D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C18-C18 (unsaturated) acyl] derivs.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1991

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Materials and methods

Objective of study:

absorption

distribution

excretion

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Deviations:

yes

Remarks:

(one dose level was used in this study against the guideline recommendation of minimum 2 dose levels).

GLP compliance:

yes

Test material

Test material information

Constituent 1

Reference substance name:

A 3:1 mixture of: 1-deoxy-1-[methyl-(1-oxododecyl)amino]-D-glucitol; 1-deoxy-1-[methyl-(1-oxotetradecyl)amino]-D-glucitol

EC Number:

407-290-1

EC Name:

A 3:1 mixture of: 1-deoxy-1-[methyl-(1-oxododecyl)amino]-D-glucitol; 1-deoxy-1-[methyl-(1-oxotetradecyl)amino]-D-glucitol

Cas Number:

287735-50-6

Molecular formula:

C19H39NO6 (C12 derivative) C21H43NO6 (C14 derivative)

IUPAC Name:

D-Glucitol, 1-deoxy-1-(methylamino)-, N-C12-14 acyl derivs.

Test material form:

other: solid

Details on test material:

- Name of test material (as cited in study report): N-Lauroyl [14C]-glucose amide (C12-GS-Base)
- Physical state: white solid
- Radiochemical purity (if radiolabelling): 99.1%
- Specific activity (if radiolabelling): 19 mCi/g
- Storage condition of test material: room temperature

Specific details on test material used for the study:

UNLABELED TEST MATERIAL
- Name of test material: C12/14 GS-base
- TSIN: SS0001.01
- Substance type: Other
- Physical state: White opaque solid gel
- Stability under test conditions: Not reported
- Storage condition of test material: Room temperature

RADIOLABELED TEST MATERIAL
- Name of test material: n-Lauroyl [14C(U)]-glucose amide (C12-GS-Base)
- TSIN: SS0001.01
- Physical state: Solid
- Substance type: Pure active substance
- Specific activity: 19 mCi/g
- Stability under test conditions: Not reported
- Storage condition of test material: Refrigerated

Radiolabelling:

yes

Remarks:

14C

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: Not reported
- Weight: Weighing 175 - 225 g after overnight fasting
- Fasting period before study: Animals were fasted overnight before dosing and until 4 hours after dosing.
- Housing: Animals were housed in Plasite 7122-H coated metabolism cages.
- Individual metabolism cages: Yes
- Diet: Purina rat chow diet, ad libitum
- Water: ad libitum
- Acclimation period: At least 4 days

ENVIRONMENTAL CONDITIONS: Environmental conditions were as per the Standard Operating Procedures of the Test Facility.

STUDY INITIATION DATE: Mar. 05, 1991
STUDY COMPLETION DATE: Mar. 08, 1991

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: Absolute ethanol/water (20:80) v/v

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: Approximately 10 grams of the dose solution was supplied by Radiochemistry. Dose solution was prepared by mixing 7.7 mg of radio-labeled and 654 mg of unlabeled test substance, and taking to a final weight of 10 grams with a solution of absolute ethanol:distilled water (20:80)(v/v).
- Mean radioactive dose: 13.8 µCi/rat

VEHICLE
- Concentration in vehicle: 30 mg/g solution (approximately 10 µCi/g)

Duration and frequency of treatment / exposure:

Once

Doses / concentrations

Dose / conc.:

152 mg/kg bw/day (actual dose received)

Remarks:

Dose volume: Approximately 1 mL/animal

No. of animals per sex per dose / concentration:

4 male rats

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Urine, faeces, CO2, blood, plasma, tissues, cage washes, GI tract wash. Tissue collected were liver (entire), kidneys, testes or (Ovaries and uterus), heart, lung (entire), spleen, pancreas, brain, bone marrow, muscle (Hind limb; right), bone (femur; both), adipose (at the psoas), Gl tract and Carcass.
- Time and frequency of sampling: Urine and feces were collected at 24, 48 and 72 hours after treatment. CO2 was collected from the rats at 24, 48 and 72 hours. CO2 safety trap (one/rat) was collected at the end of the 72 hour test period. At the end of the 24-, 48- and 72-hour collection period, cages were washed with 3A alcohol followed by distilled water. These cage washes were submitted separately to Radiochemistry for analysis. Tissue samples were collected after sacrifice of animals.
- Blood sampling and sacrifice: At the end of the 72 hour test period, rats were sacrificed with an overdose of carbon dioxide. Blood was collected from the inferior vena cava in a heparinized syringe. A portion of this sample was submitted to Radiochemistry as ‘blood’. The plasma fraction from the remainder of the blood was prepared by centrifugation. This sample was submitted to Radiochemistry as ‘plasma’.

