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EPA Ambient 

United States 

Environmental Protection 

Agency 

Office of Water 

Regulations and Standards 

Criteria and Standards Division 

Washington DC 20460 

EPA 440/5-80-059 

October 1980 

Water Quality 

Criteria for 

Naphthalene 
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 

i 
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. 

ii 
FOREWORD 

Section 304 (a)(1) 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 

criteria for the 65 pollutants. This criterion document is also 

published in satisfaction of paragraph 11 of the Settlement Agreement 

in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120 

(D.D.C. 1976), modified, 12 ERC 1833 (D D C 1979). 

The term "water quality criteria" is used in two sections of the 

Clean Water Act, section 304 (a)(1) 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 effects. 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 

303 become enforceable maximum acceptable levels of a pollutant in 

ambient waters. The water quality criteria adopted 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 

adoption as part of the State water quality standards that the criteria 

become regulatory. 

Guidelines to assist the States in the modification of criteria 

presented in this document, in the development of water quality 

standards, and in other water-related programs of this Agency, are being 

developed by EPA. 

STEVEN SCHATZOW 

Deputy Assistant Administrator 

Office of Water Regulations and Standards 

iii 
ACKNOWLEDGEMENTS 

Aquatic Life Toxicology: 

William A. Brungs, ERL-Narragansett 

U.S. Environmental Protection Agency 

John H. Gentile, ERL-Narragansett 

U.S. Environmental Protection Agency 

Mammalian Toxicology and Human Health Effects: 

Woodhall Stopford (author) 

Duke University Medical Center 

Mark Greenberg, ECAO-RTP 

U.S. Environmental Protection Agency 

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 

Frederick C. Kopfler, HERL 

U.S. Environmental Protection Agency 

Frederick W. Dehme 

Kansas State University 

Herbert Schumacher 

National Center for Toxicological 

Research 

Herbert Cornish 

University of Michigan 

Anne Trontell 

Energy Resources Company, Inc. 

Patrick Durkin 

Syracuse Research Corporation 

Jonathan Ward 

University of Texas Medical Branch 

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.J. Quesnell, C. Russom, B. Gardiner. 

iv 
TABLE OF CONTENTS 

Page 

Criteria Summary 

Introduction 

Aquatic Life Toxicology 

Introduction 

Effects 

Acute Toxicity 

Chronic Toxicity 

Plant Effects 

Residues 

Miscellaneous 

Summary 

Criteria 

References 

Mammalian Toxicity and Human Health Effects 

Introduction 

Exposure 

Ingestion from Food and Water 

Inhalation 

Dermal 

Pharmacokinetics 

Absorption, Distribution, and Excretion 

Metabolism 

Effects 

Acute, Subacute and Chronic Toxicity 

Synergism and/or Antagonism 

Teratogenicity 

Mutagenicity 

Carcinogenicity 

Criterion Formulation 

Existing Guidelines and Standards 

Current Levels of Exposure 

Special Groups at Risk 

Basis and Derivation of Criteria 

References 

A-1 

B-1 

B-1 

B-1 

B-1 

B-2 

B-2 

B-2 

B-2 

B-3 

B-4 

B-12 

C-1 

C-1 

C-1 

C-2 

C-3 

C-3 

C-6 

C-6 

C-7 

C-12 

C-16 

C-21 

C-21 

C-22 

C-22 

C-31 

C-31 

C-31 

C-31 

C-34 

C-36 
CRITERIA 

CRITERIA DOCUMENT 

NAPHTHALENE 

Aquatic Life 

The available data for naphthalene indicate that acute and chronic toxicity to freshwater aquatic life occur at concentrations as low as 2,300 and 

620 μg/l, 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 aquatic life occurs at concentrations as low as 2,350 μg/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. 

Human Health 

Using the present guidelines, a satisfactory criterion cannot be derived 

at this time because of the insufficiency in the available data for naphthalene. 

vi 
INTRODUCTION 

Naphthalene 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 solvents, lubricants, and motor fuels. One of the principal uses of naphthalene 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 insecticide as well as an antihelminthic, vermicide, and an intestinal antiseptic. 

Naphthalene 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 1OO°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'denblat, et al. 1960). 

The solubility of naphthalene in water has been reported to range between 30,000 μg/l (Mitchell, 1926) and 40,000 μg/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-1 
naphthalene is approximately 33,000 μg/l (Gordon and Thorne, 1967). Naphthalene 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 CO2 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 CO2 (Kirk and Othmer, 1967). However, this oxidation process 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 18O°C, naphthalene can be nitrated at 

the alpha position (Alama and Okon, 1964). In the presence of oxygen, 

K2SO4, a vanadium oxide catalyst, and Si04, naphthalene can be converted to phthalic anhydride (Morotskii and Kharlampovich, 1968). 

