_ TECHNICAL REPORT DATA
fntatftta liuovettont on tkt rtvtnt before eompJetuifj
L REPORT MO.
EPA/600/8-89/094
4. TITLE AND SUBTITLE
Updated Health Effects Assessment for Naphthalene
3. REClUENT-S ACCESSION NO
PB90-142464/AS
*. REPORT DATE
*. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
PERFORMING ORGANIZATION REPORT NO
B. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cineinnati. OH 45268
13. TYPE Or REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
IS SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
OMCRIPTORS
b.lDENTlHERS/OPEN ENDED TERMS
c. COSATi Field/Croup
•. DISTRIBUTION STATEMENT
Public
It SECURITY CLASS (Thu Rrport)
Unclassified
21. NO. Of PACES
90. SECURITY CLASS (This ptft/
Unclassified
22. PRICE
Fw» 2220-1 («•». 4-77) VRKVIOU* COITION if OMOLCTK
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EPA/600/8-89/094
May, 1988
HEALTH EFFECTS ASSESSMENT
FOR NAPHTHALENE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has-been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with naphtha-
lene. All estimates of acceptable Intakes and carcinogenic potency pre-
sented In this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to Hay, 1987. Secon-
dary sources of Information have also been relied upon 1n the preparation of
this report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1980a. Ambient Water Quality Criteria for Naphthalene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Water Regulations and Standards, Washington, DC.
EPA-440/4-80-059. NTIS PB 81-117707.
U.S. EPA. 1982. Revision and Update of Hazard Profile on Naphtha-
lene. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Solid Waste and Emergency Response, Washington,
DC.
U.S. EPA. 1983. Reportable Quantity Document for Naphthalene.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for
Naphthalene. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. Summary Review for Health Effects Associated
with Naphthalene: Health Issue Assessment. Prepared by the Office
of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Research Triangle Park, NC for the Office of Air
Quality Planning and Standards and the Office of Air and Radiation,
Washington, DC.
The Intent In these assessments Is to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
111
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Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$o)
exposures.
The RfD (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD 1s route-specific and estimates acceptable exposure for either oral
(RfD0) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained In U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carclnogenldty
RfD$ and RfD/ values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-j*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context.
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates.
An RfD$o and RfDg for naphthalene of 29 mg/day was derived from a
chronic dietary study In rats. Data were Insufficient for derivation of an
RfD$i or RfDj for naphthalene. A CS of 13.2 was based on kidney lesions
1n rats 1n a subchronlc gavage study.
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation for EPA's Environmental Criteria and Assessment Office,
Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the
Technical Project Monitors and Helen Ball was the Project Officer. The
final documents 1n this series were prepared for the Office of Emergency and
Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of Air Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDcr)
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TABLE OF CONTENTS (cont.)
Page
6.2. REFERENCE DOSE (RfD) 13
6.2.1. Oral (Rf00) 13
6.2.2. Inhalation (RfDi) 13
6.3. CARCINOGENIC POTENCY (q-|*) 14
6.3.1. Oral 14
6.3.2. Inhalation 14
7. REFERENCES 15
APPENDIX: Summary Table for Naphthalene 24
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
CS Composite score
Koc Soil sorptlon coefficient
HEO Minimum effective dose
NOEL No-observed-effect level
PAH Polycycllc aromatic hydrocarbons
PEL Permissible exposure limit
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfD0 Oral reference dose
RfD$ Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The physical and chemical properties and environmental fate of naphtha-
lene (CAS No. 91-20-3) are as follows:
Chemical class: polycycllc aromatic hydrocarbon
Molecular weight: 128.19 (Callahan et al., 1979)
Vapor pressure at 25°C:: 0.082 mm Hg (MacKay et al., 1982)
Water solubility at 25°C: 31.7 mg/l (MacKay et al., 1980)
Log octanol/water
partition coefficient: 3.30 (Hansch and Leo, 1985)
Koc: 1288 (Sabljlc, 1984)
BCF: 20-567 (U.S. EPA, 1986a; Correa and
Venables, 1985)
Half-lives 1n
A1r: 8-12 hours (U.S. EPA, 1986a)
Mater: 2.3 days (Zoeteman et al., 1980)
Soil: 3.6 months (U.S. EPA, 1986a;
NLM, 1987)
The dominant removal mechanism for napthalene 1n air 1s predicted to be
reaction with photochemically generated hydroxyl radicals. In photochemical
smog situations, reaction with NO. radicals 1s expected to occur but the
half-life of this process (15 hours) 1s longer than the half-life because of
Us OH radical reaction (8-12 hours) (U.S. EPA, 1986a). Significant removal
from the atmosphere by wet or dry deposition 1s unlikely (U.S. EPA, 1986a).
