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EC number: 287-673-6 | CAS number: 85566-63-8
- 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:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- Study conducted outside the EU over 10 years before the EU cosmetic testing ban came into effect.
Cross-reference
- Reason / purpose for cross-reference:
- read-across: supporting information
Reference
- Endpoint:
- developmental toxicity
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Justification for type of information:
- Full read-across information is appended.
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The source substance and target substances behave in substantially similar ways in water, and are considered to be functionally similar when inside the body. The target substance has a higher molecular weight and lower dermal absorption coefficient, and is therefore considered to be less likely to enter the body through the skin or via oral absorption. The potential for acute dermal toxicity, repeated dose toxicity and toxicity to reproduction is therefore lower in the target substance than the source substance.
2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Both substances are esters, with the carbonyl (C=O) part of each ester separated by 2 carbons. In addition, the two carbons are unsaturated as they share a double bond. In both cases this double bond is present in the cis geometry. The principle difference between the two substances is that the maleic anhydride is a ring structure, with the esters sharing the hydroxy group between them; whereas in the target substance there are two distinct ester components with branching chains (a methyl (odd) and a hexyl (even)).
Both substances can undergo hydrolysis to produce the same carboxylic acid as shown in the appended .pdf (Table 4). However, Maleic anhydride undergoes this process more readily as it is hygroscopic. The carboxylic acid formed is maleic acid, which can undergo hydration upon further reaction with water to produce malic acid.
The principle difference between how the source and target substances undergo hydrolysis is that one mole of maleic anhydride only produces one mole of maleic acid and no other organic species, whereas one mole of the target substance bis(1-methylheptyl) maleate produces one mole of maleic acid and two moles of 2-octanol. The 2-octanol is a branched alcohol, with an odd numbered branch (due to the methyl chain) and an even numbered branch (due to the hexyl chain).
3. ANALOGUE APPROACH JUSTIFICATION
Due to the similarities of the source and target substance with regards to chemical structure, physico-chemical properties, and Lipinski’s rule of 5, the target substance is expected to behave in a substantially similar manner in vivo.
The target substance is therefore predicted to also have a reproductive NOEL of >55 mg/kg/day after repeated oral dosing in the rat. The target substance is also predicted to show no treatment-related effects on fetal development at up to 140 mg/kg/day after repeated oral dosing in the rat. By extension, the target substance is considered not to fulfil the criteria for toxicity to reproduction under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).
4. DATA MATRIX
See appended read-across justification. - Reason / purpose for cross-reference:
- read-across source
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- pre and post implantation loss
- Abnormalities:
- no effects observed
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- skeletal malformations
- visceral malformations
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- external: tail
- external: pelvic region
- skeletal: skull
- skeletal: sternum
- visceral/soft tissue: musculoskeletal system
- Developmental effects observed:
- no
Data source
Reference
- Reference Type:
- publication
- Title:
- Teratology and Multigeneration Reproduction Studies with Maleic Anhydride in Rats
- Author:
- Short, R.D., Johannsen, F.R., Levinskas, G.J., Rodwell, D.E. & Schardein, J.L.
- Year:
- 1 986
- Bibliographic source:
- FUNDAMENTAL AND APPLIED TOXICOLOGY, Vol 7, pp. 359-366
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- not specified
- Remarks:
- Study published before adoption of OECD guideline.
- GLP compliance:
- no
- Remarks:
- Study published before adoption of GLP standards.
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
- Test material form:
- not specified
Constituent 1
- Specific details on test material used for the study:
- Maleic anhydride was supplied by Monsanto Company as white briquettes with a purity of greater than 99%
Test animals
- Species:
- rat
- Strain:
- other: CD
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: 12 weeks
- Weight at study initiation: F 242-244 g
- Fasting period before study: No
- Housing: Wire mesh cages or plastic cages with corn-cob bedding
- Diet (e.g. ad libitum): Purina Rodent Chow, Ralston-Purina, St. Louis, Mo. - Ad libitum
- Water (e.g. ad libitum): - Ad libitum
- Acclimation period: 10 days
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- 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. Rats (25 mated females/group) were treated orally with 30, 90, or 140 mg/kg/day of maleic anhydride. Mated females in the control group were treated in a similar manner with 14 ml/kg of corn oil.
- Analytical verification of doses or concentrations:
- no
- Details on mating procedure:
- One male and one female were housed together for mating. The day of mating was determined by daily inspection for a copulatory plug or a sperm-positive vaginal smear. This day was designated Day O of gestation.
- Duration of treatment / exposure:
- Day 6 through Day 15 of gestation.
- Frequency of treatment:
- Daily
- Duration of test:
- To day 20 of gestation.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 30 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 90 mg/kg bw/day (actual dose received)
- Dose / conc.:
- 140 mg/kg bw/day (actual dose received)
- No. of animals per sex per dose:
- 25 mated females
Examinations
- Maternal examinations:
- Body weights were recorded at intervals during gestation.