Microorganisms can degrade naphthalene to 1,2-dihydro-1,2dihydroxynaphthalene and ultimately to carbon dioxide and water. Studies have indicated 

a degradation rate under laboratory conditions of up to 3.3 μg/l (Lee and 

Anderson, 1977). 

Naphthalene has a varied environmental distribution and has been detected in ambient water (up to 2.0 μg/l), sewage plant effluents (up to 22 

μg/l), and drinking water supplies (up to 1.4 μg/l) (U.S. EPA, 1971-1977). 

A-2 
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 products. 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 naphthalene. Jour. Appl. Chem. 33: 245. 

Gordon, J.E. and R.L. Thorne. 1967. Salt effects on none 

tions. Beschim. Cosmochim. Acta. 31: 2433. 

lectrolyte so luJosephy, E. and F. Radt (eds.) 1948. Encyclopedia of Organic Chemistry: 

Series XII. Elsevier Publishing Co., Inc., New York. 

A-3 
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: Controlled ecosystem pollution experiment. Bull. Mar. Sci. 27: 127. 

Ludzack, F.J. and M.B. Ettinger. 1963. Biodegradability of organic chemicals 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 Physiochemical Standards. Bull. Sot. Chim. Bedgrad. 39: 590. 

Mitchell, S. 1926. A method for determining the solubility of sparingly 

soluble substances. Jour. Chem. Sot. 129: 1333. 

Morotskii, O.A. and G.D. Kharlampovich. 1968. Phthalic anhydride. Izobret., 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. Sot. Toxicol. Toronto, Canada. 

March 27-30, 1977. 

Spector, W.S. ted.) 1956. Handbook of Toxicology. Saunders Publishing 

co., Philadelphia. 

A-4 
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, Cleveland, Ohio. 

Windholz, M. (ed.) 1976. The Merck Index. 9th ed. Merck and Co., Rahway, 

New Jersey. 

A-5 
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 concentrations. All but two fifty percent effect levels for fish and invertebrate 

species are in the range of 2,300 to 8,900 μg/l. One embryo-larval test 

with the fathead minnow demonstrated adverse effects at a test concentration 

of 850 μg/l, 

Histopathological changes in the saltwater mummichog were observed at 

naphthalene concentrations as low as 2 μg/l. 

EFFECTS 

Acute Toxicity 

Daphnia magna is the only tested freshwater invertebrate species (U.S. 

EPA, 1978) and the 48-hour EC50 is 8,570 μg/l (Table 1). 

DeGraeve et al. (1980) conducted flow-through tests with measured concentrations for the rainbow trout and the fathead minnow. The trout appeared to be a little more sensitive with a 96-hour LC50 of 2,300 μg/l (Table 

1). The 96-hour LC50 for the fathead minnow tested at 14°C was 4,900 

μg/l and at 24°C the LC50 was 8,900 μg/l. The LC50 of 150,000 μg/l 

for the mosquitofish appears to be atypical but the result cannot be discounted. 

Ninety-six-hour LC50 values for the polychaete, Neanthes arenaceodentata, Pacific oyster, and the grass shrimp are 3,800, 199,000, and 2,350 

μg/l, respectively (Table 1). The 24-hour LC50 values for one fish and 

two saltwater shrimp species range from 2,400 to 2,600 μg/l (Table 6). 

*The reader is referred to the Guidelines for Deriving Water Quality Criteria for the Protection of Aquatic Life and Its Uses in order to better understand 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 toxicity as described in the Guidelines. 

B-1 
With the exception of the mosquitofish and the Pacific oyster, all 

LC50 and EC50 values, regardless of test method, fall within the narrow 

range of 2,300 to 8,900 μg/l 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 μg/l (Table 2). When this concentration 

is divided by the geometric mean LC50 value of 6,600 μg/l 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 vulqaris, occurred at a concentration of 33,000 μg/l (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). Bioconcentration 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 

Miscellaneous 

Soto, et 

of 5,000 (Table 5). 

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 

μg/l (Table 6). There was 50 percent mortality of coho salmon after an exposure of less than six hours to 5,600 μg/l (Holland, et al. 1960). 

B-2 
Saltwater species have been more extensively tested, probably the result of more interest in oil pollution. Berdugo et al. (1977) exposed the 

copepod, Eurytemora aff.inis, to a concentration of 1,000 pg/l and observed 

l 

effects on egg production and ingestion rate. The most significant data 

were produced by DiMichele and Taylor (1978). Gill hyperplasia in the mummichog was observed in 80 percent of the fish after a 15-day exposure to 2 

l&l; there was a 30 percent occurrence in the controls. All of the fish 

exposed to 20 ug/l demonstrated necrosis of the tastebuds, a change not observed in any of the controls. 

