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United States
Environmental Protection
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Health Effects Support
Document for Naphthalene
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External Review Draft
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Health Effects Support Document
for Naphthalene
EXTERNAL REVIEW DRAFT
Contract Number: 68-C-01-002
Work Assignment Number: B-02
Prepared for:
U.S. Environmental Protection Agency
Office of Water
Health and Ecological Criteria Division
Washington, DC 20460
Prepared By:
Sciences International, Inc.
1800 Diagonal Road, Suite 500
Alexandria, VA 22314-2808
EPA822-R-02-031
April 2002
Printed on Recycled Paper
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TABLE OF CONTENTS
• vi
LIST OF TABLES ........ .......... • ............. • • • • • .............. ' ..... ; ' ' V1
vii
LIST.OF FIGURES ....... . - . - ............................... .......... ......
FOREWORD ....... ........... .... ..... ........... .................. •• ..... vm
ACKNOWLEDGMENT ............. ................ • ...... .......... ........ - •*
1.0 EXECUTIVE SUMMARY ---- . ........ • • • • ....... • ....... : • • ........... 1-1
2.0 IDENTITY: CHEMICAL AND PHYSICAL PROPERTIES ........ ..... . - ..... 2-1
3.0 USES AND ENVIRONMENTAL FATE ....... ........... ............ ..... 3-1
3.1 Production and Use ....... -------- ---- -• ------- ....... ........... ?~i
3.2 Environmental Release .................. • • • • ..................... ~~^
3.3 Environmental Fate ........ ...................... ..... • ...... ; • • • "
3.4 Summary . . .................. '••-,- ..... • ........ -• .............. '
4.0 EXPOSURE FROM DRINKING WATER ..... ... ....... ....... ............ 4-1
4.1 Introduction ..... ....... ......... • • ...... • ...................... "
4.2 Ambient Occurrence . ................................. • .......... "
4.2.1 Data Sources and Methods .......................... - ........ 4-1
4.2.2 Results ... ................ • ......... • ....... • • • .......... ' JT
4.3 Drinking Water Occurrence ................ • • ---- ................ •• • yS
4 3.1 Data Sources, Data Quality, and Analytical Methods ..... . ---- ..... 4-4
4.3.2 Results . ...... . .............. • • ............ •
4.4 Conclusion ............................. ......................
5.0 EXPOSURE FROM MEDIA OTHER THAN WATER ..... ....... ...... ...... 5-1
5.1 Exposure fromFood ...................... • ---- ---- • • ............ "
5.1.1 Concentration in Non-Fish Food Items ----- ............ • ..... • • • 5-1
5.1.2 Concentrations in Fish and Shellfish ......... . ............. .... 5-1
5.1.3 Intake of Naphthalene fromFood ..... . ....................... 5'3
5.2 Exposure from Air ...... . ........... .............................
5.2.1 Concentration of Naphthalene in Air .............. . . ....... ---- ->-4
5.2.2 Intake of Naphthalene from Air ............. ............... ... 5-5
5.3 Exposure from Soil ........ ------ • ...... ---- • ......... • ........... 5~^
5.3.1 Concentration of Naphthalene in Soil ......... . ...... • • • ....... 5'5
5.3.2 Intake of Naphthalene from Soil ........ . ................. .... 5-6
5.4 Other Residential Exposures ...... ........ ..... • ........ • ..... ..... 5-7
5.5 Summary ---- ....... ............ • • • ................ • ...........
6.0 TOXICOKBSfETICS . . ....... .............. • -------- • • •'•' ....... • ........ 6~l
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6.1 Absorption 6-1
6.2 Distribution • 6'2
6.3 Metabolism 6'3
6.4 Excretion •. 6"6
7.0 HAZARD IDENTIFICATION 7-1
7.1 HumanEffects • • • 7-1
7.1.1 Short-Tenn Studies and Case Reports 7-1
7.1.2 Long-Term and Epidemiological Studies 7-3
7.2 Animal Studies 7-4
7.2.1 Acute Toxicity 7-4
7.2.2 Short-Tenn Studies 7-6
7.2.3 Subchronic Studies 7-7
7.2.4 Neurotoxicity • • 7-10
7.2.5 Developmental/Reproductive Toxicity 7-10
7.2.6 Chronic Toxicity 7-15
7.2.7 Carcinogenicity 7-19
7.3 Other Key Data 7-24
7.3.1 Mutagenicity and Genotoxicity 7-24
7.3.2 Ocular Toxicity • 7-25
7.3.3 Hematological Effects 7-30
7.3.4 Immunotoxicity 7-30
7.3.5 Hormonal Disruption 7-31
7.3.6 Physiological or Mechanistic Studies 7-31
7.3.7 Structure-Activity Relationship 7-36
7.4 Hazard Characterization 7-36
7.4.1 Synthesis and Evaluation of Major Noncancer Effects 7-36
7.4.2 Synthesis and Evaluation of Carcinogenic Effects 7-39
7.4.3 Mode of Action and Implications in Cancer Assessment 7-56
7.4.4 -Weight of Evidence Evaluation for Carcinogenicity 7-56
7.4.5 Potentially Sensitive Populations 7-57
8.0 DOSE-RESPONSE ASSESSMENT 8-1
8.1 Dose-Response for Noncancer Effects 8-1
8.1.1 RfD Determination 8-1
8.1.2 RfC Determination 8-2
8.2 Dose-Response for Cancer Effects 8-2
9.0 REGULATORY DETERMINATION AND CHARACTERIZATION OF RISK
FROMDRINKING WATER 9-1
9.1 Regulatory Determination for Chemicals on the CCL 9-1
9.1.1 Criteria for Regulatory Determination 9-1
9.1.2 National Drinking Water Advisory Council Recommendations 9-2
9.2 HealthEffects • 9~2
9.2.1 Health Criterion Conclusion 9-3
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9.2.2 Hazard Characterization and Mode of Action Implications 9-3
9.2.3 Dose-Response Characterization and Implications in Risk
Assessment 9-4
9.3 Occurrence in Public Water Systems • • 9-7
93.1 Occurrence Criterion Conclusion , • • 9-7
9.3.2 Monitoring Data - • • • -9-8
9.3.3 Use and Fate Data • • • • 9-9
9.4 Risk Reduction.... - 9-10
9.4.1 Risk Criterion Conclusion 9-10
9.4.2 Exposed Population Estimates 9-11
9.4.3 Relative Source Contribution • • 9-12
9.4.4 Sensitive Populations . • • 9-13
9.5 Regulatory Determination Decision - 9-14
10.0 REFERENCES -• .-' 1(M
APPENDIX A: Abbreviations and Acronyms A-1
APPENDIX B: Naphthalene Occurrence Data
for Public Water Systems (Round 1 and Round 2) • • - B-l
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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 B6C3Fj Mice Exposed to
Naphthalene by Inhalation for Their Lifetime 7-16
Table 7-4. Incidence and Severity of Nonneoplastic Lesions in the Noses of Rats in a
Two-year Naphthalene Inhalation Study 7-18
Table 7-5. Incidence of Neoplasms in Male and Female F344/N Rats in a Two-year
Naphthalene Inhalation Exposure Study 7-22
Table 7-6. Summary of Studies of Naphthalene Ocular Toxicity in Animals 7-26
Table 7-7. Summary of Key Studies of Noncancer Toxic Effects of Naphthalene 7-41
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 9-13
Table 9-4. Ratios of Exposures from Various Media to Exposures from
Drinking Water 9-13
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LIST OF FIGURES
Figure 2-1.
Figure 4-1.
Figure 4-2.
Figure 4-3.
Figure 4-4.
Figure 6-1.
Chemical Structure ofNaphthalene 2'1
Geographic Distribution of Cross-section States. Round 1 (left) and
Round 2 (right) 4"7
States with PWSs with Detections ofNaphthalene for all States with Data in
URCIS (Round 1) and SDWIS/FED (Round 2). ., • • 4-H
States with PWSs with Detections ofNaphthalene (any PWSs with Results
Greater than the Minimum Reporting Level JMRL]) for Round 1 (above) and
Round 2 (below) Cross-section States •,
Cross-section States (Round 1 and Round 2 Combined) with PWSs with
Detections ofNaphthalene (above) and Concentrations Greater than the Health
Reference Level (HRL; below)
Proposed Pathways For Naphthalene Metabolism - 6-4
4-16
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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.
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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). la 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-evjdence 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), Guidelinesfor 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.
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ACKNOWLEDGMENT
This document was prepared under the U.S. EPA contract No. 68-C-01-002. Lead
Scientist, Joyce Morrissey Donohue, Ph.D., Health and Ecological Criteria Division, Office of
Science and Technology, Office of Water.
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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 hi 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 CioH8. 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, phannaceuticals, 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 hi 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
Substances and Disease Registry (ATSDR) HazDat and Comprehensive Environmental
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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 ug/L and the 99th
percentile concentration is 900 ug/L. Median and 99th percentile concentrations for Round 2
detections are 0.74 ug/L and 73 ug/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 inhalatiori. 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 conditions. There
are no reliable human toxicity data for subchronic or chronic exposure to naphthalene.
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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 lower 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 hi 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 com 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
hi body weight reaching a maximum of 24.5% hi females receiving 200-mg/kg-day. A second
oral exposure study hi mice observed changes hi organ weight and enzyme alterations indicative
of impacts on liver function at 133 mg/kg-day.
Relatively little information is available regarding the neurological effects of naphthalene
exposure in experimental animals. Two studies (one each hi rabbits and pregnant rats) have noted
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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 hi 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.
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r
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".
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2.0 IDENTITY: CHEMICAL AND PHYSICAL PROPERTIES . ' .
Naphthalene is a bicyclic aromatic hydrocarbon with the chemical formula CjoHg (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
Naphthalene
Table 2-1. Chemical and Physical Properties of Naphthalene
Property
Chemical Abstracts Registry
(CAS) No.