The removal of naphthalene from a shallow, rapidly flowing stream Is
predicted to be as follows: volatilization, 80%; sediment sorptlon, 15.5%;
0014H -1- 04/26/88
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microblal degradation, 4.4X; photolysis, <1% (U.S. EPA, 1986a). Bloaccumula-
tlon In aquatic organisms Is not expected to be significant (U.S. EPA, 1986a;
NLM, 1987). The aquatic half-life reported (Zoeteman et al., 1980) Is for the
overall half-life of naphthalene 1n a river.
Naphthalene 1s adsorbed moderately to soil and 1s expected to blodegrade.
Blodegradatlon may be rapid In soils previously contaminated with PAHs
(half-life hours to days) but will be slow otherwise (NLM, 1987). Significant
amounts of naphthalene may be lost by volatilization from soil surfaces.
Groundwater contamination has been detected at waste disposal sites and spill
sites (U.S. EPA, 1986a). The estimated volatilization half-life of naphtha-
lene from a soil containing 1.25% organic carbon was 1.1 day at a depth of
1 cm and 14 days at a depth of 10 cm (U.S. EPA, 1986a).
0014H -2- 05/20/88
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Information regarding the absorption of naphthalene 1n humans and animals
1s limited. When Ingested as a solid, naphthalene 1s sufficiently absorbed to
cause toxlclty 1n man (Chusld and Fried, 1955; Zuelzer and Apt, 1949; Nash,
1903; Gross et al., 1958; Haggerty, 1956). Furthermore, naphthalene seems to
be more toxic when dissolved 1n oil before 1ngest1on (Talakln, 1966). Summer
et al. (1979) observed a dose-related Increase In the 24-hour urinary
excretion of thloethers by adult male SPF Wlstar rats given single gavage
doses of naphthalene In oil of 30-200 mg/kg. Urinary thloether accounted for
26-39% of the administered dose of naphthalene, which suggests 26-39% as a
minimum estimate of the extent of gastrointestinal absorption. Bock et al.
(1979) measured the uptake of radioactivity from the Isolated In situ jejunum
of rats given a dose of 14C-naphthalene. Approximately 84% of the dose of
radioactivity was found 1n the portal blood within 30 minutes of
administration. These data suggest that gastrointestinal absorption of
naphthalene 1n rats Is both rapid and extensive. Sanborn and Mallns (1977)
suggested that naphthalene may be absorbed to a greater extent when Ingested
In water than In food.
2.2. INHALATION
Data regarding the absorption of Inhaled naphthalene are limited; however,
Valaes et al. (1963) reported toxldty and death In newborn Infants exposed to
naphthalene vapors from clothes or blankets that were stored 1n or near the
Infants' rooms.
0014H -3- 04/20/88
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Several Investigators (Anz1ulew1cz et al., 1959; Zlnkham
and Chllds, 1958) reported the occurrence of hemolytlc anemia 1n Infants
born to mothers who had "sniffed" and Ingested unspecified quantities of
naphthalene (1n the form of mothballs) during pregnancy. The mothers
themselves were also anemic, but to a lesser extent than were the Infants.
Several animal studies focused upon ocular effects of naphthalene, but
failed to mention whether any other signs of toxlclty were measured or
observed. Fltzhugh and Buschke (1949) observed slight cataracts In weanling
rats exposed to 2% naphthalene 1n the diet for 60 days. Assuming a rat
consumes food equivalent to 5% of Us body weight/day, this dietary level 1s
equivalent to a dose of 1 g/kg bw/day. In two separate studies, rabbits
exposed to 1 g naphthalene/kg bw/day by gavage (either In light paraffin or
an unspecified vehicle) for -46 days developed cataracts (Ghettl and
MaManl, 1956; Van Heynlngen and P1r1e, 1976) and degeneration of the retina
(Van Heynlngen and P1r1e, 1976) within the first few days of treatment.
In an NTP (1980a) sponsored study, groups of 10 male and 10 female F344
rats were treated by gavage with naphthalene 1n corn oil at 0, 25, 50, 100,
200 or 400 mg/kg, 5 days/week for 13 weeks. At 400 mg/kg, two males died
and rats of both sexes experienced diarrhea, lethargy, hunched posture and
rough hair coats. A >10% decrease In body weight gain was observed 1n males
at >200 mg/kg and In females at >100 mg/kg. Kidney lesions occurred In
males at >200 mg/kg and lymphold depletion of the thymus occurred 1n females
at 400 mg/kg. Mild changes 1n hematologlc parameters were observed 1n both
sexes at 400 mg/kg. Eye lesions were not observed. The 50 mg/kg dosage was
a NOEL 1n rats 1n this study.
