For definition of Groups, see Preamble Evaluation.
VOL.: 65 (1996) (p. 309)
Chem. Abstr. Name: Dinitrotoluene
Chem. Abstr. Name: 1-Methyl-2,4-dinitrobenzene
Chem. Abstr. Name: 2-Methyl-1,3-dinitrobenzene
Chem. Abstr. Name: 1-Methyl-3,5-dinitrobenzene
5.1 Exposure data
2,4-, 2,6- and 3,5-Dinitrotoluenes are produced by nitration of toluene or nitrotoluenes. Dinitrotoluenes are used primarily as chemical intermediates in the production of toluene diamines and diisocyanates (mainly as the mixture of 2,4- and 2,6-isomers), while smaller amounts of the three isomers are also used to produce dyes, explosives and propellants. Human exposure to dinitrotoluenes can occur by inhalation or skin absorption during their production and use as intermediates. They have been detected in wastewater from dinitrotoluene production and use, and in surface and groundwater in the vicinity of these manufacturing facilities.
5.2 Human carcinogenicity data
A cohort study of workers from a munitions factory in the United States found an increased risk for cancer of the liver and gall-bladder among workers exposed to a mixture of 2,4- and 2,6-dinitrotoluenes, based on six cases. No such increase was detected in a previous study based on a smaller group of workers from the same and another munitions factory in the United States. These findings were not considered to be strong or consistent enough to permit a conclusion on the carcinogenicity of dinitrotoluenes in humans.
5.3 Animal carcinogenicity data
2,4-Dinitrotoluene was tested by oral administration in two adequate studies in mice and two adequate studies in rats. In one study in mice, no tumorigenic effect was reported. In the second study in mice, using higher doses, tumours of the renal tubular epithelium were observed in males. In both studies in rats, the incidence of various tumours of the integumentary system was increased in males. The incidence of hepatocellular carcinomas was increased in treated males and females in one study. The incidence of fibroadenomas of the mammary gland was increased in females in both studies.
2,6-Dinitrotoluene was tested for carcinogenicity by oral administration in two studies in male rats and increased the incidence of hepatocellular neoplastic nodules and carcinomas.
3,5-Dinitrotoluene has not been tested for carcinogenicity in experimental animals.
Technical-grade dinitrotoluene (approximately 80/20 2,4/2,6-isomers) was tested for carcinogenicity in two studies in rats by oral administration producing hepatocellular neoplastic nodules and hepatocellular carcinomas in male rats in one study and in both sexes in a second study.
5.4 Other relevant data
Dinitrotoluenes are absorbed following dermal and inhalation exposure of workers.
The most abundant metabolites of dinitrotoluenes found in urine from exposed workers were dinitrobenzoic acids. In addition, amino metabolites have been reported. The appearance of reduced metabolites suggests either that human hepatic enzymes are capable of reduction of the nitro group of dinitrotoluene or that dinitrotoluene (or its metabolites) gains access to the intestinal microflora which is capable of reduction, after which the metabolites are reabsorbed and excreted into urine. Limited data indicate a sex difference in humans as regards the urinary metabolite pattern. In humans, the elimination half-life for the urinary metabolites is 1-2.7 h.
The metabolism and excretion of dinitrotoluenes by rats seem to be qualitatively similar to those in humans. However, there are quantitative differences as regards prevalence of different metabolites. Thus, the major urinary metabolites of 2,4-dinitrotoluene are 2,4-dinitrobenzoic acid in humans and 2,4-dinitrobenzyl alcohol in rats.
Heavy human exposure to technical-grade dinitrotoluene may cause a variety of symptoms and signs, including cyanosis - presumably because of methaemoglobinaemia - anaemia and toxic hepatitis. Further, dinitrotoluenes may give rise to allergic contact dermatitis.
A variety of toxic effects are observed in animals following acute administration of various dinitrotoluene isomers. Certain dinitrotoluene isomers, most notably 2,6-dinitrotoluene, produce extensive centrilobular hepatic necrosis following administration in vivo.