Registry of Toxic Effects of
Chemical Substances No.
RCRA Waste No.
EPA Pesticide Chemical Code
Synonyms
Registered Trade Name
Chemical Formula
Molecular Weight
Boiling Point
Melting Point
Vapor Pressure
Partition Coefficients
Solubility in Water
Organic Solvents
Information
91-20-3
QJ0525000
U165
055801
Tar Camphor; Albocarbon;
Naphthene; Naphthalin;
Naphthaline; Mothballs;
Mothflakes; White Tar,
Dezodorator, Mighty 150;
Mighty RD1
Caswell No. 587 ®
C10H8
128.19
218°C
80.5°C
0.087 mm Hg
LogK^ 3.29
LogS^ 2.97
0.0031 g/lOOmL
Benzene, Alcohol,
Ether, Acetone
Source: ATSDR (1995); CheadDplus (2000)
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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)
(Merckmdex, 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 x 10s metric tons of naphthalene in 1996 (CEH, 2000).
Naphthalene production in the United States dropped from 900 million pounds per year
(Ibs/yr) in 1968 to 354 million Ibs/yr in 1982. Approximately 7 million Ibs of naphthalene were
imported and 9 million Ibs were exported in 1978. By 1989, imports had dropped to 4 million Ibs,
and exports increased dramatically to 21 million Ibs (ATSDR, 1995).
U.S. consumption of naphthalene was 1.08 x 10s 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 anthehninthic, 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 Release Inventory
(TRI) of hazardous chemicals. Created under the Superfund Amendments and Reauthorization
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Act (SARA) of 1986, EPCRA is also sometimes known as SARA Title HI. TheEPCRA
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 Mi-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
1998
1997
1996
1995
1994
1993
1992
1991
1990
1989
1988
On-Site Releases
Air
Emissions
3,374,439
2,449,488
2,863,431
2,690,669
2,889,514
2,744,887
2,626,986
2,927,511
3.912,253
3,523,562
5.165,426
Surface Water
Discharges
34,148
13,333
1 1 ,836
43,311
28,557
31,179
28,925
31,508
36,821
146,983
22,518
Underground
Injection
191,677
187,927
296,776
44,318
97,186
79,814
78,227
39,112
28,130
39,552
50,946
Releases
to Land
1,251,040
82,204
301,513
32,085
47,017
49,886
1,667,150
55,278
143,196
118,409
123,697
Off-Site
Releases
827,708
491,124
582,717
474,106
496,501
334,985
667,556
983,371
919,225
1,054,602
1,359,184
Total On- &
Off-site
Releases
5,679,012
3,224,076
4,056,273
3,284,489
3,558,775
3,240,751
5,068,844
4,036,780
5,039,625
4,883,108
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 Ibs/yr, or use of more than 10,000 Ibs/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 Ibs/yr in 1988 to
50,000 Ibs/yr in 1989 to 25,000 Ibs/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
records detections of listed chemicals in site samples. Naphthalene was detected in 44 States;
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States without detections are AK, AZ, HI, NV, ND, and UT (ATSDR, 2000). The National j
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-thre,atening 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). . '' :
l
3.3 Environmental Fate . [' •
Direct releases to the air account for more than 90% of the naphthalene entering i
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 repellents. 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).
' . ' i
• i
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 j
naphthalene releases are discharged to land, but that number increased to 37% in the most recjent
year for which data are available (Table 3-1). Sources for release to land include coal tar j
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 N2OS, nitrate radicals, and ozone. The
major products of these reactions are 1- and 2-naphthol and 1- and 2-nitronaphthalene. The hjalf-
life of atmospheric naphthalene is less than 1 day (ATSDR, 1995).
i
• (
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. Southworih (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). . !
i
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 of
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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 LI 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).
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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 hi
surface waters and aquifers before treatment. The most comprehensive and nationally
representative data describing ambient water quality hi 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 then: 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).
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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 ug/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 pot 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 ug/L in'NURP samples and 5.1 ug/L in
NPDES samples.
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Table 4-1. Naphthalene Detections and Concentrations in Ground Water.
Location
Urban
Rural
Detection frequency
(% of sampled wells > MRL*)
3.0%
0.2%
Concentration percentiles
(of detections; jtig/L)
median
3.9
0.4
maximum
43
70
Percent exceeding HAL**
(20|ig/L)
all wells
0.4
0.1
drinking
water wells •
0
0
* MRL for naphthalene in water: 0.001 ftg/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 ug/L cited by Lop.es 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 ug/L HAL
(Squillace et al., 1999). The maximum values for runoff and groundwater are considerably less
than the current HAL of 100 ug/L (U.S. EPA, 2000e) and even more so for the Health Reference
Level (HRL) of 140 ug/L used as a preliminary health effects level for the drinking water data
analysis presented below.
4.3 Prinking 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 non-
transient 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 data
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for a regulatory determination. This obviated the need for continued monitoring under the new
UCMRlist.
43.1 Data Sources, Data Quality, and Analytical Methods
Currently there is no complete national record of unregulated or regulated contaminants
in drinl£rwS^mpubUc waSr systems collected under SDWA. Many States have submitted
The National Contaminant Occurrence Database (NCOD) is an mterface to the actual
occurrence dl stored in the Safe Drinking Water ^^f^^^^!^
IS/FED) and can be queried to provide a summary of the data in S^/FED fora
ar contaminant. The data used in this report were derived from *e ^^
another database called the Unregulated Contaminant Information System (URCIS).
The data in this report have been reviewed, edited, and filtered to meet various data
(for further details see Cadmus, 2000a, b);
VCM Rounds 1 and 2
The 1987 UCM contaminants include 34 volatile organic compounds (VOCs) < divided
intotwo^ouplne^OVOCs for mandatory ***^^£?^£™£
. °^ ... rco TJTJ o^Tom NanVithalene was among the 14 vucs inciuaea 101
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 ^ .also VOCs.
and regulated VOCs are analyzed using the same sample and the same
HencerSe URCIS database includes data on all of Ihese 62 contammants:
VOCs the 21 regulated Phase 1 VOCs, 2 regulated synthetic organic
miscellaneous contaminants that were voluntarily reported by some
cn,
States (e.g., isomers of other organic contaminants).
The 1993 UCM contaminants include 13 SOCs and 1 inorganic compound (IOC.) I [56 FR
3526]. Moniforiag for the UCM (1993) contaminants began coincident with lie Phase H/V
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regulated contaminants in 1993 through I998.v This is often referred to as "Round 2" monitoring.
The UCM (1987) contaminants were also included in the ILound 2 monitoring. As with other
monitoring data, PWSs reported these results to the States. During the past several years, EPA
has requested that the Slates 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 IE).
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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 IH.A.
and HI.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 in.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 IH.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).
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Table 4-2. Cross-section States for Round 1 (24 States) and Round 2 (20 States).
Round 1 (URCIS)
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
Round 2 (SDWIS/FED)
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).
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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 HLB.l).
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) cross-
sections. The 4-State cross-section is apparently too small to provide balance both geographically
and with pollution potential, a rinding 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 HI.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."
External Review Draft—Naphthalene — April 2002
4-8
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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 detections) of the
contaminant (simple detection, > MRL) at any time during the monitoring period; or a
detections) greater than half the Health Reference Level (HRL); or a detections) greater than the
Health Reference Level. The Health Reference Level, 140 ug/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 (RED) for naphthalene of 2 x 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
External Review Draft—Naphthalene — April 2002
4-9
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Table 4-3. Summary Occurrence Statistics for Naphthalene.
_--
Frequency Factors .;
Total Number of Samples •
Percent of Samples with Detections
99* Percentile Concentration (all samples)
Health Reference Level
Minimum Reporting Level (MRL)
99* Percentile Concentration of Detections
Median Concentration of Detections
Total Number of PWSs
Number of GWPWSs
Number of SW PWSs
Total Population
Population of GWPWSs
Population of SW PWSs
24-State :
Crass-Section*;
4ROUJMJ1) '
45,567
0.43%
< (Non-detect)
140|ig/L
Variable4
900ug/L
l.Oug/L
13,452
12,034
1,502
77,209,916
42^18,746
41,987,010
jjjUStatp"-',
' Cross-Section*
(Round 2)
94,915
0.24%
< (Non-detect)
140|ig/L
Variable4
73ug/L
0.74 |tg/L
22,926
20,525
2,401
67,498,059
25,185,032
42,313,027
Occurrence by System
% PWSs with detections (> MRL)
• Range of Cross-Section States
GW PWSs with detections
SW PWSs with detections
% PWSs > 1/2 Health Reference Level (HRL)
Range of Cross-Section States
GW PWSs > 1/2 Health Reference Level
SW PWSs > 1/2 Health Reference Level
% PWSs > Health Reference Level
Range of Cross-Section States
GW PWSs > Health Reference Level
SW PWSs > Health Reference Level
1.18%
0-28.24%
1.08%
1.93%
0.01%
0-1.53%
0.02%
0.00%
0.01%
0-1.53%
0.02%
0.00%
0.75%
0-4.48%
0.62%
1.92%
0.01%
0-0.06%
0.01%
0.00%
0.00%
0.00%
0.00%
0.00%
f ,/ x^s, ' ' ,
: National System &
Population Numbers8''
-
-
-
-
-
-
-
65,030
59,440
5,590
213,008,182
85,681,696
127326,486
National Extrapolation5
Round 1
769
N/A
642
108
10
N/A
10
0
10
N/A
10
0
Round 2
491
N/A
368
107
6
N/A
6
0
0
N/A
0
0
External Review Draft—Naphthalene—April 2002
4-10
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Table 4-3 (continued)
iV"? -/• 'ijf>C • "• *-f p'fKSp! .<- ' -'. !>'''*%":' \:'>.:-. ' fW^'i
r* ^S^'J^Cr^Wp-M'';;- •*-. J'--\". ";: %".
