NOTE: Although the toxicity values presented in these toxicity profiles were correct at the time they were produced, these values are subject to change. Users should always refer to the Toxicity Value Database for the current toxicity values.
Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health and Safety Research Division, *, Oak Ridge, Tennessee.
Prepared for: Oak Ridge Reservation Environmental Restoration Program.
*Managed by Martin Marietta Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400.
Naphthalene (CAS Reg. No. 91-20-3), a white solid with a characteristic odor of mothballs, is a polycyclic aromatic hydrocarbon composed of two fused benzene rings. The principal end use of naphthalene is as a raw material for the production of phthalic anhydride. It is also used as an intermediate for synthetic resins, celluloid, lampblack, smokeless powder, solvents, and lubricants. Naphthalene is used directly as a moth repellant, insecticide, anthelmintic, and intestinal antiseptic (ATSDR, 1990; U.S. EPA, 1986).
Naphthalene can be absorbed by the oral, inhalation, and dermal routes of exposure and can cross the placenta in amounts sufficient to cause fetal toxicity. The most commonly observed effect of naphthalene toxicity following acute oral or inhalation exposure in humans is hemolytic anemia associated with decreased hemoglobin and hematocrit values, increased reticulocyte counts, presence of Heinz bodies, and increased serum bilirubin levels (ATSDR, 1990). Hemolytic anemia has been observed in an infant dermally exposed to naphthalene (Schafer, 1951) and in infants whose mothers were exposed to naphthalene during pregnancy (Anziulewicz et al., 1959; Zinkham and Childs, 1958). Infants and individuals having a congenital deficiency of erythrocyte glucose-6-phosphate dehydrogenase are especially susceptible to naphthalene-induced hemolytic anemia (Wintrobe et al., 1974).
Acute oral and subchronic inhalation exposure of humans to naphthalene has resulted in neurotoxic effects (confusion, lethargy, listlessness, vertigo), gastrointestinal distress, hepatic effects (jaundice, hepatomegaly, elevated serum enzyme levels), renal effects, and ocular effects (cataracts, optical atrophy). Cataracts have been reported in individuals occupationally exposed to naphthalene (Ghetti and Mariani, 1956) and in rabbits and rats exposed orally to naphthalene (Van Heyningen and Pirie, 1976; Fitzhugh and Buschke, 1949). A number of deaths have been reported following intentional ingestion of naphthalene-containing mothballs (ATSDR, 1990). The estimated lethal dose of naphthalene is 5-15 g for adults and 2-3 g for children. Naphthalene is a primary skin irritant and is acutely irritating to the eyes of humans (Sandmeyer, 1981).
Increased mortality, clinical signs of toxicity, kidney and thymus lesions, and signs of anemia were observed in rats treated by gavage with 400 mg/kg of naphthalene for 13 weeks (NTP, 1980a). No adverse effects occurred at 50 mg/kg. Transient clinical signs of toxicity were seen in mice exposed by gavage to 53 mg/kg for 13 weeks (NTP, 1980b). Subchronic oral exposure to 133 mg/kg/day for 90 days produced decreased spleen weights in female mice (Shopp et al., 1984). Reduced numbers of pups/litter were observed when naphthalene was administered orally to pregnant mice (Pflasterer et al., 1985). Negative results in a two-year feeding study with rats receiving 10-20 mg naphthalene/kg/day (Schmahl, 1955) and equivocal results in a mouse lung tumor bioassay (Adkins et al., 1986) suggest that naphthalene is not a potential carcinogen.
A subchronic and chronic oral reference dose (RfD) of 4E-2 mg/kg/day for naphthalene has been calculated by U.S. EPA (1992). These values are based on a NOEL of 50 mg/kg/day derived from a subchronic oral toxicity study with rats (NTP, 1980a). The RfD is currently under review by U.S. EPA and may be subject to change (U.S. EPA, 1992). A reference concentration (RfC) for chronic inhalation exposure has not been derived by U.S. EPA. Available cancer bioassays were insufficient to assess the carcinogenicity of naphthalene. Therefore, U.S. EPA (1991, 1992) has placed naphthalene in weight-of-evidence group D, not classifiable as to human carcinogenicity.