- Fetal examinations:
- 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 (Wilson, 1965). The remaining fetuses were fixed in alcohol, cleared with potassium hydroxide, stained with Alizarin Red S (Dawson, 1926), and examined for skeletal abnormalities.
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.
- 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% (Table 1).
- Body weight and weight changes:
- effects observed, 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 (Table 1). However, this effect was reversible, and there were no statistically significant effects on body weight at any of the times examined.
Maternal developmental toxicity
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There was no evidence of postimplantation loss (Table 1).
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- clinical signs
- mortality
- pre and post implantation loss
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.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Dams from all test groups produced normal-sized litters (Table 1).
- External malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- 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):
- 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):
- The fetal variations were comparable both in type and frequency in the control and treated groups.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 140 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- fetal/pup body weight changes
- changes in litter size and weights
- external malformations
- skeletal malformations
- visceral malformations
Fetal abnormalities
- Abnormalities:
- effects observed, non-treatment-related
- Localisation:
- external: tail
- external: pelvic region
- skeletal: skull
- skeletal: sternum
- visceral/soft tissue: musculoskeletal system
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
TABLE 1. MATERNAL AND FETAL DATA FROM RATS TREATED WITH MALEIC ANHYDRIDE DURING GESTATION
Maleic anhydride (mg/kg/day) | ||||
0 | 30 | 90 | 140 | |
Number treated | 25 | 25 | 25 | 25 |
Pregnant | 23 | 24 | 20 | 21 |
Alive | 23 | 23 | 19 | 21 |
Nonpregnant | 2 | 1 | 5 | 4 |
Alive | 2 | 1 | 5 | 3 |
Body weight (g) | ||||
Day 0 | 242 | 244 | 242 | 243 |
Day 6 | 261 | 264 | 266 | 264 |
Day 9 | 272 | 264 | 264 | 258 |
Day 12 | 293 | 286 | 283 | 282 |
Day 15 | 315 | 302 | 303 | 298 |
Day 20 | 397 | 377 | 385 | 378 |
Implants/dam | 13.3(14)a | 13.4(14) | 13.2(13) | 13.5(14) |
Viable fetuses/dam | 12.6(13) | 12.7(13) | 12.5(13) | 12.7(13) |
Resorptions/dam | 0.8 (0) | 0.7(0) | 0.7(1) | 0.8 (0) |
Fetal weight (g) | 4.0(3.8) | 3.7(3.8)b | 3.8(3.8) | 3.7 (3.6)b |
a Mean (median).
b Mean significantly different from control. The historical control value for fetal weight was 3.6 g for 1774 fetuses
TABLE 2. OBSERVATIONS OF FETUSES FROM RATS TREATED WITH MALEIC ANHYDRIDE DURING GESTATION
Maleic anhydride (mg/kg/day) | ||||
0 | 30 | 90 | 140 | |
Number examined | ||||
Litters | 23 | 23 | 19 | 23 |
Fetuses | ||||
External | 289 | 292 | 237 | 267 |
Skeletal | 189 | 190 | 155 | 174 |
Soft tissue | 100 | 102 | 82 | 93 |
Malformations | ||||
Short tail | 1 (1)a | |||
Omphalocele | 1 (1) | |||
Spherical enlargement on ribs | 1 (1) | |||
Fused sternebrae | 1 (1) | |||
Bent ribs | 1 (1) | |||
Multiple anomalies | 1 (1)b | |||
Total with above malformations | 1 (1) | 2 (2) | 0 (0) | 3 (3) |
Variations | ||||
Rudimentary 14th rib(s) | 51 (17) | 62 (20) | 46 (16) | 37 (13) |
Full 14th rib(s) | 1 (1) | 2 (2) | 3 (3) | 1 (1) |
27 presacral vertebrae | 5 (4) | 2 (1) | 2 (2) | |
Sternebrae 5 and/or 6 unossified | 12 (9) | 16 (7) | 12 (6) | 20 (12) |
7th cervical rib | 3 (2) | 1 (1) | 1 (1) | |
Misaligned centra | 1 (1) | |||
Reduced ossification of skull | 1 (1) | 1 (1) | ||
Hyoid unossified | 5 (3) | |||
Pubis unossified | 1 (1) | |||
Renal papillar not developed | 2 (2) | 1 (1) |
a Number of fetuses (number of litters).
b Includes malformed humerus, stemoschisis, and ossification defects of the pubis, cervical arches, and skull
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, it is concluded that maleic anhydride is not teratogenic.
- Executive summary:
In the teratology study, pregnant rats (19-23/group) received 0, 30, 90, or 140 mg/kg/day maleic anhydride in corn oil orally from Days 6-15 of gestation and fetuses were examined for gross soft tissue and skeletaldefects. A reduced weight gain or weight loss was observed in all maleic anhydride-treated groups between Days 6 and 9; however, mean weights of all groups were within 5% of control on Days 15 and 20. No treatment-related effects on fetal development were observed.
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