Magnesium

Carcinogenicity

Description of key information

One key study with oral administration of magnesium chloride to mice was identified (Kurate 1989), and one further supportive study with inhalation exposure of rats (Hori 1994) to magnesium sulphate whiskers. Both studies did not indicate a carcinogenic potential.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

In the current study, magnesium was administered in the form of magnesium chloride, the chloride ion being ubiquitious component of mammalian mineral supply via the diet, omnipresent in body fluids and involved in osmoregulation, and therefore of limited toxicologically relevance at the tested doses. The objective of the study was the evaluation of any effects of magnesium.

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

The study examined the potential carcinogenicity of MgCl2*6 H2O in B6C3F1 mice. Groups of 50 male and 50 female B6C3F1 mice were given magnesium chloride (MgCl2*6H2O) at dose levels of 0 (control), 0.5 and 2 % in the diet for 96 weeks, after which all animals received the control diet for 8 weeks and were then necropsied.

GLP compliance:

not specified

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Japan Inc.
- Age at study initiation: 5 weeks
- Housing: housed in plastic cages (5 animals/cage) containing bedding of wood chips.
- Diet: ad libitum, prior study, the animals received a commercial diet
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 +/- 2
- Humidity (%): 55 +/- 10
- Photoperiod: 12 hours dark/light cycle
No further details are given.

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

Magnesium chloride hexahydrate was mixed with the commercial powdered diet at the appropriate concentrations.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

96 weeks

Frequency of treatment:

continuously

Post exposure period:

8 weeks

Remarks:

Doses / Concentrations:
0.5% test substance
Basis:
nominal in diet

Remarks:

Doses / Concentrations:
2% test substance
Basis:
nominal in diet

No. of animals per sex per dose:

50 females and 50 males per dose

Control animals:

yes

Details on study design:

- After 96 weeks of test compound feeding, all aimals received the control diet for further 8 weeks.
- The dietary levels of MgCl2 were selected on the basis of results from a preliminary investigation of the effects of MgCl2 x 6H2O at dose levels of 0, 0.3, 0.6, 1.25, 2.5 and 5% in the diet to male and female mice for up to 13 weeks.

Positive control:

no data

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were observed daily for clinical signs.

BODY WEIGHT: Yes
- Time schedule for examinations: mice were weighed weekly for the first 14 weeks and then every other week.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Time schedule for examinations: food consumption were measured over the 2-day period before each weighing.

FOOD EFFICIENCY: No data

WATER CONSUMPTION: Yes
- Time schedule for examinations: water consumption were measured over the 2-day period before each weighing.

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- How many animals: 10 mice/sex/group.
- Parameters checked: haemoglobin concentration, haematocrit, erythrocyte, leukocyte and platelet counts; red blood cell indices of mean corpuscular haemoglobin concentration were calculated; differential leukocyte counts and an estimate of the percentage of nucleated red blood cells, anisocytosis and polychromasia were calculated.

CLINICAL CHEMISTRY: Yes
- How many animals: 10 mice/sex/group.
- Parameters checked: glutamic-pyruvic transaminase, glutamic-oxaloacetic transaminase, alkaline phosphatase, total cholesterol, total protein albumin-globulin ratio and urea nitrogen in serum.

URINALYSIS: Yes
- Time schedule for collection of urine: during week 104 of the study.
- Fresh urine samples were obtained.
- How many animals: 10 mice/sex/group.
- Parameters checked: pH, protein, glucose, ketones, bilirubin, occult blood, urobilinogen and specific gravity.

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

Gross and microscopic examinations were performed on all mice found dead or killed if moribund or at the end of the study.

PATHOLOGY
- The following organs were removed from animals necropsied at the end of the study: liver, kidneys, brain, heart and testes or ovaries.
- The organs were weighed and organ-to-body weight ratios were calculated.

HISTOPATHOLOGY
- Organs and tissues were preserved in 10% phosphate-buffered formaline and stained with haematoxylin and eosin.
- Organs examined: liver, kidneys, brain, heart and testes or ovaries, salivary glands, trachea, lungs, thymus, lymph nodes, stomach, small intestine, large intestine, pancreas, urinary bladder, pituitary, thyroids, adrenals, prostate, seminal vesicles, eyes, Harderian glands, spinal cord, sciatic nerve and any macroscopic pathological lesions.

