Itaconic acid

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

1 001 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Additional information

Based on guideline OECD 408, EEC 87/302, The potential toxicity of itaconic acid has been evaluated by daily oral administration (dietary admixture) to Sprague Dawley rats for 13 weeks.

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

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 when itaconic acid was 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).

Justification for classification or non-classification

Itaconic acid is not classified as toxic after repeated dose exposure as the NOAEL is > 100 mg/kg/d in the 13 weeks study for iral toxicity (1001 mg/kg/d), according to Regulation (EC) No 1272/2008.

Also, in the 4 weeks oral repeated dose toxicity study, there is a NOAEL = 500 mg/kg/d.