Metformin hydrochloride

Carcinogenicity

Description of key information

Objective / Study Design

The objective of the study was to evaluate the effect of the test article, Metformin hydrochloride, on the incidence and morphology of tumours following oral administration to the rat for 104 weeks. However, owing to reduced survival in females, the necropsies of the females were performed after 99 weeks of dosing when their survival was of the order of 50%.

Group number	Group description	Dose level mg/kg bw/day	Number of animals
			Male	Female
1	control	0	60+20^#	60+20^#
2	low	150	60+20^#	60+20^#
3	intermediate I	300	60	60
4	intermediate II	600	60	60
5	high	900	60+20^#	60+20^#

# satellite animals for laboratory investigations

Dose levels were selected on the basis of findings from a preliminary study in the rat and following a recommendation from the Department of Health and Human Services of the US Food and Drug Administration.
Analysis of diets prepared during the study demonstrated that they had been accurately prepared.

Results

Metformin hydrochloride was detected in the plasma of the low and high dose animals sampled. High dose animals had a considerably greater concentration of the test article than the low dose animals although the relationship was not linear. The results obtained demonstrated that a steady state of absorption/elimination had been achieved by week 7 of the study. There were no differences in the nature or incidence of clinical signs to indicate an effect of treatment. Treatment was not associated with an increased incidence of palpable masses; indeed, high dose females had a lower incidence of movable masses than the controls.

Intermediate I, II and high dose ma1es had a lower incidence of morbidity/mortality than the ccntro1s. The same was true of high dose females. In males the reduced mortality was due to various conditions including skin/appendage lesions and glomerulonephropathy together with a reduction in pituitary tumours of high dose males. In females the decrease was mainly due to a reduction in mammary tumours. Intermediate I, II and high dose animals gained less weight than their controls.
Intermediate I, II and high dose males consumed less food than their controls but there was no difference in the food consumption of treated and control females.
There were no visible differences in the water consumption of treated and control animals.
Calculated compound consumption values showed good agreement with the nominal dose levels.
The total white blood cell counts of intermediate I, II and high dose males and high dose females were lower than those of the controls.
There were no differences in the plasma glucose concentration of treated and control animals.
There was a dose-related reduction in the body weight of ma1es and females at necropsy. The ovary weight of treated females exceeded that of controls.
At necropsy, treated animals had a lower incidence of a variety of lesions including enlarged/mass of the pituitary; enlarged kidneys; skin masses and sore feet/legs. The animals had a higher incidence of uterine distension. ovarian cysts and soft/enlarged testes. The findings correlated with histopathology findings.
There was no evidence of specific target organ toxicity in low and intermediate dose animals. High dose males had an increased incidence of unilateral testicular atrophy. Other intergroup variations in the incidence of non-neoplastic conditions included the following: increased Leydig cell hyperplasia; increase in pituitary altered cell foci (smaller proliferations counting as foci not tumours); reduction in adrenal medullary hyperplasia; reduced glomerulonephropathy.
The types of neoplastic findings of treated and control animals were similar out there was variation in the incidence of the findings, predominantly in endocrine and endocrine-dependent tissues. The findings included: decreased adrenal medullary tumours in high dose males; increased testicular Leydig cell tumours in intermediate I and high dose males; decreased mammary tumours and increased uterine stromal polyps in high dose females.

Conclusion

In conclusion, treatment of rats with Metformin hydrochloride at doses up to and including 900 mg/kg/day was associated with a marked reduction in body weight gain which had a pronounced effect on the age-related pathology of the animals. including their overall survival.
There were no tumour types of an unusual nature or incidence to suggest a direct carcinogenic or anticarcinogenic effect of the test article. At the high dose of 900 mg/kg/day, there was an increased incidence of uterine stromal polyps and an increased incidence of unilateral testicular atrophy but the toxicological significance of this latter finding remains unclear.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 August 1990 - 06 May 1993

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes

Species:

rat

Strain:

other: Crl:CD(SD)BR

Details on species / strain selection:

Species: Rat
Strain: Crl:CD(SD)BR
Source: Charles River (UK) Ltd. Margate.

