Toxicity Profiles

Formal Toxicity Summary for 2,4,6-TRINITROTOLUENE

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

Prepared by: Dennis M. Opresko, Ph.D., Chemical Hazard Evaluation Group in the Biomedical and Environmental Information Analysis Section, Health Sciences Research Division, Oak Ridge National Laboratory*.

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

2,4,6-Trinitrotoluene (TNT) is used as a high explosive in military armaments and as a chemical intermediate in the manufacture of dyestuffs and photographic chemicals (Sax and Lewis 1987). TNT is likely to enter the environment in wastewater effluents from production facilities and from leachates at waste disposal sites. Mobility in soil may be limited by strong adsorption to soil particles (EPA 1990).

TNT is absorbed through the gastrointestinal tract, skin, and lungs; is distributed primarily to the liver, kidneys, lungs, and fat; and is excreted mainly in the urine and bile (El-hawari et al. 1981). Metabolism occurs by nitroreduction to amino and hydroxylamino derivatives and by oxidation to benzyl alcohol and benzoic acid derivatives (El-hawari et al. 1981).

In animals, signs of acute toxicity to TNT include ataxia, tremors, and mild convulsions. Splenic hemosiderosis, leukopenia, thrombocytosis, slight hepatomegaly, and increase in kidney weight occurred in mice fed a dietary level equivalent to 700 mg TNT/kg/day for 28 days (Levine et al. 1984b). Oral LD50 values of 660 to 1320 mg/kg have been reported for rats (Dilley et al. 1982).

The primary target organs for TNT toxicity in experimental animals following subchronic and chronic oral exposures are (1) liver (hepatocytomegaly and cirrhosis), (2) blood (hemolytic anemia with secondary alterations in the spleen), and (3) testes (degeneration of the germinal epithelium lining the seminiferous tubules). The LOAEL for hepatotoxicity in dogs was 0.5 mg/kg/day (Levine et al. 1990a).

Chronic oral toxicity studies on rats have also demonstrated TNT-induced anemia and hepatotoxicity, as well as adverse effects on the kidney (hypertrophy and nephropathy) and sternal bone marrow fibrosis (Furedi et al. 1984a).

The reference dose (RfD) for chronic oral exposures, 0.0005 mg/kg/day, is based on a LOAEL of 0.5 mg/kg/day for liver effects in dogs (EPA 1991b). The subchronic oral RfD is the same as the chronic RfD and is based on the same study (EPA 1991a).

Information on the inhalation toxicity of TNT is derived mainly from occupational exposure studies, which indicate that the major effects of chronic exposure to TNT are anemia (decreases in Hgb, Hct, and RBC count), liver dysfunction (increases in serum lactic dehydrogenase, glutamic oxaloacetic transaminase, and bilirubin), and cataracts (equatorial lens opacities) (EPA 1989, 1990). Other reported effects of TNT exposure include dermatitis, leukocytosis, neurological disorders, and nephrotoxicity (Cone 1944, Zakhari and Villaume 1978).

An inhalation reference concentration (RfC) for TNT has not been derived.

Limited information is available on the reproductive or developmental toxicity of TNT to animals or humans following inhalation exposures. Information from occupational exposure studies suggests that TNT may cause menstrual disorders and male impotency (Zakhari and Villaume 1978, Jiang et al. 1991).

No epidemiological evidence is available showing an association between chronic TNT exposure and tumorigenicity in humans. In animal carcinogenicity studies, a significant increase in urinary bladder papillomas and carcinomas was seen in female F344 rats dosed with 50 mg TNT/kg/day for 24 mo (Furedi et al. 1984a). This study was used by EPA to calculate a slope factor of 0.03 (mg/kg/day)-1 (EPA 1991). TNT is classified in weight-of-evidence Group C, possible human carcinogen (EPA 1991a, b).

1. INTRODUCTION

2,4,6-Trinitrotoluene (TNT) is a yellow crystalline solid used as a high explosive in military armaments and as a chemical intermediate in the manufacture of dyestuffs and photographic chemicals (Sax and Lewis 1987). It is slightly soluble in water (104 to 113 mg/L) and soluble in alcohol, ether, acetone, benzene and carbon disulfide (EPA 1990). It has a density of 1.654 g/mL, a vapor pressure of 8.02 x 10-6 mm Hg at 25C, and a log Kow of 1.60 (EPA 1990).

TNT is likely to enter the environment in wastewater effluents from production facilities and from leachates at waste disposal sites. Direct photolysis (half-life 14 hr) and microbial degradation are expected to be the major loss pathways. Mobility in soil may be limited by strong adsorption to soil particles. Volatilization to the atmosphere from water or soil is not expected to be significant (EPA 1990).

