Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 203-328-4 | CAS number: 105-76-0
- 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
- Remarks:
- based on test type (migrated information)
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- study well documented, meets generally accepted scientific principles, acceptable for assessment
- Justification for type of information:
- Based on the expected metabolism of diesters, n-butyl hydrogen maleate was selected as one of the most suitable read across substances for DBM, as it represents one of the metabolic/chemical breakdown products of DBM. For further information, please refer to Sect 13: " Updated Version Comprenhensive read across rationale for waiving further studies on reprodutive and developmental toxicity".
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Reference
- Endpoint:
- developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: GLP Guideline study
- Justification for type of information:
- Based on the expected metabolism of diesters, n-butyl hydrogen maleate was selected as one of the most suitable read across substances for DBM, as it represents one of the metabolic/chemical breakdown products of DBM. For further information, please refer to Sect 13: " Updated Version Comprenhensive read across rationale for waiving further studies on reprodutive and developmental toxicity".
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- read-across: supporting information
- Qualifier:
- according to guideline
- Guideline:
- other: Ministry of Health and Welfare, Japan; Guidelines for Toxicity Studies of Drugs
- Principles of method if other than guideline:
- Pregnant rats were given drinking water containing 1-butanol at 0.2%, 1.0% or 5.0% (316, 1454 or 5654 mg/kg/day) on days 0–20 of pregnancy. The rats were sacrificed on day 20 of pregnancy and both the dams and fetuses were examined.
- GLP compliance:
- not specified
- Limit test:
- no
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Tsukuba Breeding Center
- Age at study initiation: males: 10 weeks; females: 9 weeks
- Weight at study initiation: females: 217-273 g
- Housing: individually
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25 °C
- Humidity (%): 40-70 %
- Photoperiod (hrs dark / hrs light): 12/12 - Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
1-butanol was mixed with water to the according target concentrations. The stability of formulations in a dark and cool place under airtight conditions has been confirmed for up to 3 days. During use, the formulations were maintained under such conditions for no more than 3 days and were 95.7–103.5% of the target concentration. - Analytical verification of doses or concentrations:
- yes
- Details on mating procedure:
- - Impregnation procedure: [cohoused]
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: over night
- Verification of same strain and source of both sexes: [yes]
- Proof of pregnancy: [sperm in vaginal smear] referred to as [day 0] of pregnancy - Duration of treatment / exposure:
- day 0 through day 20 of pregnancy
- Frequency of treatment:
- continuous through drinking water
- Duration of test:
- until day 20 of pregnancy
- No. of animals per sex per dose:
- 20 females per dose
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dosage levels were determined based on the results of our range-finding study in which administration of 1-butanol in the drinking water on days 0–20 of pregnancy caused decreases in maternal body weight gain and food and water consumption and tended to reduce in fetal weight at 4% and 7% in rats.
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: not specified
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: not not specified
BODY WEIGHT: Yes
- Time schedule for examinations: once daily
FOOD CONSUMPTION: Yes
- Time schedule for examinations: every 3 or 4 days
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 10
- Organs examined: not specified - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- - External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]
- Skeletal examinations: Yes: [half per litter]
- Head examinations: Yes: [half per litter] - Statistics:
- The statistical analysis of fetuses was carried out using the litter as the experimental unit. The initial body weight, body weight gain and food and water consumption of pregnant rats, numbers of corpora lutea, implantations and live fetuses per litter, fetal weight and crown-rump length and placental weight were analyzed with Bartlett's test for homogeneity of variance at the 5% level of significance.
