United States Office of Water EPA 440/5-80-059
Environmental Protection Regulations and Standards October 1980
Agency Criteria and Standards Division
Washington DC 20460 j -j
vvEPA Ambient
Water Quality
Criteria for
Naphthalene
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AMBIENT WATER QUALITY CRITERIA FOR
NAPHTHALENE
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P L 95-217)
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926) July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies State
agencies, special interest groups, and individual scientists' The
criteria contained in this document replace any previously published EPA
CrMe^a/0r the 65 P°11utants. This criterion document is also
published in satisfaction of paragraph 11 of the Settlement Agreement
,n Natural Resources Defense Council, et. al . vs Train 8 ERC ?l?n
(D.D.C. 19V6), modified. 12 F.RC l8Jj (U.D.C. 19/i)).'
ria Jh,? ^termn i!Water.-qual^y ,cr,1t?r1a" is used 1n two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304 the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
JIM become enforceable maximum acceptable levels of a pollutant in
nl^mv c^nHS*H The ?atfr QUauity criteria ad°Pted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
bewme°?eaulator °f ^ St3te ^^^ quality standards that the criteria
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
a Water-related pr°9rams of this Agency, are being
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects
Woodhall Stopford (author)
Duke University Medical Center
Steven D. Lutkenhoff (doc. mgr.)
ECAO-Cin
U.S. Environmental Protection Agency
Bonnie Smith, ECAO-Cin
U.S. Environmental Protection Agency
Richard Carchman
Medical College of Virginia
Herbert Cornish
University of Michigan
Patrick Durkin
Syracuse Research Corporation
Betty LaRue-Herndon
Midwest Research Institute
Alfred D. Garvin
University of Cincinnati
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, D. Jones, B.J. Bordicks,
B.O. Quesnell, C. Russom, B. Gardiner.
John H. Gentile, ERL-Narragansett
U.S. Environmental Protection Agency
Mark Greenberg, ECAO-RTP
U.S. Environmental Protection Agency
Frederick C. Kopfler, HERL
U.S. Environmental Protection Agency
Frederick W. Oehme
Kansas State University
Herbert Schumacher
National Center for Toxicological
Research
Anne Trontell
Energy Resources Company, Inc.
Jonathan Ward
University of Texas Medical Branch
IV
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TABLE OF CONTENTS
Criteria Summary
Introduction A_1
Aquatic Life Toxicology B-l
Introduction B_1
Effects B_1
Acute Toxicity B-l
Chronic Toxicity B-2
Plant Effects B-2
Residues B-2
Miscellaneous B-2
Summary B-3
Criteria B-4
References B-l2
Mammalian Toxicity and Human Health Effects C-l
Introduction C_1
Exposure Q.-J
Ingestion from Food and Water C-2
Inhalation Q_3
Dermal c_3
Pharmacokinetics CI6
Absorption, Distribution, and Excretion c-6
Metabolism Q_7
Effects c_12
Acute, Subacute and Chronic Toxicity c-16
Synergism and/or Antagonism C-21
Teratogenicity * r.pi
Mutagenicity c"22
Carcinogenicity r'oo
Criterion Formulation r'of
Existing Guidelines and Standards r~31
Current Levels of Exposure r 31
Special Groups at Risk r 3-1
Basis and Derivation of Criteria r~34
References c ^
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CRITERIA DOCUMENT
NAPHTHALENE
CRITERIA
Aquatic Life
The available data for naphthalene indicate that acute and chronic tox-
icity to freshwater aquatic life occur at concentrations as low as 2,300 and
620 yg/1, respectively, and would occur at lower concentrations among spe-
cies that are more sensitive than those tested.
The available data for naphthalene indicate that acute toxicity to salt-
water aquatic life occurs at concentrations as low as 2,350 ug/1 and would
occur at lower concentrations among species that are more sensitive than
those tested. No data are available concerning the chronic toxicity of
naphthalene to sensitive saltwater aquatic life.
Human Health
Using the present guidelines, a satisfactory criterion cannot be derived
at this time because of the insufficiency in the available data for naphtha-
lene.
VI
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INTRODUCTION
Napthalene is the most' abundant single constituent of coal tar
(Schmeltz, et al. 1977). In 1974, 1.8 x 105 metric tons of naphthalene
were produced from coal tar, and 1.1 x 105 metric tons were produced from
petroleum (Brown, et al. 1975; U.S. EPA, 1976). This compound is used as an
intermediate in the production of dye compounds and the formulation of sol-
vents, lubricants, and motor fuels. One of the principal uses of naphtha-
lene as a feedstock in the United States is for the synthesis of phthalic
anhydride. It has also been used directly as a moth repellant and insecti-
cide as well as an antihelminthic, vermicide, and an intestinal antiseptic.
Napthalene is a bicyclic aromatic hydrocarbon with the chemical formula
C10H8 and a molecular weight of 128.16. Pure naphthalene forms a white
crystalline solid at room temperature whereas the crude or technical grades
may range in color from brown to tan. Naphthalene vapor and dust can form
explosive mixtures with air (Windholz, 1976).
Pure naphthalene melts at 80.2°C; the less pure forms of the compound
will melt at temperatures ranging from 74 to 80°C. The boiling point of
naphthalene is 217.96°C at atmospheric pressure (Manufacturing Chemists
Assoc., 1956). At 15.5°C, the density is 1.145 (Manufacturing Chemists
Assoc., 1956) and at 100°C the density is 0.9625 (Marti, 1930; Weast, 1975).
At 19.8°C the vapor pressure of solid naphthalene is 0.0492 mm Hg (Gil'den-
blat, et al. 1960).
The solubility of naphthalene in water has been reported to range be-
tween 30,000 ug/1 (Mitchell, 1926) and 40,000 ug/l (Josephy and Radt, 1948)
at 25°C. The solubility of naphthalene in seawater will vary according to
the degree of salinity; in seawater of average composition the solubility of
A-l
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naphthalene is approximately 33,000 ug/1 (Gordon and Thorne, 1967). Naph-
thalene has also been reported to be soluble in organic solvents (Spector,
1956).
Naphthalene can oxidize in the presence of light and air, and it was
determined that 50 percent of the theoretical C02 was liberated after 14
days (Ludzack and Ettinger, 1963). The process involves initial conversion
to naphthoquinone with subsequent rupture of one of the aromatic rings and
the release of C02 (Kirk and Othmer, 1967). However, this oxidation pro-
cess occurs only at elevated temperatures (Josephy and Radt, 1948).
When combined with alcohol and ozone, cyclic alkoxyhydroxyperoxides are
formed. In an acidic medium, these peroxides will be converted to methyl
phthalaldehydate; in a basic medium, they are converted to phthalaldehydic
acid (Bailey, et al. 1964). When combined with nitrate salts with metals
within a temperature range of 55*C to 180°C, naphthalene can be nitrated at
the alpha position (Alama and Okon, 1964). In the presence of oxygen,
K^SO^, a vanadium oxide catalyst, and Si04, naphthalene can be con-
verted to phthalic anhydride (Morotskii and Kharlampovich, 1968).
Microorganisms can degrade naphthalene to l,2-dihydro-l,2-dihydroxynaph-
thalene and ultimately to carbon dioxide and water. Studies have indicated
a degradation rate under laboratory conditions of up to 3.3 yg/1 (Lee and
Anderson, 1977).
Naphthalene has a varied environmental distribution and has been de-
tected in ambient water (up to 2.0 ug/l)> sewage plant effluents (up to 22
ug/1), and drinking water supplies (up to 1.4 ug/1) (U.S. EPA, 1971-1977).
A-2
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REFERENCES
Alama, W. and K. Okon. 1964. Direct nitration of benzene, naphthalene, and
phenol by inorganic nitrates. Buil. Wojskowa Akad. Tech. 13: 51.
Bailey, P.S., et al. 1964. Ozonolysis of naphthalenes; the aromatic pro-
ducts. Jour. Org. Chem. 29: 697.
Brown, S.L., et al. 1975. Research program on hazard priority ranking of
manufactured chemicals. Phase II - Final Rep. Prepared by Stanford Res.
Inst. Natl. Sci. Foundation, Washington, D.C.
