gain
was
dose­
related,
ranging
from
2.5%
in
the
12.5­
mg/
kg­
day
females
to
24.5%
in
the
200­
mg/
kg­
day
females.
The
authors
of
the
study
indicated
that
the
weight
gain
reduction
"
was
not
large
enough
to
conclusively
indicate
a
toxic
effect".
Complete
histological
evaluations
were
performed
on
all
control
and
high­
dose
animals
at
the
end
of
the
study.
No
exposure­
related
lesions
were
observed
in
any
organ
system.
Mild
focal
or
multifocal
subacute
pneumonia
was
observed
in
similar
proportions
for
both
control
and
high­
dose
animals.
Hematological
evaluation
indicated
an
increase
in
circulating
lymphocytes
of
18%
in
the
high­
dose
males
relative
to
these
in
control
groups.
A
decrease
of
38.8%
in
segmented
neutrophils
was
also
noted
in
high­
dose
males.
No
significant
differences
were
observed
in
hematological
parameters.

The
authors
of
the
study
indicated
that
given
the
"
marked
indication"
of
sex
differences
in
body
weight
responses,
the
observed
weight
gain
differences
did
not
constitute
an
adverse
effect.
If
this
interpretation
is
accepted,
a
LOAEL
of
200
mg/
kg­
day
(
adjusted
dose:
143
mg/
kgday
can
be
identified
from
this
study
based
on
the
occurrence
of
transient
clinical
signs
of
7­
9
Naphthalene
 
February
2003
toxicity
discussed
above
(
U.
S.
EPA,
1998a).
The
corresponding
NOAEL
would
be
100
mg/
kgday
(
adjusted
dose
71
mg/
kg­
day).

Shopp
et
al.
(
1984)
employed
larger
numbers
of
mice
to
evaluate
the
subchronic
toxicity
of
naphthalene.
Groups
of
76
male
and
40
female
CD­
1
mice
were
exposed
by
gavage
to
daily
doses
of
5.3
or
53
mg/
kg­
day
naphthalene
in
corn
oil
for
90
consecutive
days.
In
addition,
a
high­
dose
group
of
96
male
and
60
female
mice
received
a
daily
dose
of
133
mg/
kg­
day.
Toxicological
responses
were
measured
against
naive
control
groups
of
76
male
and
40
female
mice,
and
against
vehicle
control
groups
of
112
male
and
76
female
animals.
No
differences
in
survival
or
terminal
body
weights
were
seen
between
the
control
and
exposed
groups.
In
the
high­
dose
females,
significant
decreases
were
seen
in
absolute
weights
of
the
brain,
liver,
and
spleen,
and
in
the
relative
spleen
weight.
No
differences
in
organ
weights
were
seen
in
males
in
any
exposure
group.
Histopathological
examinations
were
not
performed,
but
the
authors
noted
an
absence
of
cataracts
in
all
dose
groups.
In
general,
serum
chemistry
parameters
for
naphthalene
treatment
groups
did
not
differ
significantly
from
control
groups.
However,
hematological
evaluation
showed
slight
but
significant
increases
in
hemoglobin
levels
in
highdose
females.
All
of
the
exposed
female
groups
had
significantly
decreased
blood
urea
nitrogen
(
BUN)
levels.
Significant
changes
in
serum
globulin
levels
were
observed
in
females,
but
a
consistent
dose­
response
relationship
was
not
evident.
Hematological
parameters
for
males
were
normal.
No
exposure­
related
impacts
on
immunological
function
were
observed.
Assays
for
enzyme
activity
indicated
that
hepatic
benzo(
a)
pyrene
hydroxylase
activity
was
decreased
significantly
in
males
and
females
treated
with
the
53
and
133
mg/
kg­
day
doses,
and
in
males
treated
with
the
5.3
mg/
kg­
day
dose.
Aniline
hydroxylase
activity
was
significantly
increased
in
females
receiving
the
133
mg/
kg­
day
dose.
The
authors
of
this
study
did
not
report
a
NOAEL.
Because
the
effects
on
serum
chemistry
parameters
and
hepatic
enzymes
are
not
clearly
adverse,
U.
S.
EPA
(
1998a)
identified
a
NOAEL
of
53
mg/
kg­
day.
The
LOAEL
of
133
mg/
kg­
day
reflects
the
observed
effects
on
organ
weight
and
suggestive
evidence
for
impacts
on
hepatic
enzyme
function.

Dermal
Exposure
Frantz
et
al.
(
1986)
applied
doses
of
0,
100,
300,
or
1,000
mg
naphthalene/
kg­
day
to
the
skin
of
albino
rats
for
6
hours/
day,
5
days/
week,
for
13
weeks.
Following
exposure,
clinical
signs,
food
consumption,
body
weight,
clinical
chemistry,
hematology,
and
urinalysis
were
evaluated.
A
significantly
increased
incidence
of
excoriated
skin
lesions
and
papules
was
reported
in
the
high­
dose
group
relative
to
those
in
the
controls.
Similar
lesions
were
observed
in
the
control
group
and
low­
dose
groups.
The
severity
of
the
lesions
appeared
to
increase
with
dose.

Inhalation
Exposure
No
studies
that
addressed
subchronic
exposures
by
inhalation
were
identified
in
the
materials
reviewed
for
this
document.
7­
10
Naphthalene
 
February
2003
7.2.4
Neurotoxicity
Relatively
little
information
is
available
regarding
the
neurological
effects
of
naphthalene
exposure
in
experimental
animals.
PRI
(
1986)
observed
treatment­
related
signs
of
labored
breathing,
body
drop,
and
decreased
activity
(
incidence
data
not
provided)
in
New
Zealand
White
rabbits
exposed
to
200
or
400
mg/
kg­
day.
In
a
study
of
developmental
toxicity
(
NTP,
1991),
pregnant
Sprague­
Dawley
rats
received
daily
gavage
doses
of
0,
50,
150,
or
450
mg/
kg­
day
naphthalene
for
10
days
during
organogenesis
(
gestation
days
6
to
15).
Animals
in
all
dose
groups
showed
signs
of
neurotoxicity,
including
lethargy,
slow
respiration
(
including
periods
of
apnea),
and
apparent
inability
to
move
after
dosing.
Incidence
of
symptoms
in
the
low­
dose
group
was
73%,
while
incidence
in
the
highest­
dose
group
was
over
90%.
These
effects
were
transient,
however,
and
diminished
as
the
animals
apparently
acclimatized
to
the
treatment.
Animals
in
the
low­
dose
group
appeared
to
acclimatize
to
naphthalene
exposures
after
a
few
days.
Incidence
in
the
higher­
dose
groups
declined
with
continued
exposure,
but
never
dropped
below
15%
(
ATSDR,
1995).

Male
mice
exposed
to
10
or
30
ppm
naphthalene
in
a
two­
year
inhalation
study
exhibited
increased
huddling
behavior
during
exposure
and
a
reduced
inclination
to
fight
(
NTP,
1992a).
Although
the
observed
activities
may
indicate
neurological
effects,
the
authors
of
this
study
did
not
speculate
on
the
underlying
basis
for
the
behavioral
changes,
and
no
additional
signs
of
neurotoxicity
were
reported.

Other
large
studies
found
no
evidence
of
neurotoxicity
at
naphthalene
doses
similar
to
those
producing
symptoms
mentioned
in
the
studies
above.
No
neurological
effects
were
found
in
Fischer
344
rats
(
BCL,
1980a)
or
B6C3F
1
mice
(
BCL,
1980b),
at
gavage
doses
up
to
400
mg/
kg­
day
and
200
mg/
kg­
day,
respectively.

7.2.5
Developmental/
Reproductive
Toxicity
Studies
of
the
reproductive
and
developmental
toxicity
of
naphthalene
are
summarized
in
Table
7­
2.

PRI
(
1985)
conducted
a
range­
finding
developmental
study
in
New
Zealand
White
rabbits.
Gavage
doses
of
0,
50,
250,
630,
or
1,000
mg/
kg­
day
were
administered
to
pregnant
rabbits
(
4/
dose)
by
gavage
in
1%
methylcellulose
on
gestation
days
(
GD)
6
to
18.
All
does
in
the
high­
dose
group
died.
At
630
mg/
kg­
day,
2
of
4
animals
died.
The
surviving
animals
experienced
decreased
weight
gain
and
aborted
their
pregnancies.
No
exposure­
related
changes
were
observed
in
the
incidence
of
early
resorption,
postimplantation
loss,
number
of
corpora
lutea,
fetal
survival,
or
gross
fetal
structural
development.

In
a
subsequent
study
of
developmental
toxicity,
PRI
(
1986)
administered
doses
of
0,
40,
200,
or
400
mg/
kg­
day
by
gavage
in
1%
methyl
cellulose
to
pregnant
New
Zealand
White
rabbits
(
18/
dose).
Dosing
occurred
on
GD
6
 
18.
Caesarean
sections
were
performed
on
GD
29.
7­
11
Naphthalene
 
February
2003
Table
7­
2.
Summary
of
Developmental
and
Reproductive
Data
on
Naphthalene
Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
PRI
(
1985)
Rabbit
(
New
Zealand
White)
Female
4
0
50
250
630
1,000
Gavage
Methylcellulose
GD
6
 
18
Maternal
250
Fetal
250
Maternal
630
(
FEL)

Fetal
630
(
abortion)
Maternal:
Mortality
and
decreased
wt.
gain
at
630
mg/
kg­
day
Fetal:
Aborted
at
630
mg/

kgday
PRI
(
1986)
Rabbit
(
New
Zealand
White)
Female
18
0
40
200
400
Gavage
Methylcellulose
GD
6­
18
Maternal
400
Fetal
400
Maternal
­
Fetal
­
Maternal:
survival,
body
wt.

and
body
wt.
gain
unaffected
Fetal:
No
effect
on
reproduction
or
development
of
fetus
Plasterer
et
al.

(
1985)
Mouse
(
CD­
1)
Female
33
 
40
0
300
Gavage
oil
GD
7
 
14
­
300
(
FEL)
Maternal:
Reduced
wt.
gain;

reduced
survival
Fetal:
Reduced
no.
of
pups/
litter;
no
abnormalities
in
surviving
pups
NTP
(
1991)
Rat
(
Sprague­

Dawley
CD)
Female
25
 
26
0
50
150
450
Gavage
GD
6
 
15
Maternal
 
Fetal
450
Maternal
50
(
central
nervous
system
depression)

Fetal
­­
Maternal:
Two
deaths;
central
nervous
system
depression
manifested
as
lethargy,
slow
breathing,
prone
body
posture,

and
increased
rooting
Fetal:
no
finding
of
fetoxicity
or
embryotoxicty
Table
7­
2
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
12
Naphthalene
 
February
2003
NTP
(
1992b)
Rabbit
(
New
Zealand
White)
Female
25
 
27
0
20
80
120
Gavage
oil
GD
6
 
19
Maternal
120
Fetal
120
Maternal
­
Fetal
­
Maternal:
No
consistently
observed
toxicity
Fetal:
No
effect
on
reproduction
or
development
of
fetus
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
76
 
112
0
27
53
267
Gavage
oil
14
267
­
No
effect
on
testicular
weight
Male
76
 
96
53
133
Gavage
oil
90
133
­
No
effect
on
testicular
weight
BCL
(
1980a)
Rat
(
F344)
Male
10/
dose
0
25
50
100
200
400
Gavage
oil
13
weeks
5
days/
week
400
­
Absence
of
gross
testicular
lesions
BCL
(
1980b)
Mouse
(
B6C3F
1)
Male
10/
dose
0
12.5
25
50
100
200
Gavage
oil
90
days
200
­
Absence
of
gross
testicular
lesions
GD
=
gestation
day
FEL
=
fetal
effect
level
7­
13
Naphthalene
 
February
2003
Maternal
survival,
body
weight,
and
body
weight
gain
were
unaffected
by
naphthalene
treatment.
Treatment­
related
signs
of
labored
breathing,
cyanosis,
body
drop,
decreased
activity
and
salivation
were
reportedly
noted
in
animals
receiving
the
200
and
400
mg/
kg­
day
doses,
but
incidence
data
were
not
provided.
No
effect
of
treatment
was
noted
on
number
of
corpora
lutea,
total
implantations,
fetal
viability,
pre­
or
postimplantation
loss,
fetal
body
weight,
fetal
sex
distribution,
or
fetal
skeletal
or
visceral
abnormalities.

Plasterer
et
al.
(
1985)
examined
the
developmental
toxicity
of
naphthalene
in
CD­
1
mice.
Doses
of
0
or
300
mg/
kg­
day
(
40
and
33
animals/
group,
respectively)
were
administered
by
gavage
in
corn
oil
on
GD
7
to
14.
Mortality
occurred
in
5/
33
exposed
dams,
while
all
control
dams
survived
the
treatment.
Average
weight
gain
was
significantly
reduced
in
exposed
dams
when
compared
with
controls.
The
average
number
of
live
pups
per
litter
was
significantly
reduced
by
naphthalene
treatment,
but
the
average
body
weight
of
the
living
pups
was
not
affected
by
exposure.
No
treatment­
related
gross
structural
abnormalities
were
seen
in
the
surviving
pups.
The
300
mg/
kg­
day
dose
is
considered
a
frank
effect
level
(
FEL)
based
on
maternal
(
death
and
reduced
body
weight)
and
fetal
(
decreased
live
pups
per
litter)
effects.

NTP
(
1991)
conducted
a
developmental
study
of
naphthalene
toxicity
in
pregnant
Sprague­
Dawley
CD
rats
(
25
 
26/
dose).
Doses
of
0,
50,
150,
or
450
mg/
kg
naphthalene
were
administered
by
gavage
in
corn
oil
on
gestational
days
6
to
15.
The
dams
were
examined
daily
for
clinical
signs
until
sacrifice
on
GD
20.
Fetuses
were
examined
on
GD
20
for
gross,
visceral,
and
skeletal
malformations.
Maternal
mortality
was
limited
to
two
deaths
in
the
low­
dose
group.
Treatment
with
naphthalene
produced
clinical
signs
of
toxicity,
including
lethargy,
slow
breathing,
prone
body
posture,
and
increased
rooting
behavior.
The
effects
subsided
in
the
50
and
150
mg/
kg­
day
groups
before
the
end
of
the
treatment
period,
but
persisted
throughout
the
treatment
period
in
the
450
mg/
kg­
day
treatment
group.
Dams
exposed
to
the
150
and
450
mg/
kg
doses
showed
significant
decreases
in
weight
gain.
The
average
reductions
in
weight
gain
were
31%
and
53%
respectively.
No
unequivocal
treatment­
related
effects
on
fetal
development
were
noted.
The
study
authors
identified
the
highest
dose
of
450
mg/
kg­
day
as
a
NOAEL
for
fetal
effects.
U.
S.
EPA
(
1998a)
identified
50
mg/
kg­
day
as
the
LOAEL
for
maternal
toxicity
in
this
study.

Mild
developmental
abnormalities
were
noted
in
some
offspring
of
New
Zealand
rabbits
that
were
administered
0,
20,
80,
or
120
mg/
kg­
day
naphthalene
on
gestation
days
6
 
19
(
NTP,
1992b).
Slight
increases
in
the
incidence
of
fused
sternebrae
were
seen
in
the
female
pups
in
2
of
20
litters
of
animals
given
80
mg/
kg­
day,
and
in
3
of
20
litters
of
animals
given
120
mg/
kg­
day.
However,
these
increases
were
not
statistically
significant.
No
significant
differences
were
observed
for
average
litter
size,
average
fetal
body
weight,
or
incidence
of
other
malformations
on
a
per
fetus
or
per
litter
basis.
The
highest
dose
in
this
study
was
the
NOAEL
for
maternal
and
developmental
toxicity.

Naphthalene
does
not
cause
testicular
lesions
in
rats
or
mice.
Testicular
weight
was
unaffected
in
B6C3F
1
mice
given
267
mg/
kg
naphthalene
for
14
days
or
133
mg/
kg
for
90
days
(
Shopp
et
al.,
1984).
Two
other
subchronic
studies
also
found
no
gross
histopathological
testicular
lesions
in
Fischer
344
rats
receiving
up
to
400
mg/
kg­
day
naphthalene
(
BCL,
1980a)
or
in
B6C3F
1
mice
receiving
up
to
200
mg/
kg­
day
(
BCL,
1980b)
for
13
weeks.
7­
14
Naphthalene
 
February
2003
7.2.6
Chronic
Toxicity
The
few
chronic
animal
studies
that
are
available
for
naphthalene
were
conducted
primarily
to
characterize
its
carcinogenic
potential
effects.
Noncancer
endpoints
reported
in
these
studies
are
summarized
below.

Oral
Exposure
Schmähl
(
1955)
examined
the
long­
term
(
300
 
700
day)
exposure
of
rats
(
in­
house
strain
BDI
or
BDII)
to
naphthalene
in
food.
High­
purity
naphthalene
(
as
judged
by
absorption
spectra)
was
dissolved
in
oil,
mixed
in
the
diet,
and
administered
to
28
rats,
6
times
a
week.
Estimated
daily
doses
were
between
10
and
20
mg/
rat.
Assuming
that
the
body
weight
of
the
test
strain
was
similar
to
the
reference
weight
of
0.36
kg
for
a
male
Fischer
344
rat
(
U.
S.
EPA,
1988),
the
average
daily
dose
was
approximately
42
mg/
kg­
day.
Dosing
was
stopped
at
700
days
when
the
total
dose
for
each
animal
reached
10
grams.
Animals
were
then
observed
until
spontaneous
death,
usually
between
the
700th
and
800th
experimental
day.
Survival
of
the
exposed
animals
was
similar
to
that
of
the
control
group.
Autopsy
and
histological
results
did
not
identify
signs
of
adverse
noncancer
effects
in
any
organ
system,
including
the
eye.
This
study
is
not
considered
adequate
to
support
the
development
of
a
NOAEL
or
LOAEL
value
(
U.
S.
EPA,
1998a),
on
the
basis
of
the
administration
of
a
single
dose
level,
inadequate
reporting
of
results,
incomplete
histopathological
examinations,
lack
of
hematological
examinations,
and
examination
of
some
animals
at
time
points
up
to
300
days
following
termination
of
exposure.

Dermal
Exposure
No
studies
evaluating
chronic
naphthalene
exposure
by
the
dermal
route
were
identified.

Inhalation
Exposure
Adkins
et
al.
(
1986)
investigated
the
impacts
of
less­
than­
lifetime
inhalation
exposures
to
naphthalene
on
rats.
Groups
of
30
female
A/
J
strain
rats
were
exposed
to
0,
10,
or
30
ppm
naphthalene
vapors
for
6
hours
per
day,
5
days
per
week,
for
6
months.
All
animals
were
sacrificed
at
the
end
of
the
exposure
period
and
their
lungs
excised
and
examined
for
tumors.
No
adverse
noncancer
effects
on
the
lung
were
reported
(
U.
S.
EPA,
1998a).
Other
organs
were
not
examined
in
study.

A
chronic
inhalation
study
of
naphthalene
toxicity
was
conducted
in
B6C3F
1
mice
by
NTP
(
1992a).
Naphthalene
exposure
concentrations
in
air
were
0,
10
ppm,
or
30
ppm.
The
concentration
of
10
ppm
was
chosen
because
it
was
equal
to
the
ACGIH
TLV
®
for
naphthalene,
while
the
30
ppm
concentration
was
chosen
because
it
was
one­
half
the
air
saturation
concentration.
The
control
and
low­
exposure
groups
consisted
of
75
mice
of
each
sex,
while
the
high­
exposure
group
consisted
of
150
mice
of
each
sex.
Exposure
was
for
6
hours
per
day,
5
days
per
week,
for
2
years.
Comprehensive
histopathological
evaluations
were
performed
on
all
control
and
high­
exposure
mice,
and
on
all
low­
exposure
mice
that
died
or
were
sacrificed
during
the
first
21
months
of
exposure.
The
original
study
plan
called
for
50
animals
per
sex
to
be
exposed
for
2
years,
and
5
animals
per
sex
to
be
sacrificed
for
hematological
evaluations
at
14
7­
15
Naphthalene
 
February
2003
days,
3,
6,
12,
and
18
months.
However,
as
a
result
of
excessive
mortality
in
the
control
males,
only
the
14­
day
hematological
evaluation
was
conducted.
All
of
the
remaining
animals
were
incorporated
into
the
two­
year
study.

A
statistically
significant
decrease
in
survival
was
noted
in
the
male
control
group
(
Table
7­
3).
This
phenomenon
was
attributed
to
the
frequent
fighting
that
occurred
among
the
control
group
mice.
In
contrast,
the
exposed
groups
tended
to
huddle
together
during
exposure
periods,
and
fought
less.
Statistically
significant
increases
were
seen
in
several
types
of
noncancer
respiratory
tract
lesions
in
both
exposed
groups
(
Table
7­
3).
The
observed
responses
included
chronic
lung
inflammation,
chronic
nasal
irritation
with
hyperplasia
of
the
nasal
epithelium,
and
metaplasia
of
the
olfactory
epithelium.
The
authors
of
the
study
described
the
lung
lesions
as
a
chronic
inflammatory
response
with
granuloma.
These
lesions
consisted
of
"
focal
intra­
alveolar
mixed
inflammatory
cell
exudates
and
interstitial
fibrosis."
The
more
advanced
lesions
consisted
primarily
of
"
large
foamy
macrophages
sometimes
accompanied
by
giant
cells."

No
changes
in
hematological
parameters
were
seen
among
the
exposed
animals
at
14
days.
No
cataract
formation
was
observed
after
2
years
of
exposure.
Histopathological
examination
did
not
reveal
treatment­
related
effects
on
the
liver,
gastrointestinal
system,
reproductive
system,
brain,
or
any
other
organs.
The
results
of
this
study
have
been
interpreted
by
U.
S.
EPA
(
1998a)
to
support
a
chronic
LOAEL
for
nasal
and
respiratory
irritation
of
10
ppm.

Table
7­
3.
Survival
and
Incidence
of
Non­
neoplastic
Lesions
in
B6C3F
1
Mice
Exposed
to
Naphthalene
by
Inhalation
for
Their
Lifetime
Dose
(
ppm)
Survival
Chronic
Lung
Inflammation
Chronic
Nasal
Inflammation,
Hyperplasia
of
Nasal
Epithelium
Metaplasia
of
Olfactory
Epithelium
Male
Female
Male
Female
Male
Female
Male
Female
0
26/
70
59/
69
0/
70
3/
69
0/
70
0/
69
0/
70
1/
69
10
52/
69*
57/
65
21/
69*
13/
65*
66/
69*
65/
65*
67/
69*
65/
65*

30
118/
133*
102/
135
56/
135*
52/
135*
134/
135*
135/
135*
133/
135*
135/
135*

Source:
NTP
(
1992a)
*
Significantly
different
from
control
by
logistic
regression
(
p#
0.001).
7­
16
Naphthalene
 
February
2003
NTP
(
2000)
conducted
a
chronic
inhalation
study
in
F344/
N
rats.
Male
and
female
rats
(
49/
sex/
dose)
were
exposed
to
naphthalene
vapor
concentrations
of
0,
10,
30,
and
60
ppm
for
6
hours
per
day
plus
T
90
(
the
theoretical
time
to
achieve
90%
of
the
target
concentration
in
the
vapor
chamber:
12
minutes),
5
days
per
week
for
105
weeks.
Additional
groups
of
rats
were
similarly
exposed
for
up
to
18
months
for
evaluation
of
toxicokinetic
parameters.
Dose
calculations
were
based
upon
model
estimates
of
the
amount
of
naphthalene
inhaled
by
rats
at
the
exposure
concentrations
used
in
the
two­
year
study,
the
total
amount
of
naphthalene
metabolized
following
a
six­
hour
exposure
period
(
21%
to
31%
of
inhaled
naphthalene),
and
average
weights
of
125
grams
(
male
rats)
and
100
grams
(
female
rats).
Because
essentially
all
of
the
naphthalene
that
is
absorbed
into
the
bloodstream
is
metabolized,
the
total
amount
of
naphthalene
metabolized
was
assumed
to
represent
the
internalized
dose
to
rats
from
the
exposure
concentrations
used
in
this
two­
year
study.
The
estimated
daily
doses
determined
by
this
method
were
0,
3.6,
10.7,
20.1
mg/
kg­
day
for
males,
and
0,
3.9,
11.4,
and
20.6
mg/
kg­
day
for
females.

Rats
were
clinically
examined
twice
daily
and
findings
were
recorded
every
four
weeks
beginning
at
week
4
and
every
two
weeks
beginning
at
week
92.
Body
weights
were
recorded
at
study
initiation,
every
four
weeks
beginning
at
week
4,
and
every
two
weeks
beginning
at
week
92.
Full
necropsies
and
complete
histopathologies
were
performed
on
all
core
study
animals.

There
were
no
clinical
findings
related
to
naphthalene
exposure
from
the
two­
year
inhalation
study.
The
mean
body
weights
all
exposed
groups
of
male
and
female
rats
were
similar
to
those
observed
in
the
appropriate
control
chamber
group.
No
significant
difference
in
survival
rate
was
observed
for
any
exposed
group
when
compared
to
the
chamber
control.
The
mean
body
weights
of
female
rats
were
generally
similar
to
the
body
weights
of
the
control
group,
while
the
mean
body
weights
of
naphthalene­
exposed
male
rats
were
generally
less
than
the
chamber
control
for
all
exposed
groups.

Although
naphthalene
is
a
known
cataractogen
and
ocular
irritant
(
see
Section
7.3.2),
no
naphthalene­
related
cataractogenic
effects
or
ocular
abnormalities
were
observed
in
rats
during
this
study.
Treatment­
related
non­
neoplastic
lesions
were
observed
in
the
nose
and
lungs
of
male
and
female
rats.
The
incidence
and
average
severity
of
nasal
lesions
(
glands,
goblet
cells,
respiratory
epithelium
and
olfactory
epithelium)
are
summarized
in
Table
7­
4.
The
incidences
of
these
lesions
were
significantly
greater
than
those
in
the
chamber
controls
for
all
male
and
female
exposed
groups,
with
the
exception
of
squamous
metaplasia
of
glands
in
male
and
female
rats
in
the
10
ppm
exposure
groups
(
NTP,
2000).
In
general,
the
severities
of
olfactory
epithelial
and
glandular
lesions
increased
with
increasing
exposure
concentrations.