0014H -4- 04/20/88
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A similar study was performed 1n groups of 10 male and 10 female B6C3F1
mice treated by gavage with naphthalene 1n corn oil at 0, 12.5, 25, 50, 100
or 200 mg/kg, 5 days/week for 13 weeks (NTP, 1980b). Seven mice (three
males and two females of the 200 mg/kg group, one female of the 25 mg/kg
group and one control male) died during the 2nd, 3rd and 4th weeks of the
study from gavage trauma or accident. Transient signs of toxldty
(lethargy, rough halrcoats and decreased food consumption) occurred 1n both
sexes at 200 mg/kg. Body weight gains of treated males exceeded controls;
treated females had slight but probably not biologically significant dose-
related decreases In body weight gain. There were no treatment-related
hlstopathologlc lesions or hematologlc effects.
Shopp et al. (1984) administered naphthalene 1n corn oil by gavage to
groups of 40-112 CD-I mice/sex at 0 (untreated control), 0 (vehicle
control), 5.3, 53 or 133 mg/kg/day for 90 consecutive days. There were no
effects on survival, body weights, serum enzyme or electrolyte levels, or
1mmunolog1c parameters, although females at 133 mg/kg/day had reduced abso-
lute and relative spleen weights. There was no evidence of a naphthalene-
Induced hemolytlc anemia, cataract formation or pathologic damage to the
lungs. A dose-related Inhibition of hepatic aryl hydrocarbon hydroxylase
activity was observed In both sexes, but the toxlcologlcal significance of
this observation 1s unclear.
3.1.2. Inhalation. Pertinent data regarding the subchronlc toxlclty of
Inhaled naphthalene were not located 1n the available literature.
3.2. CHRONIC
3.2.1. Oral. In the only chronic study available, Schmahl (1955)
administered naphthalene 1n the diet to BDI and BDIII rats at a dose of
10-20 mg/rat/day for 700 days. The total cumulative dosage was 10 g/rat.
The rats were observed until they died spontaneously; a comprehensive gross
0014H -5- 05/20/88
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and limited hlstopathologlc examination was then performed. There were no
treatment-related effects on survival (the "Hfespan of these rats exceeded
800 days) or on hlstopathology. No other signs of toxldty were reported.
3.2.2. Inhalation. Chronic data regarding the Inhalation of naphthalene
are limited to two studies of occupational exposure. Van der Hoeve (1906)
reported that one man who worked with powdered naphthalene developed
cataracts and retinal hemorrhage, while another man exposed similarly had
choMoretlnltls. Ghettl and Mar1an1 (1956) reported that 8/21 workers
exposed to unspecified "high" concentrations of naphthalene in a dye-manu-
facturing process developed cataracts. Since these men were <50 years of
age, 1t 1s unlikely that they would have developed cataracts spontaneously.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Hatorova and Chetverlkova (1981) administered naphthalene
by gavage at 0.075, 0.15 or 70 mg/kg/day to pregnant white mongrel rats on
days 1-19 of gestation. There 1s a dlscrepency In this paper In that 1n the
abstract the highest dose 1s IVsted a 7 mg/kg/day. However, 70 mg/kg/day Is
consistently specified 1n the remainder of the paper. The rats were sacri-
ficed for examination on gestation day 19. No grossly visible developmental
defects were observed at any dosage and no microscopic anomalies were noted
at 0.075 mg/kg/day. At >0.15 mg/kg/day, there was an Increased Incidence of
fetuses with subcutaneous hematomas; embryonic mortality and prelmplantatlon
loss were also Increased. The length of gestation 1n rats allowed to deliver
appeared to be Increased to up to 27 days 1n the treated groups. At >0.15
mg/kg/day, rats were born with black tails that fell off 6-8 hours later.
Plasterer et al. (1985) administered naphthalene 1n corn oil by gavage
to 50 mated CO-1 mice at 300 mg/kg/day on days 7-14 of gestation. A vehicle
control group was maintained. Maternal toxldty was manifested as Increased
mortality and reduced body weight gain. Fetal toxldty was manifested as a
0014H -6- 05/20/88
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reduced number of live young at birth, which the authors attributed to early
fetal resorptlons. The young were not examined for terata.
Naphthalene or Us metabolites are known to cross the placenta In
sufficient quantities to cause fetotoxlc effects (Anz1ulew1cz et al., 1959;
Van der Hoeve, 1913). These effects Included hemolytlc anemia 1n humans and
cataracts and retinal damage 1n rabbits. Doses either were not estimated or
were not reported In the secondary sources. The 1.p. Injection of 395
mg/kg/day naphthalene 1n corn oil to Sprague-Dawley rats on days 1-15 of
gestation did not result In any evidence of maternal or fetotoxldty (Hardln
et al., 1981).
3.3.2. Inhalation. Pertinent data regarding the teratogenlclty of
Inhaled naphthalene were not located 1n the available literature.
3.4. TOXICANT INTERACTIONS
A woman exposed for 3 weeks to a combination of naphthalene and para-
dlchlorobenzene (while mothproofing clothing) developed aplastlc anemia 1
month after exposure (Harden and Baetjer, 1978). No other cases of aplastlc
anemia associated with exposure to either napthalene or paradlchlorobenzene
alone have been reported 1n the literature.
