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Diss Factsheets

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study was not conducted under OECD GLP conditions but was well documented.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Objective of study:
other: Elimination half-life
Test guideline
Qualifier:
according to guideline
Guideline:
other: Internal protocol based on TOX SOP 0950
Principles of method if other than guideline:
12 male Sprague Dawley rats received a single 5 mg/kg dose of the test article in propylene glycol via oral gavage. Each animal was observed daily and urine was collected in individual metabolism cages from three animals on study Days 1-4. Serum, liver and urine were collected at necropsy for test compound analysis.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
T-7684
IUPAC Name:
T-7684
Test material form:
solid: crystalline
Details on test material:
- Name of test material (as cited in study report): MV31 K-Salz
- Substance type: Mono-constituent
- Physical state: Solid (Grey granules)
- Analytical purity: 88%
- Purity test date: 19 September 2000
- Lot/batch No.: Lot no. 1268147/1-1268154/1
- Expiration date of the lot/batch:31 December 2001
- Stability under test conditions: Guranteed for 4 hours
- Storage condition of test material: Darkness at approximately 20 C in a fume cupboard

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Harlan Teklad, Madison WI, USA
- Age at study initiation: 6-8 weeks
- Weight at study initiation: Mean: 241.7 g
- Fasting period before study: None
- Housing: All rats were housed in metabolism cages for the Days 1-4 and group housed in standard cages thereafter.
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Harlan Teklad LM-485 Mouse/Rat Sterilizable Diet, ad libitum
- Water (e.g. ad libitum): Tap Water, ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6-23.9 C
- Humidity (%): 30-70 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 December 2001 To: 14 January 2002

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test article was prepared in propylene glycol and administered via oral gavage.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Test article solubility
- Concentration in vehicle: 1 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg
- Lot/batch no. (if required): No data
- Purity: No data

HOMOGENEITY AND STABILITY OF TEST MATERIAL: No data
Duration and frequency of treatment / exposure:
Animals were dosed once via oral gavage
Doses / concentrations
Remarks:
Doses / Concentrations:
All test group animals received 5 mg/kg of the test article.
No. of animals per sex per dose / concentration:
12 male rats recieved the test article and 6 male rats received the vehicle alone.
Control animals:
yes, concurrent vehicle
Positive control reference chemical:
None
Details on study design:
- Dose selection rationale: No data
- Rationale for animal assignment (if not random): Random
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled : urine, serum, liver.
- Time and frequency of sampling: Urine and feces: Days 1-4, daily. Blood/serum and liver: At necropsy (Days 1, 4, 14, and 28)

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled : urine, liver, serum
- Time and frequency of sampling: All samples were analyzed
- From how many animals: All animals were sampled and samples were not pooled
- Method type(s) for identification: LC-MS
- Limits of detection and quantification: LOQ: 5.0 ng/mL
Statistics:
Data collected was analyzed for statistically significant differences between groups using Students T-test.

Results and discussion

Main ADME resultsopen allclose all
Type:
absorption
Results:
Based on test article concentrations in the liver and serum samples, the test article is readily absorbed via ingestion.
Type:
excretion
Results:
Based on the concentration of test article in urine samples, urinary excretion was a major route of elimination.

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The test article was found in liver samples at concentrations of 23.1, 7.2 and 0.8 ppm on study Days 1, 4 and 14 post-dose, respectively. On day 28 post-dose, no measureable levels of the test article were detected in the liver tissue. The liver elimination half-life is approximately 2 days. Test article serum concentrations of 16.2, 3.6, 0.15 and 0.01 ppm on Days 1, 4, 14, and 28 post-dose, respectively were detected. The serum elimination half-life is approximately 3 days. The avaerage univary concentrations of the test article were 17.5, 6.7, 3.9, and 1.3 ppm on Days 1, 4, 14, and 28 post-dose, respectively. Approximately 21% of the dosed test article was present in the urine on Day 1 post-dose and decreased thereafter. A total of 34.3% of the dose had been excreted in the urine by Day 4 post-dose.
Details on distribution in tissues:
Taken together, fully 60% of the dose could be accounted for on Day 1 post-dose in the combined liver, serum and urine that were analyzed. These data indicate that the test article was rapidly absorbed from the digestive tract and distributed to liver and serum.
Details on excretion:
Taken together, fully 60% of the dose could be accounted for on Day 1 post-dose in the combined liver, serum and urine that were analyzed. These data indicate that the test article was rapidly absorbed from the digestive tract and distributed to liver and serum and that urinary excretion was the major route of elimination.
Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
half-life 1st: Serum half-life: approximately 3 days
Toxicokinetic parameters:
half-life 2nd: Liver half-life: approximately 2 days

Metabolite characterisation studies

Metabolites identified:
no

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Taken together, fully 60% of the dose could be accounted for on Day 1 post-dose in the combined liver, serum and urine that were analyzed. These data indicate that the test article was rapidly absorbed from the digestive tract and distributed to liver and serum and that urinary excretion was the major route of elimination. Based on the results of the study, the test article has an elimination half-life in the serum of approximately 3 days and in the liver of approximately 2 days.
Executive summary:

The absorption, distribution, metabolism, and excretion as well as bioaccumulative potential of the test article (Grey granules, purity 88%, Lot 1268147/1-1268154/1) was evaluated in Sprague Dawley rats following a single dose. The study was not performed to conform to GLP guidelines. The study design was a 3M custom protocol and was conducted for research and development purposes. The test article was prepared in propylene glycol to appropriate concentration to allow for dosing at 5 mg/kg body weight. Eighteen rats were used in the study. Six vehicle control group rats received a single 5 mL/kg dose of propylene glycol. Necropsies of the vehicle control group were performed on Day 1, and Day 28 post-dose, (N=3/exposure period). Twelve rats received a single 5 mg/kg dose of the test article in propylene glycol by oral gavage at a volume of 5 mL/kg. Necropsies of the test article-dose group were performed 1, 14, and 28 Days post-dose, (N=3/exposure period). The concentration of each test compound in serum, liver and urine were determined by Liquid Chromatography mass Spectroscopy (LCMS) following sample extraction with formic acid buffer (pH 3.0) and solid phase extraction (SPE). At necropsy, there were no toxicologically significant differences in body weight, liver weights, or gross macroscopic observations between the treatment groups and the control groups. The test article was found in liver samples at concentrations of 23.1, 7.2 and 0.8 ppm on study Days 1, 4 and 14 post-dose, respectively. On day 28 post-dose, no measureable levels of the test article were detected in the liver tissue. The liver elimination half-life is approximately 2 days. Test article serum concentrations of 16.2, 3.6, 0.15 and 0.01 ppm on Days 1, 4, 14, and 28 post-dose, respectively were detected. The serum elimination half-life is approximately 3 days. The average urinary concentrations of the test article were 17.5, 6.7, 3.9, and 1.3 ppm on Days 1, 4, 14, and 28 post-dose, respectively. Approximately 21% of the dosed test article was present in the urine on Day 1 post-dose and decreased thereafter. A total of 34.3% of the dose had been excreted in the urine by Day 4 post-dose. Taken together, fully 60% of the dose could be accounted for on Day 1 post-dose in the combined liver, serum and urine that were analyzed. These data indicate that the test article was rapidly absorbed from the digestive tract and distributed to liver and serum and that urinary excretion was the major route of elimination. Based on the results of the study, the test article has an elimination half-life in the serum of approximately 3 days and in the liver of approximately 2 days.