Disodium sebacate

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Objective of study:

absorption

excretion

metabolism

toxicokinetics

Principles of method if other than guideline:

The pharmacokinetics of disodium sebacate (Sb) was studied In Wistar rats of both sexes. Sebacate was administered either as intraperitoneal (i.p.) bolus or as oral bolus. Plasma and urinary concentrations of Sb and urinary concentrations of Sb and its products of ß-oxidation (suberic and adipic acid) were measured.

GLP compliance:

not specified

Radiolabelling:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 120-250 g
- Diet: ad libitum (standard pellet diet; 20 % protein, 4 % fat, 50 % carbonhydrate)
- Water: ad libitum

Route of administration:

other: i.p. and oral

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single dose application of the test substance
Disposition study: 5.3 h (320 min)
Excretion study: 48 h

Dose / conc.:

40 other: mg

Remarks:

i.p. administration and oral administration, disposition study

Dose / conc.:

80 other: mg

Remarks:

i.p. administration and oral administration, disposition study

Dose / conc.:

160 other: mg

Remarks:

i.p. administration and oral administration, disposition study

Dose / conc.:

10 other: mg

Remarks:

i.p. administration, excretion study

Dose / conc.:

40 other: mg

Remarks:

i.p. administration, excretion study

Dose / conc.:

80 other: mg

Remarks:

i.p. administration, excretion study

Dose / conc.:

160 other: mg

Remarks:

i.p. administration, excretion study

Dose / conc.:

240 other: mg

Remarks:

i.p. administration, excretion study

Dose / conc.:

320 other: mg

Remarks:

i.p. administration, excretion study

No. of animals per sex per dose / concentration:

Disposition study: 14 rats (7 ♂ / 7 ♀)
Excretion study: 5-11 animals per dose (♂ and ♀)

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Blood, urine
- Time and frequency of sampling:
blood: 0-4h, 4-24h, 24-48h,
urine: before dosing, 5, 10, 20, 40, 80, 160, 320 min post dose.

Details on excretion:

URINE:
After i.p. administration of the test substance, about 50 % of the dose was recovered in urine over 48 h. The majority of the test substance was excreted in the first 6-9 h. Gradually the urinary sebacate concentration decreased with time and in the urine samples collected 29 to 48 h after bolus administration only traces of the diacid were detected.

Key result

Toxicokinetic parameters:

half-life 1st: global plasma half-life = 31.5 min

Toxicokinetic parameters:

other: Volume of distribution (Vd): 26.817 mL / 100 g bw

Toxicokinetic parameters:

other: Pooled estimate of total urinary sebacate excretion (Xu): 35.6 mg

Toxicokinetic parameters:

other: Renal elimination constant (Ke) = 0.00977 per min

Toxicokinetic parameters:

other: Computed tissue elimination rate Km = 0.01221 per min

Toxicokinetic parameters:

other: Renal Clearance: 0.291 mLmin/100 g bw

Metabolites identified:

yes

Details on metabolites:

- URINARY EXCRETION:
Suberic (C8) and adipic (C6) acids amounted for approximately 3 % and 1 %, respectively, of the dicarboxylic acid.

Pooled parameter estimates (K, Co) were obtained by fitting all plasma concentrations together, normalized by dividing them by the administered dose and multiplying them for a common dose value of 80 mg (D) (see table below)

Volume of distribution (Vd) = dose/Co

A pooled estimate (Xu) of total drug excreted in the urine was obtained by averaging the recovered amount for each rat divided by the dose given to that rat and multiplied by the common dose value 80 mg.

Computed renal elimination constant (Ke) = KXu/D

Renal elimination rate Km = K-Ke

Renal clearance was evaluated by multiplying the value of the sebacate apparent volume of distribution (Vd) and the first order elimination constant (Ke) of the diacid urinary excretion.

Table1 : Parameter estimates computed for each i.p. dose separately.

Administered dose	K (1/min)	Co (µg/mL)
40	- 0.020 ± 0.0030	550 ± 20
80	- 0.030 ± 0.0075	1906 ± 227
160	- 0.016 ± 0.0016	2718 ± 101

Reference 2

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

Objective of study:

distribution

excretion

metabolism

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

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

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

Route of administration:

intravenous

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single dose i.v. application of the test substance

Dose / conc.:

80 other: mg i.v.

Remarks:

enriched with 25 µCi tracer; Group A

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.

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.

Type:

metabolism

Results:

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

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:

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

Toxicokinetic parameters:

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

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.

Description of key information

Based on its physicochemical properties systemic availability of disodium sebacate is evident. When taken up by the oral route, the substance is likely to be absorbed through the walls of the gastrointestinal tract by absorption and/or diffusion. The physicochemical properties do not favor transdermal absorption. Considering its solid state and is very low vapour pressure of 1x10^-6 hPa of the test substance it is expected to be non-inhalable under normal use conditions. The substance is distributed and metabolized within the body if becoming systemically available (Favuzzi, 1999; Tataranni, 1992). Based on the chemical characteristics renal excretion is assumed to be the major route (Favuzzi, 1999) followed by expiration of metabolic generated CO₂ (Tataranni, 1992). According to the physiochemical properties and the fast degradation/excretion of the test substance, bioaccumulation is unlikely.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

69.09

Additional information

Toxicokinetic analysis of Disodium Sebacate

The test substance is a solid at room temperature with a molecular weight (MW) of 246.21 g/mol. The water solubility is very high (198.8 g/L). A log Pow of -4.9 was determined. Particles of the test substance have a MMD of 4 µm (D10 = 1 µm, D90 =11 µm).

