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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
Toxicity to reproduction
Administrative data
- Endpoint:
- multi-generation reproductive 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:
- other: comparable to guideline study
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 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- three-generation 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:
- Maleic anhydride (99.7%)
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Adult CD rats (Charles River Breeding Laboratories, Wilmington, Mass.), approximately 12 weeks of age, were used in the teratology study.
All rats were acclimated to the laboratory for at least 10 days prior to initiating a study. Rats were individually housed, except during mating and lactation, in wire mesh cages or plastic cages with corn-cob bedding. All animals were maintained in environmentally controlled rooms with 12-hr photoperiods and given free access to feed (Purina Rodent Chow, Ralston-Purina, St. Louis, Mo.) and water.
Administration / exposure
- Route of administration:
- oral: unspecified
- Vehicle:
- corn oil
- Details on exposure:
- Maleic anhydride was suspended in corn oil as described previously; however, the concentration was varied so that the desired dose could be administered orally in a volume of 10 ml/kg.
- Details on mating procedure:
- During the mating period each male was housed with two females for up to 15 days. The females were examined daily for evidence of mating as revealed by vaginal plugs or sperm-positive vaginal smears.
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- no data
- Duration of treatment / exposure:
- Exposure period: Pre-mating and throughout mating, gestation and lactation.
Premating exposure period: F0 and F1, a minimum of 80 days - Frequency of treatment:
- Frequency of treatment: 7 days/week
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0,20, 55, and 150 mg/kg
Basis:
nominal in diet
- No. of animals per sex per dose:
- 10 males and 20 females per group
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- no data
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- yes
- Oestrous cyclicity (parental animals):
- no data
- Sperm parameters (parental animals):
- no data
- Litter observations:
- yes
- Postmortem examinations (parental animals):
- yes
- Postmortem examinations (offspring):
- yes
- Statistics:
- Statistical analysis: 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 analysis of variance and Dunnett's test (Steel and Torrie, 1960) for adult body weights, litter size, and pup body weights; Fisher's exact probability test (Siegel, 1956) for mortality and fertility data; Mann-Whit-ney 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.
- Reproductive indices:
- no data
- Offspring viability indices:
- no data
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Organ weight findings including organ / body weight ratios:
- not specified
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Other effects:
- effects observed, treatment-related
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not specified
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- not specified
Details on results (P0)
While no cause could be identified, the three other deaths in this group are not believed to be compound-related because no deaths among mid-dose males were attributed to the test material and characteristic compound-induced lesions discussed subsequently were not noted.
Adult body weights were not affected in the low-dose groups. While there were some differences in mean body weights between control animals and those of the mid-dose group, none of the differences was statistically significant. In the high-dose group, mean body weights of both sexes of the F0 generation were significantly reduced by Week 11, and this reduction persisted for the remainder of the test. The F1 generation showed a pattern that was roughly similar, except that the only significantly depressed mean body weight occurred in high-dose males at 30 weeks.
Fertility was significantly reduced in the experimental groups at several times. However, there was neither a dose-related reduction nor a pattern within a generation hat suggested the presence of a treatment-reated effect.
Effect levels (P0)
- Dose descriptor:
- LOAEL
- Effect level:
- 20 mg/kg bw/day
- Sex:
- male/female
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
In addition, the examination of tissues from F2b pups revealed no compound-related changes in organ weights or in incidences of microscopic lesions.
Effect levels (F1)
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- 55 mg/kg bw/day
- Sex:
- male/female
Results: F2 generation
Effect levels (F2)
- Dose descriptor:
- NOAEL
- Generation:
- F2
- Effect level:
- 55 mg/kg bw/day
- Sex:
- male/female
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
In addition to treatment-related deaths, there were also gavage-related deaths in this study. If allowance is made for the latter, it appears that treatment-related mortality in the F0 generation occurred primarily in the high-dose group. Although mortality was observed at lower doses in the Fl generation, there was no dose-related pattern at these levels that suggested an effect related to treatment. Therefore, in the Fl generation, mortality that can reasonably be attributed to treatment also occurred primarily at high dose. As a result of increased mortality, this dose group was terminated during the F1 generation.
Since there was a significant reduction in neither the percentage of pregnant females nor the percentage of fertile males, it is concluded that no adverse effects on fertility were observed with maleic anhydride at doses up to 55 mg/kg/day administered over two generations. At 150 mg/kg/day, maleic anhydride was toxic to parental animals.
No adverse effects on litter size and on pup survival were observed with maleic anhydride at doses up to 150 mg/kg/day in F1 and F1 b litters or 55 mg/kg/day in F2a and F2b litters. Although a few statistically significant changes in pup body weights were observed, they were too inconsistent to be considered treatment-related. Microscopic examination of tissues from pups in the F2b litters revealed no treatment-related changes. Therefore, treatment with up to 55 mg/kg/day for two generations had no adverse effects on pups.