Cox, B.A., et al. 1975. An Experimental Oil Spill: The Distribution of
Aromatic Hydrocarbons in the Water, Sediment, and Animal Tissues within a
Shrimp Pond. In: Proc. Conf. Prevent. Con. Oil Pollut., San Francisco,
March 25-27, 1975. Am. Petrol. Inst., Washington, D.C.
Gil'denblat, I.A., et al. 1960. Vapor pressure over crystalline naphtha-
lene. Jour. Appl. Chem. 33: 245.
Gordon, J.E. and R.L. Thome. 1967. Salt effects on nonelectrolyte solu-
tions. Beschim. Cosmochim. Acta. 31: 2433.
Josephy, E. and F. Radt (eds.) 1948. Encyclopedia of Organic Chemistry:
Series III. Elsevier Publishing Co., Inc., New York.
A-3
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Kirk, R.E. and D.F. Othmer. 1967. Encyclopedia of Chemical Technology.
2nd ed. John Wiley and Sons, Inc., New York.
Lee, R.F. and J.W. Anderson. 1977. Fate and effect of naphthalene: Con-
trolled ecosystem pollution experiment. Bull. Mar. Sci. 27: 127.
Ludzack, F.J. and M.B. Ettinger. 1963. Biodegradability of organic chemi-
cals isolated from rivers. Purdue Univ. Eng. Bull. Ser. No. 115: 278.
Manufacturing Chemists Association. 1956. Chemical safety data sheets
SD-58: Naphthalene. Washington, D.C.
Marti, F.B. 1930. Methods and equipment used at the Bureau of Physiochemi-
cal Standards. Bull. Soc. Chim. Bedgrad. 39: 590.
Mitchell, S. 1926. A method for determining the solubility of sparingly
soluble substances. Jour. Chem. Soc. 129: 1333.
Morotskii, O.A. and G.D. Kharlampovich. 1968. Phthalic anhydride. Izo-
bret., Prom. Obraztsy, Tovarnye Znaki. 45: 22.
Schmeltz, I., et al. 1977. The role of naphthalenes as carcinogens. A
paper presented at the 16th Annu. Meet. Soc. Toxicol. Toronto, Canada.
March 27-30, 1977.
Spector, W.S. (ed.) 1956. Handbook of Toxicology. Saunders Publishing
Co., Philadelphia.
A-4
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U.S. EPA. 1971-1977. Unpublished data from Region IV, Atlanta, Georgia.
U.S. EPA. 1976. Organic chemical producer's data base program. Chem. No.
2701. Radian Corp.
Weast, R.C. 1975. Handbook of Chemistry and Physics. CRC Press, Cleve-
land, Ohio.
Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway,
New Jersey.
A-5
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Aquatic Life Toxicology*
INTRODUCTION
A variety of aquatic species has been exposed to naphthalene and most
acute tests were under static procedures with unmeasured test concentra-
tions. All but two fifty percent effect levels for fish and invertebrate
species are in the range of 2,300 to 8,900 ug/1. One embryo-larval test
with the fathead minnow demonstrated adverse effects at a test concentration
of 850 ug/1.
Histopathological changes in the saltwater mummichog were observed at
naphthalene concentrations as low as 2 ug/1.
EFFECTS
Acute Toxicity
Daphnia magna is the only tested freshwater invertebrate species (U.S.
EPA, 1978) and the 48-hour EC5Q is 8,570 Pg/l (Table 1).
DeGraeve et al. (1980) conducted flow-through tests with measured con-
centrations for the rainbow trout and the fathead minnow. The trout appear-
ed to be a little more sensitive with a 96-hour LC5Q of 2,300 ug/1 (Table
1). The 96-hour LC5Q for the fathead minnow tested at H°C was 4,900
yg/1 and at 24°C the LC5Q was 8,900 wg/l. The LCgo of 150,000 ug/1
for the mosquitofish appears to be atypical but the result cannot be dis-
counted.
Ninety-six-hour LCgo values for the polychaete, Neanthes arenaceo-
dentata, Pacific oyster, and the grass shrimp are 3,800, 199,000, and 2,350
ug/1, respectively (Table 1). The 24-hour LC5Q values for one fish and
two saltwater shrimp species range from 2,400 to 2,600 yg/1 (Table 6).
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of each table are calculations for deriving various measures of tox-
icity as described in the Guidelines.
B-l
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With the exception of the mosguitofish and the Pacific oyster, all
LCgg and ECgQ values, regardless of test method, fall within the narrow
range of 2,300 to 8,900- yg/1 for 9 freshwater and saltwater species,
Chronic Toxicity
An embryo-larval test has been conducted with the fathead minnow and
the resultant chronic value is 620 ug/1 (Table 2). When this concentration
is divided by the geometric mean LC^Q value of 6,600 ug/1 for this species
(Table 1) an acute-chronic ratio of 11 is obtained. No other species have
been tested under chronic conditions.
A summary of species mean acute and chronic values is presented in
Table 3.
Plant Effects
A 50 percent reduction in the number of cells of the freshwater alga,
Chlorella vulgaris, occurred at a concentration of 33,000 yg/1 (Table 4).
Residues
There is only one reported test (Harris, et al. 1977b) that determined
an apparent equilibrium bioconcentration factor for naphthalene. After nine
days, the bioconcentration factor for a copepod was 5,000 (Table 5). Bio-
concentration data for other species for exposures of one hour to one day
are listed in Table 6. These factors range from 32 to 77 and indicate that
equilibrium does not occur rapidly when those results are compared to the
nine-day value of 5,000 (Table 5).
Miscellaneous
Soto, et al. (1975a) observed the death in 24 hours of 61 percent of
the cells of the alga, Chlamydomonas angulosa, at a concentration of 34,400
wg/l (Table 6). There was 50 percent mortality of coho salmon after an ex-
posure of less than six hours to 5,600 ug/1 (Holland, et al. 1960).
B-2
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Saltwater species have been more extensively tested, probably the re-
sult of more interest in oil pollution. Berdugo et al. (1977) exposed the
copepod, Eurytemora af f in i s, to a concentration of 1,000 ug/1 and observed
f
effects on egg production and ingestion rate. The most significant data
were produced by DiMichele and Taylor (1978). Gill hyperplasia in the mum-
michog was observed in 80 percent of the fish after a 15-day exposure to 2
ug/1; there was a 30 percent occurrence in the controls. All of the fish
exposed to 20 wg/1 demonstrated necrosis of the tastebuds, a change not ob-
served in any of the controls.
Summary
The LCj-Q and ECcn values for one freshwater invertebrate and two
fish species are within the range of 2,300 to 8,900 ug/1. The LC5Q for
the mosquitofish is 150,000 u9/l» which result appears to be atypical but
cannot be rejected at this time. The results of an embryo-larval test with
the fathead minnow demonstrated adverse effects at a naphthalene concentra-
tion of 850 u9/l« The resultant chronic value, 620 u9/U provides an acute-
chronic ratio of 11. Freshwater algae appear to be less sensitive with
effect concentrations of about 33,000 to 34,000 u9/l. The bioconcentration
factor for naphthalene and a copepod is 5,000 and this high result suggests
a need for additional testing.
The saltwater fish and invertebrate species tested are of about similar
sensitivity to the freshwater species, with LC50 values of 3,800 u9/l for
a polychaete and 2,350 u9/l for the grass shrimp. There was an apparently
atypical 48-hour value for the Pacific oyster of 199,000 ug/1. The most
cri- tical data are those on histopathological effects on a high percentage
of mummichog exposed to concentrations of naphthalene between 2 and 20 u9/l.
B-3
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CRITERIA
The available data for naphthalene indicate that acute and chronic
toxicity to freshwater jauatic life occur at concentrations as low as 2,300
and 620 vg/1, respectively, and would occur at lower concentrations among
species that are more sensitive than those tested.
The available data for naphthalene indicate that acute toxicity to
saltwater aauatic life occurs at concentrations as low as 2,350 wg/l and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
naphthalene to sensitive saltwater aquatic life.