0014H -7- 05/20/88
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4. CARCINOGENICITY
4.1. HUNAN DATA
4.1.1. Oral. Pertinent data regarding the carclnogenldty of Ingested
naphthalene 1n humans were not located 1n the available literature.
4.1.2. Inhalation. Wolf (1976) reported that 6/15 workers exposed for up
to 32 years to vapors of both naphthalene and coal tar developed laryngeal
carcinomas (4) or neoplasms of the pylorus and cecum (2). There was no
control group.
4.2. 8IOASSAYS
4.2.1. Oral. Schmahl (1955) Investigated the carcinogenic potential of
napthalene administered orally 1n rat strains BOI and BDII. A group of 28
rats were exposed to 10-20 mg/day 1n the feed for 700 days (total cumulative
dose of 10 g naphthalene/rat) and monitored for up to 1000 days. A
carcinogenic response was not observed.
4.2.2. Inhalation. Adklns et al. (1986) tested naphthalene 1n the mouse
pulmonary adenoma Induction test using groups of 30 female strain A/J mice
at 6-8 weeks of age. Exposure to 0, 10 or 30 ppm (0, 52 or 157 mg/m3), 6
hours/day, 5 days/week for 6 months did not elicit a carcinogenic response.
Positive controls consisted of 20 female mice given a single Intraperltonal
Injection of urethane and sacrificed after a 26-week observation period.
All positive controls developed tumors. NTP (1987) 1s currently examining
the effects of 10 and 30 ppm napthalene on mice 1n a 2-year Inhalation study.
4.3. OTHER RELEVANT DATA
The genotoxlc activity of naphthalene has been tested in several Uj
vitro systems. Cell transformation was not seen 1n rodent embryo cells
pretreated with leukemia virus and exposed to concentrations of naphthalene
up to 100 mg/8, of culture medium (Freeman et al., 1973; Rh1m et al.,
1974). Similarly, cell transformations were not seen In a murlne mammary
0014H -8- 04/26/88
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gland organ culture system at naphthalene concentrations up to 1000 mg/a.
of culture medium (TonelH et al., 1979). Naphthalene did not cause £NA
damage In a rat hepatocyte alkaline elutlon assay (S1na et al., 1983).
Naphthalene was not found to be mutagenlc In a number of bacterial/
mlcrosomal assay systems (McCann et al., 1975; Kraemer et al., 1974;
Mortelmans et al., 1986).
Knake (1956) administered coal tar napthalene 1n sesame oil subcuta-
neously to 40 white rats every 2 weeks for 7 doses, and observed the rats
for 18 months. A control group of 40 rats received Injections of corn oil
alone. Carbolfuchsln, a known carcinogen, was painted on the skin before
Injection. The naphthalene contained Impurities that were equivalent to 10%
methyl naphthalene. Thirty-four of 40 naphthalene treated rats survived to
termination and 5 of these developed Invasive or metastatlc lymphosarcomas.
In the controls, 32 survived and only 1 developed lymphosarcoma. In a skin
painting study, Knake (1956) applied coal tar naphthalene In benzene or
benzene alone to Inbred black mice 5 days/week for life. Lymphatic leukemia
developed In 4/25 naphthalene treated mice compared with 0/21 In benzene
treated controls and 5/1227 historical controls.
Naphthalene was negative for Induction of j-Gtf foci, which was
considered to be a preneoplastlc response, 1n the livers of partially
hepatectomlzed rats (Tsuda et al., 1980). U.S. EPA (1980a, 1986a) listed
other studies, which were Insufficiently reported or otherwise flawed, that
provided no evidence of cardnogenldty for naphthalene (Boyland et al.,
1964; Kennaway, 1930; Kennaway and Helger, 1930; Bogdat'eva and Bid, 1955;
Schmeltz et al., 1978).
0014H -9- 04/20/88
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4.4. WEIGHT OF EVIDENCE
IARC has not evaluated the risk to humans that 1s associated with oral
or Inhalation exposure to naphthalene. Naphthalene was negative for
carclnogenlclty 1n oral (Schmahl, 1955; Oruckrey and Schmahl, 1955) and
Inhalation (Adklns et a!., 1986). However, each of these studies
Individually appear to have been Inadequately designed. Applying the
criteria for evaluating the overall weight of evidence for carclnogenlclty
adopted by the EPA (U.S. EPA, 1986c), the evidence for carclnogenlclty of
naphthalene 1n humans and animals 1s Inadequate and the chemical 1s
designated as Group 0 -- not classifiable as to carclnogenlclty to humans.
This qualitative assessment Is consistent with that of U.S. EPA (1986a).
The assessment should be reevaluated pending the final results of the NTP
bloassay of naphthalene.
