Maleic anhydride

Endpoint summary

Description of key information

Sub-chronic toxicity:
Inhalation: NOAEC = 3.3 mg/m3 for rat (similar to OECD TG 413)
Inhalation: NOAEC = 9.8 mg/m3 for monkey (similar to OECD TG 413)
Chronic toxicity:
Oral: NOAEL = 10 mg/kg bw/day for rat (similar to OECD TG 452)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEC

3.3 mg/m³

Study duration:

subchronic

Species:

rat

Additional information

In a six-month inhalation study in which rats, hamsters, and monkeys were exposed to 0, 1.1, 3.3, or 9.8 mg/m3 (0, 0.3, 0.8, or 2.4 ppm), respiratory tract and eye irritation were observed in rats and hamsters exposed to 3.3 or 9.8 mg/m3 (0.8 or 2.4 ppm) and monkeys to 9.8 mg/m3(2.4 ppm), with body weight reductions only in male rats from the high-exposure group at study termination.  Hyperplastic changes in the nasal tissues, which ranged in severity from trace to mild, were present in rats at all exposure levels and in hamsters in the mid- and high-exposure levels.  Metaplastic changes in the nasal tissues occurred in both rats and hamsters at all exposure levels.  Both the hyperplastic and metaplastic changes in the nasal passages are considered indicative of irritation and judged to be reversible.  The NOAEC for rats is 3.3 mg/m3 (0.8 ppm) and the NOAEC for hamsters and monkeys is 9.8 mg/m3 (2.4 ppm). The NOAECs are taken forward in preference to the NOAEC which was identified in a 4-week inhalation study in which rats were dosed at concentrations of 0, 12, 32 and 86 mg/m3 as it was derived from a study of longer duration.

Oral feeding studies with maleic anhydride have resulted in kidney damage in rats at relatively high doses (> 100 mg/kg/day after 90 days of exposure), with the effects being more severe in males than in females. The effects appear to be largely in the tubular cells, with some effects also occurring in the glomeruli. The kidney effects are likely due to maleic acid, since maleic anhydride rapidly hydrolyzes to maleic acid under aqueous conditions and maleic acid is known to cause kidney damage with the target site being tubular cells. However, no kidney effects were observed in rats that were fed diets containing 32 and 100 mg/kg/day maleic anhydride for two years. A dietary study in dogs dosed at 0, 20, 40, or 60 mg/kg maleic anhydride, seven days a week for 90 days, showed no adverse effects related to maleic anhydride exposure, except for decreased food intake for the first few weeks in the high-dose group. The NOAEL (10 mg/kg bw/day) in the two-year study is taken forward in preference to the other N(L)OAELs as it was derived from a study of longer duration. Maleic anhydride could cause local irritation after inhalation exposure, but no severe systemic effects after dietary intake.

Justification for classification or non-classification

This substance could not be presumed to have the potential to produce significant toxicity in humans at generally low to moderate exposure concentrations in repeated-dose toxicity studies.