Summary 

The LCso and EC50 values for one freshwater invertebrate and two 

fish species are within the range of 2,300 to 8,900 ug/l. The LC50 for 

the mosquitofish is 150,000 pg/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 concentration of 850 pgfl. The resultant chronic value, 620 wg/l, provides an acutechronic ratio of 11. Freshwater algae appear to be less sensitive with 

effect concentrations of about 33,000 to 34,000 pg/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 LCSO values of 3,800 ,,g/l for 

a polychaete and 2,350 ug/l for the grass shrimp. There was an apparently 

atypical 48-hour value for the Pacific oyster of 199,000 pg/l. 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 ug/l. 

B-3 
CRITERIA 

The available data for naphthalene indicate that acute and chronic 

toxicity to freshwater aquatic life occur at concentrations as low as 2,300 

and 620 μg/l, 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 aquatic life occurs at concentrations as low as 2,350 μg/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 
SpOCleS 

Cladoceran, 

Daphnla magna 

Ralnbou trout, 

Saimo gairdneri 

Fathead minnow, 

Plmephales prcmelas 

Fathead mlnnow, 

Pimephales promeias 

Mosquitofish, 

Gambusla aff lnis 

Polychaete, 

Neanthes arenaceodentata 

Pacific oyster, 

Crassostrea gigas 

Grass shrimp, 

Paiaemonetes pug10 

Table 1. 

Method* 

s, u 

m, M 

m, M 

fl, M 

n, M 

s, u 

s, u 

s, H 

Acute values for naphthalena 

LC5O/ECXl species Aart* 

(IQ/ I 1 Value (w/l) 

FRESHWATER SF’ECIES 

8,570 8,570 

2,300 2,300 

4,900 

8,900 6,600 

15o,ocHl 150,DOo 

SALTWATER SPECIES 

3,800 3,BoO 

199,000 199,000 

2,350 2,350 

Ref erenco 

U.S. EPA, 1978 

DeGraeve, et al. 1980 

Dffiraeve, et at. 1980 

Dffiraeve, et al. 1980 

Wallen, et al. 1957 

Rossi 6 Neff, 1978 

LeGore, 1974 

Tatem, 1976 

* S = static, FT = f low-through, U = unmeasured, M = measured 

No Flnai Acute Values are calculable since the mininnrm data base requirements are not met. 

B-5 
Tablo 2. Chronic values for naphthalone (Wraovo, ot al. 1980) 

Chroalc 

Lllitr Vale0 

SprIes Mathod* era/t 1 WI/l) 

FRESHWATER SPECIES 

Fathead mlnnow, E-L 450- 620 

Plmephales pranelas 850 

l E-L = embryo-larval 

AcuteChronIc Ratio 

Species 

Chronic 

Value 

(w/l 1 

Acute 

Value 

(w/l 1 Ratio 

Fathead mlnnou, 

Plmephales prcmelas 

620 6,600 ii 

Geometric mean acute-chronic ratio = ii 

B-6 
NUf’bW4 

3 

2 

I 

3 

2 

1 

Table 3. Specla~ mean acute and cfwonlc values for nnphthalsne 

Speclms Mean species Mean 

Acute Va I ue* Chronic Value Acute-chrom I c 

Speclss fug/l) (pg/ I 1 Ratio*’ 

FRESHWATER SPECIES 

Mosquitof Ish, 

Gambusla aff lnis 

150,000 

Cladoceran, 

Oaphn la magna 

Fathead minnow, 

Pimephales promelas 

0,570 

6,600 620 11 

Ralnbow trout, 

Salmo galrdneri 

2,300 

SALTWATER SPECIES 

Paclfic oyster, 

Crassostrea gl gas 

Poiychaete, 

Neanthes arenacecdentata 

I99,GGO 

3,800 

Grass shrimp, 

Pa I aernonetes pug lo 

2,350 

* Rank from high concentration to low concentration by species mean acute value. 

fiaSae the Guidelines for derivation of this ratio. 

B-7 
Tablo 4. Plant values for naphthalone (Kwsr & HutchInson, 1975) 

Result 

Spocles Effect Jug/t 1 

FRESHWATER SPECIES 

A Iga, 

Chiorella vuigaris 

Extrapolated 

ccl I numbers 

48-hr EC50 

33,000 

B-8 
Table 5. Residues for wphthaleno Warrls, et al. 1977b) 

Bloconcentratlon Duretlm 

SpeCles Tlrsue Factor* (days) 

SALTWATER SPECIES 

CoPepW 

Eurytemora afflnls 

whole body 5,000 9 

l Dry weight to wet weight converslons. 

