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EC number: 818-033-1 | CAS number: 1629579-82-3
- 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
- Type of information:
- experimental study
- Adequacy of study:
- weight of evidence
- Study period:
- 6/12/2017 to 15/2/2018
- Reliability:
- 1 (reliable without restriction)
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2018
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 21 July 1997
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- 3-{2-[2-(3-azaniumylpropoxy)ethoxy]ethoxy}propan-1-aminium di[(2Z)-3-carboxyprop-2-enoate]
- EC Number:
- 818-033-1
- Cas Number:
- 1629579-82-3
- Molecular formula:
- C18H32N2O11
- IUPAC Name:
- 3-{2-[2-(3-azaniumylpropoxy)ethoxy]ethoxy}propan-1-aminium di[(2Z)-3-carboxyprop-2-enoate]
- Test material form:
- liquid
- Details on test material:
- CAS Number: 1629579-82-3
EC Number: 818-033-1
Molecular formula: C18H32N2O11
Constituent 1
- Specific details on test material used for the study:
- Identification: Bis-Aminopropyl Diglycol Dimaleate
Appearance: Clear to transparent yellow liquid
Batch: 11_13_17_1
Purity/Composition: Not indicated
Test item storage: At room temperature
Stable under storage conditions until: 13 November 2019 (expiry date)
Additional information
Test Facility test item number: 207396/C
Purity/Composition correction factor: Contains 74% water
Test item handling: No specific handling conditions required
Stability at higher temperatures: Yes, maximum temperature: 40°C, maximum duration: 60 minutes
Chemical name (IUPAC, synonym or trade name: Bis-Aminopropyl Diglycol Dimaleate
CAS number: 11629579-82-3
Molecular formula: C18H32N2O11
Molecular weight: 452.46
Solubility in vehicle: Water: Highly
Stability in vehicle: Water: Stable
Method
Species / strain
- Species / strain / cell type:
- S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102
- Metabolic activation:
- with and without
- Metabolic activation system:
- Mammalian liver post-mitochondrial fraction (S-9).
- Test concentrations with justification for top dose:
- Selection of an adequate range of doses was based on a dose-range finding test with the strains TA100 and WP2uvrA, both with and without S9-mix. Eight concentrations, 0.44, 1.4, 4.4, 14, 43, 133, 416 and 1299 µg/plate were tested in triplicate.
The highest concentration of the test item used in the first and second mutation experiment was 5000 µg/plate. At least five different doses (increasing with approximately half-log steps) of the test item were tested in triplicate in each strain in the absence and presence of S9-mix. The first experiment was a direct plate assay and the second experiment was a pre-incubation assay.
The negative control (vehicle) and relevant positive controls were concurrently tested in each strain in the presence and absence of S9-mix.
Bis-Aminopropyl Diglycol Dimaleate was initially tested in the tester strains TA100 and WP2uvrA as a dose-range finding test with concentrations of 0.44, 1.4, 4.4, 14, 43, 133, 416 and 1299 µg/plate in the absence and presence of S9-mix.
Based on the results of the dose-range finding test, the following dose-range was selected for the first mutation assay with the tester strains, TA1535, TA1537 and TA98, in the absence and presence of S9-mix: 41, 129, 403, 1259, 3935 μg/plate.
Since in the dose-range finding test, no toxicity and no precipitate on the plates was observed at the highest dose level tested, the tester strains TA100 and WP2uvrA were again tested in the first mutation experiment. The test item was tested at the dose level of 3935 μg/plate in the tester strains TA100 and WP2uvrA in the absence and presence of S9-mix. - Vehicle / solvent:
- The vehicle of the test item was Milli-Q water (Millipore Corp., Bedford, MA., USA).
Controls
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- Positive controls:
- yes
- Positive control substance:
- 4-nitroquinoline-N-oxide
- 2-nitrofluorene
- sodium azide
- methylmethanesulfonate
- other: 2-aminoanthracene, ICR-191 (Sigma)
- Remarks:
- Solvents for Positive Control Items; Saline = physiological saline DMSO = dimethyl sulfoxide
- Details on test system and experimental conditions:
- Preparation of Test Item
A correction factor of 3.85 (according to the water content) was applied in this study.
A solubility test was performed based on visual assessment. The test item was dissolved in Milli-Q water.
Test item concentrations were used within 2.5 hours after preparation.
Any residual volumes were discarded.
Test System
Test System Salmonella typhimurium bacteria and Escherichia coli bacteria
Rationale Recommended test system in international guidelines (e.g. OECD, EC).
