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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: inhalation
Administrative data
- Endpoint:
- sub-chronic toxicity: inhalation
- 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:
- A 6-month multispecies inhalation study with maleic anhydride.
- Author:
- Short RD, Johannsen FR & Ulrich C.
- Year:
- 1 988
- Bibliographic source:
- Fundam. Appl. Toxicol. 10: 517-524
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
- 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 (as cited in study report): Maleic anhydride
- Physical state: white briquettes
- Analytical purity: >99%
- Other: Maleic anhydride was supplied by Monsanto Co.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, MI
- Age at study initiation: 8 weeks
- Housing:
- Diet (ad libitum): Purina Laboratory Chow (Ralston Purina, St. Louis, MO) except during exposure
- Water (ad libitum): except during exposure
Administration / exposure
- Route of administration:
- inhalation: vapour
- Type of inhalation exposure:
- whole body
- Vehicle:
- other: unchanged (no vehicle)
- Remarks on MMAD:
- MMAD / GSD: no data
- Details on inhalation exposure:
- TEST ATMOSPHERE
- Brief description of analytical method used: Concentrations in the chambers were monitored three times a day by drawing samples through Tenax (Supelco, Belle- fonte, PA) columns and by quantifying the retained material, after thermal desorption into a nitrogen steam, using a gas chromatograph equipped with a flame ionization detector and a 5 X 1/8-in. stainless-steel column packed with 1.5% OV- 101 on 100-120 Chromosorb GHP (Supelco. Bellefonte, PA). The range of column and detector temperatures was 115 to 150°C and 205 to 220°C respectively. Standards were prepared by thermally desorbing a known amount of maleic anhydride, which was applied in an acetone solution to a Tenax column, and quantifying the material by gas chromatography. Although this method measures maleic anhydride, it does not distinguish between maleic anhydride and maleic acid. Therefore All concentrations are expressed in terms of total maleic. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Concentrations in the chambers were monitored three times a day by drawing samples through Tenax (Supelco, Bellefonte, PA) columns and by quantifying the retained material, after thermal desorption into a nitrogen steam, using a gas chromatograph equipped with a flame ionization detector and a 5 X 1/8-in. stainless-steel column packed with 1.5% OV- 101 on 100-120 Chromosorb GHP (Supelco. Bellefonte, PA). The range of column and detector temperatures was 115 to 150°C and 205 to 220°C, respectively. Standards were prepared by thermally desorbing a known amount of maleic anhydride, which was applied in an acetone solution to a Tenax column, and quantifying the material by gas chromatography. Although this method measures maleic anhydride, it does not distinguish between maleic anhydride and maleic acid. Therefore all concentrations are expressed in terms of total maleic.
- Duration of treatment / exposure:
- I32 to I36 days of treatment during a 6-month period
- Frequency of treatment:
- 6 hours/day, 5 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 1.1, 3.3, 9.8 mg/m3
Basis:
analytical conc.
- No. of animals per sex per dose:
- 15 female and 15 male in each dose group
- 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: Animals were observed before and after each exposure for signs of toxicity.
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were determined at weekly intervals.
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
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
WATER CONSUMPTION: No data
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Direct and indirect opthalmoscopic examinations were performed monthly.
- Dose groups that were examined: on all test animals
HAEMATOLOGY: Yes
- Time schedule for collection of blood: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- Parameters examined: hemoglobin. hematocrit. total erythrocyte count. and total and differential leukocyte count
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Animals fasted: No data
- Parameters examined: glucose. urea nitrogen, serum glutamic pyruvic transaminase activity, serum alkaline phosphatase activity, carbon dioxide. erythrocyte and plasma cholinesterase activity. and terminal brain cholinesterase activity
URINALYSIS: Yes
- Time schedule for collection of urine: Blood and urine were collected from control and high-dose rats (5/sex/group) at 3 months and from all groups of rats at 6 months.