B-9 
Table 6. Other data for nphtha)eao 

Spector 

Alga, 

Chlsmydomonas angulosa 

A ha, 

Chlamydomonas angulosa 

Coho salmon, 

Oncorhynchus klsutch 

CoPewb 

Eurytemora afflnis 

Coww4 

Eurytemora affinls 

CoPe9od, 

Calanus helgoiandlcus 

Coww4 

Calanus helgolandlcus 

Blue mussel, 

Hytllus edulls 

Grass shrimp, 

Palaemonetes puglo 

Brown shr Imp, 

Penaeus aztecus 

-- 

Sheepshead minnow, 

Cypr I nodon var I egatus 

Owatlon 

24 hrs 

24 hrs 

d hrs 50% mortality 5,600 Hot land, et al. I%0 

0.16 days 

I day B ioconcentrat Ion 

factor = 50 

liarrls, et al. 1977b 

I day 6 locona3ntrat Ion 

factor = 60 

Harris, et al. 1977s 

4 hrs B loconcentrat ion 

factor = 44 

Lea, et al. i972b 

24 hrs LC50 2,600 Anderson, et a I. 1974 

24 hrs LC50 2,500 Anderson, et al. I974 

24 hrs LC50 2,400 Anderson, et al. 1974 

Ef fact 

FRESHWATER SPECIES 

Death of 61% 

of Eslls 

Loss of photosynthet Ic 

capacl ty 

SALTWATER SPECIES 

Reduct Ion in 

Ingest ion rate 

of IO% (P = 0.05) 

Reduction in egg 

product Ion by 83s 

(P - 0.05) 

Result 

LWQ/l) 

34,400 

iO$ 

saturation 

1,000 

1,000 

Rot wemce 

Soto, et a 1. i975a 

Soto, et al. 1975b 

Berdugo, et al. 1977 

Berdugo, et al. 1977 

B-10 
Table 6. UZoatinued) 

Species 

Mummlchog, 

Fundulus heteroclitus 

Duration 

15 days 

Effect 

Gl I I hyperplasla 

Mummlchog, 

Fundulus heteroclitus 

15 days Tastebud necrosis 

Sand goby, lhr Bloconcentratlon 

Glllichtus mltabllls factor = 63 

Sculpln, 

OIlgocottus maCUlOSUS 

3 hrs B loconcentrat Ion 

factor = 32 

Sand dab, 

Cltharlchtys stlgmaeus 

I hr Bloconcentration 

factor = 77 

Result 

(w/l 1 Reference 

2 DlMlchele 6 Taylor, 

1976 

20 DlMlchele 6 Taylor, 

1978 

Lee, et al. 1972a 

Lee, et al. 1972a 

Lee, et al. 1972a 

B-11 
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 reproduction of an estuarine planktonic copepod in laboratory cultures. Mar. Pollut. Bull. 8: 138. 

DeGraeve, G.M., et al. 1980. Effects of naphthalene and benzene on fathead 

minnows and rainbow trout. Submitted to Trans. Amer. Fish. Sot. 

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 Symposium 286. 

Harris, R.P., et al. 1977b. Accumulation of carbon-14-1-naphthalene by an 

oceanic and an estuarine copepod during long-term exposure to low-level concentrations. Mar. Biol. 42: 187. 

B-12 
Holland, GA., et al. 1960. Toxic effects of organic and inorganic pollutants 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 petroleum 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 hydrocarbon 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 hydrocarbons to the polychaete Neanthes arenaceodentata. Mar. Pollut. Bull. 

9: 220. 

Soto, C., et al. 1975a. Effect of naphthalene and aqueous crude oil extracts 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 extracts on the green flagellate Chlamydomonas angulosa. II. Photosynthesis 

and uptake and release of naphthalene. Can. Jour. Bot. 53: 118. 

B-13 
Tatem, H.E. 1976. Toxicity and physiological effects of oil and petroleum 

hydrocarbons on estuarine grass shrimp Palaemonetes pugio Holthuis. Ph.D. 

Thesis. Texas A dr 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. 684X4646. 

Wallen, I.E., et al. 1957. Toxicity to Gambusia affinis of certain pure 

chemicals in turbid waters. Sewage Ind. Wastes. 29: 695. 

B-14 
Mammalian Toxicology and Human Health Effects 

INTRODUCTION 

Naphthalene, C10H8, is an aromatic hydrocarbon with two orthocondensed 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 insecticides. In the manufacture of insecticides, 12.2 percent was used 

to make insecticides such as l-naphthyl-N-methylcarbamate (carbaryl). Eleven percent was used for the production of mothballs 

and 2-naphthol which is used as an intermediate in the manufacturing 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), alkylnaphthalenes (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 distillates originating from the high temperature coking of bituminous coal (Brown, et al. 1975; U.S. EPA, 1976). This coal tar naphthalene in its crude state contains impurities such as alkylnaphthalenes, alkylcoumarones, and thianaphthene. This latter impurity 

C-1 
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 environment are from industrial effluents and from oil spills. Industrial 

effluents have been found to have up to 32,000 μg/l naphthalene. 

