Toxicity Profiles
Formal Toxicity Summary for 2,6-DINITROTOLUENE
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 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
2,6-Dinitrotoluene (2,6-DNT; 2-methyl-1,3-dinitrobenzene; CAS Reg. No. 606-20-2) is a pale yellow crystalline solid and one of six possible chemical forms of dinitrotoluene (DNT). Technical grade DNT (t-DNT) is typically composed of 78% 2,4-DNT, 19% 2,6-DNT, and small amounts of 3,4-DNT, 2,3-DNT, and 2,5-DNT (Dunlap 1978). DNT is primarily used as a chemical intermediate in the manufacture of polyurethanes. It is also used as a component of military and commercial explosives, as an intermediate in dye processes (Etnier 1987, Hawley 1981), and as a propellant additive (Sears and Touchette 1982).
The DNTs are absorbed through the gastrointestinal tract, respiratory tract, and skin in most species (EPA 1986). Human data regarding potential health effects of 2,6-DNT are very limited. A significant increase in the death rate due to ischemic heart disease has been associated with occupational exposure to t-DNT (Levine et al. 1986). The evidence for potential reproductive effects (reduction of sperm counts) in male workers exposed to a mixture of DNT isomers is equivocal (Hamill et al. 1982, Ahrenholz 1980).
Oral subchronic toxicity studies with rats, mice, and dogs indicate that the blood, liver, and reproductive system are targets affected by 2,6-DNT in all three species (Lee et al. 1976). These effects were generally observed at doses of 35 mg/kg/day in rats, 51 mg/kg/day in mice, and 20 mg/kg/day in dogs. The primary hematologic effect in all three species was methemoglobinemia with sequelae such as Heinz bodies, reticulocytosis, anemia, and extramedullary hematopoiesis. Also seen in all three species was bile duct hyperplasia, decreased spermatogenesis and testicular atrophy. In addition, dogs exhibited neurotoxic effects (incoordination, weakness, tremors, and paralysis) as well as inflammatory and degenerative kidney changes.
According to EPA (1991a), available data are inadequate for the calculation of a Reference Dose (RfD) or Reference Concentration (RfC) for 2,6-DNT.
In a 1-year carcinogenesis bioassay, 2,6-DNT at oral doses of 7 and 14 mg/kg/day, respectively, produced hepatocellular carcinomas in 85% and 100% of male rats. t-DNT, containing about 76% 2,4-DNT and 19% 2,6-DNT, also yielded a positive hepatocarcinogenic response (Leonard et al. 1987). In another study on the effects of t-DNT, dietary doses of 14 mg/kg/day induced hepatocellular carcinomas in rats (CIIT 1982). Initiating and promoting activities of 2,6-DNT in rat liver have been reported (Popp and Leonard 1982). Although EPA has not evaluated 2,6-DNT for evidence of human carcinogenic potential, the dinitrotoluene mixture (containing 2,4- and 2,6-DNT) has been classified as a B2 carcinogen, probable human carcinogen (EPA 1991a,b). A slope factor of 6.8E-1 (mg/kg/day)-1 was calculated for oral exposure to dinitrotoluene mixture. The drinking water unit risk is 1.9E-5 (µg/L)-1 (EPA 1991b).
1. INTRODUCTION
2,6-Dinitrotoluene (2,6-DNT; 2-methyl-1,3-dinitrobenzene; CAS Reg. No. 606-20-2) is a pale yellow crystalline solid and one of six possible chemical forms of dinitrotoluene (DNT). Having a molecular weight of 182.14 and a melting point of 66C, 2,6-DNT is soluble in alcohol (Weast et al. 1988, Dean 1979). 2,6-DNT does not occur naturally and is produced by dinitration of toluene with nitric acid in the presence of sulfuric acid, a reaction that produces a mixture of several DNT isomers (Etnier 1987). Technical grade DNT (t-DNT) is typically composed of 78% 2,4-DNT, 19% 2,6-DNT, and small amounts of 3,4-DNT, 2,3-DNT, and 2,5-DNT (Dunlap 1978).