Other examinations:

no data

Statistics:

Data were analysed where appropriate using the F- and Student's t-tests. The significance of differences in the incidences of non-neoplastic or neoplastic lesions between the different groups was evaluated by chi-square or Fisher's exact probability tests. Differences at p<0.05 were considered significant.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

not specified

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY:
- No abnormal clinical signs were observed in any of the treated mice throughout the test period.
- Survival rate were not affected; at week 104, survival rates of females fed 0, 0.5 and 2% magnesium chloride were 66, 72 and 72%, respectively.

BODY WEIGHT AND WEIGHT GAIN:
- Mean body weight of females given a diet containing 2% were significantly decreased from week 8 until the end of the study.
- Male body weights were comparable among groups.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Average food consumption of female mice given 2% magnesium chloride in the diet was greater than that for male mice given the same dose.
- Average compound intakes were 0.57 or 2.81 g/kg bw/d in males and 0.73 or 3.93 g/kg bw/d in females of the 0.5 and 2.0% groups, respectively.

HAEMATOLOGY/CLINICAL CHEMISTRY/URINALYSIS:
- No treatment-related changes were noted.

ORGAN WEIGHTS:
- In high-dose females (2% in the diet), significant increased absolute and relative brain weights and relative heart and kidney weights were observed.
- In the same group, a significant decrease was noted in the absolute liver weights.

HISTOPATHOLOGY: NON-NEOPLASTIC:
- No treatment-related changes were noted.

HISTOPATHOLOGY: NEOPLASTIC (if applicable):
- The only tumour that showed an increased incidence, although not strictly in a dose-related manner, was malignant lymphoma/leukaemia in females and to a lesser extent in males. The incidences were within the range seen in previous studies conducted in the laboratory.
- In males, a dose-related decrease in the incidence of hepatocellular carcinoma was observed (significantly (p<0.05) at 2% in the diet).
- A decrease in the incidence of hyperplastic nodules in the liver was also noted in males of both treated groups.
- Two cases of bone osteosarcomas were noted in females of the high-dose groups, and sarcomas of the uterus were observed in both the control and treated groups; these tumours sometimes metastasised to the lung, liver and a number of other organs.

No further details are given.

Dose descriptor:

NOAEL

Effect level:

> 2 810 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

> 336 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

magnesium

Sex:

male

Basis for effect level:

other: No evidence of a carcinogenic potential was seen in male and female mice fed dose levels up to 2810 and 3930 mg/kg bw/d magnesium chloride, respectively, equivalent to 336 and 470 mg Mg/kg bw/d for males and females.

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

> 3 930 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Dose descriptor:

NOAEL

Effect level:

> 470 mg/kg bw/day (actual dose received)

Based on:

element

Remarks:

magnesium

Sex:

female

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Conclusions:

No evidence of a carcinogenic potential of magnesium chloride was observed in mice after 96 weeks of feeding up to 2% in the diet.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Species:

mouse

Quality of whole database:

One key study with oral administration in mice and one further supportive study with inhalation exposure of rats.

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

An increased rate of tumour formation was not observed in studies on magnesium chloride in mice. Hence magnesium is not considered to be carcinogenic. Classification for carcinogenicity is not required according to Regulation (EC) 1272/2008 and subsequent adaptations.

Additional information

Read across MgCl2 * 6H2O to Mg:

In view of the the limited relevance of the anionic counter-ions discussed here, magnesium chloride can be considered as structurally equivalent, and the results of the study can be used by read-across.

No evidence of a carcinogenic potential was found in male and female B6C3F1 mice fed diets containing up to 2% MgCl2*6 H2O corresponding to 2810 and 3930 mg/kg bw/d.These values can be recalculated to 336 and 470 mg Mg/kg bw/d for males and females, respectively.

Chronic inhalation exposure of rats to long or short magnesium sulphate whiskers indicated slightly higher incidences of adenoma and carcinoma (lung, liver) in the treatment groups one year after chronic exposure, but these were not significantly different from control.

Justification for selection of carcinogenicity via oral route endpoint:
Reliable chronic dietary study including relevant examinations. No evidence of a carcinogenic potential of magnesium chloride observed in mice after 96 weeks of feeding up to 2% in the diet.