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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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1984-04-24 to 1984-11-16
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 984
- Report date:
- 1984
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Deviations:
- no
- Principles of method if other than guideline:
- The daily oral treatment of pregnant rats was from day 6 through day 15 of gestation covering the period of organogenesis (as described in OECD 414, 2001 and earlier).
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
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
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Labs
- Age at study initiation: 20 weeks at start of mating
- Weight at study initiation: Females: 271 +/- 17 g
- Fasting period before study: no
- Housing: stainless steel wire mesh bottom cages; polypropylene cages with hardwood chips as bedding for females after mating
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- according to "Guide for the Care and Use of Laboratory Animals"
- Air changes (per hr): 15-18
- Photoperiod (hrs dark / hrs light): 12 / 12 hours
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
- Concentration in vehicle: adjusted
- Amount of vehicle: 2.5 mL/kg bw
- Purity: distilled
- Gavage solutions were prepared fresh weekly and dispensed as needed for daily dosing. The test article and gavage solutions were stored at room temperature in light-protective containers. - Analytical verification of doses or concentrations:
- yes
- Remarks:
- UV Spectrophotometry
- Details on analytical verification of doses or concentrations:
- The stability of Metformin in gavage solutions was verified prior to study initiation. Solutions containing 48, 120 and 240 mg/ml Metformin were prepared and the test article concentration of each determined on the day of preparation and 7 and 14 days thereafter. In addition, the Metformin content in gavage solutions were verified prior to use.
UV Spectophotometry
Perkin Elmer Lambda 5 UV VIS spectrophotometer
Calibration with linear standard curve (R=0.99994)
Results (Mean concentrations of 3 measurements):
----------------------------------------------------------------
Dose Group Target Concentration Analytical Concentration
(mg/mL) (mg/mL)
----------------------------------------------------------------
A 0 -
B 48 47.2
C 120 120.0
D 240 238.0
----------------------------------------------------------------
Conclusion: Metformin concentration in gavage solutions was stable up to 14 days when stored at room temperature in light protective containers. Metformin concentrations were within 4% of the target level for all gavage solutions. - Details on mating procedure:
- Mating procedures were initiated after conclusion of the acclimation phase. The animals were approximately 105 days of age at this time.
Two females were randomly assigned to and cohabited with each male. Vaginal smears were obtained daily and insemination confirmed by the presence of sperm therein. The day on which insemination was confirmed was designated as day 0 of gestation. One hundred twenty five inseminated females were randomly assigned to five experimental groups (25 dams/group).
Each dam was assigned an identification number and treated as follows:
-----------------------------------------------------
Group Treatment Dose (mg/kg)
-----------------------------------------------------
A Vehicle -
B Acetylsalicylic acid 250
C Test Material 120
D Test Material 300
E Test Material 600
-----------------------------------------------------
No male was allowed to impregnate more than one female per group. - Duration of treatment / exposure:
- days 6 - 15 of gestation
- Frequency of treatment:
- daily
- Duration of test:
- 11 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 120 mg/kg bw/day
- Dose / conc.:
- 300 mg/kg bw/day
- Dose / conc.:
- 600 mg/kg bw/day
- No. of animals per sex per dose:
- 25 dams per group,
5 groups: 1 control, 3 treatment groups, 1 positive control - Control animals:
- yes, concurrent vehicle
- other: positive control: Acetylsalicylic acid (dose: 250 mg/kg bw/day)
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality; once daily for detailed observation
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily
BODY WEIGHT: Yes
- Time schedule for examinations: on days 0, 6, 11, 15 and 20 of gestation
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day #20
- Organs examined:
Special attention was given to examination of the urogenital system. The uterus and ovaries were excised, the uterus weighed and its contents examined. The following data were recorded for each dam:
Number of corpora lutea
Number and position of resorption and implantation sites
Number and position of live and dead fetuses
Sex, body weight and crown to rump length of each live fetus - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Fetal examinations:
- Each fetus was visually examined for external anomalies. One third of the fetuses from each litter were randomly selected for and fixed in Bouin's solution and examined-for visceral anomalies using the Wilson free hand slicing technique (Wilson, 1965). All fetuses having external anomalies were also processed and examined in this manner.
