Hazard Identification

What is melamine?

Melamine (chemical name 2,4,6-triamino-1,3,5-triazine, CAS number 108-78-1) is a synthetic triazine compound and an organic base with the chemical formula C₃N₆H₆. It is an important industrial chemical and has been used as a component in various products since the late 1930s. The best known use of melamine is in combination with formaldehyde to produce melamine resin, a very hardwearing thermosetting plastic. Melamine resin has been widely used to make durable tableware, worktops and whiteboards. Melamine is important in a number of other applications, including fire retardants, fertilizers, pigments and glues.

Melamine also has analogues produced by successive deamination reactions. These are ammeline, ammelide and cyanuric acid. It is now generally accepted that melamine in food, in combination with an analogue, can have potentially serious health consequences for animals and for humans.

Occurrence in foods

Melamine was first identified in foods in the spring of 2007 when it was discovered in pet food linked to kidney failure in dogs and cats. It was found to have originated in wheat gluten and rice protein concentrate imported from China by the pet food producer and used as a thickening and binding ingredient. Levels of between 0.2% and 8% were detected in batches of the two ingredients. This would correspond to a dose around 400 mg/kg per day for animals fed with the contaminated pet food. Since then, melamine has been found in animal feed samples and in animal tissues at low concentrations. It has also been found in beverages, including coffee and orange juice, at levels of up to 2 mg/kg, but this is thought to be as a result of migration from plastic cups at high temperatures. Very low levels of melamine are thought to be occasionally present in some processed foods as a result of migration from packaging or processing equipment. It is also possible that melamine could be generated at very low levels as a by-product of processing.

More recently, melamine has been found in dairy products from China, especially powdered milk used to make infant formula associated with widespread kidney disease in babies. Samples of infant formula were found to contain melamine at maximum concentrations between 0.09 mg/kg and 619 mg/kg, although a sample from one producer gave a maximum of 2,563 mg/kg, equating to 350 mg/kg in reconstituted product. Melamine has also been found in liquid milk in China (highest concentration 8.6 mg/kg) and a wide variety of other products made using Chinese sourced milk powder. These include chocolate and milk-based confectionery, biscuits and other bakery products, coffee and tea whiteners and milk-based beverages. There have also been some unconfirmed reports that it has been found in Chinese egg products. Contaminated foods have been found all over the world, particularly in other Asian countries, but also in the EU, the USA, Canada and Australia

There is little information on the likely dietary exposure that would result from such levels in processed foods, but the European Food Safety Authority (EFSA) has estimated that chocolate with high levels of contaminated milk powder could result in an exposure (1.35 mg/kg bodyweight per day) more than double the tolerable daily intake (TDI) for children. It is thought that infants in China, fed exclusively on contaminated formula, are likely to have been exposed to melamine at potentially high levels well above the TDI.

Hazard characterization

Effects on health

Melamine and its analogues are not particularly toxic compounds when considered individually. An oral LD₅₀ of more than 3,000 mg/kg has been reported for rats. Both animals and infants affected by melamine-contaminated foods suffered from kidney damage, especially kidney stones and in some cases kidney failure. However, toxicology studies have shown no acute renal toxicity caused by melamine, although high doses have diuretic properties in animals. It is not genotoxic, or teratogenic, and does not cause skin irritation except at high doses. However, some animal studies of chronic toxicity have shown that kidney and bladder calculi (stones) can form when high levels (1% or more) of melamine are included in the diet over a long period. These calculi can result in bladder cancer in rats as a result of irritation.

