MELAMINE

:''This article is about the chemical substance called melamine. The term "melamine" is also used to describe melamine resin, a plastic material made from melamine by polymerization.''
'Melamine' is an organic base with the chemical formula C₃ H₆ N₆, with the IUPAC name '1,3,5-triazine-2,4,6-triamine'. It is only slightly soluble in water.
Melamine is a trimer of cyanamide. Like cyanamide, it is 66% nitrogen (by mass) and provides fire retardant properties to resin formulas by releasing nitrogen when burned or charred. Dicyandiamide (or cyanoguanidine), the dimer of cyanamide, is also used as a fire retardant.
Melamine is a metabolite of cyromazine, a pesticide. It is formed in the body of mammals who have ingested cyromazine.^[1] It was also reported that cyromazine is converted to melamine in plants.^[2]^[3]

Synthesis

Melamine was first synthesized by Liebig in 1834. In early production, first calcium cyanamide is converted into dicyandiamide, then heated above its melting temperature to produce melamine. However, today most industrial manufacturers use urea in the following reaction to produce melamine
: 6 (NH₂)₂CO → C₃H₆N₆ + 6 NH₃ + 3 CO₂
It can be understood as two steps. First, urea decomposes into cyanic acid in an endothermic reaction (NH₂)₂CO → HCNO + NH₃. Then cyanic acid polymerizes to form melamine and carbon dioxide: 6 HCNO → C₃H₆N₆ + 3 CO₂. The second reaction is exothermic and the overall process is endothermic.
The above reaction can be carried out by either of two methods:catalyzed gas-phase production or high pressure liquid-phase production. In one method, molten urea is introduced onto a fluidized bed with catalyst for reaction. Hot ammonia gas is also present to fluidize the bed and inhibit deammonization. The effluent then is cooled. Ammonia and carbon dioxide in the off-gas are separated from the melamine-containing slurry. The slurry is further concentrated and crystallized to yield melamine.^[4] Major manufacturers such as DSM and BASF have developed some proprietary methods.
The off-gas contains large amounts of ammonia. Therefore melamine production is often integrated into urea production which uses ammonia as feedstock.
Crystallization and washing of melamine generates a considerable amount of waste water, which is a pollutant if discharged directly into the environment. The waste water may be concentrated into a solid (1.5-5% of the weight) for easier disposal. The solid may contain approximately
70% melamine, 23% oxytriazines (ammeline, ammelide and cyanuric acid), 0.7% polycondensates (melem, melam and melon). ^[5]

Uses

Melamine is used combined with formaldehyde to produce melamine resin, a very durable thermosetting plastic, and of melamine foam, a polymeric cleaning product. The end products include countertops, fabrics, glues and flame retardants.
Melamine is one of the major components in Pigment Yellow 150, a colorant in inks and plastics.
Melamine is also used to make fertilizers.
Melamine derivatives of arsenical drugs are potentially important in the treatment of African trypanosomiasis ^[6]
Melamine use as non-protein nitrogen (NPN) for cattle was described in a 1958 patent.^[7] In 1978, however, a study concluded that melamine "may not be an acceptable nonprotein N source for ruminants" because its hydrolysis in cattle is slower and less complete than other nitrogen sources such as cottonseed meal and urea.^[8]

Regulation

Toxicity

Little is known with respect to melamine toxicity in human subjects. Animal studies have shown that
melamine is not metabolized in rats, and is excreted unchanged.^[9]

Acute toxicity

Melamine is reported to have an oral LD50 of >3000 mg/kg based on rat data, which makes it only minimally toxic (table salt has a similar LD50 value). It is also an irritant when inhaled or in contact with the skin or eyes. The reported dermal LD50 is >1000mg/kg for rabbits. In a 1945 study, large doses of melamine were given orally to rats, rabbits and dogs with "no significant toxic effects" observed. ^[10]
There does not seem to be any reported human case of acute intoxication directly caused by melamine.
A study by USSR researchers in the 1980s suggested melamine cyanurate (a salt formed between melamine and cyanuric acid, commonly used as a fire retardant^[11]) could be more toxic than either melamine or cyanuric acid alone.^[12] For rats and mice, the reported LD50 for melamine cyanurate was 4.1g/kg (given inside the stomach) and 3.5g/kg (via inhalation), compared to 6.0 and 4.3 g/kg for melamine and 7.7 and 3.4 g/kg for cyanuric acid, respectively.

