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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 1997 - August 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1997

Materials and methods

Objective of study:
absorption
excretion
Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Qualifier:
according to
Guideline:
EU Method B.36 (Toxicokinetics)
Version / remarks:
EC Commission Directive 87/302/EEC of November 18, 1987; Part B: Methods for the determination of Toxicity, Toxicokinetics; Official Journal of the European Communities No. L 133, p. 51-54, 1988
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Trilon A 92 (Tri-sodium salt of nitrilo tri (acetic) acid, monohydrate)
- Substance type: pure substance
- Physical state: solid, white powder
- Analytical purity: 92.4 %
- Impurities (identity and concentrations): no data
- Purity test date: IR- and UV-spectroscopy- analysis of Oct. 95, confirmation in Oct. 1997
- Lot/batch No.: Abl. Nr. 05-5056
- Expiration date of the lot/batch: no data
- Stability under test conditions: stability was checked in all experiments
- Storage condition of test material: at ambient temperature, tightly closed
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dr. Karl Thomae, Biberach a.d. Riss (Germany)
- Age at study initiation: 8 weeks at the beginning of acclimatization
- Weight at study initiation: between 281 and 308 g
- Fasting period before study: no data
- Housing: During acclimatization and prior to the experiment in type III Macrolon cages. During balance experiments in all-glass metabolism cages; type Metabowl (Jencons, Leighton Buzzard, UK)
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum. Kliba lab diet for rat-mouse-hamster either pelleted (e.g. during acclimatization) or granulated (e.g. in metabolism cages). Origin: Klingentalmühle AG, CH-4303 Kaiseraugst, Switzerland
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: period unspecified

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24 °C
- Humidity (%): 30 - 70 %
- Air changes (per hr): air conditioned
- Photoperiod (hrs dark / hrs light): no data

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Trilon A 92 was dissolved in the respective amount of a solution of 0.5 % Tylose CB 30.000 in aqua bidest .
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): Trilon A 92 in 0.5 % Tylose CB 30.000 in aqua bidest
- Storage temperature of food: at ambient temperature

VEHICLE
- Justification for use and choice of vehicle (if other than water): Recognized by international guidelines as the recommended test system (OECD No. 417). Study results will be used in. relation to already available data from the same test system.
- Concentration in vehicle:
- Amount of vehicle (if gavage): About 1 ml of the Tylose solution / 100 g bw were administered by gavage


HOMOGENEITY AND STABILITY OF TEST MATERIAL:
The analytical investigations performed in the context of this study demonstrated the stability of Trilon A 92 in 0.5 % Tylose CB 30.000 in aqua bidest . and the correctness of the concentrations.
Duration and frequency of treatment / exposure:
single dose (low and high) and
repeated dose (high): once daily at about the same time for 7 days
Doses / concentrations
Remarks:
Doses / Concentrations:
Single oral administration:
high dose 500 mg/kg bw
low dose 25 mg/kg bw

Repeated oral administration:
high dose 500 mg/kg bw
No. of animals per sex per dose:
4 males for each Experiment (dose)
Control animals:
no
Details on study design:
- Dose selection rationale:
According to the relevant guidelines (OECD No. 417), experiments shall be performed using one "high" dose level which should cause slight toxic effects and at which there might be changes in toxicokinetic parameters and one "low" dose level causing no toxic effects. The above mentioned doses of 500 and 25 mg/kg bw have been selected using the results from previously performed studies on the biokinetics and subacute or subchronic toxicity with Trilon A 92 (ref. 1-3).
As the study results should be set in relation to already available data from the same test system, the same mode of administration (oral) was used.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): urine, cage washes
- Time and frequency of sampling:
For single oral administration experiments: urine collection in time intervals: 0-6 h, 6-12 h, 12-24 h, 24-48 h, and 48-72 h
For repeated oral administration experiments: Collection of urine in 24 h intervals and 6, 12, 24 48 and 72 h after the last administration

Statistics:
Analysis of kinetic data was performed based on the group mean values using the PC program system TOPFIT Version 2.0
Calculation of group mean value and standard deviation

Results and discussion

Preliminary studies:
Based on theoretical considerations and published data, it was assumed that the systemically available portion of dose, i.e. the absorbed portion of dose, is exclusively excreted via urine and no metabolism of Trilon A 92 occurs. The portion of dose of Trilon A 92 which is found
in urine, thus, directly gives the bioavailability of Trilon A 92. For this reason only urine samples were analyzed for Trilon A 92.
Main ADME resultsopen allclose all
Type:
absorption
Results:
rapid but incomplete (~50% after 72h)
Type:
excretion
Results:
rapid for single and repeated dosing with an urinary excretion half-life of about 5 to 6 h

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Single oral administration of high dose:
(nominally 500 mg/kg bw (actually received on average: 440.9 mg/kg bw) corresponding to 132.05 mg per animal.)
Within 72 hours after single oral administration to male rats 40.71 % of the applied dose was found in urine. => bioavailability 40.71 %

Single oral administration of low dose:
(nominally 25 mg/kg bw (actually received on average: 21.8 mg/kg bw) corresponding to 6.6 mg per animal.)
Within 72 hours after single oral administration to male rats 53.03 % of the applied dose was found in urine. => bioavailability 53.03 %


Repeated oral administration of high dose:
(nominally 500 mg/kg bw /day (actually received on average: 453.4 mg/kg bw/day) resulting in a mean total dose of 878.91 mg per animal over 7 days of treatment.)
Continuously decreasing body weight during treatment period.
Increasing body weight during 72 hour observation period after last administration.
47.81 % of the total dose applied could be found in the urine collected during the treatment period and up to 72 hours after the last administration. => bioavailability over 7 days = 47,81 % (with some variations on a daily basis: range: 27.89 % on day 3 and 62.09 on day 4)
Details on excretion:
Single oral administration of high dose:
The urinary excretion half-life of Trilon A 92 was calculated to be 6.2 hours.
Kinetic analysis revealed a mean residence time of Trilon A 92 of 11.9 hours.