Two
noteworthy
type
of
lesions
occurred
in
the
lungs
of
exposed
rats:
alveolar
epithelial
hyperplasia
and
minimal
chronic
inflammation.
Female
rats
in
all
exposure
groups
had
increased
incidences
of
alveolar
epithelial
hyperplasia
when
compared
to
the
chamber
control
(
chamber
control:
4/
49,
10ppm:
11/
49,
30
ppm:
11/
49,
60
ppm:
9/
49).
This
effect
reached
statistical
significance
in
the
10
and
30
ppm
exposure
groups.
The
incidences
of
alveolar
epithelial
hyperplasia
in
male
rats
(
chamber
control:
23/
49,
10
ppm:
12/
49,
30
ppm:
9/
48,
60
7­
17
Naphthalene
 
February
2003
Table
7­
4.
Incidence
and
Severity
of
Nonneoplastic
Lesions
in
the
Noses
of
Rats
in
a
Two­
year
Naphthalene
Inhalation
Study
Lesion
Type
Incidence
and
Severity
(
average)
of
Lesions
Chamber
Control
10
ppm
30
ppm
60
ppm
MALE
Atypical
Hyperplasia
of
the
Olfactory
Epithelium
0/
49
48/
49*
(
2.1)
45/
48*
(
2.5)
46/
48*
(
3.0)

Atropy
of
the
Olfactory
Epithelium
3/
49
(
1.3)
49/
49*
(
2.1)
48/
48*
(
2.8)
47/
48*
(
3.5)

Chronic
Inflammation
of
the
Olfactory
Epithelium
0/
49
49/
49*
(
2.0)
48/
48*
(
2.2)
48/
48*
(
3.0)

Hyaline
Degeneration
of
the
Olfactory
Epithelium
3/
49
(
1.3)
45/
49*
(
1.7)
40/
48*
(
1.7)
38/
48*
(
1.5)

Hyperplasia
of
the
Respiratory
Epithelium
3/
49
(
1.0)
21/
49*
(
2.2)
29/
48*
(
2.0)
29/
48*
(
2.2)

Squamous
Metaplasia
of
the
Respiratory
Epithelium
0/
49
15/
49*
(
2.1)
23/
48*
(
2.0)
18/
48*
(
1.8)

Hyaline
Degeneration
of
the
Respiratory
Epithelium
0/
49
20/
49*
(
1.2)
19/
48*
(
1.4)
19/
48*
(
1.2)

Hyperplasia
of
the
Respiratory
Epithelium
Goblet
Cells
0/
49
25/
49*
(
1.3)
29/
48*
(
1.2)
26/
48*
(
1.2)

Hyperplasia
of
Glands
1/
49
(
1.0)
49/
49*
(
2.2)
48/
48*
(
2.9)
48/
48*
(
3.5)

Squamous
Metaplasia
of
Glands
0/
49
3/
49
(
3.0)
14/
48*
(
2.1)
26/
48*
(
2.5)

FEMALE
Atypical
Hyperplasia
of
the
Olfactory
Epithelium
0/
49
48/
49*
(
2.0)
48/
49*
(
2.4)
43/
49*
(
2.9)

Atropy
of
the
Olfactory
Epithelium
0/
49
49/
49*
(
1.9)
49/
49*
(
2.7)
47/
49*
(
3.2)

Chronic
Inflammation
of
the
Olfactory
Epithelium
0/
49
47/
49*
(
1.9)
47/
49*
(
2.6)
45/
49*
(
3.4)

Hyaline
Degeneration
of
the
Olfactory
Epithelium
13/
49
(
1.1)
46/
49*
(
1.8)
49/
49*
(
2.1)
45/
49*
(
2.1)

Hyperplasia
of
the
Respiratory
Epithelium
0/
49
18/
49*
(
1.6)
22/
49*
(
1.9)
23/
49*
(
1.7)

Squamous
Metaplasia
of
the
Respiratory
Epithelium
0/
49
21/
49*
(
1.6)
17/
49*
(
1.5)
15/
49*
(
1.8)

Hyaline
Degeneration
of
the
Respiratory
Epithelium
8/
49
(
1.0)
33/
49*
(
1.2)
34/
49*
(
1.4)
28/
49*
(
1.2)

Hyperplasia
of
the
Respiratory
Epithelium
Goblet
Cells
0/
49
16/
49*
(
1.0)
29/
49*
(
1.2)
20/
49*
(
1.0)

Hyperplasia
of
Glands
0/
49
48/
49*
(
1.9)
48/
49*
(
3.1)
42/
49*
(
3.3)

Squamous
Metaplasia
of
Glands
0/
49
2/
49
(
2.0)
20/
49*
(
2.5)
20/
49*
(
2.8)

Source:
Adapted
from
NTP
Technical
Report
on
the
Toxicology
and
Carcinogenesis
Studies
of
Naphthalene
in
Rats
(
Inhalation
Studies),
Table
6
(
NTP,
2000).
*
Significantly
different
(
P<
0.01)
from
chamber
control
using
the
Poly­
3
test
7­
18
Naphthalene
 
February
2003
ppm:
16/
49)
were
significantly
decreased
in
the
10
and
30
ppm
exposure
groups.
The
incidences
of
minimal
chronic
inflammation
of
the
lung
were
increased
in
males
and
females
exposed
to
naphthalene.
This
lesion
is
characterized
by
small
focal
interstitial
and
intra­
alveolar
collections
of
macrophages,
neutrophils,
and
lymphocytes
and
minimal
interstitial
fibrosis.
As
noted
by
the
NTP
study
authors,
foci
of
minimal
inflammation
are
common
in
chamber
control
rats
(
as
evident
in
this
study).
Therefore,
this
change
could
not
be
confidently
related
to
naphthalene
exposure.

The
study
conducted
by
NTP
(
2000)
identified
an
estimated
inhalation
LOAEL
of
3.6
mg/
kg­
day
based
on
the
occurrence
of
nasal
lesions
in
male
rats
in
the
10
ppm
exposure
group.
A
NOAEL
was
not
identified
in
this
study.
The
10
ppm
concentration
associated
with
the
LOAEL
corresponds
to
the
threshold
limit
value
for
naphthalene
(
ACGIH,
2000).

7.2.7
Carcinogenicity
Oral
Exposure
One
study
was
available
that
evaluated
the
carcinogenic
potential
of
naphthalene
following
oral
exposure
in
experimental
animals.
Schmähl
(
1955)
administered
10
to
20
mg
naphthalene/
rat
(
dissolved
in
oil)
in
the
diet
for
6
days/
week
to
a
group
of
28
rats.
Compound
administration
was
continued
until
a
total
dose
of
10
g/
rat
was
achieved.
A
concurrent
control
group
was
reported,
but
the
number
of
animals
was
not
specified.
Administration
of
the
diet
containing
naphthalene
was
terminated
on
the
700th
day
of
the
study,
with
animals
observed
until
spontaneous
death
(
approximately
700
 
800
days
of
age).
An
average
daily
dose
of
42
mg/
kg
body
weight/
day
was
estimated
by
U.
S.
EPA
(
1998a)
for
this
study,
assuming
that
animals
ingested
15
mg
naphthalene/
day
and
had
an
average
default
body
weight
of
0.36
kg
(
U.
S.
EPA,
1988).
Gross
necropsies
were
conducted
on
all
animals,
with
histopathological
examinations
conducted
only
on
those
organs
that
appeared
unusual.
Reported
results
were
limited
to
a
statement
that
indicated
that
no
toxic
effects
were
observed,
including
eye
damage
or
tumors.
This
study
has
inadequacies
in
study
design,
implementation,
and
reporting
that
limit
the
conclusions
that
can
be
drawn
regarding
the
carcinogenicity
of
naphthalene.
These
limitations
include
administration
of
only
one
dose
level,
inadequate
reporting
of
results,
incomplete
histopathological
examinations,
lack
of
hematological
examinations,
and
examination
of
some
animals
at
time
points
up
to
300
days
following
termination
of
exposure.
Based
on
the
absence
of
toxicity,
the
dose
tested
is
not
considered
an
adequately
high
dose
for
detection
of
carcinogenic
effects
(
U.
S.
EPA,
1998a).

Inhalation
Exposure
Three
studies
were
identified
which
evaluated
the
carcinogenic
potential
of
inhalation
exposure
to
naphthalene
in
animals.
Adkins
et
al.
(
1986)
exposed
groups
of
30
female
A/
J
mice
to
0,
10,
or
30
ppm
naphthalene
via
inhalation
for
6
hours/
day,
5
days/
week
for
6
months.
An
additional
group
of
20
mice
served
as
a
positive
control,
and
animals
in
this
group
were
administered
a
single
intraperitoneal
injection
of
1g
urethane/
kg.
At
termination
of
exposure,
animals
were
sacrificed
and
lungs
excised
and
examined
for
tumors,
with
tumors
examined
histologically.
Lung
tumors
were
observed
in
all
positive
control
mice,
with
an
average
of
28.9
7­
19
Naphthalene
 
February
2003
tumors/
animal.
An
increase
in
the
number
of
mice
with
alveolar
adenomas
was
observed
in
the
naphthalene­
exposed
groups
(
6,
10,
and
11
in
the
0,
10,
and
30
ppm
groups,
respectively).
The
increases
were
not
statistically
significant
when
compared
with
the
incidence
of
alveolar
adenomas
observed
in
the
concurrent
control
group.
Statistically
significant
increases
in
the
number
of
adenomas
per
tumor­
bearing
mouse
were
reported
in
the
exposed
mice;
however,
there
was
no
increase
in
response
with
increasing
dose.
The
average
number
of
tumors
per
tumor­
bearing
animal
(
standard
deviation
in
parentheses)
was
1.00
(
0.00),
1.25
(
0.07),
and
1.25
(
0.07)
for
the
0,
10,
and
30
ppm
groups,
respectively.
This
study
is
limited
for
use
in
evaluating
the
carcinogenic
potential
in
humans
following
lifetime
exposure
due
to
the
less­
than­
lifetime
exposure
and
observation
period
and
due
to
the
limited
histopathological
examinations
(
U.
S.
EPA,
1998a).

NTP
(
1992a)
conducted
a
two­
year
inhalation
exposure
study
in
B6C3F
1
mice.
Groups
of
male
and
female
mice
were
housed
5
to
a
cage
and
were
exposed
(
whole
body)
to
atmospheres
containing
0
(
75
mice/
sex),
10
(
75
mice/
sex),
or
30
ppm
(
150
mice/
sex)
naphthalene
(
99%
pure)
for
6
hours/
day,
5
days/
week
for
2
years.
The
high­
dose
group
contained
twice
as
many
animals
as
the
low­
dose
group
to
ensure
that
a
sufficient
number
of
animals
lived
until
termination
of
the
study,
and
because
of
the
insufficient
information
on
the
long­
term
toxicity
of
naphthalene.
Comprehensive
histopathological
examinations
were
performed
on
all
control
and
high­
dose
mice,
and
on
low­
dose
mice
that
died
or
were
sacrificed
before
21
months
of
exposure.
In
the
remaining
low­
dose
animals
that
survived
longer
than
21
months
of
exposure,
only
the
nasal
cavity
and
lung
were
histologically
examined.
Initially,
50
animals/
sex/
dose
group
were
designated
for
the
two­
year
study,
with
5
animals/
sex/
dose
group
designated
for
an
interim
hematology
examination
at
14
days,
and
3,
6,
12,
and
18
months
of
the
study.
However,
because
of
high
mortality
in
the
male
control
group
(
discussed
below),
only
the
14­
day
hematology
examination
was
conducted,
with
the
remaining
animals
incorporated
into
the
two­
year
study.

In
the
male
control
group,
statistically
significant
decreases
in
survival
were
observed
due
to
wound
trauma
and
secondary
lesions
resulting
from
increased
fighting
in
this
group,
compared
to
the
exposed
groups.
In
the
exposed
groups,
male
mice
tended
to
huddle
in
the
cage
corners
during
exposure.
At
study
termination,
survival
was
37%
(
26/
70),
75%
(
52/
69),
and
89%
(
118/
133)
for
the
male
mice
exposed
to
0,
10,
or
30
ppm,
respectively.
Survival
percentages
in
exposed
female
mice
were
similar
to
that
of
the
control
group.
Survival
percentages
were
86%
(
59/
69),
88%
(
57/
65),
and
76%
(
102/
135)
for
female
mice
exposed
to
0,
10,
or
30
ppm,
respectively.
The
occurrence
of
nonneoplastic
lesions
observed
in
this
study
is
summarized
in
Table
7­
3
(
Section
7.2.6
above).

Apparent
dose­
related
increases
were
noted
for
the
incidence
of
alveolar/
bronchiolar
adenomas
in
female
and
male
mice.
In
females,
the
incidence
of
this
tumor
type
was
5/
69,
2/
65
and
28/
135
at
the
0,
10
and
30
ppm
concentrations,
respectively.
An
additional
female
mouse
in
the
30
ppm
group
displayed
an
alveolar/
bronchiolar
carcinoma.
The
incidence
of
alveolar/
bronchiolar
adenomas
reached
statistical
significance
at
the
30
ppm
concentration
and
the
occurrence
of
this
tumor
type
was
considered
compound­
related.
In
male
mice,
the
incidence
of
alveolar/
bronchiolar
adenomas
was
7/
70,
15/
69,
and
27/
135
in
the
control,
10,
and
30
ppm
groups,
respectively.
However,
when
these
incidence
data
were
analyzed
using
a
logistics
7­
20
Naphthalene
 
February
2003
regression
test
(
a
statistical
test
that
adjusts
for
intercurrent
mortality),
the
incidence
of
tumors
in
the
10
and
30
ppm
groups
did
not
differ
significantly
from
the
control.

Hemangiosarcomas
were
also
reported
in
5/
135
female
mice
in
the
30
ppm
group.
This
tumor
type
was
not
observed
in
male
mice
or
in
control
or
10
ppm
female
mice.
However,
this
occurrence
of
hemangiosarcomas
did
not
reach
statistical
significance,
and
the
incidence
of
this
tumor
type
was
within
the
range
of
historical
incidence
(
17/
467)
observed
in
control
animals
in
multiple
NTP
inhalation
studies
(
NTP,
1992a).

NTP
(
2000)
exposed
F344/
N
rats
(
49/
sex/
dose)
to
naphthalene
vapor
concentrations
of
0,
10,
30,
and
60
ppm
for
6
hours
plus
T
90
(
the
theoretical
time
to
achieve
90%
of
the
target
concentration
in
the
vapor
chamber:
12
minutes)
per
day,
5
days
a
week
for
105
weeks.
The
10
ppm
concentration
corresponded
to
the
threshold
limit
value
for
naphthalene
(
ACGIH,
2000).
Naphthalene
concentrations
were
monitored
by
an
on­
line
gas
chromatograph
and
average
chamber
concentrations
were
maintained
within
1%
of
the
target
concentrations
throughout
the
study.
A
physiologically­
based
toxicokinetic
model
was
used
to
estimate
the
daily
doses
of
naphthalene.
Data
for
modeling
were
obtained
from
additional
groups
of
male
and
female
rats
exposed
to
10,
30,
or
60
ppm
for
up
to
18
months.
Dose
calculations
were
based
upon
model
estimates
of
the
amount
of
naphthalene
inhaled
by
rats
at
the
exposure
concentrations
used
in
the
two­
year
study,
the
total
amount
of
naphthalene
metabolized
following
a
six­
hour
exposure
period
(
21%
to
31%
of
inhaled
naphthalene),
and
average
body
weights
of
125
grams
(
male
rats)
and
100
grams
(
female
rats).
Because
essentially
all
of
the
naphthalene
absorbed
into
the
bloodstream
is
metabolized,
the
total
amount
of
naphthalene
metabolized
was
assumed
to
represent
the
internalized
dose
to
rats
from
the
exposure
concentrations
used
in
this
study.
The
estimated
daily
doses
determined
by
this
method
were
0,
3.6,
10.7,
and
20.1
mg/
kg­
day
for
male
rats,
and
0,
3.9,
11.4,
and
20.6
mg/
kg­
day
for
female
rats.

The
study
animals
were
clinically
examined
twice
daily.
Body
weights
were
recorded
on
day
1,
every
4
weeks
beginning
at
week
4,
and
every
2
weeks
beginning
at
week
92.
Clinical
findings
were
recorded
every
4
weeks
beginning
at
week
4
and
every
2
weeks
beginning
at
week
92.
Surviving
rats
were
sacrificed
at
the
end
of
the
study
and
full
necropsies
and
complete
histopathological
examinations
were
performed
on
all
core
study
animals.

There
were
no
treatment­
related
clinical
findings.
All
exposed
groups
of
male
and
female
rats
had
survival
rates
similar
to
those
of
the
chamber
controls.
Mean
body
weights
of
females
were
generally
similar
to
the
body
weights
of
the
control
group.
The
mean
body
weights
of
male
rats
in
all
exposure
groups
were
generally
less
than
those
of
the
control
group
for
most
of
the
study.
The
mean
body
weights
for
the
10,
30,
and
60
ppm
exposure
groups
of
male
rats
at
4
and
104
weeks
were
9%
and
5%,
9%
and
5%,
and
11%
and
6%
lower
than
those
of
chamber
controls,
respectively.

Neoplasms
were
observed
in
the
nose
of
male
and
female
rats
in
all
exposure
groups
(
Table
7­
5).
However,
neoplasm
incidence
in
the
lungs
was
not
affected
by
naphthalene
exposure
of
male
or
female
rats
in
any
exposure
group
(
respective
tumor
incidences
for
the
chamber
control,
10
ppm,
30
ppm
and
60
ppm
exposure
groups
were
2/
49,
3/
49,
1/
48,
and
0/
49
for
males,
and
1/
49,
0/
49,
0/
49,
and
0/
49
for
females).
The
observed
nasal
neoplasms
were
7­
21
Naphthalene
 
February
2003
identified
as
neuroblastomas
of
the
olfactory
epithelium
and
adenomas
of
the
respiratory
epithelium.
Neuroblastomas
of
the
olfactory
epithelium
occurred
with
positive
trends
in
both
male
and
female
exposure
groups.
The
incidence
of
neuroblastomas
for
female
rats
in
the
control,
low­,
mid­
and
high­
exposure
groups
were
0/
49
(
0%),
2/
49
(
4%),
3/
49
(
6%),
12/
49
(
24%),
respectively.
Tumor
incidence
for
female
rats
in
the
60
ppm
exposure
group
was
significantly
greater
(
p<
0.001)
than
control.
Incidences
of
neuroblastomas
in
the
male
rat
control,
low­,
mid­
and
high­
exposure
groups
were
0/
49
(
0%),
0/
49
(
0%),
4/
48
(
8%),
and
3/
48
(
6%),
respectively.
Neuroblastomas
of
the
olfactory
epithelium
have
not
been
historically
observed
in
chamber
control
rats
in
other
NTP
two­
year
inhalation
studies.
Positive
trends
in
the
incidence
of
respiratory
epithelium
adenomas
in
the
nose
were
also
observed
for
both
male
and
female
exposure
groups.
Tumor
incidences
were
significantly
increased
(
p#
0.01)
in
all
male
rat
exposure
groups
relative
to
the
control
group.
Male
rats
in
the
control,
low­,
mid­,
and
highexposure
groups
had
respiratory
epithelium
adenoma
incidences
of
0/
49
(
0%),
6/
49
(
12%),
8/
48
(
17%),
and
15/
48
(
31%),
respectively.
Female
rats
exposed
to
the
same
concentrations
had
incidences
of
respiratory
epithelium
adenomas
of
0/
49
(
0%),
0/
49
(
0%),
4/
49
(
8%),
and
2/
49
(
4%),
respectively.
The
increased
tumor
incidence
observed
in
female
rats
in
the
30
and
60
ppm
exposure
groups
was
not
statistically
significant.
No
historical
incidence
(
0/
299)
of
respiratory
epithelium
adenomas
has
been
observed
in
chamber
control
rats
utilized
in
previous
NTP
studies
using
the
same
diet
as
the
current
study.

Table
7­
5.
Incidence
of
Neoplasms
in
Male
and
Female
F344/
N
Rats
in
a
Two­
year
Naphthalene
Inhalation
Exposure
Study
Tumor
Type
Incidences
of
Neoplasms
Chamber
Control
10ppm
30ppm
60ppm
MALE
Adenoma
of
the
Respiratory
Epithelium
0/
49
(
0%)
6/
49*
(
12%)
8/
48*
(
17%)
15/
48*
(
31%)

Neuroblastoma
of
the
Olfactory
Epithelium
0/
49
(
0%)
0/
49
(
0%)
4/
48
(
8%)
3/
48
(
6%)

Alveolar/
bronchiolar
Adenoma
or
Carcinoma
2/
49
(
4%)
3/
49
(
6%)
1/
48
(
2%)
0/
49
(
0%)

FEMALE
Adenoma
of
the
Respiratory
Epithelium
0/
49
(
0%)
0/
49
(
0%)
4/
49
(
8%)
2/
49
(
4%)

Neuroblastoma
of
the
Olfactory
Epithelium
0/
49
(
0%)
2/
49
(
4%)
3/
49
(
6%)
12/
49*
(
24%)

Alveolar/
bronchiolar
Adenoma
1/
49
(
2%)
0/
49
(
0%)
0/
49
(
0%)
0/
49
(
0%)

*
Significantly
different
from
chamber
control
(
P<
0.01)
from
chamber
control
using
the
Poly­
3
test
Source:
NTP
(
2000)
7­
22
Naphthalene
 
February
2003
Based
upon
the
absence
of
neuroblastomas
and
adenomas
in
the
chamber
control
rats
of
this
two­
year
study
and
historically
in
NTP
two­
year
inhalation
studies,
the
increased
incidences
of
these
neoplasms
are
considered
to
be
related
to
naphthalene
exposure.
The
increased
incidences
of
respiratory
epithelial
adenoma
and
olfactory
epithelial
neuroblastoma
of
the
nose
observed
in
this
study
are
considered
by
the
study
authors
to
be
clear
evidence
of
carcinogenic
activity
of
naphthalene
in
male
and
female
F344/
N
rats.

Other
Routes
of
Exposure
In
a
study
conducted
by
Schmähl
(
1955),
groups
of
10
rats
were
given
subcutaneous
or
intraperitoneal
injections
of
naphthalene
in
oil
(
20
mg/
rat/
injection)
once
a
week,
starting
at
100
days
of
age
and
continuing
for
40
weeks,
for
a
total
dose
of
820
mg/
rat.
Rats
were
observed
following
the
administration
of
naphthalene
until
natural
death
(
700
 
900
days).
Necropsies
were
performed
on
animals
at
death,
and
organs
that
appeared
unusual
were
examined
histologically.
Results
were
limited
to
the
statements
indicating
that
no
toxic
effects
or
tumors
were
observed
in
either
treatment
group
(
U.
S.
EPA,
1998a).

Boyland
et
al.
(
1964)
implanted
naphthalene
into
the
bladders
of
stock
Chester
Beatty
mice
to
determine
the
suitability
of
naphthalene
as
a
potential
vehicle
of
carcinogenicity
testing.
Thirty
animals
received
the
naphthalene
implants,
with
examinations
conducted
30
weeks
following
implantation.
Twenty­
three
of
the
30
animals
survived
the
implantation
period.
One
mouse
(
1/
23
or
4%)
implanted
with
naphthalene
developed
a
bladder
carcinoma.
No
adenomas
or
papillomas
were
reported
in
the
naphthalene­
implanted
group.
When
compared
to
the
paraffin
wax
or
cholesterol­
implanted
groups,
tumor
incidence
in
the
naphthalene­
implanted
group
was
as
low
as
the
incidence
in
the
paraffin­
implanted
groups
(
2
 
4%),
and
lower
than
in
groups
implanted
with
cholesterol
(
12%).
The
limitations
of
this
study
that
make
it
inadequate
for
assessing
the
carcinogenic
potential
of
naphthalene
include
the
short
exposure
and
observation
periods
and
the
lack
of
untreated
controls
(
U.
S.
EPA,
1998a).

La
Voie
et
al.
(
1988)
administered
naphthalene
dissolved
in
dimethyl
sulfoxide
by
intraperitoneal
injection
to
a
group
of
49
male
and
female
newborn
CD­
1
mice
on
days
1,
8,
and
15
of
life.
The
doses
at
each
injection
time
were
0.25,
0.5,
and
1.0
:
mol,
for
a
total
dose
of
1.75
:
mol
naphthalene.
A
separate
group
of
46
pups
served
as
a
vehicle
control
group
and
received
dimethyl
sulfoxide
alone.
Mice
were
maintained
(
10
mice/
cage)
until
moribund,
or
until
study
termination
at
52
weeks.
Histopathological
examinations
were
conducted
on
all
gross
lesions
and
on
liver
sections.
Incidences
of
liver
tumors
reported
in
the
mice
that
lived
at
least
6
months
were
0/
16
and
2/
31
for
exposed
females
and
males,
and
0/
21
and
4/
21
for
vehicle
control
females
and
males.
This
study
is
limited
for
assessing
the
carcinogenic
potential
of
naphthalene
by
the
short
exposure
(
2
weeks)
and
observation
(
52
weeks)
periods,
and
because
complete
histopathological
examinations
were
not
conducted
(
U.
S.
EPA,
1998a).
7­
23
Naphthalene
 
February
2003
7.3
Other
Key
Data
7.3.1
Mutagenicity
and
Genotoxicity
Numerous
in
vitro
and
in
vivo
assays
have
been
conducted
to
evaluate
the
potential
genotoxicity
of
naphthalene
and
its
metabolites.
The
results
of
most
studies
were
negative,
suggesting
that
the
genotoxic
potential
of
naphthalene
and
its
metabolites
is
weak
(
U.
S.
EPA,
1998a),
and
is
probably
not
an
area
of
concern
for
exposure
to
naphthalene
(
ATSDR,
1995).
The
results
of
naphthalene
genotoxicity
studies
are
summarized
below.