Naphthalene (CAS Reg. No. 91-20-3), also referred to as naphthene, naphthalin, tar camphor, aldocarbon, or mothballs, is a white solid that exhibits a typical mothball odor at ambient temperature. Having a molecular weight of 128.19, naphthalene is a polycyclic aromatic hydrocarbon composed of two fused benzene rings with the empirical formula of C10H8 (ATSDR, 1990; Budavari et al., 1989; Sandmeyer, 1981). It has a melting point of 80.5C, a boiling point of 218C (Weast et al., 1988), a vapor pressure of 0.082 mm Hg at 25C (Mackay et al., 1982), and a log octanol/water coefficient of 3.30 (Hansch and Leo, 1985). Naphthalene is almost insoluble in water, but is soluble in benzene, toluene, ether, and several other organic solvents (Budavari et al., 1989; Weast et al., 1988). Naphthalene is flammable; the vapors and dusts can produce explosive mixtures with air. It occurs in crude oil, from which it may be recovered directly as white flakes; it can also be isolated from cracked petroleum, coke-oven emissions, or from high-temperature carbonization of bituminous coal. Naphthalene is used as raw material and chemical intermediate in the chemical, plastics, and dye industries (Sandmeyer, 1981). The principal end use of naphthalene is for the manufacture of phthalic anhydride (ATSDR, 1990). It is also used as an intermediate for the manufacture of synthetic resins, celluloid, lampblack, smokeless powder, solvents, and lubricants. Naphthalene is used directly as a moth repellant, insecticide, anthelmintic, and intestinal antiseptic (U.S. EPA, 1986).
Most of the naphthalene entering the environment is released directly to the air from sources such as burning of fossil fuels and use of naphthalene-containing mothballs. Other sources include urban air pollution and cigarette smoke. Small amounts of naphthalene are released to the aqueous environment as a result of discharges from coal tar production and distillation processes. In the atmosphere, naphthalene undergoes a number of degradation processes including reaction with photochemically produced hydroxyl radicals. In natural waters and soils, volatilization and biodegradation are major removal processes. Naphthalene has a short half-life and is not thought to bioaccumulate over time (ATSDR, 1990).
Absorption of naphthalene by the oral, inhalation, and dermal routes can be inferred in humans from the systemic toxic effects of the compound. However, the rate and extent of absorption is not known. An oral study with rats suggests that the rate of absorption remains fairly constant at doses up to 200 mg/kg (Summer et al., 1979). The oral absorption of naphthalene is enhanced by solution in oil or ingestion in water rather than in food (U.S. EPA, 1986).
Data on the tissue distribution of naphthalene in humans are very limited. Naphthalene or its metabolites can cross the placenta in humans in amounts sufficient to cause fetal toxicity (U.S. EPA, 1986). Oral and intraperitoneal studies with animals showed that naphthalene distributes to several tissues. Following oral exposure, naphthalene was detected in the fat, liver, lungs, and heart of swine; in the liver and milk of dairy cows; and in the liver, kidneys, lungs, fat, and yolk of laying pullets (Eisele, 1985). Intraperitoneal injection of radiolabeled naphthalene resulted in covalent binding of radioactivity to tissue macromolecules in mice. The highest levels of binding occurred in the lung, liver, and kidneys, with levels reaching a maximum 2-4 hours after injection (Warren et al., 1982).
The metabolism of naphthalene is thought to proceed via formation of an epoxide, naphthalene 1,2-oxide. This epoxide then can undergo conversion to the dihydrodiol, can be conjugated with glutathione, or can spontaneously convert to 1- or 2-naphthol (U.S. EPA, 1986). After ingestion of naphthalene-containing mothballs, Mackell et al. (1951) identified the metabolites alpha-naphthol, beta-naphthol, 1,2-naphthoquinone, and 1,4-naphthoquinone in the urine of an 18 month-old child.
