Magnesium hydroxide

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Sex:

female

Details on absorption:

The analysis of data from eight experiments with magnesium chloride infusion alone demonstrated a reabsorptive Tm for magnesium of approximately 140 ug/min per kg body weight. This Tm was reached when filtered magnesium was 280 µg/min per kg body weight. There was a substantial decrease in Tm magnesium during saline or calcium infusion and following chronic treatment with DCA; the Tm values were 80, 85, and 75 µg/min per kg body weight respectively. Under these conditions the Tm values were reached at filtered loads of 150 µg/min per kg body weight.

Details on excretion:

In the majority of experiments glomerular filtration rate (GFR) remained relatively stable during the infusion of magnesium salts, although a fall in GFR of 10-30% occurred in 8 of 32 experiments when the blood levels of magnesium were highest. In both the anesthetized and unanesthetized dogs, magnesium infusion caused a rapid increase in magnesium excretion. The percent of filtered magnesium excreted ((magnesium clearance (Cmg)/creatinine clearance (Ccr)) X 100) rose steeply as diffusible serum magnesium was elevated from 1.5 to 7.0 mg/100mL with a further increase in the levels of diffusible serum magnesium (7.0-12.0 mg/100mL), the fraction of filtered magnesium excreted increased much more slowly, reaching 60-75%. The relationship between (Cmg/Ccr) X 100 and the diffusible magnesium content of the serum was similar whether serum magnesium was rising or falling. The percent of filtered magnesium excreted during MgSO4 infusion was not different from that observed with MgCl2 infusion for any given level of diffusible serum magnesium.

With the rise in urinary magnesium, calcium excretion increased immediately. Urinary calcium constituted 15-20% of the filtered load when the diffusible levels of serum magnesium reached 7.0-12.0 mg/100mL. Sodium excretion also increased with magnesium infusion, but the increment was less pronounced than that of calcium and did not occur until 2 hours after the initiation of the magnesium infusion.

The simultaneous infusion of MgCl2 and normal saline to normal and DCA-treated dogs and the infusion of MgCl2, normal saline, and CaCl2 to normal dogs resulted in the excretion of a greater percent of filtered mangesium for any given level of serum magnesium as compared to the data from MgCl2 infusion alone.

Parathyroid extract administration during magnesium infusion caused a decrease in the percent of filtered magnesium excreted in all experiments as compared with results observed during MgCl2 infusion alone. This effect became apparent 4 to 5 hours after the first injection of PTE. With PTE administration, urinary calcium was also lower when compared to results from experiments with MgCl2 infusion alone.

The data strongly suggest that the decrease in tubular reabsorption of magnesium observed at physiological serum magnesium levels and filtered loads during saline infusion, calcium infusion, or following chronic DCA treatment is probably the result of reduced Tm magnesium. The observations that acute reduction in glomerular filtration rate had little or no effect on Tm magnesium indicate that the latter is independent of glomerular filtration rate. The tubular mechanism for reabsorption of magnesium may be saturated by a sufficient rise in plasma concentration and filtered load. Reduction in glomerular filtration rate would be expected to have no influence on maximum reabsorptive capacity if filtered load exceeds the saturation limit. A similar lack of dependence of maximal tubular reabsorption on glomerular filtration rate has been reported for other substances such as phosphate and glucose for which a maximum reabsorptive capacity exists.

 

The lack of difference in the relationship between (Cmg/Ccr) X 100 and the concentration of diffusible magnesium in serum while the latter was either rising during MgCl2 infusion of falling after the infusion had been discontinued indicates that the change in filtered magnesium is the primary determinant of urinary excretion at these serum levels. Furthermore, these observations suggest that hormonal factors, which might be brought into play by hypermagnesemia, have little if any effect on renal handling of magnesium under these experimental conditions.

 

In the present study, magnesium excretion did not exceed filtered load during the infusion of large amounts of magnesium chloride or sulphate. Even when factors known to decrease tubular magnesium reabsorption such as NaCl infusion, CaCl2 infusion and chronic DCA treatment were superimposed on magnesium chloride infusion, the percent of filtered magnesium excreted did not exceed unity.

 

The data show that in every case the Cmg/Ccr fell with the reduction in GFR and filtered magnesium. It appeared, therefore, that magnesium, like sodium and calcium, is handled by the kidney by filtration and tubular reabsorption alone. However, a secretory process of small magnitude, if at all present, might not be identified with the clearance technique. Such a theoretical secretory system, if quantitatively limited and quickly saturated, at or near the normal serum magnesium level, would be obscured as serum magnesium increases. The subsequent behavior of the renal handling of magnesium would appear to be entirely the result of filtration and reabsorption alone.

