Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
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
Toxicity to reproduction
Administrative data
- Endpoint:
- one-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1984-04-16 to 1984-11-20
- 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 guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
- Version / remarks:
- 26 May 1983
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: FDA Segment I study
- Qualifier:
- according to guideline
- Guideline:
- other: ICH S5 Detection of Toxicity to Reproduction for Medicinal Products
- Version / remarks:
- March 1994
- Deviations:
- no
- Principles of method if other than guideline:
- The design of the the study follows the Guidelines for Reproductive Toxicity Testing of Medicinal Products. The parameters investigated reflects the requirements of OECD 421 and OECD 415.
- Principle of test: Fertility Study in Rats
- Short description of test conditions: The potential effect of Metformin on fertility and reproductive performance was evaluated in Sprague-Dawley rats. Twelve males and 24 females were given daily oral doses of 120, 300 or 600 mg/kg body weight of the drug, beginning nine and two weeks, respectively before mating. Daily dose administration continued to study termination at weaning. A control group, also consisting of 12 males and 24 females, was given distilled-deionized water under the requisite experimental conditions.
- Parameters analysed / observed:The animals were observed daily, and body weight recorded weekly prior to and during cohabitation.
The dams were observed daily for physical and behavioral abnormalities during gestation, parturition and lactation. Individual body weights were recorded on gestation days 0, 6, 14 and 19. Approximately one-half of the pregnant females were euthanized on gestation day 14 and subjected to gross necropsy. The number of implantations, viable fetuses, resorptions and corpora lutea were recorded. Remaining females were allowed to deliver. Dam body weights were recorded on lactation days 0, 7, 14 and 21. All litters were observed daily to determine the viability, general appearance and physical development of the offspring.
Offspring body weights were determined on lactation days 0, 7, 14 and 21. The sex ratio of each litter was determined on days 0, 4, 14, and 21 of lactation. The dams and their offspring were subjected to
gross necropsy on day 21 postpartum or, for dams not delivering litters, at least 23 days after the final day of cohabitation.
All lesions or physical anomalies were recorded. The genitourinary tract of the dams was carefully examined for identification and quantification of implantation scars. The sex of each pup was confirmed by gonadal inspection. Males were euthanized at conclusion of the cohabitation period and examined grossly. The testes of all males were weighed and examined microscopically. - 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
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Breeding Labs
- Age at study initiation: 5 weeks (m) and 12 weeks (f) @ start of dosing
- Weight at study initiation: (P) Males: 165 +/- 9 g; Females: 141 +/- 6 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 (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): 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. - Details on mating procedure:
- - M/F ratio per cage: 1 / 2
- Length of cohabitation: 10 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- After 10 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: no - Analytical verification of doses or concentrations:
- yes
- 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 48.7
C 120 122.8
D 240 241.2
----------------------------------------------------------------
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. - Duration of treatment / exposure:
- Twelve males and 24 females were given daily oral doses of 120, 300 or 600 mg/kg body weigth, beginning nine and two weeks, respectively before mating until lactation day 21 for the females.
- Frequency of treatment:
- daily
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:
- 12 (m), 24 (f)
- Control animals:
- yes, concurrent vehicle
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights of males were recorded weekly. Individual body weights of females were recorded weekly prior
to insemination, on gestation days 0, 6, 14 and 19 and on lactation days 0 (as soon as possible after delivery), 7, 14 and 21. - Oestrous cyclicity (parental animals):
- not examined
- Sperm parameters (parental animals):
- not examined
- Litter observations:
- viability: daily
general appearance : daily
physical development: daily
Offspring body weights were determined on lactation days 0, 7, 14 and 21.
The sex ratio of each litter was determined on days 0, 4, 14 and 21 of lactation. - Postmortem examinations (parental animals):
- The dams and their offspring were subjected to gross necropsy on day 21 postpartum or, for dams not delivering litters, at least 23 days after the final day of cohabitation.
All lesions or physical anomalies were recorded.
The genito urinary tract of the dams was carefully examined for identification and quantification of implantation scars.
The sex of each pup was confirmed by gonadal inspection.
Males were euthanized at conclusion of the cohabitation period and examined grossly.
The testes of all males were weighed and examined microscopically.
The following data was recorded for females sacrifice at midgestation:
- number of corpora lutea
- number and distribution of viable fetuses
- number and distribution of resorptions
- number and distribution of all implantations - Postmortem examinations (offspring):
- offspring were subjected to gross necropsy on day 21 postpartum
- Statistics:
- Standard statistical methods have been applied for data processing.
- Reproductive indices:
- Fertility index, Litter Size, Litter Sex Ratio
- Offspring viability indices:
- Lacation index, Viability Index
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No findings attributable to Metformin treatment were noted.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- No findings attributable to Metformin treatment were noted.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No significant differences in absolute body weight or body weight gain were noted among groups for either sex.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- No deviation from normal morphology was observed during histopathological evaluation of the testes.
