Maleic anhydride

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions.

Data source

Reference

Reference Type:

publication

Title:

Chronic Dietary Administration of Maleic Anhydride. Vol. 1: Narrative.

Author:

USEPA

Year:

1983

Bibliographic source:

Microfiche No. OTS 1283-0277.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 452 (Chronic Toxicity Studies)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Maleic anhydride

EC Number:

203-571-6

EC Name:

Maleic anhydride

Cas Number:

108-31-6

Molecular formula:

C4H2O3

IUPAC Name:

furan-2,5-dione

Details on test material:

- Name of test material: Maleic Anhydride
- Batch No.: 52.31
- Storage condition of test material: The bulk supply compound was kept at R.T. initially and later refrigerated at about 27 degrees F.
- Other: received from Denka Chemical Corporation, Houston, Texas

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI
- Age at study initiation: 7 weeks
- Weight at study initiation: 130-169 g (male); 105-129 g (female)
- Fasting period before study: no data
- Housing: Rats were housed in groups of three per polycarbonate cage (19*10.5*8 in) and the control animals were housed separately in an adjacent room. A bedding of hardwood chips (Ab-sorb-dri, Garfield, NJ) was used; cages, water bottles and bedding were changed once weekly for the first 22 weeks on test and then twice weekly.
- Diet (ad libitum): The basal laboratory diet consisted of Wayne Laboratory powdered meal (No. 86-04, supplied by Locke-Erickson, Melrose Pk, IL).
- Water (ad libitum): tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C):
- Humidity (%):
- Air changes (per hr):
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): The maleic anhydride bricks (approxiately 2" * 1" * 1") were placed in a plastic bags and broken into a powder with a mallet. The powder was then passed through a sieve (Size 50, 0.297 sq mm opening) before weighing. The various quantities of maleic anhydride, depending on the dietary level, were first added to 500 grams of the basal diet and premixed by hand by stirring with a large spatula. The premix was then added to a twin-shell blender (Patterson-Kelly) and mixed for at least one minute per kg of meal to privide the appropriate dose level.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A sample of each diet was removed, refrigerated or frozen and stored for future chemical determination of the concentration of maleic anhydride. At the time this study was conducted, no appropriate analytical method for determining maleic anhydride in feed was available. Subsequently, a method based on gas chromatography-mass spectrometry was developed and utilized to analyze randomly selected diets from those prepared at high dose level for this study. At the time of analysis, the diet samples were from 2 to 4 years old. The concentrations observed in this analysis were (on the average) 69% and 75% of the expected for male and female diets, respectively. Analysis of freshly prepared maleic anhydride in feed yielded 95-106% of expected, while samples prepared 2.25 years earlier gave identical results (63-79% with an average of 69%) as the test diets used in the feeding study.

Duration of treatment / exposure:

24 months

Frequency of treatment:

7 days/week, ad libitum

Doses / concentrations

Remarks:

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

No. of animals per sex per dose:

504 m and 501 f in all groups

Control animals:

yes, concurrent no treatment

Details on study design:

no data

Positive control:

no

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (7 days/week)


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations:


FOOD CONSUMPTION AND COMPOUND INTAKE:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
weekly for the first 13 weeks, bi-weekly for the succeeding 12 weeks and monthly thereafter


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at 6, 12, 18 and 24 months
- Dose groups that were examined:


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 6, 12, 18 and 24 months
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes (16 hrs)
- How many animals: 5 animals of each sex from each group at 6 and 12 months, 20 animals from each group at 18 and 24 months
- Parameters examined:


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at 6, 12, 18 and 24 months
- Animals fasted: Yes (16 hrs)
- How many animals: 5 animals of each sex from each group at 6 and 12 months, 20 animals from each group at 18 and 24 months
- Parameters examined:


URINALYSIS: Yes
- Time schedule for collection of urine: at 6, 12, 18 and 24 months
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes (16 hrs)
- How many animals: 5 animals of each sex from each group at 6 and 12 months, 20 animals from each group at 18 and 24 months
- Parameters examined:


NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested:


OTHER:

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
at the 6, 12, 18 and 24 month intervals

Other examinations:

no data

Statistics:

All data obtained by quantitative methods were statistically evaluated by the analysis of variance. All comparisons were limited to within-sex analysis. A "two-tail" distribution was used for evaluation of mean differences. If significant differences (p<0.05) occurred in the preliminary analysis, Tukey's procedure was employed to determine the differences between the control and treated groups.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

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:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
There was no distinct treatment-related clinical signs at any of the periods considered.
There was no difference between the control and treatment group on mortality.

BODY WEIGHT AND WEIGHT GAIN
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 AND COMPOUND INTAKE
Food consumption was also slightly reduced during limited periods during the study for animals in the mid- and high-dose groups.

FOOD EFFICIENCY


OPHTHALMOSCOPIC EXAMINATION
no differences between treated and control animals

HAEMATOLOGY
no differences between treated and control animals

CLINICAL CHEMISTRY
no differences between treated and control animals

URINALYSIS
no differences between treated and control animals

NEUROBEHAVIOUR
no data

ORGAN WEIGHTS
a higher brain weight for female in the low-dosage group at 12 months
a lower liver weight for male in the mid-dosage group at 24 months

GROSS PATHOLOGY
no differences between treated and control animals

HISTOPATHOLOGY: NON-NEOPLASTIC
no differences between treated and control animals


OTHER FINDINGS
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.

Effect levels

Dose descriptor:

NOAEL

Effect level:

ca. 10 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL for rats is based on the decreased body weight and is considered to be 10 mg/kg bw/day.

Executive summary:

Male and female F344 rats were exposed to 0, 10, 32, or 100 mg/kg bw/day maleic anhydride in feed, seven days a week for two years. 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 NOAEL is based on the decreased body weight at mid- and high-dose group, and is considered as 10 mg/kg bw/day.