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Administrative data

Description of key information

Oral route (mg/kgbw/day):
Rat NOAEL (90 day): 1730, 3250 (male), 3900 (male/female), <4400 (female). LOAEL (90 day): 3160
Mouse NOAEL (90 day) >9400 (female), <9700 (male)
Monkey NOEL (chronic) <6200mg/kg/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 730 mg/kg bw/day

Additional information

ORAL ROUTE

In a 90 day study, SD rats were fed a mixture containing 16.25% USP ethanol at 3 dose levels. A single dose 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 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 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 and there were increases in absoluted 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 statisticall 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 ot 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 repeat dose toxicity data available 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 repeat dose toxicity information available by the inhalation route. The only reliable studies identifed 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.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

It is clear that adverse findings are only seen at extremely high dose, well above those that would trigger classification for repeat dose effects.