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EC number: 203-571-6 | CAS number: 108-31-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
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:
- 1 983
- 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
- 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
Constituent 1
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.
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