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EC number: 214-230-6 | CAS number: 1115-70-4
- 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:
- 1989-01-19 to 1990-01-19
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- bacterial reverse mutation assay
Test material
- Reference substance name:
- Metformin hydrochloride
- EC Number:
- 214-230-6
- EC Name:
- Metformin hydrochloride
- Cas Number:
- 1115-70-4
- Molecular formula:
- C4H11N5.ClH
- IUPAC Name:
- N,N-dimethylimidodicarbonimidic diamide hydrochloride
- Test material form:
- solid: bulk
Constituent 1
Method
- Target gene:
- HIS Operon
Species / strainopen allclose all
- Species / strain / cell type:
- S. typhimurium TA 1535
- Details on mammalian cell type (if applicable):
- his G46 rfa uvrB
- Species / strain / cell type:
- S. typhimurium TA 1537
- Details on mammalian cell type (if applicable):
- his C3076 rfa uvrB
- Species / strain / cell type:
- S. typhimurium TA 1538
- Details on mammalian cell type (if applicable):
- his D3052 rfa uvrB
- Species / strain / cell type:
- S. typhimurium TA 98
- Details on mammalian cell type (if applicable):
- his D3052 rfa uvrB pKM 101
- Species / strain / cell type:
- S. typhimurium TA 100
- Details on mammalian cell type (if applicable):
- his G46 rfa uvrB pKM 101
- Metabolic activation:
- with and without
- Metabolic activation system:
- Type and composition of metabolic activation system:
- source of S9 : isolated from livers of Aroclor 1254 pretreated rats
- method of preparation of S9 mix:
All steps were at 0 - 4°C usinq sterile solutions and glassware. The livers were placed in beakers containinq 0.15 M potassium chloride. After weighinq, the livers were transferred to a beaker containing 0.15 M KCl (3 ml KCl per 1g liver), minced with a sterile scalpel and homogenised in an Ultra Turrax homoqeniser. This homogenate was centrifuqed for 10 minutes at 9000g and the supernatant divided into aliquots were stored at -80°C.
- quality controls of S9: tested with the carcinoqen 7,12-dimetbylbenzanthracene before use - Test concentrations with justification for top dose:
- Dose Range Finder: 5, 50, 500, 5000 µg/plate
Main Test: 50, 150, 500, 1500, 5000 µg/plate - Vehicle / solvent:
- water
Controls
- Untreated negative controls:
- no
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 9-aminoacridine
- 2-nitrofluorene
- N-ethyl-N-nitro-N-nitrosoguanidine
- other: 2-Aminoanthracene
- Details on test system and experimental conditions:
- METHOD OF APPLICATION: in medium; in agar (plate incorporation); preincubation; in suspension; as impregnation on paper disk
DURATION
- Exposure duration: 3 days
SELECTION AGENT (mutation assays): HIS
NUMBER OF REPLICATIONS: 3
NUMBER OF INDEPENDENT EXPERIMENTS: 2 - Evaluation criteria:
- Number of revertant colonies was compared to those of the solvent controls.
The substance is considered mutagenic if:
a) an increase in revertant colony number of at least twice the concurrent solvent control is obtained and
b) there exists evicendence of a positive dose response relationsship and
c) reproducibility of the results is obtained - Statistics:
- no
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:
- not examined
- True negative controls validity:
- not examined
- 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:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1538
- 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:
- not examined
- True negative controls validity:
- not examined
- 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:
- not examined
- True negative controls validity:
- not examined
- 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:
- not examined
- True negative controls validity:
- not examined
- Positive controls validity:
- valid
Any other information on results incl. tables
Summary 1st Series
Metabolic Activation |
Test compound |
Concentration / [µg/plate] |
Revertants per plate (Mean ± SD) |
||||
|
|
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
TA 1538 |
|
Without activation |
Water |