Major urinary metabolites of naphthalene identified in rats and rabbits following oral exposure and in mice, rats, and guinea pigs following intraperitoneal exposure included 1- and 2-naphthol, 1,2-dihydroxynaphthalene-1,2-diol, 1-naphthyl sulfuric acid, and with the exception of guinea pigs, 1-naphthyl glucuronic acid (Corner and Young, 1954). Although glutathione conjugation of naphthalene is a major metabolic pathway for rats as evidenced by urinary excretion of thioethers (Summer et al., 1979), metabolism of naphthalene to thioethers was not demonstrated in rhesus monkeys or chimpanzees (Rozman et al., 1982; Summer et al., 1979). In the eyes of rodents, the 1,2-naphthoquinone metabolite has been shown to bind irreversibly to lens protein and amino acids or to undergo conjugation with glutathione (U.S. EPA, 1986).
Naphthol was found in the urine of patients four days after naphthalene ingestion; smaller amounts were detected at five days and none thereafter (Zuelzer and Apt, 1949). The urine of an 18-month-old child contained alpha-naphthol, beta-naphthol, 1,2-naphthoquinone, and 1,4-naphthoquinone, but no naphthalene approximately nine days after ingestion of naphthalene. With the exception of 1,4-naphthoquinone, these metabolites were still detected on day 13 but not on day 17 following exposure (Mackell et al., 1951).
Following oral administration of radiolabeled naphthalene to rats, 77-93% of the radioactivity was recovered in urine and 6-7% in feces within 24 hours (Bakke et al., 1985). Administration of single oral doses of naphthalene (up to 200 mg/kg) to rats resulted in a dose-related increase in the 24-hour urinary excretion of thioethers (Summer et al., 1979). However, rhesus monkeys and chimpanzees treated orally with naphthalene did not excrete thioethers in urine, suggesting that glutathione conjugation of naphthalene may not occur to any great extent in nonhuman primates (Rozman et al., 1982; Summer et al., 1979).
Although ingestion of naphthalene-containing mothballs has resulted in no ill effects in some cases described (Sandmeyer, 1981), a number of adverse effects have been reported in others. The most commonly observed effect after accidental or intentional ingestion of naphthalene is hemolytic anemia, associated with decreased hemoglobin and hematocrit values, increased reticulocyte counts, presence of Heinz bodies, and increased serum bilirubin levels. Individuals having a congenital deficiency of erythrocyte glucose-6-phosphate dehydrogenase (G6PDH) are especially susceptible to hemolytic anemia from exposure to naphthalene. G6PDH-deficiency is rare in caucasians, but ranges from 20% in blacks to 50% in some Jewish populations. Infants also appear to be more sensitive to the effects of naphthalene than adults (ATSDR, 1990; U.S EPA, 1983; Wintrobe et al., 1974).
Other effects resulting from acute oral exposure to naphthalene include gastrointestinal disorders (nausea, vomiting, abdominal pain, and diarrhea); renal effects (increased creatinine and blood urea nitrogen, hematuria, tubular necrosis, and renal failure); neurological effects (confusion, listlessness, lethargy, vertigo, muscle twitching, convulsions, decreased responses to painful stimuli, cerebral edema, and coma); hepatic effects (jaundice, hepatomegaly, and elevated serum enzyme levels); and ocular effects (restricted visual fields, optic atrophy, and bilateral cataracts). Symptoms of naphthalene poisoning may not appear for several hours or days following ingestion. A number of deaths have been reported following intentional ingestion of naphthalene-containing mothballs (ATSDR, 1990). The estimated lethal dose of naphthalene is 5-15 g for adults and 2-3 g for children (Sandmeyer, 1981).
Oral LD50 values for male and female rats are 2200 and 2400 mg/kg, respectively (Gaines, 1969), and 533 and 710 mg/kg, for male and female mice, respectively (Shopp et al., 1984). One dog administered a single 1525-mg/kg/day dose of naphthalene in food developed hemolytic anemia (Zuelzer and Apt, 1949).
Fifty cases of poisoning from repeated ingestion of a naphthalene-isopropyl alcohol "cocktail" have been recorded (Sandmeyer, 1981). The symptoms, resembling those of ethanol intoxication, consisted of tremors, restlessness, extreme apprehension, and hallucinations. The effects subsided within a few days.
