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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
not specified
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was conducted prior to GLP and test guidelines, but sufficient data is available for interpretation of results

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1976

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Principles of method if other than guideline:
Study was conducted prior to OECD guidelines but essentially followed guideline
GLP compliance:
no
Type of assay:
chromosome aberration assay

Test material

Constituent 1
Chemical structure
Reference substance name:
1-chloro-2,3-epoxypropane
EC Number:
203-439-8
EC Name:
1-chloro-2,3-epoxypropane
Cas Number:
106-89-8
Molecular formula:
C3H5ClO
IUPAC Name:
2-(chloromethyl)oxirane
Details on test material:
Epichlorohydrin (ECHH) to be tested was manufactured in Czechoslovakia.

Test animals

Species:
mouse
Strain:
ICR
Sex:
female
Details on test animals or test system and environmental conditions:
Female ICR mice, 8-10 weeks of age, weighing approximately 32-35 g were used.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
DMSO obtained from Merck.
Details on exposure:
Test material was administered via oral gavage to mice for a single application (5, 20, 40 and 100 mg/kg) or for 5 repeated doses over 5 days or for 5 repeated doses over 7 days (test material was administered on days 1, 2, 5, 6 and 7) (20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.

In addition, the test material was administered intraperitoneally to mice for a single dose (1, 3, 5, 10, 20 and 40 mg/kg) or for 5 repeated doses over 5 days (10 mg/kg) or for 5 repeated doses over 7 days (test material administered on days 1, 2, 5, 6 and 7) (5, 10 or 20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.
Duration of treatment / exposure:
Test material was administered via oral gavage to mice for a single application (5, 20, 40 and 100 mg/kg) or for 5 repeated doses over 5 days or for 5 repeated doses over 7 days (test material was administered on days 1, 2, 5, 6 and 7) (20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.

In addition, the test material was administered intraperitoneally to mice for a single dose (1, 3, 5, 10, 20 and 40 mg/kg) or for 5 repeated doses over 5 days (10 mg/kg) or for 5 repeated doses over 7 days (test material administered on days 1, 2, 5, 6 and 7) (5, 10 or 20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.
Frequency of treatment:
Test material was administered via oral gavage to mice for a single application (5, 20, 40 and 100 mg/kg) or for 5 repeated doses over 5 days or for 5 repeated doses over 7 days (test material was administered on days 1, 2, 5, 6 and 7) (20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.

In addition, the test material was administered intraperitoneally to mice for a single dose (1, 3, 5, 10, 20 and 40 mg/kg) or for 5 repeated doses over 5 days (10 mg/kg) or for 5 repeated doses over 7 days (test material administered on days 1, 2, 5, 6 and 7) (5, 10 or 20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.
Post exposure period:
Test material was administered via oral gavage to mice for a single application (5, 20, 40 and 100 mg/kg) or for 5 repeated doses over 5 days or for 5 repeated doses over 7 days (test material was administered on days 1, 2, 5, 6 and 7) (20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.

In addition, the test material was administered intraperitoneally to mice for a single dose (1, 3, 5, 10, 20 and 40 mg/kg) or for 5 repeated doses over 5 days (10 mg/kg) or for 5 repeated doses over 7 days (test material administered on days 1, 2, 5, 6 and 7) (5, 10 or 20 mg/kg). Mice were sacrificed 6, 24 or 48 hr after a single dose or 6 hrs after the administration of the final dose in the scheme of repeated applications.
Doses / concentrations
Remarks:
Doses / Concentrations:
Oral gavage: 5, 20, 40 or 100 mg/kg (single application), 20 mg/kg for 5 applications over 5 or 7 days. IP: 1, 3, 5, 10, 20 or 40 mg/kg (single application), 20 mg/kg (5 applications over 5 days) or 5, 10 or 20 mg/kg (5 applications over 7 days).
Basis:
no data
No. of animals per sex per dose:
no data
Control animals:
yes, concurrent vehicle
Positive control(s):
no data

Examinations

Tissues and cell types examined:
The mouse bone marrow was prepared according to the modification of Tjino and Whang's method (Goetz et al., 1975). 250 metaphases were analyzed in each group. Gaps, breaks and exchanges were evaluated. Cells bearing some of these changes were considered abnormal. Cells with more than 10 aberrations were counted separately (Adler et al., 1971, Nichols et al., 1972).

Adler, I.D., Ramarao, G., and Epstein, S.S. (1971). In vivo cytogenetic effects of trimethylphosphate and of TEPA on bone marrow cells of male rats. Mutation Research 13:263-273.

Goetz, P., Sram, R.J., and Dohnalova, J. (1975). Relationship between experimental results in mammals and man. I. Cytogenetic analysis of bone marrow injury induced by a single dose of cyclophosphamide. Mutation Research 31:247-254.

Nichols, W.W., Moorhead, P. and Brewen, G. (1972)., Chromosome methodologies in mutation testing. Toxicol. Appl. Pharmacol. 22:269-275.
Details of tissue and slide preparation:
No additional information available.
Evaluation criteria:
Gaps, breaks and exchanges were evaluated. Cells bearing some of these changes were considered abnormal.
Statistics:
Statistical evaluation was apparently not conducted.

Results and discussion

Test results
Sex:
female
Genotoxicity:
positive
Toxicity:
not specified
Vehicle controls validity:
valid
Negative controls validity:
not specified
Positive controls validity:
not specified
Additional information on results:
The time-effect relationship was evaluated after applying an i.p. injection of 50 mg ECHH/kg and after application of p.0.100mg ECHH/kg. Since no difference was found in the frequency of abnormal cells after i.p. application in the 6 and 24 h groups and in all the groups after p.o. application, the dose-effect relationship and the routes of applications were compared always 24 h after the administration of ECHH.

Dose-effect relationship expressed in the frequency changes of abnormal cells was found after a single ip. application of a dose ranging from 1-20 mg ECHH/kg and after p.0. application especially in, a range of 5-20 mg ECHH/kg. Dose-effect relationship was found also after repeated i.p. application of 5 doses ranging between 5-20 mg ECHH/kg. The comparative evaluation of thc effect of the total dose applied in a single or repeated scheme, showed that the same total dose - if applied in repeated doses - induced both a higher frequency of abnormal cells and a higher frequency of breaks per cell. As to the comparison of the routes of administration at the same dose, the intraperitoneally applied ECHH induced approx. twice as many chromasomal abnormalities than ECBH applied perorally.

ECHH induced mostly breaks and exchanges. The cells bearing more than 10 aberrations were found quite exceptionally.

Any other information on results incl. tables

Dose-effect relationship expressed in the frequency changes of abnormal cells was found after a single ip. application of a dose ranging from 1-20 mg ECHH/kg and after p.o. application especially in, a range of 5-20 mg ECHH/kg.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): positive
This cytogenetic study showed a positive response following oral or ip administration of epichlorohydrin.
Executive summary:

Epichlorohydrin (ECH) is one of the more commercially important aliphatic epoxides used extensively as an industrial intermediate, a laboratory reagent, and as an insecticide. It is a volatile, colourless liquid with an ethereal odour. This cytogenetic study showed a positive response following oral or ip administration of epichlorohydrin.