DNT is primarily used as a chemical intermediate in the manufacture of polyurethanes. It is also used as a component of military and commercial explosives, as an intermediate in dye processes (Etnier 1987, Hawley 1981), and as a propellant additive (Sears and Touchette 1982). DNT isomers are formed as by-products during the manufacture of trinitrotoluene (TNT) (Etnier 1987) and are commonly found in wastewater released from TNT production facilities (Spanggord and Suta 1982). DNT has also been identified in soil, surface water, and ground water of hazardous waste sites that contain buried ammunition wastes (Etnier 1987).
2. METABOLISM AND DISPOSITION
2.1. ABSORPTION
The DNTs are absorbed through the gastrointestinal tract, respiratory tract, and skin in most species (EPA 1986). Lee et al. (1975) reported that female CD rats absorbed 60% of orally administered 2,6-DNT within 24 hours. The presence of 2,6-DNT metabolites in the urine of workers in DNT manufacturing plants, where inhalation was considered the major route of exposure, indicates that inhaled 2,6-DNT can be absorbed (Levine et al. 1985, Woolen et al. 1985). The two studies also suggested that dermal absorption of DNT can be a significant route of entry for DNT isomers in humans.
2.2. DISTRIBUTION
No information was available concerning the tissue distribution of 2,6-DNT in humans. A study with strain A mice using radiolabeled 2,6-DNT showed that the distribution of radioactivity was similar in the blood, liver, kidneys, lungs, and intestines 8 hours after dosing, with very low levels of radioactivity occurring in brain, heart, and spleen (Schut et al. 1983). Following an oral dose of 2,6-DNT, hepatic concentrations of radioactivity in rats occurred in two stages, with the first peak occurring within 1-2 hours and the second peak within 8-12 hours after dosing. The second peak was attributed to enterohepatic cycling. The half-life of radioactivity was estimated as 3.4-4.4 days (Rickert et al. 1983).
2.3. METABOLISM
Metabolism of the DNTs is extensive and occurs in the liver and also by the intestinal microflora. The primary metabolic pathway for DNT isomers, including 2,6-DNT, is reduction of the nitro group(s) to amino group(s) and/or oxidation of the methyl group to an alcohol. Secondary pathways involve N-acetylation of the amino moiety and further oxidation of the alcohol to a benzoic acid derivative. Both oxidized and reduced metabolites may undergo subsequent conjugation to form glucuronides, sulfates, and other compounds (ATSDR 1989, EPA 1986).
Rickert et al. (1984) reported that only two major metabolites of 2,6-DNT, 2,6-dinitrobenzoic acid and 2,6-dinitrobenzyl alcohol glucuronide, were detected in human urine, indicating a lack of reductive metabolism for 2,6-DNT. Oral administration of 2,6-DNT to rats resulted in three major urinary metabolites, 2,6-dinitrobenzoic acid, 2-amino-6-nitrobenzoic acid, and 2,6-dinitrobenzyl alcohol glucuronide (Long and Rickert 1982).
2.4. EXCRETION
No information was available regarding excretion in humans following oral exposure to 2,6-DNT. In experimental animals, urine appears to be the major route of 2,6-DNT excretion (EPA 1986). Rats excreted 55-90% of orally administered 2,6-DNT in the urine and 15-30% in the feces within 72 hours after dosing (Long and Rickert 1982). Mice eliminated about 50% of orally administered 2,6-DNT in the urine after 8 hours (Schut et al. 1983).
A study of workers employed at a t-DNT manufacturing plant showed that urinary metabolites of 2,4- and 2,6- DNT roughly corresponded to the isomeric composition of t-DNT. The principal metabolites were dinitrobenzoic acids (2,4- and 2,6-), 2-amino-4-nitrobenzoic acid, and dinitrobenzyl alcohol glucuronides (2,4- and 2,6-) (Levine et al. 1985).
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 2,6-DNT in humans was unavailable.
3.1.1.2. Animal
Oral LD50 values for 2,6-DNT range from 177 to 795 mg/kg for rats and from 621 to 1000 mg/kg for mice (Ellis et al. 1980, Vernot et al. 1977). Characteristic signs of acute DNT intoxication include central nervous system depression, respiratory depression, and ataxia (EPA 1986).