2. METABOLISM AND DISPOSITION

2.1. ABSORPTION

TNT is absorbed through the gastrointestinal tract, the skin, and the lungs. Studies on laboratory animals dosed with radiolabeled TNT have shown that rates of absorption, as indicated by the 24-hr recovery of radioactivity in the urine, can be as high as 74.3% following oral dosing and 52.8% after dermal exposures. Following intratracheal dosing to rats, urinary recovery was 12.7 to 19.3% after 4 hr (El-hawari et al. 1981).

2.2. DISTRIBUTION

In laboratory animals dosed orally, dermally, or intratracheally with radiolabeled TNT, recovery of radioactivity was highest in blood, liver, kidneys, lungs, and fat (El-hawari et al. 1981).

2.3. METABOLISM

TNT is extensively metabolized by nitroreduction to various derivatives, including hydroxylamino-dinitrotoluenes, amino-dinitrotoluenes, and diamino-nitrotoluenes (El-hawari et al. 1981). The methyl group can also be oxidized to form benzyl alcohol and benzoic acid derivatives. Some metabolites may undergo conjugation reactions with glucuronic acid.

2.4. EXCRETION

TNT and its metabolities are excreted primarily in the urine and bile (El-hawari et al. 1981).Only a small fraction (~0.1%) is eliminated through the lungs.

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 TNT to humans was not available.

3.1.1.2. Animal

Oral LD50s of 660 mg/kg in male and female mice and 1320 and 795 mg/kg in male and female rats, respectively, have been reported (Dilley et al. 1982). Signs of acute toxicity may include ataxia, tremors, cyanosis, respiratory paralysis, and mild convulsions (EPA 1989).

Twenty-eight day treatment of B6C3F1 mice with dietary TNT equivalent to 700 mg/kg resulted in splenic hemosiderosis, leukopenia, thrombocytosis, slight hepatomegaly, and increase in kidney weight (Levine et al. 1984b).

3.1.2. Subchronic Toxicity

3.1.2.1. Human

Information on the subchronic oral toxicity of TNT to humans was not available.

3.1.2.2. Animal

The subchronic oral toxicity of TNT has been evaluated in several animal species, including dogs, rats, mice, and monkeys. In a 90-day study on beagles, the test animals (3/sex/group) were fed TNT (purity not reported) in a commercial feed at concentrations equivalent to dose levels of 0 (control), 0.02, 0.1, or 1.0 mg/kg/day (Hart 1974). Hematological parameters, serum chemistry tests, and urinalysis, as well as gross and microscopic appearance of organs and tissues, were not affected by the treatment. Temporary episodes of emesis occurred but tolerance appeared to develop.

In a study conducted by Dilley et al. (1982), beagles (5/sex/group) received TNT (>99% pure) in gelatin capsules, daily for one or 13 weeks, in doses equivalent to 0 (control), 0.2, 2.0, or 20 mg/kg/day. Changes in hematological parameters and in the gross and microscopical appearance of the spleen were suggestive of hemolytic anemia at the highest dose.

In a third study on beagles, Levine et al. (1983, see also Levine et al. 1990a), administered TNT (99.1%) in gelatin capsules at dose levels equivalent to 0 (controls), 0.5, 2.0, 8.0, or 32 mg/kg/day (6 animals/sex/dose) for 26 weeks. Clinical signs of toxicity attributed to TNT treatment included transient ataxia, darkening of the tongue and gums, evidence of jaundice, orange-brown urine, and orange-red feces. Reductions in body weight and food consumption occurred primarily in the high-dose animals. Dose-related anemia (decreased hematocrit, hemoglobin, and erythrocyte counts), methemoglobinemia, reticulocytosis, microcytosis, and increased numbers of nucleated RBCs were seen in animals receiving 8 and 32 mg/kg/day. Serum chemistry effects, also seen primarily at the highest doses, included a decrease in SGPT (serum glutamic pyruvic transaminase) and increases in globulin, LDH (lactic dehydrogenase), and total and direct bilirubin. Urinary bilirubin was also elevated. Significant (p<0.05) increases in relative and absolute liver weights occurred in males receiving 8 and 32 mg/kg/day and in females receiving 32 mg/kg/day. There was also a dose-related increase in hepatocytomegaly and in the incidence and severity of cloudy swelling of the hepatocytes. Microscopic evidence of cirrhosis, observed only in the treated animals, was reported in one male in the 8 mg/kg/day dose group and in six males and one female in the 32 mg/kg/day group. One female receiving 2 mg/kg/day and all animals receiving 8 and 32 mg/kg/day exhibited hemosiderosis in the histocytes of the liver. A dose level of 0.5 mg/kg/day was identified as a LOAEL for effects on the liver. Relative and absolute spleen weights increased significantly (p<0.05) in females receiving 8 and 32 mg/kg/day and in males receiving 32 mg/kg/day. Enlargement of the spleen with marked to severe congestion was attributed to TNT treatment. A slight but statistically insignificant increase in relative kidney weight was seen in high-dose females but not in males.

