Dodecamethylpentasiloxane

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:

weight of evidence

Study period:

1980-11-26 to 1981-09-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

It was not compliant with GLP.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1982

Report date:

1982

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

- 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

Key result

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: test substance (total number of aberrations observed)

		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

Table 2 Results of chromosome analysis in rat bone marrow cells: control substances (total number of aberrations observed)

		Vehicle control			Positive control
Sampling time (h)		6	24	48	48
Number of cells evaluated		500 approx	450 approx	500 approx	250 approx
Chromosome aberrations	Gaps	6	19	15	ND
	Breaks	3	12	8	145
	Other aberrations	0	0	0	4 quad, 6 tri, 5 del
Mitotic index (% range)		2-7	1-4	3-4	2-4

 N.R = Not Reported

quad = quadriradial tri = triradial del = deletion

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 conducted according to a protocol that is similar to OECD 475. There was no evidence of induction of chromosomal damage in the bone marrow cells of rats following intraperitoneal 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.