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Toxicological information

Basic toxicokinetics

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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:
other: Peer reviewed, published data, comparable to guideline, non GLP, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Metabolism of straight saturated medium chain length (C9 to C12) dicarboxylic acids
Author:
Passi, S., Nazzaro-Porro, M., Picardo, M., Mingrone, G., Fadla, P.
Year:
1983
Bibliographic source:
Journal of Lipid Research 24, 1983, 1140-1147

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Rats were treated orally
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Radiolabelling:
yes
Remarks:
[ 10,11-³H]dodecandioic acid (sp act 20 mCi/mM, Radiochemical Center, Amersham, England)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
bw: 250-270 g
age. 7 weeks

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Duration and frequency of treatment / exposure:
single dose
Doses / concentrations
Remarks:
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:
10
Positive control:
no

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, C 10, C8an, d 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:
yes
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

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
Dodecanedioic acid is rapidly and completely absorbed from the gastrointestinal tract and rapidly distributed. The compound is metabolised to shorter diacids and excretion is low and exclusively via urine. There is no potential for accumulation.
Executive summary:

Groups of 10 male Wistar rats received a singel dose of 5, 12.5, or 25 mg dodecanedioic acid by gastric intubation.

In a second experiment ³H-labelled dodecanedioic acid was administered.

Absorption was complete, and excretion was independent of dosage in rats. About 1.6% of C12 were excreted in the urine over a period of 5 days. No dodecanedioic acid was recovered from faeces. The serum concentration and the urinary excretion of the diacids reached a maximum at the second day after the oral dose. The dicarboxylic acids found in serum and urine were 2, 4, or 6 carbon atoms shorter than the corresponding administered diacid. This indicates that there was beta-oxidation of the ingested diacids to some extent. The administration of [10,11-³H]dodecandioic acid confirmed the occurrence of beta-oxidation, and led to elucidation of the fate of the ingested diacids that were not excreted as such in the urine.