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

Oral:

LD50 > 1187-2769 mg/kg bw for rats (BASF 1975, BASF 1961)

LD50 = 7000-9000 mg/kg bw for monkeys (Cooper and Felig 1961; in the study from Potts et al. 1955, the LD50 value was 6000 mg/kg bw, but following bicarbonate supplementation)

Dermal:

LD50 ca. 17100 mg/kg bw for rabbits (Rowe and McCollister, 1981)

Inhalation:

LC50 = 128200 mg/m³ air for rats after 4-hour exposure (BASF 1980b)

LC50 = 85400 mg/m³ air for cats after 4.5-hour exposure, and 43700 mg/m³ after 6-hour exposure

Mg(OH)2

Oral:

LD50 > 2000 mg/kg bw for rats

Inhalation:

LC50> 2100 mg/m³

Additional information

MeOH

Animal data:

Oral:

In rats, LD50 values after single oral administration range from 1187 to 2769 mg/kg bw, depending on the concentration of the aqueous solution used (BASF 1975, concentrations 15 to 35%, not further specified).

In Rhesus monkeys orally dosed with 6000 mg/kg bw, the retina and the optic papilla showed extended oedema, and the pupils were wide and non-responsive. Six of 8 animals exhibited cystic degeneration of the outer retinal granular layer, and in one animal there was evidence of significant demyelinisation of the optic nerve. Histological lesions were seen in the putamen and nucleus caudatus in 3 of 8 animals. All of these effects were most pronounced after early compensation of acidosis using bicarbonate application, because the monkeys generally did not survive those high doses of methanol without an early treatment with bicarbonate (Potts, 1955; Potts et al., 1955).

There was no evidence of marked acidosis in 12 Rhesus monkeys (28 applications) after sublethal doses up to 6000 mg/kg bw. Specifically, there was no hyperventilation, no increase in urinary excretion of organic acids, or shift in serum bicarbonate. Blindness was seen in only one surviving monkey dosed with 9000 mg/kg bw; the effect was transient four days after exposure. The LD50 was between 7000 and 9000 mg/kg bw (Cooper and Felig, 1961).

Inhalation:

In male and female rats, LC50 values of 87.5 mg/L (6 hours) and 128.2 mg/L (4 hours) were determined (BASF, 1980a,b). Clinical signs of toxicity were aqueous secretion of eyes and nose, labored breathing, staggering, apathy, and narcosis.

A similar range of toxicity values is reported for the mouse: LC50 (2.25 h) = approx. 79 mg/L (Von Burg, 1994).

In cats, a LC50 value of approx. 43.7 mg/L was obtained after a 6 hour exposure (Von Burg, 1994). A shorter duration of 4.5 hours led to a LC50 value of 85.4 mg/L (Von Burg, 1994).

Studies in Rhesus monkeys indicated lethal concentrations (% mortality not reported) of 1.3 mg/L (after 41 hours), 13 mg/L (after 18 hours) and 52 mg/L methanol (after 1–4 hours). Blindness associated with optic nerve atrophy was reported. Eventual recovery from this lesion was observed (McCord, 1931; only limited documentation).

Dermal:

Methanol is classified as acute toxic Cat.3 (H301,H311,H331) according to the EU Regulation 1272/2008. Therefore, animal testing regarding acute dermal toxicity is not necessary.

In rabbits, a dermal LD50 of about 17,000 mg/kg bw was found. No further details were reported (Rowe and McCollister, 1981).

Human data:

Due to misuse of methanol in the production of alcoholic beverages, oral ingestion is the most frequent route of poisoning, death and blindness from methanol. However, there are also case reports from percutaneous absorption or vapor inhalation having elicited the methanol acute toxic syndrome.

A blood level of 500 mg/L methanol in acutely poisoned patients is generally regarded as an indication for hemodialysis. This blood concentration can transiently be achieved in an adult person (70 kg) by ingestion of 0.4 mL methanol/kg bw (Kavet and Nauss, 1990). Generally, in humans, transient central nervous system (CNS) effects appear at blood methanol levels of 200 mg/L and serious ocular symptoms appear above 500 mg/L ranging from mild photophobia, misty or blurred vison to markedly reduced visual acuity and total blindness (Kavet and Nauss, 1990; Dethlefs and Naraqi, 1978). Acute methanol intoxication evolves in a well-defined pattern. First, a mild depression of the CNS occurs, which is followed by an asymptomatic latent period commonly lasting 12 to 14 hours. Thereafter, clinical symptoms include headache, dizziness, nausea and vomiting, abdominal pain, and labored, periodic breathing and mag progress to coma and death from respiratory failure (Kavet and Nauss, 1990).

