Magnesium ethanolate

Endpoint summary

Description of key information

No bioaccumulation potential, oral absorption 50%, inhalation absorption 100%, dermal absorption: negligible.)
Short description of key information on absorption rate for ethanol: 
Dermal absorption from in vitro studies: 21% maximum absorption (worst case)  Real life absorption typically ~1-2%. Evaporation half life around 12 seconds from skin.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Magnesium ethanolate rapidly hydrolyzes in aqueous environments (t1/2 < 1 minute) into ethanol and magnesium hydroxide (detailed description in section 5.1.2).

 

Ethanol:

ABSORPTION

Ethanol has a low molecular weight (46.07g/mol) and is highly soluble in both water and lipid, allowing absorption across the surface of the gastrointestinal (GI) tract, the lungs and skin. Following ingestion, absorption of ethanol begins immediately with greater than 90% of the consumed dose being absorbed by the GI tract.  The consumption of two alcoholic beverages (approximately 20g ethanol) results in a maximum BEC of approximately 300 mg ethanol/L within one hour; the concentration of ethanol in blood then rapidly declines, reaching endogenous levels after several hours.

 

Ethanol can also be absorbed by inhalation. A recent study using lower levels of ethanol exposure (25 – 1000 ppm) reported a value of between 70 to 80 % absorption (Tardif, 2004), which may be more representative of occupational exposure levels. Once absorbed by this route, the degree of ethanol retention is generally low due to the ‘wash-in-wash out effect’ observed with water soluble chemicals.  Seeber et al., (1994) exposed 24 volunteers to ethanol at 80, 400 and 800 ppm for 4 hours with resulting blood ethanol levels of 0.25, 0.85 and 2.1 mg/l respectively.

It is also possible to make a similar calculation from the Seeber data, from which it is possible to derive a function of BEC(blood ethanol concentration)=exposure (ppm) × 0.0029 (with a 7% error for 95% confidence).  This would give a BEC of 2.9mg/l and an AUC over 8hrs of 23mg.hr/l (lower but not dissimilar).  This can be compared to a similar estimation from the oral data.  Assuming instantaneous distribution and linear kinetics for elimination, a dose of 11.4g would give a BEC of 302mg/l (assuming a volume of distribution of 0.54l/kg and a 70kg person).  If this is eliminated at a rate of 127mg/kg/hr (8.9g/hr), total elimination would occur in 11.4/8.9=1.29hrs.  The area under the triangle is then 194mg.hr/l.  Calculating the other extreme (lighter person – 60kg, slower elimination – 83mg/kg/hr or 4.99g/hr) would lead to a peak BEC of 352mg/l, an elimination time of 2.28hrs and an AUC of 401mg.hr/l.  This demonstrates that a simple calculation of quantitative uptake based on inhalation concentration, duration and percentage uptake significantly overestimates the exposure by a factor of approximately 5-15x compared to when a more relevant measure is used.

 

DISTRIBUTION

Irrespective of the route of exposure, following absorption into the bloodstream, ethanol is distributed throughout the body with the final volume of distribution close to that of total body water, estimated as 50 – 60 % of lean body weight in adults. Ethanol perfuses organs with the greatest blood supply most quickly (brain, lungs and liver) and equilibrium between tissues and blood is generally achieved within 1 – 1.5 hr after ingestion (Bevan, 2009-J Tox Env Hlth B Crit Rev, 12(3), 188-205).

 

METABOLISM

Prior to absorption, ingested ethanol undergoes limited metabolism (first pass metabolism) in the stomach by gastric alcohol dehydrogenase.  The role of first-pass metabolism is, however, not relevant for exposure to ethanol via inhalation and dermal routes. Once absorbed, ethanol is metabolised, principally by the liver, which accounts for 92-95% of capacity with minor amounts metabolised in other tissues such as the kidney and lung (Crabb et al., 1987; Lieber & DeCarli, 1977). A number of metabolic paths are available but only one is relevant to the low blood ethanol concentrations likely to result from either inhalation or dermal exposure and only this mechanism is described here.  In such cases, Ethanol metabolism in the liver is carried out in three steps, namely, (i) oxidation of ethanol to acetaldehyde (AcH), (ii) conversion of AcH to acetate and (iii) oxidation of acetate to carbon dioxide and water. In the first step, ethanol is converted to AcH by alcohol dehydrogenase (ADH) which occurs in the soluble fraction of liver cells (cytosol).  The conversion of ethanol to AcH by ADH is the rate-limiting step in ethanol metabolism as ADH has a low Michaelis-Menten constant (Km).  ADH has been shown to exhibit polymorphisms that affect functional activity (Pastino et al., 2000) accounting for ethnic variations in the pharmacokinetics of ethanol (Norberg et al., 2003).   In a study to examine the metabolism of ethanol and in particular the difference between humans with normal and humans with deficient ALDH, 60 volunteers were given a single oral dose of ethanol and the elimination kinetics determined by following subsequent blood ethanol levels with time. The data showed that there is a slight but not a significant difference in the ethanol elimination rates between those with normal ALDH and those with deficient ALDH.  In a study to examine the metabolism of ethanol and in particular the difference between humans with normal and humans with deficient ALDH and the contribution of first pass metabolism, male volunteers were given oral doses of ethanol and the elimination kinetics were determined by following subsequent blood ethanol levels with time. This was compared to similar doses given intravenously. The effect of fasting versus eating prior to dosing was also examined. The data showed that resultant blood ethanol concentrations were always lower by the oral route and that oral dosing on a full stomach greatly reduced oral uptake. The study also showed that deficient ALDH resulted in greatly increased blood acetaldehyde concentrations but not significantly increased ethanol levels. Skin has many of the enzymes that occur in the liver but its metabolising potential is considered too small to be considered for most chemicals (Bando et al., 1997) at an estimated 2% of that of the liver (Pannatier et al., 1978). However, there is some evidence from a more recent ex vivo animal study that repeated dermal exposure may result in increased metabolic activity in the skin (Lockley et al., 2005) . In the second step of ethanol metabolism, AcH is rapidly converted to acetate by the enzyme acetaldehyde dehydrogenase (ALDH).  Acetate formed in the liver following oxidation of ethanol has a high ratio of NADH/NAD+ and as a consequence cannot be incorporated into the citric acid cycle. In the final step of ethanol metabolism, acetate produced from the oxidation of AcH is therefore released into the blood and oxidised extra-hepatically to carbon dioxide and water by peripheral tissues.