In a subchronic oral toxicity study, 10 male and 10 female F344 rats were treated by gavage with naphthalene in corn oil at doses of 0, 25, 50, 100, 200, or 400 mg/kg, 5 days/week for 13 weeks (NTP, 1980a). At 400 mg/kg, two males died and rats of both sexes had diarrhea, lethargy, hunched posture, and rough hair coats. Lymphoid depletion of the thymus occurred in females and slight changes in several hematological parameters suggestive of anemia occurred in males and females receiving 400 mg/kg. A >10% decrease in body weight gain was observed in males at 200 mg/kg and in females at 100 mg/kg. Renal lesions consisting of focal cortical lymphocyte infiltration and tubular degeneration were seen in some males at 200 mg/kg. No signs of toxicity were observed at 50 mg/kg. A similar study was performed with B6C3F1 mice that were treated by gavage with naphthalene in corn oil with 0, 12.5, 25, 50, 100, or 200 mg/kg, 5 days/week for 13 weeks (NTP, 1980b). Frank, but transient signs of toxicity (lethargy, rough hair coats, and decreased food consumption) occurred only at 200 mg/kg, the highest dose tested.
Shopp et al. (1984) administered naphthalene in corn oil to male and female CD-1 mice at doses of 0, 5.3, 53, or 133 mg/kg/day for 90 consecutive days. Survival, body weights, serum enzyme or electrolyte levels, and immunological parameters were not affected by naphthalene treatment. Females treated with 133 mg/kg/day exhibited reduced absolute and relative spleen weights. A dose-related decrease of hepatic hydrocarbon hydroxylase activity was observed in both sexes. Rao and Pandya (1981) observed increased liver weights and modest increases in aniline hydroxylase and lipid peroxidase activity in tissues in male rats treated with 1000 mg/kg for 10 days.
Slight cataracts were seen in weanling rats exposed to 2% naphthalene in the diet for 60 days (Fitzhugh and Buschke, 1949). Cataracts also developed in rabbits administered 1 g naphthalene/kg/day by gavage for 28 days, with degeneration of the retina occurring within the first few days of treatment (Van Heyningen and Pirie, 1976).
Information on the chronic oral toxicity of naphthalene in humans was not available.
Schmahl (1955) administered naphthalene in the diet to BDI and BDII rats at a dose of 10-20 mg/rat/day for 600 days (treatment was stopped when the total dose was 10 g/rat). There were no treatment-related effects on survival or histopathology.
Ingestion of naphthalene as mothballs (Anziulewicz et al., 1959) or ingestion and "sniffing" of mothballs (Zinkham and Childs, 1958) by pregnant women during the last trimester of pregnancy has resulted in hemolytic anemia in their infants. The mothers were also affected, but not as severely.
Pflasterer et al. (1985) administered naphthalene to 50 mated CD-1 mice in corn oil by gavage at a dose of 300 mg/kg/day on days 7-14 of gestation. Treatment was associated with increased mortality and reduced body weight gain in the dams and in a reduced number of live young at birth. Matorova and Chetverikova (1981) reported no visible or microscopic anomalies after intragastric administration of 0.075 mg/kg of naphthalene to pregnant rats, but embryonic and preimplantation mortality was significantly higher and subcutaneous hematomas on the spine and extremities of fetuses were observed at 0.15 mg/kg.
ORAL RfDs: 4E-2 mg/kg/day (U.S. EPA, 1992)
NOEL: 50 mg/kg/day
PRINCIPAL STUDY: NTP, 1982a
COMMENTS: The same study applies to the subchronic and chronic RfD (U.S. EPA, 1992).
ORAL RfD: 4E-2 mg/kg/day (U.S. EPA, 1992)
UNCERTAINTY FACTOR: 1000
NOEL: 50 mg/kg/day
PRINCIPAL STUDY: NTP, 1980a
COMMENTS: The RfD is based on a subchronic gavage study with rats. The uncertainty factor includes a factor of 10 for interspecies extrapolation, 10 to protect sensitive subpopulations, and 10 for use of a subchronic study. The RfD for naphthalene is currently under review and may be subject to change (U.S. EPA, 1991, 1992).
