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Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
prior to GLP, no data on purity
Objective of study:
excretion
Principles of method if other than guideline:
To generate background values, the ether soluble fraction of the urine for each test animals was determined on a daily basis for 5-6 days before application of the test substance. The test substance was administered daily by gavage in 2 doses on 2 consecutive days. After application, urine was collected for a total of 4 days at intervals of 24h starting on the day of application. Urine analysis was performed according to the method described in Emmrich and Hoehne 1940 (Ber. d . mathemat.-physikal. Kl. d. Sächsichen Akademie zu Leipzig XCII. 15) to determine the percent urinary elimination of the test substance.
GLP compliance:
not specified
Radiolabelling:
no
Species:
rabbit
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
Diet: grass or white beetroot
Route of administration:
oral: gavage
Vehicle:
other: sodium bicarbonate
Details on exposure:
Test substance was diluted in a 13% sodium bicarbonate. A maximum volumeof 84ml of the test substance was applied per animal. The test substance was described in the publication as acidic. Before application, the substance were heated to 40°C to prevent precipitation which normally occured at room temperature. Control animals were administered 100 ml of a saline solution.
Duration and frequency of treatment / exposure:
daily application for 2 days
Dose / conc.:
3 370 mg/kg bw/day
No. of animals per sex per dose / concentration:
4 animals
Control animals:
yes, plain diet
Details on absorption:
not determined
Details on distribution in tissues:
not determined
Observation:
not determined
Details on excretion:
On the average, 72 % of the applied substance (Detection method does not exclude its metabolites.) was eliminated via urine. The test substance was almost totally eliminated 2 days after application with about 55% elimination after 24h (reference is one dose applied), 83% after 48h (reference is one dose applied) and only 4% on day 3 (reference is one dose applied). On day 4 sebacic acid was no longer detectable in urine samples.
Metabolites identified:
not measured
Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1941
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
prior to GLP, no data on purity
Objective of study:
excretion
GLP compliance:
not specified
Radiolabelling:
no
Species:
rat
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: adult
- Weight at study initiation: 300g
- Diet: bread (60% corn flour, 30% dry-milk, 8 % dried yeast, 2% cod-liver and table salt)
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Test substance was diluted in water. Before application, the substance were heated to 40°C to prevent precipitation which normally occured at room temperature. Control animals were administered equivalent volume of water.
Duration and frequency of treatment / exposure:
daily application for 4 weeks
Dose / conc.:
1 010 mg/kg bw/day
No. of animals per sex per dose / concentration:
2 animals
Control animals:
other: water
Details on study design:
Urine analysis was performed according to the method described in Emmrich and Hoehne 1940.

Emmrich und Hoehne: Ber. d . mathemat.-physikal. Kl. d. Saechsichen Akademie zu Leipzig XCII. 15 .I 1940
Details on dosing and sampling:
The animals were dosed on a daily basis for 4 weeks. Urine sampling was performed accordingly:
-before feeding was commenced (5-6 days): 4 times (background)
- Week 1: 4 times
- Week 2: 3 times
- Week 3: 3 times
- Week 4: 4 times
- After termination of infusion: 4 times each on 2 days back to back

As a rule, 24h urine was collected for each animal. After collection, urine samples were adjusted to 250ml with water. 72 h after end of the substance intubation, the animals were sacrificed. The bodies of the 6 animals were minced, treated with alcohol and the water and ether soluble components quantified.
Details on absorption:
not determined
Details on distribution in tissues:
not determined
Observation:
not determined
Details on excretion:
On the average, 62.5 % of the applied substance (Detection method does not exclude its metabolites.) was eliminated via urine per day. Within the entire feeding period, elimination of the test substance was always constant. Within 24h after termination of substance intubation, the test substance became totally eliminated. Quantification of the ether as well as water soluble rests of the bodies of sacrificed rats (after termination of substance feeding) indicated that sebacic acid did not accumulate in the bodies of the rats.
Toxicokinetic parameters:
other: not determined
Metabolites identified:
not measured
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The justification for the type of information are discussed in the attached read-across document.
Reason / purpose for cross-reference:
read-across source
Details on excretion:
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.
Toxicokinetic parameters:
half-life 1st: global plasma half-life = 31.5 min
Metabolites identified:
yes
Details on metabolites:
Suberic (C8) and adipic (C6) acids amounted for approximately 3 % and 1 %, respectively, of the dicarboxylic acid.
Endpoint:
basic toxicokinetics in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Justification for type of information:
The justification for the type of information are discussed in the attached read-across document.
Reason / purpose for cross-reference:
read-across source
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