Negative
Results
in
vitro
Naphthalene
was
not
mutagenic
in
several
bacterial/
microsomal
assay
systems,
including
Salmonella
tester
strains
TA
97,
98,
100,
199,
667,
1535,
and
1537,
in
the
presence
or
absence
of
Aroclor­
1254­
induced
hamster
or
rat
liver
microsomes
(
McCann
et
al.,
1975;
Kaden
et
al.,
1979;
Florin
et
al.,
1980;
Gatehouse,
1980;
Seixas
et
al.,
1982;
Connor
et
al.,
1985;
Godek
et
al.,
1985;
Sakai
et
al.,
1985;
Mortelmans
et
al.,
1986;
Nakamura
et
al.,
1987;
Narbonne
et
al.,
1987;
Bos
et
al.,
1988;
NTP,
1992a,
2000).
There
was
no
evidence
of
naphthalene­
induced
DNA
damage
in
Escherichia
coli
WP2/
WP100
(
Mamber
et
al.,
1983),
PQ37
(
Mersch­
Sundermann
et
al.,
1992),
GY5027/
GY4015
(
Mamber
et
al.,
1984),
or
Salmonella
typhimurium
TA
1535/
p5K
1002
(
Nakamura
et
al.,
1987).

The
frequency
of
sister
chromatid
exchanges
(
SCE)
was
not
increased
upon
incubation
of
human
peripheral
lymphocytes
in
a
medium
containing
naphthalene
or
in
a
human
liver
metabolic
activation
system,
when
compared
with
control
frequencies
(
Tingle
et
al.,
1993;
Wilson
et
al.,
1995).
Naphthalene
did
not
induce
unscheduled
DNA
synthesis
in
cultured
rat
hepatocytes
(
Barfknecht
et
al.,
1985).
Naphthalene
did
not
induce
transformations
of
Fischer
rat
embryo
cells
(
Freeman
et
al.,
1973)
or
Swiss
mouse
embryo
cells
(
Rhim
et
al.,
1974)
in
vitro.
Sina
et
al.
(
1983)
reported
that
naphthalene
did
not
induce
single­
strand
DNA
breaks
in
cultured
rat
hepatocytes,
as
detected
by
alkaline
elution
(
U.
S.
EPA,
1998a).

Negative
Results
in
vivo
Several
experiments
have
investigated
the
genotoxicity
of
naphthalene
in
vivo.
Naphthalene
did
not
increase
the
number
of
micronuclei
in
bone
marrow
cells
of
mice
following
intraperitoneal
injection
of
a
single
dose
of
250
mg
naphthalene/
kg
body
weight
(
Sorg
et
al.,
1985).
Harper
et
al.
(
1984)
reported
no
increase
in
the
frequency
of
micronucleated
erythrocytes
in
mice
exposed
to
single
oral
doses
of
naphthalene
as
high
as
500
mg/
kg
when
compared
to
frequencies
observed
in
control
mice.

Tsuda
et
al.
(
1980)
reported
no
evidence
of
the
neoplastic
transformation
of
liver
cells
in
a
group
of
10
young
adult
Fischer
344
rats
administered
single
gavage
doses
of
100
mg
naphthalene/
kg
in
corn
oil,
when
compared
with
the
results
from
a
group
of
10
vehicle
control
animals
(
U.
S.
EPA,
1998a).
Rats
were
administered
the
doses
of
naphthalene
or
corn
oil
following
partial
hepatectomy,
but
prior
to
dietary
treatment
with
2­
acetylaminofluorene
and
carbon
tetrachloride.
Gamma­
glutamyl
transpeptidase
foci
were
used
as
an
indicator
of
7­
24
Naphthalene
 
February
2003
neoplastic
transformation.
These
foci
were
observed
in
both
exposed
and
control
animals
following
the
dietary
treatments.
In
contrast
to
the
results
observed
with
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
(
U.
S.
EPA,
1998a).

Positive
results
Four
studies
were
available
that
reported
a
positive
genotoxic
response
(
ATSDR,
1995;
U.
S.
EPA,
1998a).
NTP
(
1992a,
2000)
reported
that
naphthalene
caused
sister
chromatid
exchanges
(
concentration
range
of
27
 
90
:
g/
mL)
in
Chinese
Hamster
ovary
cells
when
assayed
in
the
presence
or
absence
of
metabolic
activation
with
rat
liver
S9
fraction.
Chromosomal
aberrations
were
observed
(
concentration
range
of
30
 
67.5
:
g/
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).
Gollahon
et
al.
(
1990)
observed
a
10­
fold
increase
in
chromosomal
damage
in
mouse
embryos
cultured
in
a
medium
containing
0.16
mM
naphthalene,
when
compared
with
untreated
culture
controls.
This
response
was
amplified
by
the
inclusion
of
a
hepatic
metabolic
activation
system
in
the
medium.

Genotoxicity
Studies
of
Naphthalene
Metabolites
Studies
have
been
conducted
with
several
known
or
possible
metabolites
of
naphthalene,
including
1­
naphthol,
2­
naphthol,
naphthoquinone,
and
naphthalene­
1,2­
dione
(
U.
S.
EPA,
1998a).
The
metabolites
1­
naphthol
and
2­
naphthol
were
not
mutagenic
in
Salmonella
typhimurium
with
or
without
metabolic
activation
(
McCann
et
al.,
1975;
Florin
et
al.,
1980;
Narbonne
et
al.,
1987).
The
metabolite
1­
naphthol
gave
negative
results
in
several
other
genotoxicity
assays,
including
tests
for
sex­
linked
recessive
lethal
mutations
in
Drosophila
melanogaster
(
Gocke
et
al.,
1981),
tests
for
mutations
in
mouse
L5178Y
cells
(
Amacher
and
Turner,
1982),
tests
for
unscheduled
DNA
synthesis
in
cultured
rat
hepatocytes
(
Probst
and
Hill,
1980),
and
acute
in
vivo
tests
for
the
induction
of
micronuclei
in
the
bone
marrow
cells
of
mice
(
Gocke
et
al.,
1981)
and
rats
(
Hossack
and
Richardson,
1977).
Naphthoquinone
was
not
mutagenic
in
several
strains
of
Salmonella
typhimurium,
with
or
without
metabolic
activation
(
Sakai
et
al.,
1985).
Flowers­
Geary
et
al.
(
1994)
reported
that
naphthalene­
1,2­
dione
was
mutagenic
in
strains
of
Salmonella
typhimurium
without
metabolic
activation
(
U.
S.
EPA,
1998a).

7.3.2
Ocular
Toxicity
The
ocular
toxicity
of
naphthalene
has
been
studied
extensively,
and
the
association
between
naphthalene
exposure
and
the
development
of
cataracts
in
animals
is
well­
established.
Table
7­
6
summarizes
the
results
of
representative
ocular
toxicity
studies
of
naphthalene
in
various
animal
species.
7­
25
Naphthalene
 
February
2003
Table
7­
6.
Summary
of
Studies
of
Naphthalene
Ocular
Toxicity
in
Animals
Study
Species
(
Strain)
Exposure
Route
Dose
mg/
kg­
day
Duration
NOAEL
LOAEL
Result
Van
Heyningen
and
Pirie
(
1976)
Rabbits
(
Dutch,
albino)
Gavage
1,000
3
 
28
consecutive
daily
doses
­­
1,000
Cataracts
in
10/
16
Dutch
and
11/
12
albino
animals)

Srivastava
and
Nath
(
1969)
Rabbits
(
NS*)
Gavage
2,000
5
days
­­
2,000
Cataracts
in
8/
8
animals
Rossa
and
Pau
(
1988)
Rabbits
(
Chinchilla
Bastard)
Oral
1,000
Single
dose
­­
1,000
Cataracts
Rabbit
(
New
Zealand)
Oral
1,000
4
biweekly
doses
­­
1,000
Cataracts
Orzalesi
et
al.
(
1994)
Rabbit
(
pigmented)
Gavage
500
5
weeks
­­
500
Cataracts,
retinal
degeneration,
subretinal
neovascularization
Fitzhugh
and
Buschke
(
1949)
Weanling
rats
(
NS)
Diet
2,000
(
estimated)
2
months
(
approx.)
­­
2000
Mild
cataracts
Koch
et
al.
(
1976)
Rats
(
Sprague­
Dawley,
Wistar,
and
others)
Gavage
1,000
Total
duration
unknowna;
cataracts
developed
within
16­
28
days.
Doses
administered
on
alternate
days
­­
1,000
Cataracts
Rao
and
Pandya
(
1981)
Rat
(
NS)
Gavage
1,000
10
days
1,000
­­
No
effects
observed
Yamauchi
et
al.
(
1986)
Rat
(
Wistar)
Oral
1,000
18
days
­­
1,000
Cataracts
Rathbun
et
al.
(
1990)
Rat
(
Black­
Hooded)
Gavage
5,000
79
days
­­
5,000
Lens
opacities
Tao
et
al.
(
1991a,
b)
Rat
(
Brown
Norway)
Gavage
700
102
days
­­
700
Lens
opacities
Kojima
(
1992)
Rat
(
Brown
Norway)
Gavage
500
(
1,000
mg/
kg­
day
every
second
day)
4
weeks
­­
500
Lens
opacities
Table
7­
6
(
continued)

Study
Species
(
Strain)
Exposure
Route
Dose
mg/
kg­
day
Duration
NOAEL
LOAEL
Result
7­
26
Naphthalene
 
February
2003
Xu
et
al.
(
1992a)
Rat
(
Long­
Evans,
Brown
Norway,
Sprague­
Dawley,
Wistar,
Lewis)
Gavage
1,000
28
days
­­
1,000
Cataracts
Ikemoto
and
Iwata
(
1978)
Rabbits
(
Albino)
Oral
1,000
2
days
­
1,000
Cataracts
Murano
et
al.
(
1993)
Rat
(
Sprague­
Dawley,
Brown
Norway)
Gavage
1,000
6
weeks
(
administered
every
other
day)
­­
1000
Cataracts
Schmähl
(
1955)
Rat
(
in­
house
strain
BDI,
BDIII)
Food
41
2
years
Study
not
adequate
to
support
LOAEL
OR
NOAEL
­­
No
cataracts
observed
BCL
(
1980a)
Rat
(
Fischer)
Gavage
0
25
50
100
200
400
13
weeks
5
days/
week
400
­­
No
cataracts
observed
BCL
(
1980b)
Mouse
(
B6C3F
1)
Gavage
0
12.5
25
50
100
200
90
days
5
days/
week
200
­­
No
cataracts
observed
Shopp
et
al.
(
1984)
Mouse
(
CD­
1)
Gavage
0
53
133
90
days
133
­­
No
cataracts
observed
Shopp
et
al.
(
1984)
Mouse
(
CD­
1)
Gavage
corn
oil
0
27
53
267
14
days
267
­­
No
cataracts
observed
NTP
(
1992a)
Mouse
B6CF1
Inhalation
0
ppm*
10ppm
30
ppm
2
years
(
6
hr/
day;
5
days/
wk)
30ppm*
­­
No
cataract
formation
observed
NTP
(
2000)
Rat
(
F344/
N)
Inhalation
0
3.6
 
3.9
10.7
 
11.4
20.1
 
20.6
2
years
20.1
 
20.6
­­
No
cataractogenic
effects
or
ocular
abnormalities
observed.
Table
7­
6
(
continued)

Study
Species
(
Strain)
Exposure
Route
Dose
mg/
kg­
day
Duration
NOAEL
LOAEL
Result
7­
27
Naphthalene
 
February
2003
Shichi
et
al.
(
1980)
Mouse
(
C57BL/
6N,
DBA/
2N)
Diet
0
60
120
(
injected
twice
weekly
with
cytochrome
P­
450
inducer)
60
days
C57BL/
6
N
mice:
­­

DBA/
2N
mice:
120
C57BL/
6N
mice:
60
DBA/
2
N
mice:
­­
Cataracts
observed
in
1/
15
C57BL/
6N
mice
at
each
dose.

No
cataracts
observed
in
DBA/
2N
mice)

Holmen
et
al.
(
1999)
Rat
(
Brown
Norway)
Gavage
0
100
500
1,000
1,500
10
weeks
2
doses/
week
100
adjusted:
29
500
adjusted
:
143
First
signs
of
ocular
changes
occurred
within
2.5
weeks
after
start
of
treatment.
All
treated
with
doses
of
500
mg/
kg
or
more
developed
cataracts.

*
NS
=
Not
specified
a
Information
obtained
from
secondary
source
in
which
the
indicated
data
were
not
provided
Cataract
formation
has
been
documented
primarily
in
rabbits
and
rats.
Almost
all
studies
have
evaluated
oral
exposures.
In
rabbits,
Van
Heyningen
and
Pirie
(
1976)
noted
the
formation
of
cataracts
as
soon
as
two
days
after
initiation
of
daily
administration
of
1,000
mg/
kg
by
oil
gavage.
The
incidence
of
cataract
formation
was
higher
in
albino
rabbits
(
11/
12)
than
in
the
pigmented
(
Dutch)
strain.
Srivastava
and
Nath
(
1969)
reported
cataracts
in
8/
8
rabbits
(
strain
not
stated)
treated
with
naphthalene
doses
of
2,000
mg/
kg­
day
for
5
days
via
gavage.
Rossa
and
Pau
(
1988)
found
that
cataracts
appeared
in
two
different
strains
of
rabbits
after
administering
between
one
and
four
1,000
mg/
kg
oral
doses
of
naphthalene
(
U.
S.
EPA
1998a).
Orzalesi
et
al.
(
1994)
found
that
pigmented
rabbits
developed
cataracts
after
5
weeks
gavage
exposure
at
500
mg/
kg­
day
and
retinal
degeneration
starting
at
3
weeks.
Retinal
degeneration
was
extensive
by
the
end
of
the
exposure
period,
resulting
in
almost
complete
obliteration
of
the
pigmented
layer
and
extensive
neovascularization.

In
rats,
Fitzhugh
and
Buschke
(
1949)
reported
the
development
of
mild
cataracts
in
five
weanling
rats
(
strain
unspecified)
consuming
two
percent
naphthalene
in
their
diet
for
two
months.
U.
S.
EPA
(
1998a)
estimated
that
this
amount
is
equivalent
to
a
total
dose
of
approximately
2,000
mg/
kg
per
animal.
Tao
et
al.
(
1991a,
b)
reported
lense
opacities
(
unspecified
incidence)
in
a
group
of
female
Brown
Norway
rats
exposed
by
gavage
at
700
mg/
kg­
day
for
102
days.

Holmen
et
al.
(
1999)
administered
doses
of
0,
100,
500,
1,000,
or
1,500
mg/
kg
twice
weekly
by
gavage
to
female
pigmented
Brown
Norway
rats
(
3
to
15
animals/
dose
group).
When
adjusted
for
duration,
these
doses
correspond
to
0,
29,
143,
285,
or
429
mg/
kg­
day,
respectively.
Ocular
changes
were
monitored
by
slit
illumination
and
retro­
illumination.
All
rats
treated
with
7­
28
Naphthalene
 
February
2003
doses
of
naphthalene
equal
to
or
greater
than
500
mg/
kg
developed
cataracts.
The
first
ocular
changes
were
evident
after
2.5
weeks
of
treatment
when
eyes
were
examined
by
retroillumination.
In
contrast,
no
evidence
of
cataractous
change
was
noted
in
control
rats
or
rats
administered
the
100
mg/
kg
dose.

Strain
differences
have
been
reported
for
the
incidence
and
rate
of
development
of
cataracts
in
rats.
Koch
et
al.
(
1976)
administered
1,000
mg/
kg
naphthalene
per
day
by
gavage
to
rats
of
several
strains
(
Sprague­
Dawley,
Wistar,
and
others)
on
alternate
days.
All
of
the
pigmented
rats
developed
cataracts
within
16
to
28
days,
whereas
cataract
incidence
was
lower
in
the
albino
strains.
Xu
et
al.
(
1992a)
administered
gavage
doses
of
1,000
mg/
kg
naphthalene
per
day
in
oil
to
both
pigmented
(
Long­
Evans
and
Brown
Norway)
and
unpigmented
(
Sprague­
Dawley,
Wistar,
and
Lewis)
rats
for
up
to
28
days.
Eyes
were
examined
(
by
slit­
lamp
with
focal
and
retro­
illumination
techniques)
twice
a
week
for
the
first
2
weeks
and
weekly
thereafter.
All
rats
of
both
pigmented
and
unpigmented
strains
were
found
to
have
cataracts
at
the
end
of
the
exposure
period.
However,
the
rate
of
cataract
development
differed
among
strains,
with
the
order
being
Brown
Norway
>
Long­
Evans
=
Lewis
=
Sprague­
Dawley
>
Wistar.
Murano
et
al.
(
1993)
found
that
gavage
doses
of
1,000
mg/
kg
naphthalene
administered
every
other
day
for
6
weeks
resulted
in
the
development
of
cataracts
in
all
exposed
male
Brown
Norway
and
Sprague­
Dawley
rats.
Cataracts
developed
more
rapidly
in
the
Brown
Norway
than
in
the
Sprague­
Dawley
rats,
an
observation
that
is
consistent
with
the
findings
of
Xu
et
al.
(
1992a),
above.

Shichi
et
al.
(
1980)
observed
a
very
low
incidence
(
1/
15)
of
cataracts
in
C57BL/
6N
mice
following
administration
of
doses
of
approximately
60
or
120
mg/
kg­
day
in
the
diet
for
60
days.
The
mice
were
injected
twice­
weekly
with
an
inducer
of
cytochrome
P­
450.
No
cataracts
were
observed
in
DBA/
2N
mice
treated
under
the
same
regimen.

NOAELs
for
naphthalene­
induced
cataract
formation
have
been
identified
in
chronic
and
subchronic
exposure
studies
in
rats
and
mice.
Schmähl
(
1955)
found
no
cataracts
in
rats
treated
orally
with
naphthalene
at
41
mg/
kg­
day
for
2
years,
although
the
method
of
examination
was
not
documented.
BCL
(
1980a)
did
not
observe
cataracts
in
Fischer
rats
receiving
up
to
400
mg/
kgday
5
days
per
week
for
13
weeks.
In
B6C3F
1
mice,
(
BCL,
1980b)
identified
a
NOAEL
of
200
mg/
kg­
day
(
administered
5
days
per
week).
Shopp
et
al.
(
1984)
found
no
cataracts
(
method
of
cataract
examination
was
not
indicated)
in
CD­
1
mice
treated
by
gavage
at
133
mg/
kg­
day
for
90
days.
Cataracts
were
not
observed
in
B6C3F
1
mice
exposed
to
concentrations
of
naphthalene
as
high
as
30
ppm
by
inhalation
for
two
years
(
NTP
1992a).
Cataracts
or
other
ocular
changes
were
not
observed
in
F344/
N
rats
exposed
to
concentrations
up
to
60
ppm
(
estimated
dose
20.6
mg/
kgday
for
males)
for
two
years
(
NTP,
2000).

Based
on
the
above
findings,
the
relationship
between
oral
naphthalene
exposure
and
the
development
of
cataracts
has
been
clearly
demonstrated
in
rodents.
LOAELs
range
from
500
mg/
kg­
day
(
Brown
Norway
rats)
to
5,000
mg/
kg­
day
(
black
rats)
across
studies
of
all
durations.
NOAELs
for
naphthalene­
induced
cataractogenesis
in
subchronic
studies
ranged
from
29
mg/
kg­
day
(
duration­
adjusted
dose
administered
to
Brown
Norway
rats
on
a
biweekly
dosing
regimen)
and
133
mg/
kg
(
CD­
1
mice)
to
400
mg/
kg
(
Fischer
rats).
7­
29
Naphthalene
 
February
2003
7.3.3
Hematological
Effects
Hemolytic
anemia
has
been
observed
in
humans
exposed
to
naphthalene
via
inhalation,
combined
inhalation
and
dermal
exposure,
and
combined
oral
and
inhalation
exposure
(
see
Section
7.3.3).
In
animals,
naphthalene­
induced
hemolytic
anemia
has
been
observed
only
in
the
dog.
Zuelzer
and
Apt
(
1949)
administered
naphthalene
incorporated
into
a
meat
diet
to
three
dogs.
One
dog
(
7.3
kg
body
weight)
received
a
single
dose
of
3
g
(
equivalent
to
a
410
mg/
kg
dose).
A
second
dog
(
5.9
kg
body
weight)
received
a
single
9
g
dose
(
equivalent
to
a
1,530
mg/
kg
dose).
The
third
dog
(
6.8
kg)
was
administered
seven
consecutive
daily
doses
ranging
from
0.5
to
3.0
g
(
equivalent
to
74
to
144
mg/
kg).
The
total
dose
in
the
third
dog
was
12.5
g,
which
is
equivalent
to
an
average
daily
dose
of
262
mg/
kg­
day.
The
blood
of
the
treated
animals
was
characterized
by
decreased
hemoglobin
concentration
and
hematocrit;
development
of
Heinz
bodies
in
erythrocytes,
erythrocyte
fragmentation,
and
reticulocytosis.
Similar
indications
of
hemolytic
anemia
were
not
observed
when
hematological
parameters
were
examined
in
F344
rats
treated
with
gavage
doses
of
up
to
400
mg/
kg­
day
(
BCL,
1980a),
5
days/
week
for
13
weeks;
in
B6C3F
1
mice
treated
with
gavage
doses
of
up
to
200
mg/
kg­
day,
5
days/
week
for
13
weeks
(
BCL,
1980b);
or
in
CD­
1
mice
given
gavage
doses
of
up
to
133
mg/
kg­
day
for
90
consecutive
days
(
Shopp
et
al.,
1984).

7.3.4
Immunotoxicity
A
limited
number
of
studies
document
potential
immunotoxic
effects
of
naphthalene
exposure.
Based
on
the
available
data,
adverse
effects
on
the
immune
system
do
not
appear
to
be
a
prominent
feature
of
naphthalene
toxicity.

An
enlarged
spleen
was
reported
in
one
human
subject
that
died
as
a
result
of
ingesting
naphthalene
(
Kurz,
1987).
Enlarged
spleens
were
also
observed
in
two
human
subjects
that
were
dermally
exposed
to
naphthalene
(
Schafer,
1951;
Dawson
et
al.,
1958).
However,
these
effects
were
believed
to
be
associated
with
hemolysis,
rather
than
indicative
of
a
direct
toxic
effect
on
the
spleen.

Shopp
et
al.
(
1984)
reported
no
effects
on
humoral
immune
responses,
delayed
hypersensitivity
responses,
bone
marrow
DNA
synthesis,
or
bone
marrow
stem
cell
number
in
CD­
1
mice
that
received
naphthalene
at
oral
doses
as
high
as
267
mg/
kg­
day
for
14
days.
Thymic
weight
decreased
approximately
30%
in
the
high­
dose
male
mice.
In
the
high­
dose
females,
mitogenic
responses
to
concanavalin
A
were
reported.
This
effect
was
not
observed
with
lipopolysaccharide
or
in
mice
that
received
naphthalene
at
27
or
53
mg/
kg­
day.
In
addition,
no
immune
system
effects
or
alterations
in
thymic
weights
were
observed
in
male
mice
that
received
133
mg
naphthalene/
kg/
day
for
13
weeks.
An
approximately
20%
decrease
in
spleen
weight
was
reported
in
female
mice
that
received
267
mg
naphthalene/
kg/
day
for
14
days,
while
a
25%
decrease
was
observed
in
female
mice
that
received
133
mg/
kg­
day
for
13
weeks
(
Shopp
et
al.,
1984).

In
other
studies,
thymic
lymphoid
depletion
was
reported
in
2
of
10
female
rats
that
received
400
mg
naphthalene/
kg/
day
for
13
weeks
(
BCL,
1980a).
Dermal
application
of
pure
naphthalene
once
weekly
for
3
weeks
to
the
skin
of
rabbits
did
not
result
in
evidence
of
a
delayed
7­
30
Naphthalene
 
February
2003
hypersensitivity
reaction
(
PRI,
1985;
Papciak
and
Mallory,
1990).
The
results
of
an
in
vivo
study
in
C57B1/
6
mice
indicated
that
a
single
oral
dose
of
naphthalene
did
not
suppress
antibody
responses
(
Silkworth
et
al.,
1995).

An
in
vitro
study
conducted
by
Kawabata
and
White
(
1990)
indicated
that
naphthalene
did
not
have
an
immunosuppressive
effect
in
the
antibody
response
of
splenic
cell
cultures
to
sheep
red
blood
cells.

7.3.5
Hormonal
Disruption
No
studies
were
located
that
document
disruptive
effects
on
the
endocrine
system
associated
with
naphthalene
exposure.

7.3.6
Physiological
or
Mechanistic
Studies
Information
on
the
mode
of
action
of
naphthalene
is
available
for
three
health
effects
associated
with
exposure:
hemolysis,
cataract
formation,
and
pulmonary
toxicity
(
ATSDR,
1995;
U.
S.
EPA,
1998a).

Hemolysis
Humans
and
dogs
are
susceptible
to
naphthalene­
induced
hemolysis
following
inhalation,
oral,
or
dermal
exposures.
Naphthalene
metabolites
are
believed
to
be
involved
in
naphthaleneinduced
hemolytic
anemia,
but
the
mode
of
action
of
naphthalene
induced
hemolysis
is
not
clearly
understood.
Individuals
deficient
in
glucose­
6­
phosphate
dehydrogenase
(
G6PD)
are
particularly
sensitive
to
naphthalene
hemolysis.
G6PD­
deficient
cells
have
a
reduced
capacity
to
generate
reduced
nicotinamide
adenine
dinucleotide
phosphate
(
NADPH),
which
serves
as
a
cofactor
in
the
reduction
of
oxidized
glutathione.
G6PD­
deficient
cells,
therefore,
cannot
quickly
replenish
reduced
glutathione
(
Dawson
et
al.,
1958;
Gosselin
et
al.,
1984),
a
compound
that
plays
a
key
role
in
defense
against
oxidative
damage,
and
in
the
conjugation
and
excretion
of
some
toxicants.
Deficits
in
reduced
glutathione
levels
are
thought
to
decrease
the
rate
of
conjugation
and
the
excretion
of
naphthalene
metabolites,
thereby
leading
to
elevated
levels
of
toxic
naphthalene
metabolic
intermediates
(
U.
S.
EPA,
1987b).
In
the
absence
of
glutathione,
the
metabolites
promote
damage
to
red
blood
cell
membranes
and
the
oxidization
of
hemoglobin
to
methemoglobin.
Both
of
these
actions
likely
contribute
to
cell
lysis
(
U.
S.
EPA,
1998a).
Other
possible
causes
of
hemolysis
include
inhibition
of
the
enzymes
glutathione
peroxidase
or
glutathione
reductase
by
a
naphthalene
metabolite
(
Rathbun
et
al.,
1990;
Tao
et
al.,
1991a,
b).

