Azides have varied uses in the chemical, dye-stuff, plastics, rubber and metal industries. Several compounds are used in wastewater treatment and as chemical intermediates, food additives, and sanitizing agents in dishwashing detergent and swimming pools.
1,1'-Azobis(formamide) is a blowing agent for synthetic and natural rubber and ethylene-vinyl acetate copolymers. It is also useful as a foaming agent added to increase the porosity of plastics. Trichlorinated isocyanuric acid and sodium dichloroisocyanurate are used as sanitizing agents for swimming pools and as active ingredients in detergents, commercial and household bleaches, and dishwashing compounds. Sodium dichloroisocyanurate is also used in water and sewage treatment.
Edetic acid (EDTA) has numerous functions in the food, metal, chemical, textile, photography and health care industries. It is an antioxidant in foods. EDTA is used as a chelating agent to remove unwanted metal ions in boiler water and cooling water, in nickel plating and in wood pulping. It also acts as a bleaching agent for film processing in the photography industry, an etching agent in metal finishing and a dyeing agent in the textile industry. EDTA is found in detergents for textiles, industrial germicides, metal cutting fluids, semiconductor production, liquid soaps, shampoos, pharmaceuticals and cosmetics industry products. It is also used in medicine to treat lead poisoning.
Phenylhydrazine, aminoazotoluene and hydrazine are useful in the dye-stuff industry. Phenylhydrazine is also utilized in the preparation of pharmaceutical products. Hydrazine is a reactant in fuel cells for military uses and a reducing agent in plutonium extraction from reactor waste. It is used in nickel plating, wastewater treatment, and electrolytic plating of metals on glass and plastics. Hydrazine is employed for nuclear fuel reprocessing and as a component of high-energy fuels. It is a corrosion inhibitor in boiler feedwater and in reactor cooling water. Hydrazine is also a chemical intermediate and a rocket propellant. Diazomethane is a powerful methylating agent for acidic compounds such as carboxylic acids and phenols.
Sodium azide is used in organic synthesis, explosives manufacture and as a propellant in automobile air-bags. Hydrazoic acid is used to make contact explosives such as lead azide.
Other azides, including methylhydrazine, hydrazobenzene, 1,1-dimethylhydrazine, hydrazine sulphate and diazomethane, are used in numerous industries. Methylhydrazine is a solvent, a chemical intermediate and a missile propellant, while hydrazobenzene is a chemical intermediate and an antisludging additive to motor oil. 1,1-Dimethylhydrazine is used in rocket fuel formulations. It is a stabilizer for organic peroxide fuel additives, an absorbent for acid gases, and a component of jet fuel. Hydrazine sulphate is used in the gravimetric estimation of nickel, cobalt and cadmium. It is an antioxidant in soldering flux for light metals, a germicide and a reducing agent in the analysis of minerals and slags.
Fire and explosion hazards. Either in the gaseous or liquid state, diazomethane explodes with flashes and even at –80 °C the liquid diazomethane may detonate. It has been the general experience, however, that explosions do not occur when diazomethane is prepared and contained in solvents such as ethyl ether.
Health hazards. Diazomethane was first described in 1894 by von Pechmann, who indicated that it was extremely poisonous, causing air hunger and chest pains. Following this, other investigators reported symptoms of dizziness and tinnitus. Skin exposure to diazomethane was reported to produce denudation of the skin and mucous membranes, and it was claimed that its action resembles that of dimethyl sulphate. It was also noted that the vapours from the ether solution of the gas were irritating to the skin and rendered the fingers so tender that it was difficult to pick up a pin. In 1930, exposure of two persons resulted in chest pains, fever and severe asthmatic symptoms about 5 hours after exposure to mere traces of the gas.
The first exposure to the gas may not produce any noteworthy initial reactions; however, subsequent exposures in even minute amounts may produce extremely severe attacks of asthma and other symptoms. The pulmonary symptoms may be explained as either the result of true allergic sensitivity after repeated exposure to the gas, particularly in individuals with hereditary allergy, or of a powerful irritant action of the gas on the mucous membranes.
At least 16 cases of acute diazomethane poisoning, including fatalities from pulmonary oedema, have been reported amongst chemists and laboratory workers. In all cases, symptoms of intoxication included irritating cough, fever and malaise, varying in intensity according to the degree and duration of exposure. Subsequent exposures have led to hypersensitivity.
