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EC number: 700-188-0 | CAS number: 1333481-90-5
- 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
Genetic toxicity: in vitro
Administrative data
- Endpoint:
- in vitro gene mutation study in bacteria
- Remarks:
- Type of genotoxicity: gene mutation
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 08 January 2008 - 18 January 2008
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Report includes a statement of GLP compliance and study was performed according to most recent OECD and EEC guidelines.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.13/14 (Mutagenicity - Reverse Mutation Test Using Bacteria)
- Deviations:
- no
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 2-{2-[(2R,4R,6R)-4,6-dihydroxyoxan-2-yl]ethyl}-2,3-dihydro-1H-isoindole-1,3-dione
- EC Number:
- 700-188-0
- Cas Number:
- 1333481-90-5
- Molecular formula:
- C15H17NO5
- IUPAC Name:
- 2-{2-[(2R,4R,6R)-4,6-dihydroxyoxan-2-yl]ethyl}-2,3-dihydro-1H-isoindole-1,3-dione
- Reference substance name:
- Lactol
- IUPAC Name:
- Lactol
- Reference substance name:
- Phthalamido Lactol
- IUPAC Name:
- Phthalamido Lactol
- Details on test material:
- - Name of test material (as cited in study report): Lactol
- Physical state: Solid (Whte powder)
- Analytical purity: Not indicated by the sponsor; treated as 100% pure.
- Impurities (identity and concentrations): None specified.
- Purity test date: Not specified
- Lot/batch No.: PDC-010-194
- Expiration date of the lot/batch: 13 December 2008 (allocated by NOTOX, 1 year after receipt of the test substance)
- Stability under test conditions: Not indicated (stable under storage conditions)
- Storage condition of test material: At room temperature in the dark
Constituent 1
Constituent 2
Constituent 3
Method
- Target gene:
- . gene of histidine-requiring Salmonella typhimurium bacterial strains resulting in histidine-independent strains
. gene of tryptophan-requiring Escherichia coli bacterial strain resulting in a tryptophan-independent strain
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- Species / strain / cell type:
- E. coli WP2 uvr A
- Metabolic activation:
- with and without
- Metabolic activation system:
- S9-mix
- Test concentrations with justification for top dose:
- Dose range finding test: 3, 10, 33, 100, 333, 1000, 3330, and 5000 µg/plate.
Mutation assay: At least five different doses (increasing with approximately half-log steps) of the test substance were tested in triplicate in each strain. The highest concentration of Lactol used in the mutation assay was 5 mg/plate (based on dose range finding test). Concentrations used: 100, 333, 1000, 3330, and 5000 µg/plate. - Vehicle / solvent:
- Dimethylsulphoxide (DMSO)
Controlsopen allclose all
- Negative solvent / vehicle controls:
- yes
- Remarks:
- DMSO
- Positive controls:
- yes
- Positive control substance:
- sodium azide
- Remarks:
- Without metabolic activiation (-S9-mix)
Migrated to IUCLID6: Solvent : saline
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- Remarks:
- Without metabolic activiation (-S9-mix)
Migrated to IUCLID6: Solvent : Milli-Q water
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- Remarks:
- Without metabolic activiation (-S9-mix)
Migrated to IUCLID6: Solvent : DMSO
- Positive controls:
- yes
- Positive control substance:
- methylmethanesulfonate
- Remarks:
- Without metabolic activiation (-S9-mix)
Migrated to IUCLID6: Solvent : DMSO
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- Remarks:
- Without metabolic activiation (-S9-mix)
Migrated to IUCLID6: Solvent : DMSO
- Positive controls:
- yes
- Positive control substance:
- other: 2-aminoanthracene (2AA); Solvent : DMSO
- Remarks:
- With metabolic activiation (+S9-mix)
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in agar (plate incorporation)
DURATION
- Incubation period: 48 hours at 37±1ºC
DETERMINATION OF CYTOTOXICITY
- Method: relative total growth (observation of bacterial background lawn and number of revertants)
OTHER EXAMINATIONS:
OTHER: - Evaluation criteria:
- No formal hypothesis testing was done.