Sex:

male/female

Details on test animals or test system and environmental conditions:

- Source: Charles River (UK) Ltd. Margate.
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 28 day upon arrival
- Weight at study initiation: upon treatment start males weighed 202.0 to 334.1 g, females 141.6 to 239.8 g
- Fasting period before study: no
- Housing: groups of five
- Diet (e.g. ad libitum): ad libitum except during an overnight fast before necropsy
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 28 days

DETAILS OF FOOD AND WATER QUALITY:
Samples were taken from each diet prepared in weeks 1, 2, 3, 4, 8, 13, 26, 39, 52, 65, 78, 91 and 104 and analysed at HUK for achieved concentration. Because the females were terminated before the males, the reserve diets from week 99, the final week of dosing for females were analysed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-25 °C
- Humidity (%): 40-70%
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 h /12 h

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on exposure:

The dose levels for this study were those suggested by the Department of Health and Human Services of the US Food and Drug Administration (letter cf 6 April 1990) following a preliminary
study (HUK Project Number 537/10). This letter acknowledged that doses above 900 mg/kg/day could cause complete inhibition of weight gain or weight less and that 900 mg/kg/day might
itself be too high. To allow for this eventuality, three lower dose levels, namely 600, 300 and 150 mg/kg/day, were selected in order to provide adequate information on which to draw a
conclusion about the oncogenic potential of the test article.
The concentration of the test article in the diet was adjusted weekly for the first 16 weeks and then four weekly on the basis of the group mean body weight and an estimate of the food
consumption of main study animals. Satellite animals received the same diet as the main study animals.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The concentration of the test article in the diet was adjusted weekly on the basis of the predicted midweek group mean body weight and an estimate of the food consumption.

Proof of absorption
Blood samples were analysed from satellite animals in weeks 7, 25 and 52.

Duration of treatment / exposure:

104 days

Frequency of treatment:

continous

Dose / conc.:

150 mg/kg bw/day (actual dose received)

Dose / conc.:

300 mg/kg bw/day (actual dose received)

Dose / conc.:

600 mg/kg bw/day (actual dose received)

Dose / conc.:

900 mg/kg bw/day (actual dose received)

No. of animals per sex per dose:

0 mg/kg (control) 60 m, 60 f, 20 m satellite, 20 f satellite
150 mg/kg (low dose) 60 m, 60 f, 20 m satellite, 20 f satellite
300 mg/kg (intermediate I dose) 60 m, 60 f
600 mg/kg (intermediate II dose) 60 m, 60 f
900 mg/kg (high dose) 60 m, 60 f, 20 m satellite, 20 f satellite

Control animals:

yes, plain diet

Details on study design:

- Toxicokinetic data: yes, absorption was measured
- Dose selection rationale: suggested by FDA
- Rationale for animal assignment: random
- Rationale for selecting satellite groups: dose verification
- Post-exposure recovery period in satellite groups: no
- Section schedule rationale: random

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly
BODY WEIGHT: Yes
- Time schedule for examinations: weekly up to week 16, and monthly thereafter until necropsy
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each cage of animals determined and mean daily diet consumption calculated: Yes weekly intervals up to week 16 and for one week un four weeks thereafter
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: weekly by cage of animals up to week 16 and for one in four weeks until the end of the study
OPHTHALMOSCOPIC EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
HAEMATOLOGY: Yes
- Time schedule for collection of blood:
- Anesthetic used for blood collection: Yes
- Animals fasted: No
- Details: Blood samples were obtained from all animals at the terminal kills and were taken from the dorsal aorta/vena cava. The blood was collected into EDTA anticoagulant and the total white
blood cell count measured. Blood films were prepared for the measurement of differential white blood cell count but were not examined as there was no evidence of an effect of treatment.
Samples were also collected from moribund animals at necropsy. The total white cell count was measured. Blood films were prepared but were not examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: during week 7
- Animals fasted: No
- How many animals: 5 from each satellite group
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: No
OTHER:

Sacrifice and pathology:

The animals were killed in cage position order, by an intraperitoneal injection of sodium pentobarbitone. For the scheduled kill animals this followed an overnight period
without food. Following exsanguination, a full internal and external examination was made under the general supervision of a pathologist and all lesions were recorded.

