Magnesium

Neurotoxicity

Description of key information

There are conclusive but not suffcient data for the classification of substance Magnesium (CAS No. 7439-95-4)  with regard to Neurotoxicity.

Key value for chemical safety assessment

Effect on neurotoxicity: via oral route

Link to relevant study records

Reference

Endpoint:

neurotoxicity: short-term oral

Type of information:

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

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Materials and methods well described; results presented properly in the text and tables.

Qualifier:

according to guideline

Guideline:

other: All experiments were carried out in accordance with the European Communities Council Directive of 24 November 1986 (86/609/EEC)

Deviations:

not applicable

GLP compliance:

not specified

Limit test:

no

Species:

mouse

Strain:

other: OF1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Centre d'Elevage Depre, Doulcharel, France
- Weight at study initiation: 20-25g
- Fasting period before study: 12 hours
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 1
- Photoperiod: 12 hours dark/light cycle

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Drugs and vehicle were administered per os (PO) in a constant volume of 10 ml/kg body weight.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

no data

Frequency of treatment:

single

Remarks:

Doses / Concentrations:
100-300 mg/kg body weight
Basis:
nominal conc.

No. of animals per sex per dose:

groups of 10-15 animals

Control animals:

yes

Details on study design:

Examination of the protective effect of magnesium salts against seizures induced by NMDA, pentylenetetrazol, bicuculline and strychnine in naive animals. Magnesium salts were given 30 minutes before administration of convulsant. Immediately after administration of the convulsant drug, animals were individually placed in plastic cages. A full seizure was recorded when clonic movements of the limbs were observed, accompanied by loss of posture. The presence or absence of convulsions, time to the first convulsive period, and lethality during the observation period were noted.

Observations and clinical examinations performed and frequency:

Determination of plasma magnesium level: Blood samples were collected from mice at different times after oral administration of magnesium salts. Plasma aliquots were stored at -20°C until analysis. Magnesium level was determined.

Specific biochemical examinations:

no data

Neurobehavioural examinations performed and frequency:

Forced swimming test: The swimming test was performed in glass cylinders (18 cm in diameter and 40 cm high) containing 10 cm deep water at 25°C. The total immobility time was assessed throughout a 6-minute observation period. The test was started 1 hour after drug administration.
Locomotor activity: Locomotor activity was measured in photoresistor actometers in which the animals were placed individually 1 hour after drug administration. Activity counts were recorded for 15 minutes.
Motor coordination: 1 hour after administration of the test compound, animals were placed for 180 seconds on a rotarod apparatus revolving at 16 rpm. The frequency with which mice fell from the rod during this period was scored.

Sacrifice and (histo)pathology:

no data

Other examinations:

no data

Positive control:

no data

Statistics:

Student's t-test

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Clinical biochemistry findings:

effects observed, treatment-related

Behaviour (functional findings):

effects observed, treatment-related

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Other effects:

not examined

Description (incidence and severity):

Migrated information from 'Further observations for developmental neurotoxicity study'



Details on results (for developmental neurotoxicity):no (migrated information)

Details on results:

A rapid increase in plasma Mg2+ level was observed as early as 30 minutes after treatment. This hypermagnesia persisted over the next two hours and declined after 6 hours. No lethal effect was observed.
A single oral dose of Mg revealed a significant dose-dependent antagonistic effect on the latency of NMDA-induced convulsions. An anticonvulsive effect was also observed with strychnine- induced convulsions (but not with bicuculine-, picrotoxin and pentylenetetrazole). In the forced swim test, Mg reduced the immobility time indicating anti-depressant-like activity. Administration of Mg strongly potentiates yohimbine lethality and did not prevent reserppine-induced hypothermia.

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: oral administration of magnesium to normal mice can antagonise NMDA-mediated responses and lead to anti-depressant-like effects.

