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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:
key study
Study period:
13 February 2006 to 17 February 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study not conducted under GLP conditions, but followed sound scientific principles.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2007

Materials and methods

Objective of study:
excretion
Test guideline
Qualifier:
according to
Guideline:
other: Custom 3M protocol
Principles of method if other than guideline:
Objective was to assess the urinary elimination and potential toxicity of the test material following a single oral dose. Each animal recieved a single dose of 72.6 micromoles of the test material or vehicle per kg body weight. The test material was prepared in water and gentle mixing performed before each sample is drawn for dosing. Urine was collected between 0-6 hours, 24-48 hours, and 72-96 hours post dose. Necropsy of each animal performed at 96 hours post dose.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): MTDID 6675
- Substance type: Clear liquid
- Physical state: Liquid
- Analytical purity: 28.9% active ingredient in water.
- Purity test date: January 25, 2006
- Lot/batch no.: 140499-8/25
- Storage condition of test material: Tightly sealed at room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories
- Age at study initiation: 6-8 weeks
- Weight at study initiation: Approx. 200-250 grams
- Fasting period before study: No data
- Housing: In metabolism cages for urine collection for up to 96 hours after exposure. When not in metabolosm cages animals are group housed in standard solid bottomed cages.
- Diet (e.g. ad libitum): Harlan Teklad LM-485 Mouse/Rat Sterilizable Diet (Harlan Teklad, Madison, WI, USA) ad libitum.
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-23.9
- Humidity (%): 30-70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 13 February 2006 To: 17 February 2006

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water): Water
- Concentration in vehicle: 72.6 micromolar solution of the test article per dose.
- Amount of vehicle (if gavage): Dose volume: 5.0 mL/kg body weight.
HOMOGENEITY AND STABILITY OF TEST MATERIAL: Solutions mixed gently prior to drawing dose.
Duration and frequency of treatment / exposure:
One dose was administered by oral gavage.
Doses / concentrations
Remarks:
Doses / Concentrations:
A single 5.0 mL/kg bw dose of the test article at a concentration of 72.6 micromolar was administered.
No. of animals per sex per dose:
3
Control animals:
yes, concurrent vehicle
Positive control:
No
Details on study design:
- Duration of observation period following administration: 96 hours following test article administration
- Frequency of observations and weighing: Daily
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, urinary analysis, organ weights.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (excretion)
- Tissues and body fluids sampled: Urine
- Time and frequency of sampling: Urine was collected between 0-6 hours, 24-48 hours, and 72-96 hours post dose.
- Other:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: Urine
- Time and frequency of sampling: Urine was collected between 0-6 hours, 24-48 hours, and 72-96 hours post dose.
- From how many animals: All animals
- Method type(s) for identification: F-NMR

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parameters
Toxicokinetic parameters:
other: The test article was eliminated in the urine of male rats following single oral doses. 84.0% of the administered dose was recovered between 0 and 96 hours post treatment.

Metabolite characterisation studies

Metabolites identified:
no
Details on metabolites:
There was no evidence of significant metabolism of the test article.

Any other information on results incl. tables

No treatment-related gross lesions were noted at necropsy.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other: Based on the results of the study the test article was elim. in the urine of male rats following single oral doses. 84.0% of the admin. dose was recovered between 0 and 96 h post treatment. There was no evidence of sign. metabolism of the test article.
Based on the results of the study the test article was eliminated in the urine of male rats following single oral doses. 84.0% of the administered dose was recovered between 0 and 96 hours post treatment. There was no evidence of significant metabolism of the test article.
Executive summary:

This study assessed the urinary elimination and potential toxicity of MTDID 6675 (28.9% in water, lot 140499-8/25), following single oral gavage administration to male Sprague Dawley rats using a custom 3M protocol. The test article was supplied as a liquid. The test article was administered as received to rats (3 animals/dose) via oral gavage at a dose of 72.6 µmol/kg body weight which corresponds to 27.4 mg/kg of the test article. A control group received the vehicle, Milli-Q water, by oral gavage. The dose volume was 5.0 mL/kg. After dosing, animals were placed in metabolism cages and urine was collected at specified intervals for 96 hours. Animals were observed daily for clinical signs of toxicity. Body weights were measured prior to dosing and approximately daily thereafter. On Day 4, necropsies were performed and liver weights were recorded for all animals. Blood specimens were collected at necropsy, processed to serum, and frozen for possible future analysis. Urine samples were analyzed for the test article parent compound and for evidence of metabolites by 19F NMR spectroscopy. No test article-related mortalities occurred and no abnormal clinical signs were observed during the study for any test article. No treatment-related gross lesions were noted at necropsy in animals treated with the test article. Urinary recoveries between 0 and 96 hours postdose were 84.0% of the administered dose for the test article. No significant urinary metabolites were detected for the test article. In conclusion, the test article was eliminated in the urine of male rats following a single oral dose of 72.6 µmol/kg body weight. There was no evidence of significant metabolism.