0014H -10- 05/20/88
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5. REGULATORY STANDARDS AND CRITERIA
The ACGIH (1986a) has recommended a TLV-TWA of 10 ppm (50 mg/m3) and a
STEL of 15 ppm (75 mg/m3) for occupational exposure to naphthalene. Since
eye Irritation was seen at 15 ppm, this criterion was chosen "to prevent
ocular effects but possibly not blood changes 1n hypersusceptlbles" (ACGIH,
1986b). The OSHA (1985) standard for exposure to naphthalene In the
workplace 1s a PEL of 10 ppm (50 mg/m3).
0014H -11- 04/20/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfOc)
%>
6.1.1. Oral (RfDgg). The only subchronlc oral studies that were suffi-
cient to be considered for risk assessment are the NTP (1980a,b) 90-day
gavage studies (rats and mice) and the Shopp et al. (1984) 90-day gavage
study (mice). Rats appear to be somewhat more sensitive than mice to
naphthalene and, therefore, are selected as the model of choice for deriving
an RfD-Q. Rats were treated with naphthalene 1n corn oil at 0, 25, 50,
100, 200 or 400 mg/kg, 5 days/week (NTP, 1980a). Gross signs of toxlclty
and mortality occurred 1n both sexes at 400 mg/kg, hlstopathologlc lesions
and reduced body weight gain occurred 1n both sexes at 200 mg/kg, reduced
body weight gain occurred In females at 100 mg/kg, and 50 mg/kg appeared to
be a NOEL. When the NOEL of 50 mg/kg 1s multiplied by 5/7 to expand from
treatment on 5 days/week to dally treatment, 1t corresponds to a transformed
dose of 36 mg/kg/day.
Application of an uncertainty factor of 100, 10 to extrapolate from rats
to humans and 10 to protect more sensitive humans, to the NOEL of 36 mg/kg/
day would result 1n an RfDSQ of 0.36 mg/kg/day, which 1s lower than the
chronic RfDQ derived 1n Section 6.2.1. The subchronlc NTP (1980a) rat
study, therefore, Is not chosen as the basis for an RfDso but Is
considered to support the chronic oral NOEL of 41 mg/kg/day In the Schmahl
(1955) study that served as the basis for the chronic RfDg. Because of
the similarity In the chronic and subchronlc NOELs, the chronic RfD of 0.4
mg/kg/day or 29 mg/day from the Schmahl (1955) study 1s adopted as the
RfD™ for naphthalene. Medium confidence Is placed 1n this cn.
discussed In Section 6.2.1.
6.1.2. Inhalation (RfD.j). The lack of pertinent, quantitative data
precludes assessment of risk associated with Inhalation of naphthalene.
0014H -12- 04/26/88
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6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDg). The only chronic oral study located 1n the avail-
able literature was the dietary cancer study by Schmahl (1955) In which rats
received a total dose of 10 g of naphthalene over a 700-day period.
Assuming a reference body weight for rats of 0.35 kg, naphthalene was
consumed at a dosage rate of 41 mg/kg/day. No effects were observed In the
treated rats. The NOEL of 41 mg/kg/day Is supported by the NOEL for rats of
36 mg/kg/day In the subchronlc NTP (1980a) gavage study. Application of an
uncertainty factor of 100, 10 to extrapolate from rats to humans and 10 to
protect more sensitive humans, results In an RfDQ of 0.4 mg/kg/day or 29
mg/day for a 70 kg human. This analysis 1n consistent with an earlier U.S.
EPA (1986a) derivation. Confidence 1n the data base Is medium because the
cardnogenldty, developmental and reproductive tox1c1ty have not been
Investigated sufficiently. Confidence In the key study Is low because only
one dosage level was tested, hlstopathologlc examination was limited and
dosing was not precisely controlled. Because of the support provided by the
NTP (1980a,b) and Shopp et al. (1984) studies, confidence 1n the RfOQ 1s
rated medium. Naphthalene 1s currently listed as under review by the RfD
workgroup.
U.S. EPA (1986a) derived a CS for naphthalene from the subchronlc NTP
(1980a) gavage study. Hlstopathologlc lesions were observed In the kidneys
of male rats treated with 200 mg/kg, 5 days/week (143 mg/kg/day). An
uncertainty factor of 10 was applied to expand from subchronlc to chronic
exposure. From an estimated rat body weight of 0.31 kg, a human MED of
164.4 mg/day was calculated, which corresponds to an RV. of 2.2. An RV
of 6 was chosen to represent the kidney lesions and the CS was calculated as
13.2. This CS 1s adopted for the purposes of this document.
0014H -13- 05/20/88
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6.2.2. Inhalation (RfOj). Data regarding chronic exposure to naphtha-
lene by Inhalation were not located In the available literature. NTP (1987)
1s currently examining the effects of 10 and 30 ppm naphthalene on mice 1n a
2-year Inhalation study (see Section 6.3.2.).