In animals, exposure to diazomethane at 175 ppm for 10 minutes caused haemorrhagic emphysema and pulmonary oedema in cats, resulting in death in 3 days.
Toxicity. One explanation for the toxicity of diazomethane has been the intracellular formation of formaldehyde. Diazomethane reacts slowly with water to form methyl alcohol and liberate nitrogen. Formaldehyde, in turn, is formed by the oxidation of methyl alcohol. The possibilities of liberation in vivo of methyl alcohol or of the reaction of diazomethane with carboxylic compounds to form toxic methyl esters may be considered; on the other hand, the deleterious effects of diazomethane may be primarily due to the strongly irritant action of the gas on the respiratory system.
Diazomethane has been shown to be a lung carcinogen in mice and rats. Skin application and subcutaneous injection, as well as inhalation of the compound, have also been shown to cause tumour development in experimental animals. Bacterial studies show it is mutagenic. The International Agency for Research on Cancer (IARC), however, places it in Group 3, unclassifiable as to human carcinogenicity.
Diazomethane is an effective insecticide for the chemical control of Triatoma infestations. It is also useful as an algicide. When the ichthyotoxic component of the green alga Chaetomorpha minima is methylated with diazomethane, a solid is obtained which retains its toxicity to kill fish. It is noteworthy that in the metabolism of the carcinogens dimethylnitrosamine and cycasin, one of the intermediary products is diazomethane.
Hydrazine and derivatives
Flammability, explosion and toxicity are major hazards of the hydrazines. For example, when hydrazine is mixed with nitromethane, a high explosive is formed which is more dangerous than TNT. All hydrazines discussed here have sufficiently high vapour pressures to present serious health hazards by inhalation. They have a fishy, ammoniacal odour which is repulsive enough to indicate the presence of dangerous concentrations for brief accidental exposure conditions. At lower concentrations, which may occur during manufacturing or transfer processes, the warning properties of odour may not be enough to preclude low-level chronic occupational exposures in fuel handlers.
Moderate to high concentrations of hydrazine vapours are highly irritating to the eyes, nose and the respiratory system. Skin irritation is pronounced with the propellant hydrazines; direct liquid contact results in burns and even sensitization type of dermatitis, especially in the case of phenylhydrazine. Eye splashes have a strongly irritating effect, and hydrazine can cause permanent corneal lesions.
In addition to their irritating properties, hydrazines also exert pronounced systemic effects by any route of absorption. After inhalation, skin absorption is the second most important route of intoxication. All hydrazines are moderate to strong central nervous system poisons, resulting in tremors, increased central nervous system excitability and, at sufficiently high doses, convulsions. This can progress to depression, respiratory arrest and death. Other systemic effects are in the haematopoietic system, the liver and the kidney. The individual hydrazines vary widely in degree of systemic toxicity as far as target organs are concerned.
The haematological effects are self-explanatory on the basis of haemolytic activity. These are dose dependent and, with the exception of monomethylhydrazine, they are most prominent in chronic intoxication. Bone marrow changes are hyperplastic with phenylhydrazine, and blood cell production outside the bone marrow has also been observed. Monomethylhydrazine is a strong methaemoglobin former, and blood pigments are excreted in the urine. The liver changes are primarily of the fatty degeneration type, seldom progressing to necrosis, and are usually reversible with the propellant hydrazines. Monomethylhydrazine and phenylhydrazine in high doses can cause extensive kidney damage. Changes in the heart muscle are primarily of fatty character. The nausea observed with all of these hydrazines is of central origin and refractory to medication. The most potent convulsants in this series are monomethylhydrazine and 1,1-dimethylhydrazine. Hydrazine causes primarily depression, and convulsions occur much less frequently.
All hydrazines appear to have some kind of activities in some laboratory animal species by some route of entry (feeding in drinking water, gastric intubation or inhalation). IARC considers them Group 2B, possibly carcinogenic in humans. In laboratory animals, with the exception of one derivative not discussed here, 1,2-dimethylhydrazine (or symmetrical dimethylhydrazine), there is a definite dose response. In view of its Group 2B rating, any exposure of humans should be minimized by proper protective equipment and decontamination of accidental spills.
