1,3,5-triazine-2,4,6-triamine phosphate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

For Read Across Justification please refer to section 13.

Type:

absorption

Results:

Tmax= 30 min (blood)

Type:

distribution

Results:

high level in bladder after 24 h

Type:

metabolism

Results:

no metabolites detected

Type:

excretion

Results:

urine major route of elimination (t1/2 elemination=30 min)

Description of key information

There is no study available with melamine phosphate but with melamine. Main facts derived from data on melamine:

 

- Oral absorption: Fast, with a distribution/absorption half-life of 0.25 h in rats.

- Absorption: Rather complete; 73 to 98 % are reported in rats. The time of  maximal plasma concentration is 0.75 to 2.7 h in rats, 2.7 h in monkey. No first pass effect was observed. Absorption occurs mainly in the small intestine.

- Plasma elimination: half-lives of 1.6 to 4.9 h are reported for rats; 4.4 h in monkey, 4.1 h in pig.

- Distribution: Mainly to body water. Distribution volume: 0.1 to 1.3 mL/g are reported for rats. Melamine passes the placental barrier and is detected in foetal tissues.

- Elimination: mainly with urine, in rats. The excretion peak in urine of monkeys is delayed, compared to rats.

- Metabolism: none; melamine is excreted unchanged.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic profile is derived from melamine because both melamine and melamine phosphate have a similar solubility in water and Melamine phosphate dissociates into melamine cations and phosphate anions.

 

Studies on the kinetics and metabolism of melamine were performed in rat, human, monkey, pig, cow and sheep. The placental transfer and transfer to milk were investigated.

 

Rat:

- Melamine is not metabolized by male Fischer 344 rats (Mast 1983). After a single oral dose of melamine (14C-radiolabelled) it is rapidly absorbed, to 90 per cent excreted in the urine within 24 hours, maximal plasma concentrations being reached within 60 min. Melamine appears to distribute in body water as the concentrations in blood, plasma and liver are similar. Urinary excretion is essentially the sole route of elimination and occurs so rapidly that no calculation of a distribution-phase half-life was possible. The elimination-phase half-life calculated from plasma data of 2.7 h was in good agreement with the urinary-excretion half-life of 3.0 h. The renal clearance of melamine was 2.5 ml/min.

- The fate of melamine was studied in rats (Sugiata 1991). The compound was not absorbed in the stomach but was absorbed in the small intestine, and was excreted in urine.

- Yang 2009: Melamine was administered intravenously and orally to Sprague-Dawley rats and the pharmacokinetic characteristics were investigated. The mean values of major pharmacokinetic parameters of melamine in Sprague-Dawley rats were: oral availability 73 %, clearance 20 mL/h/kg, and plasma elimination half-life (T1/2) 4.9 h. The rats pharmacokinetic study results suggested that melamine was predominantly restricted to blood or extracellular fluid and is not extensively distributed to most organ tissues.

- Similar results were obtained by Jacob 2012: A maximum concentration in serum of 581 ng/mL for males and 571 ng/mL for females was obtained at 1.0 h for males and 0.75 h for females after oral dosing of 1 mg/kg bw. The distribution/absorption half-life was 0.26 h for males and 0.25 h for females. The elimination half-life was 1.62 h for males and 1.92 h for females. Bioavailability was calculated from the areas under the curves to 0.83 for males and 0.98 for females.

- Toxicokinetics parameters of melamine were studied by Pang 2013 after a single oral dose of 100 mg/kg to rats. Derived toxicokinetic parameters: Plasma: Cmax = 78 +-11 µg/mL; AUC = 296 +-94 µg.h/mL; plasma elimination half-life = 2.5 +-0.3 h; Volume of distribution = 1310 +-340 mL/kg. Concentration of MEL in rat kidney <1 µg/g.