The subchronic toxicity of TNT has also been evaluated in several studies on rats. In a 13-week study, Levine et al. (1984a) fed F344 rats (10/sex/dose group) a commercial diet containing TNT (99.1% pure) at dose levels equivalent to 1, 5, 25, 125 or 300 mg/kg/day. Lethargy, ataxia, and reductions in food intake and body weight gain were observed in animals receiving doses 125 mg/kg/day. Two deaths, in rats receiving 300 mg/kg/day, were attributed to severe anemia. Dose-related anemia (decreased hematocrit, hemoglobin, and erythrocyte counts) was observed in treated rats. These changes were statistically significant (p0.05) for males receiving 25 mg/kg/day, and for females receiving 125 mg/kg/day. Methemoglobinemia occurred in both males and females administered doses of 300 mg/kg/day. Serum cholesterol levels and relative spleen weights increased significantly in both males and females receiving 125 mg/kg/day. Dose-dependent congestive lesions were observed in the spleen. Hyperplasia was found in the liver of animals receiving doses of 125 mg/kg/day. Histological examination of the testes revealed dose-related degeneration of the germinal epithelium lining the seminiferous tubules in rats in the 125 and 300 mg/kg/day dose groups. The investigators concluded that the liver, testes and blood were the main targets of TNT toxicity and that the splenic lesions were secondary to the hemolytic effect. In addition, in rats dosed with 300 mg/kg/day degenerative lesions were seen in tracts of cerebellar folia. In a more recent study, Levine et al. (1990b) administered TNT to F344 rats for 13 weeks at dietary levels equivalent to 5 and 125 mg/kg/day. Adverse toxic effects, occurring in the high-dose groups, were similar to those reported in the earlier study (i.e., anemia, hypercholesterolemia, hepatomegaly, splenomegaly and testicular atrophy, with accompanying histological lesions).

In another study, Dilley et al. (1982) fed Sprague-Dawley rats (20/sex/group) a commercial diet containing TNT at concentrations of 0.002, 0.01, 0.05, or 0.25%. Dose levels were equivalent to 1.40, 6.97, 34.7 and 160 mg/kg/day for males and 1.45, 7.41, 36.4 and 164 mg/kg/day for females. Treatment lasted for 4 or 13 weeks. Red-colored urine, observed in animals on the 0.05 and 0.25% TNT diets, was the only clinical sign observed during treatment. Hematologic changes included decreased hemoglobin and hematocrit concentrations and RBC count, and increased mean corpuscular volume and leukocyte count, particularly at the highest dose level. Other effects were confined to those rats on the 0.25% TNT diet. Body weight gain was significantly (p<0.01) reduced, spleen weight and the spleen/brain weight ratios (both sexes) were significantly increased, and absolute and relative testes weight were significantly decreased. At weeks 4 and 13, the treated rats showed a significant (p<0.01) increase in serum cholesterol. Also at week 13, SGPT and serum iron levels were markedly (p<.01) reduced in males but not in females. Hemosiderosis of the spleen (both sexes) and testicular atrophy accompanied by hyperplasia were found in animals sacrificed immediately after treatment. Males allowed to recover for 4 weeks showed atrophy of the epididymis.

Swiss-Webster mice were fed a commercial diet containing TNT at concentrations of 0.001, 0.005, 0.025, 0.125% for 4 or 13 weeks (Dilley et al. 1982). Dose levels were equivalent to 1.56, 7.46, 35.7, or 193 mg/kg/day for males and 1.57, 8.06, 37.8, or 188 mg/kg/day for females. Mild hematological changes, indicative of hemolytic anemia, occurred in animals in the high-dose groups. Histological examination revealed hemosiderosis of the spleen in animals on the 0.025% and 0.125% TNT diets and hepatic necrosis in some males in the high-dose group.

Martin (1974) conducted a study using cynomolgus monkeys (3/sex/group) in which TNT (purity not reported) was suspended in methylcellulose and administered by gavage at dose levels of 0 (solvent alone), 0.02, 0.1, or 1.0 mg/kg/day for 90 days. Hematology, serum chemistry, urinalysis, and liver function tests revealed no alterations attributable to TNT treatment. Gross lesions, observed only with the two higher doses, included two cases of subcapsular renal hemorrhage and one case of mucosal reddening and focal thickening of the large intestine. Histological examination revealed increases in the numbers of necrotic megakaryocytes in bone marrow and increased amounts of iron-positive material in the liver.

