The Risk Assessment Information System

Toxicity Profiles

Formal Toxicity Summary for DIBENZ[A,H]ANTHRACENE

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: 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

May 1995

Prepared by Rosmarie A. Faust, Ph.D., Chemical Hazard Evaluation Group, Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, ^*, Oak Ridge, Tennessee.

Prepared for OAK RIDGE RESERVATION ENVIRONMENTAL RESTORATION PROGRAM

*Managed by Lockheed Martin Energy Systems, Inc., for the U.S. Department of Energy under Contract No. DE-AC05-84OR21400

EXECUTIVE SUMMARY

Dibenz[a,h]anthracene is a polycyclic aromatic hydrocarbon (PAH) with five aromatic rings. No commercial production or use of dibenz[a,h]anthracene is known. It occurs as a component of coal tars, shale oils, and soots (IARC, 1985) and has been detected in gasoline engine exhaust, coke oven emissions, cigarette smoke, charcoal broiled meats, vegetation near heavily traveled roads, and surface water and soils near hazardous waste sites (ATSDR, 1993; IARC, 1983).

Dibenz[a,h]anthracene is poorly absorbed from the gastrointestinal tract and is primarily excreted via feces (Chang, 1943). Following absorption, dibenz[a,h]anthracene is distributed to various tissues, with highest accumulation in the liver and kidneys (Daniel et al., 1967). Dibenz[a,h]anthracene is metabolized by mixed function oxidases to dihydrodiols. Epoxidation of the 3,4-dihydrodiol may lead to the formation of a diol-epoxide, the putative ultimate carcinogenic metabolite of dibenz[a,h]anthracene (Buening et al., 1979).

No human studies were available to evaluate the toxicity of dibenz[a,h]anthracene. In animals, depressed immune responses were observed in mice following single or multiple subcutaneous injections of dibenz[a,h]anthracene (White et al., 1985). Weekly subcutaneous. injections of 0.05% dibenz[a,h]anthracene for 40 weeks produced lymphoid tissue changes, decreased spleen weights, and liver and kidney lesions in mice (Hoch-Ligeti, 1941). Weekly intramuscular injections of 20 mg/kg promoted the development of arteriosclerotic plaques in chickens (Penn and Snyder, 1988).

The EPA has not derived an oral reference dose (RfD) or inhalation reference concentration (RfC) for dibenz[a,h]anthracene (EPA, 1995).

No epidemiologic studies or case reports addressing the carcinogenicity of dibenz[a,h]anthracene in humans were available. In animals, dibenz[a,h]anthracene has produced tumors by different routes of administration, having both local and systemic carcinogenic effects.

After oral administration, dibenz[a,h]anthracene produced tumors at several sites. Male and female mice fed dibenz[a,h]anthracene (0.85 mg/day for males, 0.76 mg/day for females) in an aqueous olive oil emulsion developed pulmonary adenomatosis, alveologenic carcinomas of the lung, hemangio-endotheliomas of the pancreas and mesentery/abdominal lymph nodes, and mammary carcinomas (females) after 200 days (Snell and Stewart, 1962). A single oral dose of 1.5 mg dibenz[a,h]anthracene in polyethylene glycol produced a low incidence of forestomach papillomas in mice (Berenblum and Haran, 1955). Mammary carcinomas developed in mice treated by gavage with a total dose of 15 mg over a 15-week period (Biancifiori and Caschera, 1962).

Carcinogenic as well as tumor-initiating activity of dibenz[a,h]anthracene has been demonstrated in topical application studies with mice. Repeated dermal application of 0.001 to 0.01% solutions produced a high incidence of skin papillomas and carcinomas in mice (Wynder and Hoffmann, 1959; Van Duuren et al., 1967). In initiation-promotion assays, the compound was active as an initiator of skin carcinogenesis in mice (Buening et al., 1979; Platt et al., 1990). However, no skin tumors were observed in Syrian golden hamsters that received topical dibenz[a,h]anthracene applications over a 10-week period (Shubik et al., 1960).

Injection site sarcomas developed in mice injected subcutaneously with dibenz[a,h]anthracene (Pfeiffer, 1977). In newborn mice, a single subcutaneous injection of dibenz[a,h]anthracene induced local sarcomas and lung adenomas (Platt et al., 1990) and three intraperitoneal injections induced a high incidence of pulmonary tumors (Buening et al., 1979). A number of earlier studies have also demonstrated the carcinogenicity of dibenz[a,h]anthracene when administered by various parenteral routes in several animal species (IARC, 1973).