If it was homogeneous, the data were analyzed using Dunnett's multiple comparison test to compare the mean of the control group with that of each dosage group, and if it was not homogeneous, the mean rank of the 1-butanol-treated groups was compared with that of the control group with the Dunnett type test. The Dunnett type test was used for the incidences of pre- and postimplantation embryonic loss and fetal anomalies and sex ratio of fetuses to compare the mean rank of groups treated with 1-butanol and that of the control group. The incidence of dams with anomalous fetuses was analyzed by Chi-square test or Fisher's exact test. The significance of differences from the control group was estimated at probability levels of 1% and 5%. - Indices:
- no data
- Historical control data:
- International Genetic Standard (Crj: CD (SD) IGS) rats were used throughout this study. This strain was chosen because it is most commonly used in reproductive and developmental toxicity studies and historical control data are available.
- Details on maternal toxic effects:
- Details on maternal toxic effects:
No death was found in female rats of any group. All females in all groups became pregnant. The body weight gains on days 0–7 of pregnancy were significantly reduced at 5.0%. The body weight gain during the whole period of pregnancy was also significantly decreased at 5.0%. No significant decrease in the body weight gain was noted at 0.2 or 1.0, except for a transient decrease on days 0–2 of pregnancy at 1.0%. The food consumption on days 0–7, days 7–14, days 14–20 and days 0–20 of pregnancy was significantly lower in the 1.0% and 5.0% groups than the control group. The water consumption on days 0–7 at 1.0 and 5.0% and on days 7–14, days 14–20 and days 0–20 at 5.0% was significantly decreased. The mean daily intakes of 1-butanol were 316 mg/kg for the 0.2% group, 1454 mg/kg for the 1.0% group and 5654 mg/kg for the 5.0% group. - Dose descriptor:
- NOAEL
- Effect level:
- 1 454 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
- Details on embryotoxic / teratogenic effects:
- Details on embryotoxic / teratogenic effects:
No litters totally resorbed were found in any group. No effects of the administration of 1-butanol were observed on the numbers of corpora lutea, implantations, pre- or postimplantation loss, resorptions or dead or live fetuses or sex ratio of live fetuses. The body weights of male and female fetuses were significantly lower in the 5.0% group than in the control group. There was no significant difference in the crown-rump length of male and female fetuses or placental weight between the control and groups treated with 1-butanol.
One fetus with spina bifida in the control group and one fetus with thread-like tail and anal atresia in the 0.2% group were observed. Skeletal examination revealed one fetus with supernumerary thoracic vertebral bodies and malpositioned thoracic vertebrae at 1.0%. Although the total number of fetuses with skeletal variations was significantly increased at 5.0%, the number of fetuses with individual skeletal variations was not significantly increased, except for fetuses with short supernumerary ribs at 5.0%. A significantly lower number of forepaw proximal phalanges was observed at 5.0%. Membranous ventricular septum defect occurred in one fetus of the control and 0.2% groups and 3 fetuses in 3 dams of the 5.0% group. One fetus with a double aorta in the control group and one fetus with a left umbilical artery in the control and 2.0% groups were observed. Thymic remnants in the neck were found in 4–11 fetuses of the control and groups treated with 1-butanol.
However, there was no significant difference in the incidence of fetuses with internal abnormalities between the control and groups treated with 1-butanol. - Dose descriptor:
- NOAEL
- Effect level:
- 5 654 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- 1 454 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
- Abnormalities:
- not specified
- Developmental effects observed:
- not specified
Summary:
A significant decrease in maternal body weight gain accompanied by reduced food and water consumption was found at 5.0%. No significant increase in the incidence of pre- and postimplantation embryonic loss was observed in any groups treated with 1-butanol. Fetal weight was significantly lowered at 5.0%. Although a significant increase in the incidence of fetuses with skeletal variations and decreased degree of ossification was found at 5.0%, no increase in the incidence of fetuses with external, skeletal and internal abnormalities was detected in any groups treated with 1-butanol. The data demonstrate that 1-butanol is developmental toxic only at maternal toxic doses. No evidence for teratogenicity of 1-butanol was noted in rats. Based on the significant decreases in maternal body weight gain and fetal weight which NOAEL (maternal toxicity) was determined at 1454 mg/kg/day, it is concluded that the no observed adverse effect levels (NOAELs) of 1-butanol for both dams and fetuses are 1.0% (1454 mg/kg/day) in rats.