 

The intramuscular injection of parathyroid extract decreased fractional magnesium excretion in every animal despite the presence of high filtered magnesium which favors increased excretion. Fractional calcium excretion was also reduced raising the possibility that the change in urinary magnesium was secondary to that of calcium. This supposition seems remote. Since the augmentation of urinary calcium occurred secondary to magnesium loading and since the relative rates of magnesium reabsorption and excretion was so great, it is unlikely that changes in urinary calcium can influence magnesium excretion under these experimental conditions. It is more reasonable that both magnesium and calcium excretion were affected simultaneously by thyroid extract. The present data, therefore, support the concept that parathyroid hormone can enhance tubular magnesium reabsorption per se.

Conclusions:

The authors studied the renal excretion of magnesium sulphate in dogs under various conditions. They concluded that magnesium like sodium and calcium is filtrated and reabsorbed in the kidneys of dogs. They did not find any evidence of tubular secretion. A maximum tubular reabsorption capacity of 140 μg/min/kg bw was reported.

Executive summary:

In a study from Massry et al., renal handling of Mg was evaluated in 30 dogs receiving 1.0 -3.0 µg Mg/min per kg body weight with gradual elevation of diffusible serum magnesium (dSMg) to 12 mg/100mL. The fraction of filtered Mg excreted (Cmg/Ccr) rose steeply as dSMg increased to 7.0 mg/100mL; with further rise in dSMg the Cmg/Ccr increased more slowly. Relationship between dSMg and Cmg/Ccr increased more slowly. Relationship between dSMg and Cmg/Ccr was not different during a rising or falling dSMg or with infusion of MgCl₂ or MgSO₄. Magnesium reabsorption increased to reach a Tm of 140 µg/in per kg body weight when filtered load was 280 µg/min per kg body weight. When factors known to decrease magnesium reabsorbtion were superimposed on MgCl2 infusioin, Cmg/Ccr was higher for any level of dSMg compared to MgCl₂ infusion alone but never exceeded unity; with acute reduction in GFR, Cmg/Ccr invariably fell and magnesium reabsorption remained unchanged. Parathyroid extract administration during MgCl₂ infusion caused a fall in Cmg/Ccr. Results indicate that 1) Magnesium excretion is determined by filtration and reabsorption without evidence of tubular secretion; 2) There is a maximum tubular reabsorptive capacity for magnesium; 3) Extracellular volume expansion produced by NaCl infusion, CaCl₂ infusion, or chronic CDA treatment are associated with a decrease in magnesium Tm; 4) Parathyroid hormone may directly enhance magnesium reabsorption.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reference 2

Endpoint:

basic toxicokinetics in vivo

Type of information:

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

Adequacy of study:

supporting study

Justification for type of information:

For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Details on absorption:

When magnesium sulphate is administered intramuscularly, the plasma concentration shows a slow increase which reaches a plateau in about 1 to 2 hours and is followed by a slow decline back to the control level during the next 6 to 8 hours. After 4 hours when another dose is injected, the rates of absorption, distribution and excretion are about equal and the plasma magnesium concentration remains fairly constant.

Details on distribution in tissues:

The pharmacokinetic profile has been described by a 2 -compartment model, with a rapid distribution phase followed by a relatively slow phase of elimination. Magnesium administered parenterally is initially distributed into the intravascular compartment. The intravascular unbound ion diffuses into the extravascular-extracellular space, into bone, and across placenta and fetal membranes and into the fetus and amniotic fluid. There is a fairly large amount in the cells, and only a small quantity in the extracellular fluid. It is only this part which is measured by plasma or serum concentrations of magnesium that is available for study.

Details on excretion:

Magnesium sulphate is excreted by the maternal kidney, which represents the sole route of elimination. Urinary excretion is very rapid and increases 20-fold during magnesium sulphate infusion. At the end of 4 hours, from 38 to 53 % of the total injected magnesium has been excreted. By 24 hours after the infusion more than 90 % has been eliminated. Once all extracellular fluid magnesium concentrations have reached equilibrium with serum, the rate of urinary magnesium excretion equals the rate of infusion, and the 24 -hour excretion of magnesium is almost equal to the amount administered. The half-life of magnesium sulphate in patients with normal renal function is 4 hours.

Details on metabolites:

Magnesium sulphate is not metabolised.

Protein binding: After administration, about 40% of plasma magnesium is protein bound. The injected magnesium is promptly bound to plasma proteins to the same degree as that of endogenous magnesium. The serum ionised magnesium concentrations were determined during intravenous magnesium sulphate therapy in 6 pre-eclamptic women. The amount of ionised magnesium was found to rise proportionately to the total serum concentration of magnesium.

