Toxicity Profiles
Formal Toxicity Summary for PHENANTHRENE
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.
- EXECUTIVE SUMMARY
- 1. INTRODUCTION
- 2. METABOLISM AND DISPOSITION
- 1. INTRODUCTION
- 2.1 ABSORPTION 2.2 DISTRIBUTION 2.3 METABOLISM 2.4 EXCRETION
- 3. NONCARCINOGENIC HEALTH EFFECTS
- 3.1 ORAL EXPOSURES 3.2 INHALATION EXPOSURES 3.3 OTHER ROUTES OF EXPOSURE 3.4 TARGET ORGANS/CRITICAL EFFECTS
- 4. CARCINOGENICITY
- 4.1 ORAL EXPOSURES 4.2 INHALATION EXPOSURES 4.3 OTHER ROUTES OF EXPOSURE 4.4 EPA WEIGHT-OF-EVIDENCE 4.5 CARCINOGENICITY SLOPE FACTORS
- 5. REFERENCES
Prepared by: Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental, Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*, 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.
EXECUTIVE SUMMARY
Phenanthrene is a polycyclic aromatic hydrocarbon (PAH) that can be derived from coal tar. Currently, there is no commercial production or use of this compound (U.S. EPA, 1987). Phenanthrene is ubiquitous in the environment as a product of incomplete combustion of fossil fuels and wood and has been identified in ambient air, surface and drinking water, and in foods (U.S. EPA, 1988; IARC, 1983).
Phenanthrene is absorbed following oral and dermal exposure (Storer et al., 1984; Chang, 1943). Data from structurally related PAHs suggest that phenanthrene would be absorbed from the lungs (U.S. EPA, 1987). Metabolites of phenanthrene identified in in vivo and in vitro studies indicate that metabolism proceeds by epoxidation at the 1-2, 3-4, and 9-10 carbons, with dihydrodiols as the primary metabolites (Nordqvist et al., 1981; Chaturapit and Holder, 1978; Sims, 1970; Boyland and Sims, 1962; Boyland and Wolf, 1950).
Although a large body of literature exists on the toxicity and carcinogenicity of PAHs, primarily benzo[a]pyrene, toxicity data for phenanthrene are very limited. No human data were available that addressed the toxicity of phenanthrene. Single intraperitoneal injections of phenanthrene produced slight hepatotoxicity in rats (Yoshikawa et al., 1985). Data regarding the subchronic, chronic, developmental, or reproductive toxicity in experimental animals by any route of exposure could not be located in the available literature.
Data were insufficient to derive an oral reference dose (RfD) or inhalation reference concentration (RfC) for phenanthrene (U.S. EPA, 1988). The chemical is not currently listed in IRIS or HEAST (U.S. EPA, 1993a,b).
No inhalation bioassays were available to assess the carcinogenicity of phenanthrene. A single oral dose of phenanthrene did not induce mammary tumors in rats (Huggins and Yang, 1962) and a single subcutaneous injection did not result in treatment-related increases in tumor incidence in mice (Steiner, 1955). Neonate mice administered intraperitoneal or subcutaneous injections of phenanthrene also did not develop tumors (Buening et al., 1979). No skin tumors were reported in two skin painting assays with mice (Roe and Grant, 1964; Kennaway, 1924). Phenanthrene was also tested in several mouse skin initiation-promotion assays. It was active as an initiator in one study (Scribner, 1973), inactive as an initiator in four others (LaVoie et al., 1981; Wood et al., 1979; Roe, 1962; Salaman and Roe, 1956), and inactive as a promoter in one study (Roe and Grant, 1964).
Based on no human data and inadequate data from animal bioassays, U.S. EPA (1993a, 1987) has placed phenanthrene in weight-of-evidence group D, not classifiable as to human carcinogenicity.