Chronic toxicity

Ingestion of melamine may lead to reproductive damage, or bladder or kidney stones, which can lead to bladder cancer.^[13]^[14]^[15]^[16]^[17]
A study in 1953 reported that dogs fed 3% melamine for a year had the following changes in their urine: (1) reduced specific gravity, (2) increased output, (3) melamine crystalluria, and (4) protein and occult blood.^[18]

2007 pet food recalls

In 2007 a pet food recall was initiated by Menu Foods and other pet food manufacturers who had found their products had been contaminated and caused serious illnesses or deaths in some of the animals that had eaten them.^[19]^[20]^[21] On 30 March 2007, the US Food and Drug Administration reported finding white granular melamine in the pet food, in samples of white granular wheat gluten imported from a single source in China, Xuzhou Anying Biologic Technology ^[22] as well as in crystalline form in the kidneys and in urine of affected animals.^[23] Further vegetable protein imported from China was later implicated. See 2007 pet food recalls.
The practice of adding "melamine scrap" to animal feed is reported to be widespread in China in order to give the appearance of increased protein content in animal feed. Melamine has also been purposely added as a binder to fish and livestock feed manufactured in the United States and traced to suppliers in Ohio and Colorado. The presence of melamine has not been conclusively linked to the deaths of animals, as this chemical was previously thought to be non-toxic at low doses.