Conclusions:

Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted by 24 hours after the infusion. The half-life in patient with normal renal function is 4 hours. About 40% of plasma magnesium is protein bound. Magnesium ions can cross the placental membrane and are distributed in the fetus. Maternal and fetal blood levels were reported to equilibrate in about 2 hours. Distribution to breast milk is very limited. Urinary excretion of magnesium ions is very rapid in humans with normal renal function. The half life was reported to be 4 h.

Executive summary:

In a publication from Lu et al., the currently available knowledge of the pharmakokinetics of magnesium sulphate and its clinical usage for women with pre-eclampsia and eclampsia is outlined.

Magnesium is almost exclusively excreted in the urine, with 90% of the dose excreted by 24 hours after the infusion. The half-life in patient with normal renal function is 4 hours. About 40% of plasma magnesium is protein bound. Magnesium ions can cross the placental membrane and are distributed in the fetus. Maternal and fetal blood levels were reported to equilibrate in about 2 hours. Distribution to breast milk is very limited. Urinary excretion of magnesium ions is very rapid in humans with normal renal function. The half-life was reported to be 4 h.

This information is used in a read-across approach in the assessment of the target substance. For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Qualifier:

no guideline available

Principles of method if other than guideline:

- Principle of test: Estimation of the time required to achieve steady-state concentrations (i.e. saturation of metabolism) after oral ingestion of magnesium hydroxide
- Short description of test conditions: 10 patients were given 2 to 6 oral magnesium hydroxide tablets (125 to 750 mg of Mg2+) daily for six months, followed by 2 tablets daily until a steady-state serum concentration was achieved.
- Parameters analysed / observed: Measurement of the initial serum magnesium concentration and steady-state, mean 24-hour urinary magnesium, clinical signs

GLP compliance:

no

Radiolabelling:

not specified

Species:

human

Sex:

female

Details on test animals or test system and environmental conditions:

10 female hypomagnesaemic patients consecutively admitted to the Back Rehabilitation Unit of Ichilov Hospital with complaints of musculoskeletal pain on non-malignant origin, who had normal serum creatinine concentrations and no history of kidney disease, who were free from hypotension, atrio-ventricular block and myasthenia gravis and were aged 41 to 66 years, were included in an open study.

Route of administration:

oral: capsule

Duration and frequency of treatment / exposure:

The patients were first given 2 magnesium hydroxide tablets to chew (on an empty stomach) at bedtime. If diarrhoea occurred, they were instructed to stop the treatment for 8 days and restart it with only 1 tablet daily. The dose was titrated upwards according to individual tolerance, to reach a maximum of 2 tablets 3 times daily (750mg Mg++) chewed and swallowed on an empty stomach (to prevent formation of insoluble complexes). This dose was given for 6 months, after which patients received 2 tablets once daily.

Remarks:

250 to 750 mg daily for the first 6 months

No. of animals per sex per dose / concentration:

10 female hypomagnesaemic patients aged between 41 and 66 years were included in this study. All patients were treated with with magnesium hydroxide in oral tablets.

Statistics:

Means and standard deviations were calculated for serum magnesium concentration before treatment, throughout the study, and after achievement of steady-state. Means of the 2 consecutive urinary magnesium measurements were calculated for each estimation. Mean time of treatment until steadystate was achieved was calculated.

Preliminary studies:

Using oral magnesium hydroxide tablets in a dosage of 250 to 750 mg daily for the first 6 months, and 250 mg/day thereafter, the mean time to steady-state was 12.4 ± 6.2 months (range 3.2 to 20).
The only side effect observed in the treated patients was lowering of serum phosphate concentrations in 3 patients.

Since there is a positive correlation between urinary magnesium and the intracellular content (Sjogren et al. 1987; Setending-Lindberg et al. unpublished data) urinary magnesium may serve as an index for the intracellular status of the ion.

 

Mean time to steady state after oral treatment with 250 to 750 mg/day over 6 months followed by 250 mg/day thereafter was 12.4 ± 6.2 months (3.5 to 20 months). Steady state serum levels ranged between 0.82 and 1.06 mmol/L. Urinary excretion at steady state was 5.7 ± 1.14 mmol/L (range 4.3 to 7.7) The wide range of the times to steady state cannot be attributed to differences in absorption but are also related to the state of magnesium depletion in the patients. The authors report results of other studies on bioavailability: after oral administration of magnesium hydroxide bioavailability was reported to be between 33 and 50% in humans. Bioavailability in rats for different magnesium salts ranged between 54 and 65 %.