B-4
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Table I. Acute values for naphthalene
00
I
Species Method*
Cladoceran, S, U
Daphnla magna
Rainbow trout, FT, M
Sal mo galrdneri
Fathead minnow, FT, M
Plmephales promelas
Fathead minnow, FT, M
Plroephales promelas
Mosqultoflsh, FT, M
Gambusla af finis
Polychaete, S, U
Neanthes arenaceodentata
Pacific oyster, S, U
Crassostrea glgas
Grass shrimp, S, M
Pal aemonetes pugio
LC50/EC50 Species Acute
(ug/l) Value (uq/l)
FRESHWATER SPECIES
8,570 8,570
2,300 2,300
4,900
8,900 6,600
150,000 150,000
SALTWATER SPECIES
3,800 3,800
199,000 199,000
2,350 2,350
Reference
U.S. EPA, 1978
DeGraeve, et al. 1980
DeGraeve, et al. 1980
DeGraeve, et al. 1980
Wallen, et al. 1957
Rossi & Neff, 1978
LeGore, 1974
Tatem, 1976
* S = static, FT = flow-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
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Table 2. Chronic values for naphthalene (DeGroeve, et al. 1980)
Chronic
Limits Value
Species Method* (ug/l) (ug/|)
FRESHWATER SPECIES
Fathead minnow, E-L 450- 620
Plmephales promelas 850
* E-L = embryo-larva I
Acute-Chronic Ratio
Chronic Acute
Value Value
CD Species (yig/l) (ug/l) Ratio
I
°* Fathead minnow, 620 6,600 11
Plmephales promelas
Geometric mean acute-chronic ratio = 11
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Table 3. Species nean acute and chronic values for naphthalene
03
I
Number
4
3
2
1
3
2
1
Species
Mosqultof Ish,
Gambusla afflnls
Cladoceran,
Daphnla tnagna
Fathead minnow,
Plmephales promelas
Rainbow trout,
Sal mo galrdnerl
Pacific oyster,
Crassostrea 3! gas
Polychaete,
Neanthes arenaceodentata
Grass shrimp,
Palaemonetes pucjlo
Species Mean Species Mean
Acute Value* Chronic Value
(ug/l) (ug/l)
FRESHWATER SPECIES
150,000
8,570
6,600 620
2,300
SALTWATER SPECIES
199,000
3,800
2,350
Acute-Chronic
Ratio"
11
* Rank from high concentration to low concentration by species mean acute value.
**See the Guidelines for derivation of this ratio.
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Table 4. Plant values for naphthalene (Kauss & Hutchlnson, 1975)
Result
Species Effect (ng/l)
FRESHWATER SPECIES
Alga, Extrapolated 33,000
Chiorel la vulgarls ce11 numbers
48-hr EC50
to
I
00
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Table 5. Residues for naphthalene (Harris, et al. 1977b)
Bloconcentratlon Duration
Species Tissue Factor* (days)
SALTWATER SPECIES
Copepod, whole body 5,000 9
Eurytemora afflnls
* Dry weight to wet weight conversions.
03
I
ID
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ta
i
Species
Sheepshead minnow,
Cyprlnodon varlegatus
Table 6. Other data for naphthalene
Result
Reference
Alga,
Chlamydomonas angulosa
Alga,
Chlamydomonas angulosa
Coho salmon,
Oncorhynchus klsutch
Copepod,
Eurytemora at finis
Copepod,
Eurytemora af finis
Copepod,
Cat anus helqolandlcus
Copepod,
Calanus helqolandlcus
Blue mussel,
Mytl lus edulis
Grass shrimp.
Pa 1 aemonetes puqlo
Brown shrimp,
Penaeus aztecus
24 hrs
24 hrs
<6 hrs
0. 16 days
1 day
1 day
1 day
4 hrs
24 hrs
24 hrs
FRESHWATER SPECIES
Death of 61* 34,400
of cells
Loss of photo- 10*
synthetic saturation
capacity
50* mortality 5,600
SALTWATER SPECIES
Reduction In 1,000
Ingest Ion rate
of 10* (P - 0.05)
Reduction In egg 1,000
production by 83*
(P = 0.05)
B loconcentrat Ion
factor = 50
B loconcentrat Ion
factor = 60
B loconcentrat ion
factor = 44
LC50 2,600
LC50 2, 500
Soto, et
Soto, et
Holland,
Berdugo,
Berdugo,
Harris,
Harris,
Lee, et
Anderson
Anderson
al. 1975a
al. 1975b
et al. 1960
et al. 1977
et al. 1977
et al. 19775
et al. 1977a
al. 19726
, et al. 197'
, et al. 1974
24 hrs LC50
2,400 Anderson, et al. 1974
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Table 6. (Continued)
Species
Mummlchog,
Fundulus heteroc 1 Itus
Mummlchog,
Fundulus heteroc 1 Itus
Sand goby,
Gllllchtus mlrabllls
Sculpln,
Ollgocottus maculosus
Sand dab,
Cltharlchtys stlgmaeus
Result
Duration Effect (ug/l) Reference
15 days 6(11 hyperplasla
15 days Tastebud necrosis
1 hr Bioconcentratlon
factor = 63
3 hrs Bioconcentratlon
factor = 32
1 hr Bioconcentratlon
factor - 77
2 OlMlchele & Taylor,
1978
20 DIMIchele & Taylor,
1978
Lee, et al. 1972 a
Lee, et al. 1972 a
Lee, et al. 1972a
to
I
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REFERENCES
Anderson, J.W., et al 1974. The effects of oil on estuarine animals:
Toxicity, uptake and depuration, respiration. _In: Pollution and Physiology
of Marine Organisms. Academic Press, Inc. New York.
Berdugo, V. et al. 1977. The effect of petroleum hydrocarbons on reproduc-
tion of an estuarine planktonic copepod in laboratory cultures. Mar. Pol-
lut. Bull. 8: 138.
DeGraeve, 6.M., et al. 1980. Effects of naphthalene and benzene on fathead
minnows and rainbow trout. Submitted to Trans. Amer. Fish. Soc.
DiMichele, L. and M.H. Taylor. 1978. Histopathological and physiological
responses of Fundulus heteroditus to naphthalene exposure. Jour. Fish. Res.
Board Can. 35: 1060.
Harris, R.P., et al. 1977a. Factors affecting the retention of a petroleum
hydrocarbon by marine planktonic copepods. In: Fate and Effects of Petro-
leum Hydrocarbons in Marine Ecosystems and Organisms. Proceedings of Sympo-
sium 286.
Harris, R.P., et al. I977b. Accumulation of carbon-14-l-naphthalene by an
oceanic and an estuarine copepod during long-term exposure to low-level con-
centrations. Mar. Biol. 42: 187.
B-12
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Holland, G.A., et al. 1960. Toxic effects of organic and inorganic pollu-
tants on young salmon and trout. Washington Dep. Fish. Res. Bull. 5: 162.
Kauss, P.B. and T.C. Hutchinson. 1975. The effects of water-soluble petro-
leum components on the growth of Chlorella vulgaris Beijerinck. Environ.
Pollut. 9: 157.
Lee, R.F., et al. 1972a. Uptake, metabolism and discharge of polycyclic
aromatic hydrocarbons by marine fish. Mar. Biol. 17: 201.
Lee, R.F., et al. 1972b. Petroleum hydrocarbons: Uptake and discharge by
the marine mussel Mytilus edulis. Science. 177: 344.
LeGore, R.S. 1974. The effect of Alaskan crude oil and selected hydrocar-
bon compounds on embryonic development of the Pacific oyster, Crassostrea
gigas. Doctoral Thesis, Univ. of Washington.
Rossi, S.S. and J.M. Neff. 1978. Toxicity of polynuclear aromatic hydro-
carbons to the polychaete Neanthes arenaceodentata. Mar. Pollut. Bull.
9: 220.
Soto, C., et al. 1975a. Effect of naphthalene and aqueous crude oil ex-
tracts on the green flagellate Chlamydomonas angulosa. I. Growth. Can.
Jour. Bot. 53: 109.
Soto, C., et al. 1975b. Effect of naphthalene and aqueous crude oil ex-
tracts on the green flagellate Chlamydomonas angulosa. II. Photosynthesis
and uptake and release of naphthalene. Can. Jour. Bot. 53: 118.
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Tatem, H.E. 1976. Toxicity and physiological effects of oil and petroleum
hydrocarbons on estuarine grass shrimp Palaemonetes pugip Holthuis. Ph.D.
Thesis. Texas A & M Un-fv.
