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EC number: 203-570-0 | CAS number: 108-30-5
Toxicological information
Genetic toxicity: in vitro
Currently viewing:
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 1980-01-01 to 1990-01-31
- 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:
- 1 990
- Report date:
- 1990
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 987
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Principles of method if other than guideline:
- The methods followed those first described by Ames et al. (1975) and were consistent with subsequently adopted international test guidelines. Succinic anhydride was not tested for mutagenicity using strain TA 102. Succinic anhydride was tested in two laboratories for induction of gene mutations in several strains of Salmonella typhimurium by a preincubation protocol with and without Aroclor 1254-induced male Sprague Dawley rat or Syrian hamster liver S9 (Zeiger et al., 1987); no mutagenic activity was observed in any of the strains (TA97, TA98, TA100, TA1535, or TA1537).
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Succinic anhydride
- EC Number:
- 203-570-0
- EC Name:
- Succinic anhydride
- Cas Number:
- 108-30-5
- Molecular formula:
- C4H4O3
- IUPAC Name:
- oxolane-2,5-dione
Constituent 1
- Specific details on test material used for the study:
- - Name of the test material used in the report: Succinic anhydride
- Source: Aldrich
- Purity: 99.9%
Method
- Target gene:
- histidine-dependence
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- S. typhimurium TA 97
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9 from Aroclor 1254-induced male Sprague Dawley rat or Syrian hamster liver
- Test concentrations with justification for top dose:
- 0, 3, 10, 33, 100, 333, 666, 1000, 3333, and 10000 ug succinic anhydride/plate. The high dose was limited by toxicity or solubility but did not exceed 10 mg/plate.
- Vehicle / solvent:
- DMSO
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- sodium azide
- other: with metabolic activation (+S9): all strains: 2-aminoanthracene; -S9: TA98: 4-nitro-o-phenylenediamine
- Details on test system and experimental conditions:
- Succinic anhydride was incubated with Salmonella typhimurium tester strains TA97, TA98, TA100, TA1535, and TA1537 either in buffer or S9 mix (metabolic activation enzymes and cofactors from Arochlor 1254-induced male Sprague Dawley rat or Syrian hamster liver) for 20 minutes at 37° C before the addition of soft agar supplemented with L-histidine and D-biotin and subsequent plating on minimal glucose agar plates. Incubation was continued for an additional 48 hours. Succinic anhydride was tested in a series (four strains used) in each of two different laboratories. If all results were negative, the chemical was retested in all strains. In the second laboratory, repeat trails were performed with a different concentration of S9. Each test consisted of triplicate plates of concurrent positive and negative controls and of at least five doses of the study chemical. The high dose was limited by toxicity or solubility but did not exceed 10 mg/plate.
- Evaluation criteria:
- A positive response was defined as a reproducible, dose-related increase in histidine-independent (revertant) colonies in any one strain/activation combination. An equivocal response was defined as an increase in revertant which was not dose related, not reproducible, or of insufficient magnitude to support a determination of mutagenicity. A response was considered negative when no increase in revertant colonies was observed after chemical treatment.
- Statistics:
- Not applicable
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 97
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 3333 µg/plate (+S9)/ 333 µg/plate (-S9)
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 3333 µg/plate (+S9)/ 333 µg/plate (-S9)
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 3333 µg/plate (+S9)/ 1000 µg/plate (-S9)
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- at 3333 µg/plate (+S9)/ 333 µg/plate (-S9)
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
- In the first laboratory trial, cytotoxicity was not seen at any concentration with or without metabolic activation. In the second laboratory trial, slight toxicity was seen in the absence of S9 at concentrations of 333 ug/plate succinic anhydride and greater. In the presence of 10% and 30% S9, slight toxicity was seen at concentrations of 3333 ug/plate succinic anhydride and greater.