The following organs were dissected free from fat and other contiguous tissue and weighed before fixation:
adrenals
brain
heart
kidneys
liver
ovaries
pituitary
prostate
spleen
testes
thyroids (with parathyroids)
uterus
Samples of the following tissues were fixed in 10% neutral buffered formalin with the exception of the eyes which were fixed in Davidson's fluid:
adrenals
aorta
brain (including brain stem}
caecum
colon
ovaries
pancreas
pituitary
prostate
rectum (with anus)
duodenum
epididymides
salivary gland (submaxillary)
sciatic nerve
eyes
femur
heart
ileum
jejunum
kidneys
liver
lungs (with mainstem bronchi}
lymph nodes (mandibular and mesenteric)
mammary gland (females only)
esophagus
optic nerve
all gross lesions and tissue masses
seminal vesicles
skeletal muscle (quadriceps)
Skin
spinal cord {lumbar, high cervical, thoracic)
spleen
sternum (with bone marrow)
stomach (fundus. pylorus)
testes
thymus (where identified)
thyroids (with parathyroids}
trachea
urinary bladder
uterus (corpus and cervix)

Statistics:

All variables were analysed for each sex separately using analysis of variance (ANOVA). Pairwise comparisons were made using Dunnett's test. apart from the starting body weights for which pairwise comparisons were made using a protected t-test; the t-test is protected in the sense that the results are reported only if the overall ANOVA is significant.
For each post-dose parameter, a test was also performed to determine whether there was a linear relationship between increasing dose and response. In order to avoid multiplicity of testing, where the dose response test gave a significant result and at least one of the pairwise comparisons was significant, the results of the dose response test were not reported.

Levene's test for equality of variances between groups was performed for all variables.
Organ weights at the terminal kill were analysed for each sex separately using analysis of covariance (ANCOVA} and Dunnett's test.
with the necropsy body weight as a covariate. This analysis depends on the assumption that the relationship between the organ weights and the covariate are the same for all groups and the validity of this assumption was tested.
Levene's test for equality of variances between groups was performed for all organ weights analyses.

Clinical signs:

no effects observed

Description (incidence and severity):

There were no clinical signs observed during the study which were considered to be related to treatment.

Mortality:

mortality observed, non-treatment-related

Description (incidence):

The incidence and causes of morbidity and mortality in controls were consistent with the expected profile in this strain of rat. In control males, non-neoplastic causes included skin/appendage lesions and glomerulonephropathy and the commonest neoplastic causes were tumours of skin, haemolymphoreticular tissues and pituitary. Morbidity and mortality in females were mostly due to neoplasia, notably pituitary and mammary tumours.
Morbidity and mortality were decreased in intermediate I, intermediate II and high dose males and in high dose females such that at the end of the treatment period the survival was 47%, 45%, 63%, 60% and 75% for control to high dose males respectively and 48%, 43%, 47%, 52% and 63% for control to high dose females.
At the intermediate I and high dose in males the difference was statistically significant {p<0.05 and p<0.01 respectively). In males, the decrease in morbidity/mortality was due to reductions in various conditions, including skin/appendage lesions and glomerulonephropathy, together with a reduction in deaths due to pituitary tumours (high dose only).
In females, the decrease was mainly due to a reduction in mammary tumours. The increased survival was considered to be due to treatment-associated
decreases in body weight gain and the consequent reduction in age related pathology.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Intermediate I, intermediate II and high dose males gained less weight than the controls during the study (p<0.01. p<0.001 and p<0.001 respectively for weeks 0 to 104).
At the end of the study the difference in group mean body weights was 13%, 28% and 31% for intermediate I. II and high dose males respectively when compared with the control mean.
Intermediate I, II and high dose females also gained less weight than the controls during the study (p<0.05, p<0.001 and p<0.001 respectively for weeks 0 to 96). At week 96, the difference in group mean body weights was 10%, 21% and 32% for intermediate I. II and high dose females respectively when compared with the control mean.
During the latter part of the study, low dose females gained slightly less weight than the controls which led to a difference in group mean body weight of 6%. This difference was not statistically significant.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Intermediate I, II and high dose males consumed less food than controls during the study, 6% (p<0.01), 13% (p<0.001) and 15% (p<0.001} respectively. Treated and control females consumed a similar amount of food during the study.
The calculated compound consumption values generally showed agreement with the nominal dose levels. More variation is expected at the start of the study since estimates of body weight and food consumption are used to calculate the required dietary concentration. Achieved consumption was lower than expected owing to differences in the predicted food consumption and the actual amount of food consumed.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

