Sodium ethanolate

Endpoint summary

Additional information

No data are availble for sodium ethanolate. But it rapidly hydrolyses to sodium hydroxide (NaOH) and ethanol in the presence of water.

Several information are available for NaOH and ethanol.

NaOH is highly corrosive, but is not expected to become systemically available under normal handling conditions (at non-irritating concentrations). Sodium is a normal constituent of the blood and an excess is excreted in the urine. Most of the sodium is taken up via the food because the normal uptake of sodium via food is 3.1-6.0 g per day according to Fodor et al. (1999). Exposure to NaOH could potentially increase the pH of the blood. However, the pH of the blood is regulated between narrow ranges to maintain homeostasis. Via exhalation of carbon dioxide and via urinary excretion of bicarbonate, the pH is maintained at the normal pH of 7.4-7.5 (EU RAR, 2007, section 4.1.2.1, page 63).

Mean daily sodium intakes of populations in Europe range from about 3-5 g (about 8 -11 g sodium hydroxide) and are well in excess of dietary needs (about 1.5 g sodium/day in adults) (EFSA, 2006). The main source of sodium in diet is from processed foods (about 70 -75% of the total intake), with about 10 -15% from naturally occuring sodium in unprocessed foods and about 10 -15% from discretionary sodium added during cooking and at the table. The major effect of increased sodium intake is elevated blood pressure which is linked to that of chloride. This is a continuous relationship which embraces the levels of sodium habitually consumed. For that reason, it is not possible to determine a threshold level of habitual sodium consumption below which there is unlikely to be any adverse effect on blood pressure. Evidence that high sodium intake might have a direct adverse effect on heart function, independent of any secondary effect due to changes in blood pressure, is not conclusive. The Panel (EFSA, 2006) concludes that the available data are not sufficient to establish an upper level (UL) for sodium from dietary sources.

Ethanol 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 more than 90% of the consumed dose being absorbed by the GI tract. The consumption of approximately 20 g ethanol results in a maximum BEC (blood ethanol concentration) of approximately 300 mg ethanol/L within one hour. The concentration of ethanol in blood rapidly declines.

Ethanol can also be absorbed by inhalation. An approximate value of 60% absorption of inhaled ethanol could be shown in human studies with levels of ethanol ranging from 5000 to 10,000 ppm (Lester, 1951). This is supported by a further study where lower levels of ethanol were used (25 – 1000 ppm). Here, a value of between 70 to 80 % absorption was documented (Tardif, 2004).

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. A PBPK model for inhaled ethanol was established by Lester and Greenburg (1951) for mice and rats which has subsequently been adjusted and applied to humans by Conolly et al., (1999). Here, it has been calculated that at exposure levels of up to 9500 mg/m3 (5000 ppm) for 8 hours (ventilation rate of 9 l/min) ethanol metabolism was not saturated and the liver was able to metabolize the ethanol at the rate that it entered the body. With this knowledge, an estimation showed that at occupational ethanol levels of 1000 ppm for a man using 10 m3 of breath per day with an absorption rate of 60%, pulmonary absorption would be equivalent to 11.4 g of ethanol. Regarding peak exposure, it was demonstrated 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.

Data from animal studies have shown that ethanol can penetrate the skin and is absorbed. In an in vitro skin penetration study, ethanol penetration was greater under occlusive conditions than non-occlusive conditions. Absorption rates were approximately 21% and 1%, respectively (Pendlington, 2001). The evaporation half-life was found to be 11.7 seconds, suggesting that systemic doses of ethanol resulting from skin absorption will be very low due to rapid evaporation. A third part of the same study assessed the potential for skin uptake of ethanol from the use of personal care products, human volunteers applied ethanol over their whole bodies delivered from an aerosol can. The mean dose of ethanol applied was just under 10 g per subject. Ethanol could not be unequivocally detected in the blood of any of the 16 volunteers in the hour immediately after application.

A male human volunteer was exposed to ethanol vapour at 1900 mg/m3 in an exposure chamber for 3 hours. Exposures were carried out at different ventilation rates. Ethanol in blood samples remained consistently below the limit of detection of 2 mg/L. It was concluded that exposure to ethanol vapour at 1900 mg/m3 will not produce a significant blood alcohol concentration. Another study using five male exposed for six hours to air containing ethanol at concentrations of up to 1000 ppm produced a similar result. Ethanol was not detected in the blood of volunteers exposed to 250 and 500 ppm, whereas blood concentrations measured at 3 and 6 hr during exposure to 1000 ppm (about 1884 mg/m3) were 0.229 mg/100 ml and 0.443 mg/100 ml, respectively. Ethanol concentrations in expired alveolar air "reached a steady-state 3 h after the start of exposure" and ranged from 241 to 249 ppm in the volunteers exposed to air containing ethanol at 1000 ppm (suggesting that absorption of ethanol from the lungs is approximately 75%)

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).

Prior to absorption, ingested ethanol undergoes limited metabolism (first pass metabolism) in the stomach by gastric alcohol dehydrogenase. 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 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 2000 ppm 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 maximum blood ethanol concentration of 2.9 mg/l results from an (indefinite) exposure to 1000 ppm of ethanol.

The majority of absorbed ethanol is eliminated from the body by metabolism (95 –-98 %; Norberg et al., 2003) but the process is limited. 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. 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 where ethanol was found to be rapidly eliminated with a typical elimination rate constant of 11 -15 mg/dl/hr over the range of doses examined (0.5 -0.8 g/kg). It was noted that the elimination rate increases slightly but dose-dependently.

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. The rate of disappearance of ethanol is 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 constant 1.64.