Any other information on results incl. tables
Table 1. Mutagenicity of succinic anhydride in Salmonella typhimurium (Laboratory 1)
| Revertants/Platea | |||||||
| - S9 | + S9 (hamster) | + S9 (rat) | |||||
| Strain | Dose (ug/plate) | Trail 1 | Trial 2 | Trial 1 | Trial 2 | Trial 1 | Trial 2 |
| TA100 | 0 (solvent control) | 94 + 4.4 | 123 + 7.5 | 131 + 8.5 | 111 + 9.9 | 111 + 6.1 | 115 + 5.2 |
| 3 | 118 + 16.5 | -- | -- | -- | -- | -- | |
| 10 | -- | 99 + 12.3 | -- | -- | -- | -- | |
| 33 | 114 + 6.1 | 120 + 3.7 | -- | -- | -- | -- | |
| 100 | 101 + 1.5 | 103 + 6.0 | 124 + 8.2 | 93 + 4.0 | 129 + 1.2 | 110 + 7.5 | |
| 333 | 113 + 6.1 | 93 + 9.3 | 116 + 11.5 | 104 + 6.6 | 127 + 7.3 | 120 + 5.0 | |
| 666 | 87 + 12.0 | 41 + 2.3 | -- | -- | -- | -- | |
| 1000 | -- | -- | 111 + 9.6 | 107 + 5.0 | 114 + 8.3 | 103 + 6.4 | |
| 3333 | -- | -- | 107 + 9.3 | 81 + 7.0 | 97 + 6.1 | 105 + 4.4 | |
| 10000 | -- | -- | 105 + 16.7 | 71 + 8.5 | 99 + 9.2 | 77 + 9.5 | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 431 + 13.3 | 411 + 28.4 | 1500 + 142.6 | 1358 + 108.2 | 481 + 28.2 | 721 + 14.5 | |
| TA 1535 | 0 (solvent control) | 19 + 2.5 | 30 + 2.2 | 9 + 2.0 | 7 + 1.2 | 9 + 2.3 | 11 + 2.7 |
| 3 | 27 + 0.6 | -- | -- | -- | -- | -- | |
| 10 | -- | 32 + 2.1 | -- | -- | -- | -- | |
| 33 | 20 + 0.3 | 25 + 3.0 | -- | -- | -- | -- | |
| 100 | 25 + 2.1 | 30 + 4.9 | 10 + 2.6 | 6 + 0.6 | 9 + 2.2 | 10 + 2.6 | |
| 333 | 22 + 1.7 | 19 + 3.5 | 8 + 2.1 | 6 + 0.6 | 9 + 1.5 | 7 + 0.3 | |
| 666 | 7 + 3.1 | 6 + 4.3 | -- | -- | -- | -- | |
| 1000 | -- | -- | 11 + 2.5 | 7 + 1.2 | 11 + 1.2 | 6 + 0.6 | |
| 3333 | -- | -- | 6 + 1.2 | 6 + 1.3 | 5 + 0.3 | 9 + 0.0 | |
| 10000 | -- | -- | 4 + 0.7 | 6 + 0.0 | 4 + 0.9 | 6 + 0.0 | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 511 + 11.6 | 436 + 10.7 | 503 + 14.7 | 389 + 3.5 | 186 + 15.3 | 167 + 3.2 | |
| TA 1537 | 0 (solvent control) | 5 + 1.2 | 7 + 2.0 | 6 + 1.5 | 9 + 1.7 | 8 + 2.3 | 9 + 2.0 |
| 3 | 5 + 0.9 | -- | -- | -- | -- | -- | |
| 10 | -- | 5 + 1.0 | -- | -- | -- | -- | |
| 33 | 4 + 0.9 | 7 + 2.5 | -- | -- | -- | -- | |
| 100 | 6 + 1.2 | 5 + 1.2 | 8 + 2.0 | 10 + 2.9 | 9 + 2.1 | 5 + 0.6 | |
| 333 | 5 + 1.8 | 5 + 2.0 | 8 + 0.6 | 7 + 0.3 | 11 + 1.2 | 6 + 1.5 | |
| 666 | 3 + 0.9 | 2 + 0.7 | -- | -- | -- | -- | |
| 1000 | -- | -- | 7 + 1.7 | 8 + 0.0 | 5 + 1.5 | 5 + 1.2 | |
| 3333 | -- | -- | 6 + 2.8 | 5 + 1.5 | 6 + 0.9 | 7 + 1.2 | |
| 10000 | -- | -- | 5 + 2.2 | 6 + 1.0 | 8 + 2.2 | 7 + 0.9 | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 248 + 86.7 | 166 + 31.4 | 462 + 22.6 | 321 + 25.6 | 147 + 16.6 | 179 + 19.8 | |
| TA98 | 0 (solvent control) | 22 + 5.0 | 16 + 2.1 | 25 + 2.3 | 23 + 3.3 | 24 + 3.2 | 26 + 2.0 |
| 3 | 16 + 1.5 | -- | -- | -- | -- | -- | |
| 10 | -- | 15 + 0.3 | -- | -- | -- | -- | |
| 33 | 19 + 3.4 | 14 + 0.9 | -- | -- | -- | -- | |
