Itaconic acid

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

review article or handbook

Title:

Unnamed

Year:

1993

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

Itaconic acid

EC Number:

202-599-6

EC Name:

Itaconic acid

Cas Number:

97-65-4

Molecular formula:

C5H6O4

IUPAC Name:

2-methylidenebutanedioic acid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

every day

Doses / concentrations

Remarks:

Doses / Concentrations:

Basis:
nominal in diet

No. of animals per sex per dose:

10 males and 10 females rats

Control animals:

yes, concurrent no treatment

Details on study design:

Three groups of 10 males and 10 females rats were given the test substance at 1500, 4700 or 14000 ppm, daily by oral route (dietary admixture) for 13 weeks. A group of 10 males and 10 females received the untreated died and acted as a control group.
The stability and the homogeneity of itaconic acid in the feed were checked. The achieved administered doses to the animals are established as follows (in mg/kg/day) :
males females

1500 ppm 106 119
4700 ppm 341 358
14000 ppm 1001 1088

Results and discussion

Effect levels

Dose descriptor:

NOEL

Effect level:

1 001 mg/kg bw (total dose)

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No clinical signs attributable to the treatment were noted in any group. No deaths were observed in any group during the study. The mean food consumption and the mean bodyweight gain of the treated males and females were similar to that of the respective controls. No treatment related findings were observed in any group.

At week 13, slight, but statistically significant differences from the control were noted :

Among the haematological parameters : increase of the erythrocyte count (males, 14 000 ppm), decrease of the mean cell haemoglobin quantity (males, 14 000 ppm), increase of the mean cell volume (females,14 000 ppm) and decrease of activated partial thromboplastin time (males, 14 000 ppm). They were minor and the individual values within the normal range of laboratory background data. Therefore they were considered to be of no toxicological significance.

In the blood biochemistry : decrease of Ca++ (females,14 000 ppm), decrease of inorganic phosphorus (males , all treated groups), decrease of glucose (females, 1500 and 14 000 ppm), decrease of alanine aminotransferase (males, 15 000 ppm),

Increase of bilirubin (males, 14 000 ppm), increase of total proteins (males, 4 700 and 14 000 ppm and ,females 14 000 ppm), increase of albumin (males, 4 700 ppm).

There were minor, not clearly dose ‑ related and the individual values within the normal range of laboratory background data. Therefore they were considered to be of no toxicological significance.

In urinalysis : a slightly higher specific gravity was noted in the males given 4 700 and 14 000 ppm together with a lower pH in males given 14 000 ppm when compared to the controls. A slight decrease of the pH was noted in the females given 4 700 ppm. No further qualitative or quantitative treatment ‑ related abnormalities were noted. Again these findings were considered to be of no toxicological significance.

A statistically significant increase of ovary weight was found in females given 1 500 ppm. Such a variation was not found in the animals given higher doses. No relevant morphological changes were observed. This observation was considered to be of no toxicological significance. Moreover no microscopic findings were observed in that organs in the highest dosed animals. No variations in testes weight nor macro- and microscopic findings were observed in the highest dosed animals compared to the controls.

Macroscopic and microscopic changes observed were those which are commonly observed as spontaneous in the strain used and were not related to the treatment.

 

Based on these results, no toxicologically significant observations were noted whenitaconic acidwas administered daily by oral route at 1 500, 4 700 and 14 000 ppm to Sprague‑Dawley rats for 13 weeks. Under this experimental conditions, a No Observed Effect Level (NOEL) of 14 000 ppm is established (i.e. a mean dose level of 1 001 mg/kg/day in the males and 1 088 mg/kg/day in the females).