A test substance is considered negative (not mutagenic) in the test if:
a) The total number of revertants in tester strain TA100 is not greater than two (2) times the concurrent control, and the total number of revertants in tester strains TA1535, TA1537, TA98 or WP2uvrA is not greater than three (3) times the concurrent control.
b) The negative response should be reproducible in at least one independently repeated experiment.
A test substance is considered positive (mutagenic) in the test if:
a) The total number of revertants in tester strain TA100 is greater than two (2) times the concurrent control, or the total number of revertants in
tester strains TA1535, TA1537, TA98 or WP2uvrA is greater than three (3) times the concurrent control.
b) In case a positive response will be repeated, the positive response should be reproducible in at least one independently repeated experiment.
The preceding criteria were not absolute and other modifying factors might enter into the final evaluation decision. - Statistics:
- No formal hypothesis testing was done (refer to evaluation criteria, above).
Results and discussion
Test resultsopen allclose all
- Species / strain:
- S. typhimurium TA 1535, TA 1537, TA 98 and TA 100
- 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
- Species / strain:
- E. coli WP2 uvr A
- 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:
- TEST-SPECIFIC CONFOUNDING FACTORS
- Precipitation: Precipitation of Lactol on the plates was not observed at the start or at the end of the incubation period.
RANGE-FINDING/SCREENING STUDIES:
Lactol was tested in the tester strains TA100 and WP2uvrA with concentrations of 3, 10,33,100,333,1000,3330 and 5000 µg/plate in the absence and presence of S9-mix.
Precipitate
Precipitation of Lactol on the plates was not observed at the start or at the end of the incubation period in both tester strains.
Toxicity
To determine the toxicity of Lactol, the reduction of the bacterial background lawn, the increase in the size of the microcolonies and the reduction of
the revertant colonies were examined.
No reduction of the bacterial background lawn and no biologically relevant decrease in the number of revertants were observed.
Mutagenicity
In the dose range finding test, no increase in the number of revertants was observed upon treatment with Lactol under all conditions tested.
COMPARISON WITH HISTORICAL CONTROL DATA:
The negative and strain-specific positive control values were within the laboratory historical control data ranges indicating that the test conditions
were adequate and that the metabolic activation system functioned properly.
ADDITIONAL INFORMATION ON CYTOTOXICITY:
Any other information on results incl. tables
Table 1: Experiment 1: Mutagenic response of Lactol in the Salmonella typhimurium reverse
mutation assay and in the Escherichia coli reverse mutation assay
Dose (µg/plate) |
Mean number of revertant colonies/ 3 replicate plates (± S.D.) with different strains of Salmonella typhimurium and one Escherichia coli strain |
||||
|
TA1535 |
TA1537 |
TA98 |
TA100 |
WP2uvrA |
|
Without S9-mix |
||||
Positive control |
1043 ± 34 |
325 ± 36 |
961 ± 56 |
956 ± 45 |
1256 ± 47 |
Solvent control |
8 ± 1 |
3 ± 1 |
13 ± 4 |
130 ± 3 |
20 ± 3 |
3 |
|
|
|
132 ± 12 |
16 ± 3 |
10 |
|
|
|
142 ± 4 |
21 ± 2 |
33 |
|
|
|
123 ± 19 |
13 ± 3 |
100 |
8 ± 2 |
5 ± 1 |
21 ± 9 |
123 ± 15 |
16 ± 3 |
333 |
12 ± 1 |
4 ± 0 |
20 ± 3 |
111 ± 6 |
16 ± 3 |
1000 |
12 ± 0 |
8 ± 3 |
23 ± 3 |
116 ± 2 |
16 ± 5 |
3330 |
14 ± 3 |
4 ± 1 |
24 ± 3 |
120 ± 7 |
18 ± 1 |
5000 |
21 ± 4 |
3 ± 1 |
25 ± 1 |
129 ± 18 |
18 ± 4 |
|
With S9-mix1 |
||||
Positive control |
279 ± 18 |
387 ± 61 |
736 ± 11 |
1016 ± 64 |
324 ± 21 |
Solvent control |
13 ± 1 |
5 ± 2 |
22 ± 3 |
104 ± 14 |
21 ± 2 |
3 |
|
|
|
99 ± 12 |
17 ± 1 |
10 |
|
|
|
100 ± 10 |
17 ± 3 |
33 |
|
|
|
95 ± 5 |
21 ± 1 |
100 |
10 ± 4 |
4 ± 2 |
26 ± 4 |
103 ± 4 |
18 ± 1 |
333 |
10 ± 5 |
4 ± 1 |
24 ± 6 |
100 ± 5 |
17 ± 2 |
1000 |
8 ± 4 |
7 ± 3 |
23 ± 3 |
94 ± 2 |
19 ± 4 |
3330 |
8 ± 1 |
4 ± 2 |
22 ± 4 |
93 ± 7 |
17 ± 2 |
5000 |
12 ± 4 |
3 ± 2 |
24 ± 5 |
95 ± 16 |
21 ± 8 |
Solvent control: 0.1 mL Dimethylsulphoxide
1The S9-mix contained 5% (v/v) S9 fraction
n.b. Dose-finding range tests for TA100 and WP2uvrA used for first mutation assay test.