Based on no human data and sufficient evidence for carcinogenicity in animals, EPA has assigned dibenz[a,h]anthracene a weight-of-evidence classification of B2, probable human carcinogen (EPA, 1995).

1. INTRODUCTION

Dibenz[a,h]anthracene (CAS No. 53-70-3), also referred to as 1,2,5,6-dibenz(a,h)anthracene, 1,2:4,6-dibenz(a,h)anthracene, 1,2:5,6-dibenz(a,h)anthracene, DB(a,h)A, or DBA, is a polycyclic aromatic hydrocarbon (PAH) with five aromatic rings (ATSDR, 1993; Budavari et al., 1989). It has a molecular formula of C₂₂H₁₄, a molecular weight of 278.33, and a melting point of 266C. Dibenz[a,h]anthracene exists as crystalline plates or leaflets and is insoluble in water, slightly soluble in alcohol and ether, and soluble in petroleum ether, benzene, toluene, xylene, oils, and other organic solvents (Budavari et al., 1989). It has a vapor pressure of 1 10^-10 mm Hg at 20C and an estimated log octanol/water partition coefficient of 6.84 (Mabey et al., 1982).

No commercial production or use of dibenz[a,h]anthracene is known. It occurs as a component of coal tars, shale oils, and soots (IARC, 1985) and has been detected in gasoline engine exhaust, coke oven emissions, cigarette smoke, charcoal broiled meats, vegetation near heavily traveled roads, and surface water and soils near hazardous waste sites (ATSDR, 1993; IARC, 1983). Dibenz[a,h]anthracene is one of a number of PAHs on EPA's priority pollutant list (EPA, 1991).

2. METABOLISM AND DISPOSITION

2.1 ABSORPTION

No human data and very limited animal data are available concerning the absorption of dibenz[a,h]anthracene. One animal study by Chang (1943) indicates that dibenz[a,h]anthracene is poorly absorbed from the gastrointestinal tract. Rats given dibenz[a,h]anthracene in starch solution by gavage (200 mg) or in the diet (250 mg) absorbed less than 10% of the administered dose.

2.2 DISTRIBUTION

Following gavage administration of radiolabeled dibenz[a,h]anthracene to rats, radioactivity was distributed to several tissues (Daniel et al., 1967). About 5% of the radiolabel entered the thoracic lymph duct within 24 hours with peak levels occurring at 3-4 hours. In blood plasma, peak levels were seen approximately 7 hours after dibenz[a,h]anthracene administration, suggesting metabolite reabsorption. The highest concentrations of radiolabel were found in the liver and kidneys, followed by adrenal glands, ovaries and blood. Maximum concentrations in these organs were not reached until 10 hours after dosing. Three to four days after dosing, radiolabel was found only in the adrenal glands, ovaries, and fat. Heidelberger and Weiss (1951) reported that 90 minutes after an intravenous injection of radiolabeled dibenz[a,h]anthracene, 89% of the radioactivity was found in the liver of mice.

2.3 METABOLISM

Dibenz[a,h]anthracene is metabolized by mixed function oxidases to dihydrodiols (Nordqvist et al., 1979; Slaga et al., 1980; Wood et al., 1978). The 3,4-dihydrodiol is the major metabolite formed from dibenz[a,h]anthracene by rat liver microsomes, representing 24% to 28% of the total metabolites (Buening et al., 1979). Other metabolites are the 1,2- and 5,6-dihydrodiols, representing 10% to 15% of total metabolites. The 3,4-dihydrodiol is thought to be the immediate metabolic precursor of the diol-epoxide of dibenz[a,h]anthracene, a compound designated as the ultimate carcinogenic metabolite of dibenz[a,h]anthracene. Platt et al. (1983) identified the 3,4-, 5,6-, and 1,2-diols, as well as the 5-phenol and 5,4-oxide, as potential metabolites of dibenz[a,h]anthracene.

2.4 EXCRETION

Following gavage (200 mg) or dietary (250 mg) administration of dibenz[a,h]anthracene, rats excreted >90% of the dose in the feces (Chang, 1943).

3. NONCARCINOGENIC HEALTH EFFECTS

3.1 ORAL EXPOSURES

3.1.1 Acute Toxicity

Information on the acute oral toxicity of dibenz[a,h]anthracene in humans or animals was not available.

3.1.2 Subchronic Toxicity

Information on the subchronic oral toxicity of dibenz[a,h]anthracene in humans or animals was not available.

3.1.3 Chronic Toxicity

3.1.3.1 Human

Information on the chronic oral toxicity of dibenz[a,h]anthracene in humans was not available.

