Registration Dossier

Diss Factsheets

Toxicological information

Repeated dose toxicity: other routes

Currently viewing:

Administrative data

Endpoint:
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:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: The methods used do not comply with OECD guidelines, as intravenous administration is not the preferred method. However a large number of blood chemistry and haematological parameters are examined, as would be expected under OECD guidelines.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1998

Materials and methods

GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Magnesium sulphate
EC Number:
231-298-2
EC Name:
Magnesium sulphate
Cas Number:
7487-88-9
Molecular formula:
MgO4S
IUPAC Name:
magnesium sulfate

Test animals

Species:
dog
Strain:
Beagle
Sex:
female

Administration / exposure

Route of administration:
intravenous
Vehicle:
other: 10 % grape juice injection solution
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
Continuously
Doses / concentrations
Remarks:
Doses / Concentrations:
Dosage levels: 12.5, 50 and 100 mg/kg/hr
No. of animals per sex per dose:
3 animals per dose
Control animals:
yes, concurrent vehicle

Results and discussion

Effect levels

Dose descriptor:
NOAEL
Effect level:
50 other: mg/kg/hr
Sex:
female
Basis for effect level:
other: Over four weeks, decrease in body weight and food consumption, anaemia, increase in urine volume, decrease in serum calcium, increase in inorganic phosphorous, delayed conduction and tubular basophilia.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

1. General clinical examinations:

No changes in general condition attributable to infusion of the test article were observed during the infusion period.

Body weight and food consumption in the 100 mg/kg/hr infusion group decreased. No significant changes were observed in the groups treated with 50 mg/kg/hr or less.

Electrocardiogram tests showed mild prolongation of QTc, as well as P-R, QRS and Q-T intervals in the 100 mg/kg/hr group, indicating delayed conduction. No abnormalities were noted in the groups treated with 50 mg/kg/hr or less.

2. Urinalysis:

The groups treated with 50 and 100 mg/kg/hr showed a significant increase in urine volume during week 2 of the infusion.

3. Haematology:

Red blood cell test values decreased in the 100 mg/kg/hr infusion group, indicating anaemia. Meanwhile, there was a significant increase in MCV, while one dog in this group exhibited an elevated reticulocyte ratio. An increase in white blood cells was observed in teh 12.5 and 100 mg/kg/hr infusion groups.

4. Blood chemical analysis:

The 100 mg/kg/hr infusion group exhibited a significant decrease in serum calcium levels throughout the infusion period. A significant increase in serum inorganic phosphorous was also observed in the 50 and 100 mg/kg/hr infusion groups.

5. Pathological analysis:

A darkening of the spleen was observed in teh 100 mg/kg/hr infusion group, a change most likely attributable to magnesium sulphate infusion. With the exception of one dog, all dogs exhibited blood clots and colour degradation in venous walls adjacent to the tip of the catheter in the caudal vena cava, along with induration of the surrounding tissue. White macules were found in the heart and lungs, the thymus gland was reduced in size and there was enlargement of the kidneys. However these were considered incidental findings and unrelated to infusion of the test article.

An increase in the weight of the spleen was observed in the 100 mg/kg/hr infusion group. No other notable changes were detected in organ weights.

Kidneys: Slight to mild tubular basophilia was observed in the 100 mg/kg/hr infusion group. This was deemed attributable to magnesium sulphate infusion.

Spleen: The autopsy revealed darkening, slight congestion and increased extramedullary hematopoiesis in the 100 mg/kg/hr infusion group. These changes were deemed reactive changes to anaemia. A slight increase in hemosiderosis was observed.

Bone marrow: A moderate increase in hematopoietic celss was observed in the femur and breastbone. This was considered predominantly a reactive change to anaemia.

Liver: Kupffer cells were found laden with brown pigment in the 100 mg/kg/hr infusion group. Although this was observed in the other infusion groups, including the control group, it was determined to have been caused by magnesium sulphate.

Caudal vena cava: While nearly every dog exhibited phlebitis comprising localised venous intimal thickening and cellular infiltration into the venous wall proximal to the tip of the catheter, there were no significant lesions in any of the dogs approximately 2 cm from the tip of the catheter and no excitovascular properties attributable to the test article were observed.

6. Plasma drug concentration levels:

At 2.0 -2.1 mg/dl, pre-infusion plasma magnesium sulphate concentration levels for all animals were within the range of physiological variation for all animals. After beginning the infusion, these levels were elevated at all points in time relative to dosage, reaching the maximum plasma concentration level in the 50 and 100 mg/kg/hr infusion groups approximately 24 hours after beginning the infusion. On day 29 after finishing the infusion, values decreased over time relative to dosage, returing to pre-infusion levels 4 hours later in the 12/5 mg/kg/hr infusion group and 24 hours later for all other groups. While plasma drug concentration levels 24 hours after beginning the infusion and just before finishing the infusion were almost identical in the 12.5 mg/kg/hr infusion group, despite slight elevation in the 50 and 100 mg/kg/hr infusion groups, these levels were deemed insufficient to indicate accumulation.

Applicant's summary and conclusion

Conclusions:
The NOAEL of magnesium hydroxide in beagle dogs was determined to be 50 mg/kg/hr over four weeks.
Executive summary:

A continuous infusion of magnesium sulphate was administered 24 hours/day for 4 weeks. This resulted in a decrease in body weight and food consumption, anaemia, increased urine volume, decreased serum calcium, increased inorganic phosphorous, delayed conduction and tubular basophilia in the 100 mg/kg/hr infusion group. Changes in the groups treated with an infusion of 50 mg/kg/hr or less were either unobserved or extremely mild. All the changes in the 100 mg/kg/hr infusion group exhibited recoverability upon drug withdrawal at the same doses in a 2 week infusion study, which confirmed reversibility in all changes that occurred in this study. From the above results, the nontoxic dose of magnesium sulphate under the conditions of this study was determined to be 50 mg/kg/hr.