- test substance is oxidized by tissues and partially eliminated in the urine

- linear kinetics expected to occur for elimination in plasma

- large apparent volume of distribution (62.65 ml/ l 00 g body weight), suggesting wide diffusion and/or tissue binding

- plasma elimination rate (half-life 38.71 min) reflects the contribution of both, uptake and metabolism by tissues and elimination by the kidney

- 25% of administered tracer in expired CO2 but the total recovered tracer was only about 85% of that administered

- 60% of the total administered radioactivity was recovered from urine, only 35% of administered substance was recovered unchanged from urine

- it is likely that about 30-50 % of administered test substance 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

Description of key information

Bioavailablility: similar after i.p. and oral administration

Metabolism: completely oxidized in organisms to CO2 and H2O

Elimination: rapid elimination of the substance (and its dicarboxylic metabolites) via urine within the first 4 days after oral or i.p administration in rat or rabbit; afterwards not detectable anymore

Bioaccumulation: not observed, supported by the rapid elimination

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Four studies are available with the analogon disodium sebacate (CAS 17625-14-4) concerning metabolism, excretion, formation of ketone bodies and interference with glucose metabolism in human volunteers. The studies are described in detail in the section for human data. The key findings are as follows: A definite amount of disodium sebacate infused is taken up and oxidized in human tissues. After bolus or continuous infusion the urinary excretion of disodium sebacate and its products of beta-oxidation was found to be low and the energy production high with sebacate being completely oxidized in the organism to CO2 and H2O. Disodium sebacate did not increase the formation of ketone bodies or interfere with glucose metabolism after infusion in human volunteers. No change in sebacate steady-state levels was observed during hyperinsulinemia, suggesting that insulin does not influence disodium sebacate (Sb) plasma clearance.

Assessment of toxicokinetic behaviour based on physicochemical properties of the substance and results from available toxicological studies:

1. Phys-Chem properties of the substance

- substance is solid, a free-flowing powder at 20 °C and 1013 hPa

- volatility: negligible; negligible vapour pressure (extrapolated to be 7.4E-6 Pa) at 25 °C, melting point 135 °C

- molecular weight: 202.25 g/mol

- purity: > 99 %

- logPow: 1.5 at 23 °C and pH 3

- water solubility: 0.2 g/l at 20°C; very soluble in alcohols, esters, ketones; slightly soluble in hydrocarbons, chlorinated hydrocarbons

 

2. Data from Acute-Toxicity studies and Repeated-Dose Toxicity (RDT) studies

Most studies (toxicokintic; oral acute and RDT) were done with the analogon disodium sebacate (CAS 17265-14-4), supported by older sebacic acid data.

There are data on acute oral toxicity in rats (LD50 > 5000 mg/kg bw) and acute dermal toxicity in rabbits (LD50 > 2000 mg/kg bw). There are also data on oral RDT available, with a NOAEL (rat) >= 1000 mg/kg bw and NOAEL (rabbit) >= 1500 mg/kg bw.

After oral single or repeated application as well as after dermal single application, no mortalities, clinical effects, specific target organs or any other changes were observed.

 

3. Absorption/Distribution/Metabolism/Excretion (ADME)

ABSORPTION: The bioavailability of the analogon disodium sebacatae was regarded as similar after i.p. and oral administration (Favuzzi et al., 1999), indicating a good GIT absorption. This is supported by the physiological factors for GIT absorption: MW < 500 g/mol and logPOW between -1 and 4. According to the Danish (Q)SAR Database (EPI Suite, DERMWIN v2.09), the dermal absorption is regarded as low with an estimated Kp value of 0.00329 cm/hr.

 

DISTRIBUTION: Although systemic distribution is expected after oral exposure, no organ specific adverse effects, e.g. to the kidney, were observed in acute and RDT studies (Greco et al., 1990; AMRL, 1976, Enders 1941). A large apparent volume of distribution (62.65 ml/ l00 g body weight) is described in an in vivo study with rats (Tataranni, 1992).

