D-Glucitol, 1-deoxy-1-(methylamino)-, N-[C8-16 (even numbered) and C18 unsaturated acyl] derivs.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

migrated 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:

other: Well documented study conducted according to valid scientific standards including GLP

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:

Glucamide 24

IUPAC Name:

Glucamide 24

Constituent 2

Reference substance name:

287735-50-6

Cas Number:

287735-50-6

IUPAC Name:

287735-50-6

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

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
- Weight at study initiation: 175 - 225 g
- Fasting period before study: overnight before dosing
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 4 days

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: ethanol:water (20:80)

Details on exposure:

Administration of the dosing solution by a syringe

Duration and frequency of treatment / exposure:

Single administration via gavage followed by 3 day collecting period in metabolism cages designed for separation of urine, faeces and expired CO2

Doses / concentrations

Remarks:

Doses / Concentrations:
150 mg/kg body weight

No. of animals per sex per dose / concentration:

4 males

Control animals:

no

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’.

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

oral absorption was high (greater 80%) over the 72 hour period

Main ADME results 2

Type:

distribution

Results:

An overall low level of radioactivity was present in all analyzed tissues. Individual tissue distribution at 72 hours indicated highest levels in liver followed by kidneys, spleen, carcass, lungs and GI-tract

Main ADME results 3

Type:

excretion

Results:

Excretion occurred primaryl via urine (greater 99% of absorbed dose).

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

Metabolite characterisation studies

Metabolites identified:

not specified

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
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.