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No. 68-01-
4646.
Wallen, I.E., et al. 1957. Toxicity to Gambusia affinis of certain pure
chemicals in turbid waters. Sewage Ind. Wastes. 29: 695.
B-14
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
Naphthalene, CIQEQI is an aromatic hydrocarbon with two ortho-
condensed benzene rings. In 1965, 74.4 percent of the napthalene
produced in this country was used for the manufacture of phthalic
anhydride. Phthalic anhydride was used in the manufacture of alkyd
and polyester resins, dyes, pigments, Pharmaceuticals, and insecti-
cides. In the manufacture of insecticides, 12.2 percent was used
to make insecticides such as 1-naphthyl-N-methylcarbamate (car-
baryl). Eleven percent was used for the production of mothballs
and 2-naphthol which is used as an intermediate in the manufactur-
ing of dyestuffs, pigments, and Pharmaceuticals. The remainder was
used in the manufacture of alkyl-naphthalenesulfonates (used in the
manufacture of detergents and textile wetting agents), alkylnaph-
thalenes (used in making textile spinning lubricants), chlorinated
naphthalenes and tetra- and decahydronaphthalenes (used in solvent
mixtures). In 1965, the total U.S. production of naphthalene was
373,000 metric tons while in 1976 production of petroleum derived
naphthalene was 48,720 metric tons.
In 1973, 91 percent of the production was from petroleum while
the remainder originated from coal tar distillates. In 1974, 35
percent was from petroleum while 58 percent was from coal tar dis-
tillates originating from the high temperature coking of bitumi-
nous coal (Brown, et al. 1975; U.S. EPA, 1976). This coal tar naph-
thalene in its crude state contains impurities such as alkylnaph-
thalenes, alkylcoumarones, and thianaphthene. This latter impurity
C-l
-------
has been hypothesized as being the active ingredient in moth balls
(Thiessen, 1967).
EXPOSURE
Ingestion from Food and Water
The two major sources of naphthalene in the aquatic environ-
ment are from industrial effluents and from oil spills. Industrial
effluents have been found to have up to 32,000 jug/1 naphthalene.
The final effluents of sewage treatment plants receiving discharges
from these facilities have been noted to have up to 22 jug/1 naph-
thalene. Natural waters have been noted to have up to 2.0 ug/1 of
naphthalene while drinking water supplies have been found to have
up to 1.4 ug/1 naphthalene (U.S. EPA, Region IV, unpublished data).
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average
percent lipids of consumed fish and shellfish, and a steady-state
BCF for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day .(Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
C-2
-------
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
A measured steady-state bioconcentration factor of 350 was
obtained for naphthalene using Eurytemora affinis (Harris, et al.,
1977). Another species of copepod produced a lower BCF but may not
have reached steady-state. This BCF was calculated on a lipid
basis, and so corresponds to 100 percent lipids. An adjustment
factor of 3.0/100 = 0.030 can be used to adjust the measured BCF
from the 100 percent lipid basis of the BCF to the 3.0 percent
lipids that is the weighted average for consumed fish and shell-
fish. Thus, the weighted average bioconcentration factor for naph-
thalene and the edible portion of all freshwater and estuarine
aquatic organisms consumed by Americans is calculated to be 350 x
0.030 = 10.5.
Inhalation
Unusual exposure to naphthalene can occur to cigarette smok-
ers, naphthalene being identified as one of the polynuclear aroma-
tic hydrocarbons found in cigarette smoke condensate (Akin, et al.
1976). Under industrial conditions individuals can be exposed to
levels of naphthalene up to 1.1 g/m3 (220 ppm) as vapor and up to
4.4 jig/m3 as particulates (Table 1). Potential exposure categories
in this group are outlined in Table 2.
Dermal
Data on dermal exposure to naphthalene are very sparse. See
the "Effects" section for discussion of effects from possible der-
mal exposure.
C-3
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TABLE 1
Air Levels of Naphthalene
Area Investigated
Air Level (ug/m )
Vapor Particulate
Reference
o
i
*>.
Industr ial;
Naphthalene melt present
Coke Oven
Aluminum Reduction Plant
Providence, R.I.
Kingston, R.I.
Narragansett Bay, R.I.
1,600 - 1.1 x 10
11.35 - 1,120
.72 - 311.3
0.0001
0.00003
0.00005
0-4.40
.090-4.00
0.00025
0.00003
0.000003
Robbins, 1951
s
Bjjzfrseth, et al. 1978a
Bjjrfrseth, et al. 1978b
Krstulovic, et al. 1977
Krstulovic, et al. 1977
Krstulovic, et al. 1977
-------
TABLE 2
Workers with Potential Naphthalene Exposure*
Beta naphthol makers
Celluloid makers
Coal tar workers
Dye chemical makers
Fungicide makers
Hydronaphthalene makers
Lampblack makers
Moth repellant workers
Phthalic anhydride makers
Smokeless powder makers
Tannery workers
Textile chemical workers
Aluminum reduction plant workers
*Source: Tabershaw, et al. , 1977
C-5
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PHARMACOKINETIC S
Absorption, Distribution, and Excretion
Little detailed* information is available on the absorption,
distribution, or excretion of naphthalene in man or animals. Ade-
quate amounts of naphthalene can be absorbed when ingested as a
solid to cause toxicity in man (Chusid and Fried, 1955; Zuelzer and
Apt, 1949; Nash, 1903; Gross, et al. 1958; Haggerty, 1956). When
taken as a solid, fragments of naphthalene can appear in the stool
(MacGregor, 1954). The toxicity appears to be increased if taken
dissolved in oil (Solomon, 1957). The oral toxicity of a metabo-
lite of naphthalene, 1,4-naphthoquinone, is increased at least 5-
fold when dissolved in oil and administered to rabbits, as compared
to an aqueous solution (Talakin, 1966). Sanborn and Malins (1977)
found a marked decrease in absorption of protein bound naphthalene
in shrimp. The authors give this as evidence that naphthalene
would be less likely to be absorbed when exposure was from food
than when from water.
When dissolved in a nonpolar solvent, absorption of naphtha-
lene by skin application caused less experimental toxicity than
when taken orally (Gaines, 1969). Dawson, et al. (1958), however,
found that two infants exposed to naphthalene-treated clothes
developed toxic effects after their skin was covered with baby oil.
These authors suggest that skin absorption might be significant
under these circumstances.
Enough absorption can occur by inhalation of naphthalene vapor
to cause significant toxicity. Valaes, et al. (1963) found toxi-
city in newborn infants when the only exposure was to naphthalene
C-6
-------
vapor from clothes or blankets treated with naphthalene stored in
the infants' rooms or in an adjacent hall. One of these infants
died.
Naphthalene distributes widely after absorption. Lawler, et
al. (1978) found that in mallards given naphthalene in oil over a
period of two weeks, naphthalene could be identified in all tissues
examined. Its relative distribution was as follows: skin>liver>
brain = blood> muscle> heart. Naphthalene has not been identified
in urine after absorption. With sufficient absorption of naphtha-
lene to result in toxicity to an 18-month-old infant, Mackell, et
al. (1951) noted metabolites of naphthalene in the urine that were
still identifiable two weeks after exposure but which had dis-
appeared 18 days after exposure.
Metabolism
The metabolism of naphthalene in mammals has been extensively
studied. Naphthalene is first metabolized by hepatic mixed func-
tion oxidases to the epoxide, naphthalene-l,2-oxide (Figure 1).
This epoxide has the distinction of being the first arene oxide
metabolite to have been isolated (Jerina, et al. 1970). Epoxide
formation is an obligatory step. The epoxide can be enzymatically
converted into the dihydrodiol, l,2-dihydroxy-l,2-dihydronaphtha-
lene or conjugated with glutathione. The dihydrodiol can then be
conjugated to form a polar compound with glucuronic acid or sulfate
or be further dehydrogenated to form the highly reactive 1,2-
dihydroxynaphthalene. This too can be enzymatically conjugated
with sulfate or glucuronic acid or spontaneously oxidized to form
another highly reactive compound, 1,2-naphthoquinone.
