Registration Dossier

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:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1986

Materials and methods

Principles of method if other than guideline:
Assessing the possible effects of ethylene glycol for reproduction and dominant lethal mutagenesis.
GLP compliance:
no
Type of assay:
rodent dominant lethal assay

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
Further details see Reproduction Toxicity.

Administration / exposure

Route of administration:
oral: feed
Vehicle:
Further details see Reproduction Toxicity.
Details on exposure:
Further details see Reproduction Toxicity.
Duration of treatment / exposure:
Further details see Reproduction Toxicity.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
40 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
15
Positive control(s):
Further details see Reproduction Toxicity.

Examinations

Tissues and cell types examined:
Further details see Reproduction Toxicity.
Details of tissue and slide preparation:
Further details see Reproduction Toxicity.
Statistics:
Continuous data such as body weights were compared by analysis of variance validated by Bartlett's test for homogeneity of variance. Duncan's multiple range test wes used to identify individual mean differences when indicated by a significant F value. Where Bartlett's test indicated heterogeneous variances, t tests for equal or unequal variances were used to delineate differences between groups. Pup weights were compared by the method of Weil (Weil, 1970). Discontinuous data such as implantations and reproductive indices were compared by a multiple sum of ranks test. Frequency data were compared by the X2 test and by Fisher's exact test. The following reproductive indices were calculated and evaluated statistically by the previously described nonparametric methods: fertility index (male and female), days from first mating to parturition, gestation index (fraction of pregnancies that resulted in litters with live pups), gestation survival index (fraction of newborn pups alive at birth), 0 to 4-day survival index, 4 to 14-day survival index, 4 to 21day survival index. The last four indices are summarized in the tables as means for ease of understanding and presentation, although the nonparametric statistical methods did not include a comparison of means.

Results and discussion

Test results
Key result
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Ethylene glycol administration did not lead to statistically significant adverse effects on any of the parameters measured in the three mating intervals. Slight apparent increases in the dominant lethal mutation index, observed during the week 2 mating for the high-dose (1.0 g/kg/day) group and during the week 3 mating for the low dose (0.04 g/kg/day) group, were probably random occurrences unrelated to EG treatment. This interpretation is consistent with the absence of a dose-response relationship and the fact that a negative index of similar magnitude (-8.2%) was observed for the low dose group in the week 2 mating. When compared to the combined control groups, significant decreases were observed as a result of TEM treatment for the number of females with implants, the total number of implants, and the number of live implants.

Any other information on results incl. tables

Summary of dominant lethal mutagenesis data:

 Dose  Mating interval (week)  Females with implants     Total implants     Dead implants     Live implants     Dominant lethal mutations (%)
     N  %  N  %  N  %  N  %  
 1 g/kg/d  1  13  87.7  128  9.8  6  0.46  122  9.4  0
   2  13  86.7  107  8.2  10  0.77  97  7.5  11.0
   3  13  86.7  116  8.9  7  0.54  109  8.4  -1.2
 0.2 g/kg/d  1  11  73.3  108  9.8  10  0.91  98  8.9  5.3
   2  14  93.3  132  9.4  14  1.00  118  8.4  1.2
   3  14  93.3  134  9.6  19  1.36  115  8.2  1.2
 0.04 g/kg/d  1  11 73.3  107  9.7  8  0.73  99  9.0  4.2
   2  13  86.7  131  10.1  11  0.85  120  9.2  -8.2
   3  14  93.3  118  8.4  18  1.29  100  7.1  14.5
 0.0A  1  13  86.7  116  8.9  10  0.77  106  8.1  
   2  13  86.7  106  8.1  7  0.54  99  7.6  
   3  13  86.7  123  9.5  12  0.92  111  8.5  
 0.0B  1  10  66.7  113  11.3  3  0.30  110  11.0  
   2  11  73.3  109  9.9  5  0.45  104  9.4  
   3  11  73.3  100  9.1  11  1.00  89  8.1  
 TEM (0.5 mg/kg)  1  3  20.0  7  2.3  3  1.00  4  0.75  92.0
   2  8  53.3  15  1.9  4  0.50  11  1.37  83.9
   3  1  6.7  1  1.0  1

 1.00

0

 0.00.

 100.0

Applicant's summary and conclusion

Conclusions:
The absence of a genotoxic effect in the dominant lethal study is consistent with negative genotoxicity results from other studies with EG. Although mutagenic activity has been demonstrated in some studies the divergent results may be explained in part by the presence of impurities in the samples tested. Unpublished data from our laboratory indicate that small amounts of impurities such as oxidation products and storage contaminants such as iron compounds may substantially affect the results of in vitro mutagenicity assays of EG samples. Of course, different mutagenicity assays have distinct end points and varying sensitivities. Therefore, when several different tests are performed, contrasting results are not unexpected.