In laboratory animals, the chronic toxic effects following exposure to dinitrotoluene include various neurotoxic effects (including paralysis), hepatotoxicity, including dysplasia, hyperplastic foci and hepatic megalocytosis, anaemia and methaemoglobinaemia.
No association was found between exposure to the compounds of male workers in a dinitrotoluene facility and the results of semen analysis, the levels of follicle-stimulating hormone or the occurrence of miscarriages or delayed conception in their partners.
In female rats, administration of technical-grade dinitrotoluene by gavage did not produce teratogenic effects even at dose levels which produce significant maternal and embryo/fetal toxicity. In studies in male rats, 2,4-dinitrotoluene induced adverse reproductive effects and anti-spermatogenic activity.
No data on the metabolism or toxicity of 3,5-dinitrotoluene were available to the Working Group.
2,4-Dinitrotoluene (technical grade) is weakly mutagenic in bacteria. It was inactive in mammalian cells in vitro in tests for gene mutation, unscheduled DNA synthesis and transformation, but inhibited intercellular communication at toxic concentrations. In rats in vivo, it induced unscheduled DNA synthesis in hepatocytes, provided the normal gut flora was present. It induced sister chromatid exchange in rat lymphocytes exposed in vivo. In mice, it was negative in the bone-marrow micronucleus test, the dominant lethal test and the spot test.
Purified 2,4-dinitrotoluene showed DNA binding in rats in vivo in several organs, the binding being highest in the liver. Three distinct adducts were identified. In bacteria, it induced DNA damage and gene mutation. In insects, it induced sex-linked recessive lethal mutations but not dominant lethal mutations or translocations. In mammalian cells in vitro, it induced DNA strand breaks, gene mutations in mouse lymphoma cells (without activation) but not in Chinese hamster ovary cells and a low frequency of sister chromatid exchange but not of chromosomal aberrations in Chinese hamster ovary cells. It inhibited intercellular communication but did not induce cell transformation. In mammals in vivo, 2,4-dinitrotoluene induced a weak response in unscheduled DNA synthesis in rat hepatocytes but was negative in the dominant lethal assay and the sperm morphology test in mice.
2,6-Dinitrotoluene is weakly mutagenic in bacteria. In mammalian cells in vitro, it induced DNA strand breaks but not gene mutation or cell transformation. Studies of the inhibition of intercellular communication gave equivocal results. With 2,6-dinitrotoluene, DNA adducts were found after in-vivo exposure of rats. In vivo, it induced unscheduled DNA synthesis in rat hepatocytes. In the urine of exposed rats, mutagenic metabolites could be detected.
Experiments indicate the following steps in the metabolic activation leading to the formation of adducts: (1) 2,6-dinitrotoluene is metabolized in the liver; (2) metabolites are excreted in the bile; (3) the biliary metabolites are hydrolysed and further metabolized in the intestine; and (4) after enterohepatic transportation of the metabolites back to the liver, the metabolites are activated further and bound to macromolecules.
3,5-Dinitrotoluene is mutagenic in bacteria but did not induce DNA damage or mutations in mammalian cells in culture.
There is inadequate evidence in humans for the carcinogenicity of 2,4-, 2,6- and 3,5-dinitrotoluenes.
There is sufficient evidence in experimental animals for the carcinogenicity of 2,4-dinitrotoluene and 2,6-dinitrotoluene.
There is inadequate evidence in experimental animals for the carcinogenicity of 3,5-dinitrotoluene.
2,4- and 2,6-Dinitrotoluenes are possibly carcinogenic to humans (Group 2B).
3,5-Dinitrotoluene is not classifiable as to its carcinogenicity to humans (Group 3).
For definition of the italicized terms, see Preamble Evaluation.
Synonyms for 2,4-dinitrotoluene
Synonyms for 2,6-dinitrotoluene
Synonym for 3,5-dinitrotoluene
See Also: Toxicological Abbreviations