C-7
-------
NMCOCH,
SCHjCKOOM
H
CH
FIGURE 1
Metabolism of Naphthalene. (1) Naphthalene; (2) naphthalene
epoxide; (3) l/2-dihydro-l,2-dihydroxynaphthalene (naphthalene
diol); (4) 1-naphthol; (5) N-acetyl-S-(l,2-dihydro-2-hydroxy-
naphthyl) cysteine; (6) 1,2-dihydroxynaphthalene; (7) 1,2-naphtho-
quinone (^-naphthoquinone); (8) 1-naphthyl sulphate
thyl glucuronide; (10) 2-hydroxy-l-naphthyl sulphate
cosiduronide of (3); (12) 2-naphthol.
Source: Van Heyningen, 1979
(9) 1-naph-
(11) 1-glu-
C-8
-------
The epoxide can also be converted spontaneously to 1-naphthol
or 2-naphthol by a keto tautomer intermediate (Boyd, et al. 1972).
1-Naphthol is the predominant spontaneous decomposition product of
the epoxide, being a more stable resonant structure than 2-naphthol
(Jerina, et al. 1970). 1-Naphthol is excreted unchanged as well
as conjugated with glucuronic acid or sulfate prior to excretion.
The finding of 1,4-naphthoquinone in the urine of a child poisoned
with naphthalene (Mackell, et al. 1951) suggests that 1-naphthol
can also be further oxidized in mammals (Cerniglia and Gibson,
1977).
A number of other metabolites have been found in liver cells,
liver microsomal preparations, or bile as noted in Table 3. The
glutathione conjugate can be progressively broken down to a cys-
teinylglycine compound and then a cysteine conjugate prior to
acetylation to the mercapturic acid, N-acetyl-S-(l,2-dihydro-2-
hydroxy-l-naphthyl)-L-cysteine either in the liver or kidney
(Booth, et al. 1960). A number of these metabolites have been
identified in the urine of mammals (Table 4). The presence of 1-
naphthyl mercapturic acid may be explained by a spontaneous de-
hydrogenation of the mercapturic acid of the dihydrodiol in acidic
urine (Jerina, et al. 1968).
Naphthalene metabolites undergo further conversions in the
eye. The eye contains beta glucuronidase and sulfatase which can
hydrolyze the glucuronide and sulfate esters of the dihydrodiol
(Van Heyningen and Pirie, 1967). Catechol reductase is also present
in the eye. This enzyme can oxidize the dihydrodiol to 1,2-di-
hydroxynaphthalene which in turn can be spontaneously oxidized to
C-9
-------
O
I
TABLE 3
Naphthalene Metabolites: Liver/Bile
Metabolite
1-naphthol
2-naphthol
1-naphthyl glucosiduronic acid
1-naphthyl mercapturic acid
l,2-dihydro-l,2-dihydroxy napthalene
l,2-dihyro-2-hydroxy-l-naphthyl-glucosiduronic acid
l,2-dihydro-l-hydroxy-2-naphthyl-glucosiduronic acid
S-(l,2-dihydro-2-hydroxy-l-naphthyl)-L-cysteine
N-acetyl-S-(l,2-dihydro-2-hydroxy-L-naphthyl)-l-cysteine
1,2-dihydroxy naphthalene
1, 2-naphthoquinone
Naphthalene-l,2-oxide
S-(l,2-dihydro-2-hydroxy-l-naph thy l)-glutath tone
S-(l,2-dihydro-2-hydroxy-l-naphthyl)-L-cysteinyl glycine
(l,2-dihydro-2-hydroxy-l-naphthyl)-sulfate
2-hydroxy-l-naphthyl-glucosiduronic acid
Found in:
Rabbit Rat
2 3,4
2 3
3,4
3
2 3,4
3,4
3
3
3
4
4
2
2 1,3
3
4
3
Fish
* 5
5
5
5
5
References: 1-Booth, et al. 1960 4-Bock, et al. 1976
2-Jecina, et al. 1970 5-Roubal, et al. 1978
3-Boyland, et al. 1961
-------
TABLE 4
Naphthalene Metabolites: Kidney/Urine
Metabolite
Rabbit
Found in;
Guinea Pig Mice
Rat
References:
1- Boyland & Sims, 1958
2- Sims, 1959
3- Booth, et al. 1960
4- Young, 1947
5- Booth & Boyland, 1949
6- Corner, et al. 1954
7- Corner & Young, 1954
8- Mackell, et al. 1951
Kan
1-naphthol
2-haphthol
Q 1-naphthyl sulfate
)_, 1-naphthyl glucosiduronic acid
1-1 S-(l-naphthyl)-L-cysteine
1-naphthyl mercapturic acid
l,2-dihydro-l,2-dihydroxy naphthalene
l,2-dihydro-2-hydroxy-l-naphthyl-glucosiduronlc acid
l,2-dihydro-l-hydroxy-2-naphthyl-glucosiduronic acid
S-(l,2-dihydro-2-hydroxy-l-naphthyl)-L-cysteine
N-acetyl-S-(l,2-dihydro-2-hydroxy-l-napthyl)-L-cysteine
2-hydroxy-l-naphthyl sulfate
l-hydroxy-2-naphthyl sulfate
1 , 2-dihydroxynapthalene
1 , 2-naphthoquinone
1 , 4 - naph thoqu i none
1,2 7
1 7
1,7 7
1
1
1,5,7 7
1,2,6,7
2
1 1
1
2
7
7 7
7 7
7 7
3
7 4,5,7
7
3
1 1,3
8
8
8
8
-------
1,2-naphthoquinone with the concomitant release of hydrogen per-
oxide. 1,2-Naphthoquinone can then oxidize ascorbic acid, which is
found in high concentration in the eye, to dihydroascorbic acid
with the release of more hydrogen peroxide. Dihydroascorbic acid
can then be broken down to oxalate or diffuse into the lens where it
is reconverted to ascorbic acid with the associated nonenzymatic
oxidation of reduced glutathione (Van Heyningen, 1970). As 1,2-
naphthoquinone is reduced by the reaction with ascorbic acid to
1,2-dihydroxynaphthalene, it oxidizes NADPH. The dihydroxide will
rapidly reduce cytochrome c (Van Heyningen and Pirie, 1967). 1,2-
Naphthoquinone also binds irreversibly to lens protein and amino
acids (Van Heyningen and Pirie, 1966).
Aryl hydrocarbon hydroxylase, a mixed-function microsomal
oxidase, is induced by many carcinogenic polycyclic aromatic hydro-
carbons. Alexandrov and Frayssinet (1973) found that the intra-
peritoneal injection of 40 mg/kg of naphthalene in corn oil into
male Wistar rats daily for a period of three days resulted in a 40
percent inhibition of this enzyme's ability to hydroxylate benzo-
(a)pyrene. Naphthalene also inhibited the induction of this enzyme
by 3-methylcholanthrene. A number of other napthtalene deriva-
tives, including 1-naphthol and 2-naphthol, were tested and were
not found to depress the activity of this enzyme.
EFFECTS
Lezenius (1902) described the case of a 36-year-old pharmacist
who, after taking 5 g of naphthalene in oil, developed near blind-
ness eight or nine hours later. An examination a year later dis-
closed constricted visual fields associated with optic atrophy and
C-12
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Age (years)
20-30
30-40
40-50
50-60
Number of
workers
4
5
8
4
bilateral cataracts made up of numerous whitish opacities. In 1906
Van der Hoeve further described a case of a 44-year-man who worked
with powdered naphthalene, and was found to have cataracts and a
retinal hemorrhage. A coworker was noted to have chorioretinitis
in one eye. Ghetti and Mariani (1956) examined 21 workers in a
plant producing a dye intermediate from naphthalene and found cata-
racts in 8 of them with the following age distribution:
Number
with cataracts
2
3
2
1
A model for the eye toxicity of naphthalene has been developed
in rabbits (Van Heyningen and Pirie, 1976) to further investigate
the disappearance of reduced glutathione from the lens and its
relationship to the cataractogenicity of naphthalene. Bourne
(1937) was the first to note the disappearance of reduced gluta-
thione from the lens. Rees and Pirie (1967) reported that the
metabolites of naphthalene released in the eye were general meta-
bolic and coenzyme inhibitors. Van Heyningen (1970) found that
1,2-dihydroxynaphthalene or 1,2-naphthoquinone combined with amino
acids or irreversibly with the thiol groups of lens protein to form
a brown precipitate; that the hydroperoxide formed in the oxidation
of 1,2-dihydroxynaphthalene and ascorbic acid can act with
the high levels of glutathione peroxidase in the eye to oxidize
C-13
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glutathione; and that oxidized ascorbic acid easily enters the lens
where it readily oxidizes reduced glutathione nonenzymatically.