1. INTRODUCTION
Phenanthrene (CAS Reg. No. 85-01-8), also known as phenanthrin, is a polycyclic aromatic hydrocarbon (PAH) with three aromatic rings. It has a chemical formula of C14H10, a molecular weight of 178.22, and exists as a colorless crystalline solid (Budavari et al., 1989; U.S. EPA, 1987). It has a melting point of 100C, a boiling point of 340C, a density of 1.179 at 25C (Budavari et al., 1989), and a vapor pressure of 9.6x10-4 torr (25) (Mabey et al., 1982). Phenanthrene is almost insoluble in water (1-1.6 mg/L), but is soluble in glacial acetic acid and a number of organic solvents including ethanol, benzene, carbon disulfide, carbon tetrachloride, diethyl ether, and toluene (Budavari et al., 1989). Phenanthrene has a log octanol/water partition coefficient of 4.45-4.57 (U.S. EPA, 1987).
Phenanthrene can be produced by fractional distillation of high-boiling coal tar oil. According to U.S. EPA (1987), there is no current commercial production of phenanthrene in the United States. Phenanthrene can be used in the manufacture of dyestuffs, explosives, drugs, in the synthesis of phenanthrenequinone, and in biochemical research (Sax and Lewis, 1987). A derivative, cyclopentenophenanthrene, has been used as a starting material for synthesizing bile acids, cholesterol, and other steroids (IARC, 1983).
Phenanthrene occurs in fossil fuels and is present in products of incomplete combustion. Some of the known sources of phenanthrene in the atmosphere are vehicular emissions, coal and oil burning, wood combustion, coke plants, aluminum plants, iron and steel works, foundries, municipal incinerators, synfuel plants, and oil shale plants (U.S. EPA, 1987). It is widely distributed in the aquatic environment and has been identified in surface water, tap water, wastewater, and dried lake sediments. It has also been identified in seafood collected from contaminated waters and in smoked and charcoal-broiled foods (U.S. EPA, 1988; IARC, 1983). Phenanthrene is one of a number of PAHs on EPA's priority pollutant list (ATSDR, 1990). Although a large body of literature exists on the toxicity and carcinogenicity of other PAHs, primarily benzo[a]pyrene, toxicity data for phenanthrene are limited.
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
Data regarding the gastrointestinal or pulmonary absorption of phenanthrene in humans were not available. However, data from structurally related PAHs suggest that phenanthrene would be absorbed readily from the gastrointestinal tract and lungs. PAHs, in general, are highly lipid-soluble and can pass across epithelial membranes (U.S. EPA, 1987). Chang (1943) reported that absorption of phenanthrene by rats was nearly complete when the compound was administered in the diet or as a suspension in starch. To study the role of bile in the intestinal absorption of PAHs, Rahman et al. (1986) administered phenanthrene to rats with bile duct and duodenal catheters, with or without exogenous bile. After 24 hours, the efficiency of phenanthrene absorption without bile (as a percentage of absorption with bile) was 96.7%, showing that absorption was not dependent on the presence of bile in the intestinal lumen.
The presence of phenanthrene in the blood of humans following dermal application of 2% crude coal tar on two consecutive days provides evidence of percutaneous absorption of phenanthrene (Storer et al., 1984).
2.2. DISTRIBUTION
Very limited data were available concerning the distribution of phenanthrene in tissues of humans or animals. Phenanthrene was detected in the blood of humans following topical applications of 2% crude coal tar on two consecutive days (Storer et al., 1984). Although many PAHs accumulate in body fat, Bock and Dao (1961) found little phenanthrene in the perirenal and mammary fat of rats administered the compound by gavage 24 hours earlier.
2.3. METABOLISM
In vivo and in vitro studies indicate that metabolism proceeds via epoxidation at the 1-2, 3-4, and 9-10 carbons, with dihydrodiols as primary metabolites of which the 9,10-dihydrodiol is the major component. The 9-10-, 1,2-, and 3,4-dihydrodiols of phenanthrene were identified unaltered or as glucuronic acid conjugates in the urine of rats and rabbits administered intraperitoneal injections of phenanthrene (Boyland and Sims, 1962; Boyland and Wolf, 1950). Also identified were the glucuronic acid conjugates of 1-, 2-, 3-, and 4-hydroxyphenanthrene, 1,2-dihydroxyphenanthrene, and 3,4-dihydroxyphenanthrene (Boyland and Sims, 1962). In vitro studies with guinea pig, rat, and mouse liver preparations also identified the 9-10-, 1,2-, and 3,4-dihydrodiols. Further oxidative metabolism to the 9,10-oxide and 1,2-diol-3,4-epoxide of phenanthrene has also been reported (Nordqvist et al., 1981; Chaturapit and Holder, 1978; Sims, 1970).