There were no visible differences in the amount of water ccnsumed by treated and control animals.

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

The mean total white blood cell count of intermediate I. II and high dose males was slightly lower than that of the controls (p<0.05, p<0.001 and p<0.001 respectively).
High dose females had a lower mean white blood cell count than their controls {p<0.05).

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

The glucose concentration of control. low and high dose animals was measured in week 7 at three different times of the day (coinciding with the measurement of plasma levels of Metformin hydrochloride).
There was no difference in glucose concentration between the groups and little difference with time.

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

There was some variation in the organ weights of the treated and control groups, but few differences were statistically significant.
The kidney/body weight ratio of treated males exceeded that of the controls (11 to 23%) although there was no relationship with dose.
A similar pattern was seen in females (6 to 18% greater than controls).
The liver/body weight ratio of treated males and females exceeded that of controls by 6 to 23% and 5 to 14% respectively (again without relationship with dose).
The relative adrenal weight of treated animals also exceeded that of the controls (12 to 32% for males and 16 to 26% for females, no dose relationship).
The ovary weight of treated females exceeded that of the controls and at the high dose, this was statistically significant (p<0.05).

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Necropsy findings in controls were consistent with the expected spectrum of background lesions in rats of this strain and age.
Frequent findings included: hydronephrosis and cysts in kidneys, areas of discoloration in liver and lungs, enlarged kidney, liver, thyroid, spleen and adrenal, fur loss, sores and skin masses, tail sores, enlarged and sore foot/leg, small seminal vesicle, uterine distension, ovarian cysts.
The spectrum of necropsy findings in treated animals was generally similar to that in controls, but with differing incidences for some findings. Findings with increased incidence included: soft and enlarged testis, uterine distension, ovarian cysts. Findings with decreased incidence included: liver discolouration, enlarged and mass in pituitary, fur loss, sores and skin masses, thickened stomach, enlarged thyroid, enlarged and sore foot/leg, enlarged kidneys.
The changes in incidence of these macroscopic findings were considered to be treatment-related and correlated with histopathology findings.

Neuropathological findings:

not examined

Description (incidence and severity):

The spectrum of non-neoplastic findings in controls was consistent with that expected for rats of this strain.
Frequent findings included: inflammatory cell foci in many organs, pododermatitis of foot/leg, dermatitis/folliculitis of skin and tail, compression of brain, altered cell foci in pituitary, sciatic nerve neuropathy, haemopoiesis, pigment and atrophy of spleen, hepatocyte vacuolation, biliary proliferation, microcystic degeneration, basophilic and clear cell focus of liver, islet fibrosis, lobular atrophy, basophilic focus and edema of pancreas, haemangiectasis, medullary hyperplasia and eosinophilic/vacuolated, clear cell, normochromic and basophilic focus of adrenal, glomerulonephropathy and tubular cell hyperplasia, mineralisation and pigment in kidney, congestion/haemorrhage and foamy histiocytes in lungs, degeneration/fibrosis in heart, C-cell hyperplasia of thyroid, atrophy and Leydig cell hyperplasia of testis, oligospermia of epididymis, mammary hyperplasia, cysts. atrophy, few/no corpora lutea, multiple/large corpora lutea and stromal hyperplasia of ovary, squamous metaplasia and cystic uterine glands.