3.1.3. Chronic Toxicity

3.1.3.1. Human

Information on the chronic oral toxicity of TNT to humans was not available.

3.1.3.2. Animal

Furedi et al. (1984a) evaluated the chronic toxicity of TNT in rats. In this study, 6- to 7-week-old F344 rats (75/sex/group) were fed TNT (>99% pure) mixed in a commercial diet. Equivalent dose levels were 0 (control), 0.4, 2, 10, or 50 mg/kg/day for 24 months. Survival rates were not affected by the TNT. There was an apparent increase in ocular discharge in high-dose males during the second year of the study. Dose-related reductions in body weight gain and in food consumption occurred in animals receiving 10 mg/kg/day. Effects of TNT treatment were seen mainly at the highest doses and included decreases in hematocrit and hemoglobin concentrations and RBC count; methemoglobinemia; thrombocytosis; increases in serum cholesterol, total protein, albumin, globulin, and BUN (blood urea nitrogen); hypotriglyceridemia in females; and hypertriglyceridemia in males.

Kidney weight was increased in the two highest dose groups, and histological examination revealed hypertrophy of the proximal convoluted tubules, increased pigmentation, and chronic nephropathy. Dose-related hepatomegaly and increased incidence of hepatocellular hyperplasia associated with peliosis and cystic degeneration were also seen in the two highest dose groups. In addition, high-dose females exhibited a significant increase in urinary bladder lesions (including hyperplasia of the mucosal epithelium) and females receiving 2 mg/kg/day exhibited a significant increase in the incidence of sternal bone marrow fibrosis. The latter effect was also seen in high-dose males. Absolute spleen weight was increased at the highest dose and was accompanied by increased pigmentation, sinusoidal congestion, and extramedullary hematopoiesis.

Furedi et al. (1984b) also investigated the chronic toxicity of TNT in mice. In this study B6C3F1 hybrid mice (75/sex/dose) were fed TNT (>99.8%) in a commercial diet for 24 months. Equivalent dose levels were 0 (control), 1.5, 10, and 70 mg/kg/day. Treatment did not reduce survival rates of the test animals; however, body weight gain was significantly reduced in both high-dose males and females. Anemia (reduced hematocrit, hemoglobin and RBC counts) and hepatomegaly (without evidence of histological changes) occurred in some animals in the high-dose group.

3.1.4. Developmental and Reproductive Toxicity

No data were available in the literature on the effects of TNT on the reproductive viability of animals or humans. However, laboratory studies have demonstrated that TNT causes adverse effects on the male reproductive system of rodents. In F344 rats, a dose-related degeneration of the germinal epithelium lining the seminiferous tubules was seen in males receiving a dietary equivalent of 125 and 300 mg/kg/day for 13 weeks (Levine et al. 1984a). In Sprague-Dawley rats, testicular atrophy, accompanied by hyperplasia, occurred in animals receiving a dietary equivalent of 160 mg/kg/day for 13 weeks (Dilley et al. 1982). Males allowed to recover for 4 weeks showed atrophy of the epididymis. In tests on Wistar rats, Jiang et al. (1991) found that treatment with TNT (200 mg/kg/day, by gavage, 6 days/wk for up to 6 weeks) resulted in significant decreases in absolute testicular weight, in testicular zinc concentration (after 2 weeks), and in testicular copper concentration (after 6 weeks).

No information is available on the developmental toxicity of TNT.

3.1.5. Reference Dose

3.1.5.1. Subchronic

ORAL RfD: 0.0005 mg/kg/day (EPA 1991a)

UNCERTAINTY FACTOR: 1000

MODIFYING FACTOR: 1

LOAEL: 0.5 mg/kg/day, 26-wk feeding study, dogs

COMMENT: The same study applies to the subchronic and chronic RfD (see Sect. 3.1.5.1).

3.1.5.2. Chronic

ORAL RfD: 0.0005 mg/kg/day (EPA 1991a,b)

UNCERTAINTY FACTOR: 1000

MODIFYING FACTOR: 1

LOAEL: 0.5 mg/kg/day, 26-wk feeding study, dogs

CONFIDENCE:

Study: Medium

Data Base: Medium

RfD: Medium

VERIFICATION DATE: 04/20/88

PRINCIPAL STUDY: U.S. DOD 1983 (Levine et al. 1990a)

COMMENT: The LOAEL was based on trace to mild evidence of hepatocellular swelling and hepatocytomegaly at 0.5 mg/kg/day; more severe effects were seen at higher doses. The Uncertainty Factor of 1000 allows for uncertainties in laboratory animal-to-human dose extrapolation, interindividual sensitivity, subchronic to chronic extrapolation, and LOAEL-to-NOAEL extrapolation.

