Sodium ethanolate

Endpoint summary

Additional information

No data/information is available for sodium ethanolate concerning repeated dose toxicity.

But several studies are available for reaction product ethanol.

Procter and Gamble reported an oral 90-day study performed equivalent to OECD guideline 408. Here, a single dose of 4 ml/kg of pure ethanol and three dose levels with 5, 10, 20 ml/kg of a test mixture containing 16.25% ethanol were applied to Sprague-Dawley rats. No significant differences were noted in body weight, haematology, opthamology, clinical chemistry or urine chemistry. Liver and kidney weights increased dose-dependently and significantly. No histopathologic findings were attributed to ethanol treatment with exception of increased minimal focal to multifocal renal tubular epithelial hyperplasia in the high dose 20 ml/kg mixture containing 16.25% ethanol and the 100% USP ethanol. The renal tubular epithelial hyperplasia is a common incidental finding in laboratory rats and it is uncertain whether the higher incidence of this lesion in the ethanol dosed rats compared with water controls is due to a random variation or to ethanol. Gonadal tissues were examined for both gross pathology and histopathology and no treatment-related effects were detected. The NOAEL for the study was set at 10 ml/kg for a mixture containing 16.25% ethanol for increased kidney weight and renal tubular epithelial hyperplasia in males (equivalent to 1.73 g/kg). The LOAEL for this study was set at 4 ml/kg for 100% USP ethanol (3.16 g/kg) for increased kidney weight and renal tubular epithelial hyperplasia in males.

Holmberg et al. (1986) published a study which was performed as a range finder to define appropriate doses for a chronic cancer study (Holmberg et al., 1986 a,b). The study followed the basic principles of an OECD 408 subchronic study. Applied doses were 1, 2, 3, 4, 5 %, 10 % w/v ethanol in liquid diet. A centrilobular and hepatic steatosis was seen in all rats in all groups. The severity increased with increasing ethanol concentration both in terms of numbers of animals affected and in degrees of changes in each animal. This is often associated with ethanol consumption but in its mild form is not considered to be a pathological condition. There was also evidence from glucose dosed animals, used as calorific controls which also showed the effect, that this finding is actually related to the caloric content of ethanol. The NOAEL from this study was 2 %, which was approximately equivalent to a dose of 3900 mg/kg/day. The 2-year study published by Holmberg and Ekstrom (1994) reported about the long-term effects (2 years) of ethanol (CAS: 64-17-5). Male and female rats were offered concentrations of 1 % and 3 % ethanol via the food. The NOAEL was found to be >3 % and the LOAEL was found to be 3 %.

NTP (1996) reported a 13-week drinking water study with ethanol (CAS: 64-17-5). Male and female rats and mice were offered a concentration of 5% for 7 days per week. Only a single dose level was used as the study was primarily looking at the toxicology of urethane. In female rats, there were histopathological changes in the liver (diaphragmatic nodules), accompanied by a non-significant increase in liver weight, and an increase in nephropathy (although male rats showed 100% evidence of this in every dose group). Male rats showed an increase in thymus weights, but it was not clear if this was biologically significant and it may have a chance observation. Male rats also showed some slight but inconsistent changes to haematology (reticulocyte count) and clinical chemistry (serum bile acid concentrations), with the latter also seen in females. It was unclear if these changes were biologically relevant. A marginal NOAEL of 5% (>3250 mg/kg) is selected for males and a LOAEL of 4400 mg/kg for females. the results from the mice study showed increased relative and absolute liver weights and there were increases in absolute heart, kidney and lung weight. There was some evidence for a marginal increase in nephropathy in male mice, but the increase was not statistically clear. Sperm count in the cauda epididymis was also decreased (~30%). Female mice showed no effects apart from a small change to the time spent in dioestrus and pro-oestrus but it was unclear whether this was biologically relevant. The cycle length was not significantly changed. A marginal NOAEL of >5 % (> 9400 mg/kg) is selected for females and a LOAEL of 9700 mg/kg for males.

Mezey et al. (1983) published a chronic ethanol feeding study in monkeys. The effect of ethanol was determined on parameters of hepatic collagen metabolism. The monkeys were fed a nutritionally adequate diet with 50% of the calories provided as ethanol (equivalent to 6200 mg/kg) with controls consuming ethanol isocalorifically substituted by carbohydrate. Feeding was carried out for 48 months, with intermediate liver biopsies taken at 3, 12 and 24 months. Blood and urine were monitored to determine ethanol concentrations. The ethanol fed animals developed various degrees of liver fatty infiltration but no necrosis, inflammation or fibrosis. There was no effect on the amount or distribution of collagen types, liver free proline or protein bound hydroxyproline levels or in collagen prolyl hydroxylase activity. A no effect level was not established due to the fatty infiltration but a no effect level for the more severe adverse liver effects normally associated with ethanol (cirrhosis and fibrosis) was established at 6200 mg/kg.

There are data available on the inhalation route. The only reliable studies identifed are sub-acute studies that do not assess all end points (Di Luzio et al., 1979; Chu et al., 2005). Both of them established no adverse effects at the single dose tested (20 mg/l and 6130 ppm for 26 and 28 days, respectively). Testing up to maximum safe concentration (~ 40 % of the lower explosive limit - 16000 ppm) produced no significant adverse effects in a 6 week study. All available information indicates that toxicity by the inhalation route is not likely to be of concern and it is clear that adverse findings are only seen at extremely high doses.

Justification for classification or non-classification

The high concentrations that showed effects in all reported studies cannot be achieved with sodium ethanolate due to its corrosive properties. The LD50 after oral uptake was 598 mg/kg. Doses of 598 mg/kg would be in accordance with doses of approximately 406 mg/kg ethanol (based on the molecular weight). For that reason, no classification is proposed.