Magnesium methanolate

Endpoint summary

Description of key information

Magnesium methanolate rapidly hydrolyzes in aqueous environments. Toxicity is mediated by its degradation products MeOH and Mg(OH)2 and assessed for these products.

MeOH

Methanol is readily absorbed after inhalation, ingestion and dermal contact and distributed rapidly throughout the body. The clearance from the body is mainly due to metabolism (up to 98%), with more than 90% of the administered dose exhaled as carbon dioxide. Renal and pulmonary excretion rates contribute to only about 2 – 3%. The metabolism and toxicokinetics of methanol varies by species and dose. In humans, the half-life time is approximately 2.5 – 3 hours at doses lower than 100 mg/kg bw. At higher doses, the half life can be 24 hours or more (IPCS/WHO, 1977; Kavet and Nauss, 1990).

The mammalian metabolism of methanol occurs mainly in the liver, where methanol is initially converted to formaldehyde, which is in turn converted to formate. Formate is converted to carbon dioxide and water. In humans and monkeys, the oxidation to formaldehyde is mediated by alcohol dehydrogenases and basically limited to the capacity of those enzymes. In rodents, the oxidation to formaldehyde predominantly employes the catalase-peroxidase pathway which is of less capacity than the ADH-pathway in humans but on the other hand produces oxygen radicals which may be involved into the developmental effects in rodents which - in contrast to humans - tolerate high methanol levels without signs of CNS or retinal toxicity. The last oxidation step, conversion of formate to carbon dioxide employes formyl-tetrahydrofolate synthetase a co-enzyme, is of comparably low capacity in primates which leads to a low clearance of formate, possibly also from sensitive target tissues (such as CNS and the retina) (DFG 1999; IPCS/WHO, 1997; Dorman et al., 1994; Medinsky et al., 1997, Medinsky and Dorman, 1995; Mc Martin et al., 1977).

In humans, when exposed to methanol via inhalation up to an air concentration 65 mg/m3, no increase of blood methanol is expected. Up to 260 mg/m3 (single or repeated exposure) the methanol blood level is likely to increase only 2- to 4- fold above the endogenous methanol concentration in humans, but still remains significantly below 10 mg/L (Lee et al., 1992; NTP, 2003). Up to air concentrations of 1600 mg/m3 the blood methanol levels increase to a similar extent in rats, monkeys, and humans. However, above this concentration rats show a steep exponential increase which apparently reflects the saturation of the catalase-dependent pathway. A smaller exponential increase was observed in monkeys, whereas in humans there appears to be a linear relationship between air concentrations and blood methanol levels.

Baseline levels of formate in blood are about 3 to 19 mg/L (0.07 – 0.4 mM) in humans. Toxic blood formate concentrations are reported to be 220 mg/L and higher (> 5 mM formate). Inhalation of about 1200 mg methanol/m3 for 2.5 hours contributed only insignificantly to the internal formate pool in monkeys (in the μM-range). This also hold true for folate-deficient conditions. After repeated inhalation of 2600 mg/m3 for 6 hours/day, 5 days/week, for 1 or 2 weeks, monkeys showed no discernible increase in formate concentrations in blood (estimated body burden 200 to 300 mg/kg bw/d). Formate accumulation, however, has been observed in primates upon bolus administration of more than 500 mg Methanol/kg bw (Horton et al., 1992; Medinsky and Dorman, 1995). The critical methanol dose that saturates the folate pathway in humans is estimated to be ≥ 200 mg/kg bw. Based on data produced in monkeys, metabolic saturation in humans is also less likely to happen upon inhalation where the dose is distributed over several hours (DFG 1999; IPCS/WHO, 1997; Burbacher et al., 1999).

There is a strong link between saturation (zero-order) kinetics and the onset of acute toxic effects. Exposure levels in humans above 5000 ppm (750 mg/kg bw in the course of 8 hrs) are prone to a zero order kinetic and a strong accumulation of methanol in the blood. Transient blindness has been reported for exposure levels between 1000 and 5000 ppm. (this saturation point could be reached after oral uptake at lower dose levels.) 10.000 ppm are still tolerated in rodents but would be highly detrimental in humans.

Mg(OH)2

In general solids need to be dissolved 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 favourable 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 15 μm 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) favours 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, dermal absorption is not considered to exceed 50%.