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EC number: 203-570-0 | CAS number: 108-30-5
- 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

Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- not specified
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
Data source
Referenceopen allclose all
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 979
- Report date:
- 1979
- Reference Type:
- publication
- Title:
- Teratology and multigeneration reproduction studies with maleic anhydride in rats
- Author:
- Short R.D. et al
- Year:
- 1 986
- Bibliographic source:
- Fundamental and Applied Toxicology 7, 359-66
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- yes
- Remarks:
- (administered volume in the control and high dose group is higher (1.4 ml/100 g bw) than the advised maximum volume in the guideline (0.4 ml/100 g bw))
- 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
Constituent 1
- Specific details on test material used for the study:
- - Appearance: White briquettes
- Purity: > 99%.
TREATMENT OF TEST MATERIAL PRIOR TO TESTING:
Briquettes of maleic anhydride were finely ground with a mortar and pestle and suspended in corn oil with the aid of a tissue homogenizer. All doses were prepared daily in corn oil in order to minimize problems with stability. A 1% (w:v) concentration was
used to administer all doses.
Test animals
- Species:
- rat
- Strain:
- other: Charles River CD rats
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories (Wilmington, Mass.)
- Age at study initiation: approximately 12 weeks
- Weight at study initiation: 242-244 g
- Fasting period before study: not applicable
- Housing: Rats were individually housed, except during mating and lactation, in wire mesh cages or plastic cages with corn-cob bedding. One male and one female were housed together for mating.
- Diet (e.g. ad libitum): Purina Rodent Chow (Ralston-Purina, St. Louis, MO.)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: All rats were acclimated to the laboratory for at least 10 days prior to initiating a study.
ENVIRONMENTAL CONDITIONS
All animals were maintained in environmentally controlled rooms
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Briquettes of maleic anhydride were finely ground with a mortar and pestle and suspended in corn oil with the aid of a tissue homogenizer. All doses were prepared daily in corn oil in order to minimize problems with stability. A 1% (w:v) concentration was used to administer all doses.
VEHICLE
- Concentration in vehicle: 1% (w/v)
- Amount of vehicle (if gavage): 0.3-1.4 ml/100g bw - Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- from gestation day 6 through day 15
- Frequency of treatment:
- daily
- Duration of test:
- day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Remarks:
- low dose
- Dose / conc.:
- 90 mg/kg bw/day (nominal)
- Remarks:
- mid dose
- Dose / conc.:
- 140 mg/kg bw/day (nominal)
- Remarks:
- high dose
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
Examinations
- Maternal examinations:
- DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations: gestation days 0, 6, 9, 12, 15, and 20 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: fetal swellings, number of viable and nonviable fetuses - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [1/3 per litter ]
- Skeletal examinations: Yes: [2/3 per litter ] - Statistics:
- Several different statistical methods were used to compare measurements made on test animals to the corresponding values determined for controls. The methods and the measurements to which they were applied are analyis of variance and Dunnett’s test (Steel and Tonie, 1960) for adult body weights, litter size, and pup body weights; Fisher’s exact probability test (Siegel, 1956) for mortality and fertility data; Mann-Whitney U test (Siegel, 1956) for fetal body weights; and x2 test with Yates’ correction or Fisher’s exact probability test (Siegel, 1956) for litters with anomalies. In all instances, p < 0.05 was selected as the level of significance.
- Indices:
- Mean implants/dam, viable fetuses/dam, resorptions/dam were calculated.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The general appearance and behavior of rats were not altered by treatment.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- While one adult died in each of the experimental groups, the overall survival in these groups was 96%.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Dams in the experimental groups either failed to gain weight or lost weight between Days 6 and 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Other effects:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss
- Total litter losses by resorption:
- no effects observed
- Description (incidence and severity):
- The number of resorptions/dam was not altered after treatment.
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- effects observed, non-treatment-related
- Description (incidence and severity):
- The number of viable fetuses/dam was comparable between treatment groups and control.
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There was a minimal reduction in the ratio of pregnant animals to the number of treated animals between control (23/25) and the low (24/25), mid (20/25) and high dose (21/25) treated animals.