Cataract
Formation
Experimental
evidence
suggests
that
naphthalene
cataractogenesis
requires
cytochrome
P­
450
catalyzed
bioactivation
to
a
reactive
intermediate.
Some
evidence
suggests
that
the
ocular
toxicity
of
naphthalene
is
mediated
by
the
production
of
1,2­
naphthalenediol
in
situ
in
the
lens
(
ATSDR,
1995).
Alternatively,
Van
Heyningen
and
Pirie
(
1967)
proposed
that
naphthalene
was
metabolized
in
the
liver
to
epoxide
intermediates
and
subsequently
to
stable
hydroxy
compounds.
These
hydroxy
compounds
then
enter
the
circulation
and
are
transported
to
the
lens,
where
1,2­
7­
31
Naphthalene
 
February
2003
naphthalenediol
is
subsequently
oxidized
to
1,2­
naphthoquinone
and
hydrogen
peroxide.
The
quinone
binds
to
lens
constituents,
thus
altering
the
integrity
and
transparency
of
the
lens
(
Uyama
et
al.,
1955;
Rees
and
Pirie,
1967;
Van
Heyningen
and
Pirie,
1967;
Van
Heyningen
and
Pirie,
1976;
Van
Heyningen,
1979;
Wells
et
al.,
1989).

Wells
et
al.
(
1989)
assessed
cataract
formation
after
administration
of
naphthalene
or
naphthalene
metabolites.
Dose­
related
increases
in
cataract
incidence
were
observed
following
administration
of
125
to
1,000
mg
naphthalene/
kg,
5
to
250
mg
1,2­
naphthoquinone/
kg,
56
to
562
mg
1­
naphthol/
kg,
or
5
to
250
mg
1,4­
naphthoquinone/
kg
to
C57BL/
6
mice
by
intraperitoneal
injection.
In
contrast,
cataract
formation
was
not
observed
following
the
intraperitoneal
administration
of
56
to
456
mg
2­
naphthol/
kg.
The
potency
of
the
quinones
was
reported
to
be
about
10
times
that
of
naphthalene.
Pretreatment
with
inducers
of
cytochrome
P­
450
and
a
glutathione­
depleting
compound
increased
the
potency
of
naphthalene
in
causing
cataracts.
Pretreatment
with
a
P­
450
inhibitor
decreased
naphthalene
toxicity.

Xu
et
al.
(
1992a,
b)
conducted
experiments
that
employed
five
different
strains
of
albino
rats.
Naphthalene
was
administered
via
gavage
at
a
dose
of
500
mg/
kg­
day
for
three
days,
followed
by
1,000
mg/
kg­
day
for
25
days.
All
of
the
naphthalene­
treated
rats
developed
cataracts.
The
concentration
of
reduced
glutathione
was
decreased
in
the
lens
following
three
weeks
of
treatment,
while
increases
in
protein­
glutathione
mixed
disulfides
and
high
molecular
weight­
insoluble
proteins
were
reported.
Analyses
of
the
aqueous
humor
indicated
that
the
only
naphthalene
metabolite
present
was
1,2­
dihydro­
1,2­
naphthalenediol.
The
authors
speculated
that
this
compound
may
have
been
metabolized
to
1,2­
naphthoquinone,
the
metabolite
believed
to
be
responsible
for
the
formation
of
cataracts.

Xu
et
al.
(
1992a)
determined
that
the
only
metabolite
that
resulted
in
formation
of
morphologically
identical
cataracts
in
vitro
and
in
vivo
was
1,2­
dihydro­
1,2­
naphthalenediol.
Opacities
were
also
formed
by
1,2­
naphthalenediol
and
naphthoquinone.
However,
these
cataracts
formed
on
the
cortex
rather
than
the
inner
surface
of
the
lens.

Xu
et
al.
(
1992a)
investigated
the
role
of
the
enzyme
aldose
reductase
in
cataract
formation
in
naphthalene
exposed
rats.
Aldose
reductase
is
found
in
the
lens,
liver,
and
in
peripheral
neurons
(
McGilvery,
1983)
and
is
thought
to
oxidize
1,2­
naphthalenediol
to
1,2­
naphthoquinone,
the
metabolite
responsible
for
cataract
formation
(
Xu
et
al.
1992a).
If
this
hypothesis
is
correct,
inhibition
of
the
reaction
catalyzed
by
aldose
reductase
should
result
in
decreased
synthesis
of
1,2­
naphthoquinone,
and
decreased
cataract
formation.
Groups
of
rats
were
dosed
with
naphthalene
alone,
naphthalene
plus
the
aldose
reductase
inhibitor
ALO1576,
or
ALO1576
alone.
All
naphthalene­
treated
rats
developed
cataracts.
Consistent
with
the
proposed
hypothesis,
rats
given
the
aldose
inhibitor
alone,
or
naphthalene
plus
aldose
inhibitor,
did
not
develop
cataracts.
The
authors
of
this
study
suggested
that
the
mechanism
of
naphthalene
cataract
formation
may
involve
the
transport
of
the
dihydrodiol
metabolite
formed
in
the
liver
into
the
lens,
where
it
is
converted
by
aldol
reductase
into
the
very
reactive
1,2­
naphthoquinone.
The
naphthoquinone
then
causes
oxidative
damage
to
the
lens,
resulting
in
opacity.

This
mode
of
action
is
supported
by
the
results
of
Xu
et
al.
(
1992b),
who
found
that
the
aldose
reductase
inhibitor
ALO1537
also
prevented
naphthalene­
related
cataract
formation.
In
7­
32
Naphthalene
 
February
2003
contrast,
Tao
et
al.
(
1991a,
b)
found
that
the
aldose
reductase
inhibitor
TK344
failed
to
prevent
cataracts
in
naphthalene­
treated
rats.
The
researchers
hypothesized
that
the
cataract­
preventive
activity
of
ALO1537
might
result
from
the
inhibition
of
a
naphthalene­
metabolizing
enzyme
other
than
aldose
reductase.

Several
studies
have
investigated
biochemical
processes
that
potentially
contribute
to
naphthalene­
induced
cataract
formation.
Srivastava
and
Nath
(
1969)
reported
markedly
decreased
lactate
dehydrogenase
activity
and
elevated
o­
diphenol
oxidase
activity
in
the
lens
and
capsule
of
rabbits
(
strain
not
stated)
treated
with
naphthalene
doses
of
2,000
mg/
kg­
day.
Yamauchi
et
al.
(
1986)
detected
decreased
levels
of
reduced
glutathione
in
lenses
of
male
Wistar
rats
treated
with
1,000
mg/
kg­
day
doses
of
naphthalene
for
18
days.
Rathbun
et
al.
(
1990)
observed
reduced
total
glutathione
levels
and
progressive
loss
of
glutathione
peroxidase
and
glutathione
reductase
activity
in
Black­
Hooded
rats
administered
approximately
5,000
mg/
kg­
day
in
the
diet
for
79
days,
suggesting
that
naphthalene
exposure
impairs
defenses
against
oxidative
damage.
However,
Rao
and
Pandya
(
1981)
did
not
detect
any
significant
increase
in
ocular
lipid
peroxidation
following
administration
of
1,000
mg/
kg­
day
to
male
rats
(
strain
not
stated)
for
10
days.

Pulmonary
Toxicity
Pulmonary
toxicity
has
been
identified
in
experimental
animals
exposed
to
naphthalene
via
inhalation
and
parenteral
pathways.
As
noted
below,
the
pulmonary
response
to
naphthalene
varies
significantly
among
species.
At
present,
there
is
no
strong
evidence
that
exposure
to
naphthalene
results
in
pulmonary
toxicity
in
humans
(
ATSDR,
1995).

Increased
incidences
of
alveolar
bronchiolar
hyperplasia
were
observed
in
F344/
N
female
rats
exposed
to
naphthalene
via
inhalation
for
two
years
(
NTP,
2000).
A
predominantly
benign
neoplastic
response
in
the
alveolar/
bronchiolar
region
following
chronic
inhalation
exposure
to
naphthalene
has
been
observed
in
male
and
female
mice
(
NTP,
1992a).
Pulmonary
bronchiolar
epithelial
cells,
primarily
Clara
cells,
may
be
damaged
following
intraperitoneal
administration
of
naphthalene
(
Mahvi
et
al.,
1977;
Tong
et
al.,
1982;
Warren
et
al.,
1982;
O'Brien
et
al.,
1985,
1989;
Honda
et
al.,
1990;
Chichester
et
al.,
1994;
Van
Winkle
et
al.,
1999).
This
toxicity
has
been
associated
with
the
metabolism
of
naphthalene
by
the
cytochrome
P­
450
system
in
the
lung
(
Warren
et
al.,
1982;
O'Brien
et
al.,
1985;
Rasmussen
et
al.,
1986;
Buckpitt
and
Franklin,
1989).
The
ultrastructural
changes
induced
by
naphthalene
are
consistent
with
the
type
of
damage
produced
by
other
P­
450­
bioactivated
toxicants
(
Van
Winkle
et
al.,
1999).

The
identity
of
the
toxic,
P­
450­
activated
metabolite
is
not
known
with
certainty.
However,
it
is
believed
to
be
one
or
more
of
the
enantiomeric
epoxides,
naphthoquinones,
or
free
radical
intermediates
(
Buckpitt
and
Franklin,
1989),
which
likely
bind
to
the
Clara
cell
proteins
or
nucleic
acids
(
Chichester
et
al.,
1994).
Local
pulmonary
metabolic
processes
are
thought
to
be
responsible
for
the
observed
toxicity,
although
there
is
some
evidence
that
other
tissues,
such
as
the
liver,
may
metabolize
naphthalene
to
reactive
metabolites
that
enter
the
circulation,
are
transported
to
the
lung,
and
result
in
pulmonary
cytotoxicity
(
Warren
et
al.,
1982;
O'Brien
et
al.,
1989;
Kanekal
et
al.,
1990).
7­
33
Naphthalene
 
February
2003
Epoxide
metabolites
are
considered
strong
candidates
for
causing
the
pulmonary
toxicity
observed
following
exposure
to
naphthalene.
This
conclusion
is
based
on
the
observations
that
some
epoxides
are
cytotoxic,
genotoxic
and
possibly
carcinogenic
(
U.
S.
EPA,
1998a),
and
that
cytotoxicity
in
isolated,
perfused
mouse
lungs
was
produced
by
1,2­
naphthalene
epoxide
at
concentrations
10­
fold
less
than
naphthalene
(
Kanekal
et
al.,
1991).
In
addition,
the
epoxide
is
capable
of
covalently
binding
to
cellular
macromolecules
resulting
in
cell
damage.
In
contrast,
the
naphthalene
metabolites
1­
naphthol,
1,2­,
and
1,4­
naphthoquinone
were
not
apparently
cytotoxic
in
the
lung
at
concentrations
equal
to
concentrations
of
naphthalene
that
produced
cytotoxicity
(
U.
S.
EPA,
1998a).
However,
Zheng
et
al.
(
1997)
treated
mouse
lung
Clara
cells
with
naphthalene
in
vitro
and
identified
1,2­
naphthoquinone
as
a
major
adduct
covalently
bound
to
cellular
protein,
suggesting
that
this
metabolite
has
the
potential
to
contribute
to
pulmonary
toxicity.

Species
differences
exist
in
the
pulmonary
metabolism
and
toxicity
of
naphthalene.
Mice
are
more
sensitive
to
the
pulmonary
effects
of
naphthalene
than
hamsters
or
rats
(
Buckpitt
and
Franklin,
1989;
Buckpitt
et
al.,
1992;
Plopper
et
al.,
1992a,
b).
Microsomes
prepared
from
mouse
lung
metabolized
naphthalene
approximately
92
times
faster
than
microsomes
prepared
from
Rhesus
monkeys
(
Buckpitt
et
al.,
1992).
The
primary
metabolites
formed
by
the
2
species
were
also
different,
with
mice
and
monkeys
forming
1R,
2S­
naphthalene
oxide
and
1S,
2Rnaphthalene
oxide,
respectively.
The
metabolic
rates
reported
for
hamsters
and
rats
were
intermediate
between
those
reported
for
mice
and
monkeys
(
Buckpitt
et
al.,
1992).
The
metabolic
rates
of
human
lung
microsomes
have
been
reported
to
be
similar
to
those
of
monkeys
(
Buckpitt
and
Bahnson,
1986).

Detailed
comparison
of
naphthalene
metabolic
potential
and
naphthalene­
induced
cytotoxicity
throughout
dissected
airways
confirms
that
there
is
a
significant
degree
of
speciesspecificity
in
metabolism
and
injury.
Clara
cells
appear
to
be
a
primary
target
cell
for
naphthalene
toxicity
in
the
lung
of
mice,
the
most
sensitive
species
among
those
tested.
This
is
consistent
with
the
putative
role
of
Clara
cells
as
one
of
the
primary
sites
for
cytochrome
P­
450­
mediated
xenobiotic
metabolism
in
the
lung.
Studies
by
Plopper
et
al.
(
1992a)
and
Buckpitt
et
al.
(
1995)
evaluated
the
association
between
Clara
cell
toxicity
and
metabolism
in
different
areas
of
the
tracheobronchial
trees
of
mice,
rats,
and
hamsters.
The
rate
of
metabolism
of
naphthalene
and
the
extent
of
1R,
2S­
naphthalene
oxide
enantiomer
formation
by
microsomal
preparations
from
specific
areas
were
reported
to
correlate
with
differences
in
pulmonary
cytotoxicity
observed
in
the
different
species.
Metabolism
of
naphthalene
in
mouse
airways
was
highly
stereoselective,
producing
the
1R,
2S­
naphthalene
oxide
enantiomer;
similar
stereospecificity
was
not
observed
in
the
airways
of
rats
or
hamsters.
Non­
ciliated
cells
in
all
airway
regions
of
the
mouse
were
heavily
labeled
when
treated
with
an
antibody
to
cytochrome
P­
450
2F2,
whereas
little
labeling
was
observed
in
any
airway
region
of
rats
or
hamsters.

Studies
of
species­
specific
responses
to
naphthalene
toxicity
in
the
nose
suggest
that
factors
other
than
metabolic
activation
may
play
a
role
in
cell
injury.
Plopper
et
al.
(
1992a)
compared
the
sensitivity
of
nasal
tissues
to
naphthalene
toxicity
in
rat,
mouse,
and
hamster.
The
close
correlation
observed
between
the
metabolism
and
stereospecificity
of
the
metabolites
in
the
lung
was
not
evident
in
the
nose.
Damage
in
the
nasal
cavity
of
the
three
species
was
limited
to
necrosis
of
the
olfactory
epithelium.
Cells
in
this
portion
of
the
nose
contain
high
concentrations
7­
34
Naphthalene
 
February
2003
of
several
cytochrome
P­
450
isoforms.
Although
the
target
site
for
naphthalene­
induced
injury
was
the
same
for
all
three
species,
the
dose
that
produced
necrosis
differed
among
them.
The
level
of
total
naphthalene
metabolizing
activity
in
a
given
species
was
not
predictive
of
the
dose
required
to
elicit
necrosis.
This
result
was
interpreted
by
the
study
authors
as
evidence
for
a
role
of
phase
II
enzymes
(
e.
g.,
epoxide
hydrolase
and/
or
glutathione­
S­
transferases)
in
modulating
the
intracellular
levels
of
naphthalene
oxides
and
thus
toxicity
in
target
cells.

Kanekal
et
al.
(
1990)
reported
that
Clara
cell
numbers
decreased
substantially
following
a
4­
hour
exposure
to
0.13
mg
naphthalene
when
tested
using
a
perfused
rat
lung
system.
It
was
also
noted
that
the
Clara
cells
exfoliated
and
were
found
in
the
airway
lumens.
As
noted
above,
non­
ciliated
Clara
cells
contain
higher
levels
of
mixed
function
oxidases
and
thus
are
believed
to
be
more
sensitive
to
damage
from
naphthalene.
Chichester
et
al.
(
1994)
reported
that
Clara
cell
viability
decreased
by
39
and
88%,
when
exposed
to
64
or
128
mg/
L
naphthalene,
respectively.
No
effect
was
seen
in
cells
exposed
to
1.3
or
6.4
mg/
L
naphthalene
for
120
or
340
minutes.
Exposure
to
equivalent
molar
concentrations
of
naphthalene
oxide
resulted
in
effects
similar
to
those
produced
by
naphthalene.
The
addition
of
glutathione
and
glutathione
transferase
decreased
Clara
cell
damage.

Relatively
little
is
known
about
repair
of
naphthalene­
induced
pulmonary
injury.
However,
the
number
of
pulmonary
neuroendocrine
cells
and
the
surface
area
covered
per
cell
increased
markedly
within
five
days
of
a
single
intraperitoneal
injection
of
naphthalene
administered
to
male
FVB/
n
mice
(
Peake
et
al.,
2000).
These
alterations
were
interpreted
as
evidence
for
a
key
role
of
this
cell
type
in
epithelial
cell
renewal
after
airway
injury.

Germansky
and
Jamall
(
1988)
investigated
the
organ­
specific
effects
of
naphthalene
(
169
mg/
kg­
day,
time­
weighted
average)
on
tissue
peroxidation,
glutathione
peroxidases,
and
superoxide
dismutase
in
lung
tissue
of
male
Blue
Spruce
pigmented
rats.
In
contrast
to
results
obtained
in
the
liver,
no
effect
of
naphthalene
exposure
was
evident
on
levels
of
peroxidation
or
activity
of
the
two
enzymes.

7.3.7
Structure­
Activity
Relationship
There
are
few
studies
that
systematically
examine
the
toxicological
structure­
activity
relationships
among
naphthalene
and
its
close
structural
analogues.
U.
S.
EPA
(
1998a)
has
summarized
information
related
to
the
metabolism
and
pulmonary
toxicity
of
the
naphthalene
structural
analogues
1­
and
2­
methylnaphthalene.

The
methylation
of
naphthalene
to
form
1­
and
2­
methylnaphthalene
presents
opportunities
for
metabolism
via
additional
oxidative
pathways.
Due
to
the
lack
of
a
functional
group
to
serve
as
a
site
for
conjugation,
naphthalene
metabolism
proceeds
via
P­
450­
catalyzed
ring
oxidation.
Presence
of
the
methyl
groups
in
1­
and
2­
methylnaphthalene
enables
the
formation
of
potentially
toxic
aldehydes
via
side­
chain
oxidation.
The
potential
toxicity
of
the
aldehydes
raises
the
possibility
that
there
are
distinct
differences
between
the
effects
of
naphthalene
and
its
methylated
derivatives
that
result
from
differences
in
metabolism
(
U.
S.
EPA,
1998a).
7­
35
Naphthalene
 
February
2003
Buckpitt
and
Franklin
(
1989)
reviewed
the
comparative
pulmonary
toxicity
of
naphthalene
and
the
related
compound
2­
methylnaphthalene.
The
researchers
noted
that,
while
2­
methylnaphthalene
is
less
acutely
toxic
than
naphthalene,
the
dose­
response
characteristics
for
subchronic
pulmonary
toxicity
(
alveolar
proteinosis,
Clara
cell
damage,
bronchiolar
necrosis)
of
naphthalene
and
the
2­
methyl
derivative
are
quite
similar.
They
suggested
that
metabolism
by
cytochrome
P­
450
was
more
clearly
implicated
in
the
toxicity
of
2­
methylnaphthalene
than
in
the
case
of
naphthalene.

Chronic
dietary
exposure
(
0.075%
and
0.15%
in
feed)
of
B6C3F
1
mice
to
either
1­
methylnaphthalene
and
2­
methylnaphthalene
for
81
weeks
results
in
an
increased
incidence
of
pulmonary
alveolar
proteinosis
(
Murata
et
al.,
1993;
Murata
et
al.,
1997).
Exposure
to
1­
methylnaphthalene
also
induced
a
small
but
statistically
significant
increase
in
the
incidence
of
bronchiolar/
alveolar
adenomas
in
the
lungs
of
male,
but
not
female
mice
(
Murata
et
al,
1993).
Dietary
exposures
to
2­
methylnaphthalene
were
not
associated
with
an
increased
tumor
incidence.

Additional
research
is
required
to
determine
if
and
how
the
pulmonary
effects
of
naphthalene
and
1­
and
2­
methylnaphthalene
are
mechanistically
related
(
U.
S.
EPA,
1998a).

7.4
Hazard
Characterization
7.4.1
Synthesis
and
Evaluation
of
Major
Noncancer
Effects
As
discussed
in
Section
7.1,
data
concerning
the
adverse
effects
of
naphthalene
exposure
in
humans
are
limited.
A
number
of
case
reports
describe
acute
accidental
and
intentional
naphthalene
ingestion
(
Lezenius,
1902;
Gerarde,
1960;
Gupta
et
al.,
1979;
Ijiri,
1987;
Kurz,
1987).
The
utility
of
these
data
for
the
evaluation
of
health
effects
associated
with
occurrence
of
naphthalene
in
drinking
water
is
potentially
limited
by
several
factors.
Quantitative
exposure
data
are
not
provided
in
these
incident
reports.
The
extent
of
naphthalene
uptake
and
the
toxic
endpoints
resulting
from
a
single,
large
dose
may
differ
from
those
that
would
occur
from
exposure
in
drinking
water.
In
addition,
the
low
aqueous
solubility
of
naphthalene
may
prevent
the
occurrence
of
concentrations
in
drinking
water
that
are
acutely
toxic
to
the
general
population.
An
additional
important
source
of
uncertainty
in
these
considerations
is
the
potentially
greater
sensitivity
of
certain
subpopulations
to
naphthalene
toxicity,
including
infants
and
children,
neonates,
fetuses,
and
individuals
deficient
in
G6PD.
At
present,
little
information
is
available
to
define
acutely
toxic
levels
of
exposure
for
these
groups.

Case
reports
of
individuals
(
primarily
infants)
exposed
to
naphthalene
by
inhalation
or
through
dermal
contact
with
mothballs
or
with
items
stored
with
mothballs
(
Schafer,
1951;
Valaes,
1963;
Owa,
1989)
are
more
informative.
While
none
of
these
studies
provides
information
on
the
exposure
levels
that
are
associated
with
adverse
effects,
they
provide
information
that
establishes
hemolytic
anemia
and
its
sequelae
as
the
most
important
toxic
effect
in
humans
exposed
to
naphthalene
at
levels
that
might
be
encountered
in
the
environment.
Case
reports
also
indicate
that
humans
with
G6PD
deficiency
are
especially
susceptible
to
naphthalene
toxicity,
particularly
infants
and
the
fetus
(
Valaes,
1963;
U.
S.
EPA,
1987b;
Owa,
1989).
7­
36
Naphthalene
 
February
2003
Studies
of
occupational
exposure
to
naphthalene
are
limited
to
a
single
report
of
possible
naphthalene­
related
cataracts
in
chemical
workers
(
Ghetti
and
Mariani,
1956)
and
to
two
limited
epidemiological
studies
(
Wolf,
1976;
Kup,
1978)
that
provide
ambiguous
evidence
of
associations
between
occupational
naphthalene
exposure
and
cancer.
Owing
to
their
numerous
limitations
(
see
Section
4.2),
neither
of
these
studies
is
useful
in
characterizing
the
potential
risks
associated
with
human
exposures
to
naphthalene
(
U.
S.
EPA,
1998a).

Because
there
are
no
reliable
human
studies
to
establish
dose­
response
relationships
for
specific
health
effects,
most
dose­
response
information
is
derived
from
animal
studies.
The
results
of
key
toxicological
studies
are
categorized
by
toxic
effect
in
Table
7­
7.
An
important
feature
of
the
data
in
this
table
is
that
hemolytic
anemia,
which
appears
to
be
the
critical
toxic
effect
in
humans,
is
not
seen
in
the
majority
of
the
animal
studies.
Thus,
mice,
rats,
and
rabbits
are
less
sensitive
to
naphthalene­
induced
hematotoxicity
than
humans.
This
is
consistent
with
the
general
observation
that
dogs
and
humans
are
generally
more
sensitive
to
chemically­
induced
hemolytic
anemia
than
are
other
species
(
ATSDR,
1995).
The
physiological
and
biochemical
mechanisms
responsible
for
this
difference
in
sensitivity
are
not
known
(
U.
S.
EPA,
1998a).
Dogs
are
apparently
more
sensitive
to
naphthalene
exposure
than
other
experimental
animals,
but
the
single
available
study
in
dogs
(
Zuelzer
and
Apt,
1949)
is
quite
old,
and
it
used
only
a
very
small
number
of
animals.
Thus,
it
cannot
be
used
to
estimate
a
dose­
response
relationship
for
naphthalene­
induced
hemolysis.

In
contrast
to
hemolytic
anemia,
naphthalene­
induced
cataract
formation
is
well­
studied
in
experimental
animals.
Acute,
short­
term,
and
subchronic
studies
of
cataractogenesis
(
see
Table
7­
6)
have
established
the
general
features
of
dose­
response
relationships
in
different
species
and
dosing
regimens.
In
addition,
these
studies
have
helped
to
elucidate
the
biochemical
basis
of
naphthalene­
induced
cataractogenesis.
The
general
mechanism
for
cataract
formation,
like
that
for
hemolysis,
appears
to
involve
oxidative
damage
of
cell
components.
However,
greater
progress
has
been
made
in
identifying
the
specific
metabolic
pathways,
enzymes,
and
toxic
metabolites
that
are
involved
in
cataract
formation.

Quinone
derivatives
of
naphthalene
appear
to
be
the
proximate
toxic
metabolites
involved
in
cataract
formation
(
U.
S.
EPA,
1998a).
Naphthalene
is
first
oxidized
by
cytochrome
P­
450
monooxygenases
to
the
1,2­
epoxide.
The
epoxide
is
then
converted
into
naphthalene
dihydrodiol
by
one
or
more
pathways.
These
metabolic
steps
probably
occur
in
the
liver,
but
it
is
known
that
naphthalene
metabolism
also
occurs
in
other
organs,
notably
the
lung.
It
is
thought
that
the
dihydrodiol
diffuses
into
the
crystalline
lens
where
it
is
converted
into
1,2­
naphthoquinone.
The
naphthoquinone
then
reacts
with
lens
components
to
cause
damage
and
opacity.
The
key
enzyme
in
the
conversion
of
the
dihydrodiol
to
the
quinone
is
aldose
reductase,
as
judged
by
studies
that
show
reduced
cataract
formation
when
reductase
inhibitors
are
administered
along
with
naphthalene
to
experimental
animals.
Glutathione
depletion
may
also
enhance
the
development
of
cataracts
(
ATSDR,
1995)
by
preventing
detoxifying
conjugation
reactions.

