Itaconic acid

Toxicological Summary

Workers - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

22.05 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

25 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

40

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - workers

According to the toxicological results the major acute toxicological effect of concern is eye irritation which was considered as severe in the experimental measurement. Repeated dose toxicity test such as a 90 day study (oral administration) allows to derive a NOEL of 1001 mg/kg/day. The same NOEL (1000 mg/kg/day) was observed in a teratogenicity test carried out recently. Both in vitro and in vivo genotoxicity tests were clearly negative.

The following DNELs were not derived:

Acute dermal and acute inhalation exposure (systemic and local): Itaconic acid has no classification for dermal and inhalation toxicity nor for sensitisation or skin irritancy. No reliable dose descriptor is available for eye irritation/corrosion, a qualitative assessment is required according to the Guidance on information requirements and chemical safety assessment, Part B (Hazard assessment); Chapter 7.1.6. (The qualitative approach when no dose descriptor is available for an endpoint).

Long-term dermal and long-term inhalation exposure (local effects): No specific local effects resulting from long term exposure have been identified. Adherence to the long term DNEL for systemic effects will protect against any local effects.

DNEL - long-term, dermal, systemic:

The key study is oral 90 days study in rats which was undertaken for the assessment of potential toxicity of itaconic acid. 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 diet and acted as a control group.

The stability and the homogeneity of itaconic acid in the feed were checked.

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).

The NOAEL from the oral rat study is taken as the point of departure for the calculation of the dermal DNEL. No further correction is necessary for bioavailability or exposure conditions. Assessment factors recommended in the REACH guidance would lead to an interspecies factor of 4, an intraspecies factor of 5 and a duration factor of 2. Assuming that in general dermal absorption will not be higher than oral absorption, no default factor should be introduced when performing oral-to-dermal extrapolation (according to Guidance on REACH Chapter R.8, Section 8.4.2.). Application of the assessment factor of 40 leads to a DNEL of 25 mg/kg/day.

DNEL- long-term, inhalation, systemic:

The key study is oral 90 days study in rats which was undertaken for the assessment of potential toxicity of itaconic acid. 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 diet and acted as a control group.

The stability and the homogeneity of itaconic acid in the feed were checked.

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).

The NOAEL from the oral rat study is taken as the point of departure for the calculation of the inhalation DNEL. Corrected inhalatory NOAEC is obtained by following calculation: 1001 × (1/0.38 m³/kg/day) × (6.7 m³/10 m³) = 1764 mg/m³.

The following assessment factors are proposed: 2 for the route-to-route extrapolation (in the absence of route-specific information on the starting route, it is proposed to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-toinhalation extrapolation), 4 for allometric extrapolation from rat to human, 5 for intraspecies variation (for workers) and 2 for duration of exposure. The resulting overall assessment factor is 80 and generates from a NOAEL of 1001 mg/kb bw/d a systemic chronic inhalation DNEL of 22.05 mg/m³.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

11.03 mg/m³

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

160

Modified dose descriptor starting point:

NOAEC

Acute/short term exposure

DNEL related information

Local effects

Acute/short term exposure

DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure

DNEL related information

General Population - Hazard via oral route

Systemic effects

Long term exposure

Hazard assessment conclusion:

DNEL (Derived No Effect Level)

Value:

12.5 mg/kg bw/day

Most sensitive endpoint:

repeated dose toxicity

DNEL related information

Overall assessment factor (AF):

80

Modified dose descriptor starting point:

NOAEL

Acute/short term exposure

DNEL related information

Additional information - General Population

As there is no consumer use, ther is no risk for consumer. However, there are possible inhalation and oral exposure for human via the environment.

The following DNELs were not derived:

Acute dermal and acute inhalation exposure (systemic and local) and acute oral exposure (systemic): Itaconic acid has no classification for an acute toxicity hazard nor for sensitisation or skin irritancy.

Long-term dermal and long-term inhalation exposure (local effects): No specific local effects resulting from long term exposure have been identified. Adherence to the long term DNEL for systemic effects will protect against any local effects.

Long-term dermal (systemic effects): dermal route exposition is not relevant for general population.

DNEL- long-term, inhalation, systemic:

The key study is oral 90 days study in rats which was undertaken for the assessment of potential toxicity of itaconic acid. 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 diet and acted as a control group.

The stability and the homogeneity of itaconic acid in the feed were checked.

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).

TThe NOAEL from the oral rat study is taken as the point of departure for the calculation of the inhalation DNEL. Corrected inhalatory NOAEC is obtained by following calculation: 1001 × (1/0.38 m³/kg/day) × (6.7 m³/10 m³) = 1764 mg/m³.

The following assessment factors are proposed: 2 for the route-to-route extrapolation (in the absence of route-specific information on the starting route, it is proposed to include a default factor of 2 (i.e. the absorption percentage for the starting route is half that of the end route) in the case of oral-to-inhalation extrapolation), 4 for allometric extrapolation from rat to human, 10 for intraspecies variation (for workers) and 2 for duration of exposure. The resulting overall assessment factor is 160 and generates from a NOAEL of 1001 mg/kb bw/d a systemic chronic inhalation DNEL of 11.03 mg/m³.

DNEL- long-term, oral, systemic:

The key study is oral 90 days study in rats which was undertaken for the assessment of potential toxicity of itaconic acid. 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 diet and acted as a control group.

The stability and the homogeneity of itaconic acid in the feed were checked.

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).

Oral point for departure: NOAEL for repeat dose toxicity =1001 mg/kg (male rats). No further correction is necessary for bioavailability or exposure conditions. Assessment factors recommended in the REACH guidance would lead to an interspecies factor of 4, an intraspecies factor of 10 and a duration factor of 2. Application of the assessment factor of 80 leads to a DNEL of 12.5 mg/kg/day.