The final effluents of sewage treatment plants receiving discharges 

from these facilities have been noted to have up to 22 μg/l naphthalene. Natural waters have been noted to have up to 2.0 μg/l of 

naphthalene while drinking water supplies have been found to have 

up to 1.4 μg/l naphthalene (U.S. EPA, Region XV, 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 compound in the tissues of various aquatic animals seem to be proportional 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 weigh ted 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 consumption 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 shellfish. Thus, the weighted average bioconcentration factor for naphthalene 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 smokers, naphthalene being identified as one of the polynuclear aromatic 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 μg/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 derma1 exposure. 

C-3 
TABLE 1 

Air Levels of Naphthalene 

Area Investigated Air Level (us/m31 

Vapor Particulate Reference 

Industrial: 

Naphthalene melt present 

Coke Oven 

Aluminum Reduction Plant 

1,600 - 1.1 x lo6 --- Robbins, 1951 

11.35 - 1,120 O-4.40 Bj$rseth, et ‘al. 1978a 

.72 - 311.3 .090-4.00 Bjarseth, et al. 1978b 

Providence, R.I. 0.0001 0.00025 Krstulovic, et al. 1977 

Kingston, R.I. 

Narragansett Bay, R.I. 

0.00003 0.00003 Krstulovic, et al. 1977 

0.00005 0.000003 Krstulovic, et al. 1977 

c-4 
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-S 
PHARMACOKINETICS 

Absorption, Distribution, and Excretion 

Little detailed' information is available on the absorption, 

distribution, or excretion of naphthalene in man or animals. Adequate 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 metabolite 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 naphthalene by skin application caused less experimental toxicity than 

when taken orally (Gaines, 1969). Dawson, et al. (19581, 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 toxicity 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 naphthalene 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 disappeared 18 days after exposure. 

Metabolism 

The metabolism of naphthalene in mammals has been extensively 

studied. Naphthalene is first metabolized by hepatic mixed function oxidases to the epoxide, naphthalene-1,2-oxide (Figure 1). 

This epoxide has the distinction of being the first arene oxide 

metabolite to have been isolated (Jerina, et al. 1970). Epox ide 

formation is an obligatory step. The epoxide can be enzymatically 

converted into the dihydrodiol, 1,2-dihydroxy-1,2-dihydronaphthalene 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 
8 

FIGURE 1 

Metabolism of Naphthalene. (1) Naphthalene; (2) naphthalene 

epoxide; (3) 1,2-dihydro-1,2-dihydroxynaphthalene (naphthalene 

diol); (41 1-naphthol; (5) N-acetyl-S-(1,2-dihydro-2-hydroxynaphthyl) cysteine; (6) 1,2-dihydroxynaphthalene; (7) 1,2-naphthoquinone (/-naphthoquinone); (8) 1-naphthyl sulphate; (9) l-naphthy1 glucuronide; (10) 2-hydroxy-1-naphthyl sulphate; (11) l-glucosiduronide of (3); (12) 2-naphthol. 

Source: Van Heyningen, 1979 

C-8 
The epoxide can also be converted spontaneously to l-naphthol 

or 2-naphthol by a keto tautomer intermediate (Boyd, et al. 1972). 

I-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 1. 

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 cysteinylglycine compound and then a cysteine conjugate prior to 

acetylation to the mercaptur ic acid, N-acetyl-S-{1,2-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 lnaphthyl mercaptur ic acid may be explained by a spontaneous dehydrogenation 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-dihydroxynaphthalene which in turn can be spontaneously oxidized to 

c-9 
Naphtha lene Hetabolites: Liver/D ile 

TADLE 3 

- 

Metaboli te 

--_____ 

-.- - 

Rabbit 

Found in: 