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&$s*$<'£3& » -«•', "*&&• '' ~~: $%$& f^ •&&>»»? , ,',?.%&> ,i?t ™ '
;B^(uencg|8ftitors ^SS-^^y
Occurrence by Population Served
% PWS Population Served with detections
Range of Cross-Section States
GW PWS Population with detections
SW PWS Population with detections
% PWS Population Served > 1/2 Health Ref Level
Range of Cross-Section States
GW PWS Population > 1/2 Health Ref Level
SW PWS Population > 1/2 Health Ref Level
% PWS Population Served > Health Ref Level
Range of Cross-Section States
GW PWS Population > Health Ref Level
SW PWS Population > Health Ref Level
*:afi%|t7y
2.910%
0-37.22%
4.005%
1.323%
0.007%
0-0.23%
0.013%
0.000%
0.007%
0-0.23%
0.013%
0.000%
^•^^ii^\$:
-.Gipo^-SfliQn^'
,?f|Rpwitd 2)*-r- .
4.790%
0-31.41%
1.162%
6.950%
0.002%
0-0.01%
0.007%
0.000%
0.000%
0.000%
0.000%
0.000%
%rf-- ?' •"•? ' ' '-fMi^^i^ >. - -•
^ i«?V^ - , J .g$!S£&s3£^~'~,
'• - Jfl|SspeiS^^
^JPoBdlitioAlNiimt>fF^^
National Extrapolation9
Round 1
6,198,000
N/A
3,431,000
1,685,000
16,000
N/A
11,000
0
16,000
N/A
11,000
0
Round 2
10,204,000
N/A
995,000
8,849,000
5,000
N/A
6,000
0
0
N/A
0
0
1 Summary Results based on data fiom24-State Cross-Section, from URCIS.UCM (1987) Round I.
Z Summary Results based on data fiom 20-State Cross-Section (minus New Hampshire), from SDWIS/FED, UCM (1993) Round 2.
3. Total PWS and population numbers are fiom EPA March 2000 Water Industry Baseline Handbook.
4. See text for discussion
5. National extrapolations are fiom the 24-State data and 20-State data using the Baseline Handbook system and population numbers.
- PWS = Public Water Systems; GW = Ground Water, SW = Surfece 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 ug/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
- Median Concentration of Detections = the median analytical value of all the detections (analytical results greater than tbJ MRL) (in ug/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 > '/2 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, 'A Health Reference Level, Health Reference Level, respectively.
- % PWS Population Served with detections, % PWS Population Served >'A 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, 'A Health Reference Level, or the Health Reference Level, respectively.
External Review Draft — Naphthalene—April 2002
4-11
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risk of adverse effects oyer a lifetime of exposure. This dose was converted to a drinking water
equivalent concentration of 700 ng/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 u.g/L. The HRL was derived as follows:
= RfDxBWxRSC
DI
Where:
RfD =
BW =
DI =
RSC =
Reference dose for HCBD in drinking water, 2 x 10"4
mg/kg-day
Body weight of an adult, 70 kg
Daily intake of water for an adult, 2 L
Relative Source Contribution, default value of 20%
Therefore:
HRL = (2 x IP'2 mg/kg-dav) x ( 70
2L
x Q.20
= 140 ng/L (rounded to 1 significant number).
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 b'e half the MRL
(0.5 x 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
External Review Draft—Naphthalene — April 2002
4-12
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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
(Table4-3).
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 hi 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 (> 1A 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 presented in Table 4-3 for the Round 1 cross-section are
reported from approximately 95% of the systems.)
External Review Draft — Naphthalene—April 2002
4-13
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Figure 4-2. States with PWSs with Detections of Naphthalene for all States with Data in
URCIS (Round I) and SDWIS/FED (Round 2).
AH States
Naphthalene Detections
in Round \ and Round 2
S States not in Round t or Round 2
No data for Naphthalene
States with No Detections (No PWSs > MRL)
States with Detections (Any PWS > MRL)
External Review Draft—Naphthalene — April 2002
4-14
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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
ug/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.
The simple spatial analysis presented hi 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).
External Review Draft — Naphthalene—April 2002
4-15
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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.
• Outliers: Stale of Alabama at 28.3X: Stale cfFlorida at 7.0X
Naphthalene Occurrence \m Round 1
I I Statei not in Cross-Section
I :::lNo data for Naphthalene
0.00% PWSs> MRL
Kf|0.01 - 1.00% PWSa> MRL
SB 1.00 - 4.00% PWSs > MRL*
* State ofNew Hampshire Is an outlier at J00%
Naphthalene Occurrence ID Round 2
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*
External Review Draft—Naphthalene—April 2002
4-16
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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).
• Ol/l/tora; State of Alabama at!S.3«: State of Florida at 7.0X; State of New Hampshire at 100%
Naphthalene Occurrence
IB Reaad 1 ami Round 2
| State: not in Cross-Section
"1 No data for Naphthalene
a o.ooy. PWSS > MRL
j|0.01- 1.00% PWSs > MRL
JI 1.00 - 4.00% PWSs > MRL*
Naphthalene Occurrence
in Round 1 and Round 2
States not in Cross-Section
No data for Naphthalene
0.00% PWSs> HRL
0.01 - 1.00% PWSs > HRL
1.00 - 4.00% PWSs > HRL
External Review Draft—Naphthalene—April 2002
4-17
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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 current HAL of 20 ug/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 hi 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 ug/L and the 99th percentile concentration is 900 ug/L. Median and
99th percentile concentrations for Round 2 detections are 0.74 ug/L and 73 ug/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).
External Review Draft—Naphthalene—April 2002
4-18
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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 hi meat samples that were not exposed to fire or smoke are listed hi 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
Hg/mL) at the time of purchase, increased to 0.1 |ig/mL 30 days later, and averaged 0.25 ng/mL
at the expiration date (Lau et al., 1994). Lau et al. (1994) hypothesized that residual naphthalene
present hi the LDPE packaging (1.5 to 2.0 fig/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 hi LDPE milk bottle material had been reduced to 0.1 to 0.4 jig/g due to a new
packaging method.
Dietary naphthalene concentrations were evaluated using duplicate diet food samples from
adults and children residing hi low-income housing hi North Carolina (Chuang et al., 1999). In the
adult diets, naphthalene concentrations were found to average 3.75 ±5.35 ng/kg (range = 0.01 to
18.7), whereas hi the child diets, naphthalene concentrations were 4.08 ± 10.9 (range = 0.01 to
54.9).,
Naphthalene concentrations from vegetables grown hi an industrial area of Thessaloniki,
Greece are summarized hi Table 5-2 (Kipopoulou et al., 1999). As shown hi the tabulated data,
naphthalene was detected in .all tissue samples and ranged from 0.37 to 63 ng/kg dry weight
depending on the vegetable type.
Naphthalene and methylnaphthalene (isomer not specified) were detected hi five male and
five female harp seals (Phoca groenlandica) caught hi southern Labrador on the eastern coast of
Canada hi 1994 (Zitko et al., 1998). Reported median concentrations of naphthalene and
methylnaphthalene hi harp seal tissues are presented hi Table 5-3.
5.1.2 Concentrations in Fish and Shellfish
In the United States, naphthalene was not detected hi 83 biota samples (median detection
limit 2.5 nag/kg) reported from 1980 to 1982 hi the STORET database (Staples et al., 1985).
Reported naphthalene concentrations ranged from 5 to 176 nanograms per gram (ng/g) hi oysters,
from 4 to 10 ng/g in mussels, and from less than 1 to 10 ng/g hi 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 hi all samples of seven fish and two shellfish species taken from Kuwaiti waters
External Review Draft—Naphthalene—April 2002
5-1
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Table 5-1. Naphthalene And Methylnaphthalene Concentrations in Meat Samples.
SAMPLE
Fried chicken
Beef
Hot dog
Young turkey '
breast
Smoked chicken
Smoked chicken
Boneless beef
Boneless turkey
breast
Cooked beef
Corned beef
Ham
Corned beef
Boneless beef
Turkey breast
Beef roast
Boneless turkey
NAPHTHALENE
CONCENTRATION
(ng/g)
26
26
25 „
17
11.7
5
5
4
3
3
2.5
1.7
LOQb
LOQ"
0
0
METHYLNAPHTHALENE"
CONCENTRATION (ng/g)
' 27
26
5
6
Not evaluated
13
2
0
2
2
Not evaluated
Not evaluated
Not evaluated
Not evaluated
Not evaluated
Not evaluated
REFERENCE
Johnston et al., 1994
Johnston etal., 1994
Johnston etal., 1994
Johnston etal., 1994
Snyder etal., 1996
Johnston etal., 1994
Johnston et al., 1994
Johnston etal., 1994
Johnston et al., 1994
Johnston etal., 1994
Snyder etal., 1996
Snyder etal., 1996
Snyder etal., 1996
Snyder etal., 1996
Snyder etal., 1996
Snyder etal., 1996
:%SSS£3K
extraction followed by gas chromatograph-mass spectrometer analysis; the concentration was determined using
naphthalene-d8 as an internal standard.
External Review Draft—Naphthalene — April 2002
5-2
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that were polluted with crude oils; reported concentrations of naphthalene ranged from 2.06 to
156.09 ng/g dry weight (SaeedetaL, 1995).
2-Methylnaphthalene was reported at concentrations ranging from 0.4 to 320 fig/g in fish
from Ohio waters, but neither isomer of methylnaphthalene was detected in muscle tissue offish
from polluted areas of Puget Sound (GDCH, 1992). Methylnaphthalenes were detected in oysters
collected in Australia at less than 0.3 to 2 \tgfg.