3.1.3.2 Animal

In a study designed to evaluate the occurrence of pulmonary adenomatosis in DBA/2 mice treated with dibenz[a,h]anthracene, Snell and Stewart (1962) observed that ad libitum ingestion of a water/olive oil emulsion containing 0.2 mg/mL dibenz[a,h]anthracene for 279 days (males) or 237 days (females) may have accelerated the development of calcareous pericarditis (see also Sect. 4.1.2.). This lesion is known to occur spontaneously in DBA/2 mice and to increase with age.

3.1.4 Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of dibenz[a,h]anthracene in humans or animals following oral exposure was not available.

3.1.5 Reference Dose

An oral reference dose (RfD) for dibenz[a,h]anthracene has not been derived.

3.2 INHALATION EXPOSURES

3.2.1 Acute Toxicity

Information on the acute toxicity of dibenz[a,h]anthracene in humans or animals following inhalation exposure was not available.

3.2.2 Subchronic Toxicity

Information on the subchronic toxicity of dibenz[a,h]anthracene in humans or animals following inhalation exposure was not available.

3.2.3 Chronic Toxicity

Information on the chronic toxicity of dibenz[a,h]anthracene 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 dibenz[a,h]anthracene in humans or animals following inhalation exposure was not available.

3.2.5 Reference Concentration

An inhalation reference concentration (RfC) for dibenz[a,h]anthracene has not been derived.

3.3 OTHER ROUTES OF EXPOSURE

3.3.1 Acute Toxicity

3.3.1.1 Humans

Information on the acute toxicity of dibenz[a,h]anthracene in humans by other routes of exposure was not available.

3.3.1.2 Animal

White et al. (1985) evaluated the immune response in mice following single or multiple subcutaneous injections of dibenz[a,h]anthracene using the antibody-forming cell response to sheep erythrocytes. A single injection of 1 mmol dibenz[a,h]anthracene resulted in a 71% depression of immune response. Fourteen daily injections of 160 mol reduced the immune response by 91% and produced a 44% reduction in absolute thymus weight.

Mice receiving three subcutaneous injections of either 50, 100, or 400 mg/kg of dibenz[a,h]anthracene over a 12-day period had reduced serum antibody levels (Malmgren et al., 1952). Depressed growth, persisting for at least 15 weeks, was reported in young rats that received one or two intraperitoneal injections of dibenz[a,h]anthracene at doses ranging from 3 to 90 mg/kg (Haddow et al., 1937).

As an indicator of potential carcinogenic activity, Bock and Mund (1958) measured the potency of a number of chemicals in suppressing sebaceous gland activity in mice. High levels of sebaceous gland suppression were seen when dibenz[a,h]anthracene was applied twice daily on three consecutive days to the skin of mice.

3.3.2 Subchronic Toxicity

3.3.2.1 Human

Information on the subchronic toxicity of dibenz[a,h]anthracene in humans by other routes of exposure was not available.

3.3.2.2 Animal

Hoch-Ligeti (1941) administered dibenz[a,h]anthracene to mice by weekly subcutaneous injections (0.05 mL of a 0.05% solution in gelatin) for 40 weeks. Treatment with dibenz[a,h]anthracene caused an increase in the number of lymph gland stem cells, an overall decrease in lymphoid cells, dilation of lymphoid sinuses, and significantly decreased spleen weights. Additional effects included signs of fatty degeneration of the liver and deposition of iron in Kupffer cells, iron deposition in adrenal cortex,; and signs of degeneration in kidney tubules and Malpighian bodies.

Rats given subcutaneous injections of 0.278 mg dibenz[a,h]anthracene 5 times weekly for several weeks exhibited pathological changes in the lymphoid tissues, characterized by extravascular red blood cells in the lymph spaces and by the presence of abnormally large pigmented cells (Lasnitzki and Woodhouse, 1944).

Weekly intramuscular injections of 20 mg/kg of dibenz[a,h]anthracene administered to male White Leghorn chickens for 16 weeks promoted the development of pre-existing arteriosclerotic plaques but did not initiate the development of new plaques (Penn and Snyder, 1988).

3.3.3 Chronic Toxicity

Information on the chronic toxicity of dibenz[a,h]anthracene by other routes of exposure in humans or animals was not available.

3.3.4 Developmental and Reproductive Toxicity

3.3.4.1 Human

Information on the developmental or reproductive toxicity of dibenz[a,h]anthracene by other routes of exposure in humans was not available.

3.3.4.2 Animal

Some degeneration of spermatogenic cells and the presence of "large" corpora lutea in the ovaries were observed in mice administered weekly subcutaneous injections of dibenz[a,h]anthracene (0.05 mL of a 0.05% solution in gelatin) for 40 weeks (Hoch-Ligeti, 1941).