The remaining fetuses were eviscerated, fixed in 70% isopropyl alcohol, macerated in a 2% aqueous potassium hydroxide solution, stained with Alizarin Red S (Dawson, 1926), cleared in glycerine and examined under low magnification for skeletal abnormalities and variations. These fetuses have been preserved in 100% glycerin. - Statistics:
- Continuous data were analyzed using analysis of variance {Snedecor and Cochran, 1967).
Differences between the vehicle control and test groups were determined using the Least Significant Differences Test.
Discrete data were evaluated using Fisher's Exact Test (Siegel, 1956).
Nonparametric litter data were analyzed using the Kruskal-Wallis Test.
Differences between the vehicle control and test groups were identified using the Mann-Whitney U Test (Siegel, 1956).
Significance was judged at the level p < 0.05 for all tests.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No finding occurred in any test group at an incidence significantly different from that of the vehicle control group.
- Dermal irritation (if dermal study):
- not examined
- Description (incidence and severity):
- not relevant
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality occurred in any test group and consequently, all dams were sacrificed on gestation day 20.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- Absolute body weight and body weight gain of dams exposed to 120, 300 and 600 mg/kg bw/day were comparable to control values at all times.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No finding occurred in any test group at an incidence significantly different (p >/= 0.05) from that of the vehicle control group.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- no effects observed
- Other effects:
- no effects observed
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- No significant differences were evident between the vehicle control and any test item-treated group for any of the following variables:
Number of corpora lutea, total implantation sites, total resorption sites, percent resorption sites (as compared to implantation sites), or incidence of dams having two or more resorption sites. - Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- No significant differences in the total number of fetuses, number of live fetuses, number of dead fetuses or number of stunted fetuses (runts) per litter were evident between the vehicle control and any Metformin HCl-treated group.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Details on maternal toxic effects:
- Maternal toxic effects: no effects
Details on maternal toxic effects: No findings occured in any test group.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 600 mg/kg bw/day
- Based on:
- test mat.
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- No significant differences in male to fetal weight or fetal crown to rump length were evident between vehicle control and any Metformin-treated group.
- Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- No significant differences in male to female ratio were evident between vehicle control and any Metformin-treated group.
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Skeletal malformations:
- no effects observed
- Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Effect levels (fetuses)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 600 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- The test material exposure produced no evidence of any teratogenic effect. No signs of maternal toxicity, treatment related embryo lethality or fetotoxicity were evident at any dosage level studied. The NOEL of the study was 600 mg/kg bw/day for developmental and maternal toxicity.
- Executive summary:
The potential teratogenicity of Metformin hydrochloride was evaluated in Sprague-Dawley rats. Dosages of 0, 120, 300 and 600 mg/kg body weight Metformin were administered daily by oral gavage to groups of 25 inseminated females on days 6 through 15 of gestation.
Acetylsalicylic acid (positive control) was administered in the same manner to a separate group of 25 inseminated females at a level of 250 mg/kg body weight.
All dams were sacrificed and subjected to uterine section on day 20 of gestation. Fetuses were excised and subjected to external and visceral or skeletal examination.
Acetylsalicylic acid exposure induced various teratogenic effects indicating that the test system could detect potential teratogenic agents.
Metformin exposure produced no evidence of any teratogenic effect. No signs of maternal toxicity, treatment-related embryo lethality or fetotoxicity were evident at any dosage level studied. External, visceral and skeletal examination of fetuses from Metformin-treated dams revealed no findings beyond those seen in vehicle control treated fetuses. The NOEL of the study was 600 mg/kg bw/day for developmental and maternal toxicity.
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