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, (Ghuang et al.,
1999) a daily average intake of 2.85 to 16.6 fig 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 pg 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
Cabbage (n=8)
Carrot (n=6)
Leek(n=5)
Lettuce (n=8)
Endive (n=3)
CONCENTRATION
(fig/kg dry weight)
Range
0.37-15
8.9-30
6.3-35
4.9-53
27-63
Median
5.0
21
18
42
29
Source: Kipopoulou et al. (1999)
Table 5-3. Median Concentrations of Naphthalene and Methylnaphthalene in Harp
Seals
Compound
Naphthalene
Methylnaphthalene
Tissue Concentration (ng/g wet weight)
Muscle
Female
3.10
1.50
Male
2.90
1.55
Kidney
Female
4.30
1.70
Male
4.15
1.40
Liver
Female
4.70
1.70
Male
4.15
1.40
Blubber
Female
21.00
8.30
Male
23.50
8.85
Source: Zitkoetal. (1998)
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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 u£/m3), andlhemajority (60) of mese samples ^emghest
concentrations were collected at source-dominated locations (Shah ^W^l™*- .
Howard (1989) reported a median naphthalene level in urban air in 11 U.S. cities of 0. ISppb
(0 94 us/m3) Chuang et al. (1991) reported an average naphthalene concentration of 170 jig/m
mlutdforimareldentia
Torrance, California, at a concentration of 3.3 ng/m3 (Propper, 1988). Patton et al- (1997)
reported a naphthalene concentration of 1.50 x 1Q-4 ug/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 ug/m3) (La Regina et al 1986). Attnosphenc «°"°*«"™ of
naphthalene in total suspended particles were reported to range fiom 0.003 to.0.095 ^ra
(median = 0.017) in the city of Ionia, Greece and from 0.002 to 0.179 ug/m3 (median - 0.030) in
the city of Sindos, Greece (Kipopoulou et al., 1999).
1-Methylnaphthalene and 2-metbylnaphthalene have also been detected in ambient air.
Shah and Heyerdahl (1988) reported average concentrations of 0.086 and 0011 ppb (£51 and
0 065 ug/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
Sgifaetal, 1986). A mean concentotion of 0.252 ppb (1.5 ug/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« al"
1991- Hung et al., 1992; Wilson et al., 1989; Lau et al., 1995). However, ATSDR (1995)
suggested Lt 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 ug/m
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 ug/m3 and less than 3 to 100
ug/m3 in office and laboratory air, respectively. Concentrations of naphthalene vapor were a so
found to be high (350 jig/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). Indoor air
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concentrations ranged from 0.33 to 9.7 |ig/m3 (mean ± Std Dev = 2.2 ± 1.9), whereas outdoor air
concentrations were lower and ranged from 0.057 to 1.82 ug/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 jig/m3 and 0.3 ug/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 |ig/m3 and 0.1 |ig/m3, respectively. Lofgren et al. (1991) reported an average concentration
of naphthalene inside automobiles in commuter traffic of about 4.5 jig /m3.
5.2.2 Intake of Naphthalene from Air
Assuming an average ambient concentration level of 5.19 [ig naphthalene/m3 and an
average inhalation rate of 15.2 m3/day (U.S. EPA, 1996c), an average daily dose of 1,127 ng/kg-
day 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 p.g/kg (measured following
Soxhlet extraction) and 350 Jig/kg (measured using sonication extraction). Measurements of
naphthalene concentrations hi 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 tig/kg,
depending on the location of sampling (Table 5-4).
Table 5-4. Concentrations of Naphthalene in Residential Dust (mg/g)
LOCATION
House Dust
Entryway Dust
Pathway Soil
CONCENTRATION (ug/kg)
Range
20-4,300
10 - 1,310
<10-40
Mean ± Std Dev
330 ±850
110 ±260
10±10
Source: Chuang et al. (1999)
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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 ug/kg. Published naphthalene concentrations in contaminated soils included
up to 66 fig/kg in sludge-treated soils (Wild et al., 1990), 6,100 jAg/kg in coal tar-contaminated
soil (Yu et al., 1990) and 16,700 |ig/kg hi soil from a former tar-oil refinery (Weissenfels et al.,
1992). Kipopoulou et al. (1999) reported naphthalene concentrations hi agricultural soil from
Thessaloniki, Greece ranging from 3.1 to 78 jig/kg dry weight (median = 17). For
methylnaphthalene (isomer not specified), Yu et al. (1990) reported a concentration of 2,900
p.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 jig/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 ng/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 ng/kg naphthalene and 50.4 and 55.3 u£/kg methylnaphthalenes
at 10 and 25 miles, respectively, from an offshore multi-well drilling platform. The study also
reported mat naphthalene and methylnaphthalene concentrations hi nearby noncontaminated
estuarine sediments were 2.1 and 1.9 ng/kg, respectively. Sharma et al. (1997) analyzed
sediments from 52 sites hi 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 ng/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 hi 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
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converted to units of 10 to 3,000 ng/kg-day (average == 20) for adults, and 200 to 43,000 ng/kg-
day (average = 3,300) for a 10-kg child (Table 5-5).
5.4 Other Residential Exposures
Naphthalene, 1-memylnaphthalene, and 2-methyhiaphthalene have been identified in
cigarette smoke (HSDB, 1999). Schmeltz et al. (1978) reported levels of 3 \ig napthalene, 1 ng
1-methylnaphthalene, and 1 jig 2-methylnaphthalene in the smoke from one commercial U.S.
unfiltered cigarette. Sidestream smoke levels of 46 u.g, 30 |ig, and 32 u.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 |xg/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. Liu 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 u.g of naphthalene vapor and 7.35 or 9.23 \ig 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 |ig/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 date 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.
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Table 5-5. Exposure to Naphthalene in Media Other than Water
PARAMETER
Concentration in
medium [average] .
Estimated daily intake
(ng/kg-day)
[average]
MEDIUM
Food
Adult
[3.75]
Hg/kg
[40.7-237]
**
Child
[4.08]
jig/kg •
[204-940]
**
Air
Adult
Child
[5.19]
ug/m3
[1,127]
[4,515]
Soil*
Adult
Child
0.02-4.3 [0.33]
mg/kg
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)
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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 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 !4C-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 jig/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 (Bloodrair partition coefficient of 571). On the
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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 hi 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.
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Turkall et al. (1994) applied 14G-radiolabeled naphthalene (3.3 |ig/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 ^-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 hi 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-l,2-dihydro-dihydroxynaphthalene, also
referred to as naphthalene- 1,2-dihydrodiol (U.S. EPA, 1998a). Trans-l,2-dihydro-
dihydroxynaphthalene 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 they depleted glutathione. In contrast, the epoxide was not
cytotoxic or genotoxic, and did not deplete glutathione (Wilson et al., 1996).
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Figure 6-1. Proposed Pathways For Naphthalene Metabolism
1,2-Dihydro-
1,2-naph!halenediol
1,2-Naptithoquinone
Cysteina Conjugates
Derivatives (Thtoetheis)
1,4-Naphthoquinone
Source: U.S. EPA (1998a)
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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-l,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
Irans-l-(S)-hydroxy-2-(S)-glutattaonyl-l ,2-d^
hydroxy-l,2-dihydronaphthalene; and trans-l-(S)-hydroxy-2rS-glutathionyl-l,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-l ,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-naphthoquinpne 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, l,2-dihydro-l,2-naphthalenediol, 1-naphthyl sulfate, and
1-naphthylglucuronic acid (Comer 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
identified were: 1-riaphthol, 2-naphthol, 1,2-naphthalenediol, cis- and trans-l,2-dihydro-l,2-
naphthalenediol, cis- ahdtrans-l,4-dihydro-l,4-naphthalenediol, and 1,1-, 2,7- and 2,6-
naphthalenediol.
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Stillwell et al. (1982) identified 1-naphthol,trans-l-hydroxy-2-methylthio-l,2-
dihydroxynaphthalene, trans-l,2-dih.ydro-l,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-(l-hydroxy-l,2-dihydro-2-naphthenyl) cysteine being the primary sulfur metabolite identified.
Bakke et al. (1990) identified the glucuronic acid conjugate and the dihydro-l-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 post-
ingestion (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 above.
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 post-
administration, 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 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).
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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 ng/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 l-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.
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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 naphthalene over
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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.
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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 childreaand 1 of the 2 infants that died
from naphthalene exposure had a genetic polymorphism that resulted in a deficiency in glucose-6-
phosphate dehydfogenase (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 of
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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. LD50 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 LD50 values as high as 9,430 mg/kg have been reported in one study
(Union Carbide Corp., 1968). Shopp et al. (1984) reported LD50 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-I 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 for this
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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/kg-
day 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
fissunng (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 LC50 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 LD50 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.
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7.2.2 Short-Term Studies
Oral Exposure
levels were not altered in a dose-dependent pattern. in^^ters (with ^ exception of decreased
sleeping time or on various *^™°lo&™ *°™e^? females) Values for hematological and
lymphocyte response to "**^^£££^ £±£-L of decreased prothrombin
coagulation parameters were similar ^ contoolsrm. ^ ^ ^ ^ high.dose males.
gavage doses an LDjo va^e oi ^ V* nQ de^ &t 25Q m^g^y. to pregnant mice,
is based on 100% mortality at 5UITmp/J^S ^ fa tost no mOrtality was reported
-i^^sass^s-—"^"1'
naphthalene exposure.
7-6
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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.
7.23 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 neutropbils 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.
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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 )
Unadjusted
0
25
50
100
200
400
Duration-
adjusted
0
17.9
35.7
71.4 -
142.9
285.7
Average Terminal
Body Weight
Males (g)
348.9
353.4
351.2
333.4
306.7*
250.6*
Average Terminal
Body Weight
Females (g)
203.4
197.8
203.5
197.2
190.5
156.7*
"Decrease > 10% relative to controls
Source: U.S. EPA (1998a)
In a'second study (BCL, 1980b), the same investigators exposed B6C3Fj mice to
naphthalene in corn oil by gavage. The administered doses were 0,12.5,25,50,100, and 200
rag/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 highest-
dose 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/kg-day) can
be identified from this study based on the occurrence of transient clinical signs of toxicity
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discussed above (U.S. EPA, 1998a). The corresponding NOAEL would be 100 mg/kg-day
(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-I mice were exposed by gavage to daily
doses of 5.3 or 53 mg/kg-day naphthalene in com 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. lexicological
responses were measured against naive control groups of 76 male and 40 female mice, and against
vehicle control groups of 11-2 male and 76 female animals. No differences in survival or terminal
body weights were seen between the control and exposed groups. In Ihe 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 high-dose 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 nig 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 hi 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.
