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Toxicological information

Basic toxicokinetics

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Administrative data

basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Peer reviewed, published data, comparable to guideline, non GLP, acceptable for assessment

Data source

Reference Type:

Materials and methods

Objective of study:
Principles of method if other than guideline:
A method utilizing thin-layer chromatography, high performance liquid chromatography, and mass spectrometry was developed for the quantification of C9, C10, C11, and C12 dicarboxylic acids in serum, urine, and feces of human volunteers and rats after oral administration of the acids.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
C9-C12 dicarboxylic acids
C9-C12 dicarboxylic acids
Details on test material:
C9, C10, C11 , and C12 dicarboxylic acids (99% pure) were purchased from Fluka, A.G.
[ 10,11-³H]dodecandioic acid (sp act 20 mCi/mM, Radiochemical Center, Amersham, England)

Test animals

Details on test animals or test system and environmental conditions:
Weight: 250-270 g
Age: 7 weeks

Administration / exposure

Route of administration:
oral: gavage
unchanged (no vehicle)
Details on exposure:
Rats in each group were given, in a single dose, a different dicarboxylic acid in powder form by stomach intubation followed by water.
Duration and frequency of treatment / exposure:
Single dose
Doses / concentrations
Doses / Concentrations:
20mg, 50 mg, 100 mg per animal (corresponding to 5; 12.5; 25 mg/kg bw)
No. of animals per sex per dose / concentration:
10 animals per dose.
Control animals:
Positive control reference chemical:
Details on dosing and sampling:
Daily serum samples were collected and examined separately for a period of 6 days after administration of the dicarboxylic acids.
Fifty µg of internal standard was added to 1 ml of each serum sample. The internal standard was a dicarboxylic acid with one more C-atom than in the administered acid (e.g., in humans given C9 dicarboxylic acid, the internal standard was the C10 dicarboxylic acid). Sera were acidified to pH 1 with 1 N HCI, saturated
with NaCI, and extracted three times with 10 ml of warm (40°C) ethyl acetate. The combined extracts were dried over anhydrous Na2S04. The extracted solutes
were recovered after evaporation of the solvent under reduced pressure (below 40°C) in a rotatory evaporator.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
About 2% of ³H administered was recovered in feces of rats. The maximum radioactivity was detected between the 3rd and the 4th day. No traces of labeled diacids were found.
Details on distribution in tissues:
Tissue lipids.
The radioactivity levels were lower in the lipid extracts of organs (20-40%) than in the residual matter. In the phospholipid and triglyceride fractions, ³H was distributed in the whole molecule and not only in the fatty acid portion. However, radioactivity was detected in all the fatty acids, both saturated and unsaturated. Traces of C12, C10, C8 and C6 dicarboxylic acids were detected in the first 24 hr after administration.
Details on excretion:
The aim of these experiments was to determine the fate and distribution of ³H after oral administration of 100 pCi of [10,11-³H]dodecandioic acid.
Urine: In rats about 50% of the ³H were recovered from the urine collected over a period of 5 days.
Sera: As in the urine, labeled dicarboxylic acids were present up to 72 hr, mainly represented by diacid metabolites.

Metabolite characterisation studies

Metabolites identified:
Details on metabolites:
Dicarboxylic acids, mainly represented by diacid metabolites (C10, C8, and C6 when C12 was given), were found in urine up to 72 hr after the oral dose

Applicant's summary and conclusion

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Based on the results of this study, saturated medium chain length (C9 to C12) dicarboxylic acids are rapidly and completely absorbed from the gastrointestinal tract and rapidly distributed. These compounds are metabolised to shorter diacids and excretion is low and exclusively via urine. There is no potential for accumulation. Undecanedioic acid does not represent also a potential for bioaccumulation.