2.4. EXCRETION
As described in Section 2.3., metabolites of phenanthrene have been identified in the urine of intraperitoneally treated rats and rabbits. Additional data concerning the excretion of phenanthrene was not available.
3. NONCARCINOGENIC HEALTH EFFECTS
3.1. ORAL EXPOSURES
3.1.1. Acute Toxicity
3.1.1.1. Human
Information on the acute oral toxicity of phenanthrene in humans was not available.
3.1.1.2. Animal
Simmon et al. (1979) reported an oral LD50 of 750 mg/kg for mice. Single doses of 100 mg/kg/day of phenanthrene administered by gavage for 4 days suppressed carboxylestrase activity in the intestinal mucosa of rats, but did not produce other signs of gastrointestinal toxicity. Phenanthrene had no effect on hepatic or extrahepatic carboxylesterase activities (Nousiainen et al., 1984).
3.1.2. Subchronic Toxicity
Information on the subchronic oral toxicity of phenanthrene in humans or animals was not available.
3.1.3. Chronic Toxicity
Information on the chronic oral toxicity of phenanthrene in humans or animals was not available.
3.1.4. Developmental and Reproductive Toxicity
Information on the developmental and reproductive toxicity of phenanthrene in humans or animals following oral exposure was not available.
3.1.5. Reference Dose
Data were insufficient to derive a subchronic or chronic oral reference dose (RfD) for phenanthrene (U.S. EPA, 1993a,b).
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
Information on the acute toxicity of phenanthrene in humans or animals following inhalation exposure was not available.
3.2.2. Subchronic Toxicity
Information on the subchronic toxicity of phenanthrene in humans or animals following inhalation exposure was not available.
3.2.3. Chronic Toxicity
Information on the chronic toxicity of phenanthrene in humans or animals following inhalation exposure was not available.
3.2.4. Developmental and Reproductive Toxicity
Information on the developmental and reproductive toxicity of phenanthrene in humans or animals following inhalation exposure was not available.
3.2.5. Reference Concentration
Data were insufficient to derive a subchronic or chronic inhalation reference concentration (RfC) for phenanthrene (U.S. EPA, 1993a,b).
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Phenanthrene can cause photosensitization of the skin (Budavari et al., 1989).
3.3.1.2. Animal
For mice, the intravenous LD50 for phenanthrene is 56 mg/kg (RTECS, 1993) and the intraperitoneal LD50 is 700 mg/kg (Salamone, 1981).
A single intraperitoneal (i.p.) injection of 150 mg/kg of phenanthrene produced liver congestion in rats; a distinct lobular pattern was seen after 24 and 72 hours (Yoshikawa et al., 1985). Small but significant increases in serum aspartate aminotransferase and gamma-glutamyl transpeptidase were seen 24, but not 72 hours after treatment.
3.3.2. Subchronic Toxicity
Information on the subchronic toxicity of phenanthrene by other routes of exposure in humans or animals was not available.
3.3.3. Chronic Toxicity
Information on the chronic toxicity of phenanthrene by other routes of exposure in humans or animals was not available.
3.3.4. Developmental and Reproductive Toxicity
Information on the developmental or reproductive toxicity of phenanthrene by other routes of exposure in humans or animals was not available.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
Information on target organs for oral exposure to phenanthrene was not available.
3.4.2. Inhalation Exposures
Information on target organs for inhalation exposure to phenanthrene was not available.
3.4.3. Other Routes of Exposure
Skin: Phenanthrene can cause photosensitization.
