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Description of key information

Diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) is considered to be absorbed by oral and inhalation route but absorption via skin is considered to be unlikely. No bioaccumulation potential is assumed and a rapid excretion via urine expected.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

There are no experimental studies available in which the toxicokinetic behaviour of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) (CAS 13518-93-9) was investigated. In accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) 1907/2006 and with ‘Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance’ (ECHA, 2017), an assessment of the toxicokinetic behaviour of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) was conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017) and taking into account further available information on structural analogue substances.

Diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) is a white solid with a molecular weight of 430.215 g/mol. The log Pow is -1.24 at pH7. The water solubility is determined as 385.6 mg/L.

Diphosphoric acid, compound with 1,3,5-triamine (1:2) dissociates in aqueous environments forming melamine and pyrophosphate ions. Therefore, toxicokinetic information on melamine and phosphate was also taken into account for the toxicokinetic assessment.

ABSORPTION

Oral:

No specific data regarding oral absorption of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) are available. ECHA guidance suggests that absorption is considered favourable for substances with a molecular weight (MW) below 500 g/mol (ECHA, 2017). The MW (430.215 g/mol) of the test substance might be indicative of absorption. For a substance to be absorbed efficiently from the gastrointestinal tract it must be in solution. A recent study determined the water solubility of the test substance to be 385.6 mg/L. It could be assumed that the test substance dissolves in the gastrointestinal fluids and the substance may be carried through the epithelial barrier by the bulk passage of water (ECHA, 2017). However, dissociation of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) in melamine and pyrophosphate will occur in solution. Phosphate is a key element in various cellular processes, its import and export over cell membranes is regulated via pore systems and usually tightly regulated. Melamine is known to be rapidly absorbed from the gastrointestinal tract. In an available acute oral toxicity study with diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) no signs of systemic toxicity were observed. Thus, a conclusion on oral absorption cannot be drawn based on this study but based on the knowledge of melamine and phosphor an oral absorption can also be assumed for diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) or its dissociation products.

 

Dermal

ECHA guidance suggests that absorption is considered favourable for substances with a MW below 100 g/mol (ECHA, 2017). Therefore, the MW (430.215 g/mol) suggests dermal absorption is not likely. For a compound to penetrate the stratum corneum, it must be sufficiently water soluble i. e. above 1 mg/L (ECHA, 2017). The aqueous solubility of the test substance (385.6 mg/L) indicates that dermal absorption will be moderate to high (ECHA, 2017). For substances with log P values <0, poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. Values <-1 suggest that a substance is not likely to be sufficiently lipophilic to cross the stratum corneum, therefore dermal absorption is likely to be low. As the test substance has a log P value of -1.24 the dermal absorption is considered to be low (ECHA, 2017). In addition, as the test substance is a solid, hindered dermal absorption has to be considered as dry particulates first have to dissolve into the surface moisture of the skin before uptake via the skin is possible (ECHA, 2017). QSAR-based dermal permeability prediction (DERMWIN V2.00.2009) using molecular weight, log P value and water solubility results in a permeability constant (Kp) of 9.38E-07 cm/h and a flux of 0.00036 µg/cm²/h which leads to a conclusion that the dermal absorption potential will be very low (1%). In an acute dermal toxicity study no signs of systemic toxicity were observed which can be an indication that no dermal absorption occurred. For melamine QSAR evaluation revealed a higher dermal absorption rate compared to diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2). A permeability constant (Kp) of 4.88E-05 cm/h and a flux of 0.16987 µg/cm²/h lead to a conclusion that the dermal absorption potential will be medium low (20%).

 

Inhalation

According to ECHA (2017) guidance, particles with aerodynamic diameters below 100 µm have the potential to be inhaled.

A granulometry study shows that diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) consists of approximately 98% of particles with a particle size of about 21 µm and 50% 4.99 µm. Therefore, diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) particles can be inhaled and may reach the thoracic region of the respiratory tract (ECHA, 2017). Besides, the substance is not lipophilic therefore would not have the potential to be absorbed directly across the respiratory tract epithelium. However, in an acute inhalation study systemic toxicity was observed (animals died in the highest dose group and showed difficulty in breathing, chromodacryorrhea and chromorrhinorrhea were observed in all groups), indicating that absorption has occurred. Non-resorbed particles in the oral-nasal cavity, the airways and the lungs will be transferred to the gastro-intestinal tract with the mucus and absorbed there. Therefore absorption from the gastrointestinal tract will contribute to the total systemic burden of the substance that is inhaled. On this basis, a default of 100% inhalation absorption is proposed.

 

DISTRIBUTION/METABOLISM

No data were found regarding the distribution and metabolism for diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2). Looking at the physical/chemical parameters of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) (MW=430.215 g/mol, log P = -1.24, water solubility of 385.6 mg/L) a wide tissue distribution is not assumed (ECHA, 2017). But the structure suggests diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) will dissociate to phosphate anions and melamine. Phosphate is dissolved as ions in blood. Phosphate is indispensable to life; its distribution is tightly regulated systemically as well as intra-cellular. It is inorganic and stable to reduction or oxidation in biological systems. Phosphate is condensed to di- and triphosphates (e. g. AMP, ADT, ATP). Melamine is known to be rapidly excreted from the body, with a half-life of 4-5 hours in the rat and rhesus monkey, and little or no metabolism (EFSA, 2010). It is not considered to bioaccumulate. Thus, no bioaccumulation potential is considered for diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2).

 

EXCRETION

Assuming dissociation of diphosphoric acid, compound with 1,3,5-triazine-2,4,6-triamine (1:2) to melamine and phosphate the excretion is considered the same as for phosphate and melamine. Phosphate is generally excreted mainly via kidneys but also via faeces and sweat. Melamine is known to be rapidly excreted from the body mainly via urine (EFSA, 2010).

 

References:

ECHA (2017). Guidance on information requirements and chemical safety assessment. Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017.

EFSA (2010): Scientific Opinion on Melamine in Food and Feed, EFSA Journal 2010; 8(4): 1573