Dichloro(methyl)silane

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

10-06-2008 to 12-08-2009

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: 1a The study was conducted according to the appropriate OECD test guideline, and in compliance with GLP.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2009

Report date:

2009

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: OECD 422

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Dimethylsilanediol

EC Number:

213-915-7

EC Name:

Dimethylsilanediol

Cas Number:

1066-42-8

IUPAC Name:

dimethylsilanediol

Details on test material:

- Name of test material (as cited in study report): Dimethylsilanediol (DMSD)
- Substance type: silanol
- Physical state: White solid
- Stability under test conditions: Not stable
- Storage condition of test material: -20 to -80oC over desiccant

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc, NC
- Age at study initiation: Minimum nine weeks
- Weight at study initiation: Males: 231.5 to 255.7 g ; Females: 167.0 to 198.8 g
- Fasting period before study: No
- Housing: Individually in suspended wire-mesh cages. Pregnant females were housed in shoebox-type cages.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.19-23.24
- Humidity (%): 50-67
- Air changes (per hr): 13.3
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 15-06-2008 To: 25-02-2009

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:DMSD was ground to a fine powder using a mortar and pestle. Dosing solutions were prepared by weighing the appropriate amount of the test substance into a tared container and adding the appropriate amount of corn oil to yield the desired dose level. Solutions were prepared every seven days, based on the stability of the test substance in corn oil.

VEHICLE
- Justification for use and choice of vehicle (if other than water): Most appropriate based on physical and chemical properties of test substance.
- Concentration in vehicle: Not given
- Amount of vehicle (if gavage): Total volume 5ml//kg
- Lot/batch no. (if required): 117K0127
- Purity: No data, used as provided.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

A GC/FID method was used to verify concentration, stability and homogeneity of the test substance in corn oil. Concentration verification was conducted for the initial dose preparations.

Details on mating procedure:

M/F ratio per cage: 1:1
- Length of cohabitation: Up to two weeks
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no, not required
- After successful mating each pregnant female was caged (how): individually in shoe-box type cage

Duration of treatment / exposure:

Toxicity group males and females were treated for 28 and 29 days, respectively. Reproductive phase females were treated to post-partum day 3.

Frequency of treatment:

Daily

Duration of test:

Toxicity group males and females were treated for 28 and 29 days, respectively. Reproductive phase females were treated to post-partum day 3.

Doses / concentrations

Remarks:

Doses / Concentrations:
50, 250, 500 mg/kg bw/day
Basis:

No. of animals per sex per dose:

Ten females in toxicity group; ten females in reproductive toxicity group; ten males to determine reproductive and toxicological endpoints.

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Based on the results of a range-finding study.
- Rationale for animal assignment (if not random): Random

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yesa
- Time schedule: Once before first dose, and then weekly. Skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic ctivity (lacrimation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypies (for example excessive grooming and repetitive circling), difficult or prolonged parturition or bizarre behaviour (such as self mutilation, walking backwards) were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations:During gestation, the reproductive females were weighed on gestation days 0, 7, 14 and 20, within 24 hours of parturition, and on post-partum day four.

FOOD CONSUMPTION: For reproductive group females, feeder weights were taken on days 1, 8, 15, and on gestation days 0, 7, 14, 20 and on post-partum days 0 and 4.

OTHER: The duration of gestation was calculated from day 0 gestation for each female. From gestation day 20 after evidence of mating, pregnant animals were checked at least three times daily (twice daily on weekends and holidays) for evidence of parturition. If difficulties were observed, progress of the parturition process was monitored.

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: No
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes: [all per litter]
- Soft tissue examinations: No
- Skeletal examinations: No
- Head examinations: No

Statistics:

See section 7.5.1

Indices:

Each litter was examined as soon as possible after delivery to determine the number and sex of the pups, the number of pups alive, number of dead pups, runts, and the presence of any gross abnormalities. Pups were counted and sexed and litter weights were taken within 24 hours of parturition and on day 4 post-partum. The day parturition was observed as complete was considered day 0 post-partum. Any abnormal behavior of the offspring was recorded.

Historical control data:

None

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg/day.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): There were no statistically significant differences across exposure groups for mean body weights. There were no statistically significant differences in body weight gain for the reproductive females in any of the treatment groups during any of the measured intervals. There were no differences in the average daily food consumption.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (actual dose received)

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 500 mg/kg bw/day (actual dose received)

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There were no treatment-related effects apparent for any of the reproductive endpoints: gestation length, litter size, litter weight, ratio live births/litter size, litter sex ratio, number of implantation sites, number of corpora lutea, mating and fertility indices.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

See Section 7.5.1 for full results regarding parent animals.

Applicant's summary and conclusion

Conclusions:

In a well conducted, GLP, OECD 422 study (reliability score 1) the NOAEL for dimethylsilanediol for general systemic toxicity was 250 mg/kg bw/day, and ≥500 mg/kg bw/day for reproductive and developmental toxicity. It is considered appropriate to use this result as the basis for reproductive toxicity of dichloromethylsilane, since this substance hydrolyses rapidly to produce the closely related susbtance methylsilanediol and hydrogen chloride.

Executive summary:

In a well conducted, GLP, OECD 422 study (reliability score 1) the NOAEL for dimethylsilanediol for general systemic toxicity was 250 mg/kg bw/day, and ≥500 mg/kg bw/day for reproductive and developmental toxicity. Abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group adult females at 500 mg/kg/day. None of the pair wise comparisons showed a difference between a treated group and control when adjusting for the litter size. The litter size was a significant contributor to explaining any differences in endpoints. There were no treatment-related effects apparent for any of the reproductive endpoints: gestation length, litter size, litter weight, ratio live births/litter size, litter sex ratio, number of implantation sites, number of corpora lutea, post-implantation loss, post-natal loss, mating and fertility indices. For further details on the results for males and toxicity group females, see Section 7.5.1.