Liver: A single i.p. injection produced liver changes in rats.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
Information on the carcinogenicity of phenanthrene in humans following oral exposure was not available.
4.1.2. Animal
In a comparative study of mammary tumor induction, single oral doses of 200 mg phenanthrene in sesame oil administered by gavage to female Sprague-Dawley rats did not induce tumors 60 days following treatment (Huggins and Yang, 1962). Tissues other than the mammary gland were not examined.
4.2. INHALATION EXPOSURES
Information on the carcinogenicity of phenanthrene in humans or animals following inhalation exposure was not available.
4.3. OTHER ROUTES OF EXPOSURE
4.3.1. Human
Information on the carcinogenicity of phenanthrene in humans by other routes of exposure was not available.
4.3.2. Animal
Complete carcinogenic activity was not shown in two skin painting assays with mice. No tumors were seen in mice treated with a solution of phenanthrene in benzene (dose and frequency of treatment not specified) for a period of nine months (Kennaway, 1924). Dermal application of 5% phenanthrene (solvent not reported), 3 times weekly for one year, also failed to induce skin tumors in mice (Roe and Grant, 1964).
Phenanthrene has also been tested in mouse skin initiation-promotion assays with several strains of mice. Phenanthrene was active as a tumor initiator in only one study in which tetradecanoylphorbol acetate (TPA) was used as a promoter (LaVoie et al., 1981), but was inactive in two other studies (Wood et al., 1979; Scribner, 1973). The compound did not exhibit initiating activity when croton oil (Salaman and Roe, 1956; Roe, 1962) or benzo[a]pyrene and croton oil were used as promoters (Roe and Grant, 1964). Phenanthrene was also inactive as a promoter following initiation by benzo[a]pyrene (Roe and Grant, 1964).
A single dose of 40 g phenanthrene administered by subcutaneous injection did not increase the tumor incidence in neonatal mice compared with controls (Grant and Roe, 1963). Intraperitoneal injections of phenanthrene in dimethyl sulfoxide (DMSO) at a total dose 0.25 mg on days 1, 8, and 15 after birth did not produce a statistically significant increase in tumors in newborn Swiss-Webster mice (Buening et al., 1979). Of 35 phenanthrene-treated mice still alive at week 42, 17% displayed pulmonary adenomas compared with 15% of DMSO-treated controls. Experiments involving a single subcutaneous injection of 5 mg phenanthrene in tricaprylin did not produce tumors in C57BL mice (Steiner, 1955).
Although phenanthrene is metabolized to reactive diol epoxides, which have been shown to be weakly mutagenic in some bacterial and mammalian cell assays (Wood et al., 1979), in vivo studies with the 1,2-, 3,4-, and 9,10-dihydrodiol metabolites did not show tumor-initiating activity in mouse skin-painting assays (Wood et al., 1979). Injected into newborn mice, the 1,2-diol-3,4-epoxides of phenanthrene did not produce lung tumors (Buening et al., 1979).
Induction of injection-site sarcomas in C57B1 mice by dibenz[a,h]anthracene (in ethyl laurate) was inhibited in a dose-related manner by phenanthrene applied by subcutaneous injection to the same site (Falk et al., 1964). However, when triethylene glycol was the vehicle, a substantial (50%) increase in the rate of tumor induction was observed. In the same study, phenanthrene had substantial inhibiting effects on the ability of benzo[a]pyrene to produce injection site sarcomas. By contrast, Pfeiffer (1977) found no inhibitory effects of phenanthrene on benzo[a]pyrene- or dibenz[a,h]anthracene-induced carcinogenicity.
4.4. EPA WEIGHT-OF-EVIDENCE
Classification D -- Not classifiable as to human carcinogenicity (U.S. EPA, 1993a, 1987) Basis -- Based on no human data and inadequate data from a single gavage study in rats and skin painting and injection studies in mice.
Comment: A weight-of-evidence classification for phenanthrene is not currently listed in HEAST or IRIS (U.S. EPA, 1993a,b).