Source Trinova Biochem GmbH, Germany [Master culture from Dr. Bruce N. Ames (TA1535: 2016, TA1537: 2015, TA98: 2017, TA100: 2017; and Master culture from The National Collections of Industrial and Marine Bacteria, Aberdeen, UK (WP2uvrA: 2008)]
The characteristics of the different Salmonella typhimurium strains were as follows:
Strain Histidine mutation Mutation type
TA1537 hisC3076 Frameshift
TA98 hisD3052/R-factor* Frameshift
TA1535 hisG46 Base-pair substitutions
TA100 hisG46/R-factor* Base-pair substitutions
*: R-factor = plasmid pKM101 (increases error-prone DNA repair)
Each tester strain contained the following additional mutations:
rfa : deep rough (defective lipopolysaccharide cellcoat)
gal : mutation in the galactose metabolism
chl : mutation in nitrate reductase
bio : defective biotin synthesis
uvrB: loss of the excision repair system (deletion of the ultraviolet-repair B gene)
The Salmonella typhimurium strains were regularly checked to confirm their
histidine-requirement, crystal violet sensitivity, ampicillin resistance (TA98 and TA100),
UV-sensitivity and the number of spontaneous revertants.
The Escherichia coli WP2uvrA strain detects base-pair substitutions. The strain lacks an excision repair system and is sensitive to agents such as UV. The sensitivity of the strain to a wide variety of mutagens has been enhanced by permeabilization of the strain using
Tris-EDTA treatment (Ref.1). The strain was regularly checked to confirm the
tryptophan-requirement, UV-sensitivity and the number of spontaneous revertants.
Stock cultures of the five strains were stored in liquid nitrogen (-196°C).
Cell Culture
Preparation of bacterial cultures
Samples of frozen stock cultures of bacteria were transferred into enriched nutrient broth (Oxoid LTD, Hampshire, England) and incubated in a shaking incubator (37 ± 1°C,
150 rpm), until the cultures reached an optical density of 1.0 ± 0.1 at 700 nm (109 cells/mL). Freshly grown cultures of each strain were used for a test.
Agar plates
Agar plates (ø 9 cm) contained 25 mL glucose agar medium. Glucose agar medium contained per liter: 18 g purified agar (Oxoid LTD) in Vogel-Bonner Medium E, 20 g glucose (Fresenius Kabi, Bad Homburg, Germany). The agar plates for the test with the Salmonella typhimurium strains also contained 12.5 µg/plate biotin (Merck) and 15 µg/plate histidine (Sigma) and the agar plates for the test with the Escherichia coli strain contained 15 µg/plate tryptophan (Sigma).
Top agar
Milli-Q water containing 0.6% (w/v) bacteriological agar (Oxoid LTD) and 0.5% (w/v) sodium chloride (Merck) was heated to dissolve the agar. Samples of 3 mL top agar were transferred into 10 mL glass tubes with metal caps. Top agar tubes were autoclaved for
20 min at 121 ± 3°C.
Environmental conditions
All incubations were carried out in a controlled environment at a temperature of 37.0 ± 1.0°C (actual range 34.8 - 40.1°C). The temperature was continuously monitored throughout the experiment. Due to addition of plates (which were at room temperature) to the incubator or due to opening and closing the incubator door, temporary deviations from the temperature may occur. Based on laboratory historical data these deviations are considered not to affect the study integrity.
Metabolic Activation System
S9-Fraction
Rat liver microsomal enzymes (S9 homogenate) were obtained from Trinova Biochem GmbH, Giessen, Germany and were prepared from male Sprague Dawley rats that had been injected intraperitoneally with Aroclor 1254 (500 mg/kg body weight).
Each S9 batch was characterized with the mutagens benzo-(a)-pyrene (Sigma) and
2-aminoanthracene, which require metabolic activation, in tester strain TA100 at concentrations of 5 µg/plate and 2.5 µg/plate, respectively.
Preparation of S9-Mix
S9-mix was prepared immediately before use and kept on ice. S9-mix contained per 10 mL: 30 mg NADP (Randox Laboratories Ltd., Crumlin, United Kingdom) and 15.2 mg
glucose-6-phosphate (Roche Diagnostics, Mannheim, Germany) in 5.5 mL Milli-Q water (Millipore Corp., Bedford, MA., USA); 2 mL 0.5 M sodium phosphate buffer pH 7.4; 1 mL 0.08 M MgCl2 solution (Merck); 1 mL 0.33 M KCl solution (Merck). The above solution was filter (0.22 µm)-sterilized. To 9.5 mL of S9-mix components 0.5 mL S9-fraction was added (5% (v/v) S9-fraction) to complete the S9-mix.
