Iron digluconate

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:

1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference Type:

other: Journal

Title:

Unnamed

Year:

1979

Report date:

1979

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

equivalent or similar to guideline

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)

Principles of method if other than guideline:

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

Test material information

Constituent 1

Reference substance name:

D-glucono-1,5-lactone

EC Number:

202-016-5

EC Name:

D-glucono-1,5-lactone

Cas Number:

90-80-2

Molecular formula:

C6H10O6

IUPAC Name:

3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-one (non-preferred name)

Constituent 2

Reference substance name:

Sodium D-gluconate

EC Number:

238-976-7

EC Name:

Sodium D-gluconate

Cas Number:

14906-97-9

Molecular formula:

C6H12O7.xNa

IUPAC Name:

sodium 2,3,4,5,6-pentahydroxyhexanoate (non-preferred name)

Details on test material:

- Name of test material (as cited in study report): Two separate studies with the read-across compound D-glucono-d-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-d-lactone and [U-14C]sodium-D-gluconate

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system 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:

oral: gavage

Vehicle:

other: aqueous solution (since D-glucono-d-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-d-lactone or sodium-D-gluconate) = 0.8-1.6 g/kg body weight
Experiment 2: labelled test substance (D-glucono-d-lactone or sodium-D-gluconate) = 0.8 g/kg body weight
Experiment 3: labelled test substance (D-glucono-d-lactone or sodium-D-gluconate) = 0.8 g/kg body weight (24.6 kBq (0.6655 µCi))

No. of animals per sex per dose / concentration:

Experiment 1: 4 to 14 animals for D-glucono-d-lactone or sodium-D-gluconate
Experiment 2: 9 to 10 animals for D-glucono-d-lactone and 9 to 23 animals for sodium-D-gluconate
Experiment 3: 11 to 19 animals for D-glucono-d-lactone and 6 to 18 animals for sodium-D-gluconate

Control animals:

other: concurrent no treatment (for experiment 1 only)

Positive control reference chemical:

None used.

Details on study design:

Experiment 1:
Sodium gluconate or glucono-d-lactone, in aqueous solutions (200-400 g/L equating to 0.8-1.6 g/kg bw) were administered by gavage after 15-24 hr fasting.
Five hours after test article administration or after a total of 20 to 29 hours fasting for the control animals and after anesthesia, liver and muscle samples were collected. The removal of the liver was obtained by freeze-stop procedure. Muscle was immediately frozen in liquid nitrogen.
The activity of enzymes (6-phosphogluconate dehydrogenase, transketolase, glucokinase) was measured in liver.
Metabolites glucose-6-phosphate and 6-phosphogluconatewere measured in liver.
Glycogen was measured in liver and muscle.

Experiment 2:
U-14C-labelled substrate (D-glucono-d-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).
Urine and faeces were collected during 5 hours after administration.
The intestinal tract was collected after 5 hours following adminstration.
Blood was collected at various times after administration.
Radioactivity was measured in all samples collected.

Experiment 3:
[U-14C]-substrates (200 g/L equating to 0.8 g/kg; 24.6 kBq in 0.8 ml aqueous solution) was administered by intravenous injection. The volume of distribution was determined in blood from 2.5 and 10 min after intravenous injection given in % of body weight. 14C incorporation into liver glycogen was also determined.

Details on dosing and sampling:

Experiment 1:
- Tissues and body fluids sampled: liver and muscle
- Time and frequency of sampling: 5 hours following administration, liver and muscle were collected and stored in liquid nitrogen, after which levels of enzymes (6-phosphogluconate dehydrogenase, transketolase, glucokinase)enzymes (6-phosphogluconate dehydrogenase, transketolase, glucokinase) and metabolites glucose-6-phosphate and 6-phosphogluconate were measured in the liver, and glycogen was measured in both liver and muscle.

Experiment 2:
- Tissues and body fluids sampled: urine, faeces, blood and intestine
- Time and frequency of sampling: Five hours following the administration of the test substance, radioactivity in faeces, 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: blood and liver
- Time and frequency of sampling: 5 hours following administration, glycogen levels in the liver were measures. readioactivity in the blood was measrued 2.5 to 10 mins after administration to measure the volume of distribution.

Statistics:

Not applicable.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Results from experiment 2: According to the results observed in the blood, faeces, and intestine, intestinal absorption is rapid following oral administration of D-glucono-d-lactone. The authors noted that D-glucono-d-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-d-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-d-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-d-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-d-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

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Results from experiment 1:

D-glucono-d-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-d-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-d-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
Bioaccumulation potential cannot be judged based on study results

Executive summary:

There are no toxoicokinetic studies on ferrous gluconate. Results of a study conducted with a structurally similar compounds, D-glucono-1,5 -lactone and sodium D-gluconate, are reported and used for read across.

Bioaccumulation potential cannot be judged based on study results