COLLECTION AND STORAGE OF SAMPLES: Urine and faeces were kept in freeze until analyzed. After sacrifice, the tissues and organs were removed, rinsed with water and blotted on a paper towel. Any fat or connective tissue from the organs were removed and placed in tared sample jars. Organs that had internal cavities (the heart and the urinary bladder) were cut open and rinsed with water. Bone sample from both femurs were taken after removing the bone marrow. Adipose tissues were sampled from the area of the psoas muscle. Carcasses were freezed before grinding in Wiley mill.

METABOLITE CHARACTERISATION STUDIES: No metabolite characterisation was performed.

Results and discussion

Preliminary studies:

None

Main ADME results

Main ADME results 1

Type:

absorption

Results:

Oral absorption of the test substance was high (80%).

Main ADME results 2

Type:

distribution

Results:

A low level of radioactivity was present in all analyzed tissues

Main ADME results 3

Type:

excretion

Results:

The test substance was excreted principally in the urine

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The extent of radioactivity absorption following the oral administration of the radio-labeled test substance at 150 mg/kg bw was estimated to be 80% over the 72-hour test period.

Details on distribution in tissues:

Inspection of individual tissue radioactivity distribution at 72 hours showed the presence of low levels of radioactivity in all tissues.
The liver contained the highest radioactivity [16 times background (plasma radioactive content) followed by kidneys, spleen, carcass, lungs and GI tract.
All other tissues were ≤ 3 times background level.

Details on excretion:

At the end of the 72-hour test period, 79.7% of the dosed radioactivity was recovered in the urine plus cage wash, 16.03% in the feces plus GI tract wash, 0.31% in the expired carbon dioxide and 0.18% in the tissues plus carcass.
The amount of radioactivity recovered in urine plus cage wash, expired carbon dioxide and feces decreased during each 24- hour collection period with the largest amount of radioactivity collected in the 0-24 hour test period.
Of the absorbed radioactivity, >99% was excreted in the urine, 0.3% was eliminated in the expired CO2 and residual radioactivity detected in tissues and carcass at 72 hours accounted for 0.2% of the absorbed radioactivity.

Any other information on results incl. tables

Total Recovery: The % total recovery was 96 ± 0.48% (Mean ± S.E., n=4).

Applicant's summary and conclusion

Conclusions:

n-Lauryl [14C(U)]-glucose amide ([14C]-C12-GS-Base) when administered once orally to Sprague-Dawley rats was rapidly and extensively absorbed (80%) from the gastrointestinal tract. Of the absorbed radioactivity, >99% was excreted in the urine, 0.3% was eliminated in the expired CO2 and residual radioactivity detected in tissues and carcass at 72 hours accounted for 0.2% of the absorbed radioactivity.

Executive summary:

The absorption, distribution and excretion of n-Lauryl [14C(U)]-glucose amide ([14C]-C12-GS-Base) after oral administration was determined by following the methods similar to the OECD guideline 417 (Toxicokinetics).

Male Sprague Dawley rats (from) were used in study. One group (number of animals = 4) of rats was used in the study to determine absorption, distribution and excretion (ADE) of the test substance. Animals were housed in metabolism cages during the study period.

Test formulation (30 mg/g solution) was prepared in absolute ethanol:distilled water (20:80)(v/v). Animals were treated once orally with 152 mg/kg bw (Dose volume: Approximately 1 mL/animal). Urine and faeces were collected at 24, 48 and 72 h after treatment. CO2 was collected from the rats at 24, 48 and 72hours. Animals were sacrificed by an overdose of CO2 after 72 hour of treatment. Tissue samples were collected after sacrifice of animals.

The extent of radioactivity absorption following oral administration of the radio-labeled test substance at 150 mg/kg bw was estimated to be 80% over the 72-hour test period.

Inspection of individual tissue radioactivity distribution at 72 hours showed the presence of low levels of radioactivity in all tissues. The liver contained the highest radioactivity [16 times background (plasma radioactive content) followed by kidneys, spleen, carcass, lungs and GI tract. All other tissues were ≤ 3 times background level.

Of the absorbed radioactivity, >99% was excreted in the urine, 0.3% was eliminated in the expired CO2 and residual radioactivity detected in tissues and carcass at 72 hours accounted for 0.2% of the absorbed radioactivity.

The radioactivity material balance (% Total recovery) was 96 ± 0.48% (Mean ± S.E., n=4) in the study.

In conclusion, n-Lauryl [14C(U)]-glucose amide ([14C]-C12-GS-Base) when administered once orally to Sprague-Dawley rats was rapidly and extensively absorbed (80%) from the gastrointestinal tract. Of the absorbed radioactivity, >99% was excreted in the urine, 0.3% was eliminated in the expired CO2 and residual radioactivity detected in tissues and carcass at 72 hours accounted for 0.2% of the absorbed radioactivity.

This toxicokinetics test is classified as acceptable, and satisfies the guideline requirements of the OECD 417 method.