3.1.2. Subchronic Toxicity
3.1.2.1. Human
Information on the subchronic oral toxicity of 2,6-DNT in humans was unavailable.
3.1.2.2. Animal
Lee et al. (1976) studied the subchronic effects of 2,6-DNT in rats, mice, and dogs. CD rats were fed 2,6-DNT at dose levels of 7, 35, or 145 mg/kg/day (males) or 7, 37, or 155 mg/kg/day (females) for 13 weeks. No adverse effects were observed at the lowest dose. The mid dose produced decreased food consumption and weight gain, increased alanine aminotransferase (ALT) activity, extramedullary hematopoiesis in the spleen and/or liver, bile duct hyperplasia, and/or depression of spermatogenesis and testicular atrophy. The high dose also caused methemoglobinemia, an increase of Heinz bodies, anemia, and compensatory reticulocytosis. There was partial recovery 4 weeks after cessation of treatment. When the high dose was fed to rats for 4 weeks, there was an increase in drug-metabolizing activity, as reflected in decreased zoxazolamine paralysis time and increased hepatic nitroanisole O-demethylase activity.
Mice were administered 2,6-DNT at dose levels of 11, 51, or 289 mg/kg/day (males) or 11, 55, or 299 mg/kg/day (females) in the feed for 13 weeks. No effects were seen at the lowest dose. The mid and high doses produced decreased food consumption and weight gain, extramedullary hematopoiesis, decreased spermatogenesis and atrophy of the testes, bile duct hyperplasia, and death. Mice fed the highest dose were more severely affected. As with rats, there was partial recovery 4 weeks after cessation of treatment (Lee et al. 1976).
Beagle dogs were given 4, 20, or 100 mg 2,6-DNT/kg/day in capsule form for 13 weeks. Mild splenic hematopoiesis was seen in some dogs given the lowest dose. The two higher doses produced weight loss and pronounced neurotoxic effects including weakness, incoordination, tremors, and paralysis. Other effects noted were methemoglobinemia, an increase of Heinz bodies, anemia, reticulocytosis, extramedullary hematopoiesis, lymph depression leading to peripheral lymphocytopenia, bile duct hyperplasia, degenerative and inflammatory changes in the liver and kidney with increased serum alkaline phosphatase and ALT activities, and testicular atrophy and aspermatogenesis. All high-dose dogs died between week 2 and 8. The effects of 2,6-DNT were partially reversed within 4 weeks of cessation of treatment, and completely reversed within 19 weeks (Lee et al. 1976).
3.1.3. Chronic Toxicity
3.1.3.1. Human
Information on the chronic oral toxicity of 2,6-DNT in humans was unavailable.
3.1.3.2. Animal
Leonard et al. (1987) noted significant reductions in body weight gain and increases in liver weight in male rats following administration of 7 or 14 mg 2,6-DNT/kg/day for 1 year. Increased serum ALT activity was seen at both doses and increased serum gamma-glutamyl transpeptidase activity was seen at the high dose of 2,6-DNT. Hepatocytic degeneration and vacuolation as well as bile duct hyperplasia were apparent in most animals fed 2,6-DNT.
In a study with t-DNT (76% 2,4 DNT, 19% 2,6-DNT), rats were fed doses of 3.5, 14, or 35 mg/kg/day for 104 weeks (CIIT, 1982). General signs of toxicity included high mortality in the high-dose group and a dose-related decrease in body weight gain. In the mid- and high-dose groups, degenerative and proliferative alterations of hepatocytes and bile duct epithelium were observed in the first 26 weeks of treatment. These changes generally involved necrotic and vacuolated hepatocytes and necrosis and hyperplasia of the biliary epithelium. The high- and mid-dose males exhibited an increased incidence of testicular degeneration with decreased spermatogenesis. The high-dose group also had a low-grade regenerative anemia.
3.1.4. Developmental and Reproductive Toxicity
3.1.4.1. Human
Information on the developmental and reproductive toxicity of 2,6-DNT in humans following oral exposure was unavailable.
