Hydroxytrimethylsilane

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian germ cell study: cytogenicity / chromosome aberration

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1983

Report date:

1983

Reference 2

Reference Type:

publication

Title:

Genotoxicity studies on selected organosilicon compounds: in vitro assays.

Author:

Isquith, A. et al.

Year:

1988

Bibliographic source:

Fd Chem Toxicol 26: 255-261

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

other: OECD 426

Deviations:

no

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test)

Principles of method if other than guideline:

Extended Dominant Lethal Assay as recommended by the U.S. Food and Drug Administration (Green, et al 1977)

GLP compliance:

not specified

Type of assay:

rodent dominant lethal assay

Test material

Test material information

Constituent 1

Reference substance name:

Hydroxytrimethylsilane

EC Number:

213-914-1

EC Name:

Hydroxytrimethylsilane

Cas Number:

1066-40-6

Molecular formula:

C3H10OSi

IUPAC Name:

hydroxytrimethylsilane

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS

- Source: Harlan Research, Haslett, Michigan

- Age at study initiation: 10 - 12 weeks

- Weight at study initiation: mean 355 - 375 g

- Assigned to test groups randomly: [yes, under following basis: randomly selected using a computer program]

- Housing: wire-bottomed stainless steel cages

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

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

- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS

- Temperature (°C): 20 - 24 °C

- Humidity (%): 45 - 55 % relative humidity

- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

- Vehicle(s)/solvent(s) used: none

- Justification for choice of solvent/vehicle: N/A

- Concentration of test material in vehicle: test material was given neat

- Amount of vehicle (if gavage or dermal): none

- Type and concentration of dispersant aid (if powder): N/A

- Lot/batch no. (if required): N/A

- Purity: N/A

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION

- Rate of preparation of diet (frequency): daily, 5 days per week for 8 weeks

- The test substance was administered undiluted by oral gavage.

- Storage temperature of food: no data

Duration of treatment / exposure:

The exposure period lasted 8 weeks

Frequency of treatment:

Daily, for 5 days per week

Post exposure period:

2 weeks

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 20, 100, 200 mg/kg
Basis:
analytical conc.

No. of animals per sex per dose:

15 males per dose group. 4 females per male (2 matings per week over 2 weeks)

Control animals:

yes, concurrent no treatment

Positive control(s):

triethylenemelamine

- Justification for choice of positive control(s): no data

- Route of administration: Oral gavage

- Doses / concentrations: 0.05 mg/kg/day

Examinations

Tissues and cell types examined:

Ovaries and uteri examined at necropsy. The number of corpora lutea and living and dead implantations were counted and recorded for each pregnant female.

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION: A two week subchronic dosing assay was conducted on sexually mature male Sprague-Dawley rats to determine a maximum tolerated dose level (MTD). The test material was administered undiluted by oral gavage. A level was selected which gave some evidence of biological effect (transient sedation) without producing sufficient toxicity to interfere with the test system. Based on this determination, male rats were randomly assigned to one of five experimental dosing groups (15 males/group).

DETAILS OF SLIDE PREPARATION: microscopic examination (no other information)


METHOD OF ANALYSIS: Number of corpora lutea, preimplantation loss, total number of implants, live and dead implants (restorations) counted for each mated female.

Evaluation criteria:

Examine for evidence that the test substance reaches mammalian germinal tissue and induces chromosomal aberrations. The analysis considers both effects per litter and total number of effects / total number of pups.

Statistics:

Data analysed for statistical significance (p <0.05 for all cases) by a computer program specifically designed for analysis of dominant lethal studies.

The program first tests the data for goodness to fit. Parametrically distributed data is analysed for statistical significance by Fishers Exact Probability Test while non-parametric data is automatically shifted to an analysis by the Wilcoxon Test as modified by Haseman and Hoel (1974).

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Additional information on results:

One male from the high dose group died acutely due to lung damage caused by a dosing accident. One animal from the intermediate dose group failed to gain weight and was eating and drinking poorly. The animal was sacrificed and evidence of erosion of the gastric mucosa noted. The death was not attributed to TMS.