Positive Controls
Without Metabolic Activation
Strain Chemical Solvent Concentration/plate Concentration/plate
Direct plate assay Pre-incubation assay
TA1535 sodium azide (SA) Saline 5 µg 5 µg
TA1537 ICR-191 DMSO 2.5 µg
TA1537 2-nitrofluorene (NF) DMSO 15 µg
TA98 2-nitrofluorene (NF) DMSO 10 µg 10 µg
TA100 methylmethanesulfonate (MMS) DMSO 650 µg 650 µg
WP2uvrA 4-nitroquinoline N-oxide DMSO 10 µg 10 µg
With Metabolic Activation
Strain Chemical Solvent Concentration/plate Concentration/plate
Direct plate assay Pre-incubation assay
TA1535 2-aminoanthracene (2AA) DMSO 2.5 µg 2.5 µg
TA1537 2-aminoanthracene (2AA) DMSO 2.5 µg 2.5 µg
TA98 2-aminoanthracene (2AA) DMSO 1 µg 1 µg
TA100 2-aminoanthracene (2AA) DMSO 1 µg 5 µg
WP2uvrA 2-aminoanthracene (2AA) DMSO 15 µg 15 µg
Solvents for Positive Control Items
Saline = physiological saline (Eurovet Animal Health, Bladel, The Netherlands)
DMSO = dimethyl sulfoxide (Merck, Darmstadt, Germany) - Evaluation criteria:
- ACCEPTABILITY CRITERIA
A Salmonella typhimurium reverse mutation assay and/or Escherichia coli reverse mutation assay is considered acceptable if it meets the following criteria:
a) The vehicle control and positive control plates from each tester strain (with or without
S9-mix) must exhibit a characteristic number of revertant colonies when compared against relevant historical control data generated at Charles River Den Bosch.
b) The selected dose-range should include a clearly toxic concentration or should exhibit limited solubility as demonstrated by the preliminary toxicity range-finding test or should extend to 5 mg/plate.
c) No more than 5% of the plates are lost through contamination or some other unforeseen event. If the results are considered invalid due to contamination, the experiment will be repeated.
All results presented in the tables of the report are calculated using values as per the raw data rounding procedure and may not be exactly reproduced from the individual data presented.
Results and discussion
Test resultsopen allclose all
- Key result
- Species / strain:
- S. typhimurium TA 1535
- 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
- Untreated negative 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
- Untreated negative 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:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative 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:
- no cytotoxicity nor precipitates, but tested up to recommended limit concentrations
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
- Key result
- 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
- Untreated negative controls validity:
- valid
- Positive controls validity:
- valid
Any other information on results incl. tables
First Experiment: Direct Plate Assay
Bis-Aminopropyl Diglycol Dimaleate was initially tested in the tester strains TA100 and WP2uvrAas a dose-range finding test with concentrations of 0.44, 1.4, 4.4, 14, 43, 133, 416 and 1299 µg/plate in the absence and presence of S9-mix.
Based on the results of the dose-range finding test, the following dose-range was selected for the first mutation assay with the tester strains, TA1535, TA1537 and TA98, in the absence and presence of S9-mix: 41, 129, 403, 1259, 3935 μg/plate.
Since in the dose-range finding test, no toxicity and no precipitate on the plates was observed at the highest dose level tested, the tester strains TA100 and WP2uvrAwere again tested in the first mutation experiment. The test item was tested at the dose level of 3935 μg/plate in the tester strains TA100 and WP2uvrAin the absence and presence of S9-mix.
The results are shown inTable 1andTable2. The individual data are presented inAppendix 3.
Precipitate
Precipitation of the test item on the plates was not observed at the start or at the end of the incubation period in any tester strain.
Toxicity
To determine the toxicity of the test item, the reduction of the bacterial background lawn, the increase in the size of the microcolonies and the reduction of the revertant colonies were observed. The definitions are stated inAppendix 2.
No reduction of the bacterial background lawn and no biologically relevant decrease in the number of revertants were observed.
Mutagenicity
In the direct plate test, no increase in the number of revertants was observed upon treatment with the test item under all conditions tested.
First Experiment (additional): Direct Plate Assay
Since in the first mutation assay,
no toxicity and no precipitate on the plates was observed at the highest
dose level tested in all five tester strains, an additional mutation
experiment was performed. In the additional experiment the test item was
tested at the dose level of
5000 µg/plate in the absence and presence of S9-mix in the tester
strains TA1535, TA1537, TA98, TA100 and WP2uvrA.
The results are shown inTable 1andTable2. The individual data are presented inAppendix 3.
Precipitate
Precipitation of the test item on the plates was not observed at the start or at the end of the incubation period in any tester strain.