3.1.4.2. Animal
Rats and mice fed 2,6-DNT at doses up to 155 mg/kg/day (rats) or 299 mg/kg/day (mice) for 13 weeks, exhibited testicular atrophy and aspermatogenesis. Similar effects were reported in dogs fed capsules containing up to 100 mg 2,6-DNT/kg/day for 13 weeks (Lee et al. 1976).
3.1.5. Reference Dose
The health effects data for 2,6-DNT were reviewed by EPA and determined to be inadequate for derivation of an oral RfD (EPA 1991a).
3.2. INHALATION EXPOSURES
3.2.1. Acute Toxicity
Information on the acute toxicity of 2,6-DNT in humans or animals following inhalation exposure was unavailable.
3.2.2. Subchronic Toxicity
3.2.2.1. Human
Data regarding the subchronic toxicity in humans resulting from inhalation exposure to 2,6-DNT alone are lacking. However, Levine et al. (1986) reported a significant increase in mortality due to ischemic heart disease and other circulatory diseases in workers employed in munition plants in the 1940s and 1950s over that seen in white U.S. males and in persons living in the vicinity of the plants. At one plant, the workers were potentially exposed to t-DNT containing 19% 2,6-DNT as well as 2,4-DNT containing 1% 2,6-DNT. The median employment time was 2.1 years. According to Levine (1987), exposure to DNT occurred by inhalation as well as dermal contact and frequently exceeded 1 mg DNT/kg/day.
3.2.2.2. Animal
Information on the subchronic toxicity of 2,6-DNT in animals following inhalation exposure was unavailable.
3.2.3. Chronic Toxicity
Information on the subchronic toxicity of 2,6-DNT in humans or animals following inhalation exposure was unavailable.
3.2.4. Developmental and Reproductive Toxicity
3.2.4.1. Human
Data regarding the human developmental and reproductive toxicity of 2,6-DNT alone were unavailable. A significant reduction in sperm counts and normal sperm morphology was reported in one study in which workers were exposed to t-DNT (Ahrenholz 1980), but in a study designed to corroborate these findings, Hamill et al. (1982) found no detectable reproductive effects among male workers exposed to DNT in another facility.
3.2.4.2. Animal
Information on the developmental and reproductive toxicity of 2,6-DNT in animals following inhalation exposure was unavailable.
3.2.5. Reference Concentration
The health effects data for 2,6-DNT were reviewed by EPA and determined to be inadequate for derivation of an inhalation RfC (EPA 1991a).
3.3. OTHER ROUTES OF EXPOSURE
3.3.1. Acute Toxicity
3.3.1.1. Human
Information on the acute toxicity of 2,6-DNT in humans by other routes of exposure was unavailable.
3.3.1.2. Animal
Dogs survived a subcutaneous injection of 0.05 mg 2,6-DNT/kg, but died 2-8 days following a 0.1 mg/kg dose (Perkins 1919).
2,6-DNT was a mild primary skin irritant in rabbits and mild skin sensitizer in guinea pigs, but was not an ocular irritant in rabbits (Lee et al. 1975).
3.3.2. Subchronic Toxicity
Information on the subchronic toxicity of 2,6-DNT in humans or animals by other routes of exposure was unavailable.
3.3.3. Chronic Toxicity
Information on the chronic toxicity of 2,6-DNT in humans or animals by other routes of exposure was unavailable.
3.3.4. Developmental and Reproductive Toxicity
Information on the developmental and reproductive toxicity of 2,6-DNT in humans or animals by other routes of exposure was unavailable.
3.4. TARGET ORGANS/CRITICAL EFFECTS
3.4.1. Oral Exposures
3.4.1.1. Primary Target Organ(s)
1. Blood: Subchronic oral exposure to 2,6-DNT produced methemoglobinemia, an increase in Heinz bodies, anemia, and compensatory reticulocytosis in rats and dogs, and extramedullary hematopoiesis in rats, mice, and dogs.
2. Liver: Effects seen in rats following chronic exposure to 2,6-DNT included increased liver weight, bile duct hyperplasia, degenerative changes in hepatocytes, and increased serum enzyme activities indicative of liver dysfunction. Subchronic exposure induced bile duct hyperplasia in rats, mice, and dogs.