Following the widespread deaths among dogs and cats fed with melamine contaminated feed in 2007, an investigation into the toxic mechanism involved was undertaken. The results of this study suggest that the effects observed in animals were caused by a stable, insoluble melamine/cyanuric acid complex present in the food and ingested. The complex is thought to form a lattice-like structure held together by hydrogen bonds. It is suggested that the two compounds are then absorbed in different regions of the gut, because melamine is a base and has a much lower pKa value than that of cyanuric acid. They are then thought to re-form the insoluble complex as crystals in the kidneys, leading to kidney and bladder calculi, or even blocking the renal tubules in severe cases and causing potentially fatal kidney failure. It is suspected that a similar mechanism was responsible for the kidney problems experienced by infants fed on contaminated formula in China during 2007-2008. Although this seems likely, there is still much uncertainty about the exact toxicological mechanisms involved.

EFSA has applied a TDI of 0.5 mg/kg bodyweight for melamine, based on the data available. The US Food and Drug Administration (FDA) has developed a similar TDI of 0.63 mg/kg bodyweight.

Incidence and outbreaks

The recent incident involving contaminated infant formula in China is reported to have affected at least 54,000 children (source WHO). Some 14,000 of these required hospital treatment and at least three deaths have been associated with the contamination.

Sources

Melamine is reported to be widely available in China as a by-product of the plastics industry. Media reports suggest that it was added to certain food ingredients and to milk because of its very high nitrogen content. This would give a falsely high result in tests designed to determine protein content and cause the material to be assigned a higher quality rating and commercial value. If this is indeed the case, then melamine is an adulterant and has been deliberately added to milk, wheat gluten and rice protein concentrate in a fraudulent attempt to increase profits and disguise watered down, or poor quality products.

Melamine in food may also come from other sources, especially plastic packaging, or processing equipment, but usually only at levels not harmful to health. It is also produced in animals as a metabolite of the insecticide cyromazine, which is widely used to prevent insect damage to fruit and vegetables.

Stability in foods

There is little information as yet as to the stability of the melamine/cyanuric acid complex, but its poor solubility and its survival at high temperatures during pet food processing and powdered milk production suggests that it is relatively stable. However, the complex is thought to dissociate at low pH.

Control options

Since melamine at detectable levels is likely to have been added as an adulterant, its presence should not be acceptable under any circumstances.

Sourcing raw materials

Since melamine contamination appears at present to be associated mainly with food ingredients from China, food manufacturers should exercise caution when sourcing ingredients. Traceability to the point of origin is essential. Materials such as milk powder, dried egg products and high-protein ingredients should be purchased only from known low-risk sources.

Testing and analysis

The only practical control for melamine in foods at present, other than careful sourcing, is testing and analysis of all ingredients that carry a risk of contamination.

A number of chemical methods have been developed, based on gas chromatography or HPLC. However, both the European Commission and the FDA recommend a gas chromatography - mass spectrometry (GC-MS) method for the analysis of melamine in foods. A number of commercial laboratories can analyse samples for clients using this method.

Recently, a method based on enzyme-linked immunoassay (ELISA) has been developed and is available commercially (Romer Labs®). This is suitable for screening ingredients and can be used by smaller laboratories. It is likely that other methods will be developed in the coming months.

Legislation

In Europe, melamine can be used as a component in plastics and has been assigned a specific migration limit of 30 mg/kg food for materials in direct contact with foodstuffs.

Melamine is not a permitted additive or ingredient in food and therefore limits have not been set in food legislation before now. However, following the recent incident in China both the European Commission and the US FDA have applied an acceptable limit of 2.5 mg/kg for melamine in imported foods, particularly foods containing powdered milk from China. Products containing the contaminant at higher cannot be imported and will be destroyed at the point of entry.

The legislation position is likely to change as more information becomes available and should be regularly reviewed.

Sources of Further Information

Published

Dobson, R.L.M. et al.
Identification and characterization of toxicity of contaminants in pet food leading to an outbreak of renal toxicity in cats and dogs.
Toxicological Sciences, 2008, 106(1) 251-62.

On the web

EFSA statement on melamine in Chinese milk products
http://www.efsa.europa.eu/cs/BlobServer/Statement/contam_ej_807_melamine.pdf

FDA risk assessment
http://www.cfsan.fda.gov/~dms/melamra3.html