Dinitrogen tetraoxide

Endpoint summary

Description of key information

The substance is mostly absorbed by inhalation. Absorption occurs mainly in the lower resrpiratory tract. The substance can react with water in the respiratry tract undegoing hydrolysis to nitric and nitrous acid, which have irritating to corrosive properties. The salts of these acids have also been detected in the blood stream and in the urine. Furhtermore, the substance can react with components of the alveolar fluid and epithelial cells, causing lipid membrane peroxidation and cell damage. There is no evidence of the bioaccumulation of the substance in tissues, although some data indicate that the substance can remain in the lungs for a longer period. Excretion is presumed to occur mainly by respiratory route, although salts of nitrous and nitric acidhave also been detected in the urine, suggesting that the substance is also partially excreted via urine. 

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

0

Absorption rate - dermal (%):

0

Absorption rate - inhalation (%):

100

Additional information

The test item is composed as listed in the Section 2.2. It is a gas and the molecular weight is 92.01 g/mol. Dinitrogen tetraoxide exists in equilibrium with nitrogen dioxide, with ca. 25% present in the form of NO₂ at 25 °C. At greater dilution, e.g. with air, the amount of NO₂ is greater. Therefore it would seem inevitable that the toxicity studies conducted with either of these gases would share a common mechanism. Therefore read-across from NO₂ to its dimer N₂O₄ is considered to be justified.

Due to the natural state of the material being a gas, inhalation is the most significant potential route of exposure.

Absorption:

Dinitrogen tetraoxide enters the terminal airways via the nose and the upper respiratory tract. In water, dinitrogen tetraoxide reacts slowly to form nitric acid and nitrous acid, both of which have irritating to corrosive effects. In was concluded from the a study with monkeys with radioactively labelled NO₂ that nitric acid and nitrous acid are formed also in the respiratory tract (MAK 2005, SCOEL 2014 and references reported therein). In man, 80-90% of NO₂ is taken up via the respiratory tract during normal breathing, and over 90% at maximum breathing. Dosimetric model calculations showed that NO₂ is absorbed mainly in the lower respiratory tract, where it accumulates particularly in the area between the conductive and respiratory airways (pulmonary acinus), in which the morphological changes are observed (MAK 2005, SCOEL 2014 and references therein).

Distribution:

Systemic distribution can occur following absorption from the lungs into the blood stream. The small molecular size of the material and the equilibrium that forms with nitrous oxide will mean the material can be readily distributed systemically. The nature of the product precludes accumulation in body fat. In the study with monkeys with radioactively labelled NO₂, salts of nitric and nitrous acids (nitrates and nitrites) were detected in blood and urine, indicating their absorption and distribution within the body. Experimental studies also showed that NO₂ or its products can remain in the lungs for a longer period (MAK 2005, SCOEL 2014 and references reported therein).

Metabolism:

Dinitrogen tetraoxide does not undergo a hepatic or enzymatic metabolism. Instead, the substance reacts slowly with water resulting in the formation of nitric and nitrous acids, the salts of which have been detected in blood and urine of experimental animals (MAK 2005, SCOEL 2014 and references therein). Furthermore, a monomer of dinitrogen tetraoxide, NO₂, is a free radical, which can react with components of the alveolar fluid and the epithelial cells in different ways, causing lipid membrane peroxidation and oxidative cell damage. The concentration dependence of the oxidative cell damage is determined by the antioxidative capacity of the alveolar fluid and the target cells.

Excretion:

As the route of administration is inhalation, it is likely that the route of excretion is via respiration for this or any gaseous breakdown products. However, the salts of nitrous and nitric acids were detected in urine of experimental animals (monkeys), suggesting that the substance is also partially excreted via urine.