TABLE 1 MORTALITY AND BODY WEIGHT OF ADULT RATS TREATED WITH MALEIC ANHYDRIDE DURING A MULTIGENERATION REPRODUCTION STUDY
Maleic anhydride (mg/kg/day) |
||||
0 |
20 |
55 |
150 |
|
Fo generation |
|
|
|
|
Males |
||||
Mortality a |
0(0) |
10(10) |
10(0) |
70b(60)b |
Body weight c |
143 |
142 |
143 |
143 |
502 |
524 |
506 |
431b |
|
700 |
697 |
666 |
562b |
|
Females |
|
|
|
|
Mortality a |
0(0) |
0(0) |
5(0) |
65(65)b |
Body weight c |
129 |
130 |
130 |
127 |
289 |
281 |
280 |
259b |
|
|
368 |
345 |
337 |
317b |
Fl generation |
|
|
|
|
Males |
|
|
|
|
Mortality a |
20(0) |
40(40)b |
40(0) |
75b(58)b |
Body weight c |
113 |
107 |
103 |
85b |
495 |
500 |
445 |
431 |
|
|
722 |
703 |
683 |
— |
Females |
|
|
|
|
Mortality a |
20(0) |
30(5) |
52b(10) |
100b(14) |
Body weight c |
96 |
100 |
95 |
84 |
265 |
272 |
265 |
247 |
|
334 |
343 |
347 |
— |
a Total dead/total treated X 100 (% mortality minus gavage-related deaths). Groups contained 10 to 12 males and 20 to 21 females.
b Significantly different from the appropriate control.
c Body weight (g/rat) at Weeks 0, 11, and 32 of the study.
d Body weights (g/rat) at Weeks 30,41, and 61 of the study.
Table 2FERTILITY OF RATS TREATED WITH MALEIC ANHYDRIDE DURING A MULTIGENERATION REPRODUCTION STUDY
Maleic anhydride (mg/kg/day) |
||||
|
0 |
20 |
55 |
150 |
Females |
|
|
|
|
Fla |
14/20(70)a |
7/20(35)b |
14/20(70) |
7/20(35)b |
Fib |
10/20(50) |
8/2(40) |
11/19(58) |
6/10(60) |
F2a |
14/20(70) |
13/15(87) |
9/11(82) |
— |
F2b |
12/16(75) |
12/14(86) |
8/10(80) |
— |
Males |
|
|
|
|
Fla |
8/10(80)c |
5/10(50) |
9/10(90) |
4/10(40)b |
Fib |
6/10(60) |
5/9 (100) |
7/10(70) |
5/9(56) |
F2a |
9/10(90) |
6/6 (100) |
6/6 (100) |
— |
F2b |
8/8(100) |
7/7 (100) |
5/5 (100) |
— |
a Number pregnant/number mated * 100 (% pregnant).
b Significantly different from control.
c Number fertile/number mated * 100 (% fertile).
Table 3LITTER SIZE OF RATS TREATED WITH MALEIC ANHYDRIDE DURING A MULTIGENERATION REPRODUCTION STUDY
Maleic anhydride (mg/kg/day) |
|||||
Litter |
Days after birth |
0 |
20 |
55 |
150 |
F1a |
0 |
12.2a |
11.0 |
11.6 |
13.1 |
|
4 |
12.0(9.9)b |
10.5(9.3) |
11.2(9.3) |
13.4(10.0) |
|
21 |
9.9 |
9.3 |
8.8 |
10.0 |
F1b |
0 |
13.3 |
10.3 |
13.4 |
11.3 |
|
4 |
13.0(9.8) |
9.6 (9.0) |
13.2(9.9) |
10.8(9.7) |
|
21 |
9.8 |
8.9 |
9.8 |
9.3 |
F2a |
0 |
13.4 |
12.2 |
12.0 |
— |
|
4 |
13.1(9.9) |
11.6(10.0) |
11.8(9.8) |
— |
|
21 |
9.9 |
9.9 |
9.8 |
— |
F2b |
0 |
10.5 |
13.6 |
14.0 |
— |
|
4 |
10.4(8.2) |
13.3(9.8) |
13.8(10.0) |
— |
|
21 |
8.2 |
9.7 |
9.0 |
— |
a Mean live pups/litter on indicated day. The number of pregnant females that gave birth on Day 0 is presented in Table 2.
b Mean live pups/litter before litter reduction (mean live pups/litter after reduction to five pups/sex/litter when possible).
Table 4 BODY WEIGHT OF PUPS FROM RATS TREATED WITH MALEIC ANHYDRIDE DURING A MULTIGENERATION REPRODUCTION STUDY
Maleic anhydride (mg/kg/day) |
|||||
Litter |
Days after birth |
0 |
20 |
55 |
150 |
Fla |
0 |
6.7a |
6.6 |
6.7 |
5.8b |
|
4 |
12(11)c |
11(11) |
12(11) |
10 (9) |
|
21 |
58(56) |
54(53) |
58(55) |
46b (44)b |
f1b |
0 |
6.4 |
7.1b |
6.2 |
6.3 |
|
4 |
11(10) |
12(12) |
11(10) |
10 (10) |
21 |
53(50) |
54 (54) |
51(50) |
47 (46) |
|
F2a |
0 |
6.6 |
6.4 |
6.7 |
— |
4 |
11(10) |
10(10) |
10(10) |
— |
|
|
21 |
47(45) |
47 (46) |
46 (45) |
— |
F2b |
0 |
6.8 |
6.4 |
6.1 |
— |
|
4 |
11(11) |
10(9) |
9(9) |
— |
|
21 |
50(57) |
45 (44)b |
43 (44)b |
— |
a Mean weight (g) of both males and females.
b Significantly different from control.
Applicant's summary and conclusion
- Conclusions:
- The NOAEL for reproductive effects was 55 mg/kg/day. For parental toxicity, however, the LOAEL was 20 mg/kg/day.
- Executive summary:
These effects are likely to reflect the toxicity of maleic acid since maleic anhydride is rapidly hydrolyzed to maleic acid in the body, particularly by the oral route of exposure.
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