In a metabolism study disodium sebacate (¹⁴C-labeled, specific activity 102 mCi/mmol) was administered to 14 adult male wistar rats, single doses i.v. at dose levels of 80 and 160 mg. (Tataranni, 1992). In another metabolism study disodium sebacate was administered to 5-11 adult male and female wistar rats, single doses i.p. at dose levels of 10, 40, 80, 160, 240, and 320 mg (Favuzzi, 1999).

Absorption

After oral uptake, the chance of systemic absorption through the gastrointestinal (GI) barrier depends on the physicochemical properties of the substance. For a conclusive judgment on the substance' potential to reach systemic circulation, important physiochemical factors such as molecular weight, water solubility and the log Pow value should be considered. The substance is highly hydrophilic (log Pow -4.9) and is highly soluble in water (198.8 g/L) and in combination with the moderate molecular weight (MW) of 246.21 g/mol, the substance will dissolve readily into the GI fluids. Absorption can occur either by transporter mediated uptake or by passive diffusion via aqueous pores. The possible gastrointestinal uptake is supported by the structure of the substance which is in close relation to nutritional fatty acids. Toxicokinetic studies in rats showed a bioavailability of 69.09 % (Favuzzi, 1999) and metabolic degradation of the test substance (Tataranni, 1992).

According to the solid state of disodium sebacate, exposure to the test substance as vapor is very limited if handled at room temperature. Inhaled particles may reach the alveolar region of the respiratory tract. If inhaled, the hydrophilic and highly water soluble test substance will readily dissolve in the mucus of the respiratory tract and will be absorbed. No data of inhalation studies were available.

Particles of the test substance will have to dissolve into the surface moisture of the skin before absorption. Considering the hydrophilic character and the high solubility, the test substance will dissolve readily in the surface moisture. Dermal uptake of substances <100 g/mol is favored. The MW of the test substance of 246.21 g/mol hinders dermal absorption. According to the solubility (198.8 g/L) a moderate dermal uptake can be anticipated. However, due to the log Pow of -4.9, the poor lipophilicity will limit penetration into the stratum corneum and hence dermal absorption. The assumption that limited dermal absorption occurs is strengthened by results of an acute dermal study in rabbits showing an LD50 > 2000 mg/kg body weight (Ausimont, 1999).

Distribution

Based on basic toxicokinetic studies in rats (Favuzzi, 1999), the test substance has a relative bioavailability of 69.09 %. According to a radioactive tracer study in rats (Tataranni, 1992) the volume of distribution was determined (62.65 mL/100 g body weight), indicating a wide diffusion. Target organs were identified (highest to lowest radioactivity): liver, kidney, muscle, heart, lung, and fat, indicating the longest half-life in liver and adipose tissue.

Metabolism

Considering the close molecular relation of disodium sebacate to physiological occurring free fatty acids, a metabolic degradation via beta-oxidation can be assumed. This assumption is supported by the results of a metabolism study in humans (Mingrone, 1992) and by the results of a radioactive tracer study in rats (Tataranni, 1992). In humans the i.v. administered Disodium sebacate (1000 mg) was completely oxidized in the organism to CO₂ and H₂O. In rats, 25 % of the administered tracer was retrieved as CO₂ and 58 % in urine after 24 h. Furthermore the amount of recovered unchanged test substance after 24 h in urine was 35 %. These results indicate a metabolic degradation via beta-oxidation.

Excretion

According to the physicochemical properties of disodium sebacate, molecular weight, hydrophilic properties and high water solubility, the main route of excretion is urine (58 % of the administered tracer) (Tataranni, 1992). However, based on the metabolism of the test substance, only a smaller part of the test substance will be excreted unchanged (35 % unchanged test substance after 24 h in urine). Beta-oxidation degradation products, e.g. C8- or C6- bodies are likely to be found in urine (suberic acid, 3 %, adipic acid 1 % of the dicarboxylic acids) (Favuzzi, 1999) as well as CO₂ in expired air (25 % of administered tracer) (Tataranni, 1992). No tracer was found in feces. After 24 h no tracer was detected in target organs, indicating a very low potential for bioaccumulation.

Summary

Based on its physicochemical properties disodium sebacate is systemically available. When taken up by the oral route, the substance is likely to be absorbed through the walls of the gastrointestinal tract by absorption and/or diffusion. The physicochemical properties do not favor transdermal absorption. Considering the solid state of the test substance it is expected to be non-inhalable under normal use conditions. The substance is expected to be distributed and metabolized within the body. Based on the chemical characteristics renal excretion is assumed to be the major route followed by expiration of metabolic generated CO₂. According to the physiochemical properties and the fast degradation/excretion of the test substance, bioaccumulation is unlikely.

References

ECHA (2014) Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance, Version 2.0.

Tataranni PA et al. (1992) Tracer Study of Metabolism and Tissue Distribution of Sebacic Acid in Rats, Annals of Nutrition and Metabolism.

Ausimont S.p.A. (1999) Study Report.

Favuzzi AMR et al. (1999) Pharmacokinetics of sebacic acid in rats, European review  for medical and pharmacological sciences.

Mingrone G et al. (1992) Use of Even-Numbered Carbon Atom Dicarboxylic Salts in Parenteral Nutrition as Fuel Substrate, J. Parenteral and Enteral Nutrition.