There were decreases of incidence and/or severity of inflammatory and degenerative lesions in several non-endocrine dependent organs including degeneration/fibrosis of the heart, various liver lesions and glomerulonephropathy. Apart from the decreased glomerulonephropathy, there were no kidney findings of an unusual nature or incidence in the dosed animals. All the variations in non-endocrine dependent organs were attributed to the treatment-associated decrease in body weight gain.

Treatment related changes were found in most endocrine/endocrine-dependent tissues. These changes were attributed to reduced body weight gain and included reductions in adrenal medullary hyperplasia and increased pituitary altered cell foci in males. The increase in pituitary altered cell foci reflected the tendency of pituitary tumours to be reduced in both number and size, smaller proliferations classified as foci rather than tumours.
The incidence of testicular Leydig cell hyperplasia was increased in intermediate I and high dose groups. The only other unusual finding in the male reproductive tract was a slight increase in unilateral testicular atrophy in high dose animals.
There was no clear-cut explanation for this finding its relationship to treatment was uncertain. In dosed females, the ovaries tended to be less atrophic when compared with controls. This was suggestive of prolongation of hormonal activity in the dosed groups and correlated with the increase in cystic uterine glands in intermediate I, intermediate II and high dose animals.

Histopathological findings: neoplastic:

not specified

Description (incidence and severity):

The types of neoplastic findings of treated and control animals were similar out there was variation in the incidence of the findings predominantly in endocrine and endocrine-dependent tissues. The findings included: decreased adrenal medullary tumours in high dose males, increased testicular Leydig cell tumours in intermediate I and high dose males, decreased mammary tumours and increased uterine stromal polyps in high dose females.

Other effects:

no effects observed

Details on results:

Test diets were shown to be accurately prepared. The results ranged between 85% and 109% of nominal concentration.

Proof of absorption
In week 7 of the study. plasma concentrations of Metformin hydrochloride were within the range 919 to 2598 ng/mL for low dose males and 411 to 2692 ng/ml for low dose females. At the high dose concentrations ranges from 2183 to 11299 ng/mL for males and 4978 to 7469 ng/mL for females. Similar concentrations were measured by the University of San Francisco.
In week 52, plasma samples from high dose animals were sent to the University of San Francisco for analysis. Similar concentrations were found to those measured in week 7 and therefore it can be concluded that a steady state had been achieved.

Key result

Dose descriptor:

NOAEL

Effect level:

900 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Objective / Study Design

The objective of the study was to evaluate the effect of the test article, Metformin hydrochloride, on the incidence and morphology of tumours following oral administration to the rat for 104 weeks. However, owing to reduced survival in females, the necropsies of the females were performed after 99 weeks of dosing when their survival was of the order of 50%.

Group number	Group description	Dose level mg/kg bw/day	Number of animals
			Male	Female
1	control	0	60+20^#	60+20^#
2	low	150	60+20^#	60+20^#
3	intermediate I	300	60	60
4	intermediate II	600	60	60
5	high	900	60+20^#	60+20^#

# satellite animals for laboratory investigations

Dose levels were selected on the basis of findings from a preliminary study in the rat and following a recommendation from the Department of Health and Human Services of the US Food and Drug Administration.
Analysis of diets prepared during the study demonstrated that they had been accurately prepared.

Results

Metformin hydrochloride was detected in the plasma of the low and high dose animals sampled. High dose animals had a considerably greater concentration of the test article than the low dose animals although the relationship was not linear. The results obtained demonstrated that a steady state of absorption/elimination had been achieved by week 7 of the study. There were no differences in the nature or incidence of clinical signs to indicate an effect of treatment. Treatment was not associated with an increased incidence of palpable masses; indeed, high dose females had a lower incidence of movable masses than the controls.