- Other effects:
- not examined
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
Respiratory involvement and red nasal discharge were observed in all dosage groups. The incidence of these was higher in the treated groups, though not in a dose-related pattern. No treatment-related deaths (one rat in each dosage group died during the first part of treatment; the cause of death was not determined) nor abnormal behavior was observed in any of the maleic anhydride treated groups. Mean body weight gain was reduced in the 30 mg/kg/day dosage group for the first three days of treatment. There was a slight mean body weight loss in the 90 and 140 mg/kg/day dosage groups for the first three days of treatment. These reductions in weight gains resulted in reduced mean body weight gains over the entire treatment period in all treatment groups compared to the control (however, mean weight of all groups was within 5% of control on days 15 and 20. No biologically meaningful differences in the mean number of viable fetuses, implantations, post implantation losses, corpora lutea, or in the male to female sex ratio between any of the maleic anhydride treated groups and the control group. The general appearance and behavior of rats were not affected by treatment.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- Remarks on result:
- other: Only slight effects on the body weight in the 90 and 140 mg/kg treatment groups. These effect were reversible, and there were no statistically significant effects on body weight at any of the times examined.
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Compared with concurrent controls, fetal body weights were slightly reduced for all test groups, but the reductions were statistically significant only in the low- and high-dose groups, However, this is not considered to be compound-related, because fetal weights for concurrent control and all treated groups were slightly greater than the values for historical controls.
- Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- The number of viable fetuses/dam was not affected by treatment.
- Changes in sex ratio:
- not examined
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Dams from all test groups produced normal-sized litters.
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups. - Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Malformations were observed in one fetus (one litter) from the control group, two fetuses (two litters) from the low-dose group, and three fetuses (three litters) from the high-dose group. Since each malformation was a single occurrence and the malformations differed among the various groups, there was no evidence of a dose-related increase in any specific malformation.
The fetal variations were comparable both in type and frequency in the control and treated groups. - Other effects:
- not examined
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Mean fetal body weights were lower in the treatment groups than in the control group. This was not considered compound related due to the unusually high mean fetal body weight in this concurrent control group (mean: 4 g). External evaluation, internal examination, and skeletal observations of fetuses from all three treatment groups showed no anomalies in fetal development which could be attributed to maleic anhydride (slight increase in fetal malformations in the 30 (2/23 litters) and 140 mg/kg/day dosage group (3/21 litters) when compared to the control group (1/23 litters) is considered due to random occurrence due to the variety of abnomalities observed).
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- In developmental toxicity study (equivalent to OECD 414) maleic anhydride (>99% purity) was administered to 25 female Wistar rats/dose in corn oil at dose levels of 0, 30, 90 or 140 mg/kg bw/day from days 6 through 15 of gestation. On day 20 of gestation the animals were sacrificed. Based on the results, the NOAEL for both maternal toxicity and fetal toxicity of maleic anhydride in this study is considered to be to 140 mg/kg bw/day.
- Executive summary:
In a developmental toxicity study (equivalent to OECD 414), CD rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day of maleic anhydride from Day 6 through Day 15 of gestation. Mated females in the control group were treated in a similar manner with 14 mL/kg of corn oil. All females were sacrificed with carbon dioxide on Day 20 of gestation, and the fetuses were delivered by cesarean section. All fetuses were weighed and examined for external abnormalities. Approximately one-third of the fetuses were placed in Bouin’s fixative and examined for soft tissue abnormalities . The remaining fetuses were fixed in alcohol, cleared with potassium hydroxide, stained with Alizarin Red S and examined for skeletal abnormalities.
There were no changes in appearance or behavior attributable to treatment with maleic Anhydride at dosage levels of 30, 90 and 140 mg/kg bw/day. Respiratory involvement and red nasal discharge were observed in all dosage groups. The incidence of these was higher in the treated groups, though not in a dose-related pattern. One rat in each dosage group dl.dd during the first part of treatment. The cause of death was not determined. There were reduced mean maternal body weight gains during the first three days of treatment in the 30 mg/kg bw/day dosage group when compared to the control group. In the 90 and 140 mg/kg bw/day dosage groups mean body weight losses were observed for the first 3 days of treatment. These reductions in weight gains resulted in reduced mean weight gains over the entire treatment period in all treatment groups when compared to the control group. There were no biologically meaningful differences in the mean number of viable fetuses, implantations, post implantation losses, corpora lutea or in the male to female sex ratio between any of the maleic anhydride treated groups and the control group. Based on the results, the NOAEL for maternal toxicity is considered to be 140mg/kg bw/day.
There were no treatment-related effects in developmental parameters. Therefore, based on the result the developmental NOAEL is also considered to be 140 mg/kg bw/day.
The developmental toxicity study in the rat is classified acceptable and satisfies the guideline requirement for a developmental toxicity study (OECD 414) in rats.
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