Rat 

kl 

Fish 

l-naphthol 2 3,4 . 5 

2-naphthol 2 3 

1-naphthyl glucosiduronic acid 3r4 5 

1-naphthyl mercapturic acid 3 5 

1,2-dihydro-1,2-dihydcoxy napthalene 2 3,4 5 

1,2-dihyro-2-hydroxy-1-naphthyl-glucosiduronic acid 3.4 5 

1,2-dihydro-1-hydroxy-2-naphthyl-glucosiduronic acid 3 

S-(1,2-dihydro-2-hydroxy-1-naphthyll-L-cysteine 3 

N-acetyl-S-/1,2-dihydro-2-hydroxy-L-naphthyl)-~-cysteine 3 

1,2-dihydroxy naphthalene 4 

1,2-naphthoquinone 4 

Naphthalene-1,2-oxide 2 

S-(1,2-dihydro-2-hydroxy-1-naphthyl)-glutathione 2 1,3 

S-11,2-dihydro-2-hydroxy-1-naphthylj-L-cysteinyl glycine 3 

(1,2-dihydro-2-hydroxy-l-naphthylb-sulfate 4 

2-hydroxy-l-naphthyl-glucosiduronic acid 3 

._-~~---.-__~---____-.-~-__ - -___~-______- - 

References: 1-Dooth, et al. 1960 cl-Bock, et al. 1976 

Z-Jerina, et al. 1970 5-Roubal, et al. 1978 

3-Boyland, et al. 1961 

c-10 
TABLE 4 

Naphthalane Hetabolitesc Ridney/Ur ine 

Hetabolite Rabbit 

Pound in: 

Guinea Pig Mice Rat k* an 

1-naphthol 1,2 7 7 7 8 

2-haphthol 1 7 7 7 8 

1-naphthyl sulfate k,7 7 7 7 

1-naphthyl glucosiduronic acid 1 

s-(1-naphthyll-L-cysteine 3 

1-naphthyl mercapturic acid 1 

1,2-dihydro-1,2-dihydroxy naphthalene 1.5.7 7 4,5,7 

1,2-dihydro-2-hydroxyrl-naphthyl-glucosiduronLc acid 1.2,6,7 7 

1,2-dihydro-1-hydroxy-2-naphthyl-glucosiduronic acid 2 * 

S-(1,2-dihydro-2-hydroxy-l-naphthyl)-L-cysteine 3 

N-acetyl-S-(1,2-dihydco-2-hydroxy-l-napthyl~-L-cysteine 1 1 1,3 

Z-hydroxy-1-naphthyl sulfate 1 

1-hydroxy-2-naphthyl sulfate 2 

1,2-dihydroxynapthalene 

1,2-naphthoquinone 8 

1,4-naphthoquinone 8 

ReEerences: 

-~ 

l- Boyland 6 ShS, 1958 I- Young, 1947 7- Corner 6 Young, 1954 

2- Sims, 1959 5- Booth 6 Boyland, 1949 8- Mackell, et al. 1951 

3- Booth, et al. 1960 6- Corner, et al. 1954 

C-11 
1,2-naphthoquinone with the concomitant release of hydrogen peroxide. 1,2-Naphthoquinone can then oxidize ascorbic acid, which is 

found in high concentrati’on 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 

ox idase, is induced by many carcinogenic polycyclic aromatic hydrocarbons. Alexandrov and Frayssinet (1973) found that the intraperitoneal 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 derivatives, 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 blindness eight or nine hours later. An examination a year later disclosed constricted visual fields associated with optic atrophy and 

c-12 
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 naphttialene, 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 cataracts in 8 of them with the following age distribution: 

Number of Number 

Age (years) workers with cataracts 

20-30 4 2 

30-40 5 3 

40-50 a 2 

SO-60 4 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 glutathione from the lens. Rees and Pirie (1967) reported that the 

metabolites of naphthalene released in the eye were general metabolic 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 
glu ta thione ; and that oxidized ascorbic acid easily enters the lens 

where it readily oxidizes reduced glutathione nonenzymatically. 

Van Heyningen and Piiie (1,967) reported that the oxidized ascorbic 

acid also oxidizes protein thiols, a mechanism that is normally 

prevented by reduced glutathione; that the oxidation of NADPH prevents the reduction of oxidized glutathione by glutathione reductase; and that 1,2-naphthoquinone quickly combines irreversibly 

with lens and eye proteins thereby losing its ability to oxidize as 

corbic acid. Pirie (1968) observed that oxidized ascorbic acid 

breaks down to oxalate which in turn precipitates as calcium oxalate 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 newborn infants (Cock, 1957; Schafer, 1951) after exposure to naphthalene 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 deficiency. The former defect was more prominent. Glucose-6-phosphate 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. Xn the 

c-l.4 
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 methemoglobin 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 deficiency, 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. Xn some forms of GGPD 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 received a smaller dose. Four of those treated were found to develop 

a hemolytic anemia, two associated with splenomegaly. He identified three of those affected-as being black. 

c-15 
Acute, Subacute , and Chronic Toxicity 

The acute lethality of naphthalene has been assessed by several routes in several-&pecies as shown in Table 5. The greater toxicity by an oral versus subcutaneous route might be due to species 

variation in susceptibility but might also indicate that naphthalene 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 intraperitoneally 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, I 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 
TABLE 5 

Tests of the Acute Toxicity of Naphthalene 

Test Animal Number Route LDsO (w/kg 1 Reference 

Mice 

Sherman rats 

male 

female 

-- Subcut. 

