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

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

absorption

distribution

excretion

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

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

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

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

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.

Preliminary studies:

None

Type:

absorption

Results:

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

Type:

distribution

Results:

A low level of radioactivity was present in all analyzed tissues

Type:

excretion

Results:

The test substance was excreted principally in the urine

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.

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

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.

Reference 2

Endpoint:

dermal absorption in vivo

Type of information:

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

Adequacy of study:

key study

Study period:

1991

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well documented study according to GLP. Limitations due to low number of evaluated animals (n=2), but overall result plausible based on all available data.

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.7600 (Dermal Penetration)

Deviations:

yes

Remarks:

(limited animal number (n=2))

GLP compliance:

yes

Radiolabelling:

yes

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

Type of coverage:

open

Vehicle:

other: absolute ethanol:water (80:20)

Duration of exposure:

single dermal application for 72 hours

Doses:

9.9 mg/kg body weight (0.26 mg/cm2)

No. of animals per group:

initially 4 males; 2 animals accidentally ingested residual test material from exposed test side were removed from evaluation

Control animals:

no

Details on study design:

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, Carcass, skin (test site) and skin (adjacent).
- 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’.

Signs and symptoms of toxicity:

no effects

Dermal irritation:

not specified

Dose:

0.26 mg/cm2

Parameter:

percentage

Absorption:

< 1 %

Remarks on result:

other: 72 hours

Total Recovery: Recovery was 95 ± 5% (Mean ± S.E., n=2)

Conclusions:

The extent of radioactivity absorption following dermal administration of n-Lauryl [14C(U)]-glucose amide ([14C]-C12-GS-Base) at 9.9 mg/kg bw (0.26 mg/cm2) to rat was estimated to be <1% over 72-h test period. A very low amount of residual radioactivity was detected in all tissues and the principle route of elimination was urine.

Executive summary:

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

Male Sprague Dawley rats (from Charles River) were used in study. One group (number of animals= 2) of rats was used in the study to determine absorption, distribution and excretion (ADE) of test substance. Animals were housed in metabolism cages during the study period.

Test formulation (19.3 mg/g solution) was prepared in absolute ethanol. Animals were treated once with dose of 9.9 mg/kg bw (0.26 mg/cm2). Approximately 0.1 mL of test solution was applied within a glass ring glued on the hair clipped backs of animals, with the help of a syringe. The radioactive dose administered to animals was approximately 9 µCi/animal.

Animals were sacrificed by an overdose of CO2 after 72 hours of treatment. Urine and faeces were collected at 24, 48 and 72 h time intervals after treatment. Tissue samples were collected after sacrifice of the animals.

The extent of absorption following dermal administration of the radio-labeled test substance at 9. 9 mg/kg bw (0.26 mg/cm2) was estimated to be < 1% over a 72-hour test period.

Inspection of individual tissue radioactivity distribution at 72 hours showed the presence of very low levels of residual radioactivity in all tissues. The femur contained the highest radioactive content [20 times background (plasma radioactive content)] followed by carcass, whole blood, adipose and bone marrow. AII other tissues were five times background or less.

At the end of the 72-hour test period, 94.4% of the dosed radioactivity was recovered in the test site skin plus dose cell wash, 0.27% in the urine plus cage wash, 0.19% in the tissues plus carcass, 0.1% in the feces plus Gl tract wash and 0.02% in the expired carbon dioxide.Theprincipal route of radioactivity elimination was urine.

The % total recovery of test substance was 95±5% after treatment.

In conclusion, the extent of radioactivity absorption following dermal administration of n-Lauryl [14C(U)]-glucose amide ([14C]-C12-GS-Base) at 9.9 mg/kg bw (0.26 mg/cm2) to rat was estimated to be <1% over 72-h test period. A low amount of residual radioactivity was detected in all tissues and the principle route of elimination was urine.

Description of key information

No data are available on the absorption, distribution, metabolism or elimination (ADME) of Glucamide OL. However, based on the close structural similarity and generally comparable metabolic pathway, data can be read across from data generated on Glucamide 24 (see also comprehensive read-across justification). For this compound, oral absorption was greater 80% over a 72 hour period with more than 99% excreted in urine. No bioaccumulation potential was detected. Dermal absorption was below 1% over a 72 hour test period and thus negligible.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

80

Absorption rate - dermal (%):

1

Additional information

No data are available on the absorption, distribution, metabolism or elimination (ADME) of Glucamide OL. However, based on the close structural similarity and common metabolic pathway, data can be read across from data generated on Glucamide 24.After oral application, the absorption, distribution, metabolism and excretion (ADME) of radiolabeled n-lauryl-glucose amide ([¹⁴C]-C₁₂-G5 Base (Glucamide 24, radioactive purity 99.1%) was investigated in fasted male Sprague-Dawley rats (4 in total). Following oral administration of 150 mg/kg bw dose in ethanol:water (20:80), 79.7%, 16.03%, 0.31% and 0.18% of radioactivity was recovered in the urine (plus cage wash), feces (plus gastrointestinal tract wash), expired CO₂, and tissue plus carcass, respectively, at the end of 72 hours with the largest amount of radioactivity collected in the 8-24 hour test period. Individual tissue distribution at 72 hours indicated that the highest levels in the liver (16x plasma radioactive content) followed by kidneys, spleen, carcass, lungs and gastrointestinal tract. All other tissues were ≤ 3x background. Based on these data oral absorption was estimated to be 80% over the 72-hour period with > 99% of excreted in the urine and 0.3% eliminated in expired CO₂with only 0.2% in the tissues and carcass. The assessment of billiary elimination was beyond the scope of the study.

After dermal application, theADME of radiolabeled n-lauryl-glucose amide ([¹⁴C]-C₁₂-G5 Base; radiochemical purity 99.8%) was investigated in fasted male Sprague-Dawley rats. Following dermal administration of 9.9 mg/kg bw (0.26 mg/cm²) dose in ethanol, the material balance was 95 ± 5.0% (n=2). At the end of testing (72-hours), 94.4% of radioactivity was recovered at the test site skin (plus dose cell wash), 0.27% in the urine (plus cage wash), 0.19% tissue (plus carcass), 0.1% in the feces (plus gastrointestinal tract wash), and 0.02% in expired CO₂. Individual tissue distribution at 72 hours indicated low levels in all tissues with the highest levels in the femur (20x plasma radioactive content) followed by carcass, whole blood, adipose and bone marrow. All other tissues were ≤ 5x background. Based on these data dermal absorption was estimated to be <1% over a 72 hour test period, with the principal route of elimination being urine. The assessment of billiary elimination was beyond the scope of the study.