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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, 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.
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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-I 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 (PEL) based on
maternal (death and reduced body weight) and fetal (decreased live pups per Utter) 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, 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
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testicular lesions in Fischer 344 rats receiving up to 400 mg/kg-day naphthalene (BCL, 1980a) or
in B6C3F! mice receiving up to 200 mg/kg-day (BCL, 1980b) for 13 weeks.
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
SchmShl (1955) examined the Iong4erm (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 mat 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 hi 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 B6C3Fi mice by NTP
(1992a). Naphthalene exposure concentrations hi 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
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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
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 1,0 ppm.
Table 7-3. Survival and Incidence of Non-neoplastic Lesions in B6C3F] Mice Exposed to
Naphthalene by Inhalation for Their Lifetime
Dose
(ppm)
0
10
30
Survival
Male
26/70
52/69*
118/133*
Female
59/69
57/65
102/135
Chronic Lung
Inflammation
Male
0/70
21/69*
56/135*
Female
3/69
13/65*
52/135*
Chronic Nasal
Inflammation,
Hyperplasia of
Nasal Epithelium
Male
0/70
66/69*
134/135*
Female
0/69
65/65*
135/135*
Metaplasia of
Olfactory
Epithelium
Male
0/70
67/69*
133/135*
Female
1/69
65/65*
135/135*
Source: NTP(1992a)
*Significantly different from control by logistic regression (p^O.OOl).
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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^, (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 hi 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, lOppm: 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
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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
lOppm
SOppm
60ppm
MALE
Atypical Hypeiplasia of the Olfactory Epithelium
Atropy of the Olfactory Epithelium
Chronic Inflammation of the Olfactory Epithelium
Hyaline Degeneration of the Olfactory Epithelium
Hyperplasia of the Respiratory .Epithelium
Squamous Metaplasia of the Respiratory Epithelium
Hyaline Degeneration of the Respiratory Epithelium
Hypeiplasia of the Respiratory Epithelium Goblet Cells
Hyperplasia of Glands
Squamous Metaplasia of Glands
0/49
3/49(1.3)
0/49
3/49 (1.3)
3/49(1.0)
0/49
0/49
0/49
1/49(1.0)
0/49
48/49* (2.1)
49/49* (2.1)
49/49* (2.0)
45/49* (1.7)
21/49* (2.2)
15/49* (2.1)
20/49* (1.2) •
25/49* (1.3)
49/49* (2.2)
3/49 (3.0)
45/48* (2.5)'
48/48* (2.8)
48/48* (2.2)
40/48* (1.7)
29/48* (2.0)
23/48* (2.0)
19/48* (1.4)
29/48* (1.2)
48/48* (2.9)
14/48* (2.1)
46748* (3.0)
47/48* (3.5)
48/48* (3.0)
38/48* (1.5)
29/48* (2.2)
18/48* (1.8)
19/48* (1.2)
26/48* (1.2)
48/48* (3.5)
26/48* (2.5)
FEMALE
Atypical Hyperplasia of the Olfactory Epithelium
Atropy of the Olfactory Epithelium
Chronic Ifoflpnmmtiim of the Olfactory F.pitheliiim
Hyaline Degeneration of the Olfactory Epithelium
Hyperplasia of the Respiratory Epithelium
Squamous Metaplasia of the Respiratory Epithelium
Hyaline Degeneration of the Respiratory Epithelium
Hyperplasia of the Respiratory Epithelium Goblet Cells
Hyperplasia of Glands
Squamous Metaplasia of Glands,
0/49
0/49
0/49
1,3/49 (1.1)
0/49
0/49
8/49 (1.0)
0/49
0/49
0/49
48/49* (2.0)
49/49* (1.9)
47/49* (1.9)
46/49* (1.8)
18/49* (1.6)
21/49* (1.6)
33/49* (1.2)
16/49* (1.0)
48/49* (1.9)
2/49 (2.0)
48/49* (2.4)
49/49* (2.7)
47/49* (2.6)
49/49* (2.1)
22/49* (1.9)
17/49* (1.5)
34/49* (1.4)
29/49* (1.2)
48/49* (3.1)
20/49* (2.5)
43/49* (2.9)
47/49* (3.2)
45/49* (3.4)
45/49* (2.1)
23/49* (1.7)
15/49* (1.8)
28/49* (1.2)
20/49* (1.0)
42/49* (3.3)
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
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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-alveplar 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 LOAELof3.6
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. Schmahl (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 .lg 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
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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 LOO (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).
NIP (1992a) conducted a two-year inhalation exposure study in B6C3Fj 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 histblogically 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
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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 Tgo (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 chrornatograph 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 hi 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 hi all exposure groups
(Table 7-5). However, neoplasm incidence hi the lungs was not affected by naphthalene exposure
of male or female rats hi any exposure group (respective tumor incidences for the chamber
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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 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 epitheh'um'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^O.Ol) in all male rat exposure groups relative to the control group.
Male rats in the control, low-, mid-, and high-exposure 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
MALE
Adenoma of the Respiratory Epithelium
Neuroblastoma'of the Olfactory Epithelium
Alveolar/bronchiolar Adenoma or Carcinoma
"" Incidences of Neoplasms
Chamber
Control
lOppm
30ppm
60ppm
0/49(0%)
0/49(0%)
2/49 (4%)
6/49* (12%)
0/49 (0%)
3/49(6%)
8/48* (17%)
4/48 (8%)
1/48 (2%)
15/48* (31%)
3/48 (6%)
0/49 (0%)
FEMALE
. Adenoma of the Respiratory Epithelium
Neuroblastoma of the Olfactory Epithelium
Alveolar/bronchiolar Adenoma
0/49(0%)
0/49 (0%)
1/49 (2%)
0/49 (0%)
2/49 (4%)
0/49 (0%)
4/49 (8%)
3/49(6%)
0/49(0%)
2/49 (4%)
12/49* (24%)
0/49 (0%)
*Significantly different from chamber control (P<0.01) from chamber control using the Poly-3 test
Source: NTP (2000)
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Based upon the absence of neuroblastomas and adenomas in the chamber control rats of
this two-year study and historically in NIP 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 Schmahl (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).
Bpyland 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-I mice on days 1, 8, and
15 of life. The doses at each injection time were 0.25,0.5, and 1.0 umol, for a total dose of 1.75
limol 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).
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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 hi 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 hi the frequency of micronucleated erythrocytes
hi 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 admuiistered single gavage doses of 100 mg
naphthalene/kg hi corn oil, when compared with the results from a group of 10 vehicle control
animals (U.S. EPA, 1998a). Rats were admuiistered the doses of naphthalene or com oil
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following partial hepatectomy, but prior to dietary treatment with 2-acetylaminofluorene and
carbon tetrachloride. Gamma-glutamyl transpeptidase foci were used as an indicator of 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 |ig/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 ng/mL) only in the presence of
metabolic activation. Naphthalene was mutagenic in the marine bacterium Vibrio flscheri
(Arfsten et al., 1994) and in the Drosophtta melanogaster wing somatic mutation and
recombination test (Delgado-Rodriguez et al., 1995). Gbllahon 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-l,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 hi Drosophtta 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-l,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.
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Table 7-6. Summary of Studies of Naphthalene Ocular Toxicity in Animals
Study
VanHcyningcn
and Pine (1976)
Srivostava mid
Nath(1969)
Ross* and Pau
(1988)
Oizalesi ct ol.
(1994)
Fitzhugh and
Buschke(1949)
Koch ctal. (1976)
Rao and Paodya
(1981)
Yamauchietal.
(1986)
Rathbunetal.
(1990)
Tsoetal. (1991a,
b)
Kojima(1992)
Species
(Strain)
Rabbits
(Dutch,
albino)
Rabbits
(NS*)
Rabbits
(Chinchilla
Bastard)
Rabbit
(New
Zealand)
Rabbit
(pigmented)
Weanling rats
(NS)
Rats
(Sprague-
Dawley,
Wistar, and
others)
Rat
(NS)
Rat
(Wistar)
Rat
. (Black-
Hooded)
Rat
(Brown
Norway)
Rat
(Brown
Norway)
Exposure
Route
Gavage
Gavage
Oral
Oral
Gavage
Diet
Gavage
Gavage
Oral
Gavage
Gavage
Gavage
Dose
mg/kg-day
1,000
2,000
1,000
1,000
500
2,000
(estimated)
1,000
1,000
1,000
5,000
700
500
(1,000
mg/kg-day
every
second day)
Duration
3-28
consecutive
daily doses
5 days
Single dose
4 biweekly
doses
5 weeks
2 months
(approx.)
Total
duration
unknown";
cataracts
developed
within 16-28
days.
Doses
administered
on alternate
days
lOdays
18 days
79 days
102 days
4 weeks
NOAEL
• —
-
—
—
—
—
1,000
-
—
—
LOAEL
1,000
2,000
1,000
1,000
500
2000
1,000
—
1,000
5,000
700
500
Result
Cataracts in 10/16 Dutch
and 1 1/12 albino animals)
Cataracts in 8/8 animals
Cataracts
Cataracts
Cataracts, retina]
degeneration, subretinal
neovascularizatioa
Mild cataracts
Cataracts
No effects observed
Cataracts
Lens opacities
Lens opacities
Lens opacities
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Table 7-6 (continued)
Study
Xuetal.(1992a)
Ikemoto and Iwata
(1978)
Murano et al.
