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Toxicological information

Genetic toxicity: in vivo

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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:
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

Reference
Name:
Unnamed
Type:
Constituent
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 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.