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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restricitions (only one dose level tested)

Data source

Reference
Reference Type:
publication
Title:
Metabolism, disposition and excretion of 14C-Melamine in male Fischer 344 rats
Author:
Mast R.W. et al.
Year:
1985
Bibliographic source:
Food Chem. Toxicol., 21, 807-810, (1983)

Materials and methods

Objective of study:
other: metabolism, excretion and disposition
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Deviations:
yes
Remarks:
only one dose level tested
Principles of method if other than guideline:
The metabolism, excretion and disposition of melamine were determined after administration of a single oral dose.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
The specific activity of the melamine was 8 .1 mCi/mmol and it was 98.4 % radiochemically pure by HPLC analysis.
Radiolabelling:
yes
Remarks:
14 C (uniformly labelled in the triazine ring)

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, N)
- Weight at study initiation: 250 to 400g
- Fasting period before study: food was withheld for 12 hr before and 4 hr after dosing
12-hr light/dark cycle .
- Housing: singly in glass metabolism chambers for collection of urine, faeces and breath
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Study design 1 (excretion routes): Intubation with 1 ml of the solution
Study design 2 (tissue distribution and residues): no data (presumably equivalent to study design 1)
Duration and frequency of treatment / exposure:
Study design 1 (excretion routes): single administration
Study design 2 (tissue distribution and residues): single administration, rats were killed 0.5, 1 .0, 4 .0, 8 .0 . 24, 48 or 96 hr later .
Doses / concentrations
Remarks:
Doses / Concentrations:
Study design 1 (excretion routes): 0 .025 mCi/rat (approximately 1 .3 mg/kg body weight) .
Study design 2 (tissue distribution and residues): 0 .025 mCi/rat
No. of animals per sex per dose:
Study design 1 (excretion routes): 4
Study design 2 (tissue distribution and residues): 3-4/group
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
Study design 1 (excretion routes):
- Tissues and body fluids sampled: urine, faeces, and expired air
- Time and frequency of sampling: four consecutive 24hr periods; in one study, expired air was not collected, faeces were collected at 96 hr
and urine at 2, 4, 8, 12, 24, 48, 72 and 96 hr after dosing . The urine from each rat was assayed separately.

Study design 2 (tissue distribution and residues):
- Tissues and body fluids sampled: At autopsy, samples of liver, kidneys, ureters . rinsed bladder and blood were taken and plasma was obtained by centrifugation . The half-life of melamine in the plasma was determined.

MELAMINE DETERMINATIONS
The 14C in aliquots of plasma, urine and breath-trapping solutions was measured directly by liquid scintillation. [14C]Melamine was measured in urine and in boiling-water extracts of blood, plasma and faeces ..




Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Results obtained from study design 2:
Plasma and liver:
The plasma [14C]melamine level 30 min after treatment was 1 .1 ppm, but 30 min later, this level had dropped by 53% to 0.52 ppm .
Over the next 3 hr, the plasma [14 C]melamine level dropped by another 52% .
The terminal phase half-life of melamine in plasma was 2 .7 hr . Whole-blood and liver levels of [14C}melamine were indistinguishable from plasma levels over this period . At 24 hr or after, no 14C was detected in the blood or plasma . Melamine levels in liver were 1-2 ppb or less over these periods
Kidney and bladder:
Melamine levels in the kidney were 2-3 times greater than in the plasma . These elevated kidney levels were probably due to renal concentration
of the melamine prior to its urinary excretion . At 24 hr or after melamine levels in kidney were 1-2 ppb or less.
Bladder radioactivity levels were very high . While bladder levels were similar to the plasma levels 30 min after treatment, they increased to a
peak of 6 .6 ppm at 4 hr (26.4 times the plasma level) and showed considerable variability (1 .4, 4 .5 and 14 ppm) . At 8 hr the level was still elevated and continued to show marked variability (4.0, 11 and 1 .8 ppm) .
This elevated bladder content of 14C was probably caused by back diffusion or contamination of the tissue by urine . The cause of the high variability between bladders is unknown .
At 24 hr or after Melamine levels in the bladder and ureter were higher than those of the other tissues showing the residual effects of the high initial urinary 14C levels .
(see also Table 1)
Details on excretion:
Results obtained from study design 1:
Urine:
Virtually all the radioactivity was excreted within the first 24 hr and was present in the urine .
By 96 hr, 93 ± 4% of the administered radioactivity had been excreted in the urine .
Faeces and breath:
Only 0.20 and 0.64% of the administered radioactivity appeared in breath and faeces, respectively, during the total 96-hr period . The radioactivity in the faeces was most probably the result of urinary contamination.
(An additional 4% of the administered radioactivity was recovered in the cage washings . From the urinary data, it seems likely that this 4%
was excreted in the first 24 hr . The total recovery of 14C was 99% .
Elimination half-life and renal clearance:
Kinetic analysis of the radioactivity data from urine yielded an elimination half-life of 3 .0 hr (95% CI 2 .6-3 .5) and a renal clearance of 2 .5 ± 0 .1 ml/min (mean ± SEM).

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
While analyzing the samples by HPLC analysis no metabolites could be detected, indication that melamine was not metabolized.
Between 97 and l00% of the 14C in blood and plasma was also present as melamine at all sampling times . Although the percentage of 14C present as melamine was lower in the faeces, the total non-melamine 14C in faeces accounted for less than 0.14% of the administered radioactivity .
(see also Table 2)

Any other information on results incl. tables

Table I . Concentrations of [14C]melamine in the t issues of male Fischer 344 rats treated orally with a single dose of 0 .025 mC i

Melamine concentration (ppb) in:

Time after treatment (hr)

No of rats

Blood*

Plasma

Bladder

Liver

Kidney

Ureter

0.5

Similar to plasma levels

1.1

Similar to plasma levels

Similar to plasma levels

No data

1.0

0.52

No data

4.0

0.25

6.6 (high variability)

8.0

No data

24.0

3

0

ND

31 +/- 15

1.8 +/- 0.1

1.3 +/- 0.7

12 +/- 4

48.0

3

0

0

4 +/- 2

2.6 +/- 1.2

0.7 +/- 0.9

9 +/- 5

96.0

4

0

0

8 +/- 2

0.4 +/- 0.2

0.1

12 +/- 5

* Limit of detection 1ppb

Data are expressed as means +/- SEM for the numbers of rats indicated

Table 2: Percentage of radioactivity present as melamine in the urine, blood, plasma and faeces

14C as 14C-melamine* (% of total) in:

Time after treatment (hr)

Urine

Blood

Plasma

Faeces

0.5

98.9+/- 6.2

98.5+/- 0.4

1.0

99.3+/- 0.1

99.4+/- 0.1

4.0

99.5+/- 0.1

99.1+/- 0.1

8.0

97.4+/- 1.9

98.3+/- 0.8

24.0

98.5+/- 0.1

78.4 +/- 2.9

48.0

98.1+/- 0.2

64.2 +/- 2.8

72.0

94.9+/- 2.2

96.0

96.5+/- 0.8

* *Radiochemical purity of [14C]melamine in dosing solution was 98 %.

Values are means ± SEM for groups of three or four rats .

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results