Maleic acid

Specific investigations: other studies

Administrative data

Endpoint:

nephrotoxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: published result, well documented study

Data source

Reference

Reference Type:

publication

Title:

Renal Toxicity of Maleic Acid in the Rat

Author:

Worthen HG

Year:

1963

Bibliographic source:

Laboratory Investigation 12(8): 791-801

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Maleic acid, neutralized with sodium hydroxide, was given to adult male rats in doses of 348mg/kg, 696 mg/kg or 1044 mg/kg (3,6, or 9 mmol/kg) intraperitoneally. The presence of tubular inhibition was detected by quantitive test for urine sugar, albumin, amino acids and pH. The rats were killed as soon as urinary abnormalities were evident, usually within an hour after injection when the largest dose of maleic acid was used, and within 2 hours when the smallest dose was given. Paired control rats were given the same volume of saline and were killed at the same time as the experimental rats. A few rats in each dosage group were allowed to recover so that the duration of urinary abnormalities could be determined and correlated with histologic observations. The kidneys were removed, and portions were frozen in isopentane chilled with liquid nitrogen. Frozen sections were cut on a microtome mounted in a cryostat cabinet, and enzyme activity was determined histochemically in the fresh-frozen sections. Tissues for light microscopy were fixed in formalin and embedded in paraffin and then stained. Tissues for electron microscopy were fixed in buffered osmic acid for 2 hours, dehydrated in graded alcohols, and then embedded.

GLP compliance:

not specified

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Maleic acid

EC Number:

203-742-5

EC Name:

Maleic acid

Cas Number:

110-16-7

Molecular formula:

C4H4O4

IUPAC Name:

but-2-enedioic acid

Details on test material:

Maleic acid, neutralized with sodium hydroxide, no data on purity

Test animals

Species:

rat

Strain:

not specified

Sex:

not specified

Administration / exposure

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Duration of treatment / exposure:

one single injection

Frequency of treatment:

one single injection

Doses / concentrations

Doses / concentrations 1

Remarks:

Doses / Concentrations:
348 mg/kg
Basis:
nominal conc.

Doses / concentrations 2

Remarks:

Doses / Concentrations:
696 mg/kg
Basis:
nominal conc.

Doses / concentrations 3

Remarks:

Doses / Concentrations:
1044 mg/kg
Basis:
nominal conc.

No. of animals per sex per dose:

no data

Control animals:

yes, concurrent vehicle

Results and discussion

Any other information on results incl. tables

All of the rats given maleic acid developed glycosuria, aminoaciduria, proteinuria, polyuira, and increased urinary pH. The severity

of the urinary abnormalities roughly paralleled the amount of maleic acid given. In the animals given the largest dose the urine volume was roughly 3 times the normal volume, albumin and sugar were present in high concentration, and the urine pH was above 7, all within an hour after injection. In the rats given smaller doses, the abnormalities appeared later, and were less severe. Even in the rats given only 348 mg/kg, however, the abnormalities were present within 2 hours. In the animals not killed, normal renal function returned after intervals of 24 hours (in those given 348 mg/kg) to 72 hours (in those given 1044 mg/kg).

The only positive histochemical finding was a decrease of succinic dehydrogenase in the proximal tubules of maleic-treated rats.

Succinic dehydrogenase activity was measured in the kidneys of 13 control rats and in 13 rats that had received maleic acid 1 to 2 hours before beeing killed. Renal cortical succinic dehydrogenase activity was decreased by the administration of maleic acid. The decrease in activity was roughly correlated with the amount of maleic acid given, but too few animals were included in each group to compute the statistical validity of the differences.

The morphologic abnormalities observed by microscopy consists of dilation of the proximale tubule, with shortening of the brush border, vacuolation of the apical portion of the cells, compression of the basal infoldings of the proximale tubule. The glomeruli and distal parts of the tubule appear normal.

Both the enzymatic and morphologic defects appear worse in the animals with the most severe functinal defects, suggesting that either the enzymatic of the structural defect might be the cause of the tubular dysfunction.

Animals in which the urinalysis had returned to normal, the tubules appeared normal.