 

METABOLISM: Concerning the metabolism there are human studies available due to use for total parenteral nutrition (Mingrone et al., 1991, 1992, 1993; Raguso et al., 1994): Sebacate is oxidized in human tissues after i.v. infusion (sebacic acid --> suberic acid --> adipic acid --> succinic acid ). In rats, the disodium sebacate was oxidized by various tissues (Tataranni, 1992).

Excretion of Sb and its beta oxidation products was observed to be < 15% of sebacate administered per day. Adverse reactive metabolites are not expected to occur, as sebacic acid was negative in an Ames test with and without metabolic activation (Safepharm Laboratories Limited, 1992; Shimizu, 1985), as well as in other in vitro and in vivo studies with the analogon adipin acid (CAS 124-04-9). An in vitro binding study (Bertuzzi et al. 1993) suggested, a substantial fraction of sebacic anions is likely to be bound to human plasma albumin after i.v. application of the analogon disodium sebacate. Another published experimental study (Intrasuksri & Feller, 1991), investigating the effects on peroxisome proliferation in rat hepatocytes, showed, that sebacic acid did not influence the peroxisome-associated enzymes LH and FACO.

 

EXCRETION: A rapid elimination of 50 % of the analogon disodium sebacate via urine within the first 3-4 days after oral or i.p administration in rat or rabbit was described (Favuzzi et al., 1999); supported by another study in rats (Tataranni, 1992), an older study with sebacic acid (Enders, 1941) and available human data (Migrone et al., 1991; 1992; 1993; Ragusso et al., 1994). Furthermore, bioaccumulation was not observed, which is supported by the 1-octanole/water partition coefficient of 1.5, meaning that significant accumulation of sebacic acid in organisms is not to be expected.

 

In conclusion, after oral exposure of sebacic acid absorption and systemic distribution is expected, but the substance is rapidly eliminated via urine or metabolized via beta-oxidation, e.g. resulting in non-adverse metabolites of the citrate cycle. Dermal absorption is not fully excluded but probably low, and no adverse effects were observed after dermal exposure to rabbits.    

Discussion on bioaccumulation potential result:

In the first animal study (Favuzzi et al., 1999), using the analogon disodium sebacate (CAS 17265-14-4), rats were once i.p. treated with 10 up to 320 mg sodium sebacate. After an observation time of 320 min for disposition and of 48 h for excretion, blood and urine were analyzed, revealing an elimination of 50 % of the substance within the first 98 h; the majority within the first 6-9 h. The authors also performed concurrently, a pharmocokinetics analysis of disodium sebacate in rats after oral administration, for comparison of the bioavailability after i.p. and oral administration routes. Relative Bioavailabilty of sebacate was calculated to be 69.09%. The disposition of sebacate after oral administration was claimed to be similar to that of the i.p. route (data not shown), resulting in the interpretation that sebacate is readily and rapidly adsorbed in GIT.

In the second animal study (Tataranni et al., 1992), the analogue substance disodium sebacate (CAS 17265-14-4) was i.v. given to rats with 80 mg and 160 mg of radioactively marked (14C-labeled) dinatium sebacate. Blood, CO2, urine, feces and tissue (liver, kidney, heart, lung, muscle, fat) sampling was performed during the study or directly after sacrifice.   The tracer substance was expired by 25% of administered test substance tracer in expired CO2 but the total recovered tracer was only about 85% of that administered. From the administered labelled test substance, 60% of the radioactivity was recovered from urine, only 35% of the administered substance was recovered unchanged from urine. About 30-50 % of the administered test substance may be used by tissues for energy purposes and no appreciable accumulation of radioactivity was present in the body. After 24 h practically all of the administered tracer had disappeared from the sampled organs, fat included.

In the third, pre-GLP animal study (Enders, 1941), sebacic acid was orally applied to rabbits (3.37 g/kg bw on 2 consecutive days). 72 % were eliminated via urine during the first 3 days; no further substance was detectable on day 4. Additionally, in the same publication, rats were repetetively treated with sebacic acid for 4 weeks (daily 1010 mg/kg bw). On average, 62.5 % of the substance were eliminated via urine. The author mentioned, that the detection method in the urine does not exclude the metabolites of sebacic acid.

After quantification of the sacrificed rats at the end of exposure, no accumulation in the body was observed.