3.2. INHALATION EXPOSURES

3.2.1. Acute Toxicity

3.2.1.1. Human

General information derived from occupational exposure studies, as summarized by Zakhari and Villaume (1978), indicate that initial exposure to TNT may result in mild irritation to the respiratory passages (nasal discomfort, sneezing, epistaxis and rhinitis), skin (erythema and papulae eruptions, progressing to desquamation and exfoliation) and gastrointestinal system (nausea, anorexia, and constipation). It has also been reported that some individuals deficient in glucose-6-phosphate dehydrogenase may show signs of hemolytic anemia within 2 to 3 days of exposure to TNT (Djerassi and Vitany 1972). In cases of severe TNT poisoning, signs of cyanosis may occur as a result of methemoglobin formation (Zakhari and Villaume 1978).

3.2.1.2. Animal

Information on the acute inhalation toxicity of TNT to animals is not available.

3.2.2. Subchronic Toxicity

3.2.2.1. Human

Information on the subchronic inhalation toxicity of TNT to humans is derived mainly from occupational exposure studies. These studies demonstrate that the blood is especially susceptible to toxic effects of TNT. Friedlander et al. (1974) reported that anemic conditions occurred in workers exposed for 6 months to TNT concentrations ranging from <0.02 to >3 mg/m3. Reductions in hemoglobin and hematocrit were seen when the values were compared with pre-exposure concentrations and also with concentrations in groups of nonexposed controls (EPA 1989). Significant differences were also found in RBC counts, BUN, reticulocytes, eosinophils, and blood glucose. The signs of anemia disappeared when the 8-hr/day exposures were reduced to 0.08 to 0.59 mg/m3 (EPA 1990).

Stewart et al. (1945) reported decreases in hemoglobin and hematocrit concentrations and RBC counts and increases in reticulocytes and serum bilirubin in individuals exposed to TNT concentrations of 0.3 to 1.3 mg/m3 for 4 to 11 weeks (Stewart et al. 1945). Skin rashes were also present in some of the exposed workers.

3.2.2.2. Animal

Information on the subchronic inhalation toxicity of TNT to animals was not available.

3.2.3. Chronic Toxicity

3.2.3.1. Human

Exposure to TNT in munition plants in the early part of the 20th century resulted in numerous and occasionally fatal cases of aplastic anemia and toxic hepatitis (Zakhari and Villaume 1978). The exposure levels and durations causing such severe effects were not clearly documented; however, more recent occupational exposure studies have demonstrated that effects on the blood and liver can occur at relatively low TNT concentrations. In a study of 533 workers exposed to TNT concentrations of 0.01 to 1.84 mg/m3, Buck and Wilson (1975) found dose-response relationships in hemoglobin and hematocrit levels and in reticulocyte counts. These changes were suggestive of low grade hemolysis with a compensatory mild reticulocytosis (EPA 1989). Liver function tests did not reveal any evidence of hepatotoxicity, but it was noted that only 12.2% of the workers were exposed to TNT levels above 0.5 mg/m3. Other studies have shown that liver function may be altered by TNT exposures greater than 0.5 mg/m3. In munition plant workers, significant increases in serum LDH (lactic dehydrogenase) (p<0.005) and SGOT (serum glutamic oxaloacetic transaminase) (p<0.01) occurred when the concentration of TNT in the air increased from 0.3 to 0.8 mg/m3 over a 30-day period due to an increase in production (Morton et al. 1976). In a study conducted by Goodwin (1972), the thymol turbidity test was used to measure the irritant effect of TNT on the liver of munition plant workers. The average value of 1.80 McLagen units in the TNT workers was almost twice as high as the average pre-employment level of 0.93 McLagen units. Two percent of the 1537 workers were reported to have "classical symptoms of liver damage." Air concentrations of TNT ranged from 0.2 to 4.7 mg/m3, with a mean value of 2.38 mg/m3.

It has been reported that chronic exposure to TNT may result in the formation of cataracts (Zakhari and Villaume 1978, Hassman and Juran 1968, Harkonen et al. 1983, Makitie, et al. 1984). Harkonen et al. (1983) found that 6 of 12 workers exposed to 0.14 to 0.58 mg TNT/m3 for an average duration of 6.8 years had developed equatorial lens opacities but without adverse effects on visual acuity or visual fields. Makitie et al. (1984) reported cataracts in 18 of 21 TNT workers exposed for an average of 12.3 years to concentrations of 0.1 to 0.4 mg/m3. Cataracts, which may form in the absence of systemic effects, may be due to the direct contact and absorption of TNT into the eye (EPA 1989).

