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Description of key information

The substance does not bioaccumulate in fat tissue. Exposure to doses exceeding the solubility limit in urine results in preciptiation in the kidneys. Melamine cyanurate crystals disappear upon cessation of treatment.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
49
Absorption rate - dermal (%):
0.04

Additional information

Physico-chemical properties

Melamine cyanurate is generally of low solubility, regardless of whether the solvent is hydrophilic or lipophilic. Solubility in distilled water is 2.7 mg/L. Solubility (dissociation to melamine and cyanuric acid) increases if the solvent can disrupt the crystal lattice (eg strong acids). In stomach acid (pH 1), melamine cyanurate (at a loading rate of 100 mg/L) dissociates within 3 minutes whereas in lung, intestinal and lysosomal fluid, between 7 and 12% dissociate within 2 or 3 hours (Weisbach 2015). A molecular weight is difficult to assign because in the lattice, each melamine forms hydrogen bonds with six cyanuric acid molecules and vice versa. It is non volatile. If heated above 320°C, it decomposes with formation of nitrogen and carbon dioxide and upon energy consumption, and this determines its technical function of a flame retardent.

Melamine cyanurate is slightly hygroskopic. If bags containing milled melamine cyanurate are left open, the upper layer of the material forms aggregates.

Experimental data

Melamine cyanurate is taken up by the body after in ingestion as indicated by the presence of crystals in the kidney after 7-day feeding of rats (BASF 2010, Dobson 2008). Experimental data on the metabolism of both melamine and cyanuric acid has been published reporting that both melamine and cyanurate are eliminated without metabolism (Mast 1985, Sugita 1991, Barbee 1983). If given alone, both melamine and cyanurate are sufficiently soluble in water for renal elimination and eliminated with half lives in the range of a few hours (Liu 2010, Barbee 1983).

Uptake and elimination from the blood over a period of 8h was investigated for a single gavage exposure to either 2 mg/kg bw melamine and cyanuric acid combined or to melamine cyanurate (Jacobs 2012). Intravenous application of each 1 mg melamine or cyanuric acid was done to allow determination of toxicokinetic properties. At this dose, formation of precipitates in the kidney does not occur and elimination is unperturbed. Individual concentration curves for melamine and cyanuric acid in the combined treatment were almost indistinguishable from those resulting from the individual administration of each triazine. A detailed analysis of the main pharmacokinetic parameters failed to reveal any noteworthy differences between the individual and combined exposures, with bioavailabilities in the combined treatment ranging from 0.83 to 0.91 for melamine and 0.66–0.78 for cyanuric acid.

In contrast, the administration of melamine cyanurate revealed very substantial differences in the concentration curves in both sexes for melamine and cyanuric acid. Treatment with preformed melamine cyanurate led to lower bioavailabilities for both melamine (0.4 in males and 0.49 in females) and cyanuric acid (0.26 in males and 0.4 in females) and to substantially lower observed Cmax values, a later Tmax, and prolonged elimination half lives.  If given melamine cyanurate, the maximum concentrations in plasma were reached after 1.5h (males) and 2h (females) for melamine and after 1h for cyanuric acid. Elimination half-life of melamine was 3h and that of cyanuric acid was 1.54h (males) and 1.88h (females).

Due to the low solubility of melamine cyanurate, the substance precipitates in the kidney if a certain concentration is exceeded. This is observed at the end of the 7-day feeding study at a dose level of 66 mg/kg bw melamine cyanurate (BASF 2010).

Melamine cyanurate is not bioaccumulating in the sense that it accumulates in fat tissue. Below the threshold concentration that results in precipitation in the kidneys, the substance is not bioaccumulating. Applying the elimination half lives in rat (Jacobs 2012), complete elimination occurs within half a day.

In human urine, the pH-dependent solubility curve of combined melamine and cyanuric acid shows a U-shape, with the lowest solubility of 15 mg/L between pH 5 - 5.5. Solubility in human urine was in the range of 250 mg/L at pH 3 and 8.

(Dominguez-Esteveu 2010). A study in rats and in vitro showed that melamine cyanurate crystals can be dissolved by acidifying the urine with citrate (Chen 2013). Another study showed that melamine cyanurate crystals disappear from rat kidneys within ca 28 days after cessation of treamtent (Yasui 2014). In that study, the area of crystals was reduced by half after a two-week recovery period; crystals were no longer observed in females and reduced by ca 90% in males at the four-week recovery sacrifice.

If given in combination with each other by the oral route, the kinetic behaviour depends the following parameters: gavage versus feed, preformed melamine cyanurate versus melamine and cyanuric acid, delay between dosing of melamine and cyanuric acid (Sprando et al). Effects are least pronounced if preformed melamine cyanurate is given by feed. From the mechanism of crystal formation upon concentration in the kidney, high peak doses are more hazardous than chronic low doses.

Dermal and Inhalation routes of exposure

Uptake after ingestion is more efficient than uptake by inhalation or the dermal exposure because the hydrogen bond lattice of the melamine cyanurate complex rapidly dissociates in the highly acidic environment of the stomach. Melamine cyanurate itself is of very low solubility (2.7 mg/L) in distilled water.

In the in-vitro skin permeability study with 14C-cyanuric labelled melamine cyanurate (applied as a wet paste), the human skin permeation rate for an aqueous suspension was extremely low (0.18 μg/cm2

per hour) and only 0.04% of the total dose of 5 mg/cm2 was absorbed after 24h (BASF 2012).

For the single components, experimental data on skin permeability is available for cyanuric acid, which is present in swimming pool water and originates from the disinfectant trichloroisocyanurate. Continuous-dose automated in vitro dermal absorption studies conducted with isocyanuric acid demonstrated minimal absorption through rat, hairless guinea pig, human and commercial test skin (Moody 1993). Total cumulative absorption of isocyanuric acid from water containing 55 mg/L cyanuric acid during 24 h in test skin and human skin was 0.02 μg/cm2 in both cases.

Inhalation to vapour is not relevant since the substance is not volatile. For exposure to dusty material, the fraction dissolved in the lung surfactant should be available for direct transport into the blood. In Iung, intestinal and lysosomal fluid, between 7 and 12% dissociate within 2 or 3 hours (Weisbach 2015). Insoluble particles that have precipitated in the lung are eventually disposed off via the stomach so that in general, systemic exposure via inhalation needs to be assumed.