3. Reproduction: Subchronic oral exposure to 2,6-DNT produced decreased spermatogenesis and testicular atrophy in rats, mice, and dogs.
4. Kidney: Subchronic oral exposure to 2,6-DNT produced inflammatory and degenerative kidney changes in dogs. There were no renal effects in rats or mice.
5. Nervous system: Subchronic oral exposure to 2,6-DNT produced incoordination, weakness, tremors, and paralysis. Neurotoxic symptoms were not seen in rats or mice.
3.4.1.2. Other Target Organ(s)
Other target organs following oral exposure to 2,6-DNT were not identified.
3.4.2. Inhalation Exposures
Primary or other target organs following inhalation exposure to 2,6-DNT alone were not identified. However, a significant increase in mortality due to ischemic heart disease was reported in workers exposed to 2,4-DNT and/or t-DNT containing 19% 2,6-DNT.
3.4.3 Other Routes of Exposure
Primary or other target organs by other routes of exposure to 2,6-DNT were not identified.
4. CARCINOGENICITY
4.1. ORAL EXPOSURES
4.1.1. Human
Information on the carcinogenicity of 2,6-DNT in humans following oral exposure was unavailable.
4.1.2. Animal
In a study designed to compare the carcinogenic potential of t-DNT, pure 2,6-DNT, and pure 2,4-DNT, 47% of male F344 rats fed 35 mg/kg/day t-DNT for 1 year developed hepatocellular carcinomas, compared with 85 or 100% of rats fed 7 or 14 mg/kg/day pure 2,6-DNT, respectively. No tumors were found in rats fed 27 mg/kg/day pure 2,4-DNT or in controls (Leonard et al. 1987). Although the duration of this study was limited to 1 year, the data suggest that 2,6- rather than 2,4-DNT is the primary carcinogen in t-DNT.
A bioassay with t-DNT (76% 2,4 DNT, 19% 2,6-DNT) in which F344 rats were exposed to dietary concentrations of 3.5, 14.0, or 35.0 mg/kg/day for 2 years showed that t-DNT is a potent hepatocarcinogen (CIIT 1982). A 100% incidence of hepatocellular carcinomas was observed in male rats exposed to the highest dose after 1 year of treatment, whereas females had a 55% incidence. After 2 years, a high incidence of hepatocellular carcinomas was also reported in the mid-dose group. In addition, there was an increased incidence of hepatic neoplastic nodules in high-dose rats of both sexes after 1 year, and in low- and mid-dose rats after 2 years of treatment.
Popp and Leonard (1982) tested 2,6-, 2,4, and t-DNT using an in vivo hepatic initiation/promotion protocol with rats. The presence of GGT+ (gamma-glutamyl transpeptidase positive) foci in the liver, indicating initiating activity, was only observed for 2,6- and t-DNT. In the promotion assay, positive responses were observed for both the 2,6- and 2,4- isomers, with the 2,6-isomer yielding a stronger response.
Swenberg et al. (1983) demonstrated covalent binding of 2,6-DNT to rat hepatocyte RNA following oral dosing with 2,6-DNT, with hepatocytes of female rats showing slightly less binding than male rats. Rickert et al. (1983) reported similar hepatic binding of 2,6-DNT to protein, RNA, and DNA of rats.
4.2. INHALATION EXPOSURES
Information on the carcinogenicity of 2,6-DNT in humans or animals following inhalation exposure was unavailable.
4.3. OTHER ROUTES OF EXPOSURE
4.3.1 Human
Information on the carcinogenicity of 2,6-DNT in humans or animals by other routes of exposure was unavailable.
4.3.2 Animal
In lung-tumor assays, 2,6-DNT gave a positive response using A/J mice (Slaga et al. 1985) and a negative response in Strain A mice (Schut et al. 1983). When applied topically at doses of 1, 5, or 10 mg followed by weekly applications of a phorbol ester for 3 weeks, 2,6-DNT exhibited weak skin tumor initiating and promoting activities in SENCAR mice (Slaga et al. 1985).
