Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1980-11-26 to 1981-09-28
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to a test protocol that is comparable to the appropriate OECD test guideline. It was not compliant with GLP. Read-across to the registered substance is considered scientifically justified. The original study and the read-across are considered to be reliability 2.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991
Reference Type:
publication
Title:
Genotoxicity studies on selected organosilicon compounds: in vivo assays.
Author:
Isquith, A. et al.
Year:
1988
Bibliographic source:
Food Chem Toxicol 26: 263-266

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Deviations:
yes
Remarks:
only male animals used. Number of cells counted for determination of mitotic index not indicated - probably ca. 100, should be 1000
Principles of method if other than guideline:
The test was performed according to the Rodent Bone Marrow Cytogenetic Assay as recommended by the Ad Hoc Committee on Chromosome Methodologies in Mutagen Testing (Toxicology and Applied Pharm 22: 269-275, 1972) with modifications per the EPA Gene-Tox Program Cytogenetics Committee (12/3 to 12/5, 1980, Washington D.C.).
GLP compliance:
not specified
Type of assay:
chromosome aberration assay

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS

- Age at study initiation: 14 - 16 weeks

- Weight at study initiation: 250 - 280 g for range finding. 290 - 430 g for cytogenetic study

- Housing: 6 per cage

- Diet (e.g. ad libitum): Charles River Agway

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 68 ± 3 °F (20 ± 1.7 °C)

- Humidity (%): approx 50

Administration / exposure

Route of administration:
intraperitoneal
Vehicle:
- Vehicle(s)/solvent(s) used: paraffin oil

- Lot/batch no. (if required): A7M02

- Purity: Laboratory Grade
Duration of treatment / exposure:
single treatment
Frequency of treatment:
Single IP injection
Post exposure period:
6, 24 and 48 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
255, 515 and 1030 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
5 males/dose
Control animals:
yes, concurrent vehicle
Positive control(s):
cyclophosphamide, positive control agent, was included in the 24-hour group.  

- Route of administration: IP Injection

- Doses / concentrations: 22 mg/kg bw

Examinations

Tissues and cell types examined:
Bone marrow from femur
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: Based on two range finding studies conducted to determine the maximum dose the animals could tolerate.


Range finding studies: Range finding study 1: Animals Injected intraperitoneally with 1676, 504, 168 and 50 mg/kg and observed once a day for 7 days for signs of toxicity. Range finding study 2: 10 animals injected with 3911, 1825, 521, 183 and 52 mg/kg. In main study animals were sacrificed at 6, 24 and 48 hours


DETAILS OF SLIDE PREPARATION: Approximately 4 slides were prepared for each animal.  The chromosomes were prepared by standard methods and Giemsa stained.


TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields):
6h group: Stock solution of 321 mg/ml; volumes injected were 1.0, 0.5 and 0.25 ml, resulting in the following doses calculated from body weight: 1030 mg/kg +/- 3.2%; 515 mg/kg +/- 5.6%; 255 mg/kg +/- 1.2%

24 hour group: animals were injected with 1.0 or 0.5 ml of 321 mg/ml stock solution, or 1.0 ml of 91 mg/ml stock solution, resulting in the following doses calculated from body weight: 1030 mg/kg +/- 0.8%; 515 mg/kg +/- 5.6%; 255 mg/kg +/- 3.1%

48 hour group: animals were injected with 1.0 or 0.45 ml of 426 mg/ml stock solution, or 1 ml of 102 mg/ml stock solution. This resulted in the following doses calculated from body weight: 1030 mg/kg +/- 3.1%; 515 mg/kg +/- 9.3%; 255 mg/kg +/- 2.4%

METHOD OF ANALYSIS: metaphase cells analysed by projecting the negatives with a darkroom enlarger onto a white counter

OTHER:
Evaluation criteria:
In general, a minimum of 100 metaphase cells from each animal were scored for incidence of chromosomal aberrations.
Statistics:
Statistical methods: Chi2 test for comparison of expected and observed distribution of the number of breaks; Wilcoxon test was used as a nonparametric test.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Remarks:
on mitotic index
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY

- Dose range: Exp 1: 1676, 504, 168, 50 mg/kg. Exp 2: 3911, 1825, 521, 183, 52 mg/kg

- Clinical signs of toxicity in test animals: No deaths observed in initial study. In second study 3 of 10 animals dosed with 3911 mg/kg died, while all the other animals survived till terminal sacrifice.

- Harvest times: 7 days exp 1, 14 days exp 2.

- High dose with and without activation: 1676 exp 1, 3911 exp 2

RESULTS OF DEFINITIVE STUDY

See table 1

Any other information on results incl. tables

Negative controls: frequencies of breaks were 0.54%, 2.49% and 1.47% at sacrifice at 6, 24 and 48 hours respectively.

Table 1:Results of chromosome analysis in rat bone marrow cells

 

Low dose (255 mg/kg bw)

Mid dose (515 mg/kg bw)

High dose (1030 mg/kg bw)

Sampling time (h)

6

24

48

6

24

48

6

24

48

Number of cells evaluated

 500 approx

 500 approx

 500 approx

 500 approx

 500 approx

 500 approx

 500 approx

 500 approx

 500 approx

Toxicity,specify effects

 

 

 

 

 

 

 

 

 

Chromosome aberrations

Gaps

6

11

3

3

6

25

 2

 12

 14

Breaks

 5

 2

 9

 10

 15

 6

 5

 6

 7

Other aberrations

 0

 0

 0

 0

 0

 0

 0

 0

Mitotic index (% range)

 2 – 5

2 - 5

1 - 4

 2 - 4

 2 - 5

 4 - 7

 1 - 6

 3 - 5

 2 - 5

Polyploidy

N.R

N.R

N.R

N.R

N.R

N.R

N.R

N.R

N.R

Endo reduplication

N.R

N.R

N.R

N.R

N.R

N.R

N.R

N.R

N.R

 N.R = Not Reported


Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Hexamethyldisiloxane has been tested for the induction of chromosome aberrations in rat bone marrow cells in a valid study. It did not induce chromosomal damage in the bone marrow cells of rats following i.p. injection. The test substance is considered to be non-clastogenic (negative for the induction of chromosome aberrations) in rat bone marrow cells under the conditions of the test.