Van Heyningen and Piiie (1967) reported that the oxidized ascorbic
acid also oxidizes protein thiols, a mechanism that is normally
prevented by reduced glutathione; that the oxidation of NADPH pre-
vents the reduction of oxidized glutathione by glutathione reduc-
tase; and that 1,2-naphthoquinone quickly combines irreversibly
with lens and eye proteins thereby losing its ability to oxidize as
corbie acid. Pirie (1968) observed that oxidized ascorbic acid
breaks down to oxalate which in turn precipitates as calcium oxa-
late crystals in the vitreous humor and on the retina of the eye;
and that lens changes are preceded by evidence of injury to the
epithelium of the lens as well as retina.
A hemolytic anemia with associated jaundice and occasionally
renal disease from precipitated hemoglobin has been described both
in children and adults (Haggerty, 1956; Chusid and Fried, 1955;
Abelson and Henderson, 1951; Zuelzer and Apt, 1949; Gidron and
Leurer, 1956; Nash, 1903; Mackell, et al. 1951) as well as in new-
born infants (Cock, 1957; Schafer, 1951) after exposure to naphtha-
lene by ingestion, inhalation, or possibly, by skin contact.
Dawson, et al. (1958) identified two newborn children who had both
a naphthalene hemolytic anemia as well as a combined glucose-6-
phosphate dehydrogenase deficiency and glutathione reductase de-
ficiency. The former defect was more prominent. Glucose-6-phos-
phate dehydrogenase (G6PD) in the presence of glucose-6-phosphate
reduces NAPD to NADPH which in turn is required by glutathione
reductase to maintain glutathione in the reduced state. In the
C-14
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absence of reduced glutathione there can be oxidative denaturation
of hemoglobin with precipitation of globin as Heinz bodies and the
associated stiffening of red blood cell membranes. These abnormal
red cells are then removed from the circulation by the spleen and
liver. NADPH is also a cofactor for the reduction of methemoglobin
(Kellermeyer, et al. 1962). This can lead to the buildup of met-
hemoglobin or methemalbumin in the serum with excretion of these
compounds in the urine (Schafer, 1951). Both Valaes, et al. (1963)
and Naiman and Kosoy (1964) have noted that although most infants
with naphthalene-associated acute hemolytic anemia have G6PD defi-
ciency, there was a group of neonates that had a milder form of
hemolysis and did not have the enzyme deficiency. Both groups
noted high levels of bilirubin in the serum of their cases with
associated brain damage (kernicterus) and even death in several
infants. Gross, et al.(1958) noted that red blood cells lose G6PD
activity with aging in G6PD deficient individuals such that older
populations of red blood cells are more susceptible to hemolysis
than young ones. In some forms of G6PD deficiency, this can result
in a self-limited form of hemolysis (Wintrobe, et al. 1974).
Hemolytic anemia has also been noted in individuals exposed to
a metabolite of naphthalene, 2-naphthol. Smillie (1920) treated 79
Brazilians with 2-naphthol for hookworm disease. Adults received 6
g of 2-naphthol per day orally for three days while children re-
ceived a smaller dose. Four of those treated were found to develop
a hemolytic anemia, two associated with splenomegaly. He identi-
fied three of those affected,as being black.
C-15
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Acute, Subacute, and Chronic Toxicity
The acute lethality of naphthalene has been assessed by sever-
al routes in several-^species as shown in Table 5. The greater tox-
icity by an oral versus subcutaneous route might be due to species
variation in susceptibility but might also indicate that naphtha-
lene first has to be metabolized by the liver to produce maximum
toxicity.
Several other studies have been performed to assess sublethal
effects of naphthalene or its metabolites. Zuelzer and Apt (1949)
administered naphthalene in a solid form to dogs by the oral route.
One dog received 1800 mg/kg in divided doses over a period of five
days with resultant lethargy, ataxia, a drop in hemoglobin by 83
percent, and a leukamoid reaction (white blood cell count of
119,000). Two other dogs received 1,530 mg/kg and 420 mg/kg in
single doses with a resultant drop in hemoglobin by 33 percent and
29 percent, respectively.
Mahvi, et al. (1977) administered naphthalene in corn oil in-
traperitoneally to C57 B1/6J mice. Two groups of 63 mice received
corn oil alone or remained untreated. Groups of 21 mice each were
given 67.4, 128, or 256 mg/kg. Three animals from each dosage group
were sacrificed at ten minutes, 1 hour, 6 hours, 12 hours, 24
hours, 48 hours, and 7 days following treatment. Lung tissue was
rapidly fixed and examined by light, scanning electron microscopy,
and transmission electron microscopy. No changes were noted in
either control group. Minor bronchiolar epithelial changes were
noted in the group receiving 67.4 mg/kg. Mice in the higher dosage
groups developed necrosis of secretory nonciliated bronchiolar
C-16
-------
o
TABLE 5
Tests of the Acute Toxicity of Naphthalene
Test Animal
Mice
Sherman rats
male
female
male
female
Rat
Rat
Rat
Number Route
Subcut.
40 Orala
40 Orala
10 Skinb
10 Skinb
Oral
Oral
Inhalation
LD50 (mg/kg)
5,100
2,200
2,400
2,500
2,500
1,780
9,430
100 ppm x
8 hr.
Reference
Irie, et al. 1973
Gaines, 1969
Gaines, 1969
Gaines, 1969
Gaines, 1969
NIOSH, 1977
Union Carbide Corp. , 1968
Union Carbide Corp. , 1968
Dissolved in peanut oil
Dissolved in xylene
-------
cells. Epithelial structure returned to normal within seven days
in all cases.
Reid, et al. (£973) ,gave naphthalene dissolved in sesame oil
to C57 B1/6J mice by the intraperitoneal route and found coagula-
tive necrosis of the bronchiolar and bronchial epithelium at a dose
of 600 mg/kg. Controls received sesame oil alone and no adverse ef-
fects were reported for this group. The size of the treatment
groups was not stated.
Pilotti, et al. (1975) treated ascites tumor BP8 cells In
vitro by incubating with naphthalene solutions for 48 hours. The
authors noted 100 percent growth inhibition at a concentration of
128 mg/1 and 10 percent growth inhibition at a concentration of
12.8 mg/1.
Several studies have also been done on the metabolites of
naphthalene. Van Heyningen and Pirie (1967) dosed one rabbit with
300 mg of the dihydrodiol intravenously in divided doses over three
days and noted retinal lesions. They also noted lens changes in
four rabbits dosed externally with one percent eye drops of the
same compound (dissolved in water) over a period of two to five
days for a total dose of 40-70 mg per rabbit.
Mackell, et al. (1951) incubated blood from normal human don-
ors with naphthalene or its metabolites in various concentrations.
Hemolysis was noted as shown in Table 6. These agents were also
injected intravenously into white male rabbits in concentrations of
0,25, 0.5, 1.0, and 1.25 mg/kg. Naphthalene, 2-naphthol, 1,2-naph-
thoquinone, and 1,4-napthoquinone produced no hemolysis at 15 min-
utes after the injection; 1-naphthol, however, produced 6 percent
C-18
-------
o
I
TABLE 6
In vitro Hemolysis of Red Blood Cells Exposed to Naphthalene and its Metabolites*
Compound
Concentration (mg/1 blood) k-
13.3 20 40 100 200 1000
(Percent Hemolysis)
1-naphthol 2
2-naphthol 0
1,4-naphtho-
quinone 0
1,2-naphtho-
quinone 0
Naphthalene 0
6 14 46 53 65 74
0 3 11 32 48 60
0 00 0 4 18
0 0 0 0 <1 12
0 00 00 0
*Source: Mackell, et al., 1951
-------
and 9 percent hemolysis at the two higher dosages. Zinkham and
Childs (1958) performed similar in vitro experiments with the same
metabolites but measured a drop in reduced glutathione as an end
point. They also investigated the effect of these metabolites on
blood from a patient who had hemolysis after contact with naphtha-
lene and who had red blood cells sensitive to an oxidant (presumed
G6PD) deficiency. All four metabolites resulted in depression of
reduced glutathione levels. Naphthalene resulted in minor depres-
sion of reduced glutathione levels at concentrations of 5000 mg/1
or greater.