| 100 | 16 + 1.2 | 16 + 0.9 | 33 + 2.1 | 23 + 3.3 | 24 + 4.9 | 26 + 0.3 | |
| 333 | 12 + 1.8 | 11 + 1.9 | 27 + 2.1 | 23 + 3.7 | 24 + 2.5 | 19 + 0.3 | |
| 666 | 7 + 0.9 | 4 + 0.3 | -- | -- | -- | -- | |
| 1000 | -- | -- | 23 + 2.5 | 20 + 0.6 | 29 + 2.0 | 27 + 2.8 | |
| 3333 | -- | -- | 18 + 0.3 | 22 + 4.5 | 25 + 5.1 | 23 + 3.0 | |
| 10000 | -- | -- | 19 + 1.5 | 15 + 1.7 | 24 + 2.1 | 19 + 3.8 | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 757 + 11.3 | 793 + 19.0 | 1287 + 249.6 | 1229 + 84.4 | 355 + 43.6 | 474 + 45.7 | |
| aRevertants are presented as mean + standard error from three plates; bPositive control: 2 -aminoanthracene used on all strains in the presence of S9. In the absence of metabolic activation, 4 -nitro-o-phenylenediamine was used with TA98, sodium azide was used with TA100 and TA1535, and 9 -aminoacridine was used with TA1537 and TA97. | |||||||
Table 2. Mutagenicity of succinic anhydride in Salmonella typhimurium (Laboratory 2)
| Revertants/Platea | |||||||
| - S9 | + S9 (hamster) | + S9 (rat) | |||||
| Strain | Dose (ug/plate) | Trail 1 | Trial 2 | 10% | 30% | 10% | 30% |
| TA100 | 0 (solvent control) | 100 + 4.3 | 128 + 9.5 | 94 + 8.4 | 118 + 6.6 | 96 + 1.0 | 103 + 2.3 |
| 3.3 | -- | 141 + 9.4 | -- | -- | -- | -- | |
| 10 | -- | 124 + 8.5 | -- | -- | -- | -- | |
| 33 | -- | 126 + 15.3 | -- | 119 + 8.4 | -- | 108 + 8.1 | |
| 100 | 88 + 8.1 | 130 + 3.0 | 90 + 1.7 | 106 + 7.8 | 100 + 4.8 | 108 + 4.3 | |
| 333 | 74 + 3.5 | 112 + 10.4c | 94 + 7.2 | 103 + 2.7 | 101 + 4.9 | 107 + 11.6 | |
| 1000 | 52 + 16.5c | -- | 104 + 5.2 | 104 + 3.8 | 83 + 2.6 | 120 + 2.1 | |
| 3333 | Toxic | -- | 88 + 5.6c | 87 + 2.3 | 80 + 10.5c | 88 + 10.0 | |
| 6666 | 74 + 0.0c | -- | 89 + 6.2c | -- | Toxic | -- | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 1096 + 18.8 | 1130 + 47.3 | 890 + 31.9 | 385 + 31.2 | 1408 + 48.0 | 806 + 19.3 | |
| TA 1535 | 0 (solvent control) | 29 + 2.0 | 27 + 5.9 | 12 + 0.3 | 13 + 3.3 | 13 + 0.3 | 12 + 1.8 |
| 3.3 | 29 + 0.3 | 25 + 4.7 | -- | -- | -- | -- | |
| 10 | 20 + 3.0 | 24 + 2.2 | -- | -- | -- | -- | |
| 33 | 25 + 2.5 | 19 + 1.8 | -- | 10 + 0.9 | -- | 14 + 0.9 | |
| 100 | 22 + 3.4 | 23 + 4.5 | 9 + 1.7 | 13 + 1.5 | 7 + 2.5 | 13 + 1.9 | |
| 333 | 20 + 2.1c | 21 + 1.2c | 8 + 2.4 | 16 + 1.7 | 8 + 1.3 | 13 + 0.6 | |
| 1000 | -- | -- | 9 + 1.5 | 15 + 0.9 | 12 + 2.3 | 11 + 0.6 | |
| 3333 | -- | -- | 8 + 0.9c | 11 + 2.0 | 9 + 2.7c | 11 + 1.8 | |
| 6666 | -- | -- | 5 + 0.9c | -- | Toxic | -- | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 849 + 29.3 | 53 + 2.2 | 61 + 3.2 | 91 + 4.0 | 85 + 1.0 | 74 + 0.6 | |
| TA 97 | 0 (solvent control) | 90 + 2.5 | 98 + 11.3 | 101 + 2.7 | 118 + 4.9 | 92 + 4.3 | 188 + 6.8 |
| 3.3 | 92 + 3.1 | 106 + 3.0 | -- | -- | -- | -- | |
| 10 | 91 + 3.5 | 90 + 3.7 | -- | -- | -- | -- | |
| 33 | 86 + 7.4 | 100 + 3.7 | -- | 118 + 5.3 | -- | 185 + 6.9 | |