3.4 TARGET ORGANS/CRITICAL EFFECTS

3.4.1 Oral Exposures

No data were available to identify target organs or critical effects following oral exposure to dibenz[a,h]anthracene.

3.4.2 Inhalation Exposures

No data were available to identify target organs or critical effects following inhalation exposure to dibenz[a,h]anthracene.

3.4.3 Other Routes of Exposure

3.4.3.1 Primary target organs

Lymphatic system: Subchronic exposure by subcutaneous injection produced lymphoid tissues changes in mice and rats.

3.4.3.2 Other target organs

1. Liver: Subchronic exposure by subcutaneous injection produced fatty liver changes in mice.

2. Kidneys: Subchronic exposures by subcutaneous injection produced degenerative kidney tubule changes in mice.

3. Cardiovascular system: Subchronic exposure by intramuscular injection promoted the development of pre-existing arteriosclerotic plaques in chickens.

4. CARCINOGENICITY

4.1 ORAL EXPOSURES

4.1.1 Human

Information on the carcinogenicity of dibenz[a,h]anthracene in humans following oral exposure was not available.

4.1.2 Animal

Male and female DBA/2 mice (21/sex) were given 0.2 mg/mL dibenz[a,h]anthracene in an aqueous olive oil emulsion ad libitum in place of drinking water (Snell and Stewart, 1962). Males were estimated to have received a daily dose of 0.85 mg/day while females received 0.76 mg/day. The duration of the experiment was 279 or 237 days for males and females, respectively. The animals did not tolerate the olive-oil vehicle well and lost weight after a few weeks of exposure, becoming emaciated and dehydrated. At 200 days, all of the 27 survivors developed pulmonary adenomatosis, 24 had alveologenic carcinoma of the lung, 16 had hemangio-endotheliomas of the pancreas and mesentery/abdominal lymph nodes, and 12/13 females had mammary carcinomas; precancerous growths of the small intestines were also observed. No mammary tumors, but two pulmonary adenomatoses, were seen in 35 controls.

Twice weekly gavage administration of 0.5% dibenz[a,h]anthracene in olive oil (total dose, 15 mg) for 15 weeks produced mammary carcinomas in 1/20 female BALB/c mice and in 13/24 pseudo-pregnant females (obtained by mating virgin females with vasectomized males) (Biancifiori and Caschera, 1962). A single dose of 1.5 mg dibenz[a,h]anthracene in polyethylene glycol produced forestomach tumors in 2/42 male Swiss mice after 30 weeks. No tumors were seen in mice treated with polyethylene glycol alone (Berenblum and Haran, 1955).

4.2 INHALATION EXPOSURES

4.2.1 Human

Although there are no human data that specifically link exposure to dibenz[a,h]anthracene to human cancers, dibenz[a,h]anthracene is a component of mixtures that has been associated with human cancer. These include coal tar, soots, coke oven emissions, and cigarette smoke (EPA, 1995).

4.2.2 Animal

Information on the carcinogenicity of dibenz[a,h]anthracene in animals following inhalation exposure was not available.

4.3 OTHER ROUTES OF EXPOSURE

4.3.1 Human

Information on the carcinogenicity of dibenz[a,h]anthracene in humans by other routes of exposure was not available.

4.3.2 Animal

Dibenz[a,h]anthracene was the first pure chemical compound shown to be carcinogenic in animals (IARC, 1973). Carcinogenic activity of dibenz[a,h]anthracene has been demonstrated in numerous skin application and parenteral administration studies.

Application of dibenz[a,h]anthracene in acetone to the skin of NMRI mice (three times weekly at total doses of 136, 448, or 1358 nmol) for 112 weeks produced papillomas in 6%, 8%, or 32% of treated animals, respectively (Platt et al., 1990). Tumor-initiating activity was demonstrated when female NMRI mice received topical applications of dibenz[a,h]anthracene (300 or 600 nmol) followed by treatment with 12-O-tetradecanoyl-phorbol-13-acetate (TPA) for 24 weeks. The effect was dose-dependent, where doubling the dose resulted in a considerable increase of skin tumors as well as tumor yield and a decrease in latency period of the first tumor. Tumor-initiating activity was also observed when Sencar mice were treated with concentrations as low as 10 nmol followed by TPA applications (Buening et al., 1979). Lijinsky et al. (1965) reported that biweekly topical applications of a 0.2% solution of dibenz[a,h]anthracene (38 g/dose) in acetone-benzene for 44 weeks induced skin papillomas and carcinomas in 16/20 female Swiss mice. Van Duuren et al. (1967) reported that topical applications of dibenz[a,h]anthracene in acetone (0.001%, 0.01%, or 0.1%, administered 3 times weekly for an unspecified period) produced skin tumors in 1/30 (1 carcinoma), 43/50 (39 carcinomas), or 39/40 (32 carcinomas), respectively. A dose-related decrease in survival time and tumor latency period was also observed. Repeated skin applications of a 0.001% solution of dibenz[a,h]anthracene in acetone (duration of treatment not given) produced skin papillomas and carcinomas in 30% of mice, while a 0.01% solution produced both papillomas and carcinomas in over 90% of mice, with similar latency periods (Wynder and Hoffmann, 1959).

