Magnesium ethanolate

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

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). Therefore, no studies are available for the parent compound itself, concerning repeated-dose toxicity. Valid study data are available for the hydrolysis products magnesium hydroxide and ethanol and have been taken into account: both compounds gave no evidence of any overt toxicity in long-term feeding studies.

 

ETHANOL

ORAL ROUTE

In a 90 day study, SD rats were fed a mixture containing 16.25% USP ethanol at 3 dose levels. Single doses of 4ml/kg of pure ethanol and water were used as controls. No significant differences were noted in body weight, haematology, opthamology, clinical chemistry or urine chemistry. Dose-related increases in liver to body weight ratios of female rats were seen at final sacrifice although the absolute liver weights of the high dose ethanol treated group, while significantly increased relative to the 100% ethanol treated group, was not different from the water control group. In addition, increased liver weights were observed in the male rats. Significant increases in kidney weights were observed in the mid and high dose groups. 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 control treated rats versus the water treated controls. It should be noted however that 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 determined at 10 ml/Kg for a mixture containing 16.25% ethanol for increased kidney weight and renal tubular epithelial hyperplasia in males (equivalent to 1.73g/kg). The LOAEL for this study was determined at 4 ml/kg for 100% USP ethanol (3.16g/kg) for increased kidney weight and renal tubular epithelial hyperplasia in males.

 

In a 90 day sub-chronic repeat dose study, male rats were given a liquid diet containing ethanol at a level of 1 -5% by weight. The only significant effect seen in the 1 and 2% dose groups were centrilobular steatosis. 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 rather than being substance specific. It is not therefore considered an adverse effect. On this basis, the no effect level from this study was 2%, which was approximately equivalent to a dose of 3900mg/kg/day. It should be noted that the study did not conform fully to a guideline study in that a number of end points, e.g. haematology and urinalysis, were not carried out and only partial clinical chemistry and organ pathology/histology was undertaken. Notwithstanding this, the study did concentrate on the likely known toxicity targets for this substance.

 

In a well conducted GLP study that closely followed guidelines, rats and mice were exposed to ethanol in drinking water at a level of 5% for a period of 90 days. Only a single dose level was used as the study was primarily looking at the toxicology of urethane. To establish the effect of ethanol on urethane disposition, two parallel studies were run, one using distilled water as the vehicle for the urethane, the second using 5% ethanol solution as the vehicle. The study allowed a comparison of the two vehicles used. In female rats, there were small but clear and significant histopathological changes in the liver (diaphragmatic nodules), accompanied by a non-statistically significant liver weight increase, 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 been 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 significant. A marginal NOAEL of 5% (>3250mg/kg) is selected for males and a LOAEL of 4400mg/kg for females. In male mice, relative and absolute liver weight was increased; furthermore there were increases in absolute heart, liver, 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 either statistically or biologically significant. Cycle length was not significantly changed. A marginal NOAEL of >5% (>9400mg/kg) is selected for females and a LOAEL of 9700mg/kg for males.

 

The effect of chronic ethanol feeding was determined on parameters of hepatic collagen metabolism in monkeys. The animals were fed a nutritionally adequate diet with 50% of the calories provided as ethanol (equivalent to 6200mg/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 6200mg/kg.

 

DERMAL ROUTE

There is no repeated dose toxicity data available for ethanol by the dermal route. However, there is sufficient information available to conclude that under non-occlusive conditions, evaporation is so rapid that dermal exposure would be negligible. Available data also shows that skin absorption under practical use conditions is negligible. There is also sufficient toxicokinetic data available to enable reliable route to route extrapolation from the oral to dermal routes if required.

 

INHALATION ROUTE

There is limited repeated dose toxicity information available by the inhalation route. The only reliable studies identified are sub-acute studies that do not assess all end points. Both of these established no adverse effects at the single dose tested (20mg/l and 6130ppm for 26 and 28 days respectively). This is however supplemented by reproductive toxicity data by the inhalation route; testing up to maximum safe concentration (~50% of the lower explosive limit - 16000ppm), produce no significant adverse effects in a 6 week study (see chapter 7.8.1). Such conditions would cover all conceivable handling and use scenarios, both normal and abnormal. In addition, there is also sufficient toxicokinetic data available to enable reliable and robust route to route extrapolation from the oral to inhalation routes if required.

 

All available information indicates that toxicity by the inhalation route is not likely to be of concern.

 

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%.

 

MAGNESIUM HYDROXIDE

An oral repeated dose toxicity study (OECD 422 = Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) on magnesium hydroxide with rats yielded the highest dose tested as NOAEL of 1000 mg/kg bw/day after 28 days of exposure.

 

MAGNESIUM CHLORIDE

An oral 90d-repeated-dose study in male and female rats resulted in a NOAEL of 720 - 752 mg/kg bw/d (related to MgCl2, not to the hexahydrate). This corresponded to a dietary level of 2.5 % (MgCl2 x6H2O).

In an oral 90d study (OECD 408) using mice, a NOAEL of 1.25 % has been established, corresponding to approximately 2500 mg/kg bw/d (males).

 

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint: 

As magnesium ethanolate reacts rapidly with water and gastric fluid under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEL for magnesium ethanolate. All physiological effect concentrations are a function of the bioavailable amounts of the hydrolytic products (ethanol and magnesium hydroxide). Because magnesium hydroxide is inorganic and is well tolerated, ethanol was chosen as the most sensible reaction product.

 

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint: 

As magnesium ethanolate is very likely to instantaneously react with the humidity of the nasal cavity and the thoracic tract under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEL for magnesium ethanolate. Based on this, the amount of respirable substance is negligible to achieve significant concentrations for systemic effects. 

 

Justification for selection of repeated dose toxicity inhalation - local effects endpoint: 

As magnesium ethanolate is very likely to instantaneously react with the humidity of the nasal cavity and the thoracic tract under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEL for magnesium ethanolate. For both reaction products no adverse local effects are described. 

 

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint: 

As magnesium ethanolate reacts with perspiration or air moisture under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEL for magnesium ethanolate. Based on provided information about the hydrolysis products the amount of dermal resorption is negligible to achieve significant concentrations for systemic effects.

 

Justification for selection of repeated dose toxicity dermal - local effects endpoint: 

As magnesium ethanolate reacts with perspiration or air moisture under formation of magnesium hydroxide and ethanol, it is not considered to be useful to derive a NOAEL for magnesium ethanolate. Based on provided information about the hydrolysis products there are no adverse local effects described.

Justification for classification or non-classification

According to Regulation (EC) No. 1272/2008, classification is applicable when significant toxic effects are seen to occur at 100 mg/kg bw/day or less for an oral rat study, which means that the established NOAELs do not trigger classification.

It is concluded that these findings are directly applicable to the parent compound, magnesium ethanolate. Under this premise, prolonged dosing of magnesium ethanolate is not expected to produce pathologically significant effects that may be relevant for classification.