6.3. CARCINOGENIC POTENCY (q.,*)
6.3.1. Oral. Naphthalene has not been adequately tested 1n animal
bloassays; therefore, 1t Is not possible to derive a q,* for oral exposure
to naphthalene.
6.3.2. Inhalation. The lack of pertinent data regarding the cardnogen-
1c1ty of Inhaled naphthalene precludes assessment of carcinogenic potency.
NTP (1987) 1s currently examining the effects of 10 and 30 ppm naphthalene
on mice In a 2-year Inhalation study. Preliminary results have been
submitted to the EPA, and upon peer review by the NTP Board of Scientific
Counselors, the EPA will evaluate the results to determine 1f any changes In
the current regulatory assessment are warranted (U.S. EPA, 1988).
0014H -14- 05/20/88
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
Threshold Limit Values for Chemical Substances and Physical Agents In the
Workroom Environment Adopted by ACGIH. Cincinnati, OH. p. 25.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the Threshold Limit Values and Biologic Exposure Indices,
5th ed. Cincinnati, OH. p. 420.
Adklns, B., Jr., E.W. Van Stee, J.E. Simmons and S.L. Eustls. 1986. Onco-
gen 1c response of strain A/J mice to Inhaled chemicals. 0. Toxlcol.
Environ. Health. 17: 311-322.
Anzlulewlcz, 3.A., H.J. D1ck and E.E. ChlarulH. 1959. Transplacental
naphthalene poisoning. Am. J. Obstet. Gynecol. 78: 519-521. (Cited In
U.S. EPA, 1983)
Bock, K.W., U.C. Clausbruch and D. Wlnne. 1979. Absorption and metabolism
of naphthalene and benzo(a)pyrene In the rat jejunum In situ. Med. Blol.
57: 262-264. (Cited 1n U.S. EPA, 1986b)
Bogdat'eva, A.G. and O.Y. Bid. 1955. Effect of high molecular weight
products of pyrolysls of petroleum on the animal organisms. (CHed In U.S.
EPA, 1980a)
0014H -15- 08/27/87
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Boyland, E., et al. 1964. Further experiments on Implantation of mate-
rials Into the urinary bladder of mice. Br. 0. Cancer. 18: 575. (CHed In
U.S. EPA, 1980a)
Callahan, M.A., H.W. SUmak, N.W. Gabel, et al. 1979. Water-Related
Environmental Fate of 129 Priority Pollutants. Vol. II. Office of Water
Planning and Standards, Office of Water and Waste Management. U.S. EPA,
Washington, DC. EPA 440/4-79-029b.
Chusld, E. and C.T. Fried. 1955. Acute hemolytlc anemia due to naphthalene
1ngest1on. Am. J. 01s. Child. 89: 612-614. (CHed 1n U.S. EPA, 1980a)
Correa, M. and B.J. Venables. 1985. Bloconcentratlon of naphthalene In
tissues of the white mullet (Muq11 cureroa). Environ. Tox. Chem. 4: 227-231.
FHzhugh, O.G. and W.H. Buschke. 1949. Production of cataract In rats by
betatetralol and other derivatives of naphthalene. Arch. Opthal. 41:
572-582. (Cited In U.S. EPA, 1983)
Freeman, A.E., et al. 1973. Transformation of cell cultures as an Indica-
tion of the carcinogenic potential of chemicals. 3. Natl. Cancer Inst. 51:
799-807. (CHed 1n U.S. EPA, 1980a, 1982)
Ghettl, G. and L. MaManl. 1956. Eye changes due to naphthalene. Med.
Lav. 47: 533-538. (Cited 1n U.S. EPA, 1980a, 1983)
0014H -16- 04/20/88
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Gross, R.T., et al. 1958. An hereditary enzymatic defect 1n erythrocyte
metabolism: G1ucose-6-phosphate dehydrogenase deficiency. J. CUn. Invest.
37: 1176-1184. (CHed 1n U.S. EPA, 1980a)
Haggerty, R.J. 1956. Toxic hazards: Naphthalene poisoning. New Engl. J.
Med. 255: 919-920. (Cited In U.S. EPA, 1980a)
Hansch, C. and A.O. Leo. 1985. Medchem Project Issue No. 26. Pomona
College, Claremont, CA.
Hardln, B.D., G.P. Bond, H.R. S1kov, P.O. Andrew, R.P. Bellies and R.W.
N1eme1r. 1981. Testing of Selected Workplace Chemicals for teratogenlc
Potential. Scand. J. Work Environ. Health. 7 suppl. 466-475.