|
20 ± 2.6 |
123 ± 3.5 |
7 ± 1.0 |
9 ± 5.6 |
5 ± 1.4 |
|
Test material |
50.0 |
20 ± 6.0 |
115 ± 2.6 |
10 ± 0.0 |
9 ± 2.9 |
6 ± 1.5 |
|
|
150 |
16 ± 1.0 |
113 ± 8.5 |
7 ± 1.5 |
8 ± 1.0 |
5 ± 1.0 |
|
|
500 |
20 ± 4.0 |
113 ± 23.4 |
8 ± 3.1 |
9 ± 0.6 |
9 ± 1.5 |
|
|
1500 |
19 ± 3.5 |
126 ± 8.4 |
7 ± 3.2 |
5 ± 3.1 |
2 ± 0.0 |
|
|
5000 |
19 ± 6.1 |
121 ± 8.5 |
6 ± 1.7 |
5 ± 2.6 |
7 ± 4.7 |
|
ENNG |
5.00 |
|
340 ± 34.7 |
341 ± 129.0 |
|
|
ENNG |
3.00 |
||||||
|
9 AC |
2.00 |
|
|
|
633 ± 111.9 |
|
|
NF |
20.0 |
365 ± 1.0 |
|
|
|
31 ± 6.1 |
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
TA 1538 |
|||
With |
Water |
|
19 ± 6.4 |
113 ± 18.6 |
9 ± 2.3 |
10 ± 3.6 |
10 ± 3.6 |
|
Test material |
50.0 |
17 ± 4.4 |
120 ± 9.3 | 6 ± 4.0 |
8 ± 3.6 |
7 ± 4.6 |
|
|
150 |
16 ± 5.5 |
117 ± 14.2 | 8 ± 1.7 |
8 ± 5.0 |
13 ± 3.8 |
|
|
500 |
20 ± 6.0 |
134 ± 10.0 | 10 ± 4.0 |
6 ± 2.1 |
10 ± 4.0 |
|
|
1500 |
18 ± 2.6 |
134 ± 8.9 | 7 ± 3.1 |
5 ± 0.0 |
9 ± 5.5 |
|
|
5000 |
13 ± 3.1 |
117 ± 27.5 | 8 ± 1.2 |
6 ± 1.5 |
12 ± 4.0 |
|
2-AA |
0.50 |
266 ± 10.7 |
302 ± 32.7 | |||
|
2-AA |
1.00 |
909 ± 52.6 |
||||
|
2-AA |
2.00 |
174 ± 30.6 | 170 ± 9.2 |
Summary 2nd Series
Metabolic Activation |
Test compound |
Concentration / [µg/plate] |
Revertants per plate (Mean ± SD) |
||||
|
|
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
TA 1538 |
|
Without activation |
Water |
|
18 ± 4.0 |
90 ± 14.8 |
10 ± 2.0 |
11 ± 2.5 |
5 ± 1.4 |
|
Test material |
50.0 |
20 ± 0.0 |
104 ± 10.0 |
10 ± 6.7 |
10 ± 2.6 |
6 ± 1.5 |
|
|
150 |
18 ± 4.7 |
108 ± 16.1 |
8 ± 2.1 |
11 ± 1.5 |
5 ± 1.0 |
|
|
500 |
19 ± 6.7 |
107 ± 9.9 |
9 ± 4.7 |
12 ± 4.2 |
9 ± 1.5 |
|
|
1500 |
19 ± 1.0 |
103 ± 2.1 |
10 ± 3.1 |
10 ± 2.6 |
2 ± 0.0 |
|
|
5000 |
19 ± 3.1 |
99 ± 19.1 |
8 ± 3.2 |
10 ± 2.5 |
7 ± 4.7 |
|
ENNG |
5.00 |
|
340 ± 34.7 |
341 ± 129.0 |
|
|
ENNG |
3.00 |
||||||
|
9 AC |
2.00 |
|
|
|
633 ± 111.9 |
|
|
NF |
20.0 |
365 ± 1.0 |
|
|
|
31 ± 6.1 |
TA 98 |
TA 100 |
TA 1535 |
TA 1537 |
TA 1538 |
|||
With |
Water |
|
19 ± 6.4 |
113 ± 18.6 |
9 ± 0.6 |
12 ± 1.5 |
15 ± 4.0 |
|
Test material |
50.0 |
17 ± 4.4 |
120 ± 9.3 | 9 ± 1.5 |
12 ± 3.0 |
9 ± 3.5 |
|
|
150 |
16 ± 5.5 |
117 ± 14.2 | 12 ± 2.0 |
9 ± 1.5 |
14 ± 2.3 |
|
|
500 |
20 ± 6.0 |
134 ± 10.0 | 9 ± 1.5 |
11 ± 1.0 |
11 ± 2.9 |
|
|
1500 |
18 ± 2.6 |
134 ± 8.9 | 8 ± 2.6 |
11 ± 6.4 |
10 ± 4.5 |
|
|
5000 |
13 ± 3.1 |
117 ± 27.5 | 10 ± 1.2 |
8 ± 1.7 |
9 ± 3.6 |
|
2-AA |
0.50 |
217 ± 16.2 |
159 ± 17.4 |
|||
|
2-AA |
1.00 |
602 ± 31.1 |
||||
|
2-AA |
2.00 |
144 ± 7.2 | 141 ± 7.1 |
Key to Positive controls |
ENNG N-ethyl-N'-nitro-N-nitrosoguanidine 2-AA 2-aminoanthracene 9 AC 9-aminoacridine NF 2-nitrofluorene |
Applicant's summary and conclusion
- Conclusions:
- It is concluded that, when tested at dose levels up to 5000 µg/plate in water, Metformin Hydrochloride was not mutagenic in this bacterial test system.
- Executive summary:
Study Design
In this in vitro assessment of the mutagenic potential of Metformin Hydrochloride, histidine dependent auxotrophic mutants of Salmonella typhimurium (strains TA 1535, TA 1537, TA 1538, TA 98 and TA 100) were exposed to the test material, diluted in water which was also used as a negative control.
Two independent mutation tests were performed, in the presence and absence of liver preparations from Aroclor 1254-induced rats.
Results
In the preliminary dose range finding study with dose levels of up to 5000 µg/plate no toxicity was observed. A top dose level of 5000 µg/plate was chosen for the subsequent mutation study. Other dose levels used in the mutation assays were: 1500, 500, 150, 50 µg/plate.
The concurrent positive control compounds demonstrated the sensitivity of the assay and the metabolising activity of the liver preparations.
No evidence of mutagenic activity was seen at any dose level of Metformin Hydrochloride in either mutation test.
Conclusion
It is concluded that, when tested at dose levels up to 5000 µg/plate in water, Metformin Hydrochloride was not mutagenic in this bacterial test system.
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