4.5. CARCINOGENICITY SLOPE FACTORS
None were calculated.
5. REFERENCES
ATSDR (Agency for Toxic Substances and Disease Registry). 1990. Toxicological Profile for Polycyclic Aromatic Hydrocarbons. Acenaphthene, Acenaphthylene, Anthracene, Benzo(a)anthracene, Benzo(a)pyrene, Benzo(b)fluoranthene, Benzo(g,i,h)perylene, Benzo(k)fluoranthene, Chrysene, Dibenzo(a,h)anthracene, Fluoranthene, Fluorene, Indeno(1,2,3-c,d)pyrene, Phenanthrene, Pyrene. Prepared by Clement International Corporation, under Contract No. 205-88-0608. ATSDR/TP-90-20.
Bock, F.G. and T.L. Dao. 1961. Factors affecting the polynuclear hydrocarbon level in rat mammary glands. Cancer Res. 21: 1024-1029.
Boyland, E. and P. Sims. 1962. Metabolism of polycyclic compounds. The metabolism of phenanthrene in rabbits and rats: Dihydro-dihydroxy compounds and related glucosiduronic acids. Biochem. J. 84: 571-582.
Boyland, E. and G. Wolf. 1950. Metabolism of polycyclic compounds. 6. Conversion of phenanthrene into dihydroxydihydrophenanthrene. Biochem. J. 47: 64-69.
Budavari, S., M.J. O'Neil and A. Smith (Eds.). 1989. The Merck Index. Merck & Co., Inc. Rahway, NJ, pp. 1143-1144.
Buening, M.K., W. Levin, J.M. Karle, et al. 1979. Tumorigenicity of bay-region epoxides and other derivatives of chrysene and phenanthrene in newborn mice. Cancer Res. 39: 5063-5068.
Chang, L.H. 1943. The fecal excretion of polycyclic hydrocarbons following their administration to the rat. J. Biol. Chem. 151: 93-99.
Chaturapit, S. and G.M. Holder. 1978. Studies on the hepatic microsomal metabolism of (14C)phenanthrene. Biochem. Pharmacol. 27: 1865-1872.
Falk, H.L., P. Kotin and S. Thompson. 1964. Inhibition of carcinogenesis. The effects of polycyclic hydrocarbons and related compounds. Arch. Environ. Health 9: 169-179.
Grant, G.A. and F.J.C. Roe. 1963. The effect of phenanthrene on tumour induction by 3,4-benzopyrene administered to newly born mice. Br. J. Cancer 17: 261-265.
Huggins, C. and N.C. Yang. 1962. Induction and extinction of mammary cancer. Science 137: 257-262.
IARC (International Agency for Research on Cancer). 1983. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Polynuclear Aromatic Compounds. Part 1. Chemical, Environmental and Experimental Data, Vol. 32. World Health Organization, Lyon, France, pp. 419-430.
Kennaway, E.L. 1924. On the cancer-producing tars and tar-fractions. J. Ind. Hyg. 5: 462-488.
LaVoie, E.J., L. Tulley-Freiler, V. Bedenko and D. Hoffmann. 1981. Mutagenicity, tumor-initiating activity, and metabolism of methylphenanthrenes. Cancer Res. 41: 3441-3447.
Mabey, W.R., J.H. Smith, R.T. Podoll, et al. 1982. Aquatic fate process data for organic priority pollutants. U.S. Environmental Protection Agency, Office of Water Regulations and Standards, Washington, D.C. EPA 440/4-81-014.
Nordquist, M., D.R. Thakker, K.P. Vyas, et al. 1981. Metabolism of chrysene and phenanthrene to bay-region diol epoxides by rat liver enzymes. Mol. Pharmacol. 19: 168-178.
Nousiainen, U., R. Torronen and O. Hanninen. 1984. Differential induction of various carboxylesterases by certain polycyclic aromatic hydrocarbons in the rat. Toxicology 32: 243-251.