4.4. EPA WEIGHT-OF-EVIDENCE
2,6-DNT has not been evaluated by EPA for evidence of human carcinogenic potential. However, a carcinogenicity assessment is available for the dinitrotoluene mixture, which includes both 2,4-DNT and 2,6-DNT (EPA 1991a,b).
Classification: B2; probable human carcinogen (1991b)
Basis: Increased incidence of multiple and malignant tumor types at multiple sites in both sexes of rats (2 strains) and malignant renal tumors in male mice. This classification is supported by mutagenicity data.
4.5. CARCINOGENICITY SLOPE FACTORS
4.5.1. Oral
SLOPE FACTOR: 6.8E-1 (mg/kg/day)-1
DRINKING WATER UNIT RISK: 1.9E-5 (µg/L)-1
PRINCIPAL STUDY: Ellis et al. (1979)
VERIFICATION DATE: 05/03/89
COMMENT: The DNT used in the principal study contained 98% 2,4- and 2% 2,6-DNT. The slope factor and drinking water unit risk value also pertain to the dinitrotoluene mixture, which includes both 2,4- and 2,6-DNT (EPA 1991a,b).
4.5.2. Inhalation
An inhalation slope factor has not been assigned.
5. REFERENCES
Ahrenholz, S. H. 1980. Health Hazard Evaluation Determination Report No. HE 79-113-728. Olin Chemical Company, Brandenburg, Kentucky. National Institute for Occupational Safety and Health, Cincinnati, Ohio.
ATSDR (Agency for Toxic Substances and Disease Registry). 1989. Toxicological Profile for 2,4-Dinitrotoluene and 2,6-Dinitrotoluene. Prepared by Clement International Corporation, under Contract 205-88-0608. U.S. Public Health Service.
CIIT (Chemical Industry Institute of Toxicology). 1982. 104-Week Chronic Toxicity Study in Rats: Dinitrotoluene. Final Report, Vol. 1 and 2. CIIT Docket No. 12362. Research Triangle Park, North Carolina.
Dean, J. A., Ed. 1979. Lange's Handbook of Chemistry, 12th ed. McGraw-Hill Book Company, New York, pp. 7(198-199).
Dunlap, K. L. 1978. Nitrobenzene and nitrotoluenes. In: M. Grayson and D. Eckroth, Eds., Kirk-Othmer Encyclopedia of Chemical Technology, 3rd. ed., Vol. 15. John Wiley & Sons, New York, pp. 930-931.
Ellis, H. V., C.-B. Hong and C.-C. Lee. 1980. Mammalian Toxicity of Munition Compounds. Summary of Toxicity of Nitrotoluenes. Report No. 11. Midwest Research Institute, Kansas City, Missouri. DAMD17-74-C-4073.
EPA. 1986. Health and Environmental Effects Profile for Dinitrotoluene. Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, Ohio. ECAO-CIN-P183.
EPA. 1991a. Health Effects Assessment Summary Tables. Annual FY-1991. 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. NTIS PB91-921199.
EPA. 1991b. Dinitrotoluene mixture, 2,4-/2,6-. Integrated Risk Information System (IRIS). Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, Ohio.
Etnier, E. 1987. Water Quality Criteria for 2,4-Dinitrotoluene and 2,6-Dinitrotoluene. Final Report. , Oak Ridge, Tennessee. AD-ORNL-6312.
Hamill, P. V. V., E. Steinberger, R. J. Levine, et al. 1982. The epidemiologic assessment of male reproductive hazard from occupational exposure to TDA and DNT. J. Occup. Med. 24: 985-993.
Hawley, G. G., Ed. 1981. The Condensed Chemical Dictionary, 10th ed. Van Nostrand Reinhold Co., New York, p. 375.
Lee, C.-C., H. V. Dilley, H. R. Hogdson, et al. 1975. Mammalian Toxicity of Munition Compounds. Phase I: Acute Oral Toxicity, Primary Skin and Eye Irritation, Dermal Sensitization, and Disposition and Metabolism. AD BO11 150. Midwest Research Institute, Kansas City, MO.
