Ethanol

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1982

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This is a highly reliable study that reports the result of an interlaboratory study to the OECD protocol.

Data source

Reference

Reference Type:

publication

Title:

Analysis of results from a collaborative study of the dominant lethal assay.

Author:

James, D.A. & Smith, D.M.

Year:

1982

Bibliographic source:

Mutation Res. 97:303-314.

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)

Deviations:

no

Principles of method if other than guideline:

Method: other

GLP compliance:

not specified

Type of assay:

rodent dominant lethal assay

Test material

Test material information

Constituent 1

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): no data

Test animals

Species:

mouse

Strain:

other: CFLP and Alderley Park

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 10 days at dosing, 10-12 weeks at mating
- Source: variable across test laboratories

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

Water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: 40% in water
Gavage volume 2mls/kg

Duration of treatment / exposure:

Mice dosed with ethanol in distilled water on 5 consecutive days.

Frequency of treatment:

once per day

Doses / concentrations

Remarks:

Doses / Concentrations:
10 or 40% ethanol in water
Basis:
actual ingested

No. of animals per sex per dose:

15 per group

Control animals:

yes, concurrent vehicle

Positive control(s):

cyclophosphamide 80mg/kg/day (MTD) and 20mg/kg/day (MTDx0.25) by gavage 5 consecutive daily doses

Examinations

Statistics:

Three different methods used for analysis:
Kruskal-Wallis non-parametric analysis of variance
An analogue of analysis of variance based on comparison by F-test of chi-square values from between and within study groups
A comparison of beta-binomial distributions by likelihood ratio test.

Results and discussion

Test results

Sex:

male

Genotoxicity:

ambiguous

Toxicity:

not specified

Vehicle controls validity:

valid

Negative controls validity:

not applicable

Positive controls validity:

valid

Any other information on results incl. tables

No effect on pregnancy rate.  Occasional positive results with regard to preimplantation loss during weeks 7 and 8 (reduction in the number of implants/male).  It was suggested that in most cases this was due to a lower number of implants in the corresponding control groups.  There were also occasional increases in the number of postimplantation deaths/male although the majority of the post implantation results were not significant.

Applicant's summary and conclusion

Conclusions:

Ethanol is unlikely to be a dominant lethal mutagen, at least up to the maximum tolerated dose.

Executive summary:

In a collaborative a cross laboratory study of the dominant lethal assay conducted by the British Pharmaceutical Industry, three laboratories conducted studies using the same guideline protocol. Male mice received 0.16g/kg/day (MTD) or 0.63g/kg/day (MTD x0.25) by gavage for 5 consecutive days. After completion of the schedule the animals were paired with untreated virgin females, each week, for 8 consecutive weeks. All females were killed and examined 18 days after first being paired with males. Although there were occasional increases in the number of postimplantation deaths per male, the majority of post implantation results were not significant and it confirmed that ethanol is unlikely to produce a dominant lethal effect up to the maximum tolerated dose. On the other hand, administration of cyclophosphamide, a known dominant lethal mutagen, consistently produced a significant increase in post-implantation death in the first two weeks of mating. The authors of the study concluded that ethanol is unlikely to produce a dominant lethal effect up to the maximum tolerated dose.