Harden, R.A. and A.M. Baetjer. 1978. Aplastlc anemia following exposure to
paradlchlorobenzene and naphthalene. 3. Occup. Med. 20: 820-822. (Cited
1n U.S. EPA, 1980a)
Kennaway, E.L. 1930. LVII. Further experiments on cancer-producing sub-
stances. Blochem. J. 24: 497. (CHed In U.S. EPA, 1986a)
Kennaway, E.L. and I. Helger. 1930. Carcinogenic substances and their
fluorescence spectra. Br. Med. J. 1: 1044. (CHed 1n U.S. EPA, 1986a)
Knake, E. 1956. Uber schwache geschwulsterzengende wlrkung von naphthalln
and benzol. Vlrchows Archlv. Pathol. Anat. Physio!. 329: 141. (Ger.)
(CHed In U.S. EPA, 1986a)
0014H -17- 05/20/88
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Kraemer, M., et al. 1974. S. typhlmurlum and £. coll to detect chemical
mutagens. Arch. Pharmacol. 284: R46. (Cited 1n U.S. EPA, 1980a, 1982)
MacKay, D., A. Bobra, W.Y. Shin and S.H. Yalkowsky. 1980. Relationships
between aqueous solubility and octanol-water partition coefficients.
Chemosphere. 9: 701-711.
MacKay, D., A. Bobra, O.W. Chan and W.Y. Shin. 1982. Vapor pressure corre-
lations of low-volatility environmental chemicals. Environ. Sc1. Techno!.
16: 645-649.
Matorova, N.N. and O.N. ChetveMkova. 1981. Embryotoxlc and teratogenlc
effect of naphthalene and chloronaphthalene. Sb. Nauch. Tr. VNII Glgeny.
12: 62-65. (English translation) (Cited 1n U.S. EPA, 1986a)
McCann, J., et al. 1975. Detection of carcinogens as mutagens 1n the
Salmonella/mlcrosome test. Assay of 300 chemicals. Proc. Natl. Acad. Scl.
72: 5135-5139. (Cited 1n U.S. EPA, 1980a, 1982)
Mortelmans, K., S. Haworth, T. Lawlor, et al. 1986. Mutagenlclty test
results. II. Results from the testing of 270 chemicals. Environ. Mutagen.
8: 1-39. (CUed 1n U.S. EPA, 1986a)
Nash, L.F. 1903. Naphthalene poisoning. Br. Med. 3. 1: 251. (Cited In
U.S. EPA, 1980a)
NLM (National Library of Medicine). 1987. Hazardous Substance Data Base.
Record No. 184.
0014H -18- 05/20/88
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NTP (National Toxicology Program). 1980a. Unpublished subchronlc toxldty
study: Naphthalene (C52904), Fischer 344 rats. Prepared by Battelle's
Columbus Laboratories under Subcontract No. 76-34-106002. March 4, 1980.
NTP (National Toxicology Program). 1980b. Unpublished subchronlc toxldty
study: Naphthalene (C52904), 66C3F1 mice. Prepared by Battelle's Columbus
Laboratories under Subcontract No. 76-34-106002. March 4, 1980.
NTP (National Toxicology Program). 1987. Management Status Report. Dated
01/09/87.
OSHA (Occupational Safety and Health Administration). 1985. OSHA Occupa-
tional Standards, Permissible Exposure Limits. 29 CFR 1910.1000.
Plasterer, M.R., W.S. Bradshaw, G.M. Booth and M.M. Carter. 1985. Develop-
mental toxldty of nine selected compounds following prenatal exposure In
the mouse: Naphthalene, p-nHrophenol, sodium selenHe, dimethyl phthalate,
ethylene thlourea and four glycol ether derivatives. J. Toxlcol. Environ.
Health. 15: 25-38.
Rh1m, 3.S., et al. 1974. Evaluation of an ±n vitro assay system for
carcinogens based on prior Infection of rodent cells with nontransformlng
RNA tumor virus. J. Natl. Cancer Inst. 52: 1167-1173. (Cited 1n U.S. EPA,
1982)
Sabljlc, A. 1984. Predictions of the nature and strength of sorptlon of
organic pollutants by molecular topology. J. Agrlc. Food Chem. 32: 243-246.
0014H -19- 04/20/88
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Sanborn, H.R. and D.C. Mallns. 1977. Tox1c1ty and metabolism of naphtha-
lene: A study with marine larval Invertebrates. Proc. Soc. Exp. 81ol. Med.
154: 151-155. (Cited 1n U.S. EPA, 1980a)
Schmahl, D. 1955. Testing of maphthalene and anthracene as carcinogenic
agents In the rat. Z. Krebsforsch. 60: 697-710. (German with English
translation) (Cited 1n U.S. EPA, 1986a)
Schmeltz, I., et al. 1978. Bloassays of naphthalene and alkyl naphthalenes
for co-carcinogenic activity. Relation to tobacco cardnocjenesls. Jjn:
Cardnogenesls, Vol. 3: Polynuclear Aromatic Hydrocarbons, P. Jones and I.
