1,1,3,3-tetramethyldisiloxane

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1980-11-26 to 1981-09-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study with acceptable restrictions

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1991

Report date:

1991

Reference 2

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

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

Test material information

Constituent 1

Reference substance name:

Hexamethyldisiloxane

EC Number:

203-492-7

EC Name:

Hexamethyldisiloxane

Cas Number:

107-46-0

Molecular formula:

C6H18OSi2

IUPAC Name:

hexamethyldisiloxane

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system 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

Doses / concentrations 1

Dose / conc.:

255 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

515 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

1 030 mg/kg bw/day (nominal)

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	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:

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.