Sodium nitrite

Endpoint summary

Additional information

There are several review/evaluation documents on sodium nitrite issued by pertinent international or national organizations. JECFA (Joint FAO/WHO Expert Committee on Food Additives) has issued a series of updated evaluation documents [e.g. WHO, 2004]. National Academy of Sciences (NAS, 1981), National Institute of Environmental Health Sciences of U.S.A. (NIEHS, 1970), or National Institute of Public Health and the Environmental Hygiene, Netherlands, (1986) issued a document regarding drinking water, which included the review/evaluation on human health hazard. National Toxicology Program document (NTP, 1990, 2001) includes a review on the toxicology publications in their reports. With regard to reproductive toxicity California EPA (CAL/EPA, 2000) is a noteworthy review.

Nitrite in blood is highly reactive with haemoglobin and causes methaemoglobinaemia. Ferrous iron associated with haemoglobin is oxidized by nitrite to ferric iron, leading to the formation of methaemoglobin. The oxygen-carrying capacity of methaemoglobin is much less than that of haemoglobin. Humans are considered to be more sensitive than rat in this respect. The primary acute toxic effects of sodium nitrite in rats and mice are resulted from methaemoglobinaemia. Reduction of nitrate (NO3-) to nitrite (NO2-) occurs by mammalian nitrate reductase and nitrate reductase activity of microorganisms in the oral cavity and upper gastrointestinal tract [NAS, 1981; Walker, 1996; WHO, 1996b]. In particular, oral microorganisms are responsible for significant levels of nitrate reduction. Salivary nitrate concentrations are considered directly related to an orally ingested amount of nitrate. Allowing for considerable inter-individual variations it has been estimated that 25% of nitrate ingested by humans are secreted in the saliva. Of this 25% approximately 20 % (i.e., about 5 % of the ingested dose) is reduced to nitrite in humans. The enzyme methaemoglobin reductase catalyzes the reduction of methaemoglobin to haemoglobin and protects red blood cells against oxidative damage. The secondary toxic effects of acute sodium nitrite in animals result in vasodilation, relaxation of smooth muscle, and lowering of blood pressure.

Dermal: Saito et al (1996) report a case where a four year old boy was treated with two liniment solutions containing sodium nitrite at 30 g/L (Liniment A) and 140 g/L (Liniment B). Liniment A was applied all over the boy’s body, causing listlessness and vomiting. Liniment B was applied all over the boy’s body a few days later. The boy went into shock and suffered severe cyanosis. He was hospitalised immediately, but died after two hours in intensive care. The boy’s blood methaemoglobin level was found to be 76%. In a study using rats, the authors confirmed percutaneous absorption of nitrite from both of the liniment formulations [Saito et al, 1997].

Oral: There are numerous case reports concerning the acute toxicity of sodium nitrite in humans available in the literature, as illustrated by the following examples: Gowans (1990) reported the fatal case of a nurse who probably ingested a 1g tablet of sodium nitrite (670 mg NO2 -). Death occurred two hours after admission to hospital. Post mortem methaemoglobin level was 35%, implying a much higher level on admission. Serum nitrite level was 13 mg/L. Finan et al (1998) reported a case of methaemoglobinaemia associated with three previously healthy children (two four year old boys and a two year old girl). One of the children had mistaken a bag of sodium nitrite crystals for sugar and added it to cups of tea at concentrations of 5100, 5000 and 4900 mg/L. Methaemoglobin levels of 77% and 38% were measured for two of the children. Centers for Disease Control (1997) report two cases of methemoglobinaemia attributable to nitrite contamination of potable water through boiler fluid additives. In the first of these, 49 schoolchildren were affected after eating soup which had been diluted with hot water from the tap. The soup was found to contain 459 ppm nitrite. Methaemoglobinaemia was diagnosed in 59% of the children, with levels between 3 – 47%. In the second case, six workers were found to have methaemoglobin levels of between 6 – 16% after drinking coffee contaminated with 300 ppm nitrite. Infants under 3 months old are particularly sensitive to nitrite. A large proportion of haemoglobin in these infants is in the foetal haemoglobin form, which is more readily oxidised to methaemoglobin than adult haemoglobin. Further, reduced nicotinamide-adenine dinucleotide (NADH)-dependent methaemoglobin reductase, the enzyme responsible for reduction of methaemoglobin back to normal haemoglobin, has only about half the activity present in adults [ATSDR, 2001]. Most clinical case data refer to neonates developing methaemoglobinaemia after drinking water or water-based formulations with high nitrate or nitrite content. The great majority of cases (wellwater methaemoglobinaemia) occurred when nitrate levels in drinking water exceeded 100 mg NO3 - /L. It is generally accepted that water nitrate content of 50 mg/L is safe even for neonates. Assuming normal liquid intake of 150 mL/kg bw/day by neonates, nitrate intake of 7.5 mg NO3 -/kg bw/day is considered safe. Other review reports are as follows. The lowest acute oral lethal dose of nitrite reported for humans varied from 27-255 mg/kg bw, in which the lowest figures applied for children and elderly people. Nitrite is also more toxic to young infants (3 months) than adults giving rise to relatively higher methaemoglobin levels in the blood. The lowest toxic dose reported was 1 mg NO2/kg bw, whereas in another study 0.5-5 mg NO2/kg bw did not cause any toxic effect [National Institute of Public Health and Environmental Hygiene, Netherlands, 1986].

Repeated dose toxicity: In U.S.A, 320 cases of infant methaemoglobinaemia have been reported to be associated with the use of nitrate-containing (converted to nitrite de novo) well water [NIEHS, 1970]. Other cases, particular in Europe, have been associated with the consumption of high nitrite containing vegetables, particularly spinach [Sander and Jacobi, 1967; NIEHS, 1970; Hack and Dowes, 1983].