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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Minimal information provided on methodology, only one dog treated.

Data source

Reference
Reference Type:
publication
Title:
The absorption and excretion of allantoin in mammals.
Author:
Young, E.G., H.P. Wentworth, and W.W. Hawkins
Year:
1944
Bibliographic source:
J Pharmacol Exper. Therapeutics 81:1-9

Materials and methods

Objective of study:
excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The rate of absorption and excretion of allantoin administered intravenously to dogs was studied.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Allantoin
- Substance type: pure active substance
- Physical state: solid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: 0.6% allantoin in sterile Ringer's solution
- Isomers composition: not applicable
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Radiochemical purity (if radiolabelling): not applicable
- Specific activity (if radiolabelling): not applicable
- Locations of the label (if radiolabelling): not applicable
- Expiration date of radiochemical substance (if radiolabelling): not applicable
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: not applicable
Radiolabelling:
no

Test animals

Species:
dog
Strain:
not specified
Sex:
not specified
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: metabolism cage
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Purina dog chow daily at 4:30 p.m.
- Water (e.g. ad libitum): no data
- Acclimation period: no data

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

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: sterile Ringer's solution
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION - not applicable

VEHICLE
- Justification for use and choice of vehicle (if other than water): no data
- Concentration in vehicle: 0.6% allantoin in sterile ringer's solution.
- Amount of vehicle (if gavage): not applicable
- Lot/batch no. (if required): no data
- Purity: no data

HOMOGENEITY AND STABILITY OF TEST MATERIAL: no data
Duration and frequency of treatment / exposure:
single intravenous injection
Doses / concentrations
Remarks:
Doses / Concentrations:
100 mL of 0.6% allantoin in sterile Ringer's solution
No. of animals per sex per dose:
1
Control animals:
other: baseline obtained from 2 dogs prior to experiment
Positive control:
No
Details on study design:
- Dose selection rationale: A dose of 600 mg of allantoin is approximately equivalent to the 24 hour output of the dog
- Rationale for animal assignment (if not random): no data
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled (delete / add / specify): blood and urine
- Time and frequency of sampling: Blood was tested at approximately 10 mins, 50 mins, 1 hr 10 mins, 1 hr 50 mins, 2-1/2 hr, 3 hr, 3-1/2 hr, 4 hr, 5-1/2 hr and 6 hr. The dog was catherterized and urine was collected hourly for 6 days.
- Other: not applicable

METABOLITE CHARACTERISATION STUDIES - not measured

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): not applicable
Statistics:
no data

Results and discussion

Preliminary studies:
Not applicable
Main ADME results
Type:
excretion
Results:
concentration of allantoin in urine rose sharply during first hour, then fell rapidly for 2 hours and reached the fasting level in about 5 hours

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Not measured
Details on distribution in tissues:
Not measured
Details on excretion:
The blood allantoin reached a concentration of 9.5 mg 10 mins after injection, then fell to 2.4 mg at 50 minutes and thereafter very slowly for about 5 hours. The concentration of allantoin in the urine rose sharply during the first hour, then fell rapidly for two hours and reached the fasting level in about five hours. If the base line for the excretion of allantoin be taken at 20 mg per hour the recovery of added allantoin would be 98% . As the urinary concentration is dependent upon available fluid, a calculation of the allantoin output per hour was considered a better criterion of excretion. This was high for the first three hours and fell to normal in 4 to 5 hours.

In the second IV experiment where the dog was administered 300 mL of water via stomach tube 30 minutes prior to giving the 600 mg IV dose of allantoin, the previous observations were confirmed showing somewhat more rapid elimination than in the first experiment complete in about 4 hours. Taking the normal rate of excretion at 30 mg/hr the recovery was 674 mg or 112%.

In the third IV experiment where the dog was administered 150 mL of water via stomach tube 80 minutes prior to injecting 100 mL of 0.194% uric acid, the blood allantoin rose to a maximum value in the first hour and fell to normal in the next two while the uric acid returned to the normal level in less than one hour. The uric acid excretion was significantly higher only during the first 30 minutes. The allantoin excretion was stimulated for about four hours. Assuming the base line of excretion of allantoin to be 46 mg/hr, the recovery was 112 mg, equivalent to 120 mg of uric acid or 62%. Assuming the base line for the normal excretion of uric acid to be 2 mg/hr, the recovery as uric acid would be 9% of the amount injected or a total of 71% recovered in 3.5 hours.

Metabolite characterisation studies

Metabolites identified:
not measured
Details on metabolites:
Not measured

Any other information on results incl. tables

Baseline Allantoin in dog blood

Date Time Allantoin Concentration (mg)
Dog A Dog B
Dec. 3 11:30 a.m. 1.2 2.1
Dec. 10 11:30 a.m. 1.7 1.7
Dec. 12 11:30 a.m. 1.4 1.9
4:30 p.m. 1.3  --- 
Dec. 16 11:30 a.m. 2.3 1.8
4:30 p.m. 2.0 1.6
Dec. 17 11:30 a.m. 1.7 1.9
4:30 p.m. 1.8 2.2
Dec. 18 11:30 a.m. 1.4 1.9
4:30 p.m. 2.3 2.3
Dec. 19 11:30 a.m. 1.4 1.2
Average 1.7 1.9

Applicant's summary and conclusion

Conclusions:
Following a single intravenous injection of allantoin to a single dog, the blood allantoin reached a concentration of 9.5 mg 10 mins after injection, then fell to 2.4 mg at 50 minutes and thereafter very slowly for about 5 hours. The concentration of allantoin in the urine rose sharply during the first hour, then fell rapidly for two hours and reached the fasting level in about five hours.