- Wu 2011: The concentration-time profile of melamine in the heart, liver, spleen, lungs, kidneys, bladder, feces, urine, and plasma after melamine administration was studied. Female rats were orally dosed of 1.0 g/kg bw. Melamine was distributed rapidly into the heart, liver, spleen, lungs, kidneys, bladder, feces, urine, and plasma. Peak concentrations of melamine are reached in the livers and lungs at 12 h after dosing and in hearts, spleens, kidneys, bladders, feces, urine, and plasma at 24 h after dosing. More than 90% of the ingested melamine is excreted in feces and urine within 24 h.

 

Rat and human:

- Melamine is a metabolite of hexamethylmelamine in rat and human after demethylation steps (Worzalla 1974). The experiments indicated that the s-triazine ring is very stable and that it does not undergo cleavage. This is suggested by the fact that there is no production of 14CO2 after administration of HMM-ring-14C to either man or rats. The identification of the major urinary metabolites as methylmelamines and melamine also confirms the stability of the s-triazine ring in mammalian systems. The results show that any metabolites formed from the opening of the s-triazine ring of HMM in man or rats would be present in small quantities only.

 

Monkey:

- Liu 2010: Following a single oral administration of 1.4 mg melamine/kg bw to three rhesus monkeys, melamine in plasma and urine was determined by a LC-MS/MS method. The study suggested that melamine undergoes rapid absorption, then is distributed and cleared from plasma, and subsequently excreted primarily in the urine. Time to maximum in plasma: 2.7 h. Plasma half-time: 4.4 h. The excretion peak in urine appeared on the second day p.a., which is quite delayed compared to rats. A clear background level of cyanuric acid was observed in plasma and urine of rhesus monkeys even in the absence of melamine exposure.

 

Pig:

- Baynes 2008: Melamine was administered intravenously to five weanling pigs at a dose of 6.13 mg/kg and plasma samples were collected over 24 h, extracted for melamine, and then analysed by HPLC–UV. Melamine appears to be cleared rapidly (T1/2 = 4.07 h) and monoexponentially from plasma of pigs. The volume of distribution of 0.61 L/kg is close to total body water, suggesting that distribution is mainly to extracellular fluid compartment. Elimination is via kidney.

 

Sheep:

- Cruywagen 2011: Ingested melamine is highly absorbable from the small intestine of sheep and a pathway exists for the distribution of dietary melamine to meat.

 

Transfer to foetus and neonate:

- A study in cows on the transfer of melamine from feed to milk is presented by Cruywagen 2009, see Chapter 7.10.5.

- Ingested melamine dose-dependently passes the placental barrier of rats to reach the foetus (Jingbin 2010).

- Chan 2011: After administration of a single dose of 21.4 mg/kg per body weight of melamine to pregnant rats (16-18 days of gestation) by gavage, about 80% of melamine was found in dam's serum in 0.5 h. Melamine further reached the fetuses through placental transfer as it was found that peak melamine level of 7.15 ppm (ca. 30%) was detected in the fetuses after 2 h and 4.36 ppm (ca. 20%) was shown in amniotic fluid after 3 h of maternal intake. In the lactating rats, about 40 % of maternal intake of melamine was transferred to breast milk and peaked at 3 h. The results of this study confirmed the maternal transfer of melamine to fetuses in utero and infants through breast feeding.

- Chu 2013: Melamine was administered to pregnant rats at different gestational stages and to infants at different postnatal stages. Distribution of melamine in maternal serum was about 30% higher in late pregnancy than that in early pregnancy; and it was 2 folds higher in postnatal serum in early infants in young adulthood. Distribution of melamine in all postnatal organs was higher than that in prenatal organs. Postnatal kidneys in early infants had the highest maximum concentration and the lowest clearance of melamine than the other postnatal organs.

- Partanen 2012: In vitro experiment with human placental perfusion. Transfer was analyzed in 4-h perfusions with 10 µM or 1 mM melamine. Of added melamine 34 - 45% was transferred to fetal circulation. Conclusion: Melamine goes through human term placenta with no contribution of efflux transporters.