Several studies have been done on the subacute and chronic
toxicity of naphthalene, all involving a single dose/day regime.
Fitzhugh and Buschke (1949) fed five weanling rats 2 percent of
naphthalene or 2-naphthol in their diets for a period of at least
60 days and noted early cataracts in both groups.
Van Heyningen and Pirie (1976) dosed rabbits daily by gavage
with 1000 mg/kg of naphthalene for various periods of time for a
maximum of 28 days. They noted lens changes developing after the
first dose and retinal changes developing after the second dose.
Ghetti and Mariani (1956) fed five rabbits 1000 mg/kg/day of
naphthalene and noted the development of cataracts between days 3
and 46. Topical application of a 10 percent solution in oil to the
eyes of two rabbits did not produce cataracts after a period of 50
days. Intraperitoneal injection of 500 mg/day of naphthalene in an
oily solution to one rabbit over a period of 50 days produced
weight loss but no cataracts.
C-20
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Synergism and/or Antagonism
There is little information on the synergistic or antagonistic
effects of naphthalene. In a single case report Harden and Baetjer
(1978) described finding aplastic anemia in a 68-year-old black
female exposed to mothproofing compounds. Yearly for a period of
39 years she had intermittently worked storing garments with moth-
proofing compounds. One month prior to becoming ill she worked for
a period of three weeks in a hot, unventilated room mothproofing
garments. She handled a total of 7 kg of naphthalene and 5.5 kg of
paradichlorobenzene. It was estimated that she was exposed to near
1,400 ppm of paradichlorobenzene and 184 ppm of napththalene. The
time of her exposure was consistent with the onset of her bone mar-
row depression, estimated from her hematologic findings on admis-
sion two months after first becoming ill. No other cases of aplas-
tic anemia have been described with either a naphthalene or para-
dichlorobenzene exposure either alone or in combination with anoth-
er chemical.
Teratogenicity
Naphthalene or its metabolites can cross the placenta in suf-
ficient amounts to cause fetal toxicity. Both Zinkham and Childs
(1958) and Anziulewicz, et al. (1959) noted toxic effects in in-
fants where the only exposure was to the mother during pregnancy.
When a metabolite of naphthalene, 2-naphthol, was administered to
pregnant rabbits, their offspring were born with cataracts and evi-
dence of retinal damage (Van der Hoeve, 1913).
C-21
-------
Mutagenicity
Naphthalene has been found to be nonmutagenic in several
microsomal/bacteriallassay, systems as outlined in Table 7. Metabo-
lites of naphthalene have not been tested.
Carcinogenicity
Wolf (1976) reported six cases of malignant tumors among 15
workers exposed to vapors of naphthalene and coal tar for a period
of up to 32 years at a coal tar naphthalene production facility.
Four workers contracted laryngeal carcinoma and were all smokers.
The other 2 workers developed neoplasms of the pylorus and cecura.
There was no control group.
Knake (1956) treated 40 white rats with 500 mg/kg of coal tar
naphthalene in sesame oil subcutaneously every two weeks for a
total of seven treatments; 34 rats survived the treatment and 5
developed invasive or metastatic lymphosarcoma prior to death.
There was a two percent incidence of malignancies in an untreated
control group with a similar incidence in a group treated with
sesame oil alone. His data are detailed in Table 8. The sites of
the injections of the naphthalene/sesame oil and sesame oil treated
groups were painted with carbolfuchsin (a known experimental car-
cinogen) prior to each injection. The naphthalene contained 0.07
gram molecular weight impurities per 100 g (equivalent to 10 per-
cent methyl naphthalene).
In a second study, Knake (1956) painted a group of mice with
either benzene or a solution of coal tar naphthalene in benzene and
noted an excess of lymphatic leukemia in the naphthalene/benzene
group compared to the benzene treated group or a group of untreated
controls. His results are detailed in Table 9.
C-22
-------
o
I
to
OJ
TABLE 7
Mutagenicity of Naphthalene in Various Ir\ Vitro Microsomal Assay Systems
System
Rat microsomes/
Salmonella typhimurium
Strain
TA100
TA1535
TA1537
TA98
Result
Negative3
Negative3
Negative3
Negative3
Reference
McCann,
McCann,
McCann,
McCann,
et
et
et
et
al.
al.
al.
al.
1975
1975
1975
1975
Mouse microsome/
Salmonella typhimurium
Mouse microsome/
E. coli
G46
K12
Negative Kraemer, et al. 1974
Negative Kraemer, et al. 1974
Less than 0.09 revertants/nmol. Tested at 10, 100, 500, and 1000 jug/plate
Naphthalene-1,2-oxide used in the test system
-------
TABLE 8
Incidence of Tumors in White Rats Treated with 0.5 gm/kg Naphthalene Subcutaneously
(15% in Sesame Oil) Every Two Weeks for 14 Weeks and then Followed for 18 Months*3
Number of Animals
Treatment Total Survivors Lymphosarcoma
Fibroadenoma
Other
Malignant Tumor
n
i
NJ
Naphthalene
in sesame oil 40
Sesame oil 40
No treatment 101
0 5
4 1
0 (lifetime) 1
1
1
0
0
0
1
*Source: Knake, 1956
34 naphthalene/sesame oil treated rats survived the initial treatment. 32 rats treated with
sesame oil alone survived the initial 14 weeks of treatment.
3.3 ml/kg/treatment
-------
TABLE 9
Incidence of Tumors in Inbred Black Mice Painted with 0.5% Naphthalene in Benzene
or Benzene Alone 5 days/week for Life*
o
1
N)
Ul
Treatment Number Leukemia Lymphosarcoma
Naphthalene in
Benzene 25 4a 1
Benzene 21 0 1
No Treatment 1227 5 3
Sarcoma Other
(other) Malignancy Lung Adenoma
013
101
1 44 0
*Source: Knake, 1956
All lymphocytic leukemia
-------
Druckrey and Schmahl (1955) used naphthalene as a vehicle for
testing the carcinogenic effects of anthracene. In a preliminary
study they looked atithe p9tential carcinogenic effects of naphtha-
lene alone. BD I and BD III strain rats were used. One group of 28
rats was given 10 gm of naphthalene orally per rat over a period of
time and followed for an excess of 1,000 days. A second group of 10
rats was given a total dose of 0.82 gm of naphthalene per rat subcu-
taneously and followed for a similar period of time. No tumors
were noted in either group.
Boyland, et al. (1964) found a 4 percent incidence of bladder
carcinoma in mice with naphthalene implanted in their bladders. As
seen in Table 10, there was a similar or higher incidence of blad-
der carcinoma in mice treated with various inert control substances
including glass.
Kennaway (1930) and Kennaway and Hieger (1930) tested the car-
cinogenicity of naphthalene in mice by a skin painting experiment.
They found that naphthalene was noncarcinogenic, but did not give
the details of their protocols.
Bogdat'eva and Bid (1955) painted naphthalene onto the skin of
rabbits at a dose sufficient to cause systemic toxicity. No car-
cinomatous changes were noted after this chronic study. Details of
the protocol were not given.
The investigations of Schmeltz, et al. (1978) have indicated
the di-, tri-, and tetramethyl naphthalenes, common contaminants of
coal tar naphthalene, all show cocarcinogenic activity when applied
by painting to mouse skin in conjunction with benzo(a)pyrene. Pure
naphthalene did not show cocarcinogenic activity when tested in
C-26
-------
TABLE 10
Bladder Tumors in Mice with Naphthalene Bladder Implants*
o
1
K)
Substance
Naphthalene
Inert Controls
Magnesium stearate
n-Hexadecanol
n-Octadecanol
Smooth glass
Roughened glass
# Mice Surviving
to 30 weeks
23
41
69
50
67
63
Carcinoma Adenoma/Papilloma
1 0
1 1
6 2
6 7
3
18
*Source: Boyland, et al., 1964
-------
this manner. The alkyl-napthalenes which had shown positive activ-
ity in combination with benzo(a)pyrene for mouse skin tumors were
shown to accelerate juri vitro metabolism of benzo(a)pyrene by 3-
methylcholanthrene induced liver homogenates, while naphthalene
produced an inhibition of this _in vitro liver metabolizing
activity.