Lee, C.-C., H. V. Ellis, J. J. Kowalski, et al. 1976. Mammalian Toxicity of Munitions Compounds. Phase II: Effects of Multiple Doses. Part III: 2,6-Dinitrotoluene. Progress Report No. 4. Midwest Research Institute Project No. 3900-B. DAMD-17-74-C-4073.
Leonard, T. B., M. E. Graichen and J. A. Popp. 1987. Dinitrotoluene isomer-specific hepatocarcinogenesis in F-344 rats. J. Nat. Cancer Inst. 79: 1313-319.
Levine, R. J. 1987. Dinitrotoluene: Human atherogen, carcinogen, neither or both? In: Chemical Industry Institute of Toxicology Activities 7: 1-5. (Cited in ATSDR 1989)
Levine, J. R., M. J. Turner, Y. S. Crume, et al. 1985. Assessing exposure to dinitrotoluene using a biological monitor. J. Occup. Med. 27: 627-638. (Cited in Etnier 1987)
Levine, R. J., D. A. Andjelkovich, S. L. Kersteter, et al. 1986. Heart disease in workers exposed to dinitrotoluene. J. Occup. Med. 28: 811-816.
Long, R. M. and D. E. Rickert. 1982. Metabolism and excretion of 2,6-dinitro[14C]toluene in vivo and in isolated perfused rat livers. Drug Metab. Dispos. 10: 455-458. (Cited in EPA 1986)
Perkins, R. G. 1919. A study of the munitions intoxications in France. U.S. Pub. Health Rep. 34: 2335-2374. (Cited in Etnier 1987, EPA 1986)
Popp, J. A., and T. B. Leonard. 1982. The use of in vivo hepatic initiation-promotion systems in understanding the hepatocarcinogenesis of technical grade dinitrotoluene. Toxicol. Pathol. 10: 190-196.
Rickert, D. E., S. R. Schnell and R. M. Long. 1983. Hepatic macromolecular covalent binding and intestinal disposition of [14]dinitrotoluenes. J. Toxicol. Environ. Health 11: 555-567. (Cited in EPA 1986)
Rickert, D. E., B. E. Butterworth and J. A. Popp. 1984. Dinitrotoluene: Acute toxicity, oncogenicity, genotoxicity, and metabolism. CRC Crit. Rev. Toxicol. 13: 217-234.
Schut, H. A. J., T. R. Loeb, L. A. Grimes, et al. 1983. Distribution, elimination, and test for carcinogenicity of 2,6-dinitrotoluene after intraperitoneal and oral administration to strain A mice. J. Toxicol. Environ. Health 12: 659-670. (Cited in ATSDR 1989, EPA 1986)
Sears, J. K. and N. W. Touchette. 1982. Plasticizers. In: M. Grayson and D. Eckroth, Eds. Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 18, 3rd ed. John Wiley & Sons, New York, p. 174.
Slaga, T. J., L. L. Triplett, L. H. Smith, et al. 1985. Carcinogenesis of Nitrated Toluenes and Benzenes. Skin and Lung Tumor Assays in Mice. Final Report. , Oak Ridge, Tennessee. ORNL/TM-9645.
Spanggord, R. J. and B. E. Suta. 1982. Effluent analysis of wastewater generated in the manufacture of 2,4,6,-trinitrotoluene: 2. Determination of a representative discharge of ether-extractable components. Environ. Sci. Technol. 16: 233-236.
Swenberg, J. A., D. E. Rickert, B. L. Baranyi, et al. 1983. Cell specificity in DNA binding and repair of chemical carcinogens. Toxicol. Appl. Pharmacol. 72: 313-323. (Cited in Etnier 1987)
Vernot, E. H., J. D. MacEwen, C. C. Haun, et al. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42: 417-424.
Weast, R. C., J. A. Spadaro, R. O. Becker, et al. 1988. Handbook of Chemistry and Physics, 69th ed. CRC Press, Inc., Boca Raton, Florida, pp. C-520.
Woolen, B. H., M. G. Hall, R. Craig, et al. 1985. Dinitrotoluene: Assessment of occupational absorption during the manufacture of blasting explosives. Int. Arch. Occup. Environ. Health 55: 319-330. (Cited in Etnier 1987).
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