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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:
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.