Malic acid

Basic toxicokinetics

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: Experimental data published in peer reviewed journal

Data source

Reference

Reference Type:

publication

Title:

The metabolism of L- and DL-malic acids by rats

Author:

Daniel JW

Year:

1969

Bibliographic source:

Fd Cosmet Toxicol 7: 103-106, 1969

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

DL-malic acid

EC Number:

210-514-9

EC Name:

DL-malic acid

Cas Number:

617-48-1

Molecular formula:

C4H6O5

IUPAC Name:

2-hydroxybutanedioic acid

Details on test material:

- Name of test material (as cited in study report): DL-Malic acid
- Specific activity (if radiolabelling): 93 microcuries / m-mole
- Locations of the label (if radiolabelling): C4
- Expiration date of radiochemical substance (if radiolabelling): No data

Radiolabelling:

yes

Remarks:

C isotope 14 label

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: No data
- Age at study initiation: No data
- Weight at study initiation: Approximately 200 g
- Fasting period before study: None?
- Housing: No data
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): No data, assumed ad libitum
- Water (e.g. ad libitum): No data, assumed ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): No data
- Humidity (%): No data
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): No data

Administration / exposure

Route of administration:

other: oral gavage and intraperitoneal injection

Vehicle:

water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: No data

VEHICLE
- Concentration in vehicle: 1 mg/mL
- Amount of vehicle (if gavage): 0.5 mL

HOMOGENEITY AND STABILITY OF TEST MATERIAL: No data

Duration and frequency of treatment / exposure:

Single dose, animals monitored for 24-48 hours

Doses / concentrations

Remarks:

Doses / Concentrations:
2.5 mg/kg body weight

No. of animals per sex per dose / concentration:

No data

Control animals:

not specified

Details on study design:

- Dose selection rationale: No data
- Rationale for animal assignment (if not random): No data

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, exhaled air (carbon dioxide)
- Time and frequency of sampling: Urine and faeces - 24 hours and 48 hours. Carbon dioxide - Not detailed, possibly hourly intervals for 6 hours then at 24 and 48 hours

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

38.8% of the administered dose was eliminated as expired carbon dioxide within 1 hour of dosing indicating rapid absorption.

Details on distribution in tissues:

Not studied. However, malic acid occurs naturally and is a key part of metabolic processes being part of the Krebbs cycle. As a result it is expected to be extensively distributed throughout the body

Details on excretion:

The majority of the administered dose was eliminated as exhaled carbon dioxide, 91.6% wihin 24 hours. 3.1% was eliminated via urine and 0.6% via faeces in the same period

Any other information on results incl. tables

Excretion of radioactivity over a 24 hour period

Malic acid	Radioactivity (%) excreted
	Route	Exhaled air	Urine	Faeces	Total
DL-	Oral	91.6 (88.1-94.0)	3.1 (2.4-3.8)	0.6 (0.0-0.9)	95.3
	Intraperitoneal	83.4 (80.6-85.3)	8.8 (8.5-9.0)	0.3 (0.1-0.6)	92.5
L-	Oral	88.0 (84.8-89.9)	3.2 (2.8-3.9)	1.4 (0.1-3.0)	92.6
	Intraperitoneal	86.6 (84.8-89.6)	3.1 (1.7-4.3)	1.4 (1.1-2.1)	91.1

Mean hourly excretion rate of radioactivity in the exhaled air of rats following oral administration

Malic acid	Excretion (%) at hour
	1	2	3	4	5	6	Total
DL-	38.8	16.6	12.2	10.5	4.0	5.4	87.5
L-	45.3	16.1	11.0	4.6	4.0	3.4	84.4

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
Malic acid is rapidly absorbed following oral administration, 38.8% of the administered dosebeing eliminated as expired carbon dioxide within 1 hour of dosing. Tissue distribution has not been studied. Metabolism and elimination is rapid, the majority eliminated as exhaled carbon dioxide, 91.6% wihin 24 hours. 3.1% of was eliminated via urine and 0.6% via faeces in the same period.

Executive summary:

The absorption and elimination of both L-and DL- malic acid has been studied in rats. Both forms of malic acid are rapidly absorbed following oral administration, 38.8% of the DL- isomer administered being eliminated as expired carbon dioxide within 1 hour of dosing. Tissue distribution has not been studied. However, malic acid occurs naturally and is a key part of metabolic processes being part of the Krebbs cycle. As a result it is expected to be extensively distributed throughout the body. Metabolism and elimination is rapid, the majority eliminated as exhaled carbon dioxide, 91.6% of the DL-isomer wihin 24 hours. 3.1% of the DL-isomer was eliminated via urine and 0.6% via faeces in the same period.