Maleic acid

Endpoint summary

Description of key information

WoE. Fitzhugh 1947. Repeated dose toxicity: oral, diet, rats, 2 years: no NOEL or LOEL defined, lowest dose 0.5 % in feed, corresponding to ca. 250 mg/kg bw and day
WoE. Humiston 1975 (maleic anhydride). Repeated dose toxicity: oral, diet, rats, 90 days: LOEL = 100 mg/kg bw and day
WoE. Humiston 1975a (maleic anhydride). Repeated dose toxicity: oral, diet, rats, 90 days: NOEL = 40 mg/kg bw and day
WoE. Humiston 1977 (maleic anhydride). Repeated dose toxicity: oral, diet, rats, 183 days: LOEL = 250 mg/kg bw and day
WoE. CIIT 1983 (maleic anhydride). Repeated dose toxicity: oral, diet, rats, 2 years: LOEL = 32 mg/kg bw and day, NOEL = 10 mg/kg bw and day
SS. Humiston 1975b (maleic anhydride). Repeated dose toxicity: oral, diet, dogs, 90 days: NOEL = 60 mg/kg and day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data from handbook or collection of data, read-across from maleic anhydride

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

Deviations:

not specified

Principles of method if other than guideline:

Maleic anhydride was administered to rats in the feed for two years days. Several observations were made, including hematology, urinalysis, various clinical chemistry and others.

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

not specified

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analysis of the diet for maleic anhydride was conducted 2 to 4 years after completion of the in-life phase of the study. A sample of each diet was removed, refrigerated or frozen for future chemical determination of the concentration of maleic anhydride. The GC-MS measurements were (on average of random samples) 69-75% of the expected for male and female diets, respectively.

Duration of treatment / exposure:

24 months

Frequency of treatment:

7 days/week

Remarks:

Doses / Concentrations:
0, 10, 32 and 100 mg/kg body weight / day
Basis:
nominal in diet

No. of animals per sex per dose:

125

Control animals:

yes, concurrent vehicle

Details on study design:

Scheduled interim termination timepoints were at 6, 12, and 18 months with final study termination at 24 months.

Observations and examinations performed and frequency:

Clinical signs of toxicity, body weights and food consumption were monitored and extensive histopathological examinations were conducted. Additionally, the eyes of all animals were examined by ophthalmoscope and hematology, clinical chemistry and urine parameters were assessed in five animals/sex/dose.

Sacrifice and pathology:

Extensive histopathological examinations were conducted.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

slightly reduced in males at 32 and 100 mg/kg

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

slightly reduced at 32 and 100 mg/kg, for a limited period of time

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

high incidence of cataracts

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

There was only marginal toxicity which was evidenced by small (<6%), but dose-related, decrease in body weights of male rats fed 32 and 100 mg/kg/day compared to the controls. The female rats fed 32 and 100 mg/kg/day also had reduced body weights, but the reductions were smaller and of shorter duration than those observed in males. Food consumption was also slightly reduced during limited periods during the study for animals in the mid- and high-dose groups. Neither neurologic nor ophthalmologic evaluations revealed differences between treated and control animals. There was a high incidence of cataracts in the animals of this study, with 100% of the animals examined at 18 month and at study termination bearing cataracts. The severity of these cataracts was independent of maleic anhydride consumption. Hematology, clinical chemistry, gross or histopathological evaluations (including the kidneys) showed no differences between treated and control animals that were considered related to maleic anhydride exposure.

Dose descriptor:

LOEL

Effect level:

32 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: reduced body weights, slightly reduced food consumption

Dose descriptor:

NOEL

Effect level:

10 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: body weights, food consumption

Critical effects observed:

not specified

Conclusions:

The LOEL of a 2-years dietary feeding study with rats was 32 mg/kg/day, the NOEL was 10 mg/kg/day.

Executive summary:

Maleic anhydride was mixed with the food and administered on 7 day/week ad lib., for 2 years to Fischer 344 rats. Doses were 0, 10, 32 or 100 mg/kg body weight. 126 animals were used per group.

Scheduled interim termination timepoints were at 6, 12, and 18 months with final study termination at 24 months. Clinical signs of toxicity, body weights and food consumption were monitored and extensive histopathological examinations were conducted. Additionally, the eyes of all animals were examined by ophthalmoscope and hematology, clinical chemistry and urine parameters were assessed in five animals/sex/dose. The analysis of the diet for maleic anhydride was conducted 2 to 4 years after completion of the in-life phase of the study. A sample of each diet was removed, refrigerated or frozen for future chemical determination of the concentration of maleic anhydride. The GC-MS measurements were (on average of random samples) 69-75% of the expected for male and female diets, respectively. There was a problem with the animal room lighting control system which resulted in exposure to continuous light for an unknown period.

There was only marginal toxicity which was evidenced by small (<6%), but dose-related, decrease in body weights of male rats fed 32 and 100 mg/kg/day compared to the controls. The female rats fed 32 and 100 mg/kg/day also had reduced body weights, but the reductions were smaller and of shorter duration than those observed in males. Food consumption was also slightly reduced during limited periods during the study for animals in the mid- and high-dose groups. Neither neurologic nor ophthalmologic evaluations revealed differences between treated and control animals. There was a high incidence of cataracts in the animals of this study, with 100% of the animals examined at 18 month and at study termination bearing cataracts. The severity of these cataracts was independent of maleic anhydride consumption. Hematology, clinical chemistry, gross or histopathological evaluations (including the kidneys) showed no differences between treated and control animals that were considered related to maleic anhydride exposure.

The LOEL was defined to be 32 mg/kg/day and the NOEL was 10 mg/kg/day for both sexes.

Endpoint conclusion

Dose descriptor:

NOAEL

10 mg/kg bw/day

Study duration:

chronic

Species:

rat

Additional information

Results from various subchronic and chronic toxicity studies with maleic acid and maleic anhydride in rats and dogs with oral administration are available. Reported LOELs were between 32 and 250 mg per kg body weight and day, depending on study designs. Reported NOELs were 10 and 40 mg per kg body weight and day in rats and 60 mg per kg body weight in Beagle dogs.

Justification for classification or non-classification

No classification is derived from the results of the studies available.