Official US statements

On April 27 US FDA subjected all vegetable proteins imported from China, intended for human or animal consumption, to detention without physical examination, including: Wheat Gluten, Rice Gluten, Rice Protein, Rice Protein Concentrate, Corn Gluten, Corn Gluten Meal, Corn By-Products, Soy Protein, Soy Gluten, Proteins (includes amino acids and protein hydrosylates), and Mung Bean Protein. IMPORT ALERT #99-29, "DETENTION WITHOUT PHYSICAL EXAMINATION OF ALL VEGETABLE PROTEIN PRODUCTS FROM CHINA FOR ANIMAL OR HUMAN FOOD USE DUE TO THE PRESENCE OF MELAMINE AND/OR MELAMINE ANALOGS"
On April 28, the U.S. Department of Agriculture (USDA) and the FDA, in a joint press release acknowledged that pork from hogs fed melamine-contaminated feed had entered the human food supply, stating: "Based on information currently available, FDA and USDA believe the likelihood of illness after eating pork from swine fed the contaminated product would be very low." Joint Update: FDA/USDA Update on Tainted Animal Feed
On April 30, the USDA and the FDA updated their April 28 food safety position to include poultry, reflecting contaminated feed being fed to chickens in Indiana. Joint Update: FDA/USDA Trace Adulterated Animal Feed to Poultry
On May 7, the USDA and the FDA issued a joint press release reflecting the combined judgment of five federal agencies with regard to the risk to humans in consuming meat from animals fed feed contaminated with tainted pet food scraps, concluding: "There is very low risk to human health" in such cases involving pork and poultry. The risk assessment was conducted by scientists from FDA, the Food Safety and Inspection Service (FSIS) of USDA, CDC, the United States Environmental Protection Agency (EPA), and U.S. Customs and Border Protection: "In the most extreme risk assessment scenario, when scientists assumed that all the solid food a person consumes in an entire day was contaminated with melamine at the levels observed in animals fed contaminated feed, the potential exposure was about 2,500 times lower than the dose considered safe" FDA/USDA Joint News Release: Scientists Conclude Very Low Risk to Humans from Food Containing Melamine using criteria established prior to current research focusing on the apparent increased toxicity related to the interaction of melamine and cyanuric acid ''in vivo'' Another Chemical Emerges in Pet Food Case David Barboza , for which there is no established safe dosage. FDA and USDA are in the process of identifying a group of experts to convene a scientific advisory board that would be charged with reviewing the risk assessment and contributing to future scientific analysis related to the risk of melamine and its compounds to humans and animals.
Risks to human health from this mode of entering the human food supply have been said to be low according to a number of FDA, CDC and university toxicologists, though it was acknowledged that how melamine had harmed cats and dogs remains something of a mystery. Pet Food Chemical Unlikely to Pose Threat to Humans, Experts Say, as U.S. Continues Inquiry Donald McNeil
On May 10, on further inquiry into the risk to animal and human health of ingesting melamine and cyanuric acid in combination, Dr. David Acheson, Assistant Commissioner for Food Protection with the FDA said: "I'm not aware of any published studies on that. I have seen some preliminary data that would indicate that they are additive. When you put the two together, they are additive rather than synergistic.... The risk assessors also estimated that even if synergism were to occur, it would be unlikely to result in more than a tenfold increase in overall toxicity, and that still gives you a very large margin of safety." No data supporting additivity was produced at this time. No basis for estimating a tenfold increase in risk in the case of synergism was offered. TRANSCRIPT OF FDA-USDA UPDATE ON ADULTERATED ANIMAL FEED
On May 15 USDA announced that pigs that ate melamine-tainted food has been cleared for human consumption. About 56,000 pigs have been affected in several states. However, no tests have been carried out on the effects of cyanuric acid in pork as well as possible affects of interaction with melamine in the body. While the statement also said that there is no evidence of bioaccumulation of melamine alone, no mention was made whether bioaccumulation might be affected by the interaction of melamine and cyanuric acid ''in vivo''.
On May 25, in a US FDA/CSFAN Interim Melamine and Analogues Safety/Risk Assessment, FDA stated: "While it is entirely possible that the analogues are more or less potent than the parent compound, melamine, we have no information that assesses the relative potency of the three analogues as compared to melamine; therefore, for the purpose of this interim assessment, we have made an assumption of equal potency. It has been hypothesized that melamine may interact synergistically with its three analogues, but no studies have been conducted that specifically test this hypothesis. Very preliminary work suggests that if it does occur, the formation of lattice crystals, particularly between melamine and cyanuric acid, takes place at very high dose levels and is a threshold and concentration dependent phenomenon that would not be relevant to low levels of exposure. Although still under investigation, it now appears that the combination of melamine and cyanuric acid has been linked to the acute renal failure in cats and dogs that have eaten the suspect pet foods...." Interim Melamine and Analogues Safety/Risk Assessment
On May 30 the FDA issued a press release stating that two US-based animal feed manufacturers had been adulterating livestock feed and fish/shrimp feed with melamine. "Tembec and Uniscope Voluntary Recall Feed Ingredients, FDA Asks Feed Manufacturers to Avoid Ingredients Containing Melamine" Poison used in China is found in U.S.-made animal feed
In addition to now testing a wide variety of imported food products and ingredients for melamine contamination, FDA has also "asked the Centers for Disease Control and Prevention (CDC) to use its surveillance network to monitor for signs of human illness, such as increased renal failure, that could indicate contamination of the human food supply." Testimony By Stephen F. Sundlof, D.V.M., Ph.D., Director, FDA Center for Veterinary Medicine, Department of Health and Human Services before The Senate Agriculture, Rural Development, and Related Agencies Appropriations Subcommittee

Focus on melamine and cyanuric acid

Melamine (green) and cyanuric acid (red) easily form hydrogen bonds (blue dotted lines) with each other

