Magnesium

Repeated dose toxicity: other routes

Administrative data

Endpoint:

short-term repeated dose toxicity: other route

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: Well documented study which meets basic scientific principles

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1998

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

A 4-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion at the dosage levels of 0, 12.5, 50 and 100 mg/kg/hr in female beagle dogs was conducted

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

magnesium sulphate

IUPAC Name:

magnesium sulphate

Constituent 2

Reference substance name:

Magnesium sulphate

EC Number:

231-298-2

EC Name:

Magnesium sulphate

Cas Number:

7487-88-9

IUPAC Name:

7487-88-9

Test material form:

solid - liquid: suspension

Remarks:

migrated information: dispersion

Test animals

Species:

dog

Strain:

Beagle

Sex:

female

Administration / exposure

Route of administration:

intravenous

Vehicle:

other: 10 % grape juice injection solution

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

4 weeks

Frequency of treatment:

Continuously

Doses / concentrations

Remarks:

Doses / Concentrations:
Dosage levels: 12.5, 50, 100 and 200 mg/kg/hr

No. of animals per sex per dose:

2 animals per dose

Control animals:

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

One dog treated with 200 mg/kg/hr died on the afternoon of the 2nd day of infusion (approximately 32 hours after the beginning of infusion). The other dog from the same group, judged to be in a moribund state, was euthanized. With the exception of one dog from the groups treated with 50 and 100 mg/kg/hr, there were no notable abnormalities throughout the infusion or the recovery period.
Body weight in the 100 mg/kg/hr infusion group decreased during the infusion period, while food consumption decreased during the initial phase of the infusion period. There were no marked differences between the group treated with 50 mg/kg/hr and the control group.
Electrocardiogram tests showed prolongation of conduction time just before the death of the dog that died and the dog that was slaughtered. The blood pressure of both dogs had decreased too much to measure. The group treated with 100 mg/kg/hr also exhibited mild prolongation of conduction time. There were no abnormalities detected in the groups treated with 50 mg/kg/hr and less. There was no observable difference in blood pressure measured values in either group between the infusion period and before the infusion began.

Sacrifice and pathology:

An autopsy of the dog that died revealed dark red blood around the tissue surrounding the tip of the catheter as well as dark red blood in the lungs and stomach. A darkening of the spleen was observed in the dog that died and the one that was slaughtered. An autopsy was performed at the end of the infusion period, which revealed blood clots and colour degradation in the venous walls adjacent to the tip of the catheter of both dogs. There were dark red spots throughout the lungs and dark red tubers in the right atrioventricular valve of the heart. At the end of the recovery period, there were blood clots and colour degradation in the venous walls adjacent to the catheter, induration of the tissue surrounding the caudal vena cava, dark red tubers in the right atrioventricular valve of the heart, dark red spots in the kidneys, enlargement of the lymphatic nodes and bloating around the surgical incision on the thigh. It was determined that, other than the darkening of the spleen in the dog slaughtered in a moribund state, every observed change was a secondary effect attributable to the indwelling catheter.
No changes in organ weights were observed in any of the infusion groups, including the animal that died, the animal slaughtered in a moribund state and the animals scheduled for slaughter.
Kidneys: In the dog that died and the one that was slaughtered in a moribund state, slight enlargement of the convoluted tubules and slight to mild tubular epithelial vacuolization were observed. An examination at the end of the infusion period revealed slight tubular basophilia of the 2 dogs treated with 100 mg/kg/hr, while one of them also had slight interstitial cellular infiltration. There is a significant possibility that these effects are attributable to magnesium sulphate.Spleen: Examination of the dog that died and the one that was slaughtered revealed mild congestion on their darkened spleens. An examination conducted at the end of the infusion period revealed mild hyper extramedullary hematopoeisis and mild congestion in one dog in the 100 mg/kg/hr infusion group. While this group showed signs of anaemia, splenic extramedullary hematopeisis was probably a reactive change to anaemia. These effects were not observed at the end of the recovery period, nor were the dogs seen with significant lesions.
Caudal vena cava: Mild phlebitis was observed on examination at the end of the infusion period which occurred proximally to the tip of the catheter. Of the dog that died, and the dog slaughtered in a moribund state, one had phlebitis which occurred proximally to the tip of the cathater. Therefore, it has been determined that magnesium sulphate does not have excitovascular properties.
Pneumonia and hepatic cellular infiltration were likely secondary changes attributable to phlebitis which occurred near the indwelling catheter

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

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

no effects observed

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

A 4-week toxicity study of magnesium sulfate administered by 24-hr intravenous infusion at the dosage levels of 0, 12.5, 50 and 100 mg/kg/hr in female beagle dogs was conducted. No death occurred in any group. Changes attributable to the treatment with magnesium sulfate were decreased food consumption and body weight gain, anemic change, increased urine volume, decreased serum calcium level, increased inorganic phosphorus level, slight prolongation of conduction time in electrocardiogram and tubular basophilia in the kidneys in the group treated with 100 mg/kg/hr. In addition, essentially similar changes were also observed at the same dosage level in the 2-week study of this drug, in which recoverability was recognized with 2-week follow-up observation after drug withdrawal. In conclusion, the nontoxic dosage level was judged to be 50 mg/kg/hr under the condition of the present study.

Effect levels

Dose descriptor:

NOAEL

Effect level:

50 other: mg/kg/hr

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Over two weeks, decreased food consumption, body weight gain, anaemia, mild prolongation of conduction time in electrocardiogram and tubular basophilia in the kidneys.