Species
differences
in
sensitivity
to
naphthalene­
induced
cataracts
have
been
attributed
to
differences
in
enzyme
activity
levels.
These
results
have
not
yet
been
extrapolated
to
human
toxicity,
however.
The
relatively
low
severity
of
the
cataracts
observed
in
the
single
epidemiologic
study
(
Ghetti
and
Mariani,
1956)
of
highly­
exposed
subjects
suggests
that
humans
7­
37
Naphthalene
 
February
2003
are
not
extremely
sensitive
to
naphthalene­
induced
cataract
formation
after
combined
inhalation
and
dermal
exposures.

The
second
specific
toxic
effect
that
has
been
linked
to
naphthalene
exposure
in
experimental
animals
is
the
development
of
non­
neoplastic
lesions
in
the
nose
and
lung
(
potential
carcinogenic
responses
are
discussed
in
Section
7.4.2
below).
Mice
(
NTP,
1992a)
and
rats
(
NTP,
2000)
had
increased
incidences
of
multiple
nasal
lesions
after
inhalation
exposure
to
naphthalene
for
two
years.
Exposure­
related
increases
in
the
incidences
of
alveolar
bronchiolar
hyperplasia
were
observed
in
female
rats
(
NTP,
2000)
and
in
the
incidences
of
chronic
inflammation
in
the
lung
of
male
and
female
B6C3F
1
mice
(
NTP,
1992a).
In
addition,
respiratory
tract
lesions
have
been
observed
in
mice
after
parenteral
administration
of
naphthalene
(
summarized
in
U.
S.
EPA,
1998a).
The
occurrence
of
lung
lesions
after
noninhalation
exposure
suggests
that
lung
tissue
may
be
especially
sensitive
to
naphthalene
or
its
metabolites,
or
that
particular
metabolic
pathways
are
acting
in
the
lung
to
produce
high
concentrations
of
toxic
intermediates.

Several
studies
have
found
that
the
pattern
of
naphthalene­
induced
lesions
in
a
mouse
lung
closely
correlates
with
cytochrome
P­
450
activity
(
Warren
et
al.,
1982;
Buckpitt
and
Franklin,
1989).
In
vitro
studies
suggest
the
epoxides
may
be
the
key
cytotoxic
metabolites
in
mouse
lung,
although
down­
stream
metabolites
(
the
dihydrodiol
and
quinones)
cannot
be
conclusively
ruled
out.
Buckpitt
et
al.
(
1992)
found
that
mouse
lung
microsomes
metabolize
naphthalene
approximately
92
times
faster
than
lung
microsomes
from
Rhesus
monkeys,
and
that
the
enantiomeric
composition
of
the
metabolic
products
was
different
in
mice
than
in
monkeys
(
U.
S.
EPA,
1998a).
The
study
authors
suggested
that
these
differences
at
least
partially
explain
the
differences
in
sensitivity
to
lung
toxicity
of
mice
and
primates.
A
more
recent
study
(
Buckpitt
et
al.,
1995)
identified
the
rate
of
conversion
of
naphthalene
to
naphthalene­
1R,
2S
oxide
by
cytochrome
P­
450
2F2
as
the
most
important
determinant
of
naphthalene
toxicity
in
mouse
lung.

The
mode(
s)
of
action
for
the
other
toxic
effects
reported
in
Table
7­
7
are
not
wellunderstood
The
decreased
body
weights
seen
in
several
of
the
subchronic
studies
do
not
appear
to
be
related
to
reduced
food
intake,
but
may
indicate
generally
depressed
metabolic
function.
Changes
in
organ
weights
have
only
been
observed
sporadically,
with
different
organs
affected
in
different
studies,
and
no
specific
patterns
of
histopathological
changes
in
the
affected
organs
(
other
than
the
lung).
Numerous
studies
suggest
that
naphthalene
is
a
very
weak
reproductive
and
developmental
toxicant,
with
detectable
effects
occurring
only
at
doses
associated
with
substantial
maternal
toxicity
or
even
mortality.
Finally,
no
biochemical
explanation
has
been
put
forward
for
the
neurological
effects
seen
in
pregnant
rats
(
BCL
1980a;
NTP,
1991).
However,
the
available
studies
support
a
clearly­
defined
NOAEL
and
LOAEL
for
this
effect.

7.4.2
Synthesis
and
Evaluation
of
Carcinogenic
Effects
The
available
human
data
are
inadequate
to
evaluate
any
association
between
naphthalene
and
cancer
occurrence.
The
available
epidemiological
studies
(
Wolf,
1976;
Kup,
1978)
are
limited
due
to
the
size
of
the
populations
examined
(
n=
15)
and
co­
exposure
to
other
potential
carcinogens,
such
as
tobacco
smoke
or
other
polycyclic
aromatic
hydrocarbons,
such
as
7­
38
Naphthalene
 
February
2003
benzo[
a]
pyrene.
No
large­
scale
epidemiological
study
has
been
conducted
to
examine
the
possible
association
between
naphthalene
exposure
and
cancer
(
U.
S.
EPA,
1998a).

Data
available
from
animal
studies
are
also
limited.
Only
two
inhalation
studies
were
adequately
designed
to
examine
the
carcinogenicity
of
lifetime
naphthalene
exposure.
NTP
(
1992a)
examined
the
carcinogenicity
in
mice
exposed
to
naphthalene
for
2
years
by
inhalation.
A
statistically
significant
increase
in
the
incidence
of
alveolar/
bronchiolar
adenomas
and
carcinomas
combined
was
reported
for
female
B6C3F
1
mice,
but
not
male
mice,
exposed
via
inhalation
to
30
ppm
naphthalene
for
6
hours/
day,
5
day/
week
for
2
years
(
NTP,
1992a).
However,
NTP
(
1992a)
concluded
that
the
study
provided
"
some
evidence"
only
of
carcinogenicity
in
female
mice,
but
not
"
clear
evidence,"
because
only
one
carcinoma
was
observed
(
U.
S.
EPA,
1998a).
In
a
similar
study,
NTP
(
2000)
examined
tumor
occurrence
in
F344/
N
rats
exposed
to
naphthalene
vapor
for
2
years.
Increased
incidences
of
two
types
of
nasal
tumors
were
noted
in
naphthalene­
treated
animals.
The
incidences
of
adenoma
of
the
respiratory
epithelium
were
increased
in
male
rats
exposed
to
10,
30,
and
60
ppm
(
approximately
3.6,
10.7,
and
20.1
mg/
kg­
day,
respectively).
The
incidence
of
neuroblastoma
of
the
olfactory
epithelium
was
significantly
increased
in
female
rats
exposed
to
60
ppm
(
approximately
20.6
mg/
kg­
day).
Because
these
tumors
did
not
occur
in
control
animals
and
because
the
historical
incidence
in
NTP
chamber
control
rats
is
low,
the
increased
incidence
of
these
tumors
in
naphthalene­
exposed
animals
was
considered
by
the
study
authors
to
be
"
clear
evidence"
of
carcinogenic
activity.

In
the
Adkins
et
al.
(
1986)
study,
A/
J
strain
mice
were
exposed
to
10
or
30
ppm
naphthalene
vapors
for
6
months.
Following
the
exposure
period,
excised
lungs
were
examined
for
pulmonary
adenomas.
Histopathological
study
of
lung
tissue
was
limited
to
the
examination
of
the
tumors.
Increased
numbers
of
adenomas
were
found
in
the
lungs
of
naphthalene­
exposed
mice
when
compared
to
the
control
group,
but
the
differences
were
not
statistically
significant.
A
significant
increase
in
the
number
of
alveolar
adenomas
per
tumor­
bearing
lung
was
reported
in
both
dose
groups.
However,
the
response
did
not
increase
with
increasing
dose.
Limitations
of
this
study
include
the
less­
than­
lifetime
exposure
duration
and
the
restricted
histopathology.

Several
studies
have
been
conducted
in
which
naphthalene
was
administered
by
routes
of
exposure
other
than
inhalation
or
diet
(
Schmähl,
1955;
Boyland
et
al.,
1964;
La
Voie
et
al.,
1988).
However,
no
carcinogenic
responses
were
observed
in
these
studies,
and
each
has
at
least
one
limitation
that
makes
it
inadequate
for
assessing
the
potential
for
lifetime
naphthalene
exposure
to
produce
cancer
(
U.
S.
EPA,
1998a).
7­
39
Naphthalene
 
February
2003
Table
7­
7.
Summary
of
Key
Studies
of
Noncancer
Toxic
Effects
of
Naphthalene
Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
Hemolytic
anemia
Zuelzer
and
Apt
(
1949)
Dog
3
410
1,530
262
(
average
of
7
daily
doses
ranging
from
74
to
441
mg/
kg)
Diet
single
dose
single
dose
7
days
­­
262
Hemolytic
anemia
observed
(
decreased
hemoglobin
and
hematocrit
concentrations,

development
of
Heinz
bodies
in
erythrocytes,

erythrocyte
fragmentation
and
reticulocytosis).

BCL
(
1980a)
Rat
(
F344)
Male
and
Female
10/
sex/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
5
days/
week
400
­­
No
indications
of
hemolytic
anemia
observed
BCL
(
1980b)
Mouse
(
B6CF
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
90
days
200
­­
No
indications
of
hemolytic
anemia
observed
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
40
 
112
0
27
53
267
Gavage
corn
oil
14
days
267
­­
Red
cell
hemolysis
not
observed
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
40
Naphthalene
 
February
2003
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
40
 
76
0
53
133
Gavage
corn
oil
90
days
53
­­
No
indications
of
hemolytic
anemia
observed
NTP
(
1992a)
Mouse
(
B6CF
1)
Male
and
Female
75
 
150
0
10
30
Inhalation
2
years
(
6
hr/
day;

5
days/
wk)
30
­­
No
changes
in
hematological
parameters
observed
after
14
days
Cataracts
Van
Heyningen
and
Pirie
(
1976)
Rabbits
(
Dutch,

albino)
Sex
not
stated
39
0
1,000
Gavage
oil
3
 
28
consecutive
daily
doses
­­
1,000
Cataracts
in
10/
16
Dutch
and
11/
12
albino
animals)

Rossa
and
Pau
(
1988)
Rabbits
(
Chinchilla
Bastard)
Sex
not
stated
4
0
1,000
Oral
Single
dose
­­
1,000
Cataracts
Rabbit
(
New
Zealand)
Sex
not
stated
4
0
1,000
Oral
4
biweekly
doses
­­
1,000
Cataracts
Orzalesi
et
al.

(
1994)
Rabbit
(
pigmented
Male
31
0
1,000
durationadjusted
500
Gavage
5
weeks
­­
500
Cataracts,
retinal
degeneration,
subretinal
neovascularization
Fitzhugh
and
Buschke
(
1949)
Weanling
rats
(
NS*)
 
a
2,000
(
estimated)
Diet
2
months
(
approx.)
­­
2,000
Mild
cataracts
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
41
Naphthalene
 
February
2003
Tao
et
al.
(
1991a,

b)
Rat
(
Brown
Norway)
Female
80
0
700
Gavage
102
days
­­
700
Lens
opacities
Koch
et
al.

(
1976)
Rats
(
Sprague­

Dawley,

Wistar,

albino)
 
a
0
1,000
Gavage
total
duration
not
specified;

cataracts
appeared
in
16
to
28
days.

Doses
administered
on
alternate
days
­­
1,000
Cataracts
Xu
et
al.
(
1992a,

b)
Rats
(
Sprague­

Dawley,

Wistar,

Lewis,

Long­

Evans
and
Brown
Norway)
Male
6
 
10
0
1,000
Gavage
oil
28
days
­­
1,000
Cataracts
Murano
et
al.

(
1993)
Rats
(
Brown
Norway,
Sprague­

Dawley)
Male
6
1,000
Gavage
6
weeks
(
administered
every
other
day)
­­
1,000
Cataracts
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
42
Naphthalene
 
February
2003
Shichi
et
al.

(
1980)
Mouse
(
C57BL/
6N
and
DBA/
2N)
Male
and
Female
15/
group
60
120
Diet
60
days
C57BL/
6N
mice:

­­
DBA/
2N
mice:

120
C57BL/
6N
mice:

60
DBA/
2N
mice:

­­
Cataracts
observed
in
C57BL/
6N
mice
(
1/
15)
at
each
dose
No
cataracts
observed
in
DBA/
2N
mice
Schmähl
(
1955)
Rat
(
in­
house
strain
BDI,

BDIII)
Male
and
Female
28
41
Food
2
years
Study
not
adequate
to
develop
LOAEL
or
NOAEL
­­
No
cataracts
observed
BCL
(
1980a)
Rat
(
Fisher
344)
Male
and
Female
10/
sex/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
(
5
days/
week)
400
­­
No
cataracts
observed
BCL
(
1980b)
Mouse
(
B6CF
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
13
weeks
(
5
days/
week)
200
Adjusted
143
­­
No
cataracts
observed
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
40
 
76
0
53
133
Gavage
90
days
133
­­
No
cataracts
observed
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
43
Naphthalene
 
February
2003
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
40
 
112
0
27
53
267
Gavage
corn
oil
14
days
267
­­
No
cataracts
observed
NTP
(
1992a)
Mouse
(
B6CF
1)
Male
and
Female
75
 
150
0
ppm
10
ppm
30
ppm
Inhalation
2
years
(
6
hr/
day;

5
days/
wk)
30
ppm*
­­
No
cataract
formation
observed
NTP
(
2000)
Rat
(
F344/
N)
Male
and
Female
49/
sex/
dose
0
3.6
 
3.9
10.7
 
11.4
20.1
 
20.6
Inhalation
2
years
20.1­
20.6
­­
No
cataracts
observed.

Srivastava
and
Nath
(
1969)
Rabbits
(
NS*)
NS
6
 
8
0
2,000
Gavage
5
days
­­
2,000
Cataracts
in
8/
8
animals
Yamauchi
et
al.

(
1986)
Rat
(
Wistar)
Male
4
 
5
0
1,000
Oral
18
days
­­
1,000
Cataracts
Rathbun
et
al.

(
1990)
Rat
(
Black­
Hooded)
NS
0
5,000
Gavage
79
days
­­
5,000
Lens
opacities
Rao
and
Pandya
(
1981)
Rat
(
NS)
Male
6
0
1,000
Gavage
10
days
1,000
­­
No
effects
observed
Ikemoto
and
Iwata
(
1978)
Rabbits
(
Albino)
Male
and
Female
NS
100
Oral
2
days
­­
1,000
Cataracts
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
44
Naphthalene
 
February
2003
Holmen
et
al.

(
1999)
Rat
(
Brown
Norway)
Female
3
 
15
0
100
500
1,000
1,500
Gavage
10
weeks
2
doses/
week
100
adjusted:

29
500
adjusted:

143
First
signs
of
ocular
changes
occurred
within
2.5
weeks
after
start
of
treatment,
leading
to
cataract
formation
Kojima
(
1992)
Rat
(
Brown
Norway)
Female
3
 
12
0
1,000
every
second
day
Gavage
4
weeks
­­
1,000
adjusted:
500
Lens
opacities
Nasal
Pulmonary
Lesions
Plasterer
et
al.

(
1985)
Mouse
Male
and
Female
33
 
40
250
500
Gavage
8
days
­­
500
No
exposure­
related
lesions
observed
in
any
organ
system
Germansky
and
Jamall
(
1988)
Rats,
weanling
(
Blue
Spuce)
Male
24
100
 
750
169
mg/

kgday
(
TWA)
9
weeks
169
­­
No
effect
observed
on
peroxidation
in
lung
BCL
(
1980b)
Mouse
(
B6CF
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
13
weeks
(
5days/
week)
200
No
exposure
related
leisons
observed
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
45
Naphthalene
 
February
2003
Adkins
et
al.

(
1986)
Rats
(
A/
J)
Female
30
0
ppm*

10
ppm
30
ppm
Inhalation
2
years
(
6
hr/
day;
5
days/
wk)
30
ppm
No
adverse
non­
cancer
effects
reported
on
the
lung
NTP
(
1992a)
Mouse
(
B6CF
1)
Male
and
Female
75
 
150
0
ppm*

10
ppm
30
ppm
Inhalation
2
years
(
6
hr/
day;

5
days/
wk)
­­
10
ppm*

(
for
chronic
nasal
and
respiratory
irritaiton)
Respiratory
tract
lesions
(
chronic
lung
inflammation,
chronic
nasal
irritation
with
hyperplasia
of
the
respiratory
epithelium,

metaplasia
of
the
nasal
epithelium)

NTP
(
2000)
Rat
(
F344/
N)
Male
and
Female
49/
sex/
dose
0
3.6
 
3.9
10.7
 
11.4
20.1
 
20.6
Inhalation
2
years
­­
3.6
 
3.9
Non­
neoplastic
lesions
of
the
nose
were
observed.

Body
Weight
BCL
(
1980a)
Rat
(
Fisher
344)
Male
and
Female
10/
sex/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
(
5
days/
wk)
100
200
Reduced
body
weight
(>
10%
males)

BCL
(
1980b)
Mouse
(
B6CF
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
13
weeks
(
5
days/
wk)
200
­­
No
effect
observed
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
46
Naphthalene
 
February
2003
NTP
(
1991)
Rat
Pregnant
Female
25
 
26
0
50
150
450
GD
6
 
15
50
(
for
maternal
toxicity)
150
Significant
decrease
in
weight
gain
(
150
and
450
dose
groups)

NTP
(
1992b)
Rabbit
(
New
Zealand,

White)
Pregnant
Female
25
 
27
0
20
80
120
Gavage
corn
oil
GD
6
 
19
120
­­
Maternal:
No
consistently
observed
toxicity
No
effect
on
fetal
body
weight
NTP
(
2000)
Rat
(
F344/
N)
Male
and
Female
49/
sex/
dose
0
3.6
 
3.9
10.7
 
11.4
20.1
 
20.6
Inhalation
2
years
20.1
 
20.6
­­
No
difference
in
mean
body
weights
observed.

Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
(
40
 
112)
0
27
53
267
Gavage
corn
oil
14
days
53
267
Decreased
body
weight
(
males
and
females)

Germansky
and
Jamall
(
1988)
Rats,
weanling
(
Blue
Spuce)
Male
24
100
 
750
169
(
TWA)
9
weeks
­­
169
Decreased
body
weight
(
20%)

NTP
(
1992a)
Mouse
(
B6CF
1)
Male
and
Female
75
 
150
0
ppm*

10
ppm
30
ppm
Inhalation
2
years
(
6hr/
day;
5
days/
week)
30
­­
No
significant
change
in
mean
body
weight
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
47
Naphthalene
 
February
2003
Holmen
et
al.

(
1999)
Rat
(
Brown
Norway)
Female
3
 
15
0
100
500
1,000
1,500
Gavage
10
weeks
2
doses/
week
500
adjusted:

143
1,000
adjusted:

285
Decreased
mean
body
weights
observed
in
rats
administered
1000
and
1500
mg/
kg.

Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
(
40
 
76)
0
53
133
Gavage
corn
oil
90
days
133
­­
No
effects
observed
on
body
weight
Organ
Weight
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
(
40
 
112)
0
27
53
267
Gavage
corn
oil
14
days
53
267
Decreased
thymus
weight
(
male)

Increased
spleen
and
lung
weights
(
female)

Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
and
Female
(
40
 
76)
0
53
133
Gavage
corn
oil
90
days
53
133
Decreased
brain,
liver,

and
spleen
wts.
(
Female
only)

No
effects
observed
on
organ
weights
from
all
exposure
groups
(
male)

Rao
and
Pandya
(
1981)
Rats
(
NS)
Males
6
0
1,000
10
days
­­
1,000
Increased
liver
weight
(
39%)

Nervous
System
Depression
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
48
Naphthalene
 
February
2003
BCL
(
1980a)
Rat
(
Fisher
344)
Male
and
Female
10/
sex/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
(
5
days/
wk)
­­
400
Lethargy
observed
in
highest
dose
group
(
400
mg/
kg­
day)
for
males
and
females
BCL
(
1980b)
Mouse
(
B6CF
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
13
weeks
(
5
days/
wk)
­­
200
Transient
signs
of
lethargy
observed
in
highest
dose
groups
during
weeks
3
and
5
PRI
(
1986)
Rabbit
(
New
Zealand
White)
Female
18
0
40
200
400
Gavage
Methylcellulose
GD
6
 
18
40
200
Treatment
related
signs
of
labored
breathing,

body
drop,
decreased
activity
and
salivation
were
observed.

NTP
(
1991)
Rat
(
Sprague­

Dawley)
Pregnant
Females
25
 
26
0
50
150
450
Gavage
10
days
(
GD
6
 
15)
­­
50
Neurotoxic
effects
observed
in
all
dose
groups
(
lethargy,
slow
respiration,
periods
of
apnea,
apparent
inability
to
move
after
dosing).

Effects
were
transient,

and
diminished
with
continued
exposure.
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
49
Naphthalene
 
February
2003
NTP
(
1992a)
Mice
Male
0ppm*

10
ppm
30
ppm
Inhalation
2
years
­­
­­
Increased
huddling
behavior
during
exposure
and
reduced
inclination
to
fight
(
may
indicate
neurological
effects,

although
basis
for
behavioral
changes
were
not
speculated
on
by
authors).

No
additional
signs
of
neurotoxicity
reported.

BCL
(
1980a)
Rats
(
Fisher
344)
Male
and
Female
10/
sex/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
(
5
days/
wk)
400
­­
No
neurological
effects
found.

BCL
(
1980b)
Mice
(
B6C3F
1)
Male
and
Female
10/
sex/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
13
weeks
(
5
days/
wk)
200
­­
No
neurological
effects
found.
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
50
Naphthalene
 
February
2003
Developmental
Toxicity
Plasterer
et
al.

(
1985)
Mouse
(
CD­
1)
Female
33
 
40
0
300
Gavage
corn
oil
GD
7
 
14
­­
300
(
FEL)
Maternal:
Reduced
wt.

gain;
reduced
survival
Fetal:
Reduced
no.
of
pups/
litter;
no
abnormalities
in
surviving
pups
PRI
(
1985)
Rabbit
(
New
Zealand
White)
Female
4
0
50
250
630
1,000
Gavage
Methylcellulose
GD
6
 
18
Maternal
250
Fetal
250
Maternal
630
(
FEL)

Fetal
630
(
abortion)
Maternal:
Mortality
and
decreased
wt.
gain
at
630
mg/
kg­
day
Fetal:
Aborted
at
630
mg/
kg­
day
PRI
(
1986)
Rabbit
(
New
Zealand
White)
Female
18
0
40
200
400
Gavage
Methylcellulose
GD
6
 
18
Maternal
400
Fetal
400
Maternal
­
Fetal
­
Maternal:
survival,
body
wt.
and
body
wt.
gain
unaffected
Fetal:
No
effect
on
reproduction
or
development
of
fetus
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
51
Naphthalene
 
February
2003
NTP
(
1991)
Rat
(
Sprague­

Dawley
CD)
Female
25
 
26
0
50
150
450
Gavage
GD
6
 
15
Maternal
 
Fetal
450
Maternal
50
(
central
nervous
system
depression)

Fetal
­­
Maternal:
Central
nervous
system
depression
manifested
as
lethargy,
slow
breathing,

prone
body
posture,
and
increased
rooting
Decreased
weight
gain
(
150
and
450
mg/
kg­
day)

Fetal:
no
finding
of
fetal
toxicity
or
embryo
toxicity
NTP
(
1992b)
Rabbit
(
New
Zealand,

White)
Female
25
 
27
0
20
80
120
Gavage
oil
GD
6
 
19
Maternal
120
Fetal
120
Maternal
­­
Fetal
­­
Maternal:
Two
deaths
in
low­
dose
group
Fetal:
No
effect
on
reproduction
or
development
of
fetus
Shopp
et
al.

(
1984)
Mouse
(
CD­
1)
Male
76
 
112
0
27
53
267
Gavage
oil
14
267
­­
No
effect
on
testicular
weight
Male
76
 
96
53
133
Gavage
oil
90
133
­­
No
effect
on
testicular
weight
Table
7­
7
(
continued)

Study
Species
(
Strain)
Sex
n
Doses
mg/
kg­
day
Route
Duration
NOAEL
LOAEL
Effect
mg/
kg­
day
7­
52
Naphthalene
 
February
2003
BCL
(
1980a)
Rat
(
F344)
Male
10/
dose
0
25
50
100
200
400
Gavage
corn
oil
13
weeks
5
days/
week
400
­­
Absence
of
gross
testicular
lesions
BCL
(
1980b)
Mouse
(
B6C3F
1)
Male
10/
dose
0
12.5
25
50
100
200
Gavage
corn
oil
90
days
200
­­
Absence
of
gross
testicular
lesions
*
Dose
conversion
not
provided
in
study
or
secondary
source
material
NS
Not
stated
7­
53
Naphthalene
 
February
2003
7.4.3
Mode
of
Action
and
Implications
in
Cancer
Assessment
Data
are
not
available
to
clearly
identify
a
mode
of
action
that
would
contribute
to
the
carcinogenic
potential
of
naphthalene.
Buckpitt
and
Franklin
(
1989)
hypothesized
that
oxygenated
reactive
metabolites
of
naphthalene
produced
via
the
cytochrome
P­
450
monooxygenase
system
mediate
the
development
of
benign
respiratory
tract
tumors
and
cytotoxic
effects
by
reaction
with
cellular
macromolecules.
Because
the
majority
of
the
genotoxicity
tests
are
negative,
it
appears
unlikely
that
naphthalene
represents
a
genotoxic
hazard
(
U.
S.
EPA,
1998a).
The
development
of
benign
and
malignant
respiratory
tract
tumors
in
mice
(
NTP,
1992a)
and
rats
(
NTP,
2000)
may
alternatively
be
explained
by
the
hyperplasia
seen
in
the
epithelia
of
the
respiratory
tract
(
ATSDR,
1995).
Rapid
cell
division
in
response
to
tissue
injury
may
lead
to
tumorigenesis
when
precancerous
cells
that
are
present
in
the
tissue
are
stimulated
to
divide
(
Ames
and
Gold,
1990).