Other reported effects of TNT exposure include dermatitis, leukocytosis, neurological disorders (neurasthenia, nystagmus, irregularities in muscle reflexes and adiadochokinesia), and nephrotoxicity (Cone 1944, Hamilton 1946, Zakhari and Villaume 1978). In most cases, exposure-response data for these effects are not available, and some effects may have been due to acute exposures to high TNT concentrations, possibly superimposed on lower chronic levels.

3.2.3.2. Animal

Information on the chronic inhalation toxicity of TNT to animals was not available.

3.2.4. Developmental and Reproductive Toxicity

Little information was found in the available literature on the effects of TNT on the reproductive viability of animals following inhalation exposures. Data obtained from occupational exposure studies have identified female menstrual disorders (hypo- or hypermenorrhea) and male impotency as possible effects of prolonged exposure to TNT (Zakhari and Villaume 1978, Jiang et al. 1991).

Information on the developmental toxicity of TNT following inhalation exposures was not available.

3.2.5. Reference Concentration

Subchronic and chronic RfCs for TNT have not been derived.

3.3. OTHER ROUTES OF EXPOSURE

3.3.1. Acute Toxicity

3.3.1.1. Human

Information on the acute toxicity of TNT to humans by other exposure routes was not available.

3.3.1.2. Animal

Single intraperitoneal injections of 100 mg/kg of TNT to adult male Wistar rats resulted in membrane damage in the brain, kidneys, and liver (Zitting et al. 1982). TNT is considered to be a mild irritant to the skin but not to the eye and it is also a moderate skin sensitizing agent (EPA 1989).

3.3.2. Subchronic Toxicity

Information on the subchronic toxicity of TNT to humans or animals by other exposure routes was not available.

3.3.3. Chronic Toxicity

Information on the chronic toxicity of TNT to humans or animals by other exposure routes was not available.

3.3.4. Developmental and Reproductive Toxicity

Information on the developmental and reproductive toxicity of TNT to humans or animals by other exposure routes was not available.

3.4. TARGET ORGANS/CRITICAL EFFECTS

3.4.1. Oral Exposures

Information on target organs following oral exposures is based primarily on animal studies.

3.4.1.1. Primary Target Organ(s)

1. Liver: Hepatocytic cloudy swelling and hepatocytomegaly; cirrhosis.

2. Blood: Anemia, decreased hematocrit, hemoglobin, and RBC count.

3. Testes: Degeneration of the germinal epithelium of the seminiferous tubules; decrease in zinc and copper content.

3.4.1.2. Other Target Organ(s)

1. Kidney: Hypertrophy of the proximal convoluted tubules, increased pigmentation, and chronic nephropathy.

2. Spleen: Increased pigmentation, sinusoidal congestion, and extramedullar hematopoiesis; probably secondary to anemia.

3. Bone: Fibrosis.

3.4.2. Inhalation Exposures

Information on target organs following inhalation exposures is based primarily on occupational exposure studies.

3.4.2.1. Primary Target Organ(s)

1. Liver: Increases in serum LDH and SGOT; hepatitis.

2. Blood: Anemia; reduced hemoglobin, hematocrit, RBC count.

3. Eye: Cataracts.

3.4.2.2. Other Target Organ(s)

1. Skin: Irritation, rashes.

2. Nervous system: Neurasthenia, nystagmus, abnormal muscle reflexes.

3. Reproductive system: Menstrual disorders; male impotency.

4. Kidney: Nephrotoxicity.

4. CARCINOGENICITY

4.1. ORAL EXPOSURES

4.1.1. Human

Information on the carcinogenicity of TNT to humans following oral exposure was not available.

4.1.2. Animal

The carcinogenic effects of dietary TNT were studied in male and female F344 rats by Furedi et al. (1984a). Dose levels were 0, 0.4, 2, 10, or 50 mg/kg/day for 24 mos. A significant increase in the combined incidence of urinary bladder papillomas and carcinomas was seen in the high-dose females (17/55). There were also increased incidences of hepatocellular hyperplasia in high-dose males and renal and urinary bladder hyperplasia in high-dose females.

The carcinogenic effects of dietary TNT were also studied in male and female B6C3F1 mice by Furedi et al. (1984b). Dose levels were 0, 1.5, 10, or 70 mg/kg/day for 24 mos. A significant (p0.05) increase in the combined incidence of leukemia and malignant lymphomas in the spleen was seen in the high-dose females. However, according to NTP guidelines, it is inappropriate to combine the incidence of leukemia and malignant lymphomas for only a single organ because these tumors can occur throughout the entire hematopoietic system (EPA 1989). When the incidence of these tumors in all organs was combined, by sex or for both sexes together, it was not statistically significant (EPA 1989).

4.2. INHALATION EXPOSURES

Information on the carcinogenicity of TNT after inhalation exposures was not available.