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

1. General clinical examinations:

One dog treated with 200 mg/kg/hr died on the afternoon of the 2nd day of infusion (approximately 32 hours after the beginning of infusion). The other dog from the same group, judged to be in a moribund state, was euthanized. With the exception of one dog from the groups treated with 50 and 100 mg/kg/hr, there were no notable abnormalities throughout the infusion or the recovery period.

Body weight in the 100 mg/kg/hr infusion group decreased during the infusion period, while food consumption decreased during the initial phase of the infusion period. There were no marked differences between the group treated with 50 mg/kg/hr and the control group.

Electrocardiogram tests showed prolongation of conduction time just before the death of the dog that died and the dog that was slaughtered. The blood pressure of both dogs had decreased too much to measure. The group treated with 100 mg/kg/hr also exhibited mild prolongation of conduction time. There were no abnormalities detected in the groups treated with 50 mg/kg/hr and less. There was no observable difference in blood pressure measured values in either group between the infusion period and before the infusion began.

2. Urinalysis:

None of the groups showed changes in urine findings.

3. Haematology:

The 100 mg/kg/hr infusion group exhibited mild anaemia. This change returned to physiological values in tests conducted during the 2 -week recovery period. There were no other changes attributable to magnesium sulphate infusion.              

4. Blood chemical analysis:

Tests conducted just prior to death and did not show any observed reduction in electrolytes whereas serum calcium levels dropped for both the 50 and 100 mg/kg/hr infusion groups. These decreased levels of calcium were not present in tests conducted during the 2 -week recovery period. No other notable changes were detected.

5. Pathological analysis:

An autopsy of the dog that died revealed dark red blood around the tissue surrounding the tip of the catheter as well as dark red blood in the lungs and stomach. A darkening of the spleen was observed in the dog that died and the one that was slaughtered. An autopsy was performed at the end of the infusion period, which revealed blood clots and colour degradation in the venous walls adjacent to the tip of the catheter of both dogs. There were dark red spots throughout the lungs and dark red tubers in the right atrioventricular valve of the heart. At the end of the recovery period, there were blood clots and colour degradation in the venous walls adjacent to the catheter, induration of the tissue surrounding the caudal vena cava, dark red tubers in the right atrioventricular valve of the heart, dark red spots in the kidneys, enlargement of the lymphatic nodes and bloating around the surgical incision on the thigh. It was determined that, other than the darkening of the spleen in the dog slaughtered in a moribund state, every observed change was a secondary effect attributable to the indwelling catheter.

No changes in organ weights were observed in any of the infusion groups, including the animal that died, the animal slaughtered in a moribund state and the animals scheduled for slaughter.

Kidneys: In the dog that died and the one that was slaughtered in a moribund state, slight enlargement of the convoluted tubules and slight to mild tubular epithelial vacuolization were observed. An examination at the end of the infusion period revealed slight tubular basophilia of the 2 dogs treated with 100 mg/kg/hr, while one of them also had slight interstitial cellular infiltration. There is a significant possibility that these effects are attributable to magnesium sulphate.

Spleen: Examination of the dog that died and the one that was slaughtered revealed mild congestion on their darkened spleens. An examination conducted at the end of the infusion period revealed mild hyper extramedullary hematopoeisis and mild congestion in one dog in the 100 mg/kg/hr infusion group. While this group showed signs of anaemia, splenic extramedullary hematopeisis was probably a reactive change to anaemia. These effects were not observed at the end of the recovery period, nor were the dogs seen with significant lesions.

Caudal vena cava: Mild phlebitis was observed on examination at the end of the infusion period which occurred proximally to the tip of the catheter. Of the dog that died, and the dog slaughtered in a moribund state, one had phlebitis which occurred proximally to the tip of the cathater. Therefore, it has been determined that magnesium sulphate does not have excitovascular properties.

Pneumonia and hepatic cellular infiltration were likely secondary changes attributable to phlebitis which occurred near the indwelling catheter.

6. Plasma drug concentration levels:

Pre-infusion plasma magnesium sulphate concentration levels for all animals were within the range of physiological varioation (1.7 -2.0 mg/dl). These levels were elevated at all points in time relative to dosage, reaching the maximum plasma consentration level approximately 8 hours after beginning the infusion in all groups other than that treated with 200 mg/kg/hr. Levels in this group elevated by a factor of 7 from pre-infusion levels after 24 -hours. In the groups treated with 12.5 and 50 mg/kg/hr, levels just before the ending of infusion on day 15 were the same as those after 24 -hours of infusion. Levels were slightly elevated int eh group treated with 100 mg/kg/hr. After the infusion, dosage correlation disappeared over time. All groups returned to pre-infusion levels within 24 hours.

 

Applicant's summary and conclusion

Conclusions:

The NOAEL of magnesiumsulphate in beagle dogs was determined to be 50 mg/kg/hr over two weeks.

Executive summary:

A continuous infusion of magnesium sulphate was administered 24 hours/day for 2 weeks. As a result, one dog died from the 200 mg/kg/hr group and the other was slaughtered in a moribund state on day 2 of the infusion. In the 100 mg/kg/hr infusion group, decreased body weight and food consumption, mild anaemia, delayed conduction and tubular basophilia were observed, while in the infusion groups treated with 50 mg/kg/hr and above a decrease in serum calcium was observed. These changes in the 50 mg/kg/hr group were slight and no other changes were observed, suggesting that this level of magnesium sulphate is toxicologically insignificant. The nontoxic dose of magnesium sulphate was determined to be 50 mg/kg/hr. Furthermore, most of the changes observed in infusion groups treated with 100 mg/kg/hr or less disappeared withing 14 days upon drug withdrawal, thus confirming reversibility.