The pathology of phenylhydrazine has been studied by means of animal experiments and clinical observations. Information about the effects of phenylhydrazine in humans was obtained from the use of phenylhydrazine hydrochloride for therapy. The conditions observed included haemolytic anaemia, with hyperbilirubinaemia and urobilinuria, and the appearance of Heinz bodies; liver damage with hepatomegalia, icterus, and very dark urine containing phenols; sometimes signs of kidney manifestations occurred. Haematological effects included cyanosis, haemolytic anaemia, sometimes with methaemoglobinaemia, and leucocytosis. Among the more general symptoms were fatigue, giddiness, diarrhoea and lowering of the blood pressure. It was also observed that a student, who had received 300 g of the substance on the abdomen and thighs suffered from cardiac collapse with a coma that lasted for several hours. Individuals with hereditary glucose-6-phosphate dehydrogenase (G6PDH) deficiency would be much more susceptible to the haemolytic effects of phenylhydrazine and should not be exposed to it.
With regard to skin damage, there have been reports of acute eczema with vesicular eruption, as well as chronic eczema on the hands and forearms of workers preparing antipyrin. Also described was a case of vesicular dermatosis with the production of phlyctenae on the wrist of an assistant chemist. This appeared 5 or 6 hours after handling and took 2 weeks to heal. A chemical engineer who handled the substance suffered only from a few pimples, which disappeared in 2 or 3 days. Phenylhydrazine is therefore regarded as a potent skin sensitizer. It is very rapidly absorbed by the skin.
Because of reports of carcinogenicity of phenylhydrazine to mice, the US National Institute for Occupational Safety and Health (NIOSH) has recommended its regulation as a human carcinogen. A variety of bacterial and tissue-culture studies have shown it is mutagenic. Intraperitoneal injection of pregnant mice resulted in offspring with severe jaundice, anaemia and a deficit in acquired behaviour.
Sodium azide and hydrazoic acid
Sodium azide is manufactured by combining sodamide with nitrous oxide. It reacts with water to produce hydrazoic acid. Hydrazoic acid vapour may be present when handling sodium azide. Commercially, hydrazoic acid is produced by the action of acid on sodium azide.
Sodium azide appears to be only slightly less acutely toxic than sodium cyanide. It may be fatal if inhaled, swallowed or absorbed through skin. Contact may cause burns to skin and eyes. A lab technician accidentally ingested what was estimated to be a “very small amount” of sodium azide. Symptoms of tachycardia, hyperventilation and hypotension were observed. The authors note that the minimal hypotensive dose in humans lies between 0.2 and 0.4 mg/kg.
Treatment of normal individuals with 3.9 mg/day of sodium azide for 10 days produced no effects other than a heart-pounding sensation. Some hypertensive patients developed sensitivity to azide at 0.65 mg/day.
Workers exposed to 0.5 ppm hydrazoic acid developed headaches and nasal congestion. Additional symptoms of weakness and eye and nasal irritation developed from exposure to 3 ppm for less than 1 hour. Pulse rate was variable and blood pressure was low or normal. Similar symptoms were reported among workers making lead azide. They had definite low blood pressure which became more pronounced during the work day and returned to normal after leaving work.
Animal studies showed a rapid but temporary fall in blood pressure from single oral doses of 2 mg/kg or more of sodium azide. Associated haematuria and cardiac irregularities were observed at levels of 1 mg/kg IV in cats. Symptoms observed in animals after relatively large doses of sodium azide are respiratory stimulation and convulsions, then depression and death. The LD50 for sodium azide is 45 mg/kg in rats and 23 mg/kg in mice.
Exposure of rodents to hydrazoic acid vapour causes acute inflammation of the deep lung. Hydrazoic acid vapour is about eight times less toxic than hydrogen cyanide, with a concentration of 1,024 ppm being fatal in mice after 60 minutes (compared to 135 ppm for hydrogen cyanide).
Sodium azide was mutagenic in bacteria, although this effect was reduced if metabolizing enzymes were present. It was also mutagenic in mammalian cell studies.
Table 1 - Chemical information.
Table 2 - Health hazards.
Table 3 - Physical and chemical hazards.
Table 4 - Physical and chemical properties.