Researchers have focused on the role of melamine and related compounds in causing renal failure. Beginning on April 19, it was reported that researchers had ruled out aminopterin contamination and had found a "spoke-like crystal" in contaminated wheat gluten and rice protein concentrate and the tissues and urine of affected animals. (It was previously known that melamine and cyanuric acid can form networks of hydrogen bonds, creating a tile-like planar structure through molecular self-assembly.)^[24] The crystal has been said to serve as a biomarker for contamination and is approximately 30% melamine. The remainder has been identified as cyanuric acid, ammelide and ammeline, with crystals recovered from urine reported to be approximately 70% cyanuric acid. While some researchers have theorized that the three latter chemicals might have been formed as the animals metabolized the melamine, or as by-products of bacterial metabolism (cyanuric acid is a known intermediate byproduct of bacterial metabolism of melamine), their presence in the crystals found in contaminated protein itself, combined with media reports of widespread adulteration with both melamine and cyanuric acid in China, has focused research efforts on their combined effects in animals. Neither melamine nor cyanuric acid, a chemical commonly used in pool chlorination, have been thought to be particularly toxic by themselves. The current hypothesis is that, although these contaminants are not very toxic individually, their potency appears to be increased when they are present together. Humans at risk from tainted pet food? Karen Roebuck Were Our Pets Deliberately Poisoned? Nikhil Swaminathan ^[25] DCPAH Notices ^[26]
On April 27 researchers from the University of Guelph, in Ontario announced that they had created crystals chemically similar to the ones found in contaminated animals by combining melamine and cyanuric acid in the laboratory under pH conditions similar to that in animal kidneys. Scientists track chemical reactions in pet food Ashleigh Patterson Pet Food Recall
In light of these findings, on May 1, the American Veterinary Medical Association noted in a press release that the "extremely insoluble" crystals formed in animal kidneys are suspected of blocking kidney function. Melamine and Cyanuric Acid Interaction May Play Part in Illness and Death from Recalled Pet Food On May 7, however, Barbara Powers, president of the American Association of Veterinary Laboratory Diagnosticians and a professor of veterinary diagnostics at Colorado State University cautioned "There's something more going on than just the mechanical blockage. Because you wouldn't see so much necrosis (cell death) and inflammation.”^[27]
On May 2, in further inquiry into the source of the cyanuric acid in the contaminated ingredients and the toxic effects of the chemical combination, Richard Goldstein of the Cornell University College of Veterinary Medicine, in response to reports that the contaminant might be "melamine scrap" left over from processing coal into melamine, hypothesized: “It’s possible the other stuff they were left with was the bottom-of-the-barrel stuff, leftover melamine and possibly cyanuric acid. I think it’s this melamine with other compounds that is toxic.”^[28] The composition of the crystals analyzed in contaminated pet food ingredients is similar to the composition of a waste product produced in melamine production.^[5]

Testing methods for melamine and cyanuric acid

The Food Safety and Inspection Service (FSIS) of the United States Department of Agriculture (USDA) provides a test method for analyzing cyromazine and melamine in animal tissues in its Chemistry Laboratory Guidebook which "contains test methods used by FSIS Laboratories to support the Agency's inspection program, ensuring that meat, poultry, and egg products are safe, wholesome and accurately labeled." CYROMAZINE AND MELAMINE Chemistry Laboratory Guidebook
On April 24, Stephen Sundlof, director of the FDA's Center for Veterinary Medicine, told reporters: "We have found cyanuric acid. It is somewhat related to melamine. Another compound that is very high in nitrogen and we are testing for that compound as well."
On May 7, the FDA sent a letter to food manufacturers, to remind them "of their legal responsibility to ensure that all ingredients used in their products are safe for human consumption." Letter to Food Manufacturers Regarding Legal Responsibilities for the Safety of Food Ingredients The FDA has made available to food manufacturers a procedure providing a general guide for the sample preparation and analysis of wheat gluten and pet food matrices for melamine using gas chromatography/mass spectrometry, the same methodology used by the FERN laboratories. GC-MS Screen for the Presence of Melamine and Cyanuric Acid
On May 15, the process for testing meat from swine was validated by USDA's Food Safety and Inspection Service (FSIS). News Release

Reported widespread use in Chinese feed and food

Recent production of melamine in China

Between the late 1990s and early 2000s, both consumption and production of melamine grew considerably in China. In the United States Geological Survey 2004 Minerals Survey Yearbook, in a report on worldwide nitrogen production, the author stated that "China continued to plan and construct new ammonia and urea plants using coal gasification technology." Nitrogen
By early 2006, melamine production in China is reported to be in "serious surplus". Melamine capacity is serious surplus Wang Ruilin In April 2007, DSM's melamine industry update painted a grave global picture.^[30] Between 2002 and 2007, while the global melamine price remained stable, a steep increase in the price of urea (feedstock for melamine) has reduced the profitability of melamine manufacturing. Currently, China is the world's largest exporter of melamine, while its domestic consumption still grows by 10% per year. However, reduced profit has already caused other joint melamine ventures to be postponed there.