4.3. OTHER ROUTES OF EXPOSURE

Information on the carcinogenicity of TNT by other routes of exposure was not available.

4.4. EPA WEIGHT-OF-EVIDENCE

4.4.1. Oral

Classification: C; possible human carcinogen

Basis: Evidence of human carcinogenicity is inadequate. Urinary bladder papillomas and carcinomas were observed in female F344 rats (Furedi et al., 1984a). The compound was found to be mutagenic in Salmonella with and without metabolic activation.

Other Data: The related compounds, 2,4- and 2,6-dinitrotoluene have been shown to be carcinogenic in two species of animals and are classified as B2 carcinogens (EPA 1990). According to EPA, several of the metabolic byproducts of TNT, including N-hydroxylated compounds and aminobenzene derivatives are likely to form DNA adducts and, therefore, be potentially mutagenic and carcinogenic.

4.4.2. Inhalation

An inhalation slope factor has not been assigned.

4.5. CARCINOGENICITY SLOPE FACTORS

4.5.1. Oral

SLOPE FACTOR: 3.0E-2 (mg/kg/day)-1

DRINKING WATER UNIT RISK: 9.0E-7(g/L)-1

VERIFICATION DATE: 09/22/88 (EPA 1991b)

4.5.2. Inhalation

An inhalation carcinogenic slope factor has not been calculated.

5. REFERENCES

Buck, C. R. and S. E. Wilson. 1975. Adverse Health Effects of Selected Explosives. Occupational Health Special Study No. 32-049-75/76. (Cited in EPA 1990).

Cone, T. E. 1944. A review of the effects of trinitrotoluene (TNT) on the formal elements of blood. J. Ind. Hyg. Toxicol. 26:260-263. (Cited in EPA 1990).

Dilley, J. V., C. A. Tyson, R. J. Spanggord, D. P. Sasmore, G. W. Newell and J. C. Dacre. 1982. Short-term oral toxicity of 2,4,6-trinitrotoluene in mice, rats and dogs. J. Toxicol. Environ. Health 9(4):565-585. (Cited in EPA 1990)

Djerassi L. S. and L. Vitany. 1975. Hemolytic episode in G6PD deficient workers exposed to TNT. Br. J. Ind. Med. 32:54-58. (Cited in Zakhari and Villaume 1978).

El-hawari, A. M., J. R. Hodgson, J. M. Winston, M. D. Sawyer, M. Hainje, and C. C. Lee. 1981. Species differences in the disposition and metabolism of 2,4,6-trinitrotoluene as a function of route of administration. Final Report. Midwest Research Institute, Project No. 4274-B, Kansas City, MO. DAMD17-76-C-6066. AD-A114-025. (Cited in EPA 1989, 1990).

EPA . 1989. Trinitrotoluene - Health Advisory. Office of Drinking Water, U.S. Environmental Protection Agency, Washington, D.C.

EPA . 1990. Health and Environmental Effects Document for 2,4,6-Trinitrotoluene. Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH. ECAO-CIN-G089.

EPA . 1991a. Health Effects Summary Tables. Annual FY-91. 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, D.C. OERR 9200.6-303(91-1). NTIS PB91-921199.

EPA . 1991b. Integrated Risk Information System (IRIS). Risk Estimate for Carcinogenicity and Reference Dose for Oral Exposure for 2,4,6-Trinitrotoluene. Online file. Office of Health and Environmental Assessment, Cincinnati, OH.

Friedlander, B. R., K. W. Vorphal, R. E. Glenn, and P. T. Jordan. 1974. Occupational Health Special Study No. 99-020-74, APE1300 Wash-out Plant, U.S.A. E.H.A. (Cited in EPA 1990)

Furedi, E. M., B. S. Levine, D. E. Gordon, V. S. Rac and P. M. Lish. 1984a. Determination of the chronic mammalian toxicological effects of TNT (Twenty-four month chronic toxicity/carcinogenicity study of trinitrotoluene (TNT) in Fischer 344 rats). Final Report - Phase III. Volume 1. ITT Research Institute, Project No. L6116, Study No. 9, Chicago, IL. DAMD17-79-C-9120. AD-A168 637.

Furedi, E. M., B. S. Levine, J. W. Sagartz, V. S. Rac, and P. M. Lish. 1984b. Determination of the chronic mammalian toxicological effects of TNT (Twenty-four month chronic toxicity/carcinogenicity study of trinitrotoluene (TNT) in B6C3F1 hybrid mice). Final Report - Phase IV. Volume 1. ITT Research Institute, Project No. L6116, Study No. 11, Chicago, IL. DAMD17-79-C-9120. AD-1168 754.

