Dimethyl malonate

Basic toxicokinetics

Administrative data

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:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Metabolism of Malonic acid in Rat Brain after Intracerebral Injection.

Author:

Koeppen AH, Mitzen EJ, Papandrea JD

Year:

1978

Bibliographic source:

Journal of Neurochemistry 31 (3), 739-745.

Reference 2

Reference Type:

secondary source

Title:

SIDS Initial Assessment Report For SIAM 20 (Malonic Acid Diesters: Dimethylmalonate, 108-59-8; Diethylmalonate, 105-53-3), April 19-22, 2005 Paris.

Author:

OECD SIDS

Year:

2005

Bibliographic source:

UNEP Publications

Materials and methods

Objective of study:

metabolism

Principles of method if other than guideline:

Intracerebral injection of either C1- or C2- 14C- radiolabeled malonic acid to anesthetized adult male and female rats. The rats were killed after 2, 5, 10, 15 or 30 min and the brains removed, weighed, homogenized and analysed for radiolabeled reaction products. Venous blood and expired air was also analysed for radioactivity.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Malonic acid

EC Number:

205-503-0

EC Name:

Malonic acid

Cas Number:

141-82-2

IUPAC Name:

malonic acid

Details on test material:

C1 or C2 14-C-radiolabeled malonic acid, specific acitivity 12 mCi and 42 mCi respectively.

Radiolabelling:

yes

Remarks:

C1 or C2 14-C-radiolabeled malonic acid

Test animals

Species:

rat

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

other: intracerebral

Vehicle:

not specified

Details on exposure:

Intracerebral injection of either C1- or C2- 14C- radiolabeled malonic acid to anesthetized adult male and female rats. The rats were killed after 2, 5, 10, 15 or 30 min and the brains removed, weighed, homogenized and analysed for radiolabeled reaction products. Venous blood and expired air was also analysed for radioactivity.

Duration and frequency of treatment / exposure:

single injection

Doses / concentrations

Remarks:

Doses / Concentrations:
5 µl (equivalent to 0.5 mCi)

Results and discussion

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The authors verified that the decarboxylation of malonic acid to acetyl-CoA by various mammalian tissues also occurs in vivo after intracerebral injection. A rapid reflux of unreacted malonic acid in venous blood was reported. Labeled 14CO2 was recovered from venous blood and the expired air after administration of C-1 labeled product, but not after C-2 labeled product. High radioactivity was present in glutamate, aspartate and GABA. Sequential degradation of glutamate and aspartate proved that labeling of these amino acids occurred from [1-14C]acetyl-CoA and [2-14C]acetyl-CoA respectively via the Krebs-cycle. Malonate
activation and decarboxylation were similar to in vitro experiments with isolated mitochondria from different tissues. In vitro the radiolabel was however not incorporated into amino acids. In the in vivo experiment a minor amount of radioactivity was also incorporated in brain lipids. The authors conclude that malonic acid is metabolised via the following route:
Malonate + CoASH + ATP <---> malonyl-CoA + ADP + Pi
Malonyl-CoA --- > Acetyl-CoA + CO2
In vitro:
Acetyl-CoA --- > acetate + CoASH
In vivo: Acetyl-CoA enters the Krebs cycle and is used for the formation of aspartate, glutamate and GABA. A minor amount may also be incroporated into lipids.