40 Orala 

40 Orala 

5,100 Irie, et al. 1973 

2,200 Gaines, 1969 

2,400 Gaines, 1969 

male 

female 

Rat 

Rat 

Rat 

10 Skinb 

10 Skinb 

-- Oral 

-- Oral 

-- Inhalation 

2,500 Gaines, 1969 

2,500 Gaines, 1969 

1,780 NIOSH, 1977 

9,430 Union Carbide Corp., 1968 

100 ppm x Union Carbide Corp., 1968 

8 hr. 

i Dissolved in peanut oil 

Dissolved in xylene 

c-17 
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 coagulative necrosis of the bronchiolar and bronchial epithelium at a dose 

of 600 mg/kg. Controls received sesame oil alone and no adverse effects 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/l and 10 percent growth inhibition at a concentration of 

12.8 mg/l. 

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 donors with naphthalene or its metabolites in various concentrations. 

HemolyFis 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-naphthoquinone, and 1,4-napthoquinone produced no hemolysis at 15 minutes after the injection: 1-naphthol, however, produced 6 percent 

C-18 
TABLE 6 

In vitro Hemolysis of Red Blood Cells Exposed to Naphthalene and its Metabolites* -- 

Compound 10 13.3 

Concentration (mg/l blood) 

20 40 100 

(Percent Hemolysis) 

200 1000 

1-napht'hol 2 6 14 46 53 65 74 

2-naphthol 0 0 3 11 32 48 60 

1,4-naphthoquinone 0 0 0 0 0 4 18 

1,2-naphthoquinone 0 0 0 0 0 41 12 

Naphthalene 0 0 0 0 0 0 0 

*Source: Mackell, et al., 1951 

c-19 
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 naphthalene 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 depression of reduced glutathione levels at concentrations of 5000 mg/l 

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 
Synergism and/or Antagonism 

There is little information on the synergistic or antagonistic 

effects of naphthaleqe. 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 mothproofing 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 marrow depression, estimated from her hematologic findings on admission two months after first becoming ill. No other cases of aplastic anemia have been described with either a naphthalene or paradichlorobenzene exposure either alone or in combination with another chemical. 

Teratogenicity 

Naphthalene or its metabolites can cross the placenta in sufficient amounts to cause fetal toxicity. Both Zinkham and Childs 

(1958) and Anziulewicz, et al. (1959) noted toxic effects in infants 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 evidence of retinal damage (Van der Hoeve, 1913). 

c-21 
Mutagenicity 

Naphthalene has been found to be nonmutagenic in several 

microsomal/bacterialiassay,systems as outlined in Table 7. Metabolites 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 cecum. 

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 carcinogen) prior to each injection. The naphthalene contained 0.07 

gram molecular weight impurities per 100 g (equivalent to 10 percent 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 
TABLE 7 

Mutagenicity of Naphthalene in various In Vitro Microsomal Assay Systems -- 

System Strain Result Reference 

Rat microsomes/ 

Salmonella typhimurium 

TAlOO 

TA1535 

TA1537 

TA98 

Negativea McCann, et at: 1975 

Negativea McCann, et al. 1975 

Negativea McCann, et al. 1975 

Negativea McCann, et al. 1975 

Mouse microsome/ 

Salmonella typhimuriumb 

Mouse microsome/ 

E. coli 

G46 

K12 

Negative Kraemer, et al. 1974 

Negative Kraemer, et al. 1974 

aLess than 0.09 revertants/nmol, Tested at 10, 100, 500, and 1000 ug/plate 

b Naphthalene-1,2-oxide used in the test system 

c-23 
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*a 

Number of Animals 

Other 

Treatment Total Survivors Lymphosarcoma Fibroadenoma Malignant Tumor 

Naph thalene 

in sesame oil 40 0 5 1 0 

Sesame oilb 40 4 1 1 0 

No treatment 101 0 (lifetime) 1 0 1 

*Source: Knake, 1956 

a34 naphthalene/sesame oil treated rats survived the initial treatment. 32 rats treated with 

sesame oil alone survived the initial 14 weeks of treatment. 

b 3.3 ml/kg/treatment 

C-24 
TABLE 9 

Incidence of Tumors in Inbred Black Mice Painted with 0.5% Naphthalene in Benzene 

or Benzene Alone 5 days/week for Life* 

Treatment 

Sarcoma Other 

Number Leukemia Lymphosarcoma (other) Malignancy bung Adenoma 

Naphthalene in 

Benzene 25 4a 1 0 1 3 

Benzene 21 0 1 1 0 1 

No Treatment 1227 5 3 1 44 0 

*Source: Knake, 1956 

a All lymphocytic leukemia 

C-25 
Druckrey and Schmahl (1955) used naphthalene as a vehicle for 

testing the carcinogenic effects of anthracene. In a preliminary 

study they looked at the potential carcinogenic effects of naphthalene 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 subcutaneously 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 bladder carcinoma in mice treated with various inert control substances 

including glass. 