Takizawa (1940) painted the skin of mice with a metabolite of
naphthalene, 1,4-naphthoquinone. They noted an incidence of 15 to
20 percent skin papillomas with some degenerating into malignant
epithelomas in mice surviving 200 days. Further details of the
protocol were not given.
Pirie (1968) treated Dutch and albino rabbits with 1.0
g/kg/day of naphthalene by gavage. After three doses they noted
mitotic arrest of the epithelial cells of the lens. The arrest
persisted for 15 days when replication of the epithelial cells was
first noted. At 16 days numerous abnormal mitotic figures in meta-
phase were noted in the epithelial layer in association with cell
overgrowth. This work is significant in that one of the effects of
2 metabolites of naphthalene, 1-naphthol, and 2-naphthol, is to
interfere with the mitotic spindle function, as seen in root tips
of Vicia faba (Dean, 1978). Both metabolites cause a chromosomal
lagging in anaphase and 1-naphthol results in a colchicine-like
accumulation of chromosomes in metaphase.
Naphthalene has also been tested for carcinogenic activity in
In vitro test systems using rodent embryo cells pretreated with
Rauscher leukemia virus. No effects were seen at doses up to 100
mg/1 (Table 11).
C-28
-------
TABLE 11
Carcinogenic Activity of Naphthalene with Ir\ vitro Test Systems
o
NJ
vo
Test System Dose (ug/l)b
Rat embryo cells/
Rauscher leukemia virus3 50
1,000
5,000
10,000
50,000
100,000
Mouse embryo cells/
AKR leukemia virus3 100
500
1,000
5,000
Result
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Reference
Freeman,
Freeman,
Freeman,
Freeman,
Freeman,
Freeman,
Rhim, et
Rhim, et
Rhim, et
Rhim, et
et
et
et
et
et
et
al.
al.
al.
al.
al. 1973
al. 1973
al. 1973
\
al. 1973
al. 1973
al. 1973
1974
1974
1974
1974
In addition to transforming ability, treated cells injected into newborn rats or mice,
respectively, without any evidence of tumorigenicity
Dissolved in acetone
-------
Tonelli, et al. (1979) tested naphthalene in a marine mammary
gland organ culture system, and were unable to demonstrate cell
transformation at compound levels up to 1,000 mg/1 of culture
med i um.
C-30
-------
CRITERION FORMULATION
Existing Guidelines and Standards
The only existing U.S. standard for naphthalene is the Occu-
pational Safety and Health Administration (OSHA) standard of 10 ppm
(50 mg/m ) as a time-weighted average (39 FR 23540). This standard
was adopted from the American Conference of Governmental Industrial
Hygienists1 Threshold Limit Value which in turn was based on an
irritant threshold for naphthalene of 15 ppm (ACGIH, 1971). At
present, the ACGIH (1978) also suggests a maximum 15 minute expo-
sure value of 15 ppm (75 mg/m3).
The maximum permissible concentration of naphthalene in fish-
ery water bodies of the USSR is 4 ug/1 (Mosevich, et al. 1976).
Current Levels of Exposure
Natural waters have been found to contain up to 2 ug/1 of
naphthalene while drinking water supplies have been found to con-
tain up to 1.4 pg/1 of naphthalene (U.S.EPA, Region IV, unpublished
data). Ambient air levels have been measured at 0.35 ng/m3 in an
urban area and 0.06 ng/m3 in a small town (Krstulovic, et al.
1977). Industrial exposures can be as high as 1,100 mg/m3 for
naphthalene-using industries (Robbins, 1951), with exposures up to
1.12 mg/m for coke oven workers (Bj^rseth, et al. 1978a), and 0.31
mg/m for aluminum reduction plant workers (Bjjzfrseth, et al.
1978b). No measurements of naphthalene have been reported for mar-
ket basket foods.
Special Groups at Risk
Approximately 100 million people worldwide have glucose-6-
phosphate dehydrogenase (G6PD) deficiency which would make them
C-31
-------
more susceptible to hemolytic anemia on exposure to naphthalene. At
present, more than 80 variants of this enzyme deficiency have been
identified (Wintrobe, et al. 1974). The incidence of this defi-
ciency is 0.1 percent in American and European Caucasians but can
range as high as 20 percent in American blacks and greater than 50
percent in certain Jewish groups (Table 12).
Newborn infants have a similar sensitivity to the hemolytic
effects of naphthalene, even without G6PD deficiency. Zinkham and
Childs (1957) surveyed 26 normal white and black newborn infants
and found moderately to severely reduced glutathione levels in
blood samples incubated with acetylphenylhydrazine. This effect
was suggestive of a glutathione reductase deficiency. Brown and
Burnett (1957) also noted that newborn infants have a decreased
capacity to conjugate chemical metabolites with glucuronide second-
ary to an absolute decrease in the activity of UDP-glucuronyl
dehydrogenase and transferase. Such a lack in glucuronidation can
allow the build-up of toxic amounts of 1,2-dihydroxynaphthalene and
1,2-naphthoquinone.
A small percentage of the population might have an allergic
hypersensitivity to naphthalene. Fanburg (1940) described a 43-
year-old physician with a generalized exfoliative dermatitis who
was found to be allergic to naphthalene. Both the clinical and
histologic picture resembled a malignancy, mycosis fungoides. A
patch test with naphthalene was positive, resulting in urticaria.
When all exposure to naphthalene was discontinued, the skin con-
dition cleared rapidly and did not recur over a three year period
of followup.
C-32
-------
TABLE 12
Frequency of G6PD Deficiency in Populations*
Population G6PD Deficiency (%)
Northern European 0.1
American black male 13
American black female 20
Brazilian black male 8.2
Bantu male 37
Sardinian 14.35
Maltese 2.7
Italian 0.4
Greek 9,5
Sephardic, Oriental or Kurdish Jews >50
*Source: Wintrobe, et al. , 1974
C-33
-------
Basis and Derivation of Criteria
All chronic toxicity studies using naphthalene have failed to
demonstrate any carcinogenic activity except for those performed by
Knake (1956). This author found an excess occurrence of lymphosar-
coma when naphthalene was given by the subcutaneous route to rats
and of lymphocytic leukemia when naphthalene was chronically paint-
ed on the skin of mice using benzene as a solvent. However, the
naphthalene used in this study was derived from coal tar and con-
tained 10 percent or more unidentified impurities. Furthermore, a
known experimental carcinogen, carbolfuchsin, was applied prior to
each injection of naphthalene in the former study. In light of
these defects, carcinogenicity data derived from this study cannot
be used as a basis for a naphthalene water criterion.
No other chronic toxicity studies are available that can be
used as an adequate basis for a naphthalene criterion. Further-
more, there are no adequate epidemiologic studies that can be used
as a basis.
The ACGIH (1971) has recommended a time-weighted threshold
limit value for an industrially-exposed population of 50 mg/m of
naphthalene vapor in air. This value was set to prevent workers
with exposure to naphthalene vapors from getting eye irritation.
It is unclear, however, whether equivalent exposures to water con-
taining naphthalene might also result in mucous membrane irrita-
tion. Until further information is available on the direct irri-
tant properties of naphthalene in water, the ACGIH threshold limit
value cannot be used as a basis for a naphthalene water criterion.
C-34
-------
Mahvi, et al. (1977) noted a dose-related response by C57
B1/6J mice given intraperitoneal injections of naphthalene in
sesame oil. No brorichioLar epithelial changes were noted in two
control groups. The authors noted minimal bronchiolar epithelial
changes in the treated group receiving 6.4 mg/kg of naphthalene.
Severe, reversible damage to bronchiolar epithelial cells was noted
among two higher dosage groups.
Because of the above deficiencies as well as deficiencies in
the other toxicity studies on naphthalene, a criterion cannot be
derived. Because of the potential cocarcinogenicity of this com-
pound, it should be regarded with concern and an effort should be
made to generate adequate toxicity data on which a criterion could
be based.
C-35
-------
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