Hexadecanedioic acid

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Justification for type of information:

1. HYPOTHESIS FOR THE CATEGORY APPROACH (ENDPOINT LEVEL)
Dicarboxylic acids are organic compounds that contain two carboxylic acid functional groups. They have the general type formula HOOC-(CH2)n-COOH. The present defined category comprises dicarboxylic acids with straight carbon chain having a “n” value from 6 to 16.
The physical and chemical properties as well as the toxicology and environmental fate and effects show that substances in this category have a similar order of toxicological and environmental fate properties, which supports the grouping of these substances as a category. (see attached justification)

2. CATEGORY APPROACH JUSTIFICATION (ENDPOINT LEVEL)
There are number of unifying considerations justifying the similarity between these substances in some important aspects. These include:
(1) Similarity of Use: these dicarboxylic acids have several industrial uses in the production of adhesives, plasticizers, lubricants, copolymers (such as polyamides and polyesters), etc.
(2) Similarity of Functional groups: all these substances contain two common functional groups (2 carboxyl groups). The only difference between the substances of this group lies in the length of the carbon chain.
(3) Similarity of Physical / Chemical properties: the similarity of physical / chemical properties for these substances (see attached justification)
(4) Similarity of Metabolism: Dicarboxylic acids were shown to be rapidly absorbed from the gastrointestinal tract, introduced into the fatty acid catabolism and therefore extensively metabolized by the organism and excreted (Passi, S. et al, 1983).
(5) Similarity of Mammalian Toxicity: The constituents of this class have similar toxicological properties. They are not acutely toxic, irritating to skin or sensitizing. However, they all present, except for dodecanedioic acid, irritating effects on the eyes (from moderate to high effects). They do not produce systemic effects in repeated dose studies. They are neither mutagenic nor carcinogenic and do not produce developmental/reproductive toxicity. (see attached justification)
(6) Similarity of Environmental Toxicity and Fate Properties: The substances in this category have similar environmental effects properties. The environmental effects data are similar for most category members in that most members do not exhibit acute toxicity. (see attached justification)

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

A method using 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

Test material information

Constituent 1

Reference substance name:

C9-C12 dicarboxylic acids

IUPAC Name:

C9-C12 dicarboxylic acids

Details on test material:

C9, C10, C11 , and C12 dicarboxylic acids (99% pure) were purchased from Fluka, A.G.

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 or test system and environmental conditions:

Weight: 250-270 g
Age: 7 weeks

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

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

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 / concentration:

10 animals per dose.

Control animals:

yes

Positive control reference chemical:

no

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:

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
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. Based on a read across (category approach), hexadecanedioic acid does not represent also a potential for bioaccumulation.