7.4.4
Weight
of
Evidence
Evaluation
for
Carcinogenicity
Applying
the
criteria
described
in
U.
S.
EPA's
guidelines
for
the
assessment
of
carcinogenic
risk
(
U.
S.
EPA,
1986a),
IRIS
classified
naphthalene
as
Group
C:
possible
human
carcinogen.
This
classification
was
based
on
inadequate
human
data
following
exposure
to
naphthalene
via
the
oral
and
inhalation
routes,
and
on
evidence
of
carcinogenicity
in
animals
following
exposure
via
the
inhalation
route
(
U.
S.
EPA,
1998b).
Using
the
1996
Proposed
Guidelines
for
Carcinogen
Risk
Assessment,
the
human
carcinogenic
potential
of
naphthalene
via
the
oral
or
inhalation
routes
is
classified
in
IRIS
as
"
cannot
be
determined."

At
the
time
of
the
IRIS
review,
only
one
animal
(
mouse)
bioassay
had
been
conducted
for
naphthalene
(
NTP,
1992).
The
bioassay
in
mice
showed
no
evidence
for
carcinogenicity
in
males
and
some
evidence
in
females.
All
tumors
were
in
the
respiratory
track.
In
the
recent
(
NTP,
2000)
bioassay
in
rats,
there
was
clear
evidence
of
carcinogenicity
within
the
nasal
cavity
for
males
and
females.
Accordingly,
carcinogenicity
via
the
inhalation
route
may
need
to
be
reevaluated.
The
observed
effects
appear
to
be
route
specific
since
tumors
were
only
identified
in
the
respiratory
tract
in
both
studies.

When
considering
the
naphthalene
tumorigenicity
data
in
the
light
of
the
new
NTP
study,
there
is
a
need
to
reevaluate
the
cancer
classification
for
the
inhalation
route
of
exposure.
By
the
oral
route,
data
are
inadequate
to
support
a
judgment
and,
thus,
naphthalene
would
be
classified
as
Group
D
(
not
classifiable).
Most
of
the
studies
of
naphthalene
genotoxicity
are
negative
and
indicate
a
weak
potential
to
affect
DNA;
naphthalene
does
not
appear
to
be
mutagenic.
Hyperplastic
response
to
inflammation
and
irritation
of
the
respiratory
epithelium
appear
to
be
related
to
the
development
of
tumors
in
the
nasal
cavity
and
lungs.
7­
54
Naphthalene
 
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2003
7.4.5
Potentially
Sensitive
Populations
Glucose­
6­
phosphate
dehydrogenase
(
G6PD)­
Deficient
Populations
Increased
sensitivity
to
naphthalene­
induced
hemolysis
has
been
associated
with
reduced
levels
of
glucose­
6­
phosphate
dehydrogenase
(
G6PD).
This
enzyme
helps
to
protect
red
blood
cells
from
oxidative
damage,
and
G6PD
enzyme
deficiency
makes
the
cells
more
sensitive
to
a
wide
variety
of
toxicants,
including
naphthalene.
Higher
rates
of
inherited
G6PD
deficiencies
are
found
more
often
in
defined
subpopulations
of
males
from
Asian,
Arab,
Caucasian
(
of
Latin
ancestry),
African,
and
African­
American
ancestry
than
in
other
groups
(
U.
S.
EPA,
1987b).
Multiple
forms
of
G6PD
deficiency
have
been
identified
in
these
subpopulations.
The
mildest
forms
are
totally
asymptomatic,
while
moderate
forms
are
associated
with
an
adverse
response
to
chemical
stressors,
including
naphthalene.
The
most
severe
forms
of
G6PD
deficiency
are
associated
with
hemolytic
anemia,
even
in
the
absence
of
external
stressors
(
Beutler,
1991).
The
overall
prevalence
of
G6PD­
deficiency
in
the
United
States
is
reported
to
be
5.2
to
11.5%
(
Luzzatto
and
Mehta,
1989).

One
of
the
most
common
forms
of
G6PD
deficiency
is
the
G6PDA­
variant.
This
form
is
relatively
mild
and
is
common
in
African
populations.
It
also
occurs
in
southern
European
populations.
The
other
major
form
of
G6PD
deficiency
is
the
more
severe
"
Mediterranean"
form,
which
is
most
prevalent
in
southern
European
and
Indian
populations.
There
are
many
variants
(
corresponding
to
specific
point
mutations)
within
each
major
class
of
G6PD
deficiency.

There
is
very
little
information
related
to
the
precise
types
of
G6PD
variants
and
genotypes
that
are
most
likely
to
be
associated
with
adverse
effects
from
naphthalene.
Owa
(
1989)
found
that
the
incidence
of
neonatal
jaundice
among
G6PD­
deficient
African
neonates
was
positively
correlated
with
exposure
to
naphthalene,
while
there
was
no
correlation
in
infants
with
normal
G6PD
levels.
In
this
study,
G6PD
levels
were
measured
using
an
enzyme
screening
test,
but
the
genotype
and
severity
of
the
deficiencies
were
not
indicated.
Valaes
et
al.
(
1963)
reported
adverse
effects
in
21
Greek
infants
exposed
to
naphthalene
from
clothing,
diapers,
blankets,
and
other
items
that
had
been
stored
in
contact
with
mothballs.
Ten
of
the
21
anemic
children
and
1
of
the
2
infants
that
died
from
naphthalene
exposure
had
a
genetic
polymorphism
that
resulted
in
a
deficiency
in
G6PD.
The
genotype
of
this
polymorphism
was
not
reported
in
the
sources
reviewed
for
this
document.

Santucci
and
Shah
(
2000)
conducted
a
10­
year
retrospective
chart
review
at
an
inner­
city
hospital
to
determine
the
prevalence
and
severity
of
naphthalene­
associated
hemolysis
in
G6PDdeficient
children
aged
2
to
18
years.
The
sample
population
was
predominately
(>
90%)
African­
American.
Twenty­
four
children
were
identified
by
chart
review
as
having
experienced
an
acute
hemolytic
crisis.
Of
this
group,
14
had
documented
exposures
to
naphthalenecontaining
products.
Six
children
ingested
mothballs,
one
ate
naphthalene
flakes,
five
had
played
in
a
room
where
naphthalene­
containing
products
were
available,
and
two
were
wearing
clothing
stored
in
a
closet
with
a
naphthalene­
containing
product.
The
remaining
cases
of
hemolytic
anemia
were
attributed
to
infectious
causes.
When
a
quantitative
test
was
administered
for
G6PD
deficiency
at
admission,
58%
of
the
naphthalene
group
had
results
within
the
normal
range.
However,
when
retested
after
recovery,
all
patients
had
uniformly
deficient
levels
of
7­
55
Naphthalene
 
February
2003
G6PD.
The
study
authors
noted
that
"
normal"
levels
of
G6PD
are
to
be
expected
in
cases
with
severe
anemia
in
the
presence
of
normally
functioning
bone
marrow.
In
this
case,
reticulocytosis
will
give
a
normal
result
for
the
G6PD
analysis
because
of
the
presence
of
immature
blood
cells
which
have
adequate
G6PD
stores.
A
cross­
sectional
survey
was
conducted
in
parallel
to
the
chart
review
to
document
use
of
mothballs
in
the
study
population.
About
25%
of
the
study
population
used
mothballs
compared
to
15%
of
the
population
in
a
more
culturally
diverse
suburban
population
sample.
An
unexpected
finding
was
that
mothballs
were
used
for
previously
unrecognized
reasons,
including
air­
freshening
and
as
a
roach
repellant
in
the
inner
city.

Potential
Gender
Sensitivity
Most
forms
of
G6PD
deficiency
arise
from
X­
linked
somatic
mutations
(
Beutler,
1991),
which
means
that
males,
having
only
one
X­
chromosome,
cannot
be
heterozygous
for
the
trait.
In
contrast,
females
that
are
heterozygous
for
G6PD
deficiency
are
"
mosaic,"
and
usually
have
two
distinct
populations
of
red
blood
cells,
one
with
normal
G6PD,
and
the
other
with
the
aberrant
form
of
the
enzyme.

There
is
evidence
from
two
studies
to
suggest
that
in
humans,
males
are
more
sensitive
to
naphthalene
than
females.
Owa
et
al.
(
1993)
examined
the
relationship
between
neonatal
anemia
and
naphthalene
exposure
and
reported
a
sex
ratio
of
7:
3
(
males
to
females)
in
the
affected
infants.
This
finding
is
consistent
with
a
higher
susceptibility
to
red
cell
damage
in
homozygous
males.

Valaes
et
al.
(
1963)
also
reported
a
high
male­
to­
female
ratio
(
16:
5)
among
infants
with
neonatal
hemolysis
who
had
been
exposed
to
naphthalene.
Using
a
semi­
quantitative
enzyme
assay,
this
research
group
classified
ten
of
the
affected
infants
as
G6PD
"
deficient,"
two
as
"
intermediate,"
and
nine
as
"
normal."
All
of
the
affected
females
were
classified
as
having
normal
G6PD
levels,
but
the
study
authors
noted
that
the
possibility
of
heterozygosity
cannot
be
ruled
out
in
this
group.
Being
identified
as
G6PD­
deficient
was
positively
correlated
with
the
occurrence
of
severe
adverse
outcomes
including
kernicterus
and
death.
All
of
the
severe
outcomes
(
including
two
deaths)
were
seen
in
males.

U.
S.
EPA
(
1998a)
summarized
information
on
potential
gender
sensitivity
in
animals.
Consistent
gender
differences
in
susceptibility
have
not
been
identified
across
animal
studies
of
naphthalene.
Males
and
female
mice
displayed
similar
incidences
of
non­
tumor
nasal
and
pulmonary
tract
lesions
when
exposed
to
naphthalene
by
inhalation
for
2
years
(
NTP,
1992a).
In
the
same
study,
the
incidence
of
alveolar/
bronchiolar
adenomas
was
significantly
increased
in
females,
but
not
males.
Male
and
female
rats
both
exhibited
dose­
dependent
decreases
in
body
weight
gain
and
terminal
body
weight
following
subchronic
oral
exposure
(
BCL,
1980a).
However,
the
effect
reached
statistical
significance
at
a
lower
dose
in
males
(
200
mg/
kg­
day
vs.
400
mg/
kg­
day).
7­
56
Naphthalene
 
February
2003
Neonates,
Infants,
and
Fetuses
Neonates
and
infants
in
general
are
thought
to
be
more
susceptible
to
the
adverse
effects
of
naphthalene
exposure
than
adults
because
the
liver
enzyme
systems
that
conjugate
naphthalene
metabolites
are
not
well­
developed
(
U.
S.
EPA,
1987b).
Fetuses
may
also
experience
greater
susceptibility
for
the
same
reason.
In
addition,
the
activity
of
methemoglobin
reductase
is
low
in
infants.
This
enzyme
catalyzes
the
reduction
of
methemoglobin,
a
chemically­
oxidized
form
of
hemoglobin
that
is
formed
in
association
with
naphthalene­
induced
hemolytic
anemia.
Low
levels
of
this
enzyme
prevent
regeneration
and
may
prolong
and/
or
compound
the
effects
of
hemolytic
anemia.
8­
1
Naphthalene
 
February
2003
8.0
DOSE­
RESPONSE
ASSESSMENT
8.1
Dose­
Response
for
Noncancer
Effects
The
derivations
of
the
reference
dose
(
RfD)
and
reference
concentration
(
RfC)
for
naphthalene
are
described
below.
The
RfD
is
an
estimate
of
the
daily
oral
exposure
to
the
human
population
that
is
likely
to
be
without
appreciable
risk
of
deleterious
effects
over
a
lifetime.
The
RfC
is
an
estimate
of
the
daily
inhalation
exposure
to
the
human
population
that
is
likely
to
be
without
appreciable
risk
of
deleterious
effects
over
a
lifetime.

8.1.1
RfD
Determination
The
RfD
typically
is
derived
from
the
NOAEL
(
or
LOAEL)
identified
from
a
chronic
(
or
subchronic)
study.
Alternatively,
the
RfD
may
be
derived
using
a
benchmark
dose
modeling
approach
(
U.
S.
EPA,
1995).

U.
S.
EPA
(
1998a,
b)
extensively
evaluated
the
toxicity
data
for
naphthalene,
and
developed
the
existing
RfD
using
a
conventional
NOAEL/
LOAEL
approach.
Because
there
are
no
adequate
data
for
chronic
effects
in
humans
or
animals,
the
RfD
for
naphthalene
is
based
on
the
subchronic
rat
study
conducted
by
BCL
(
1980a).
In
this
study,
naphthalene
(>
99%
pure,
in
corn
oil)
was
administered
to
groups
of
Fischer
344
rats
(
10/
dose/
sex),
5
days
per
week
for
13
weeks.
Unadjusted
daily
dose
levels
were
0,
25,
50,
100,
200,
or
400
mg/
kg­
day.
Weekly
food
consumption
and
body
weights
were
measured,
and
rats
were
examined
twice
daily
for
clinical
signs
of
adverse
effects.
Hematological
parameters
(
hemoglobin,
hematocrit,
total
and
differential
white
cell
count,
red
blood
cell
count,
mean
cell
volume,
and
mean
cell
hemoglobin)
were
measured
in
all
animals.
All
rats
were
necropsied,
and
detailed
histopathological
examinations
were
performed
on
27
tissues
from
all
rats
in
the
control
and
400
mg/
kg­
day
groups.
The
tissues
examined
included
eyes,
stomach,
liver,
reproductive
organs,
thymus,
and
kidneys.
In
the
100­
mg/
kg­
day
group,
the
kidneys
of
males
and
thymus
of
females
were
subject
to
detailed
histopathological
examinations.
Male
and
female
rats
in
the
400
mg/
kg­
day
dose
group
exhibited
diarrhea,
lethargy,
hunched
posture,
and
rough
coats
during
the
study,
and
one
high­
dose
male
rat
died
during
the
last
week
of
exposure.
Food
consumption
was
not
affected
in
any
dose
group,
but
body
weights
were
markedly
decreased
(
by
at
least10%)
both
in
males
at
200
mg/
kg­
day
and
in
females
receiving
400
mg/
kg­
day.
NOAEL
and
LOAEL
values
of
100
mg/
kg­
day
and
200
mg/
kg­
day
were
identified
from
this
study
based
on
body
weight
reduction
in
male
rats.
The
corresponding
duration­
adjusted
NOAEL
and
LOAEL
values
are
71
mg/
kg­
day
and
143
mg/
kg­
day,
respectively.

A
composite
UF
of
3,000
was
used
to
estimate
a
chronic
RfD
from
the
duration­
adjusted
NOAEL
of
71
mg/
kg­
day.
The
composite
UF
included
a
factor
of
10
to
extrapolate
from
rats
to
humans,
a
factor
of
10
to
account
for
the
protection
of
sensitive
human
populations,
a
factor
of
10
to
extrapolate
from
subchronic
to
chronic
exposures,
and
a
factor
of
3
for
database
deficiencies
(
U.
S.
EPA,
1998a).
Dividing
the
NOAEL
by
3,000
results
in
an
RfD
value
of
2
×
10­
2
mg/
kg­
day.
8­
2
Naphthalene
 
February
2003
RfD
=
71
mg/
kg­
day
=
0.02
mg/
kg/
day
3000
A
benchmark
dose
modeling
approach
was
also
explored
for
derivation
of
the
naphthalene
RfD
(
U.
S.
EPA,
1998a).
Modeling
of
terminal
body
weight
decrease
resulted
in
benchmark
doses
of
130
and
135
mg/
kg­
day.
Following
adjustment
of
these
doses
for
a
five
day/
week
dosing
regimen
and
division
by
a
composite
UF
of
3,000
(
determined
as
for
the
NOAEL/
LOAEL
approach
above),
an
RfD
of
3
×
10­
2
mg/
kg­
day
was
obtained.
This
value
is
very
similar
to
the
value
of
2
×
10­
2
mg/
kg­
day
derived
using
the
conventional
NOAEL/
LOAEL
approach.

8.1.2
RfC
Determination
U.
S.
EPA
(
1998a,
b)
derived
an
inhalation
pathway
Reference
Concentration
(
RfC)
for
naphthalene
exposure.
This
value
may
have
some
relevance
to
naphthalene
exposure
from
drinking
water,
since
a
potential
exists
for
indoor
air
release
during
water
use.
An
overview
of
the
RfC
calculations
are
provided
below.

The
RfC
was
derived
using
data
from
the
NTP
(
1992a)
study
of
adverse
effects
from
chronic
naphthalene
inhalation
on
mice
at
10
and
30
ppm
using
the
conventional
NOAEL/
LOAEL
approach.
The
nasal
effects
from
naphthalene
were
considered
to
be
extrarespiratory
effects
of
a
category
3
gas,
as
defined
in
U.
S.
EPA
(
1994b).
Following
the
guidance
provided
by
U.
S.
EPA
(
1994b),
experimental
concentrations
were
converted
to
mg/
m3
(
0,
52,
and
28
mg/
m3)
and
converted
to
a
continuous
exposure
basis
(
mg/
m3
×
6
hours/
24
hours
×
5
days/
7days).
The
resulting
values
were
converted
to
human
equivalent
concentrations
(
HECs)
by
multiplying
the
adjusted
concentrations
by
the
ratio
of
mouse:
human
blood/
gas
partition
coefficients.
Because
blood/
gas
coefficients
were
not
available
for
naphthalene,
the
default
ratio
of
one
was
used.

The
adjusted
LOAEL
(
HEC)
for
nasal
effects
(
hyperplasia
in
respiratory
epithelium
and
metaplasia
in
olfactory
epithelium)
was
divided
by
an
UF
of
3,000.
The
UF
value
included
a
factor
of
10
to
extrapolate
from
mice
to
humans,
a
factor
of
10
to
account
for
protection
of
sensitive
human
populations,
a
factor
of
10
to
extrapolate
from
a
LOAEL
to
a
NOAEL,
and
a
factor
of
3
to
account
for
deficiencies
in
the
database.
The
resulting
chronic
RfC
value
is
3
×
10­
3
mg/
m3.

8.2
Dose­
Response
for
Cancer
Effects
Because
chronic
oral
data
are
lacking
and
because
evidence
is
weak
that
naphthalene
may
be
carcinogenic
in
humans,
no
quantitative
cancer
dose­
response
assessment
for
naphthalene
has
been
conducted.
The
available
human
data
are
inadequate
to
evaluate
a
plausible
association
with
cancer.
Although
statistically
significant
increases
in
the
incidences
of
respiratory
system
tumors
were
reported
in
mice
(
lung)
and
rats
(
nasal
cavity)
exposed
to
naphthalene
via
inhalation
for
2
years
(
NTP,
1992a,
2000),
this
evidence
is
considered
insufficient
to
assess
the
carcinogenic
potential
of
naphthalene
in
humans
exposed
via
the
oral
route
(
U.
S.
EPA,
1998a).
9­
1
Naphthalene
 
February
2003
9.0
REGULATORY
DETERMINATION
AND
CHARACTERIZATION
OF
RISK
FROM
DRINKING
WATER
9.1
Regulatory
Determination
for
Chemicals
on
the
CCL
The
Safe
Drinking
Water
Act
(
SDWA),
as
amended
in
1996,
required
the
Environmental
Protection
Agency
(
EPA)
to
establish
a
list
of
contaminants
to
aid
the
Agency
in
regulatory
priority
setting
for
the
drinking
water
program.
EPA
published
a
draft
of
the
first
Contaminant
Candidate
List
(
CCL)
on
October
6,
1997
(
62
FR
52193,
U.
S.
EPA,
1997).
After
review
of
and
response
to
comments,
the
final
CCL
was
published
on
March
2,
1998
(
63
FR
10273,
U.
S.
EPA,
1998).
The
CCL
grouped
contaminants
into
three
major
categories
as
follows:

Regulatory
Determination
Priorities
­
Chemicals
or
microbes
with
adequate
data
to
support
a
regulatory
determination,

Research
Priorities
­
Chemicals
or
microbes
requiring
research
for
health
effects,
analytical
methods,
and/
or
treatment
technologies,

Occurrence
Priorities
­
Chemicals
or
microbes
requiring
additional
data
on
occurrence
in
drinking
water.

The
March
2,
1998
CCL
included
one
microbe
and
19
chemicals
in
the
regulatory
determination
priority
category.
More
detailed
assessments
of
the
completeness
of
the
health,
treatment,
occurrence,
and
analytical
method
data
led
to
a
subsequent
reduction
of
the
regulatory
determination
priority
chemicals
to
a
list
of
12
(
one
microbe
and
11
chemicals)
which
was
distributed
to
stakeholders
in
November
1999.

SDWA
requires
EPA
to
make
regulatory
determinations
for
no
fewer
than
five
contaminants
in
the
regulatory
determination
priority
category
by
August,
2001.
In
cases
where
the
Agency
determines
that
a
regulation
is
necessary,
the
regulation
should
be
proposed
by
August
2003
and
promulgated
by
February
2005.
The
Agency
is
given
the
freedom
to
also
determine
that
there
is
no
need
for
a
regulation
if
a
chemical
on
the
CCL
fails
to
meet
one
of
three
criteria
established
by
SDWA
and
described
in
section
9.1.1.

9.1.1
Criteria
for
Regulatory
Determination
These
are
the
three
criteria
used
to
determine
whether
or
not
to
regulate
a
chemical
on
the
CCL:

The
contaminant
may
have
an
adverse
effect
on
the
health
of
persons,

The
contaminant
is
known
to
occur
or
there
is
a
substantial
likelihood
that
the
contaminant
will
occur
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern,
9­
2
Naphthalene
 
February
2003
In
the
sole
judgment
of
the
administrator,
regulation
of
such
contaminant
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.

The
findings
for
all
criteria
are
used
in
making
a
determination
to
regulate
a
contaminant.
As
required
by
the
SDWA,
a
decision
to
regulate
commits
the
EPA
to
publication
of
a
Maximum
Contaminant
Level
Goal
(
MCLG)
and
promulgation
of
a
National
Primary
Drinking
Water
Regulation
(
NPDWR)
for
that
contaminant.
The
agency
may
determine
that
there
is
no
need
for
a
regulation
when
a
contaminant
fails
to
meet
one
of
the
criteria.
A
decision
not
to
regulate
is
considered
a
final
Agency
action
and
is
subject
to
judicial
review.
The
Agency
can
choose
to
publish
a
Health
Advisory
(
a
nonregulatory
action)
or
other
guidance
for
any
contaminant
on
the
CCL
independent
of
the
regulatory
determination.

9.1.2
National
Drinking
Water
Advisory
Council
Recommendations
In
March
2000,
the
EPA
convened
a
Working
Group
under
the
National
Drinking
Water
Advisory
Council
(
NDWAC)
to
help
develop
an
approach
for
making
regulatory
determinations.
The
Working
Group
developed
a
protocol
for
analyzing
and
presenting
the
available
scientific
data
and
recommended
methods
to
identify
and
document
the
rationale
supporting
a
regulatory
determination
decision.
The
NDWAC
Working
Group
report
was
presented
to
and
accepted
by
the
entire
NDWAC
in
July
2000.

Because
of
the
intrinsic
difference
between
microbial
and
chemical
contaminants,
the
Working
Group
developed
separate
but
similar
protocols
for
microorganisms
and
chemicals.
The
approach
for
chemicals
was
based
on
an
assessment
of
the
impact
of
acute,
chronic,
and
lifetime
exposures,
as
well
as
a
risk
assessment
that
includes
evaluation
of
occurrence,
fate,
and
dose­
response.
The
NDWAC
protocol
for
chemicals
is
a
semi­
quantitative
tool
for
addressing
each
of
the
three
CCL
criteria.
The
NDWAC
requested
that
the
Agency
use
good
judgment
in
balancing
the
many
factors
that
need
to
be
considered
in
making
a
regulatory
determination.

The
EPA
modified
the
semi­
quantitative
NDWAC
suggestions
for
evaluating
chemicals
against
the
regulatory
determination
criteria
and
applied
them
in
decision­
making.
The
quantitative
and
qualitative
factors
for
naphthalene
that
were
considered
for
each
of
the
three
criteria
are
presented
in
the
sections
that
follow.

9.2
Health
Effects
The
first
criterion
asks
if
the
contaminant
may
have
an
adverse
effect
on
the
health
of
persons.
Because
all
chemicals
have
adverse
effects
at
some
level
of
exposure,
the
challenge
is
to
define
the
dose
at
which
adverse
health
effects
are
likely
to
occur,
and
estimate
a
dose
at
which
adverse
health
effects
are
either
not
likely
to
occur
(
threshold
toxicant),
or
have
a
low
probability
for
occurrence
(
non­
threshold
toxicant).
The
key
elements
that
must
be
considered
in
evaluating
the
first
criterion
are
the
mode
of
action,
the
critical
effect(
s),
the
dose­
response
for
critical
effect(
s),
the
RfD
for
threshold
effects,
and
the
slope
factor
for
nonthreshold
effects.
9­
3
Naphthalene
 
February
2003
A
full
description
of
the
health
effects
associated
with
exposure
to
naphthalene
is
presented
in
Chapter
7
of
this
document
and
summarized
below
in
Section
9.2.2
Chapter
8
and
Section
9.2.3
present
dose­
response
information.

9.2.1
Health
Criterion
Conclusion
The
available
toxicological
data
indicate
that
naphthalene
has
the
potential
to
cause
adverse
health
effects
in
humans
and
animals.
In
humans,
hemolytic
anemia
is
the
most
common
manifestation
of
naphthalene
toxicity.
The
dose­
response
relationship
for
hemolytic
anemia
is
not
well­
characterized
in
animals
or
humans,
but
one
instance
occurred
following
a
single
oral
dose
of
approximately
109
mg/
kg
(
Gidron
and
Leurer,
1956).
Indications
of
naphthalene
toxicity
in
rats
and
mice
include
reduced
body
weight,
changes
in
organ
weight,
signs
of
neurotoxicity,
and,
at
high
doses,
cataracts.
Hemolytic
anemia
has
been
observed
in
dogs
administered
naphthalene.
Review
of
animal
dose­
response
data
indicates
that
short­
term
and
subchronic
LOAEL
values
for
naphthalene
toxicity
are
in
the
range
of
50
to
267
mg/
kg­
day.
The
RfD
for
naphthalene
is
2
×
10­
2
mg/
kg­
day.
Naphthalene
does
not
appear
to
be
a
carcinogen
by
the
oral
route
of
exposure.
Based
on
these
considerations,
the
evaluation
of
the
first
criterion
for
naphthalene
is
positive:
naphthalene
may
have
an
adverse
effect
on
human
health.