Intermediate I, II and high dose ma1es had a lower incidence of morbidity/mortality than the ccntro1s. The same was true of high dose females. In males the reduced mortality was due to various conditions including skin/appendage lesions and glomerulonephropathy together with a reduction in pituitary tumours of high dose males. In females the decrease was mainly due to a reduction in mammary tumours. Intermediate I, II and high dose animals gained less weight than their controls.
Intermediate I, II and high dose males consumed less food than their controls but there was no difference in the food consumption of treated and control females.
There were no visible differences in the water consumption of treated and control animals.
Calculated compound consumption values showed good agreement with the nominal dose levels.
The total white blood cell counts of intermediate I, II and high dose males and high dose females were lower than those of the controls.
There were no differences in the plasma glucose concentration of treated and control animals.
There was a dose-related reduction in the body weight of ma1es and females at necropsy. The ovary weight of treated females exceeded that of controls.
At necropsy, treated animals had a lower incidence of a variety of lesions including enlarged/mass of the pituitary; enlarged kidneys; skin masses and sore feet/legs. The animals had a higher incidence of uterine distension. ovarian cysts and soft/enlarged testes. The findings correlated with histopathology findings.
There was no evidence of specific target organ toxicity in low and intermediate dose animals. High dose males had an increased incidence of unilateral testicular atrophy. Other intergroup variations in the incidence of non-neoplastic conditions included the following: increased Leydig cell hyperplasia; increase in pituitary altered cell foci (smaller proliferations counting as foci not tumours); reduction in adrenal medullary hyperplasia; reduced glomerulonephropathy.
The types of neoplastic findings of treated and control animals were similar out there was variation in the incidence of the findings, predominantly in endocrine and endocrine-dependent tissues. The findings included: decreased adrenal medullary tumours in high dose males; increased testicular Leydig cell tumours in intermediate I and high dose males; decreased mammary tumours and increased uterine stromal polyps in high dose females.

Conclusion

In conclusion, treatment of rats with Metformin hydrochloride at doses up to and including 900 mg/kg/day was associated with a marked reduction in body weight gain which had a pronounced effect on the age-related pathology of the animals. including their overall survival.
There were no tumour types of an unusual nature or incidence to suggest a direct carcinogenic or anticarcinogenic effect of the test article. At the high dose of 900 mg/kg/day, there was an increased incidence of uterine stromal polyps and an increased incidence of unilateral testicular atrophy but the toxicological significance of this latter finding remains unclear.

Conclusions:

In conclusion, treatment of rats with Metformin hydrochloride at doses up to and including 900 mg/kg/day was associated with a marked reduction in body weight gain which had a pronounced effect on the age-related pathology of the animals. including their overall survival. There were no tumour types of an unusual nature or incidence to suggest a direct carcinogenic or anticarcinogenic effect of the test article. At the high dose of 900 mg/kg/day, there was an increased incidence of uterine stromal polyps and an increased incidence of unilateral testicular atrophy but the toxicological significance of this latter finding remains unclear.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

900 mg/kg bw/day

Study duration:

chronic

Species:

rat

Justification for classification or non-classification

Based on the data presented there is no need for classification for carcinogenicity.

Additional information

Preliminary studies in mice (HAZLETON LAB. INC. [Report 6036-537/9] 1989) and in rats (HAZLETON LAB. INC. [Report 6050-537110] 1989) have been performed for 90 days. Their aim was to determine the doses to be used in the final trial. The highest dose (900 mg/kg) has been studied in compliance with the North American Authorities criteria (1-DA). The A2613-101 study (HAZLETON LAB. INC.) in the female rat was intended to evaluate metformin hormonal impact and was carried out prior to the carcinogenic studies. Finally two studies have been performed : one in the mouse -91 weeks- (HAZLETON LAB. UK [Report 7352-537/11] 1992), another in the rat -104 weeks- (HAZLETON LAB. UK [Report 7476-337112] . Metformin was administered dietary.

There was no carcinogenic potential in either species studied.