Hamsters appear to be more resistant to the tumorigenic properties of dibenz[a,h]anthracene than mice. Shubik et al. (1960) observed no skin tumors in Syrian golden hamsters receiving 20 topical applications of a 0.2% solution of dibenz[a,h]anthracene over a period of 10 weeks. Multiple intratracheal instillations of 0.05 or 0.25 mg dibenz[a,h]anthracene administered as 24 or 30 weekly doses, respectively, did not induce respiratory tract tumors in Syrian golden hamsters given the lower dose (Sellakumar and Shubik, 1974). Hamsters given the higher dose developed two adenocarcinomas (one each at week 45 and 108). The development of squamous cell carcinomas was reported in mice treated with dibenz[a,h]anthracene by intratracheal instillation (details not provided) (Yanisheva and Balenko, 1966).

A single subcutaneous injection of dibenz[a,h]anthracene (308 nmol/animal) led to the formation of fibrosarcomas at the injection site in 63% of treated adult NMRI mice (Platt et al., 1990). When newborn NMRI mice were given a single subcutaneous injection (400 nmol/animal) on day 2 of their life, 92% of treated animals developed lung adenomas after 40 weeks. Injection site sarcomas were reported in female NMRI mice following a single subcutaneous injection of as little as 2.35 g dibenz[a,h]anthracene (Pfeiffer, 1977). In another subcutaneous injection study, Lubet et al. (1983) found that treatment with 150 g dibenz[a,h]anthracene was associated with the development of fibrosarcomas but only in some strains. Following a 9-month observation period, fibrosarcomas were observed in 80%, 33%, 3%, or 0% of C3H/HeJ, C57B1/6J, DBA/2J, or AKR/J mice, respectively. Newborn mice injected intraperitoneally on the 1st, 8th, and 15th days of life with dibenz[a,h]anthracene at total doses of 70 or 420 nmol, 88% and 100%, respectively, developed pulmonary tumors (Buening et al., 1979). A number of earlier studies summarized by the International Agency for Research on Cancer (IARC) (1973) have also demonstrated the carcinogenicity of dibenz[a,h]anthracene when administered by various parenteral routes to several animal species.

Falk et al. (1964) evaluated the potential inhibitory effects of phenanthrene and other PAHs considered noncarcinogenic on the tumorigenicity of dibenz[a,h]anthracene. Male C57B1 mice received single subcutaneous injections of various dosages of dibenz[a,h]anthracene alone or in combination with other PAHs [hydrogenated dibenz(a,h)anthracenes]. Phenanthrene as well as hydrogenated dibenz(a,h)anthracenes exerted substantial inhibitory effects on the production of injection site sarcomas induced by dibenz[a,h]anthracene. In contrast, Pfeiffer (1977) found no inhibitory effects of 10 noncarcinogenic PAHs in NRMI mice given single subcutaneous injections of dibenz(a,h)anthracene.

4.4 EPA WEIGHT-OF-EVIDENCE

Classification--B2, probable human carcinogen (EPA, 1995).

Basis--Based on no human data and sufficient data from animal bioassays. Dibenz[a,h]anthracene produced carcinomas in mice following oral or dermal exposure and injection site tumors in several species following subcutaneous or intramuscular administration. Dibenz[a,h]anthracene has induced DNA damage and gene mutations in bacteria as well as gene mutations and transformation in several types of mammalian cell cultures.

4.5 CARCINOGENICITY SLOPE FACTORS

No carcinogenicity slope factor currently are available for dibenz[a,h]anthracene.

5. REFERENCES

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Lasnitzki, A. and D. L. Woodhouse. 1944. The effect of 1:2:5:6-dibenzanthracene on the lymph-nodes of the rat. J. Anat. 78: 121-129.

Lijinsky, W., H. Garcia, B. Terracini and U. Saffioti. 1965. Tumorigenic activity of hydrogenated derivatives of dibenz[a,h]anthracene. J. Natl. Cancer Inst. 34: 1-6.

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