9.2.2
Hazard
Characterization
and
Mode
of
Action
Implications
Data
for
the
human
health
effects
of
naphthalene
are
limited.
Medical
case
reports
of
accidental
and
intentional
ingestion
identify
hemolytic
anemia
and
cataracts
as
significant
outcomes
of
oral
exposure
in
humans.
Case
reports
of
individuals
(
primarily
infants)
exposed
to
naphthalene
via
dermal
contact,
inhalation,
or
a
combination
of
both
exposure
routes
point
to
hemolytic
anemia
and
its
sequelae
as
the
most
commonly
manifested
toxic
effects
in
humans
following
exposure
at
concentrations
that
exceed
average
environmental
levels.
There
are
no
reliable
human
toxicity
data
for
subchronic
or
chronic
exposure
to
naphthalene.

In
animals,
acute
or
subchronic
exposure
to
relatively
high
oral
doses
(
200
to
700
mg/
kg
or
greater)
of
naphthalene
resulted
in
hemolytic
anemia
(
dogs
only)
and
cataracts
(
rats
and
rabbits).
Lower
oral
doses
of
naphthalene
(
less
than
200
to
400
mg/
kg)
administered
to
rats
and
mice
in
three
subchronic
studies
resulted
in
decreased
body
weight,
central
nervous
system
depression,
and
altered
organ
weights,
but
did
not
result
in
hemolytic
anemia
or
cataracts.
No
treatment­
related
lesions
were
observed
in
studies
reporting
histopathology.
A
limitation
of
the
health
effects
database
for
naphthalene
is
the
lack
of
adequately
designed
chronic
oral
exposure
studies
in
animals.

There
is
no
evidence
of
developmental
effects
in
animals
after
exposure
to
naphthalene
doses
of
120
mg/
kg
or
less.
Developmental
studies
at
higher
doses
produced
inconsistent
results
with
regard
to
maternal
and
fetal
effects.

The
available
data
for
mode
of
action
indicate
that
oxidative
metabolism
of
naphthalene
following
oral
or
inhalation
exposure
produces
a
variety
of
reactive
metabolites.
These
metabolites
subsequently
react
with
cellular
macromolecules
to
elicit
toxicity
in
target
tissues
such
as
the
blood,
eye,
and
(
in
animal
inhalation
studies)
nose
and
lung.
Direct
exposure
of
the
9­
4
Naphthalene
 
February
2003
cells
lining
the
respiratory
track
causes
inflammation,
tissue
damage
and
hyperplasia.
Although
naphthalene
does
not
appear
to
be
directly
genotoxic,
long­
term
inhalation
exposure
of
mice
and
rats
has
caused
development
of
adenomas
and
carcinomas
in
the
nasal
cavity
(
rats)
and
lungs
(
female
mice).
Naphthalene
does
not
appear
to
be
carcinogenic
by
the
oral
route.

Individuals
with
impaired
cellular
defense
capabilities
may
be
more
susceptible
to
naphthalene
toxicity.
The
finding
that
individuals
deficient
in
the
enzyme
glucose­
6­
phosphate
dehydrogenase
(
G6PD)
are
more
likely
to
develop
hemolytic
anemia
following
exposure
to
naphthalene
confirms
this
prediction
and
identifies
this
group
as
a
potentially
susceptible
population.
Individuals
with
this
deficiency
have
lower
erythrocyte
levels
of
reduced
glutathione,
a
compound
that
normally
protects
red
blood
cells
against
oxidative
damage.
G6PDdeficient
neonates,
infants,
and
the
fetus
are
particularly
sensitive
to
naphthalene
toxicity
because
the
metabolic
pathways
responsible
for
conjugation
of
toxic
metabolites
(
a
prerequisite
for
excretion)
are
not
yet
well
developed
in
these
groups.
In
addition,
these
groups
have
low
levels
of
methemoglobin
reductase,
the
enzyme
that
catalyzes
the
reduction
of
methemoglobin,
increasing
vulnerability
in
the
period
immediately
after
birth.

9.2.3
Dose­
Response
Characterization
and
Implications
in
Risk
Assessment
Information
on
the
human
health
effects
of
naphthalene
has
been
obtained
from
medical
case
reports
of
intentional
or
accidental
ingestion.
The
usefulness
of
case
study
data
for
assessing
risk
from
drinking
water
ingestion
is
limited
by
one
or
more
of
the
following
factors:
quantitative
exposure
data
are
not
available
in
most
case
reports;
the
toxicokinetics
of
a
single
bolus
dose
may
differ
from
that
of
chronic
low­
level
exposure;
and
the
low
aqueous
solubility
of
naphthalene
may
prevent
the
occurrence
of
concentrations
in
drinking
water
that
are
comparable
to
the
doses
that
require
medical
attention.
The
limited
human
exposure
data
that
are
available
from
case
reports
suggest
that
cataracts
occurred
following
a
single
dose
of
approximately
71
mg/
kg
consumed
over
13
hours
(
Lezenius,
1902).
Indications
of
hemolytic
anemia
resulted
after
a
single
oral
dose
of
approximately
109
mg/
kg
(
Gidron
and
Leurer,
1956).

All
available
dose­
response
information
for
naphthalene
toxicity
in
animals
is
extensively
summarized
in
Table
7­
7.
Five
key
studies
are
summarized
in
Table
9­
1
below.
These
five
studies
currently
provide
the
most
reliable
information
on
threshold
levels
for
naphthalene
toxicity
in
animals
exposed
via
the
oral
route.
Included
in
this
group
are
two
short­
term
studies
and
three
subchronic
studies.
There
are
presently
no
adequately
designed
chronic
oral
exposure
studies.

In
short­
term
studies,
a
LOAEL
of
50
mg/
kg­
day
(
the
lowest
dose
tested)
was
identified
for
transient
signs
of
neurotoxicity
in
pregnant
Sprague­
Dawley
rats
administered
naphthalene
by
gavage
on
gestation
days
6
 
15
(
NTP,
1991).
NOAEL
and
LOAEL
values
of
53
mg/
kg­
day
and
267
mg/
kg­
day,
respectively,
were
identified
for
effects
on
body
weight
and
organ
weight
observed
in
a
14­
day
corn
oil
gavage
study
conducted
in
CD­
1
mice
(
Shopp
et
al.,
1984).
In
subchronic
studies,
NOAEL
and
LOAEL
values
of
100
mg/
kg­
day
and
200
mg/
kg­
day,
respectively,
were
identified
in
13­
week
gavage
studies
conducted
in
Fischer
344
rats
and
B6C3F
1
mice
(
BCL,
1980a,
b).
The
corresponding
duration­
adjusted
values
are
71
mg/
kg­
day
and
143
mg/
kg­
day,
respectively.
The
LOAEL
in
rats
was
identified
on
the
basis
of
decreased
9­
5
Naphthalene
 
February
2003
terminal
body
weight,
while
the
LOAEL
in
mice
was
identified
on
the
basis
of
transient
clinical
signs
of
toxicity
observed
during
weeks
3
to
5
of
the
study.
In
the
third
subchronic
study,
NOAEL
and
LOAEL
values
of
53
mg/
kg­
day
and
133
mg/
kg­
day,
respectively,
were
identified
on
the
basis
of
changes
in
organ
weights
and
data
suggestive
of
changes
in
enzyme
activity
observed
in
CD­
1
mice
administered
naphthalene
by
gavage
in
corn
oil
for
90
days
(
Shopp
et
al.,
1984).

For
hemolytic
anemia
and
cataracts
(
the
endpoints
of
greatest
relevance
to
humans),
the
available
animal
data
are
limited
by
deficiencies
in
study
design,
including
the
use
of
a
single
high
dose
(
typically
500
to
2,000
mg/
kg­
day)
and/
or
an
inadequate
number
of
test
animals.
NOAEL
and
LOAEL
values,
therefore,
cannot
be
identified
in
these
studies.
Holmen
et
al.
(
1999)
identified
a
LOAEL
of
500
mg/
kg­
day
for
ocular
changes
in
a
multidose
study
where
rats
were
dosed
by
gavage
twice
weekly
for
10
weeks.

To
place
short­
term
and
subchronic
dose­
response
information
in
perspective,
a
high­
end
estimate
of
naphthalene
intake
can
be
calculated.
The
solubility
of
naphthalene
in
water
is
31
mg/
L.
Assuming
that
naphthalene
is
present
at
the
limit
of
solubility,
the
dose
to
a
70
kg
adult
consuming
2
L
of
drinking
water
per
day
would
be
0.9
mg/
kg­
day.
The
dose
to
a
10
kg
child
consuming
1
L
of
drinking
water
per
day
would
be
3.1
mg/
kg­
day.
Comparison
of
these
doses
to
the
threshold
levels
for
naphthalene
toxicity
indicates
that
the
human
LOAEL
values
are
at
least
an
order
of
magnitude
greater
than
the
estimated
high­
end
dose.

The
Reference
Dose
(
RfD)
for
naphthalene
is
2
×
10­
2
mg/
kg­
day
(
U.
S.
EPA,
1998a).
The
RfD
is
an
estimate
(
with
uncertainty
spanning
perhaps
an
order
of
magnitude)
of
a
daily
oral
exposure
to
the
human
population
(
including
sensitive
subgroups)
that
is
likely
to
be
without
an
appreciable
risk
of
deleterious
effects
during
a
lifetime.
Because
there
are
no
adequate
chronic
oral
exposure
studies
for
naphthalene,
the
RfD
is
based
on
a
NOAEL
of
71
mg/
kg­
day
identified
in
a
subchronic
(
13­
week)
oral
exposure
study
in
which
no
effect
on
terminal
body
weight
in
male
rats
was
observed
(
BCL,
1980a).
An
uncertainty
factor
of
3,000
was
used
in
the
derivation
of
the
RfD
to
account
for
use
of
a
subchronic
study
(
factor
of
10),
extrapolation
from
animals
to
humans
(
factor
of
10),
variability
in
human
populations
(
factor
of
10),
and
lack
of
multidose
studies
in
species
that
are
sensitive
to
hemolytic
anemia
and
cataracts
(
factor
of
3).

The
Reference
Concentration
(
RfC)
for
naphthalene
is
3
×
10­
3
mg/
m3
(
U.
S.
EPA,
1998a).
The
RfC
is
an
estimate
(
with
uncertainty
spanning
perhaps
an
order
of
magnitude)
of
a
continuous
inhalation
dose
to
the
human
population
(
including
sensitive
subgroups)
that
is
likely
to
be
without
appreciable
risk
of
adverse
effects
over
a
lifetime
of
exposure.
The
RfC
for
naphthalene
is
based
on
lesions
of
the
nose
observed
in
a
chronic
inhalation
study
of
naphthalene
in
B6C3F
1
mice
(
NTP,
1992a).
Details
of
the
RfC
derivation
are
provided
in
Section
8.1.2
of
this
document.
Comparison
of
inhalation
doses
to
the
RfC
can
be
useful
in
the
risk
assessment
of
contaminants
that
readily
volatilize
9­
6
Naphthalene
 
February
2003
Table
9­
1.
Dose­
Response
Information
from
Five
Key
Studies
of
Naphthalene
Toxicity
Study
Species
No.
Sex
Doses
mg/
kg­
day
Duration
NOAEL
mg/
kg­
day
LOAEL
mg/
kg­
day
Effects
Short­
term
Studies
Shopp
et
al.
(
1984)
Mouse
CD­
1
76
 
112
M
40
 
76
F
0
27
53
267
14
days
53
267
Increased
mortality,
decreased
terminal
body
wt.;
altered
organ
wts.

NTP
(
1991)
Rat
Sprague­
Dawley
25
 
26
F
0
50
150
450
Gestation
Days
6
 
15
Maternal
­­

Fetal
450
Maternal
50
Fetal
­­
Maternal:
Signs
of
neurotoxicity
lethargy,
slow
respiration
and
apnea;
signs
transient
at
low
dose
Subchronic
Studies
BCL
(
1980a)
Rat
F344
10
M
10
F
0
25
50
100
200
400
13
weeks
(
5
days/
wk)
100
Duration
adj.
dose:
71
200
Duration
adj.
dose:
143
Greater
than
10%
reduction
in
body
weight
BCL
(
1980b)
Mouse
B6C3F
1
10
M
10
F
0
12.5
25
50
100
200
13
weeks
(
5
days/
wk)
100
Duration
adj.
dose:
71
200
Duration
adj.
dose:
143
Transient
signs
of
toxicity
(
lethargy,
rough
coats,
decreased
food
consumption)
during
weeks
3
­
5
Shopp
et
al.
(
1984)
Mouse
CD­
1
76
 
112
M
40
 
76
F
5.3
53
133
90
days
53
133
Decreased
organ
weights;
liver
enzyme
activity
M
=
male
adj.
=
adjusted
F
=
female
­­
=
no
data
wt.
=
weight
9­
7
Naphthalene
 
February
2003
from
drinking
water
during
household
activities.
In
the
case
of
naphthalene,
volatilization
from
water
is
expected
to
be
minimal.

9.3
Occurrence
in
Public
Water
Systems
The
second
criterion
asks
if
the
contaminant
is
known
to
occur
or
if
there
is
a
substantial
likelihood
that
the
contaminant
will
occur
in
public
water
systems
with
a
frequency
and
at
levels
of
public
health
concern.
In
order
to
address
this
question
the
following
information
was
considered:

C
Monitoring
data
from
public
water
systems
°
Ambient
water
concentrations
and
releases
to
the
environment
°
Environmental
fate
Data
on
the
occurrence
of
naphthalene
in
public
drinking
water
systems
were
the
most
important
determinants
in
evaluating
the
second
criterion.
EPA
looked
at
the
total
number
of
systems
that
reported
detections
of
naphthalene,
as
well
those
that
reported
concentrations
of
naphthalene
above
an
estimated
drinking­
water
health
reference
level
(
HRL).
For
noncarcinogens,
the
estimated
HRL
level
was
calculated
from
the
RfD
assuming
that
20%
of
the
total
exposure
would
come
from
drinking
water.
For
carcinogens,
the
HRL
was
the
10­
6
risk
level.
The
HRLs
are
benchmark
values
that
were
used
in
evaluating
the
occurrence
data
while
the
risk
assessments
for
the
contaminants
were
being
developed.

The
available
monitoring
data,
including
indications
of
whether
or
not
the
contaminant
is
a
national
or
a
regional
problem,
are
included
in
Chapter
4
of
this
document
and
summarized
below.
Additional
information
on
production,
use,
and
fate
are
found
in
Chapters
2
and
3.

9.3.1
Occurrence
Criterion
Conclusion
The
available
data
for
naphthalene
production
and
use
are
consistent
with
a
downward
trend
for
both.
The
ten­
year
pattern
of
TRI
releases
to
surface
water
is
variable
within
the
range
of
2.2
to
6.7
million
pounds.
The
physiochemical
properties
of
naphthalene
and
the
available
data
for
environmental
fate
indicate
that
naphthalene
in
surface
water
is
likely
to
be
rapidly
degraded
by
biotic
and
abiotic
processes
and
that
it
has
little
potential
for
bioaccumulation.
Monitoring
data
indicate
that
naphthalene
is
infrequently
detected
in
public
water
supplies.
When
naphthalene
is
detected,
it
very
rarely
exceeds
the
HRL
or
a
value
of
one­
half
of
the
HRL.
Chemical
treatment
of
drinking
water
and
leaching
from
drinking
water
surfaces
are
not
expected
to
contribute
to
significantly
elevated
levels
of
naphthalene
in
drinking
water.
Based
on
these
data,
it
is
unlikely
that
naphthalene
will
occur
in
public
water
systems
at
frequencies
or
concentration
levels
that
are
of
public
health
concern.
Thus,
the
evaluation
for
the
second
criterion
is
negative.
9­
8
Naphthalene
 
February
2003
9.3.2
Monitoring
Data
Drinking
Water
Naphthalene
has
been
detected
in
public
water
supply
(
PWS)
samples
collected
under
the
authority
of
the
Safe
Drinking
Water
Act.
Data
from
two
monitoring
periods
were
available
for
analysis.
Data
from
Round
1
were
collected
during
the
period
1988
to
1992.
Data
from
Round
2
were
collected
during
the
period
1993
to
1998.
Round
1
and
2
monitoring
detected
naphthalene
in
only
0.43%
and
0.24%
of
all
samples
analyzed,
respectively.
When
data
are
expressed
on
a
PWS
basis,
Round
1
and
Round
2
monitoring
detected
naphthalene
at
least
once
in
1.2%
(
769
systems)
and
0.8%
(
491
systems)
of
the
tested
water
supplies,
respectively.

The
median
and
99th
percentile
concentrations
for
all
samples
(
i.
e.,
samples
with
and
without
detectable
levels
of
naphthalene)
were
below
the
minimum
reporting
level
(
MRL).
When
subsets
of
the
data
containing
only
samples
with
detectable
levels
of
naphthalene
were
analyzed,
the
median
and
99th
percentile
concentrations
for
Round
1
were
1.0
:
g/
L
and
900
:
g/
L,
respectively.
The
median
and
99th
percentile
for
Round
2
detections
were
0.74
:
g/
L
and
73
:
g/
L,
respectively.
There
are
indications
that
the
high
concentrations
reflected
in
the
99th
percentile
value
for
the
Round
1
detections
are
outlier
values
from
two
ground
water
systems
in
one
crosssection
state
(
Appendix
B).
No
other
State
that
contributed
monitoring
data
had
any
detections
that
exceeded
the
HRL.

PWSs
with
detected
levels
of
naphthalene
were
widely
distributed
throughout
the
United
States
(
see
Figures
4­
2
and
4­
3
in
this
document)
and
no
clear
patterns
of
regional
geographic
occurrence
associated
with
geology
or
other
factors
were
evident.

Ambient
Water
Naphthalene
has
been
detected
in
ambient
ground
water
samples
reviewed
and/
or
analyzed
by
the
U.
S.
Geological
Survey
National
Ambient
Water
Quality
Assessment
(
NAWQA)
program.
The
first
round
of
intensive
monitoring
in
the
ongoing
NAWQA
was
conducted
from
1991
to
1996
and
targeted
20
watersheds.
Data
from
each
NAWQA
study
unit
were
augmented
by
additional
data
from
local,
state,
and
federal
agencies
that
met
specified
criteria
(
see
Section
4.2.1).
The
data
were
stratified
by
population
density
into
rural
and
urban
areas.

The
results
for
ambient
water
quality
monitoring
(
summarized
in
Table
4­
1
of
this
document)
indicate
that
detection
frequencies
were
low
(
3.0%
and
0.2%
for
urban
and
rural
areas,
respectively).
The
median
concentrations
for
detections
in
urban
and
rural
areas
were
3.9
:
g/
L
and
0.4
:
g/
L,
respectively.
Because
the
proportion
of
detections
in
the
sample
database
is
low
and
nondetect
samples
are
not
considered,
these
concentrations
overestimate
the
actual
concentrations
of
naphthalene
in
ambient
water
and
thus
are
conservative
approximations
for
risk
assessment
purposes.
At
the
time
the
data
were
collected
and
evaluated,
the
EPA
lifetime
Health
Advisory
for
naphthalene
was
20
:
g/
L.
This
value
was
exceeded
in
0.4%
and
1%
of
urban
and
rural
wells,
respectively.
None
of
the
drinking
water
wells
that
were
tested
exceeded
the
present
Health
Advisory
value
(
100
:
g/
L).
9­
9
Naphthalene
 
February
2003
Naphthalene
concentrations
were
examined
in
two
studies
of
urban
and
highway
runoff.
The
maximum
concentrations
of
naphthalene
observed
in
these
studies
were
well
below
the
HRL.

9.3.3
Use
and
Fate
Data
Naphthalene
is
a
natural
constituent
of
coal
tar
and
crude
oil.
Commercial
quantities
of
naphthalene
are
produced
from
these
materials
by
fractional
distillation.
Naphthalene
production
in
the
United
States
decreased
from
900
million
pounds
per
year
in
1968
to
354
million
pounds
per
year
in
1982.
U.
S.
manufacturers
produced
an
estimated
1.09
×
105
metric
tons
(
approximately
240
million
pounds)
of
naphthalene
in
1996
(
CEH,
2000).
Thus,
naphthalene
production
has
generally
declined
over
the
last
32
years.
Approximately
7
million
pounds
of
naphthalene
were
imported
and
9
million
pounds
were
exported
in
1978.
In
1989,
approximately
4
million
pounds
of
naphthalene
were
imported
and
21
million
pounds
were
exported.
These
limited
import
and
export
data
suggest
a
decreasing
trend
in
the
amount
of
naphthalene
available
for
consumption
in
the
U.
S.

Naphthalene
consumption
was
reported
to
be
1.08
×
105
metric
tons
(
approximately
238
million
pounds)
in
1996
(
CEH,
2000).
Most
consumers
use
naphthalene
as
a
moth
repellent
(
moth
balls)
or
a
solid
block
deodorant
for
diaper
pails.
A
recent
survey
of
naphthalene
use
at
an
inner­
city
location
indicated
that
naphthalene
was
used
for
unexpected
purposes,
including
air
freshening
and
as
a
roach
repellant
(
Santucci
and
Shah,
2000).
Most
industrial
naphthalene
consumption
in
the
United
States
occurs
in
the
production
of
phthalate
plasticizers,
resins,
phthaleins,
and
dyes
(
ATSDR,
2000).
Other
manufacturing
uses
include
the
production
of
carbaryl
insecticide,
synthetic
tanning
agents,
and
surface
active
agents.

Direct
releases
to
the
air
constitute
more
than
90%
of
the
naphthalene
entering
environmental
media
(
ATSDR,
1995).
In
contrast,
only
about
5%
of
environmental
naphthalene
is
released
to
water
(
ATSDR,
1995).
Examination
of
data
from
the
Toxic
Release
Inventory
(
TRI)
(
EPA,
2000b),
shown
in
Table
3­
1
of
this
document,
indicates
that
releases
to
water
varied
from
2.2
to
6.7
million
pounds
for
the
period
1988
to
1998.
No
apparent
trend
(
increasing
or
decreasing)
was
evident
over
the
reported
interval.

Naphthalene
is
lost
from
surface
water
via
several
mechanisms.
The
most
important
route
of
loss
is
volatilization.
Published
volatilization
half­
lives
for
naphthalene
in
surface
water
range
from
4.3
to
7.2
hours
(
Southworth,
1979;
Rodgers
et
al.,
1983).
Naphthalene
has
a
log
K
OC
of
2.97.
Therefore,
a
fraction
of
naphthalene
in
water
will
be
associated
with
organic
particulate
matter
and
will
settle
into
sediments.
For
naphthalene,
this
fraction
is
expected
to
be
less
than
10%
(
ATSDR,
1995).
Naphthalene
remaining
in
surface
water
is
degraded
by
photolysis
and
biodegradation
processes.
Naphthalene
undergoing
photolysis
has
an
estimated
half­
life
of
71
hours
(
ATSDR,
1995).
Biodegradation
also
occurs
quite
rapidly,
although
the
rate
of
degradation
will
vary
with
naphthalene
concentration,
water
temperature
and
the
availability
of
nutrients.
Naphthalene
has
a
log
octanol:
water
partition
coefficient
(
K
OW)
of
3.29.
Based
on
this
value,
significant
bioaccumulation
of
naphthalene
in
the
food­
chain
is
not
expected
to
occur
(
ATSDR,
1995).
9­
10
Naphthalene
 
February
2003
Naphthalene
is
not
used
as
a
drinking
water
treatment
chemical.
Although
it
is
possible
that
residual
naphthalene
may
leach
from
some
materials
(
i.
e.,
from
low
density
polyethylene;
Lau
et
al.,
1994),
no
data
were
identified
in
the
materials
reviewed
for
this
document
that
indicate
naphthalene
is
likely
to
be
a
leachate
from
drinking
water
contact
surfaces.
Therefore,
these
factors
are
not
expected
to
contribute
to
elevated
levels
of
naphthalene
in
drinking
water.

9.4
Risk
Reduction
The
third
criterion
asks
if,
in
the
sole
judgment
of
the
Administrator,
regulation
presents
a
meaningful
opportunity
for
health
risk
reduction
for
persons
served
by
public
water
systems.
In
evaluating
this
criterion,
EPA
looked
at
the
total
exposed
population,
as
well
as
the
population
exposed
to
levels
above
the
estimated
HRL.
Estimates
of
the
populations
exposed
and
the
levels
to
which
they
are
exposed
were
derived
from
the
monitoring
results.
These
estimates
are
included
in
Chapter
4
of
this
document
and
summarized
in
section
9.4.2
below.

In
order
to
evaluate
risk
from
exposure
through
drinking
water,
EPA
considered
the
net
environmental
exposure
in
comparison
to
the
exposure
through
drinking
water.
For
example,
if
exposure
to
a
contaminant
occurs
primarily
through
ambient
air,
regulation
of
emissions
to
air
provides
a
more
meaningful
opportunity
for
EPA
to
reduce
risk
than
does
regulation
of
the
contaminant
in
drinking
water.
In
making
the
regulatory
determination,
the
available
information
on
exposure
through
drinking
water
(
Chapter
4)
and
information
on
exposure
through
other
media
(
Chapter
5)
were
used
to
estimate
the
fraction
that
drinking
water
contributes
to
the
total
exposure.
The
EPA
findings
are
discussed
in
Section
9.4.3
below.

In
making
its
regulatory
determination,
EPA
also
evaluated
effects
on
potentially
sensitive
populations,
including
the
fetus,
infants
and
children.
Sensitive
population
considerations
are
included
in
section
9.4.4.