Goodwin, J. W. 1972. Twenty years handling TNT in a shell loading plant. Amer. Ind. Hyg. Assoc. J. 33(1):41-44. (Cited in EPA 1990)

Hamilton, A. M. 1946. Monocytes as an index of TNT absorption. Br. J. Ind. Med. 3:24-26. (Cited in EPA 1989).

Harkonen, H., M. Karki, A. Lahti and H. Savolainen. 1983. Early equatorial cataracts in workers exposed to trinitrotoluene. Am. J. Ophthalmol. 95(6):807-810. (Cited in EPA 1989, 1990).

Hart, E. R. 1974. Subacute toxicity of RDX and TNT in dogs. Final Report. Litton Bionetics, Inc., Project No. 1399, Kensington, MD. N00014-73-C-0162. AD-A035 717. (Cited in EPA 1990).

Hassman, P. and J. Juran. 1968. Cataracts in persons working with trinitrotoluene (TNT). Int. Arch. GewerbEPAth. Gewerbehyg. 24:310-318. In German. (Cited in EPA 1989).

Jiang, Q.-G., J.-G. Sun and X.-F. Qin 1991. The effects of trinitrotoluene toxicity on zinc and copper metabolism. Toxicol. Letters 55:343-349.

Levine B. S., J. H. Rust, J. M. Burns, and P. M. Lish. 1983. Determination of the chronic mammalian toxicological effects of TNT. Twenty-six week subchronic oral toxicity study of trinitrotoluene (TNT) in the beagle dog. Phase II, Final Report, IIT, Research Institute, Report No. L6116, Study No 5, Chicago, IL. DAMD 17-79-C-9120, AD-A157 082. (Cited in EPA 1990).

Levine, B. S., E. M. Furedi, D. E. Gordon, P. M. Lish, and J. J. Barkely. 1984a. Subchronic toxicity of trinitrotoluene in Fischer 344 rats. Toxicology 32: 253-265. (Cited in EPA 1990).

Levine, B. S., E. M. Furedi, J. M. Burns, and P. M. Lish. 1984b. Four week subchronic (exploratory/range finding) oral toxicity study of trinitrotoluene (TNT) in the B6C3F1 hybrid mouse. Final Report. IIT Research Institute. Project No. L6116, Study No. 8, Chicago, IL. As Appendix IV in Furedi et al., 1984b. (Cited in EPA 1990).

Levine, B. S., J. H. Rust, J. J. Barkely, E. M. Furedi, and P. M. Lish. 1990a. Six-month oral toxicity study of trinitrotoluene in beagle dogs. Toxicology 63:233-244.

Levine, B. S., E. M. Furedi, D. E. Gordon, J. J. Barkely, and P. M. Lish. 1990b. Toxic interactions of the munitions compounds TNT and RDX in F344 rats. Fund. Appl. Toxicol. 15:373-380.

Makitie, J, H. Harkonen, S. Someroja, and R. Ahonen. 1984. Trinitrotoluene induced lens opacities and the use of retroillumination photography. ACTA Ophthalmol. (Suppl.) 164:40. (Cited in EPA 1989).

Martin, D. P. 1974. Subacute toxicity of RDX and TNT in monkeys. Final Report. Litton Bioetics, Inc. Project No. 1366. Kensington, MD. N000014-73-C0162. NR 108-985. AD-A044 650/0. (Cited in EPA 1990).

Morton, A.R., M. V. Ranadive, and J. A. Hathaway. 1976. Biological effects of trinitrotoluene from exposure below the threshold limit value. Am. Ind. Hyg. Assoc. J. 37(1):55-60. (Cited in EPA 1990).

Sax, N. I., and R. J. Lewis. 1987. Hawley's Condensed Chemical Dictionary. 11th ed. Van Nostrand Co., New York, p 1191.

Stewart, A., L. T. Witts, G. Higgins, et al. 1945. Some early effects of exposure to trinitrotoluene. Br. J. Ind. Med. 2.:74-82.

U.S. DOD. 1983. AD-A157 002 Available from Defense Technical Center, Cameron Station, Alexandria, VA 22314. (Cited in EPA 1991b).

Zakhari, A, and J. E. Villaume. 1978. A Literature Review - Problem definition studies on selected toxic chemicals. Occupational health and safety aspects of 2,4,6-trinitrotoluene (TNT). Final report. Science Information Services Organization, Philadelphia, PA. DAMD 17-77-C-7020, AD-055 683. (Cited in EPA 1989).

Zitting, A, G. Szumanska, J. Nickels, and H. Savolainen. 1982. Acute toxic effects of trinitrotoluene in rat brain, liver and kidney; Role of radical production. Arch. Toxicol. 51(1):53-64. (Cited in EPA 1990).

Retrieve Toxicity Profiles Condensed Version

Last Updated 2/13/98