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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1980-12-22 to 1981-12-6
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
The study was conducted according to an appropriate national standard method which is similar to OECD 475, with acceptable restrictions. The restrictions are that the number of cells used for the determination of mitotic index was not stated, but appeared to be about 100 cells per animal, and the report is less detailed than required by the current guideline. Read-across to the registered substance is considered scientifically justified.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1982
Report Date:
1982

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
other: Methodologies in Mutagen Testing (Toxicology & Applied Pharm 22: 269-275, 1972).
Deviations:
no
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 475 (Mammalian Bone Marrow Chromosome Aberration Test)
Deviations:
yes
Remarks:
The number of cells evaluated to determine mitotic index was not stated, but appeared to be less than required by the current guideline. Some details were missing from the report.
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/female
Details on test animals and environmental conditions:
TEST ANIMALS

- Source: Gofmoor Farms

- Age at study initiation: 10 - 16 weeks

- Weight at study initiation: 200 - 280 g

- Assigned to test groups randomly: no information

- Housing: Six per cage

- Diet (e.g. ad libitum): ad libitum

- Water (e.g. ad libitum): ad libitum

ENVIRONMENTAL CONDITIONS

- Temperature (°F): 68 ± 3 °F

- Humidity (%): approx 50 %

Administration / exposure

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

- Justification for choice of solvent/vehicle: solubility properties

- Lot/batch no. (if required): D-128

- Purity: reagent grade
Details on exposure:
Route of exposure: intraperitoneal
Duration of treatment / exposure:
6 - 48 hours
Frequency of treatment:
A single intraperitoneal administration equivalent to doses of 420, 200 and 100 mg/kg.
Post exposure period:
Animals were sacrificed at 6, 24 or 48 hours after injection.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
100 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
200 mg/kg bw
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
420 mg/kg bw
Basis:
nominal conc.
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Positive control(s):
- cyclophosphamide

- Justification for choice of positive control(s): standard guideline positive control

- Route of administration: intraperitoneal

Examinations

Tissues and cell types examined:
Chromosomes from bone marrow examined for breaks.
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: rang-finding experiment to determine the maximum tolerated dose

DETAILS OF SLIDE PREPARATION: a small amount of cells suspended in fixative (3:1, methanol: acetic acid) were dropped onto slides which were subsequently air dried. Slides were stained with 5 % Giemsa.

METHOD OF ANALYSIS: Slides were scanned and only those of acceptable quality were retained. Suitable cells were photographed using a 100x objective. A minimum of 100 metaphase cells were analyzed per animal, and 5 animals were analysed for each dose.

Evaluation criteria:
The test substance is cytogenic if it causes a statistically significant, dose related increase in the frequency of chromosomal breaks or aberrations.
Statistics:
The significance of differences in break frequency were examined using "goodness to fit" to a Poisson distribution, compared to historical negative control data, the Wilcoxon test and Chi square.

Results and discussion

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

- Dose range: experiment 1: 175, 500, 1750, 5000 mg/kg bw; experiment 2: 75, 50, 175, 500, 1750 mg/kg bw

- Clinical signs of toxicity in test animals: none reported. Deaths occurred at the top dose in experiment 1 and in the top two doses in experiment 2.



Any other information on results incl. tables

Table 1: Results of chromosome analysis in Rat Bone Marrow Cells

 

 

Solvent Control (DMSO)

Positive Control Cyclophosphamide

Low dose

100 mg/kg

Mid dose

200 mg/kg

High dose

420 mg/kg

Sampling time (h)

6

24

48

24

6

24

48

6

24

48

6*

24

48

Number of cells analysed

551

592

523

286

552

568

502

546

593

509

499

574

534

Toxicity

No

No

No

No

No

No

No

No

No

No

No

No

No

Total number of Chromosome aberrations

Gaps

ND

ND

ND

0

2

7

12

3

5

11

6

5

8

Breaks

0

2

4

>99

2

7

5

6

3

8

3

5

12

Interchanges

ND

ND

ND

0

0

0

0

0

0

0

0

0

0

Polyploidy

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

Endo reduplication

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

ND

  ND Not determined

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Trimethylsilanol has been tested in chromosome aberration study conducted according to a protocol that is similar to OECD 475. The test substance did not cause a statistically significant, dose related increase in chromosome breaks or aberrations when administered by intraperitoneal injection to Sprague Dawley rats up to the maximum tolerated dose. It is concluded that the test substance is not clastogenic in rat bone marrow cells under the conditions of the test.