Toxicity
No reduction of the bacterial background lawn and no biologically relevant decrease in the number of revertants were observed.
Mutagenicity
In the direct plate test, no increase in the number of revertants was observed upon treatment with the test item under all conditions tested.
Second Experiment: Pre-Incubation Assay
To obtain more information about the possible mutagenicity of the test item, a pre-incubation experiment was performed in the absence and presence of S9-mix. Based on the results of the first mutation assay, the test item was tested up to the dose level of 5000 µg/plate in the tester strains TA1535, TA1537, TA98, TA100 and WP2uvrA.
The results are shown inTable3, the individual data are presented inAppendix 3.
Precipitate
Precipitation of the test item on the plates was not observed at the start or at the end of the incubation period.
Toxicity
There was no reduction in the bacterial background lawn and no biologically relevant decrease in the number of revertants at any of the concentrations tested in all tester strains in the absence and presence of S9-mix.
Mutagenicity
In the pre-incubation test, no
increase in the number of revertants was observed upon treatment with
the test item under all conditions tested.
Discussion
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.
The negative control values were
within the laboratory historical control data ranges, except the
response for TA98 in the absence of S9-mix in the additional first
experiment. However since the mean number of revertant colonies showed a
characteristic number of revertant colonies (7 revertant colonies) when
compared against relevant historical control data
(8 revertant colonies), the validity of the test was considered to be
not affected.
The 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.
Applicant's summary and conclusion
- Conclusions:
- In conclusion, based on the results of this study it is concluded that Bis-Aminopropyl Diglycol Dimaleate is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.
- Executive summary:
The objective of this study was to determine the potential of Bis-Aminopropyl Diglycol Dimaleate and/or its metabolites to induce reverse mutations at the histidine locus in several strains of Salmonella typhimurium (S. typhimurium; TA98, TA100, TA1535, and TA1537), and at the tryptophan locus of Escherichia coli(E. coli) strain WP2uvrAin the presence or absence of an exogenous mammalian metabolic activation system (S9).
The test was performed in two independent experiments, at first a direct plate assay was performed and secondly a pre-incubation assay. An additional direct plate assay was performed to complete the data of the first experiment.
The study procedures described in this report were based on the most recent OECD and EC guidelines.
Batch 11_13_17_1 of Bis-Aminopropyl Diglycol Dimaleate was a clear to transparent yellow liquid. A correction factor of 3.85 was used to correct for the water content (74%). The test item was dissolved in water.
In the dose-range finding study, the test item was initially tested up to concentrations of 1299 µg/plate in the strains TA100 and WP2uvrAin the direct plate assay. The test item did not precipitate on the plates at this dose level. The bacterial background lawn was not reduced at any of the concentrations tested and no biologically relevant decrease in the number of revertants was observed. Results of this dose-range finding test were reported as part of the first mutation assay.
In the first mutation experiment, the test item was tested up to concentrations of 3935 µg/plate in the strains TA1535, TA1537, TA98, TA100 and WP2uvrA. The test item did not precipitate on the plates at this dose level. The bacterial background lawn was not reduced at any of the concentrations tested and no biologically relevant decrease in the number of revertants was observed.
Since in the first mutation assay, no toxicity and no precipitate on the plates was observed at the highest dose level tested in any of the five tester strains, an additional direct plate assay was performed. In the additional experiment the test item was tested at the dose level 5000 µg/plate in the absence and presence of S9-mix in the tester strains TA1535, TA1537, TA98, TA100 and WP2uvrA. The test item did not precipitate on the plates at this dose level. The bacterial background lawn was not reduced at any of the concentrations tested and no biologically relevant decrease in the number of revertants was observed.
In the second mutation experiment, the test item was tested up to concentrations of 5000 µg/plate in the tester strains TA1535, TA1537, TA98, TA100 and WP2uvrAin the pre-incubation assay. The test item did not precipitate on the plates at this dose level. The bacterial background lawn was not reduced at any of the concentrations tested and no biologically relevant decrease in the number of revertants was observed.
In this study, acceptable responses were obtained for the negative and strain-specific positive control items indicating that the test conditions were adequate and that the metabolic activation system functioned properly.
The test item did not induce a significant dose-related increase in the number of revertant (His+) colonies in each of the four tester strains (TA1535, TA1537, TA98 and TA100) and in the number of revertant (Trp+) colonies in tester strain WP2uvrAboth in the absence and presence of S9-metabolic activation. These results were confirmed in a follow-up experiment.
In conclusion, based on the results of this study it is concluded that Bis-Aminopropyl Diglycol Dimaleate is not mutagenic in the Salmonella typhimurium reverse mutation assay and in the Escherichia coli reverse mutation assay.
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