Disodium sebacate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

Tracer Study of Metabolism and Tissue Distribution of Sebacic Acid in Rats

Author:

Tataranni, P.A.

Year:

1992

Bibliographic source:

Annals of Nutrition and Metabolism

Materials and methods

Objective of study:

distribution

excretion

metabolism

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 417 (Toxicokinetics)

Version / remarks:

22.06.2010

Deviations:

yes

Remarks:

According to i.v. application, no data on bioavailability; no data on enzyme induction/inhibition

Principles of method if other than guideline:

- Principle of test: Three groups of rats were treated with 14C-labeled test substance i.v.

- Short description of test conditions:
Group A: plasma elimination was examined for two doses (80 and 160 mg)
Group B: expired labeled CO2, urine tracer and faeces tracer were determined
Group C: autopsy and organ distribution of labeled test substance

- Parameters analysed / observed: plasma elimination, elimination routes and substance related pathological findings and organ distribution

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Disodium sebacate

EC Number:

241-300-3

EC Name:

Disodium sebacate

Cas Number:

17265-14-4

Molecular formula:

C10H18O4.2Na

IUPAC Name:

disodium sebacate

Test material form:

solid

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No. of test material:
14C-labeled sebacic acid tracer (specific activity 102 mCi/mmol) was purchased from Amersham (Buckinghamshire, UK).
Sebacic and azelaic acids were obtained from Sigma (St. Louis, Mo., USA).

RADIOLABELLING INFORMATION
- Specific activity: 14C-labeled sebacic acid tracer (specific activity 102 mCi/mmol)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 7-8 weeks
- Weight at study initiation: 220 - 250 g
- Diet: ad libitum, standard pellet diet containing 20% protein, 4% fat and 50% carbohydrate
- Water: ad libitum

Administration / exposure

Route of administration:

intravenous

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single dose i.v. application of the test substance

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

80 other: mg i.v.

Remarks:

enriched with 25 µCi tracer; Group A

Doses / concentrations 2

Dose / conc.:

160 other: mg i.v.

Remarks:

enriched with 25 µCi tracer, Group A, B and C

No. of animals per sex per dose / concentration:

14 male animals per dose in group A
4 male rats in group B
10 male rats in group C

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY
- Tissues and body fluids sampled: blood, urine, feces, expired air, liver, kidney, heart, lung, muscle, fat.
- Time and frequency of sampling:
Blood samples (Group A): 5, 10, 20, 40, 80, 160 and 320 min after injection
CO2 sampling (Group B): 15, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, 360, 420, 480, 540 and 1440 min post dose
Urine sample (Group B): 0-4 h and 4 -24 h post dose
Faeces sample (Group B): 24 h post dose
Tissue sampling (Group C): sacrifice of the animals at 30, 60, 120, 240 and 360 min postdose. At each time and from each sacrificed animal the following tissue samples were collectcd for radioactivity measurement: liver, kidney, heart, lung, muscle, fat.

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

After 24 h, 58.01 ±3.57 % of the injected radiocarbon dose was recovered in urine, 25 ±0.01 % in expired air.

Main ADME results 2

Type:

metabolism

Results:

The amount of recovered sebacate retrieved from the 24 h urine collection was 34.6 ±1.97 %

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:

Tracer half-life:
heart: 16 min
muscle: 32 min
kidney: 42 min
lung: 48 min
liver: 72 min
fat: 135 min

Details on excretion:

24 h feces samples did not show any beta-emission activity.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: global plasma half-life: 38.71 min

Toxicokinetic parameters 2

Toxicokinetic parameters:

other: Volume of distribution (Vd): 62.65 mL/100 g body weight

Any other information on results incl. tables

The authors could demonstrate that sebacic acid can be oxidized by tissues and that it is only partially eliminated in the urine. It seems reasonable to suppose that linear kinetics describe the elimination of Sb from plasma in the tested dose range. In their study the authors found a large apparent volume of distribution (62.65 ml/ l 00 g body weight), suggesting wide diffusion or, more likely, tissue binding of Sb. The global plasma elimination rate (half-life 38.71 min) reflects the contribution of both sebacate uptake and metabolism by tissues and of sebacate elimination by the kidney. The appearance of a ¹⁴CO₂ peak value in expired air few minutes after intravenous injection of labeled Sb indicates that this compound is readily used as an energy substrate. The authors retrieved 25% of administered tracer in expired CO₂ but the total recovered tracer was only about 85% ofthat administered, and it seems likely that thc oxidation is somewhat underestimated at 25 %. Moreover, part of the metabolites produced with the breakdown of sebacate for energy purposes can be excreted with urine, Iike ¹⁴CO₂-containing bicarbonates or succinate. While 60% of the total administered radioactivity was recovered from urine, only 35% of administered scbacate was recovered unchanged from urine. From all the above considerations, it seems likely that about 30-50 % of administered sebacate may be used by tissues for energy purposes. No appreciable accumulation of radioactivity is present in the body: after 24 h practically all of the administered tracer has disappeared from the sampled organs, fat included, although fat has the longest elimination time. A rough comparison between tissue elimination times seems to indicate that a delay in tracer elimination occurs also at the liver level. This suggests that fat and liver are possible preferential sites of Sb metabolism. On the other hand, heart, kidney, lung and skeletal muscle seem to have a faster sebacate elimination,

consistent with the hypothcsis of a simple dilution of the molecule in these areas, or of its use there eminently for energy production.