In a human volunteer study using 24 men and women, it was established that exposures of up to 2000ppm of ethanol for periods of up to 4 hours do not saturate metabolism and that elimination kinetics are first order. A linear relationship was established between exposure concentration and resultant blood ethanol concentrations, leading to the prediction that the a maximum blood ethanol concentration of 2.9mg/l results from an (indefinite) exposure to 1000ppm of ethanol.

 

ELIMINATION

The majority of absorbed ethanol is eliminated from the body by metabolism (95 –-98 %; Norberg et al., 2003), but the process has limited capacity. However, this is extremely unlikely to be overwhelmed at the blood ethanol concentrations estimated to result from occupational exposure to ethanol. The maximum amount of ethanol that can be metabolised per hour has been estimated to be between 83 – 127 mg/kg/hr, or 8 – 9 g ethanol/hr.  Elimination rates can be influenced by both environmental and genetic factors leading to intraspecies variation in rates (Jones, 1984). A small concentration of ethanol (2 – 5 %) is also eliminated unmetabolised in breath, urine and sweat (Holford, 1987; Norberg et al., 2003).  This conclusion is supported by a study which both contained original data and the results of other published studies, human volunteers were given varying oral doses of ethanol and the elimination rate followed by measuring decaying blood ethanol concentration. Ethanol was found to be rapidly eliminated with a typical elimination rate constant of 11 -15mg/dl/hr over the range of doses examined (0.5 -0.8g/kg). It was noted that the elimination rate increase slightly but significantly with dose and that the range of rate constants varied by a factor of 3 from 8 -13mg/dl/hr in the relatively large number of subjects studied.

 

Blood ethanol concentrations were estimated from breath analysis of a healthy male volunteer over time after consumption of 5 g ethanol diluted in orange juice. The elimination of exogenous ethanol took just over 2 hr, with a half-life of about 16 minutes. Expired alveolar air, from two men and one woman who had consumed between 0.26 and 0.6 g ethanol/kg bw in five separate experiments, was analysed for ethanol concentrations, in an attempt to determine the rate of ethanol disappearance from the human body. The rate of disappearance of ethanol was linear down to levels of ethanol in the serum of 100 mg/L, or in some subjects as low as 50 mg/L. Below this level, it was determined that the rate of disappearance, in mg/L serum/hr, may be calculated as the product of the concentration of ethanol in serum (mg/L) by the constanct 1.64.

 

It was noted that the elimination rate increases slightly but significantly with dose and that the range of rate constants varied by a factor of 3 from 8 -13mg/dl/hr in the relatively large number of subjects studied. Another study examined the concentration-time profiles of ethanol in capillary blood for 21 fasted men after ingesting 0.68g/kg of ethanol. The concentration-time profiles varied significantly between subjects, particularly in peak levels, however peak ethanol concentrations were close the the maximum predicted assuming 100% absorption and instant distribution in body fluids. The rate of elimination was found to be 85mg/kg/hr +/-6.4 with complete disappearance from the blood 494mins +/-38 (8.2hrs) after ingestion. In conclusion, elimination is constant and ethanol taken in at rates below the limiting rate of elimination are not likely to lead to any accumulation of ethanol in the blood.

 

 

Magnesium hydroxide

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 was estimated to be 30-50% in humans and 54 to 65% in rats. 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 water compartments 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 ionisation 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.The half life of magnesium ions in humans after i.v. administration was reported to be 4 h.

Magnesium hydroxide particles have the potential to be inhaled by humans. Particles with aerodynamic diameters below 50μm 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%.

 

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, it is considered that dermal absorption is negligible.