The minimal acute methanol dose to humans that can result in death is considered to be 300 to 1000 mg/kg by ingestion. Fatalities have occurred in untreated patients with initial methanol blood levels in the range of 1500 to 2000 mg/L (IPCS/WHO, 1997). In general, coma, seizures and prolonged acidosis were poor prognostic signs (Naraqi et al., 1979). Such high and potentially lethal blood methanol levels are less likely to be achieved from inhalation exposure. Exposure to 0.26 mg/L methanol for 4 hours was without significant physiologic effects in human volunteers (Muttray et al., 2001).

In conclusion, there are two dominating acute effects from methanol: blindness and metabolic acidosis. For the latter, formate is considered to be the ultimate toxicant in acute methanol intoxication in humans. Acidosis and ophthalmologic changes are typical effects in primates. They do not occur in rodents or rabbits, which are able to remove formate more efficiently. In these animals, CNS depression, narcosis and death are the leading symptoms of intoxication. Although the mechanism for optic nerve damage from exposure to methanol has not been established, potential mechanisms and the possible role of formate are discussed in section 5.10.3.

Mg(OH)2

Oral:

According to the key study, the oral LD50 value of Magnesium hydroxide in Wister rats was established to exceed 2000 mg/kg body weight. According to OECD 423 test guideline, the LD50 cut-off value was considered to exceed 5000 mg/kg body weight. Based on these results, magnesium hydroxide does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to the:- Globally Harmonised System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007)-Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.

Furthermore, magnesium hydroxide is extensively used as a medical drug in humans as an antacid to neutralise stomach acid and assist in the treatment of indigestion and heartburn. It is also used as a laxative and as an antiperspirant deodorant and can be useful as a topical treatment for canker sores. In its form as an indigestion and heartburn treatment, it is sold over the counter in most supermarkets, chemistries and convenience stores and does not require a prescription from a physician to be purchased. It is administered orally, usually as a chewable tablet, capsule or a suspension in water known as milk of magnesia.

The ubiquitous use of magnesium hydroxide under these therapeutic conditions, with direct skin and oral exposure, further contributes to the evidence that magnesium hydroxide is a substance of low toxicological concern.

Inhalation:

According to the key study, the inhalatory LC50 (4h) value of Magnesium hydroxide in Wistar rats exceeds 2.1 mg/L, which was the technical maximum feasible concentration that could be tested.

Dermal:

According to Annex VIII of Regulation (EC) No 1907/2006, a study on acute dermal toxicity is not required when oral and inhalation acute toxicity studies are provided. As there are studies to address oral and inhalation toxicity, a test on dermal toxicity is not scientifically justified. Furthermore it is unlikely that dermal absorption of an ionic compound will exceed its oral absorption. As the acute oral toxicity was low (LD50 > 2000 mg/kg bw in rats), this can be reasonably

expected for acute dermal toxicity as well.

Justification for classification or non-classification

Magnesium methanolate

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

Based on the classification of MeOH, magnesium methanolate is classified as acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes.

CLP:

Acute toxicity category 3: toxic if swallowed; toxic in contact with skin; toxic if inhaled.

STOT single exposure category 1 (route of exposure: oral, inhalation)

MeOH

Although the lethal dose of methanol is high for most experimental animals (> 2000 mg/kg bw after single oral administration) these data are not employed for classification. The classification is only based upon the experiences in humans and classifies methanol as acutely toxic by oral, dermal and inhalative exposure and, furthermore, as capable of inducing serious irreversible effects upon single exposure by all of these routes.

CLP:

Acute toxicity category 3: toxic if swallowed; toxic in contact with skin; toxic if inhaled.

STOT single exposure category 1 (route of exposure: oral, inhalation)

Mg(OH)2

Based on the available information, magnesium hydroxide does not have to be classified and has no obligatory labelling requirement for acute inhalation, dermal or oral toxicity according to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS) of the United Nations (2007) and Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.