| 100 | 88 + 4.6 | 89 + 9.6 | 111 + 1.2 | 155 + 9.9 | 88 + 10.7 | 184 + 5.8 | |
| 333 | 79 + 4.7c | 77 + 5.6c | 97 + 10.1 | 143 + 11.6 | 72 + 7.5 | 185 + 8.8 | |
| 1000 | -- | -- | 99 + 7.4 | 131 + 4.5 | 106 + 1.8 | 186 + 9.4 | |
| 3333 | -- | -- | 80 + 2.0c | 115 + 1.2 | 82 + 1.0c | 97 + 6.4 | |
| 6666 | -- | -- | Toxic | -- | 49 + 6.6c | -- | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 611 + 67.2 | 414 + 22.9 | 538 + 8.4 | 317 + 15.6 | 883 + 43.6 | 438 + 11.3 | |
| TA98 | 0 (solvent control) | 19 + 1.9 | 17 + 1.5 | 29 + 5.4 | 26 + 3.6 | 29 + 1.5 | 38 + 4.8 |
| 3.3 | 15 + 1.2 | 18 + 3.8 | -- | -- | -- | -- | |
| 10 | 14 + 3.2 | 23 + 5.2 | -- | -- | -- | -- | |
| 33 | 18 + 2.6 | 25 + 2.3 | -- | 23 + 2.7 | -- | 29 + 4.0 | |
| 100 | 20 + 1.7 | 18 + 1.5 | 25 + 2.0 | 28 + 2.1 | 24 + 0.7 | 37 + 3.2 | |
| 333 | 12 + 3.0c | 16 + 4.9 | 21 + 3.4 | 31 + 3.6 | 28 + 3.8 | 30 + 1.3 | |
| 1000 | -- | -- | 28 + 3.0 | 29 + 4.1 | 24 + 4.9 | 32 + 4.5 | |
| 3333 | -- | -- | 23 + 3.4c | 30 + 2.6 | 14 + 1.0c | 24 + 1.3c | |
| 6666 | -- | -- | 46 + 37.5c | -- | 7 + 0.3c | -- | |
| Trial summary | Negative | Negative | Negative | Negative | Negative | Negative | |
| Positive controlb | 168 + 8.9 | 170 + 17.2 | 480 + 20.3 | 80 + 5.8 | 993 + 26.8 | 202 + 11.9 | |
| aRevertants are presented as mean + standard error from three plates; bPositive control: 2 -aminoanthracene used on all strains in the presence of S9. In the absence of metabolic activation, 4 -nitro-o-phenylenediamine was used with TA98, sodium azide was used with TA100 and TA1535, and 9 -aminoacridine was used with TA1537 and TA97; cSlight toxicity | |||||||
Applicant's summary and conclusion
- Conclusions:
- No mutagenic response was observed when succinic anhydride was tested in the Ames assay up to 10 mg/plate which exceeds the curent limit concentration recommended by OECD TG 471.
- Executive summary:
In a reverse gene mutation assay in bacteria performed similar to OECD 471, TA 97, TA98, TA100, TA1535 and TA1537 strains of Salmonella typhimurium were exposed to Succinic acid (99.9% purity) in DMSO at concentrations of 0, 3, 10, 33, 100, 333, 666, 1000, 3333 and 10000 µg/plate by a preincubation protocol in the presence and absence of metabolic activation via Aroclor 1254 -induced male Sprague Dawley rat or Syrian hamster liver S9.
Succinic anhydride was tested up to concentrations causing cytotoxicity or exceeding the recommended limit concentration. The positive controls induced the appropriate responses in the corresponding strains.
There was no evidence of induced mutant colonies over background in any of the strains tested. Based on these results, Succinic anhydride is not considered to be mutagenic in bacterial cells.
The study is classified as acceptable.
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