(1993)
Schmahl(1955)
BCL(1980aj
BCL(1980b)
Shoppetal.
(1984)
Shopp et al.
(1984)
NTP(1992a)
NTP(2000)
Species
(Strain)
Rat
(Long-Evans,
Brown
Norway,
Sprague-
, Dawtey,
Wistar, Lewis)
Rabbits
(Albino)
Rat
(Sprague-
Dawley,
Brown
Norway)
Rat
(in-house
strain BDI,
BDIII)
Rat
(Fischer)
Mouse
(B6C3F,)
Mouse
(CD-I)
Mouse
(CD-I)
Mouse
B6CF1
Rat
(F344/N)
Exposure
Route
Gavage
Oral
Gavage
Food
Gavage
Gavage
Gavage
Gavage
com oil
Inhalation
Inhalation
Dose
mg/kg-day
1,000
1,000
1,000
41
0
25
50
100
200
400
0
12.5
25
50
100
200
0
53
133
0
27
53
267
Oppm*
lOppm
30ppm
0
3.6-3.9
10.7-11.4
20.1-20.6
Duration
28 days
2 days
6 weeks
(administered
every other
day)
2 years
13 weeks
5 days/week
90 days
5 days/week
90 days
14 days
2 years
(6hr/day;
5 days/wk)
2 years
NOAEL
-
Study not
adequate
to support
LOAEL
OR
NOAEL
400
200
133
267
SOppm*
20.1-20.6
LOAEL
1,000
1,000
1000
~~
- -~
- Result
Cataracts
Cataracts
Cataracts
No cataracts observed
No cataracts observed
No cataracts observed
No cataracts observed
No cataracts observed
No cataract formation
observed
No cataractogenic effects
or ocular abnormalities
observed.
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Table 7-6 (continued)
Study
Sbichietal.
(1980)
Holmen ct al.
(1999)
Species
(Strain)
Mouse
(C57BL/6N,
DBA/2N)
Rat
(Brown
Norway)
Exposure
Route
Diet
Gavage
Dose
mg/kg-day
0
60
120
(injected
twice
weekly
withcyto-
chrome P-
450
inducer)
0
100
500
1,000
1,500
Duration
60 days
10 weeks
2 doses/week
NOAEL
C57BIV6
Nmice:
—
DBA/2N
mice:
120
100
adjusted:
29
LOAEL
C57BL/
6N
mice: -
60
DBA/2N
mice:
—
500
adjusted:
143
Result
Cataracts observed in
l/15C57BL/6Nmiceat
each dose.
No cataracts observed in
DBA/2Nmice)
First signs of ocular
changes occurred within
2.5 weeks after start of
treatment.
All treated with doses of
500 rag/kg or more
developed cataracts.
*NS = Not specified
• 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.
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Ocular changes were monitored by slit illumination and retro-illumination. All rats treated with
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. Schmahl (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/kg-
day, 5 days per week for 13 weeks. In B6C3F, 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-I mice treated by gavage at 133 mg/kg-day for 90
days. Cataracts were not observed in B6C3F! 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/kg-day 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 hi 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
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29 mg/kg-day (duration-adjusted dose administered to Brown Norway rats on a biweekly dosing
regimen) and 133 mg/kg (CD-I mice) to 400 nag/kg (Fischer rats).
733 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 nag/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
B6C3Fj mice treated with gavage doses of up to 200 mg/kg-day, 5 days/week for 13 weeks
(BCL, 1980b); or in CD-I 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-I 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%
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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
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 immuhosuppressive 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 naphthalene-
induced 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 nieotinamide 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).
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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-riaphthalenediol 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 irydroxy compounds.
These hydroxy compounds then enter the circulation and are transported to the lens, where 1,2-
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 glutatbione 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 l,2-dihydro-l,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 l,2-dihydro-l,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 hi naphthalene exposed rats. Aldose reductase is found in the lens, liver, and hi
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
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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
contrast, Tao et al. (1991'a, 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 hi 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
hi 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 hi 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 hi 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 hi pulmonary toxicity hi humans (ATSDR, 1995).
Increased incidences of alveolar bronchiolar hyperplasia were observed hi F344/N female
rats exposed to naphthalene via inhalation for two years (NTP, 2000). A predominantly benign
neoplastic response hi the alveolar/bronchiolar region following chronic inhalation exposure to
naphthalene has been observed hi 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 hi the lung
(Warren et al., 1982; O'Brien et al., 1985; Rasmussen et al., 1986; Buckpitt and Franklin, 1989).
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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 andFranklin, 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).
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-naphthoquuione 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 lR,2S-naphthalene oxide and lS,2R-naphthalene
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 species-
specificity 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
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7-34
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extent of IR^S-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
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-trahsferases) 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. ,
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7-35
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7.3.7 Structure-Activity Relationship
There are few studies that systematically examine the lexicological 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-methyhiaphthalene 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).
Buckpitt and Franklin (1989) reviewed the comparative pulmonary toxicity of naphthalene
and the related compound 2-methyhiaphthalene. 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! 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 hi 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-memylnaphthalene are mechanistically related (U.S. EPA, 1998a).
7.4 Hazard Characterization
7.4.1 Synthesis and Evaluation of Major Noncancer Effects
As discussed hi 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
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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 toxieity, 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
toxieity, particularly infants and the fetus (Valaes, 1963; U.S. EPA, 1987b; Owa, 1989).
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 hi 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
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7-37
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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^-naphthoquinone. The
naphthoquinone then reacts with lens components to cause damage and opacity. The key enzyme
in the conversion of the dihydrodiol to the quirione 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
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.naphlhalene
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 E6C3F1 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 non-inhalation exposure suggests that lung tissue
may be especially sensitive to naphthalene or its metabolites, or that particular metabolic pathways
are acting hi 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 hi 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
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7-38
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al., 1995) identified the rate of conversion of naphthalene to naphthalene-lR,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 well-
understood. 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
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! 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/3 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
External Review Draft—Naphthalene—April2002 7-39
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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 (Schmahl, 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).
. External Review Draft—Naphthalene — April 2002
7-40
-------
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7.4.3 Mode of Action and Implications in Cancer Assessment
Data are not available to clearly identity 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 hi 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.
External Review Draft—Nephthalene — April 2002
7-56
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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 hi 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 G6PD-
deficient 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 naphthalene-containing
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
External Review Draft—Naphthalene—April 2002 7-57
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admission, 58% of the naphthalene group had results within the normal range. However, when
retested after recovery, all patients had uniformly deficient levels of 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 enzjmae
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).
External Review Draft—Naphthalene—April 2002
7-58
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Neonates, Infants, and Fetuses
.j
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.
External Review Draft—Naphthalene — April 2002
7-59
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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
com 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 bistopathological 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
bistopathological 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 leastlO%) 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 x lO'2 mg/kg-day.
External Review Draft—Naphthalene—April 2002
8-1
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RfD =
71 mg/kg-dav
3000
0.02 mg/kg/day
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 x 10'2 mg/kg-day was obtained. This value is very similar to the
value of 2 x 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 HSC 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 x 6 hours/24 hours x 5 days/7days). The
resulting values were converted to human equivalent concentrations (HECs) by multiplying the
adjusted concentrations by the ratio of mouserhuman 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
x 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
External Review Draft—Naphthalene—April 2002
8-2
-------
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).
External Review Draft — Naphthalene—April 2002
8-3
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-------
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,
External Review Draft—Naphthalene — April 2002
9-1
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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
effects), the RfD for threshold effects, and the slope factor for nonthreshold effects.
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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 lexicological 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 in 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 x iQr2
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 hi 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.
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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 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 mis 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. 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 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 hi 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 hi 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
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observed in a 14-day corn oil gavage study conducted in CD-I 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]
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 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-I
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 daywould 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 x 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 hi 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 x 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,
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
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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)
NTP (1991)
Mouse
CD-I
Rat
Sprague-
Dawley
76-112
M
40-76
F
25-26
F
0
27
53
267
0
50
150
450
14 days
Gestation
Days
6-15
53
Maternal
Fetal
450
267
Maternal
50
Fetal
—
Subcbronic Studies
BCL (1980a)
BCL(1980b)
Shopp et al.
(1984)
Rat
F344
Mouse
B6C3F,
Mouse
CD-I
10 M
10 F
10 M
10 F
76-112
M
40-76
F
0
25
50
100
200
400
0
12.5
25
50
100
200
5.3
53
133
13 weeks
(5
days/wk)
13 weeks
(5
days/wk)
90 days
100
Duration
adj. dose:
71
100
Duration
adj. dose:
71
53
200
Duration
adj. dose:
143
200
Duration
adj. dose:
143
133
Increased
mortality,
decreased
terminal body
wt; altered organ
wts.
Maternal: Signs
ofneurotoxicity
lethargy, slow
respiration and
apnea; signs
transient at low
dose
Greater than 10%
reduction in body
weight
Transient signs of
toxicity (lethargy,
rough coats,
decreased food
consumption)
during weeks 3 -5
Decreased organ
weights; liver
enzyme activity
M — male
F « female
wt = weight
adj. = adjusted
— = no data
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fhat readily volatilize 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:
• 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
naphmalene 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 contamination 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.
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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 ng/L and 900 jig/L,
respectively. The median and 99* percentile for Round 2 detections were 0.74 pg/L and 73 fig/L,
respectively. There are indications that the high concentrations reflected hi the 99th percentile
value for the Round 1 detections are outlier values from two ground water systems hi one cross-
section 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 hi 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 hi 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
u.g/L and 0.4 \igfL, respectively. Because the proportion of detections hi the sample database is
low and nondetect samples are not considered, these concentrations overestimate the actual
concentrations of naphthalene hi 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 pg/L. This value was exceeded hi 0.4% and 1% of urban and
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rural wells, respectively. None of the drinking water wells that were tested exceeded the present
Health Advisory value (100 |ig/L).