Acute hemolytic anemia, jaundice, high serum bilirubin levels, presence of Heinz bodies, and fragmentation of red blood cells were reported in 21 newborn infants exposed to naphthalene vapors from clothes or blankets that were stored in or near the infants' rooms (Valaes et al., 1963). Because the clothes were not worn next to the skin, the investigators assumed that inhalation was the primary route of exposure.
Rats exposed to 78 ppm naphthalene for 4 hours exhibited no clinical signs of toxicity during or 14 days after exposure (Fait and Nachreiner, 1985).
Eight of 21 workers developed cataracts following exposure to naphthalene for up to five years in a plant manufacturing dye intermediate. Because most of the workers were <50 years old, it is unlikely that they would have developed cataracts spontaneously (Ghetti and Mariani, 1956). In an early study, van der Hoeve (1906) reported cataracts and retinal hemorrhage in a worker using powdered naphthalene, and chorioretinitis in one eye in a coworker. Inhalation was presumed to be the major route of exposure, although exposure also may have occurred by contact of naphthalene vapor with the eyes, inadvertent ingestion, or by touching of the eyes with contaminated hands.
Vomiting, abdominal pain, nausea, headache, malaise, confusion, anemia, jaundice, and renal disease (unspecified) were effects reported in several individuals exposed to a large number of naphthalene-containing mothballs (an estimated 300-500) distributed throughout their homes (Linick, 1983). The effects were reversed after the mothballs were removed. The measured air concentration in one of the homes was 20 ppb, but this concentration could have been higher when the mothballs were fresh.
Information on the subchronic inhalation toxicity of naphthalene in animals was not available.
Information on the chronic inhalation toxicity of naphthalene in humans or animals was not available.
Information on the developmental and reproductive toxicity of naphthalene following inhalation exposure in humans or animals was not available.
A reference concentration (RfC) for inhalation exposure to naphthalene has not been derived (U.S. EPA, 1991, 1992).
Naphthalene is a primary irritant upon direct skin contact and may be acutely irritating to the eyes. Diapers and clothing stored with mothballs have caused skin rashes in infants (Sandmeyer, 1981). A lethal case of hemolytic anemia in an infant exposed to mothball-treated diapers was reported by Schafer (1951). Jaundice and cyanosis were observed within two days. Because the baby's skin was rubbed daily with oil, it was suggested that the oil might have enhanced the systemic absorption and resulting toxic effects of naphthalene.
No deaths occurred within a 14-day observation period following application of 2500 mg/kg of naphthalene to the skin of rats (Gaines, 1969). Mild dermal irritation was seen in rabbits when naphthalene was directly applied to the skin at 500 mg/site for 4 hours (PRI, 1985a). Instillation of 0.1 mg naphthalene/eye produced mild ocular irritation in rabbits (PRI, 1985b). The effects in both of the rabbit studies were reversible within seven days after exposure.
Repeated exposure to naphthalene vapor or dust has resulted in corneal ulceration and cataracts (Sandmeyer, 1981).
Information on the subchronic toxicity of naphthalene by other routes of exposure in animals was not available.
Information on the chronic toxicity of naphthalene by other routes of exposure in humans or animals was not available.
Information on the developmental or reproductive toxicity of naphthalene in humans or animals by other routes of exposure was not available.
1. Blood: Hemolytic anemia associated with decreased hemoglobin and hematocrit values, increased reticulocyte counts, Heinz bodies, and bilirubin levels is the most commonly observed effect in humans following acute exposure to naphthalene. Hematological changes indicative of anemia were observed in animals following subchronic exposure.
2. Gastrointestinal tract: Nausea, vomiting, abdominal pain, and diarrhea has been reported in humans following acute exposure to naphthalene.
3. Nervous system: Confusion, listlessness and lethargy, vertigo, muscle twitching, convulsions, decreased responses to painful stimuli, coma, and cerebral edema have been reported in humans following acute exposure to naphthalene. Some effects may be secondary to hemolysis.
4. Liver: Jaundice, enlarged liver, and increased serum enzyme activity have been reported in humans following acute exposure to naphthalene. Increased liver weight and increased liver enzyme activity have been reported in animals following subchronic exposure to naphthalene.