Media reports of melamine adulteration in China

Main articles: 2007 pet food recalls

On April 30, 2007, The New York Times reported that the addition of "melamine scrap" into fish and livestock feed to give the false appearance of a higher level of protein was an "open secret" in many parts of China, reporting that this melamine scrap was being produced at at least one plant processing coal into melamine. Filler in Animal Feed Is Open Secret in China This production has been described as also producing "melamine scrap" which is not "pure melamine but impure melamine scrap that is sold more cheaply as the waste product after melamine is produced by chemical and fertilizer factories here.”^[28]
Shandong Mingshui Great Chemical Group, the company reported by the New York Times as producing melamine from coal, produces and sells both urea and melamine but does not list melamine resin as a product. Products
As per melamine synthesis, the off-gas in production contains large amounts of ammonia. Therefore melamine production is often integrated into urea production which uses ammonia as feedstock. Crystallization and washing of melamine generates a considerable amount of waste water, which is a pollutant if discharged directly into the environment. The waste water may be concentrated into a solid (1.5-5% of the weight) for easier disposal. The solid may contain approximately 70% melamine, 23% oxytriazines (ammeline, ammelide and cyanuric acid), 0.7% polycondensates (melem, melam and melon). ^[5]
On May 3 the New York Times reported that, despite the widely reported ban on melamine use in vegetable proteins in China, at least some chemical manufacturers continue to report selling it for use in animal feed and in products for human consumption. Said Li Xiuping, a manager at Henan Xinxiang Huaxing Chemical in Henan Province: "Our chemical products are mostly used for additives, not for animal feed. Melamine is mainly used in the chemical industry, but it can also be used in making cakes." China Makes Arrest in Pet Food Case

Media reports of cyanuric acid adulteration in China

On May 8 2007, The International Herald Tribune reported that three Chinese chemical makers have said that animal feed producers often purchase, or seek to purchase, cyanuric acid from their factories to blend into animal feed to give the false appearance of a higher level of protein, suggesting another potentially dangerous way that melamine and cyanuric acid might combine in protein products.^[33]

Detection of melamine in food

Because melamine resin is often used in food packaging and tableware, melamine at ppm level (1 part per million) in food and beverage has been reported due to migration from melamine-containing resins.^[34] Small amounts of melamine have also been reported in foodstuff as a metabolite product of cyromazine, an insecticide used on animals and crops.^[35]
Melamine at even very low levels can be detected through chromatography, or chromatography coupled to mass spectroscopy. However, until the 2007 pet food recalls melamine in foodstuff has not routinely been monitored, except in the context of plastic safety or insecticide residue. This could be due to the previously assumed low toxicity of melamine, and the relatively expensive methods of detection.

