November 28, 2008
On October 3, 2008, FDA issued its Interim Safety and Risk Assessment of Melamine and its Analogues in Food for Humans. This interim safety and risk assessment indicated that melamine, in its chainlike “polymerized” form, has been used to manufacture dishes, plastic resins, and components of paper and paperboard that may come in contact with food. Additionally, trichloromelamine is approved for use as a sanitizing agent on food processing equipment and utensils, except for milk containers and equipment, and it readily decomposes to melamine during such uses. FDA estimated that the cumulative dietary concentration from these approved food uses would be less than 15 µg/kg (0.015 ppm). This is an estimate of the average concentration of melamine in food from approved uses; it is not intended as an estimate of the acceptable maximum level of melamine in an individual food. Additionally, individual products may contain more or less melamine than 0.015 ppm of melamine as a result of approved uses. The levels would depend on the type of food and the conditions of the approved uses.
The October 2008 interim safety and risk assessment considered the potential public health concerns from food, including infant formula, containing melamine and its analogues in combination. It did so based on the then current state of knowledge. The safety/risk assessment used a TDI (Tolerable Daily Intake) of 0.63 mg/kg bw/d as its starting point. This TDI was based on the results of a 13-week rat study of melamine alone. Melamine and its analogues – cyanuric acid, ammelide, and ammeline – were assumed to be of equal potency. The safety/risk assessment, however, took into account studies indicating that increased toxicity results from combined exposure to melamine and cyanuric acid, which raises a high degree of uncertainty with regard to the determination of safety/risk. For foods other than infant formula, the safety/risk assessment applied an additional 10-fold safety factor to compensate for the uncertainties regarding combined exposure to more than one of the melamine-related compounds. In applying this safety factor and using the TDI, the safety/risk assessment concluded that “levels of melamine and its analogues below 2.5 ppm in foods other than infant formula do not raise public health concerns.” For infant formula, the safety/risk assessment determined that it could not, based on current information, apply such a safety factor to establish a level of melamine and its analogues in infant formula that would not raise public health concerns. This was based on several factors specific to infant formula contaminated with more than one melamine analogue, such as the product represents the totality of caloric exposure for most infants, exposure is chronic over months, and the persons ingesting the products are infants and toddlers whose renal systems may not be fully developed.
The safety/risk assessment did not address the potential public health concerns from food containing just melamine or one of its analogues. Because FDA has found infant formula where just melamine or just cyanuric acid was present, it is updating the safety/risk assessment. These findings were in U.S.-manufactured infant formula products, and only extremely low levels of melamine or cyanuric acid have been detected in them. These levels, ranging from 0.137 ppm of melamine in one product to 0.247 ppm of cyanuric acid in another, are up to 10,000 times less than the levels of melamine reported in Chinese-manufactured infant formula.
The 2007 estimate of the TDI for melamine and its analogues serves as the starting point for the present update to the safety/risk assessment. That TDI is 0.63 mg/kg bw/d and is based on the results of a 13-week rat study, and includes a 100-fold safety factor.
Infants may be more sensitive than adults to exposures because, for example, infant formula is the sole source of nutrition, exposure continues for up to 12 months, and renal function may be more immature compared to adults. This raises a high degree of uncertainty with regard to the determination of safety/risk. Given these conditions, FDA has applied an additional 10-fold safety factor, yielding a combined safety factor of 1000-fold, to compensate for these uncertainties. This results in a TDI/10 of 0.063 mg melamine/kg-bw/d.
The next step is to convert from a dose of 0.063 mg/kg bw/d to total melamine consumed per day.
0.063 mg/kg-bw/d x 3 kg/infant = 0.189 mg melamine/infant/day.
To estimate the level of melamine that does not raise public health concerns, FDA used a worst case exposure scenario in which all of an infant’s total daily dietary intake (typically 0.15 kg powdered infant formula) is contaminated with melamine. The previously determined (see above) total amount of melamine/infant/day:
0.189 mg/infant/day divided by 0.15 kg of food = the food contamination level that would provide this amount of melamine to a 3 kg infant per day. Thus, 0.189 mg melamine divided by 0.15 kg of food = 1.26 mg melamine/kg food.
Therefore, if 100% of the diet were contaminated at a level of 1.26 ppm of melamine, an infant’s daily intake would equal 0.063 mg/kg bw/d. This value of 1.26 ppm is rounded down to 1.0 ppm melamine to provide an additional margin of safety.
The safety/risk assessment assumes the analogues to have equal effect. Thus, levels of melamine or one of its analogues alone below 1.0 ppm in infant formula do not raise public health concerns.
FDA is continuing to sponsor and conduct animal studies to assess the potential toxicity from co-ingestion of melamine and cyanuric acid. As this ongoing research is completed, FDA will update its interim safety/risk assessment for melamine and its analogues, as appropriate.