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Basic toxicokinetics

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Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
other information
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented study with acetable limitations

Data source

Referenceopen allclose all

Reference Type:
Metabolism of labelled isobutylidene diurea in sheep.
Bergner H, Görsch R
Bibliographic source:
Ann. Rech. Vét., 10/2/3): 382-384
Reference Type:
Untersuchungen zum Umsatz von markiertem Isobuylidenhdiharnstoff beim Wiederkäuer.
Görsch R
Bibliographic source:
Arch. Tierernährung, 30: 221-228

Materials and methods

Objective of study:
Principles of method if other than guideline:
Metabolic study of the test substance labeled with 14C and 15N in sheep
GLP compliance:
not specified

Test material

Details on test material:
no further data
15N-Isobutylidene diurea and 14C-Isobutylidene diurea (C1-labelled)

Test animals

other: Merino
Details on test animals and environmental conditions:
- Weight at study initiation: 44.0-52.6 kg
- Individual metabolism cages: yes/no
- Diet: semisynthetic diet containing 60 g of IBDU per animal per day as the only N-source . The diet contained 25.5% starch, 23.8% glucose, 29.0% cellulose, 10.0% straw, 1.7% sunflower seed oil, 4 .3% IBDU, 5.6% minerals and vitamin mixture. The contribution of N from straw was 4.4% of the total dietary nitrogen
- Acclimation period: 3-6 weeks to the aforementioned diet

Administration / exposure

Route of administration:
oral: feed
not specified
Duration and frequency of treatment / exposure:
single treeatment
Doses / concentrations
Doses / Concentrations:
First experiment: 2 sheep received 30 g IBDU per animal with 1259 mg 15N-excess and 680 uCi 14C-IBDU (C1-IBA labelling)
Second experiment: 4 sheep received 15N-labelled IBDU with the morning feeding (701 mg 16N-excess per animal)
No. of animals per sex per dose:
First experiment: 2 animals
Second experiment: 4 animals
Control animals:
not specified
Positive control:
no data
Details on study design:
no futher data
Details on dosing and sampling:
no further data
no further data

Results and discussion

Any other information on results incl. tables

First experiment:

The highest level of 15N incorporation into the TCA (trichloracetic acid) precipitable fraction of the ruminal fluid was noted 18-30 h after beginning the trial, as a result of the flow of urea via the rumino-hepatic circulatory system. A high concentration of 15N was shown to be present for a prolonged period in the TCA soluble fraction of the ruminal fluid (up to the 30th hour of experiment). The peak of specific 14CO2 activity in the air exhaled (including ruminal gas) was observed 2 h after beginning the trial. The atom-% 15N excess in the TCA soluble fraction of blood plasma was found

to increase, reaching a peak value 23 h after administration of ths isotope. The highest level of 14C activity in this fraction appeared 1 h after isotope

administration. The 15N incorporation into the protein fraction of blood plasma reached a constant high level between the 29th and 47th hours of the experiment. 3.5% of the administered dose of 14C activity and 23% of the supplied 15N-excess were excreted in the urine within 6 days; 20% of the total amount of 15 N excreted in urine could be detected as 14 C-isobutyl residues. An average of 22% of the total administered 15N was excreted in faeces (3.8% of the supplied 14 C-activity). Atom-% 15 N-excess was in the range of 0.05 to 0.17 in muscle and in various organs of the sheep when these were slaughtered on the 7th day of experiment (liver: 0.17; kidneys: 0.14 ; heart: 0.08; muscle:0.05).


Second experiment:

Comparison of the IBDU-concentrations in the content of the rumen bottom with the residual rumen content did not enable conclusions to be drawn regarding IBDU sedimentetion at tha bottom of the rumen. In the order of slaughtering times, the following amounts of 15N-IBDU were recorded from the rumen (% of intake): I = 15.6%, II = 24.1%, III = 3.3% and IV = 3.6%. 7.25 hours after starting the experiment, 40% of the 15 N-labelled material was found in the rumen in the form of IBDU; after 12 hours it was 10%. Except for sheep I , 15N-urea was found in small amounts in the rumen. Only sheep I and III revealed IBDU-traces in abomasum, but in the small intestine of all sheep, 2 to 6% of the amount ingested was found. This fact is explained by the endogenous influx of IBDU from the blood. All sheep revealed an almost equal urea level in blood plasma, ranging from 18 to 30 mg per 100 ml and IBDU was not detectable, except in the animal killed 12 hours after the start of the experiment, when it amounted to 17.3 mg/100 ml blood plasma. The 15N was incorporated into the blood plasma proteins, in the urine only small amounts of IBDU (max. 1% of intake) and 15N-IBDU (max. 0.2% of intake) were recovered.

Applicant's summary and conclusion