Table 2: Experiment 2: Mutagenic response of Lactol in the Salmonellatyphimurium reversemutation assay and in the Escherichia coli reverse mutation assay
Dose (µg/plate) |
Mean number of revertant colonies/ 3 replicate plates (± S.D.) with different strains ofSalmonella typhimuriumand oneEscherichia colistrain |
||||
|
TA1535 |
TA1537 |
TA98 |
TA100 |
WP2uvrA |
|
Without S9-mix |
||||
Positive control |
929 ± 15 |
292 ± 37 |
1009 ± 35 |
1009 ± 22 |
996 ± 29 |
Solvent control |
11 ± 2 |
8 ± 3 |
15 ± 2 |
115 ± 12 |
21 ± 2 |
100 |
9 ± 4 |
10 ± 2 |
15 ± 3 |
88 ± 4 |
21 ± 2 |
333 |
8 ± 3 |
7 ± 2 |
18 ± 2 |
90 ± 9 |
23 ± 2 |
1000 |
11 ± 1 |
7 ± 5 |
13 ± 2 |
109 ± 8 |
19 ± 2 |
3330 |
12 ± 2 |
9 ± 2 |
16 ± 2 |
97 ± 6 |
19 ± 7 |
5000 |
16 ± 3 |
6 ± 2 |
16 ± 2 |
101 ± 9 |
27 ± 6 |
|
With S9-mix1 |
||||
Positive control |
114 ± 8 |
280 ± 4 |
433 ± 30 |
626 ± 70 |
269 ± 25 |
Solvent control |
5 ± 2 |
6 ± 3 |
20 ± 4 |
66 ± 7 |
20 ± 3 |
100 |
5 ± 3 |
4 ± 1 |
22 ± 3 |
63 ± 3 |
22 ± 6 |
333 |
5 ± 3 |
6 ± 2 |
25 ± 2 |
69 ± 3 |
20 ± 2 |
1000 |
6 ± 3 |
8 ± 2 |
24 ± 3 |
62 ± 3 |
20 ± 6 |
3330 |
5 ± 2 |
4 ± 1 |
18 ± 3 |
63 ± 2 |
19 ± 6 |
5000 |
9 ± 4 |
6 ± 3 |
23 ± 7 |
65 ± 5 |
15 ± 5 |
1The S9-mix contained 5% (v/v) S9 fraction
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information):
negative With and without metabolic activation.
Based on the results of this study it is concluded that Lactol is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay. - Executive summary:
A bacterial reverse mutation test was performed by NOTOX B.V., the Netherlands on behalf of Pfizer Ireland Pharmaceuticals, Ltd, to assess the genotoxic potential of the test substance, Lactol. Four strains of Salmonella typhimurium (TA1535, TA1537, TA98, and TA100) and one strain of Escherichia coli (WP2uvrA) were tested against at least five concentrations of the test substance both in the presence and in the absence of metabolic activation (S9-mix). The negative and strain-specific positive control values were within the laboratory historic control data ranges indicating that the test conditions were adequate and that the metabolic activation system functioned properly. All bacterial strains showed negative responses over the entire dose range, i.e, no significant dose-related increase in the number of revertants in two independently repeated experiments. Based on the results of this study it is concluded that Lactol is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.
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