5. Kidneys: Increased creatinine and blood urea nitrogen levels, proteinuria and hemoglobinuria, anuria, and tubular necrosis have been reported in humans following acute exposure to naphthalene. Some effects may be secondary to hemolysis. Cortical lymphocyte infiltration and tubular degeneration have been reported in animals following subchronic exposure.
6. Eyes: Restricted visual fields, optic atrophy, and cataracts have been reported following acute exposure in humans. Cataracts have been reported in animals following subchronic exposure to naphthalene.
7. Reproduction: Hemolytic anemia has been reported in infants whose mothers were exposed to naphthalene during pregnancy. Decreased number of live pups, embryonic mortality, preimplantation losses, and subcutaneous hematomas in fetuses have been reported in animals following oral exposure to naphthalene during gestation.
1. Spleen: Reduced spleen weight has been reported in animals following subchronic exposure to naphthalene.
2. Thymus: Lymphoid depletion of the thymus has been reported in animals following subchronic exposure.
Although inhalation was considered the primary route of exposure to naphthalene in the cited studies, dermal/ocular exposure and inadvertent ingestion may also have occurred. Thus, it is not always possible to attribute the observed effects to a specific route of exposure.
1. Blood: Acute hemolytic anemia, high serum bilirubin levels, Heinz bodies, and fragmentation of erythrocytes have been reported in infants exposed to naphthalene vapors from blankets or clothes that were stored in or near the infants' room. Anemia occurred in individuals exposed to large numbers of naphthalene-containing mothballs in their homes.
2. Eyes: Occupational exposure to naphthalene has been associated with cataracts, retinal hemorrhage, and chorioretinitis. Also reported was corneal ulceration.
3. Gastrointestinal tract: Vomiting and abdominal pain has been reported in individuals exposed to large numbers of naphthalene-containing mothballs in their homes.
4. Nervous system: Nausea, headache, malaise, and confusion has been reported in individuals exposed to large numbers of naphthalene-containing mothballs in their homes.
5. Liver: Jaundice was reported in individuals exposed to large numbers of naphthalene-containing mothballs in their homes.
6. Kidneys: Renal disease (not specified) was reported in individuals exposed to large numbers of naphthalene-containing mothballs in their homes.
No other target organs following inhalation exposure were identified.
1. Blood: Dermal contact with naphthalene has resulted in hemolytic anemia in an infant.
2. Skin: Upon direct skin contact, naphthalene is a primary skin irritant in humans. It is acutely irritating to the eyes of humans. In animals, naphthalene is a mild skin and eye irritant.
Additional target organs by other routes of exposure to naphthalene were not identified.
Information on the carcinogenicity of naphthalene in humans following oral exposure was not available.
No carcinogenic responses were reported in BDI and BDII rats exposed daily to 10-20 mg of naphthalene in the diet for 600 days. Treatment was stopped when the total dose was 10 g/rat (Schmahl, 1955).
Information on the carcinogenicity of naphthalene in humans following inhalation exposure was not available.
In a short-term pulmonary tumor bioassay, Adkins et al. (1986) exposed female A/J mice to 10 or 30 ppm naphthalene, 6 hours/day, 5 days/week for 6 months. Exposure to naphthalene did not cause any significant change in the frequency of lung adenomas, but did show a significant increase in tumor incidence. The results of the study are equivocal, because the incidence of lung tumors in the control group was significantly lower than the incidence observed in several other concurrently conducted studies.
Information on the carcinogenicity of naphthalene in humans by other routes of exposure was not available.
No carcinogenic responses were reported in BDI and BDII rats that received intraperitoneal injections of naphthalene (20 mg/rat) once weekly for 40 weeks (Schmahl, 1955). Naphthalene had an inhibitory effect on the induction of skin tumors in mice when the compound was applied dermally in combination with benzo[a]pyrene (Schmeltz et al., 1978).
Classification D -- Not classifiable as to human carcinogenicity (U.S. EPA, 1991, 1992)
Basis -- Based on no human data and inadequate data from animal bioassays.
Data were insufficient to derive carcinogenicity slope factors for naphthalene.
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