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 x 10s 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 KQC 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 hi 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
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nutrients. Naphthalene has a log octanohwater partition coefficient (KoW) of 3.29. Based on this
value, significant bioaccumulation of naphthalene in the food-chain is not expected to occur
(ATSDR, 1995).
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.
s
9.4 Risk Reduction
The third criterion asks if, hi 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 looted 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 methemoglobmemia and possibly hemolytic anemia if exposed to
moderate-to-high doses of naphthalene. Methemoglobmemia 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.
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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
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
Served by PWS with detections
Served by PWSs with detections > (1/2 HRL)
Served by PWSs with detections > HRL
Round 1
6,198,000
16,000*
16,000*
Round 2
10,204,000
5,000
0
Source: Data taken from Table 4-4 of this document.
HRL = Health Reference Level
* Probable outlier values
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9.43 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.
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 \igfL for the most sensitive to 3.3 }ig/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.pg/L.
Assuming intake of 2 L/day of drinking water by a 70 kg adult, the average daily dose would be
1.4 x 10'3 to 47.1 x 10'3 ng/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 x 10'3 fig/kg-day (0.5 to
165 ng/kg-day). Alternatively, if the median concentration for naphthalene in samples with
detectable levels (approximately 1 u£/L) is used, the average daily doses to an adult and child
would be 28.6 x 10'3 and 100 x 10'3 ug/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 fbodrdrinking water
exposure ratio ranges from 1 to 8 for an adult and from 2 to 9 for a child. The estimated
aindrinking 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 soihdrinking
water intake ratio will be highly scenario-dependent. For an adult, the estimated soihdrinldng
water exposure ratio ranges from less than 1 to 103. For a child, the estimated soilcdrinking 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. .
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Table 9-3. Comparison of Average Daily Intakes from Drinking Water and Other
Media"
Medium
Drinking Waterb
Food
Air
Soil"
Adult (ng/kg-day)
29°
41c-237
1,127
10-3,000
Child (ng/kg-day)
100
204-940
4,515
200-43,000
1 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 ug/L)
"Rounded values
d Includes household dust
Table 9-4. Ratios of Exposures from Various Media to Exposures from Drinking Water '
Exposure Ratio
Food:Drinking Water
AirrDrinking Water
Soil:Drinking Water
Adult
1-8
39
< 1-103
Child
2-9
45
2-430
• 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 infante are generally considered to be more sensitive to naphthalene toxicity
because the metabolic pathways for conjugation of naphthalene are not well-developed. New-
born infants also have low levels of methemoglobin reductase, a result of which may be to
compound and prolong some effects of hemolytic anemia.
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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.
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External Review Draft—Naphthalene — April 2002
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External Review Draft — Naphthalene — April 2002
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Uyama, Y., S. Ogino and T. Ichihara. 1955. Biochemical study on the genesis of naphthalene
cataract: I. The cataractogenic substance excreted in the urine of rabbit treated with naphthalene.
Med. J. Osaka Univ. 6:229-239 (as cited in ATSDR, 1995).
Valaes, T., S.A. Doxiadis and P. Fessas. 1963. Acute hemolysis due to naphthalene inhalation.
J.Pediatr. 63:904-915 (as cited in ATSDR, 1995). , ,
Van Hevmngen, R. and A. Pirie. 1967. The metabolism of naphthalene and its toxic effects on
the eye. Biochem. J.- 102:842:852 (as cited in U.S. EPA, 1998a).
Van Heyningen, R. and A. Pirie. 1976. Naphthalene cataract in pigmented and albino rabbits.
Exp. Eye Res. 22:393-394. (s cited in ATSDR, 1995, and U.S. EPA, 1998a).
Van Heyningen, R. 1979. Naphthalene cataracts in rats and rabbits: a resume. Exp. Eye Res.
28:435:439 (as cited in U.S. EPA, 1998a).
Van Winkle, L.S., Z.A. Johnson, S.J. Nishio, et al. 1999. Early events in naphthalene-induced
acute Clara cell toxiciry comparison of membrane permeability and ultrastructure. .Am. J. Respir.
Cell Mol. Biol. 21:44-53.
Warren, D.L., D.L. Brown and A.R. Buckpitt. 1982. Evidence for cytochrome P-450 mediated
metabolism in the bronchiolar damage of naphthalene. Chem. Biol. Interact. 40:287-303 (as cited
inU.S.EPA, 1998a).
Weissenfels, W.D., H.J. Klewer and J. Langhoff. 1992. Adsorption of polycyclic aromatic
hydrocarbons (PAHs) by soil particles: influence on biodegradability and biotoxicity. Appl.
Microbiol. Biotechnol. 36:689-696 (as cited in ATSDR, 1995).
Wells, P.G., B. Wilson and B.M. Lubek. 1989. In vivo murine studies on the biochemical
mechanism of naphthalene cataractogenesis. Toxicol. Appl. Pharmacol. 99:466-473 (as cited in
ATSDR, 1995).
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soil with a known history of sewage sludge amendments: Polynuclear aromatic hydrocarbons.
Environ. Sci. Tech.. 24:1706-1711 (as cited in ATSDR, 1995).
Wilson, A.S., M.D. Tingle, M.D. Kelly, et al. 1995. Evaluation of the generation of genotoxic
and cytotoxic metabolites of benzo[a]pyrene, aflatoxin B, naphthalene and tamoxifen using human
liver microsomes and human lymphocytes. Human Exp. Toxicol. 14:507-515 (as cited in U.S.
EPA, 1998a).
External Review Draft—Naphthalene — April 2002
10-20
-------
Wilson, A.S., C.D. Davis, D.P. Williams, et al. 1996. Characterization of the toxic metabolite(s)
of naphthalene. Toxicology 114:233-242 (as cited in U.S. EPA, 1998a).
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semivolatile organic pollutants in indoor air. Environ. Sci. Technol. 23:1112-1116 (as cited in
ATSDR, 1995).
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Xu, G.T., J.S. Zigler and MJF. Lou. 1992a. Establishment of a naphthalene cataract model in
vitro. Exp. Eye Res. 54:73-81 (as cited in U.S. EPA, 1998a).
Xu, G.T., J.S. Zigler and M,F. Lou. 1992b. The possible mechanism of naphthalene cataract in
rat and its prevention by an aldose reductase inhibitor (AL01576). Exp. Eye Res. 54:63-72 (as
cited in U.S. EPA, 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
covalentiy 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
glutatbione 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 groenlandicd). 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 inATSDR, 1995).
External Review Draft—Naphthalene — April 2002
10-21
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APPENDIX A: Abbreviations and Acronyms
ACGIH
ATSDR
CAS
CCL
CERCLA
CMR
CWS
DWEL
EPA
EPCRA
GW
HA
HAL
HazDat
HRL
IOC
IRIS
MRL
NAWQA
NCOD
NIOSH
NPDES
NPDWR
NTis
NTNCWS
ppm
PWS
RCRA
SARA Title IE
SDWA
SDWIS
SDWIS/FED
SOC
STORET
SW
TRI
UCM
UCMR
URCIS
U.S. EPA
USGS
- American Conference of Governmental Industrial Hygienists
- Agency for Toxic Substances and Disease Registry
- Chemical Abstract Service
- Contaminant Candidate List
-Comprehensive Environmental Response, Compensation &
Liability Act
- Chemical Monitoring Reform
- Community Water System
- Drinking Water Equivalent Level
- Environmental Protection Agency
- Emergency Planning and Community Right-to-Know Act
-ground water
- Health Advisory
- Health Advisory Level
- Hazardous Substance Release and Health Effect Database
- Health Reference Level
- inorganic compound
- Integrated Risk Information System
- Minimum Reporting Level
- National Ambient Water Quality Assessment
- National Drinking Water Contaminant Occurrence Database
- National Institute for Occupational Safety and Health
- National Pollution Discharge Elimination System
- National Primary Drinking Water Regulation
- National Technical Information Service
- Non-Transient Non-Community Water System
-part per million
- Public Water System
- Resource Conservation and Recovery Act
- Superfund Amendments and Reauthorization Act
- Safe Drinking Water Act
- Safe Drinking Water Information System
- the Federal Safe Drinking Water Information System
- synthetic organic compound
- Storage and Retrieval System
- surface water
- Toxic Release Inventory
- Unregulated Contaminant Monitoring
- Unregulated Contaminant Monitoring Regulation/Rule
- Unregulated ContaminantMomtoring Information System
- United States Environmental Protection Agency
- United States Geological Survey
External Review Draft—Naphthalene — April 2002
A-l
-------
voc
mg/L
>MCL
>MRL
- volatile organic compound
- micrograms per liter
- milligrams per liter
- percentage of systems with exceedances
- percentage of systems with detections
External Review Draft—Naphthalene —April 2002
A-2
-------
APPENDIX B: Naphthalene Occurrence Data
for Public Water Systems (Round 1 and Round 2)
Napthalene Occurrence in Public Water Systems in Rou 1 1, UCM
STATE
HEfVi-i *
ak— — . —
AR
CO
DC
>E
!iUr *" .
GA
Hit, , >
^.lag^
N
fr-TT-
MA
i8iE> ^ ..,.
Ml
m~ &< ....'
MO
MS
Brf... .{•..?.....
te •:' ';;:
NE
NH
ly ..,.-: ^t;
Mil? "
NV
NY
*H ' W
SD" x' " *
TN ,-..;.: '
TX
Ot _L
VI
VT
iyAA. ^...
WV ' "
#¥ :~ , ,
TOTAL
^'StAtES „
TOTAL
UNIQUE
PWS
*" ~^- 12?
"*^MV?
«• %•>
L1 V$|
52J
15
•
• <" 982
•' ' SXjS&i
85
;
~> J20i
<
.
.." , 78<
",•>-> 59C
I
26
" ,i2(86
" 33!
' 30!