Pfeiffer, E.H. 1977. Oncogenic interaction of carcinogenic and non-carcinogenic polycyclic aromatic hydrocarbons in mice. IARC Scientific Publication No. 16. Air Pollution and Cancer in Man. International Agency for Research on Cancer, Lyon, France, pp. 69-77. (Cited in ATSDR, 1990)
Rahman, A., J.A. Barrowman and A. Rahimtula. 1986. The influence of bile on the bioavailability of polynuclear aromatic hydrocarbons from the rat intestine. Can. J. Physiol. Pharmacol. 64: 1214-1218. (Cited in ATSDR, 1990)
Roe, F.J.C. 1962. Effect of phenanthrene on tumor-initiation by 3,4-benzopyrene. Br. J. Cancer 16: 503-506.
Roe, F.J.C. and G.A. Grant. 1964. Tests of pyrene and phenanthrene for incomplete carcinogenic and anticarcinogenic activity. Br. Emp. Cancer Campaign 41: 59-60. (Abstract) (Cited in IARC, 1983)
RTECS (Registry of Toxic Effects of Chemical Substances). 1993. Computer printout.
Salaman, M.H. and F.J.C. Roe. 1956. Further tests for tumor-initiating activity: N,N-di(2-chloroethyl)-p-aminophenylbutyric acid (CB1348) as an initiator of skin tumor formation in the mouse. Br. J. Cancer 10: 363-378.
Salamone, M.F. 1981. Toxicity of 41 carcinogenic analogs. Prog. Mutat. Res. 1: 682-685. (Cited in U.S. EPA, 1988)
Sax, N.I. and R.L. Lewis (Eds.). 1987. Hawley's Condensed Chemical Dictionary, 11th ed. Van Nostrand Reinhold Company, New York, p. 895.
Scribner, J.D. 1973. Brief communication: Tumor initiation by apparently noncarcinogenic polycyclic aromatic hydrocarbons. J. Natl. Cancer Inst. 50: 1717-1719.
Simmon, V.F., H.S. Rosenkranz, E. Zeiger, and L.A. Poirier. 1979. Mutagenic activity of chemical carcinogens and related compounds in the intraperitoneal host-mediated assay. J. Natl. Cancer Inst. 62: 911-918.
Sims, P. 1970. Qualitative and quantitative studies on the metabolism of a series of aromatic hydrocarbons by rat-liver preparations. Biochem. Pharmacol. 19: 795-818.
Steiner, P.E. 1955. Carcinogenicity of multiple chemicals simultaneously administered. Cancer Res. 15: 632-635.
Storer, J.S., I. DeLeon, L.E. Millikan, et al. 1984. Human absorption of crude coal tar products. Arch Dermatol. 120: 874-877. (Cited in ATSDR, 1990)
U.S. EPA (U.S. Environmental Protection Agency). 1987. Health and Environmental Effects Profile for Phenanthrene. Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH, for the Office of Solid Waste and Emergency Response. ECAO-CIN-P226.
U.S. EPA (U.S. Environmental Protection Agency). 1988. Drinking Water Criteria Document for Polycyclic Aromatic Hydrocarbons (PAHs). Prepared by the Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, U.S. Environmental Protection Agency, Cincinnati, OH, for the Office of Drinking Water. ECAO-CIN-D010.
U.S. EPA (U.S. Environmental Protection Agency). 1993a. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH.
U.S. EPA (U.S. Environmental Protection Agency). 1993b. Health Assessment Summary Tables. Annual FY-93. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Emergency and Remedial Response, Washington, DC.
Wood, A.W., R.L. Chang, W. Levin, et al. 1979. Mutagenicity and tumorigenicity of phenanthrene and chrysene epoxides and diol epoxides. Cancer Res. 39: 4069-4077.
Yoshikawa, T., L.P. Ruhr, W. Flory, et al. 1985. Toxicity of polycyclic aromatic hydrocarbons. 1. Effect of phenanthrene, pyrene and their ozonized products on blood chemistry in rats. Toxicol. Appl. Pharmacol. 79: 218-226.
Retrieve Toxicity Profiles
Condensed Version
Last Updated 2/13/98