Any other information on results incl. tables

Table 2: Number of males / pregnant females / non-pregnant females

Dose Group (mg / kg)	0	20	100	200	Positive Control
Total Number of Males	15	15	14	14	15
Number of fertile Males	13	14	12	12	13
Number of Pregnant females	42	40	46	36	52
Number of non-pregnant females	18	20	10	20	8

 

Table 3: Effect on Fertility index

Dose (mg/kg)	Fertile/Total Males		Fertility Index*
	Mating # 1	Mating # 2	Mating # 1	Mating # 2
0	8/15	13/15	53.3	86.7
20	6/15	14/15	40	93.3
100	11/14	12/14	78.6	85.7
200	6/14	12/14	42.9	85.7
Positive control	13/15	13/15	86.7	86.7

*Number of fertile males / Total number of males x 100

Table 4: Effect on pre-implantation loss

Week of Mating	Dose Level (mg/kg)	Preimplantation Loss Rate (a)	% Loss (b)	Average % Response ± S.D (c)
1	0	5/8	62.5	10.85 ± 13.93
	20	1/6	16.7	1.23 ± 3.14
	100	7/11	63.6	7.02 ± 8.84
	200	4/6	66.7	6.67 ±5.95
	Positive Control	5/8	62.5	7.97 ± 17.81
2	0	7/13	53.8	9.05 ± 14.42
	20	9/14	64.3	7.11 ± 8.82
	100	7/13	53.8	2.75 ± 4.8
	200	7/12	58.3	12.69 ± 24.55
	Positive Control	8/13	61.5	10.68 ± 13.8
3	0	10/13	76.9	9.44 ± 10.02
	20	9/14	64.3	5.33 ± 5.6
	100	7/12	58.3	4.11 ± 4.29
	200	8/12	66.7	7.83 ± 10.39
	Positive Control	9/13	69.2	10.42 ± 10.83

(a) Total number of males producing preimplantation / Total number of fertile males

(b) Preimplantation loss rate x 100

(c) Total preimplantation loss / Total number Corpora Lutea x 100 = Mean (x) percent loss

 

Table 5 : Effect on Resorption rate

Week of Mating	Dose Level (mg/kg)	Resorption Rate (a)	Resorption%  (b)	Average % Response ± S.D (c)
1	0	1/8	12.5	1.14 ± 3.22
	20	3/6	50	3.35 ± 3.68
	100	3/11	27.3	3.05 ± 7.02
	200	1/6	16.7**	0.63 ± 1.55
	Positive Control	10/13	76.9	18.95** ± 13.34
2	0	5/13	38.5	2.19 ± 3.12
	20	4/14	28.6	2.61 ± 5.6
	100	5/12	41.7	2.3 ± 2.99
	200	3/12	25	1.69 ± 3.48
	Positive Control	9/13	69	13.8** ± 21.17
3	0	6/13	46.2	1.99 ± 2.29
	20	6/14	42.9	2.32 ± 3.24
	100	6/12	50	2.59 ± 4.17
	200	4/12	33.3	1.65 ± 3.26
	Positive Control	12/13	92.3*	16.08** ± 11.54

(a) Total number of males producing preimplantation / Total number of fertile males

(b)Resorption rate x 100

(c) Total average percent resorption rate (Total resorptions/ Total implants per fertile male / Total number fertile males

* Significant at p <0.05

** Significant at p <0.01

No dose-related deaths, clinical symptoms or behavioural changes were observed.

Male rats receiving mid to high dose showed signs of sedation immediately after dosing.

There was no significant difference between the mean body weight gain for any of the dosing groups compared to negative control group.

There was no statistically significant difference in fertility index / pre-implantation loss or resorption rate in any of the groups dosed with TMS compared to the negative control group.

A clear dominant lethal syndrome was evident in the positive control group.

Applicant's summary and conclusion

Conclusions:

Trimethylsilane has been tested in a rodent dominant lethal assay according to OECD 426 (1981) and equivalent to OECD 478. The test substance was administered by oral gavage to male rats at three dose levels, five days per week over eight weeks, gave no evidence of inducing chromosomal damage in germinal tissue; there was no substance related effect on fertility index, per-implantation loss or resorption rate. A clear dominant lethal syndrome was evident in the positive control group. Although the test material was administered at a high enough level to induce transient sedation without toxicity, no reduction in male fertility or increase in dominant lethality was obtained. It is concluded that the test substance is negative for genetic toxicity to germ cells under the conditions of the test.