References

1. Report on cyromazine of the European Medicines Agency
2. Lori 0. Lim, Susan J. Scherer, Kenneth D. Shuler, and John P. Toth. Disposition of Cyromazine in Plants under Environmental Conditions ''J. Agric. Food Chem.'' 1990, 38, 860-864 [1]
3. FAO report on cyromazine
4. Kirk-Othmer encyclopedia of chemical technology, 3rd edition, Vol.7, p303-304, 1978.
5. SM Lahalih, M Absi-Halabi, "Recovery of solids from melamine waste effluents and their conversion to useful products", Industrial & Engineering Chemistry Research, vol.28, 500-504 (1989).
6. Barrett MP, Gilbert IH. Targeting of toxic compounds to the trypanosome's interior.Adv Parasitol. 2006;63:125-83.
7. "Ruminant feed compositions, Robert W. Colby and Robert J. Mesler Jr., U.S. Patent No. 2819968, 1958
8. “Melamine as a dietary nitrogen source for ruminants", G.L.Newton and P.R.Utley, Journal of Animal Science, vol.47, p1338-44, 1978, Abstract
9. Metabolism, disposition and excretion of [14C]melamine in male Fischer 344 rats, RW Mast ''et al'', , , Food and Chemical Toxicology,
10.
11. Flame Retardants Center: Melamine Compounds
12. A.A. Babayan, A.V.Aleksandryan, "Toxicological characteristics of melamine cyanurate, melamine and cyanuric acid", Zhurnal Eksperimental'noi i Klinicheskoi Meditsiny, Vol.25, 345-9 (1985). Original article in Russian, English abstract retrieved from SciFinder on 05-07-2007.
13. International Chemical Safety Card
14. MSDS
15. OSHA – Chemical sampling information
16. WHO – Some Chemicals that Cause Tumors of the Kidney or Urinary Bladder in Rodents and Some Other Substances
17. The induction of bladder stones by terephthalic acid, dimethyl terephthalate, and melamine (2,4,6-triamino-s-triazine) and its relevance to risk assessment., HD Heck and RW Tyl, , , Regul Toxicol Pharmacol.,
18. T.W. Tusing, "Chronic Feeding - Dogs", cited by "Summary of toxicity data - trichloromelamine" by California Environmental Protection Agency, last revised on 04-02-2002, URL accessed on 05-09-2007
19. CNN: Dry food added to pet food recall list
20. AVMA: Pet food recall
21. Press release by Natural Balance Pet Foods
22. FDA FAQ: Where did the contaminated wheat gluten come from?
23. FDA:Pet food recall
24. E.E. Simanek, X. Li, I.S. Choi, G.M. Whitesides, "Cyanuric Acid and Melamine: A Platform for the Construction of Soluble Aggregates and Crystalline Materials", Comprehensive supramolecular chemistry, J.L. Atwood ed., New York:Pergamon, Vol.9, 495 (1996).
25. Gang Cheng, Nir Shapir, Michael J. Sadowsky and Lawrence P. Wackett, Allophanate Hydrolase, Not Urease, Functions in Bacterial Cyanuric Acid Metabolism, Appl Environ Microbiol. 2005 August; 71(8): 4437–4445.
doi: 10.1128/AEM.71.8.4437-4445.2005. [2]
26. Another Chemical Emerges in Pet Food Case David Barboza
27. Poison pet food woes seem to hit cats harder Elizabeth Weise
28. China Food Mislabeled, U.S. Says David Barboza
29. SM Lahalih, M Absi-Halabi, "Recovery of solids from melamine waste effluents and their conversion to useful products", Industrial & Engineering Chemistry Research, vol.28, 500-504 (1989).
30. Melamine industry update, by Royal DSM N.V., accessed on 2007-05-04
31. China Food Mislabeled, U.S. Says David Barboza
32. SM Lahalih, M Absi-Halabi, "Recovery of solids from melamine waste effluents and their conversion to useful products", Industrial & Engineering Chemistry Research, vol.28, 500-504 (1989).
33. Second chemical eyed in Chinese pet food scandal David Barboza
34. H. Ishiwata, T. Inoue, T. Yamazaki, K. Yoshihira, K. "Liquid chromatographic determination of melamine in beverages", J. Assoc. Off. Anal. Chem. Vol.70, 457-60 (1987) PUBMED, accessed 05-06-2007.
35. J.V. Sancho, M. Ibanez, S. Grimalt, O.J. Pozo, F. Hernandez, "Residue determination of cyromazine and its metabolite melamine in chard samples by ion-pair liquid chromatography coupled to electrospray tandem mass spectrometry", Analytica Chimica Acta Vol.530, p237-243 (2005) Abstract accessed 05-06-2007.

External links

★ NLM Hazardous Substances Databank – Melamine

★ Melamine Materials Safety Data Sheet (MSDS)

★ OECD Screening Information Data　Set (SIDS): Melamine (High Production Volume Chemicals Screening Information，PDF, 89 pages).

★ AP Story April 6, 2007

★ List of Recalls

★ The findings in South Africa

★ FDA Web Page with Information on Pet Food Recall (due to Melamine contanimination )

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