Single oral administration of low dose:
The urinary excretion half-life of Trilon A 92 was calculated to be 4.7 hours.
Kinetic analysis revealed a mean residence time of Trilon A 92 of 6.5 hours.

Repeated oral administration of high dose:
The urinary excretion half-life of Trilon A 92 was calculated to be 5.4 hours.
Kinetic analysis revealed a mean residence time of Trilon A 92 of 8.5 hours.

All these data do not give an indication that induction or saturation of urinary excretion of Trilon A 92 occurs after repeated oral administration.
Toxicokinetic parametersopen allclose all
Test no.:
#1
Toxicokinetic parameters:
half-life 1st: 6.2 hours (high dose single administration)
Test no.:
#2
Toxicokinetic parameters:
half-life 1st: 4.7 hours (low dose single administration)
Test no.:
#3
Toxicokinetic parameters:
half-life 1st: 5.4 hours (high dose repeated administration)

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Table 1: Excretion of Trilon A 92 after single oral administration to male rats at a dose level of 500 mg/kg bw (mena values and standard deviation)

.

Animal No.

mean

SD

Animal weight in [g]

 

 

at application

299,48

11,93

at sacrifice

284,47

16,50

Dose In [mg/kg bw]

440,90

6,60

Dose in [mg/animal]

132,05

6,31

 

 

 

Urinary excretion in

% dose (mean)

SD

Urine 0-6

19,72

4,84

Urine 6-12

10,08

2,78

Urine 12-24

7,28

1,98

Urine 24-48

2,00

0,88

Urine 48-72

1,65

1,20

Cage wash

0,00

0,00

 

 

 

Total

40,71

4,50

Table 2: Excretion of Trilon A 92 after single oral administration to male rats at a dose level of 25 mg/kg bw (mean values and standard deviation)

Animal No.  mean     SD 
Animal weight in [g]     
at application  306,12 7,60
at sacrifice  292,27 5,54
Dose In [mg/kg bw]  21,80 0,20
Dose in [mg/animal] 6,66 0,18
     
Urinary excretion in  % dose (mean)     SD 
Urine 0-6  32,16 6,64
Urine 6-12  14,04 4,76
Urine 12-24  6,83 4,90
Urine 24-48  0,00 0,00
Urine 48-72  0,00 0,00
Cage wash  0,00 0,00
     
Total  53,03 13,94

Table 3: Excretion of Trilon A 92 after daily oral administration for 7 consecutive days to male rats at a dose level of 500 mg/kg bw (mean values and standard deviation)

    Animal weight in [g]     Dosing in [mg/kg bw]    Dosing in [mg/animal]    Urinary excretion in [% of daily dose] 
  mean SD mean SD mean SD mean SD
Day 1  305,86 2,11 446,2 4,80 136,48 1,71 61,39 5,43
Day 2  280,38 4,09 443,1 7,00 124,2 0,55 52,37 5,89
Day 3  278,70 5,12 448,8 6,50 125,08 3,36 27,89 6,85
Day 4  274,64 3,76 454,1 12,70 124,75 5,02 62,09 13,14
Day 5  268,00 5,99 461,1 19,20 123,65 7,76 43,87 2,91
Day 6  270,75 5,12 459,6 1,30 124,42 2,48 42,87 11,33
Day 7  261,21 6,39 460,8 11,80 120,33 3,15 42,81 6,64
             
At sacrifice  296,46 8,90        
Mean      453,4 3,90    
Total          878,91 16,68

Table 4: Excretion of Trilon A 92 after daily oral administration for 7 consecutive days to male rats at a dose level of 500 mg/kg bw (mean values % dose and standard deviation)

Urinary excretion of test substance  % dose (mean) SD
Urine 0-24  9,54 0,95
Urine 24-48  7,4 0,75
Urine 48-72  3,97 0,96
Urine 72-96  8,8 1,84
Urine 96-120  6,18 0,65
Urine 120-144  6,07 1,61
Urine 144-150  3,57 0,63
Urine 150-156  1,29 0,34
Urine 156-168  0,69 0,15
Urine 168-192  0,19 0,13
Urine 192-216  0,11 0,11
Cage wash  0 0,00
Total  47,81 4,19

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
After single and repeated oral administration Na3NTA was rapidly absorbed from the gastrointestinal tract. Absorption, however, was incomplete amounting to about 50 % of the dose applied. The excretion of Na3NTA was rapid with an urinary excretion half-life of about 5-6 hours.
Executive summary:

In an absorption and excretion study according to OECD 417 Na3NTA was administered to male Wistar rats in single oral administration at dose levels of 500 mg/kg and 25 mg/kg bw, and repeated oral administration at a dose level of 500 mg/kg/day, nominally.

After single and repeated oral administration Na3NTA was rapidly absorbed from the gastrointestinal tract. Absorption, however, was incomplete amounting to about 50 % of the dose applied. Excretion was rapid with an urinary excretion half-life of about 5-6 hours.

The investigation does not give an indication that induction or saturation of urinary excretion of Na3NTA occurs after repeated oral administration. The experiment does not indicate any bioaccumulation potential.

This absorption and excretion study in male Wistar rats is classified acceptable and satisfies the guideline requirements in rats according to OECD 417.