Freudenthal, Ed. Raven Press, NY. p. 47-60. (Cited 1n U.S. EPA, 1980a)
Shopp, G.M., K.I. White, Jr., H.P. Holsapple, et al. 1984. Naphthalene
toxlclty In CD-I mice: General toxicology and 1mmunotox1cology. Fund. Appl.
Toxlcol. 4(3, Pt. 1): 406-419.
Slna, J.F., C.L. Bean, G.R. Dysart et al. 1983. Evaluation of the alkaline
elutlon/rat hepatocyte assay as a predictor of carclnogenlc/mutagenlc
potential. Mutat. Res. 113(5): 357-391. (Cited 1n U.S. EPA, 1986a)
Summer, K.H., K. Rozman, F. Coulston and H. Grelm. 1979. Urinary excretion
of mercapturlc adds In chimpanzees and rats. Toxlcol. Appl. Pharmacol.
50: 207-212.
Talakln, Yu.N. 1966. San1tary-tox1colog1cal characteristics of a-naph-
thoqulnone. Vop. Kommunal. G1g. 6: 37-43. (Cited 1n U.S. EPA, 1980a)
0014H -20- 04/20/88
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TonelH, Q., et al. 1979. Transformation of cultured mouse mammary glands
by aromatic amines and amides and their derivatives. Cancer Res. 39:
1784-1792. (Cited 1n U.S. EPA, 1980a, 1982)
Tsuda, H., G. Lee and E. Faber. 1980. Induction of resistant hepatocytes
as a new principle for a possible short-term Jj» vivo test for carcinogens.
Cancer Res. 40(4): 1157-1164. (Cited 1n U.S. EPA, 1986a)
U.S. EPA. 1980a. Ambient Water Quality Criteria for Naphthalene. Prepared
by the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Water Regulations
and Standards, Washington, DC. EPA-440/4-80-059. NTIS PB 81-117707.
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Ambient Water Quality Criteria
Documents. Federal Register. 45: 49347-49357.
U.S. EPA. 1982. Revision and Update of Hazard Profile on Naphthalene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
U.S. EPA. 1983. Reportable Quantity Document for Naphthalene. Prepared by
the Office of Health and Environmental Assessment, Environmental Criteria
and Assessment Office, Cincinnati, OH for the Office of Emergency and
Remedial Response, Washington, DC.
0014H -21- 04/20/88
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U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1986a. Health and Environmental Effects Profile for Naphthalene.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
U.S. EPA. 1986b. Summary Review for Health Effects Associated with
Naphthalene: Health Issue Assessment. Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment Office,
Research Triangle Park, NC for the Office of A1r Quality Planning and
Standards and the Office of Air and Radiation, Washington, DC.
U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
Register. 52(185): 33992-34003.
U.S. EPA. 1988. Assessment of Naphthalene as a Potentially Toxic Air
Pollutant. Federal Register. 53(54): 9138-9141.
Valaes, T., et al. 1963. Acute hemolysls due to naphthalene Inhalation.
J. Ped. 63: 904-915. (Cited 1n U.S. EPA, 1980a)
0014H -22- 04/20/88
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Van der Hoeve, J. 1906. Choreoret1n1t1s be 1m menschen durch die e1nw1rk1ng
von naphthalln. Arch. Augenhellk. 56: 259. (Ger.) (Cited In U.S. EPA,
1980a, 1983)
Van der Hoeve, J. 1913. Wlrkung von naphthol auf die augen von menschen,
tleren, und auf fatale augen. Graele Arch. Ophthal. 85: 305. (Ger.)
(Cited 1n U.S. EPA, 1980a)
Van Heynlngen, R. and A. P1r1e. 1976. Naphthalene cataract In plgmented
and albino rabbits. Exp. Eye Res. 22: 393-394. (Cited 1n U.S. EPA, 1983)
Wolf, 0. 1976. Cancer diseases In chemical workers 1n a former naphthalene
cleaning plant. Oeutche Gesundheltwesen. 31: 996-999. (Cited 1n U.S. EPA,
1980a, 1986a)
Zlnkham, M.J. and B. Chllds. 1958. A defect of glutathlone metabolism 1n
erythrocytes from patients with a naphthalene-Induced hemolytlc anemia.
Pediatrics. 22: 461-471. (Cited 1n U.S. EPA, 1983)
Zoeteman, B.C.J., K. Harmsen, J.B.H.J. Llnders, C.F. H. Morra and W. Slooff.
1980. Persistent organic pollutants 1n river water and groundwater of the
Netherlands. Chemosphere. 9: 231-249.
Zuelzer, W.H. and L. Apt. 1949. Acute hemolytlc anemia due to naphthalene
poisoning. J. Am. Meek Assoc. 141: 185-190. (Cited 1n U.S. EPA, 1980a)
0014H -23- 04/20/88
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