Metformin hydrochloride

Endpoint summary

Description of key information

The acute toxicity of Metformin hydrochlorid was studied in various species via the oral route of administration. The LD50 values varied between 375 mg/kg bw in dogs and 2400 mg/kg bw in mice. For rats an LD50 (m/f) of 1770 mg/kg bw is reported.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1984-04-03 to 1984-06-08

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Specific details on test material used for the study:

Metformin Hydrochloride

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: young
- Weight at study initiation: 288.2g (males) and 216.4g (females)
- Fasting period before study: overnight
- Housing: single in mesh bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Air changes (per hr): 12-15 / hour
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 1984-04-04 To: day 1984-04-24

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 25 %

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: dose range finding

Doses:

1000, 1320, 1730, 2280, 3000 mg/kg bw

No. of animals per sex per dose:

5 animals/sex/dose

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily
- Necropsy of survivors performed: no
- Other examinations performed:
clinical signs: frequently during the day of dosing and then daily thereafter for 14 days
body weight: prior to dosing and after 7 and 14 days
gross necropsy to all animals dying during the 14-day observation period

Statistics:

Probit analysis was used for LD50 calculation.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

1 770 mg/kg bw

Based on:

test mat.

95% CL:

> 1 510 - < 2 100

Sex:

female

Dose descriptor:

LD50

Effect level:

1 600 mg/kg bw

Based on:

test mat.

Sex:

male

Dose descriptor:

LD50

Effect level:

2 000 mg/kg bw

Based on:

test mat.

Mortality:

Mortality was observed starting at the lowest dose of 1000 mg/kg bw

Clinical signs:

other: decreased activity, ataxia, tremors, diarhea, salivation

Gross pathology:

no test item related leasions were reported

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an oral toxicity study in rats equivalent to OECD 401, the acute oral LD50 of the test article for both sexes combined was calculated to be 1.77 g/kg body weight with a 95% confidence interval of 1.51 to 2.10 g/kg.

Executive summary:

The test material was evaluated for acute oral toxicity in male and female Sprague-Dawley rats. The substance was orally administered (gavage) dissolved in water as the vehicle to animals (5 per sex per group) at dose levels of 1000, 1320, 1730, 2280 and 3000 mg/kg bw. After administration, the rats were observed for mortality and clinical signs up to 14 days after treatment. All animals were weighed before treatment (day1) and therafter on day 8 and day 15. All animals dying during the study were subjected to a gross necropsy.

Mortalities were dose dependent and observed starting at the lowest dose of 1000 mg/kg bw. All deaths occurred within 24 hours following dose administration. Decreased activity, ataxia, tremors, diarrhea, salivation were noted as clinical signs.

Under the conditions of this study, the acute oral LD50 of the test article in rats in both sexes combined was calculated to be 1770 mg/kg bw (1,77 g/kg body weight) with a 95% confidence interval of 1,51 to 2,10 g/kg.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 770 mg/kg bw

Quality of whole database:

For this endpoint high quality data (GLP + OECD TG compliant) are available for different species.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because exposure of humans via inhalation is not likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size

Justification for type of information:

cf. results of granulometry study, showing particles clearly exceeding a size 10 µm (296 µm (50%), of 80 µm (10%) and of 660 µm (90%)), thus, no repirable fraction was detected. Therefore inhalative exposure is highly unlikely.

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the study does not need to be conducted because the physicochemical and toxicological properties suggest no potential for a significant rate of absorption through the skin

Justification for type of information:

The octanol water distribution coefficient (logP) provides a first estimate on the skin penetration and thus the dermal exposure of a given chemical. The logP is a constant defined as the ratio of equilibrium concentrations of a chemical dissolved in a two-phase immiscible system consisting of water and octanol. A log P of 0 describes a compound that is equally soluble in organic and aqueous media. A logP of 1 indicates a 10:1 solubility ratio of the chemical in the organic:aqueous phase. The solubility ratio of a chemical with a log P value of −1 is 1:10 in the organic:aqueous phase.
Consequently, chemicals with negative log P values are more soluble in aqueous media than in organic solvents and will partition to the aqueous instead of the lipophilic phase. Metformin HCl has a logP at -3.5, i.e. clearly below 0.
The stratum corneum consists of approximately 40% water (Warner et al., 1988). Therefore, octanol serves as a simplified model of the stratum corneum. For log P, a threshold of zero determines the percutaneous penetration behaviour. The logP of Metformin is clearly below this threshold indicating that a dermal absorption can be excluded. Therefore no systemic exposure can be assumed after dermal administraion and thus there is no need for further studies on acute dermal toxicity.

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

The acute toxicity of Metformin hydrochlorid was studied in various species via the oral route of administration. The LD50 varies between 375 mg/kg bw in dogs and 2400 mg/kg bw in mice. For rats an LD50 (m/f) of 1770 mg/kg bw is reported. In monkeys the LD50 ammounts to 400 mg/kg bw.

Comparing different species, the LD50 values show significant variations. However, considering allometric scaling to account for species differences yields an acute toxicity range between 300 and 2000 mg/kg bw.

Justification for selection of acute toxicity – oral endpoint
This study was performed according to GLP using the standard species (rat) and the methods applied are fully compliant with OECD TG 401.

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