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Diss Factsheets

Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Acceptable, study with good documentation to demonstrate that study meets required scientific principles and contains enough detail to be able to judge the results reliable as a contribution to the understanding of the repeat dose toxicity of this substance. Not all end points were covered (no haematology, limited clinical chemistry). SIngle sex used.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Study was a range finder to find appropriate doses for a chronic cancer study. The study followed the basic principles of an OECD408 sub-chronic study. Two study groups were used, details of the first range finder group are not reported here. Only male rats used. No haematology or urinalysis and limited clinical chemistry performed.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethanol
EC Number:
200-578-6
EC Name:
Ethanol
Cas Number:
64-17-5
Molecular formula:
C2H6O
IUPAC Name:
ethanol
Details on test material:
- Name of test material (as cited in study report): ethanol
- Source: Svenska Spirit AB, Stockholm.
- Analytical purity: Spectroscopically pure

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Age at study initiation: 43 days. Controls and 5% ethanol dose animals run concurrently with controls used 70 day old animals
- Housing: individual. Cages rotated within room to a fixed schedule.
- Food: liquid diet based on Nutrauxil, a semi-synthetic liquid enteral diet for humans, modified to give the rats an adequate diet in the absence of solid food. 70ml/day provided per animal
- Water: not separately given.

Administration / exposure

Route of administration:
other: mixed with liquid feed
Vehicle:
other: rat adapted Nutrauxil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Ethanol supplied in nutritionally balanced liquid diet.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
90 days unless study terminated early
Frequency of treatment:
continuous
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 2, 3, 4, 5%, 10% w/v ethanol in liquid diet
Basis:

No. of animals per sex per dose:
10 (20 in controls)
Control animals:
other: two control groups. One with liquid diet only and second with glucose added equicaloric to 10% ethanol. Note that controls were run in the pre-study, ie not concurrently.

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS/CLINICAL OBSERVATION: Yes
- Time schedule: not reported.
- Cage side observations checked: no data

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examination: daily

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination from iliac bifurcation.
- Animals fasted: no data
- How many animals: all
- Parameters checked: AST and ALT activities only

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
Liver and kidneys were weighed, examined macroscopically and microscopically at necropsy. Spleen was weighed.
Statistics:
No statistical tests for significance were used.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Details on results:
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
See table below. No indication of statistical significance

GROSS PATHOLOGY
Liver yellowing was observed in some of the 3 and 4% dose animals and most of the 5% dose animals. It was considered to be dosage-related.

HISTOPATHOLOGY: NON-NEOPLASTIC
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 (see table below). In the control and two lowest dose groups, there was no occurance of Mallory bodies or acidophilic degeneration or necrosis but these were seen in the higher dose groups. Very slight Reticulo-endothelial cell proliferation and occurence of acidophilic bodies were seen in both control and the lower 2 dose groups but were seen at moderate levels in the higher dose groups. In the kidney, nephrocalcinosis was seen in both controls and dosed animals; the effects were not significant. Tubular fatty changes were also seen in the kidney. These were seen as very slight in about 25% of both controls and the 1% dose animals. They were seen in about 75% of the 2-4% dose animals (and all except 1 of the high dose animals) but the degree of severity showed no dose response relationship.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 other: % in liquid diet
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
3 other: % in liquid diet
Sex:
male/female
Basis for effect level:
other: liver changes (Mallory bodies)

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Food consumption

 Dose  litres food/kg bw animal per week
 Liquid diet  1.13 +/-0.061
 Liquid diet + glucose  0.847 +/-0.09
 1% ethanol  1.409 +/-0.31
 2% ethanol  1.363 +/-0.308
 3% ethanol  1.357 +/- 0.313
 4% ethanol  1.315 +/-0.302
 5% ethanol  1.272 +/- 0.24
 5% ethanol  0.709 +/-0.080

* run at same time as controls

Centrilobular steatosis

 Dose

#

animals

 none

very

slight

slight

slight to

moderate

 moderate

rather

severe

 Liquid diet  19  19          
 Liquid diet + glucose  19    2  2  8  7  
 1% ethanol

 10

     2  5  3  
 2% ethanol  10      2  3  5  
 3% ethanol 10      1  5  4  
 4% ethanol  10        4  6  
 5% ethanol  10        1  5  4
 5% ethanol*  20  3  8  3  6    

* run at same time as controls.

In the liver, hyaline bodies (Mallory bodies), together with centrilobular steatosis and necrotic areas, are considered evidence of irreversible liver injury which can lead to cirrhosis. These were only seen in the 4 and 5% dose animals.

Applicant's summary and conclusion

Executive summary:

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.