Registration Dossier

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: All relevant details for evaluation are given in the literature publication.

Data source

Reference
Reference Type:
publication
Title:
Pharmacokinetics of melamine and cyanuric Acid and their combinations in f344 rats.
Author:
Jacob CC, Von Tungeln LS, Vanlandingham M, Beland FA, Gamboa da Costa G.
Year:
2012
Bibliographic source:
Toxicol Sci. 2012 Apr;126(2):317-24

Materials and methods

Objective of study:
absorption
excretion
Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 417 (Toxicokinetics)
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): melamine cynurate
- Substance type: solid
- Physical state:solid
- Analytical purity: The purity and identity of the test articles were confirmed by high-performance liquid chromatography (HPLC) coupled with ultraviolet detection and electrospray mass spectrometry and by gas chromatography-mass spectrometry in electron impact mode.
- Impurities (identity and concentrations): not provided

- Purity test date: not provided
- Lot/batch No.: none, the substance was synthesized by mixing 1:1 aqueous solutions of melamine and cyanuric acid. The precipitate was filtered, thoroughly washed with hot water (80–90C), and dried under reduced pressure.
- Expiration date of the lot/batch: not relevant

- Other: The publication also describes toxicokinetic investigations with either melamine or cyanuric acid or a co-exposure to melamine and cynuric acid (not the pre-formed melaminecyanurate complex)
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: F344 rats were obtained from the breeding colony at the US NCTR.
- Age at study initiation: 10 weeks
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: individual
- Individual metabolism cages: yes/no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): 40 -70 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12/+2

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
water with 0.1% CMC
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE

- Concentration in vehicle: 0.4 mg/L
- Amount of vehicle (if gavage): 5ml/kg bw

HOMOGENEITY AND STABILITY OF TEST MATERIAL: yes
All dosing formulations were analyzed with a Thermo Surveyor Plus HPLC (Thermo, Waltham, MA) using a Synergi Polar RP 80A, 4 lm, 2 3 250 mm column (Phenomenex, Torrance, CA) eluted isocratically at 0.4 ml/min with 95% 10mM ammonium phosphate and 5% acetonitrile. The eluate was monitored at 209 nm. The melamine cyanurate suspension was determined to be at 102.3 ± 1.4% of its nominal concentration, as determined by analysis of three independent samples drawn under simulated dosing conditions.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Remarks:
Doses / Concentrations:
2 mg/kg bw
No. of animals per sex per dose / concentration:
6
Control animals:
no
Details on study design:
- Dose selection rationale: A dose of 2 mg/kg bw was selected because it was expected to afford
quantifiable serum levels and was below the threshold of exposure at which the authors have observed
significant nephrotoxic effects in subchronic studies with a combination of melamine and cyanuric acid in rats.

- Rationale for animal assignment (if not random): The rats were weight-ranked (acceptable weight: ± 20% of the mean body weight [bw]), and randomly assigned to treatment groups.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: blood
- Time and frequency of sampling: 0 (pretreatment), 0.5, 1, 2, 3, 4, 5, 6 and 8 h
Statistics:
Statistical analyses (with the exception of Tmax statistical analyses) were
conducted by one-way ANOVA, with pairwise comparisons being conducted
by the Student-Newman-Keuls method. Statistical analyses of Tmax values were
conducted, as appropriate, by Kruskal-Wallis one-way ANOVA on Ranks, with
pairwise comparisons being conducted by Dunn’s method or Mann-Whitney
Rank Sum tests. p values < 0.05 were considered to be significant.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Tmax (Melamine) = 2h, Tmax (Cyanuric acid) = 1h
Type:
absorption
Results:
Cmax (serum, melamine) = 155 ng/ml; Cmax (serum, cyanuric acid) = 180 ng/ml
Type:
other: Elimination
Results:
t1/2 (melamine) = 3h, t1/2 (cyanuric acid) = 1.6h
Type:
distribution
Results:
AUC (melamine) = 920 - 990 ng - h/ml, AUC (cyanuric acid) = 500 - 700 ng-h/ml

Toxicokinetic / pharmacokinetic studies

Details on absorption:
In both male and female rats, the oral administration of melamine cyanurate complex afforded substantially lower
Cmax and AUC values than those determined in the animals exposed orally to the nearly equimolar amounts of the triazines contained in the complex. In addition, the Tmax occurred later and t1/2 values were longer in the rats administered melamine cyanurate.
Details on distribution in tissues:
Distribution in tissues was not examined.
Details on excretion:
Elimination from the blood was examined.

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Executive summary:

Although the oral coadministration of 1 mg/kg body weight of melamine and cyanuric acid did not alter significantly the pharmacokinetic profiles in relation to those determined upon individual oral administration of each compound, the administration of equal amounts of each triazine as the preformed melamine cyanurate complex significantly altered the pharmacokinetics, with reduced bioavailability of both compounds, lower observed maximum serum concentrations, delayed peak concentrations, and prolonged elimination half lives.