Data source
Reference
- Reference Type:
- publication
- Title:
- Teratology and multigeneration reproduction studies with maleic anhydride in rats
- Author:
- Short RD, Johannsen FR, Levinskas G J, Rodwell DE, Schardein JL
- Year:
- 1 986
- Bibliographic source:
- Fundam. Appl. Toxicol. 7: 359-366
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity 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
- Reference substance name:
- 2,5-Furandione
- IUPAC Name:
- 2,5-Furandione
- Test material form:
- other: briquettes
- Details on test material:
- - Name of test material (as cited in study report): Maleic anhydride
- Molecular formula (if other than submission substance): C4H2O3
- Molecular weight (if other than submission substance): 98.06 g/mol
- Smiles notation (if other than submission substance): O=C1OC(=O)C=C1
- InChl (if other than submission substance):
- Structural formula attached as image file (if other than submission substance): see Fig. 1
- Physical state: white solid (briquette)
- Analytical purity: >99%
Constituent 1
Constituent 2
- Specific details on test material used for the study:
- Test material was supplied by Monsanto Company as white briquettes with apurity greater tha 99%
Test animals
- Species:
- rat
- Strain:
- CD-1
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories
- Age at study initiation: approximately 12 weeks
- Housing: Besides mating and lactation, animals were housed individually.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: Animals were acclimated to for at least 10 days
ENVIRONMENTAL CONDITIONS
Animals were maintained in environmentally controlled rooms with a photoperiod of 12 hrs dark / 12 hrs light
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- Ground maleic anhydride was suspended in corn oil. A 1% (w/v) concentration ws used to administer all doses.
- Analytical verification of doses or concentrations:
- not specified
- Details on mating procedure:
- - Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- From day 6 to day 15 from gestation
- Frequency of treatment:
- Daily during day 6 and day 15 from gestation
- Duration of test:
- Animals were sacrificed on day 20 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Dose / conc.:
- 90 mg/kg bw/day (nominal)
- Dose / conc.:
- 140 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25 mated females/dose group
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Doses were selected based on the results of a pilot study
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
BODY WEIGHT: Yes
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20 - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of implantations: Yes
- Number of resorptions: Yes - Fetal examinations:
- Fetuses were weighed and examined for external abnormalities, skeletal abnormalities, and abnormalities in the soft tissue.
- Statistics:
- Analysis of variance followed by Dunnett's test for adult body weights
Mann-Whitney U test for fetal body weights
chi square of Fisher's exact test for litters with anomalies
Level of significance: p<0.05 - Historical control data:
- not reported
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- Significant mortality occurred in male and female adults in the hig dose group.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Food consumption and compound intake (if feeding study):
- not specified
- Food efficiency:
- not examined
- Ophthalmological findings:
- not specified
- 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 specified
- Neuropathological findings:
- not specified
- Histopathological findings: non-neoplastic:
- not specified
- Histopathological findings: neoplastic:
- not specified
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
The general appearance and behavior of rats were not altered by treatment. One adult died in each of the experimental groups, but the overall survival in these groups was 96%. Dams in the experimental groups either failed to gain weight or lost weight between day 6 and day 9 of gestation. However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.
Dams from all test groups produced normal-sized litters, and there was no evidence of postimplantation loss.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- > 140 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: maternal toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
Fetal body weights were slightly reduced for all test groups, compared with the control groups.However, the reductions were statistically significant only in the low- and high-dose groups. But this is not considered to be compound-related, because fetal weights for control and all treated groups were slightly greater than the values for historical controls. 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.
Effect levels (fetuses)
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- > 140 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: teratogenicity
- Dose descriptor:
- NOAEL
- Effect level:
- > 140 mg/kg bw/day
- Based on:
- test mat.
- Basis for effect level:
- other: fetotoxicity
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Maleic anhydride is not teratogenic under the conditions of the present test.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.