9.4.1
Risk
Criterion
Conclusion
Approximately
6
to
10
million
people
are
served
by
systems
with
detections
greater
than
the
MRL.
An
estimated
5,000
of
these
individuals
may
be
served
by
systems
with
detections
greater
than
one­
half
the
HRL,
based
on
Round
2
monitoring
data,
but
exposures
above
the
HRL
would
be
rare
and
localized.
Prevalence
data
for
G6PD
deficiency
in
the
United
States
indicate
that
5.2
to
11.5%
of
the
exposed
individuals
may
have
reduced
activity
of
G6PD,
and
thus
may
have
an
increased
risk
for
methemoglobinemia
and
possibly
hemolytic
anemia
if
exposed
to
moderate­
to­
high
doses
of
naphthalene.
Methemoglobinemia
is
the
consequence
of
oxidation
of
the
iron
in
hemoglobin
and
is
a
precursor
event
to
hemolysis
induced
by
naphthalene,
as
well
as
by
a
variety
of
other
chemical
agents.
Hemolytic
anemia
is
an
acute
effect
that
is
precipitated
when
the
oxidative
damage
to
the
red
blood
cell
is
sufficient
to
cause
lysis
of
the
cell
membrane.
Neonates
and
infants
have
reduced
protection
against
methemoglobinemia
due
to
developmental
delays
in
the
activity
of
methemoglobin
reductase,
a
protective
enzyme.

Hemolytic
anemia
is
an
acute
effect
that
occurs
at
moderate­
to­
high
doses
of
naphthalene.
When
average
daily
intakes
from
drinking
water
are
compared
with
intakes
from
food,
air
and
soil,
drinking
water
accounts
for
a
relatively
small
proportion
of
total
naphthalene
intake.
On
the
9­
11
Naphthalene
 
February
2003
basis
of
these
observations,
the
impact
of
regulating
naphthalene
concentrations
in
drinking
water
on
health
risk
reduction
is
likely
to
be
small.
Thus
the
evaluation
of
the
third
criterion
is
negative.

9.4.2
Exposed
Population
Estimates
National
population
estimates
for
naphthalene
exposure
were
derived
using
summary
statistics
for
Round
1
and
Round
2
PWS
cross­
sectional
data
(
see
Table
4­
3
of
this
document)
and
population
data
from
the
Water
Industry
Baseline
Handbook
(
U.
S.
EPA,
2000f).
Summary
data
are
provided
in
Table
9­
2
below.
An
estimated
6
to
10
million
people
are
served
by
PWSs
with
detections
of
naphthalene
greater
than
the
MRL.
Approximately
5,000
people
are
served
by
PWSs
with
detected
naphthalene
concentrations
greater
than
one­
half
the
HRL.
These
estimates
are
based
on
data
from
Round
2
sampling.
Based
on
the
data
from
Round
1
monitoring,
a
total
of
16,000
persons
were
estimated
to
be
exposed
to
concentrations
of
naphthalene
that
exceed
both
the
HRL
and
one­
half
the
HRL.
However,
as
mentioned
in
Section
9.3.2,
this
estimate
was
heavily
influenced
by
the
results
from
samples
collected
at
two
ground
water
systems
in
one
of
the
cross­
section
states
which
can
be
considered
to
be
outlier
values.
The
Round
2­
based
estimate
of
5,000
individuals
exposed
to
concentrations
greater
than
one­
half
the
HRL,
with
no
exposures
at
concentrations
greater
than
the
HRL,
appears
to
be
a
better
estimate
of
possible
national
exposure.
These
estimates
are
conservative
(
i.
e.,
may
somewhat
overestimate
the
actual
number
of
persons
exposed),
since
more
than
98%
of
the
systems
tested
did
not
have
detectable
levels
of
naphthalene.

Table
9­
2.
National
Population
Estimates
for
Naphthalene
Exposure
via
Drinking
Water
Population
of
Concern
Round
1
Round
2
Served
by
PWS
with
detections
6,198,000
10,204,000
Served
by
PWSs
with
detections
>
(
1/
2
HRL)
16,000*
5,000
Served
by
PWSs
with
detections
>
HRL
16,000*
0
Source:
Data
taken
from
Table
4­
4
of
this
document.
HRL
=
Health
Reference
Level
*
Probable
outlier
values
9.4.3
Relative
Source
Contribution
Relative
source
contribution
analysis
compares
the
magnitude
of
exposure
expected
via
drinking
water
to
the
magnitude
of
exposure
from
intake
of
naphthalene
in
other
media,
such
as
food,
air,
and
soil.
To
perform
this
analysis,
intake
of
naphthalene
from
drinking
water
must
be
estimated.
Occurrence
data
for
naphthalene
are
presented
in
Chapter
4
of
this
document.
As
indicated
in
Table
9­
2,
the
median
and
99th
percentile
concentrations
for
naphthalene
were
below
the
MRL
when
all
samples
(
i.
e.,
those
with
detectable
and
nondetectable
levels
of
naphthalene)
from
either
Round
1
or
Round
2
were
analyzed.
9­
12
Naphthalene
 
February
2003
As
a
simplifying
assumption,
a
value
of
one­
half
of
the
MRL
is
often
used
as
an
estimate
of
the
concentration
of
a
contaminant
when
the
results
are
less
than
the
MRL.
Because
a
single
estimate
of
the
MRL
for
naphthalene
was
unavailable
(
see
Section
4.4.1),
two
alternative
approaches
were
used
to
estimate
average
daily
intakes
from
drinking
water.
The
reported
detection
limits
for
naphthalene
range
from
0.01
:
g/
L
for
the
most
sensitive
to
3.3
:
g/
L
for
the
least
sensitive
methods
(
ATSDR,
1995).
If
a
value
of
one­
half
the
detection
limit
is
used
as
a
rough
estimate
of
the
concentration
of
naphthalene,
this
equates
to
a
range
of
0.005
to
1.65
:
g/
L.
Assuming
intake
of
2
L/
day
of
drinking
water
by
a
70
kg
adult,
the
average
daily
dose
would
be
1.4
×
10­
3
to
47.1
×
10­
3
:
g/
kg­
day
(
1.4
to
47.1
ng/
kg­
day).
The
corresponding
dose
for
a
10
kg
child
consuming
1
L/
day
of
drinking
water
would
be
0.5
x
10­
3
to
165
×
10­
3
:
g/
kg­
day
(
0.5
to
165
ng/
kg­
day).
Alternatively,
if
the
median
concentration
for
naphthalene
in
samples
with
detectable
levels
(
approximately
1
:
g/
L)
is
used,
the
average
daily
doses
to
an
adult
and
child
would
be
28.6
×
10­
3
and
100
×
10­
3
:
g/
kg­
day
(
28.6
and
100
ng/
kg­
day),
respectively.

Collectively,
available
data
data
indicate
that
intake
from
drinking
water
will
often
be
relatively
low
when
compared
to
intake
from
other
media.
The
estimated
average
daily
intakes
of
naphthalene
from
drinking
water
(
based
on
median
detected
concentrations)
and
other
media
are
shown
in
Table
9­
3.
These
intakes
were
used
to
calculate
estimated
ratios
of
the
exposure
from
each
medium
to
the
exposure
from
water
(
Table
9­
4).
The
estimated
food:
drinking
water
exposure
ratio
ranges
from
1
to
8
for
an
adult
and
from
2
to
9
for
a
child.
The
estimated
air:
drinking
water
exposure
ratio
is
39
for
an
adult
and
45
for
a
child.
The
range
of
estimated
naphthalene
intake
from
soil
is
very
broad
for
both
children
and
adults;
thus
the
soil:
drinking
water
intake
ratio
will
be
highly
scenario­
dependent.
For
an
adult,
the
estimated
soil:
drinking
water
exposure
ratio
ranges
from
less
than
1
to
103.
For
a
child,
the
estimated
soil:
drinking
water
exposure
ratio
ranges
from
2
to
430.

The
data
indicate
that,
with
the
exception
of
locations
with
highly
contaminated
soils,
most
naphthalene
exposure
occurs
through
ambient
air,
especially
near
source­
dominated
locations.
Indoor
air
concentrations
tend
to
have
higher
concentrations
of
naphthalene
if
cigarette
smoking
is
permitted.

Table
9­
3.
Comparison
of
Average
Daily
Intakes
from
Drinking
Water
and
Other
Media
a
Medium
Adult
(
ng/
kg­
day)
Child
(
ng/
kg­
day)

Drinking
Water
b
29c
100
Food
41c
 
237
204
 
940
Air
1,127
4,515
Soil
d
10
 
3,000
200
 
43,000
a
See
Chapter
5
for
derivation
of
intakes
from
media
other
than
water
b
Based
on
the
median
values
for
detected
naphthalene
concentrations
in
Round
1
and
Round
2
(
data
for
Round
2
rounded
to
1
:
g/
L)
c
Rounded
values
d
Includes
household
dust
9­
13
Naphthalene
 
February
2003
Table
9­
4.
Ratios
of
Exposures
from
Various
Media
to
Exposures
from
Drinking
Water
a
Exposure
Ratio
Adult
Child
Food:
Drinking
Water
1
 
8
2
 
9
Air:
Drinking
Water
39
45
Soil:
Drinking
Water
<
1
 
103
2
 
430
a
Calculated
from
estimated
daily
intakes
in
Table
9­
2.

9.4.4
Sensitive
Populations
The
sensitive
populations
identified
for
naphthalene
include
individuals
(
including
infants,
neonates
and
the
fetus)
deficient
in
the
enzyme
glucose­
6­
phosphate
dehydrogenase
(
G6PD).
This
enzyme
helps
protect
red
blood
cells
from
oxidative
damage;
deficiency
makes
red
blood
cells
more
sensitive
to
a
variety
of
toxicants,
including
naphthalene.
The
hemolytic
response
to
naphthalene
is
enhanced
in
G6PD­
deficient
individuals.
Higher
rates
of
inherited
G6PD
deficiency
are
found
among
the
people
of
Asia,
Greece,
Italy,
the
Middle
East,
and
Africa.
In
the
United
States,
an
estimated
5.2
to
11.5%
of
the
population
has
an
inherited
G6PD
deficiency
(
Luzzato
and
Mehta,
1989).
Because
this
defect
is
linked
to
the
X­
chromosome,
males
are
more
likely
to
be
affected
than
females.

Newborn
infants
are
generally
considered
to
be
more
sensitive
to
naphthalene
toxicity
because
the
metabolic
pathways
for
conjugation
of
naphthalene
are
not
well­
developed.
Newborn
infants
also
have
low
levels
of
methemoglobin
reductase,
a
result
of
which
may
be
to
compound
and
prolong
some
effects
of
hemolytic
anemia.

Calculation
of
medium­
specific
exposure
ratios
(
Table
9­
4)
indicates
that
naphthalene
intake
from
air
is
about
40­
fold
greater
than
intake
from
water.
Therefore,
regulation
of
naphthalene
in
drinking
water
would
be
unlikely
to
significantly
reduce
the
risk
to
sensitive
populations.

9.5
Regulatory
Determination
Decision
As
stated
in
Section
9.1.1,
a
positive
finding
for
all
three
criteria
is
required
in
order
to
make
a
determination
to
regulate
a
contaminant.
For
naphthalene,
negative
findings
were
obtained
for
two
of
the
three
criteria.
While
there
is
evidence
that
naphthalene
may
have
adverse
health
effects
in
humans
at
moderate­
to­
high
doses,
it
is
unlikely
that:
1)
this
contaminant
will
occur
in
drinking
water
with
a
frequency
or
at
concentrations
that
are
of
public
health
concern;
or
2)
regulation
of
this
contaminant
represents
a
meaningful
basis
for
health
risk
reduction
in
persons
served
by
public
water
systems.
10­
1
Naphthalene
 
February
2003
10.0
REFERENCES
ACGIH.
2000.
Threshold
Limit
Values
for
Chemical
Substances
and
Physical
Agents
and
Biological
Exposure
Indices.
American
Conference
of
Government
Industrial
Hygienists,
Cincinnati,
OH.

Adkins,
B.,
E.
W.
Van
Stee,
J.
E.
Simmons,
et
al.
1986.
Oncogenic
response
of
strain
A/
J
mice
to
inhaled
chemicals.
J.
Toxicol.
Environ.
Health
17:
311­
322
(
as
cited
in
U.
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1998a).

Yamauchi,
T.,
S.
Komura
and
K.
Yagi.
1986.
Serum
lipid
peroxide
levels
of
albino
rats
administered
naphthalene.
Biochem.
Int.
13:
1­
6
(
as
cited
in
ATSDR,
1995).

Yu,
X.,
X.
Wang,
R.
Bartha,
et
al.
1990.
Supercritical
fluid
extraction
of
coal
tar
contaminated
soil.
Environ.
Sci.
Technol.
24:
1732­
1738
(
as
cited
in
ATSDR,
1995).

Zheng,
J.,
M.
Cho,
A.
D.
Jones,
et
al.
1997.
Evidence
of
quinone
metabolites
of
naphthalene
covalently
bound
to
sulfur
nucleophiles
of
proteins
of
murine
Clara
cells
after
exposure
to
naphthalene.
Chem.
Res.
Toxicol.
10:
1008­
1014
(
as
cited
in
NTP,
2000).

Zinkham,
W.
H.
and
B.
Childs.
1957.
Effect
of
vitamin
K
and
naphthalene
metabolites
on
glutathione
metabolism
of
erythrocytes
from
normal
newborns
and
patients
with
naphthalene
hemolytic
anemia.
Am.
J.
Dis.
Child
94:
420­
423
(
as
cited
in
ATSDR,
1995).

Zinkham,
W.
H.
and
B.
Childs.
1958.
A
defect
of
glutathione
metabolism
of
erythrocytes
from
patients
with
naphthalene­
induced
hemolytic
anemia.
Pediatrics
22:
461­
471
(
as
cited
in
ATSDR,
1995).

Zitko,
V.,
G.
Stenson,
and
J.
Hellou.
1998.
Levels
of
organochlorine
and
polycyclic
aromatic
compounds
in
harp
seal
beaters
(
Phoca
groenlandica).
Sci.
Total
Environ..
221(
1):
11­
29.

Zuelzer,
W.
W.
and
L.
Apt.
1949.
Acute
hemolytic
anemia
due
to
naphthalene
poisoning:
A
clinical
and
experimental
study.
J.
Am.
Med.
Assoc.
141:
185­
190
(
as
cited
in
ATSDR,
1995).
10­
21
Naphthalene
 
February
2003
A­
1
Naphthalene
 
February
2003
APPENDIX
A:
Abbreviations
and
Acronyms
ACGIH
­
American
Conference
of
Governmental
Industrial
Hygienists
ATSDR
­
Agency
for
Toxic
Substances
and
Disease
Registry
CAS
­
Chemical
Abstract
Service
CCL
­
Contaminant
Candidate
List
CERCLA
­
Comprehensive
Environmental
Response,
Compensation
&
Liability
Act
CMR
­
Chemical
Monitoring
Reform
CWS
­
Community
Water
System
DWEL
­
Drinking
Water
Equivalent
Level
EPA
­
Environmental
Protection
Agency
EPCRA
­
Emergency
Planning
and
Community
Right­
to­
Know
Act
GW
­
ground
water
HA
­
Health
Advisory
HAL
­
Health
Advisory
Level
HazDat
­
Hazardous
Substance
Release
and
Health
Effect
Database
HRL
­
Health
Reference
Level
IOC
­
inorganic
compound
IRIS
­
Integrated
Risk
Information
System
MRL
­
Minimum
Reporting
Level
NAWQA
­
National
Ambient
Water
Quality
Assessment
NCOD
­
National
Drinking
Water
Contaminant
Occurrence
Database
NIOSH
­
National
Institute
for
Occupational
Safety
and
Health
NPDES
­
National
Pollution
Discharge
Elimination
System
NPDWR
­
National
Primary
Drinking
Water
Regulation
NTIS
­
National
Technical
Information
Service
NTNCWS
­
Non­
Transient
Non­
Community
Water
System
ppm
­
part
per
million
PWS
­
Public
Water
System
RCRA
­
Resource
Conservation
and
Recovery
Act
SARA
Title
III
­
Superfund
Amendments
and
Reauthorization
Act
SDWA
­
Safe
Drinking
Water
Act
SDWIS
­
Safe
Drinking
Water
Information
System
SDWIS/
FED
­
the
Federal
Safe
Drinking
Water
Information
System
A­
2
Naphthalene
 
February
2003
SOC
­
synthetic
organic
compound
STORET
­
Storage
and
Retrieval
System
SW
­
surface
water
TRI
­
Toxic
Release
Inventory
UCM
­
Unregulated
Contaminant
Monitoring
UCMR
­
Unregulated
Contaminant
Monitoring
Regulation/
Rule
URCIS
­
Unregulated
Contaminant
Monitoring
Information
System
U.
S.
EPA
­
United
States
Environmental
Protection
Agency
USGS
­
United
States
Geological
Survey
VOC
­
volatile
organic
compound
µ
g/
L
­
micrograms
per
liter
mg/
L
­
milligrams
per
liter
>
MCL
­
percentage
of
systems
with
exceedances
>
MRL
­
percentage
of
systems
with
detections
B­
1
Naphthalene
 
February
2003
APPENDIX
B:
Naphthalene
Occurrence
Data
for
Public
Water
Systems
(
Round
1
and
Round
2)

Napthalene
Occurrence
in
Public
Water
Systems
in
Round
1,
UCM
(
1987)
results
STATE
TOTAL
UNIQUE
PWS
#
GW
PWS
#
SW
PWS
%
PWS
>
MRL
%
GW
PWS
>
MRL
%
SW
PWS
>
MRL
%
PWS
>
HRL
%
GW
PWS
>
HRL
%
SW
PWS
>
HRL
99%
VALUE
(
µ
:
g/
L)

AK
669
543
131
4.78%
5.52%
1.53%
0.00%
0.00%
0.00%
0.80
AL
131
93
42
28.24%
32.26%
16.67%
1.53%
2.15%
0.00%
8.20
AR
AZ
448
407
47
1.12%
0.98%
2.13%
0.00%
0.00%
0.00%
<
5.00
CA
609
592
27
1.15%
1.18%
0.00%
0.00%
0.00%
0.00%
<
10.00
CO
7
3
5
14.29%
0.00%
20.00%
0.00%
0.00%
0.00%
4.62
DC
1
0
1
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
DE
10
8
2
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.60
FL
114
8
106
7.02%
0.00%
7.55%
0.00%
0.00%
0.00%
8.00
GA
1,161
1,052
109
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
HI
127
112
16
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.30
IA
IL
214
150
64
1.87%
2.00%
1.56%
0.00%
0.00%
0.00%
<
2.00
IN
357
321
37
0.28%
0.31%
0.00%
0.00%
0.00%
0.00%
<
2.00
KY
524
291
233
1.15%
1.03%
1.29%
0.00%
0.00%
0.00%
<
1.00
LA
13
9
4
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
MA
2
1
1
100.00%
100.00%
100.00%
0.00%
0.00%
0.00%
0.80
MD
983
936
50
0.51%
0.53%
0.00%
0.00%
0.00%
0.00%
<
0.50
MI
MN
1,553
1,529
28
0.06%
0.07%
0.00%
0.00%
0.00%
0.00%
<
0.50
MO
85
71
14
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
50.00
MS
2
2
0
100.00%
100.00%
0.00%
0.00%
0.00%
0.00%
14.80
MT
NC
297
254
44
0.34%
0.39%
0.00%
0.00%
0.00%
0.00%
<
0.50
NE
9
9
0
100.00%
100.00%
0.00%
0.00%
0.00%
0.00%
10.60
NH
1
1
0
100.00%
100.00%
0.00%
0.00%
0.00%
0.00%
0.97
NJ
783
772
11
1.02%
1.04%
0.00%
0.00%
0.00%
0.00%
<
2.00
NM
590
555
35
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
1.00
NV
8
7
2
12.50%
14.29%
0.00%
0.00%
0.00%
0.00%
<
0.20
NY
261
187
85
0.38%
0.00%
1.18%
0.00%
0.00%
0.00%
<
5.00
OH
2,651
2,489
166
0.68%
0.68%
0.60%
0.00%
0.00%
0.00%
<
2.00
SD
335
306
29
2.39%
2.29%
3.45%
0.00%
0.00%
0.00%
0.18
TN
303
156
147
0.99%
0.64%
1.36%
0.00%
0.00%
0.00%
<
0.50
TX
3
2
1
100.00%
100.00%
100.00%
0.00%
0.00%
0.00%
18.00
UT
409
389
34
1.96%
1.80%
2.94%
0.00%
0.00%
0.00%
<
10.00
VI
3
0
3
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
1.00
VT
WA
992
937
77
0.20%
0.21%
0.00%
0.00%
0.00%
0.00%
<
0.50
WV
57
26
31
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
4.00
WY
145
116
38
3.45%
2.59%
5.26%
0.00%
0.00%
0.00%
0.80
TOTAL
13,857
12,334
1,620
1.29%
1.18%
2.04%
0.01%
0.02%
0.00%
<
5.00
24
STATES
13,452
12,034
1,502
1.18%
1.08%
1.93%
0.01%
0.02%
0.00%
<
5.00
PWS=
Public
Water
Systems;
GW=
Ground
Water
(
PWS
Source
Water
Type);
SW=
Surface
Water
(
PWS
Source
Water
Type);
MRL=
Minimum
Reporting
Limit
(
for
laboratory
analyses)
The
Health
Reference
Level
(
HRL)
is
the
estimated
health
effect
level
as
provided
by
EPA
for
preliminary
assessment
for
this
work
assignment.
"%
>
HRL"
indicates
the
proportion
of
systems
with
any
analytical
results
exceeding
the
concentration
value
of
the
HRL.
The
Health
Reference
Level
(
HRL)
used
for
Naphthalene
is
140
:
g/
L.
This
is
a
draft
value
for
working
review
only.
The
highlighted
States
are
part
of
the
URCIS
24
20
State
Cross­
Section.
B­
2
Naphthalene
 
February
2003
Naphthalene
Occurrence
in
Public
Water
Systems
in
Round
2,
UCM
(
1993)
results
STATE
TOTAL
UNIQUE
PWS
#
GW
PWS
#
SW
PWS
%
PWS
>
MRL
%
GW
PWS
>
MRL
%
SW
PWS
>
MRL
%
PWS
>
HRL
%
GW
PWS
>
HRL
%
SW
PWS
>
HRL
99%
VALUE
(
µ
g/
L)

Tribes
(
06)
22
21
1
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
10.00
AK
625
481
144
4.48%
3.53%
7.64%
0.00%
0.00%
0.00%
<
0.00
AL
2
2
100.00%
100.00%
0.00%
0.00%
0.00%
1.40
AR
517
423
94
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.00
AZ
68
60
8
1.47%
1.67%
0.00%
0.00%
0.00%
0.00%
<
1.00
CA
15
12
3
6.67%
8.33%
0.00%
0.00%
0.00%
0.00%
1.00
CO
831
619
212
3.97%
2.75%
7.55%
0.00%
0.00%
0.00%
0.42
CT
84
43
41
1.19%
2.33%
0.00%
0.00%
0.00%
0.00%
<
0.00
IN
117
107
10
0.85%
0.93%
0.00%
0.00%
0.00%
0.00%
<
2.00
KY
212
103
109
0.47%
0.00%
0.92%
0.00%
0.00%
0.00%
<
2.50
LA
1,310
1,241
69
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
MA
418
344
74
1.20%
0.58%
4.05%
0.00%
0.00%
0.00%
<
0.50
MD
976
920
56
0.51%
0.11%
7.14%
0.00%
0.00%
0.00%
<
0.50
ME
744
676
68
0.54%
0.59%
0.00%
0.00%
0.00%
0.00%
<
0.00
MI
2,737
2,645
92
0.33%
0.34%
0.00%
0.00%
0.00%
0.00%
<
0.00
MN
1,558
1,528
30
0.58%
0.46%
6.67%
0.00%
0.00%
0.00%
<
0.50
MO
1,412
1,297
115
0.07%
0.08%
0.00%
0.00%
0.00%
0.00%
<
2.00
MS
NC
1,776
1,586
190
1.18%
1.20%
1.05%
0.00%
0.00%
0.00%
<
0.00
ND
296
258
38
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
NH
3
1
2
100.00%
100.00%
100.00%
0.00%
0.00%
0.00%
3.40
NJ
7
7
0.00%
0.00%
0.00%
0.00%
<
1.00
NM
714
689
25
0.56%
0.44%
4.00%
0.00%
0.00%
0.00%
<
1.00
OH
2,232
2,050
182
1.39%
1.51%
0.00%
0.00%
0.00%
0.00%
<
0.50
OK
792
541
251
0.76%
0.92%
0.40%
0.00%
0.00%
0.00%
<
0.00
OR
17
15
2
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.00
PA
RI
100
89
11
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
1.00
SC
237
216
21
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
SD
27
19
8
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.50
TN
TX
4,412
3,825
587
0.18%
0.16%
0.34%
0.00%
0.00%
0.00%
<
1.00
VT
WA
2,554
2,435
119
0.31%
0.21%
2.52%
0.00%
0.00%
0.00%
<
0.00
WI
191
188
3
0.00%
0.00%
0.00%
0.00%
0.00%
0.00%
<
0.30
TOTAL
25,006
22,441
2,565
0.73%
0.60%
1.87%
0.00%
0.00%
0.00%
<
2.00
20
STATES
22,926
20,525
2,401
0.77%
0.62%
2.00%
0.00%
0.00%
0.00%
<
2.00
19
STATES
22,923
20,524
2,399
0.75%
0.62%
1.92%
0.00%
0.00%
0.00%
<
2.00
PWS=
Public
Water
Systems;
GW=
Ground
Water
(
PWS
Source
Water
Type);
SW=
Surface
Water
(
PWS
Source
Water
Type);
MRL=
Minimum
Reporting
Limit
(
for
laboratory
analyses)
The
Health
Reference
Level
(
HRL)
is
the
estimated
health
effect
level
as
provided
by
EPA
for
preliminary
assessment
for
this
work
assignment.
"%
>
HRL"
indicates
the
proportion
of
systems
with
any
analytical
results
exceeding
the
concentration
value
of
the
HRL.
The
Health
Reference
Level
(
HRL)
used
for
Naphthalene
is
140
:
g/
L.
This
is
a
draft
value
for
working
review
only.
The
highlighted
States
are
part
of
the
SDWIS/
FED
20
State
Cross­
Section.
