Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Guideline study without detailed documentation.

Data source

Reference
Reference Type:
publication
Title:
Investigations on the utilization of D-gluconate and d-glucono-δ-lactone in the metabolism of the normal and alloxan diabetic rat.
Author:
Tharandt V, Hübner W & Hollmann S
Year:
1979
Bibliographic source:
J. Clin. Chem. Clin. Biochem. Volume 17. 1979. p. 257-267.

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 417 (Toxicokinetics)
Version / remarks:
-reliability scoring based on 1984 guideline
Deviations:
yes
Remarks:
-only 1 dose was tested instead of a minimum of 2 dose levels, and observation period should be 7 days or up until 95% of the administered dose for excretion studies, whichever comes first (additional deviations continued in Materials and Method Section)
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Two separate studies with the registerable D-glucono-δ-lactone and a second compound sodium-D-gluconate
- Physical state: Not reported
- Analytical purity: Not reported
- Radiochemical purity (if radiolabelling): Not reported
- Specific activity (if radiolabelling): Not reported
- Locations of the label (if radiolabelling): [U-14C]D-gluconolactone and [U-14C]Na-D-gluconate
- Expiration date of radiochemical substance (if radiolabelling): Not reported
Radiolabelling:
yes
Remarks:
[U-14C]D-Glucono-δ-lactone and [U-14C]sodium-D-gluconate

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Brünger Tierzüchterei/Bokel
- Age at study initiation: Not reported
- Weight at study initiation: 180 to 250 g
- Fasting period before study: 15 to 24 hours
- Housing: Not reported
- Individual metabolism cages: Not reported
- Diet (e.g. ad libitum): Standard feed (Höveler, Immlgrath), ad libitum
- Water (e.g. ad libitum): water, ad libitum
- Acclimation period: Not reported

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Not reported
- Humidity (%): Not reported
- Air changes (per hr): Not reported
- Photoperiod (hrs dark / hrs light): Not reported

Administration / exposure

Route of administration:
other: See details on study design
Vehicle:
other: aqueous solution (since D-glucono-δ-lactone can be hydrolyzed easily in aqueous solutions, hydroxymethyl-aminomethane (Tris) was added for stabilization)
Duration and frequency of treatment / exposure:
Single exposure
Doses / concentrations
Remarks:
Doses / Concentrations:
Experiment 1: unlabelled test substance (D-glucono-δ-lactone) = 4 g/kg body weight
Experiment 2: labelled test substance (D-glucono-δ-lactone or sodium-D-gluconate) = 0.8 g/kg body weight
Experiment 3: labelled test substance (D-glucono-δ-lactone or sodium-D-gluconate) = 24.6 kBq (0.6655 μCi)
No. of animals per sex per dose:
Experiment 1: 4 to 14 animals for D-glucono-δ-lactone
Experiment 2: 9 to 10 animals for D-glucono-δ-lactone and 9 to 23 animals for sodium-D-gluconate
Experiment 3: 11 to 19 animals for D-glucono-δ-lactone and 6 to 18 animals for sodium-D-gluconate
Control animals:
other: concurrent no treatment (for experiment 1 only)
Positive control:
None used.
Details on study design:
Experiment 1:
Five hours after test article administration by gavage or after a total of 20 to 29 hours fasting for the control animals and after anesthesia, liver samples were collected to measure the activity of enzymes (6-phosphogluconate dehydrogenase, transketolase, glucokinase) and for determination of glycogen and metabolites. The removal of the liver for the determination of glycogen and metabolites was obtained by freeze-stop procedure. Muscle samples were taken from the thigh adductors, and immediately frozen in liquid nitrogen.

Experiment 2:
U-14C-labelled substrate (D-glucono-δ-lactone or sodium-D-gluconate) was administered by gavage to the 15 h-starved animals in 0.8 ml aqueous solutions, which contained 200 g/L substrate (on average 0.8 g/kg body weight). The gluconolactone solutions were adjusted to pH 5 by adding Tris (2.5 g Tris/10 g of lactone).

Experiment 3: The volume of distribution of the measured radioactivity in blood from 2.5 and 10 min after intravenous injection of [U-14C]-substrates was determined and given in % of the body weight. In this experiment, a cannula closed with a two-way stopcock was introduced during hexobarbital anesthesia after venesection into the right jugular ext. vein through which the substrate is injected and blood samples were taken.
Details on dosing and sampling:
Experiment 1:
- Tissues and body fluids sampled: liver
- Time and frequency of sampling: 5 hours following administration, examined levels of glycogen, glucose-6-phosphate, and 6-phosphogluconate in the liver

Experiment 2:
- Tissues and body fluids sampled: urine, faeces, blood, intestine
- Time and frequency of sampling: Five hours following the administration of the test substance, radioactivity in feces, intestine, urine, and whole body were measured. Carbon dioxide exhalation was measured at 5 and 10 hr following administration of the test substance.

Experiment 3:
- Tissues and body fluids sampled: liver
- Time and frequency of sampling: 5 hours following administration, examined levels of glycogen in the liver
Statistics:
Not applicable.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Results from experiment 2: According to the results observed in the blood, feces, and intestine, intestinal absorption is rapid following oral administration of D-glucono-δ-lactone. The authors noted that D-glucono-δ-lactone was absorbed to a greater degree than sodium-D-gluconate following oral administration.

Results from experiment 3: Gluconate and even more so gluconolactone are present in considerable amount intracellularly 5 minutes following intravenous administration. Approximately 0.18 and 0.51% of the applied dose (sodium-D-gluconate and D-glucono-δ-lactone was retained in the liver glycogen (14C is incorporated into liver glycogen after 5 h).
Details on distribution in tissues:
Results from experiment 3: The volume of distribution for D-glucono-δ-lactone and sodium-D-gluconate was reported to be 50.11 and 40.97% body weight.
Details on excretion:
Result from experiment 2: The radioactivity of D-glucono-δ-lactone was reported to be 25.0, 23.1, 29.5, and 7.0% from exhaled carbon dioxide, from the whole body (excluding the gastrointestinal tract), intestine and feces, and in the urine, respectively after 5 hours. The total recovered radioactivity of D-glucono-δ-lactone was reported to be approximately 84.6% of the dose. The radioactivity of sodium-D-gluconate was reported to be 12.1, 19.7, 44.9, and 5.0% from exhaled carbon dioxide, from the whole body (excluding the gastrointestinal tract), intestine and feces, and in the urine, respectively after 5 hours. The total recovered radioactivity of sodium-D-gluconate was reported to be approximately 81.7% of the dose.
Toxicokinetic parameters
Test no.:
#1
Toxicokinetic parameters:
other: Not applicable

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

Results from experiment 1:

D-glucono-δ-lactone is commonly believed to be metabolized to gluconic acid and lactone, which are intermediates in the oxidation of glucose through the pentose phosphate cycle. Although this pathway of glucose metabolism is not the main pathway, it is well recognized. In this study, the authors examined the effects of D-glucono-δ-lactone on glucose metabolism by measuring the levels of glucose-6-phosphate and 6-phosphogluconate in the liver. Five hours following the administration of D-glucono-δ-lactone, the levels of glucose-6-phosphate and 6-phosphogluconate were reported to be 163 and 27 μmol/kg wet weight, similar to normal (i.e., untreated and fed) animals.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results