Conclusions:

Since there is a positive correlation between urinary magnesium and the intracellular content (Sjogren et al. 1987; Setending-Lindberg et al. unpublished data) urinay magnesium may serve as an index for the intracellular status of the ion.
Mean time to steady state after oral treatment with 250 to 750 mg/day over 6 months followed by 250 mg/day thereafter was 12.4 ± 6.2 months (3.5 to 20 months). Steady state serum levels ranged between 0.82 and 1.06 mmol/L. Urinary excretion at steady state was 5.7 ± 1.14 mmol/L (range 4.3 to 7.7) The wide range of the times to steady state cannot be attributed to differences in absorption, but are also related to the state of magnesium depletion in the patients. The authors report results of other studies on bioavailability: after oral administration of magnesium hydroxide bioavailability was reported to be between 33 and 50% in humans. Bioavailabilities in rats for different magnesium salts ranged between 54 and 65 %.

Executive summary:

In a publication from Stendig-Lindberg, the time required to achieve steady-state concentrations of magnesium hydroxide after oral ingestion was determined.

In this study, 10 patients were given 2 to 6 oral magnesium hydroxide tablets (125 to 750 mg of Mg2+) daily for six months, followed by 2 tablets daily until a steady-state serum concentration was achieved.

The initial serum magnesium concentration was 0.703±0.008 mmol/L, measured by atomic absorption spectrophotometry, and at steady-state was 0.910 ± 0.006. The mean 24-hour urinary magnesium was initially 3.80±2.34 mmol/24h, increasing to 5.70 ± 1.14 mmol/24h. Mean time to achieve steady-state was 12.4±6.2 (range 3.5 to 20) months. The only adverse effect, apart from diarrhea at high doses, was a reduction in serum phosphate concentration after 9 months in one patient, and after 12 months in a further 2 patients.Itis suggested that the range of 0.82 to 1.06 mmol/L serum magnesium concentration observed on saturation of metabolism should serve as a basis for defining the target range of serum magnesium concentrations in magnesium therapy.

Mean time to steady state after oral treatment with 250 to 750 mg/day over 6 months followed by 250 mg/day thereafter was 12.4 ± 6.2 months (3.5 to 20 months). Steady state serum levels ranged  between 0.82 and 1.06 mmol/L. Urinary excretion at steady state was 5.7 ± 1.14 mmol/L (range 4.3 to 7.7)  The wide range of the times to steady state cannot be attributed to differences in absorption, but are also related to the state of magnesium depletion in the patients. The authors report results o f other studies on bioavailability: after oral administration of magnesium hydroxide bioavailability was reported to be between 33 and 50% in humans. Bioavailabilities in rats for different magnesium salts ranged between 54 and 65 %.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - inhalation (%):

100

Additional information

Solids need to be dissolved in general before they can be absorbed, and the water solubility of magnesium hydroxide is relatively low (~2 mg/L). Most studies suggest that magnesium is absorbed predominantly in the distal intestine. Magnesium absorption occurs primarily by intercellular diffusional and solvent drag mechanisms, as expected based on its low molecular weight. The bioavailability of orally administered magnesium salts is estimated to be 30-50%. For risk assessment purposes oral absorption of magnesium hydroxide is set at 50%. The results of the toxicity studies do not provide reasons to deviate from this proposed oral absorption factor.

Once absorbed, distribution of magnesium hydroxide throughout the body is expected based on its relatively low molecular weight. About 40% of plasma magnesium is protein bound. Signs of magnesium toxicity appear at serum magnesium concentrations of 1.5 mmol/L. Magnesium ions cross the placenta and are rapidly taken up by fetal tissues. Magnesium may be incorporated into the hair and nails. Magnesium hydroxide has characteristics favorable for fast urinary excretion: low molecular weight (below 300), reasonable water solubility, and ionization of the molecule at the pH of urine. Urinary magnesium excretion is very rapid in humans with normal renal function, the magnesium clearance increasing as a roughly linear function of the serum magnesium concentration.

Magnesium hydroxide particles have the potential to be inhaled by humans. Particles with aerodynamic diameters below 50 μm may reach the thoracic region and those below 15μm the alveolar region of the respiratory tract. Low water solubility and small particle size will enhance penetration to the lower respiratory tract. Small ions will diffuse through aqueous channels and pores. For risk assessment purposes the inhalation absorption of magnesium hydroxide is set at 100%.

The skin sensitisation study is being treated as a false positive. The low molecular weight of magnesium hydroxide (less than 100) favors dermal uptake but based on its water solubility (~2 mg/L), absorption is anticipated to be low to moderate. Although a partition coefficient cannot be determined for magnesium hydroxide, it is considered to be <-1. This suggests that magnesium hydroxide is not sufficiently lipophilic to cross the stratum corneum and dermal absorption is likely to be low. Therefore, we consider the dermal absorption not to exceed 50%.