Kennaway (1930) and Kennaway and Hieger (1930) tested the carcinogenicity 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 carcinomatous 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 lo 

Bladder Tumors in Mice with Naphthalene Bladder Implants* 

Substance 

# Mice Surviving 

to 30 weeks Carcinoma 

h* 

Adenoma/Papilloma 

Naph t!alene 23 1 0 

Inert Controls 

Magnesium stearate 

n-Hexadecanol 

n-Octadecanol 

41 1 1 

69 6 2 

50 6 7 

Smooth glass 67 3 -wRoughened glass 63 18 --- 

*Source: Boyland, et al., 1964 

C-27 
this manner. The alkyl-napthalenes which had shown positive activity in combination with benzo(a)pyrene for mouse skin tumors were 

shown to acceleratexin 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 metaphase 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/l (Table 11). 

C-28 
TABLE 11 

Carcinogenic Activity of Naphthalene with In vitro Test Systems -- 

Test System Dose (ug/Ub Result Reference 

Rat embryo cells/ 

Rauscher leukemia virus= 50 Negative Freeman, et al. 1973 

1,000 Negative Freeman, et hl. 1973 

5,000 Negative Freeman, et al. 1973 

10,000 Negative Freeman, et *al. 1973 

50,000 Negative Freeman, et al. 1973 

100,000 Negative Freeman, et al. 1973 

Mouse embryo cells/ 

AKR leukemia virusa 100 Negative Rhim, et al. 1974 

500 Negative Rhim, et al. 1974 

1,000 Negative Rhim, et al. 1974 

5,000 Negative Rhim, et al. 1974 

a In addition to transforming ability, treated cells injected into newborn rats or mice, 

respectively, without any evidence of tumorigenicity 

b Dissolved in acetone 

c-29 
Tonelli, et al. (1979) tested naphthalene in a marine mammary 

gland organ culture system, and were unable to demonstrate cell 

transformation at cpmpound levels up to 1,000 mg/l of culture 

medium. 

c-30 
CRITERION FORMULATION 

Existinq Guidelines and Standards 

The only exist&g U.S. standard for naphthalene is the Occupational Safety and Health Administration (OSHA) standard of 10 ppm 

(50 mg/m3) as a time-weighted average (39 FR 23540). This standard 

was adopted from the American Conference of Governmental Industrial 

Hygienists' 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 exposure value of 15 ppm (75 mg/m3). 

The maximum permissible concentration of naphthalene in fishery water bodies of the USSR is 4 pg/l (Mosevich, et al. 1976). 

Current Levels of Exposure 

Natural waters have been found to contain up to 2 ug/l of 

naphthalene while drinking water supplies have been found to contain up to 1.4 fig/l 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/m3 for coke oven workers (Bjarseth, et al. 1978a), and 0.31 

msh 3 for aluminum reduction plant workers (Bj#rseth, et al. 

1978b). No measurements of naphthalene have been reported for market 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 hl. 1974). The incidence of this deficiency 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 secondary 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 condition cleared rapidly and did not recur over a three year period 

of followup. 

C- 32 
TABLE 12 

Frequency of G6PD Deficiency in Populations* 

Population GGPD Deficiency (%) 

Northern European 

American black male 

American black female 

Brazilian black male 

Bantu male 

Sardinian 

Maltese 

Italian 

Greek 

Sephardic, Oriental or Kurdish Jews 

0.1 

13 

20 

8.2 

37 

14.35 

2.7 

0.4 

9.5 

250 

*Source: Wintrobe, et al., 1974 

c-33 
Basis and Derivation of Criteria 

All chronic toxicity studies using naphthalene have failed to 

demonstrate any carc&nogenic activity except for those performed by 

Knake (1956). This author found an excess occurrence of lymphosarcoma when naphthalene was given by the subcutaneous route to rats 

and of lymphocytic leukemia when naphthalene was chronically painted on the skin of mice using benzene as a solvent. However, the 

naphthalene used in this study was derived from coal tar and contained 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. Furthermore, 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/m3 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 containing naphthalene might also result in mucous membrane irritation. Until further information is available on the direct irritant 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 bronchiolar 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 compound, 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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