'30
r^ «<99J
- ""5'
'" M
13,85
#GW
PWS
-" ,;.s®
^."jS3i
"^ 40t
'69^
a
c
e
^ x f
1J5S
^^j
", '\ ' v;"
-1S<
' "^
". 2*
j
•
^" 93f
,' i,S2(
7-
^ • «,
* 2&
!
•
w,
r_ $s
18'
*,j^fe
.- . 30
V "16
;
'38
> -y93'
-v -1-2
1T
12,33
PSSI0S
#sw
PWS
-" ' '„* <$A
„..,.„?. $L
-\ f .41
- 27
5
1
2
• * »•*• 1,5$
> "tfl
^ ' 16
-v-«*
' 6^
• , 31
.'- -ma
t
* '" Sf
S^Kf ^
1'
(
^ .^
I
I
- " f
w-r;i
85
"*" "101
yj(<
'- 1*
^ j, » $
/ , rr*
fS.~ - 3,'
1,62
, ,Vt,SO!
% PWS
>MRL
"* '4:^8%
.^..Z8.2»%
- 1*12%
-'^li^
14.29%
0.00%
0.00%
, ~fJBB%
- 'vtido%
x->i,oo%
"-.
-^1J7%
k^co.as^a
•' 1»t5%
0.00%
100,00%
'-> ftj«%
*. , (J,Q68£
0.00%
100.00%
f> , -, • 1 1
. 0.34$
100.00%
ioo.ooy
•^>=t<0a,%
~ -0,00?
12.500/
0.380/
<-< v-^aess
- _;2.as%
. ro^wJ
ioo.ooy
- *$&&>&
0.00?
- * Oi20?
/4.""0085
3jW^
1.29^
,„, 14895
% GW PWS
>MRL
>' -;- MM%
;,' , U,8»%
% «'~&ti®k
0.00%
Q.QQVt
Q.QOV<
" ;,".'- D^^
* -0,905$
- ,4eoS
5'« A, r-" *<
t- - ^ ^jo5%
K'X . asiiJ
t^>3%
0.00%
100.00%
"^.~ QMVt
'• '- ''O.OB
0.000/
100.00%
' * % -* "
- 4,,"J.»!
100.00%
100.00%
_" ^fculs/
* ' ' ^0,00%
14.29?
0.008/
-,' $< »ttS8?
•*-- zSa*
" - -4,84%
100.000/
v.'',i.|p6/
0.00^
'^f- 02ifc
o»oi?
/ ^ 2^
1.180/
': - H,OS?
/oSWPWS
>MRL
"1* ,1S$%
:'^ ^1% R7^»*
->. 2.13%
i"4op?5
20.00%
0.00%
0;00%
,,-~ ?5S%
' ^.OQ.%'
-,i.^po%
* o" *
"--•i.ssi
i, , ^i^a%]
taws
0.00%
100.00%
--' * ftflO%
&fe" JB,00%
0.00%
0.000/
!f* ,^
^%:eo%
0.00%
0.00%
-^O.DO%
x ^.0JDO«
o.ooy
1.18%
060?
;„ rl&%
1h36S
100.00%
2.94%
O.OO0/
,jRfla%
-^-b.w?'
^ ftsO®
2.04%
" , f.8®
987) results
%PWS
>HRL
11 J9 JQ%
»*J6KJ»£,
sxoifti
"0.fiCJ%
0.00%
0.00%
0.00%
-. o,0a%
.eio%
" 0.0!f/S
* '*
-''^,fe
LV,«JM%
. HRL
^00%
v«'- 000%
«LOO%
0.00%
0.00%
0.00%
1-. « tLOMS
• 0CO^%
-<,'ioi%:
l~*~"
- - 8F00%
^i H,,,^.?™
"ys™'* 0,00%
0.00%
0.00%
v-0.00%
- 0.00%-
0.00%
0.00%
/ x» " *"
, >" 0.00%
0.00%
0.00%
: *"'i)uBo%
^riOSfe
0.000/
0.000/
,v"^*t|BOO%
'"^r'ojw"
' 0:007
0.00%
''^'^0jK)%
0.000/
^ "'jpacfr
:'„:" aao%
:?^- S.ws
0.02%
^^^80*63?
sSWPWS
>HRL
SffiSffi
* ^*6jo0^
*; ofl09J
*";'Hl^i
0.0035
0.00%
O.OC»i
"^¥^.00^
, 'Q's$y<
V^MW
i^1'
' \fi.00%
:, -oj«ffi
^'' -0.00°^
0.00%
o.oo°x
0,00%
""' ,O.Ot^
0.00%
0.00%
F" -" 6,00^
0.00%
0.00%
*; '/• 'ftp%
"7 0.00%
0.00%
0.00%
~ * ',.0.00$
.^.-.«8»
, ti,00^
o.ooy
. ^0,00"
0.00°
.,', ?&QW
r ;.fifflP
x , ' 0;008
0.00
9% VALUE
(MPa/L)
:;;,,, :?^
y-A« *4^E
? <5.0C
- ^jstftOt
4.62
<0.5C
<0.6C
'"S raS
• < £*8M
• _-i,_ •fo.aj
*' "- , «;2,0t
.„" ;uv'-*i-«S2JB
.:,,",:o.«
- , »-* r^e
<5.0C
^;:fc*^ffll
MRL=Minirnum 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
indicates the proportion of systems with any analytical results exceeding the concentration value of the HRL.
External Review Draft — Naphthalene —April 2002
B-l
-------
Appendix B, Round 1 Data (continued)
The Health Reference Level (HRL) used for Naphthalene is 140 ug/L. This is a draft value for working review only.
The highlighted States are part of the URCIS 24 20 State Cross-Section.
Naphthalene Occurrence in Public Water Systems in Round 2, UCM (1993) results
STATE
Tribes (06)
AK
AL
Bit •;
AZ
CA
CO
CH-
IN
KY
LA
MA
MD
ME
Mr : "^'
MN
MO
MS
fcC
ND
NH
NJ
KM
OH ~
OK
OR
PA
Rl
SC
SD
TN
tx
vT
WA
Wl
TOTAL
20 STATES
19 STATES
TOTAL
UNIQUE PWS
22
" 626
2
517
68
15
831
84
117
212
1.310
4ta
878
744
2,737
isss
1,412
1,776
296
•a
7
7U
2,232
792
17
10C
237
27
4,412
2,5W
191
25,006
22,926
22.92J
#GW
PWS
21
481
2
423
60
12
818
43
107
103
1,241
344
92C
676
2,645
1,526
1,297
1,585
25*
.1
7
68S
.2.Q5C
541
15
«
21f
1£
3.82S
. 2,435
18£
22,441
20.525
20,52'
#SW
PWS
1
,.Vi-i44
•-'•44
8
3
•212
41
10
108
69
74
56
68
92
3C
115
19C
36
2
25
182
251
2
11
21
e
••"VfW
•iUfl
:
2,565
2,401
,:/2,39$
%PWS
>MRL
0.00%
- .£*48%'
100.00%
v-Yf-aoa%'
1.47%
6.67%
. :^:-. 3;S7%
1.19%
0.85%
0.47%
0.00%
- 1.20%
051%
. 0.64%
0,33%
o.sa%
aOTfo
1.18%
- < 0,00%
100.00%
0.00%
o.ss%
1,39'%
% 0.76%
0,00%
• 0.00%
0.00%
0.00%
.** «Bt8%
w 3QJ3*%
0.00%
0.73%
0.77%
, * . mm
%GWPWS
>MRL
0.00%
100.00%
#isa$CKB$
1.67%
8.33%
2.33%
0.93%
„• - QM%
0.00%
, < 0.88%
-- 's 0,ifMRL
0.00%
0.00%
0.00%
9.00%
0.00%
0.00%
• - - 0.92%
0.00%
, <*A.(i$%
,7.14%
. ^ Cdo%
•'-- p,QO%
., ,.$,87%
^-8.00%
-„ -^wm
"^Q$m
' ioa;,oo%
"" ,4.00%
0.00%
0.40%
OJ30%
O0tt%
0.00%
0.00%
, v^tfts^i
^:.IfiS2%
0.00%
1.87%
2.00%
lilris^
%PWS
>HRL
0.00%
0.00%
, , 0.003fi
0.00%
0.00%
'Jfl.^S»
0.00%
0.00%
, J,00%
0.00%
„ ^e,gg%
re,oo%
- j^i
t wo%
0,00%
o,oa%
0,00%
jfolS
0>OOS§
0.00%
8,06%
(5,00%
ff.00%
- 0,OQ%
ajjo%
0.00%
0.00%
, 6vOO%
».(»%
0.00%
0.00%
0.00%
S:B$®&J1$
/oGWPWS
>HRL
0.00%
l^lflSKBS
0.00%
0.00%
0.00%
0.00%
0.00%
" 400%
0.00%
0,QO%
, «. , , So0%
'<^b",oo%
_vaoo%
"-'DOG*.
'O.00%
% - *a,oo%
w> (000%
0.00%
0.00%
* 0.00%
'* fl.00%
' - 0.0,0%
., 1>JO%
_ ^ jfeOt)%
0.00%
0.00%
000%
HRL
0.00%
0J6$»
•*• o,oo%»
0.00%
„ ,%OT»
S^W^i
0.00%
0.00%
; 0,00%
0.00%
OJi56%
o,og?&
/ 0.60%^
0,60%
0.00%
'"b.ot3^:
0,00%
„ Q.00i&
r fl,eo%.
0.00%
- 0.00%
ft^Q%
^ o.fijiji
,-,0.00%
0.00%
0.00%
•Q'M%
. .,ftOQ!i,
0.00%
0.00%
0.00%
fcfl|0p%
99% VALUE
(P9/L.)
<10.0C
^..«OrtK
1.4C
<&.OI
<1.0C
1,«
'/«:• L^IB^
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 ugrt_. This is a draft value for working review only.
The highlighted States are part of the SDWIS/FED 20 State Cross-Section.
External Review Draft — Naphthalene—April 2002
B-2
------- |