Remarks on result:

other:

Conclusions:

In summary, oral administration of magnesium to normal mice can antagonise NMDA-mediated responses and lead to anti-depressant-like effects.

Executive summary:

The ion channel of the N-methyl-D-aspartate (NMDA) receptor complex is subject to a voltage-dependent regulation by Mg2+ cations. Under physiological conditions, this channel is supposed to be blocked by a high concentration of magnesium in extracellular fluids. A single dose of magnesium organic salts (i.e., aspartate, pyroglutamate, and lactate) given orally to normal mice rapidly increases the plasma Mg2+ level and reveals a significant dose-dependent antagonist effect of magnesium on the latency of NMDA-induced convulsions; this effect is similar to that seen after administration of the dizocilpine (MK-801) channel blocker. An anticonvulsant effect of Mg2+ treatment is also observed with strychnine-induced convulsions but not with bicuculline-, picrotoxin-, or pentylenetetrazol-induced convulsions. In the forced swimming test, Mg2+ salts reduce the immobility time in a way similar to imipramine and thus resemble the antidepressant-like activity of MK-801. This activity is masked at high doses of magnesium by a myorelaxant effect that is comparable to MK-801-induced ataxia. Potentiation of yohimbine fatal toxicity is another test commonly used to evaluate putative antidepressant drugs. Administration of Mg2+ salts, like administration of imipramine strongly potentiates yohimbine lethality in contrast to MK-801, which is only poorly active in this test. Neither Mg2+ nor MK-801 treatment can prevent reserpine-induced hypothermia. These data demonstrate that oral administration of magnesium to normal animals can antagonize NMDA-mediated responses and lead to antidepressant-like effects that are comparable to those of MK-801. This important regulatory role of Mg2+ in the central nervous system needs further investigation to evaluate the potential therapeutic advantages of magnesium supplementation in psychiatric disorders.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Effect on neurotoxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEC

13 mg/m³

Study duration:

subchronic

Species:

mouse

Effect on neurotoxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2.4 mg/kg bw/day

Study duration:

subchronic

Species:

mouse

Additional information

oral exposure

oral administration of magnesium to normal mice can antagonise NMDA-mediated responses and lead to anti-depressant-like effects.

NOAEL=300 mg/kg bw day

dermal exposure

For dermal exposure we taken that:

-the average weight of mice is 80 g (60 -100 g),

-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg

 

corrected dermal NOAEL=    oral NOAEL

                                   300 mg/kg bw/dx 0.008 kg =                   

 NOAECmouse     2.4 mg/kg bw/day

 

Inhalation exposure:

The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the mouse (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m³), assuming 100 % absorption for both routes.

NOAEL mouse             300 mg/kg bw/day

÷1.15 m3/kgbw

÷20m3/mouse

NOAECmouse  = 13 mg/m3

 

 

 

Justification for selection of effect on neurotoxicity via inhalation route endpoint:
Inhalation exposure:
The oral dose for the rat is converted to the corresponding air concentration using a standard breathing volume for the mouse (1.15 m3/kg for 24 hours exposure. The resulting air concentration needs to be additionally corrected for 24 hlight activity (20 m3), assuming 100 % absorption for both routes.
NOAEL mose             300 mg/kg bw/day
÷1.15 m3/kgbw
÷20m3/rat
NOAECmouse   = 13 mg/m3

Justification for selection of effect on neurotoxicity via dermal route endpoint:
dermal exposure
For dermal exposure we taken that:
-the average weight of mice is 80 g (60 -100 g),
-the dose is applied over an area which is approximately 10% of the total body surface=0.008 kg
 
corrected dermal NOAEL=    oral NOAEL
                                   300 mg/kg bw/dx 0.008 kg =                   
 NOAECmouse     2.4 mg/kg bw/day

Justification for classification or non-classification

There are conclusive but not suffcient data for the classification of substance Magnesium (CAS No. 7439 -95 -4) with regard to Neurotoxicity.