- Histopathological findings: neoplastic:
- no effects observed
- Description (incidence and severity):
- No neoplastic ledions have been observed
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- Cortical red spots, probably related to routine postmortem congestion; were noted in the kidneys of one to three males per group. The presence of a skin sore, which was noted during daily observations, was confirmed for a single mid-dose male. Slight,. unilateral enlargement of the testes was observed in one high-dose male. Microscopically, the enlarged gonad appeared normal and therefore, no biological importance is given to the gross observation.
Incidental findings, which occurred in one to two females per group (when present) included discoloration of the kidneys or lungs, hydropelvis, skin sore, firm subcutaneous tissue mass, "fluid-filled" gravid uterus and peritoneal (splenic) adhesions.
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences in the number of corpora lutea per pregnant female were noted among groups.
No statistically significant differences in the total number of implantation scars per dam occurred among groups.
No statistically significant differences in the number of resorptions per dam were noted among groups
No statistically significant differences in the number of viable, non viable or total fetuses present per dam were noted between the control and any test groups.
Uterine distribution of fetuses was comparable for all groups.
No statistically significant differences in the gestation index were demonstrated between the control and any test group.
The average length of gestation was comparable for all groups.
No statistically significant differences in the total number of offspring, number of offspring cast live or number of stillbirths per litter were noted between the control and Metformin-treated groups. Likewise, the percent of total pups per litter cast live or dead were similar for all groups.
Effect levels (P0)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 600 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (P0)
- Key result
- Critical effects observed:
- no
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No evidence for any Metformin-related effect upon general appearance or behavior of offspring was observed at any dose level studied.
- Mortality / viability:
- no mortality observed
- Description (incidence and severity):
- No mortality was observed during this study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences in mean litter pup weight were noted between the control and Metformin treated groups.
- Food consumption and compound intake (if feeding study):
- not examined
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Urinalysis findings:
- not examined
- Sexual maturation:
- not examined
- Anogenital distance (AGD):
- not examined
- Nipple retention in male pups:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No gross lesions related to Metformin treatment were noted for offsprings at any dose level studied.
- Histopathological findings:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- No statistically significant differences in litter sex ratio were noted among groups on lactation days 4, 14 and 21. The mean average litter viability and lactation indices
ranged from 98.1-99.4 and 97.4-100.0, respectively for all groups.
Effect levels (F1)
- Key result
- Dose descriptor:
- NOEL
- Generation:
- F1
- Effect level:
- 600 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- not determinable due to absence of adverse toxic effects
Target system / organ toxicity (F1)
- Key result
- Critical effects observed:
- no
Overall reproductive toxicity
- Key result
- Reproductive effects observed:
- no
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this study, Metformin did not have any untoward effects upon fertility or reproductive performance at dosage levels of 120, 300 or 600 mg/kg body weight.
- Executive summary:
The potential effect of Metformin on fertility and reproductive performance was evaluated in Sprague-Dawley rats. Twelve males and 24 females were given daily oral doses of 120, 300 or 600 mg/kg body weight of the drug, beginning nine and two weeks, respectively before mating. Daily dose administration continued to study termination. A control group, also consisting of 12 males and 24 females, was given distilled-deionized water under the requisite experimental conditions.
The animals were observed daily, and body weight recorded weekly prior to and during cohabitation.
The dams were observed daily for physical and behavioral abnormalities during gestation, parturition and lactation. Individual body weights were recorded on gestation days 0, 6, 14 and 19. Approximately one-half of the pregnant females were euthanized on gestation day 14 and subjected to
gross necropsy. The number of implantations, viable fetuses, resorptions and corpora luteawererecorded. Remaining females were allowed to deliver. Dam body weights were recorded on lactation days 0, 7, 14 and 21. All litters were observed dailytodetermine the viability, general appearance and
physical development of the offspring.
Offspring body weights were determined on lactation days 0, 7, 14 and 21. The sex ratio of each litter was determined on days 0, 4, 14, and 21of lactation. The dams and their offspring were subjected to
gross necropsy on day 21 postpartum or, for dams not deliveringlitters, at least 23 days after the final day of cohabitation.
All lesions or physical anomalies were recorded. The genitourinary tract of the dams was carefully examined for identification and quantification of implantation scars. The sex of each pup was confirmed by gonadal inspection. Males were euthanized at conclusion of the cohabitation period and examined grossly.
The testes of all males were weighed and examined microscopically.
Daily, oral Metformin treatment at dosage levels of 120, 300 and 600 mg/kg body weight beginning nine and two weeks prior to mating for males and females, respectively did not have any adverse effect upon mating, fertility or reproductive performance in Sprague-Dawley rats. Continued Metformin treatment of the dams for 21 days postpartum had no untoward effect upon littersize,growth, development or viability at any dose level studied.
Furthermore, no treatment-related gross anomalies were noted in males, females or offspring at the designated dosage levels.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.