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters examined: volume. pH. specific gravity, description of color and appearance, qualitative tests for albumin, glucose, bilirubin, ketones, and occult blood. and microscopic examination of the sediment
NEUROBEHAVIOURAL EXAMINATION: No data - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete necropsies were conducted on all animals that died on test and on all survivors. Organ weights and organ/body weight ratios were recorded for adrenals, brain, heart, kidneys, liver, lungs, spleen, pituitary, thyroid and gonads from all survivors. Histopathologic examinations were performed on tissues and organs from all animals in control and high-exposure groups. The tissues examined were esophagus, stomach, liver, pancreas, small intestine, large intestine, kidneys, urinary bladder, pituitary, thymus, adrenals, thyroid, parathyroids, brain, eye with optic nerve, spinal cord, peripheral nerve, gonads, uterus, prostate, seminal vesicle, heart, aorta, skeletal muscle, submandibular (pharyngeal) lymph tissue, thoracic (mediastinal) lymph node, mesenteric lymph node, spleen, trachea, lung and any other tissue with grossly observable lesions, In addition, nasal turbinate sections from all species at all dose levels were taken immediately posterior to the upper incisors. All sections of the nasal turbinates were approximately 3 to 5 mm thick and contained primarily respiratory epithelium. - Other examinations:
- no data
- Statistics:
- A statistical evaluation of the body weight data, terminal hematology, clinical chemistry, and relative organ weights was performed using an analysis of variance and Dunnett’s test. Histopathology data for nonnasal tissue were analyzed using the x2 test. The level of significance was selected at p < 0.05.
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):
- not specified
- 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):
- not specified
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- not specified
- Details on results:
- CLINICAL SIGNS AND MORTALITY
All other effects were limited to the respiratory tract and eye. In the high-exposure groups, nasal discharge, ocular irritation, and slight dyspnea with coughing and sneezing were observed. The effects were less severe in the animals from the mid- and low-exposure groups.
BODY WEIGHT AND WEIGHT GAIN
Body weights were decreased in rats in the mid- and high-exposure groups at intervals during the study (<10%). However, at study termination, body weights were decreased only in the high-exposure group (6 – 8%).
OPHTHALMOSCOPIC EXAMINATION
HAEMATOLOGY
CLINICAL CHEMISTRY
URINALYSIS
NEUROBEHAVIOUR
ORGAN WEIGHTS
GROSS PATHOLOGY
HISTOPATHOLOGY: NON-NEOPLASTIC
Hyperplastic changes in the nasal tissues were present in the mid- and high-exposure groups only. Also metaplastic changes in the nasal tissues were present in all exposure groups. There was some mucosal and/or submucosal infiltration of neutrophils into the nasal tissues at all exposure groups.
Effect levels
- Dose descriptor:
- NOAEC
- Effect level:
- ca. 3.3 mg/m³ air (analytical)
- Sex:
- male/female
- Basis for effect level:
- other: systemic effects (decreased body weights) and localized eye/nasal irritation effects
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Repeated exposure of maleic anhydride by inhalation to rats has resulted in effects that were limited to the respiratory tract and eye irritation.
No significant effect was observed at the low dose for either sex. In general, effects were observed transiently at short intervals in the mid-dose group and for more prolonged intervals in the high-dose group.
Rats may be more susceptible to irritants and develop more severe pathological changes than primates because their nasal cavities have a greater surface area to volume ratio than primates.
The irritant effects of maleic anhydride were more pronounced in the nasal tissue of rats and hamsters than monkeys.
Applicant's summary and conclusion
- Conclusions:
- The NOAEC for rats is based on systemic effects (decreased body weights) and localized eye/nasal irritation effects and is considered to be 3.3 mg/m3 (0.8 ppm).
- Executive summary:
In the six-month inhalation study in which rats 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 exposed to 3.3 or 9.8 mg/m3 (0.8 or 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. Metaplastic changes in the nasal tissues occurred in rats 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).
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