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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
10-06-2008 to 12-08-2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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 -80 degrees C over desiccant

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals 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.
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
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.
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
Details on study schedule:
Not applicable as screening study.
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
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
Positive control:
None

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before first dose, and then weekly. Skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (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: Individual body weights were determined beginning with randomisation into the test groups, on the first day of dosing, at least weekly thereafter, and on the day of sacrifice. 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 males, feeder weights were taken on days 1, 8 and 15 during the pre-mating period. 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.
Oestrous cyclicity (parental animals):
Not applicable - screening study
Sperm parameters (parental animals):
Parameters examined in male parental animals: testis weight, epididymis weight, prostate gland weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Not applicable - screening study

PARAMETERS EXAMINED
The following parameters were examined in offspring: number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities, other:]


GROSS EXAMINATION OF DEAD PUPS:
[no / yes, for external and internal abnormalities; possible cause of death was/was not determined for pups born or found dead.]
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 28 days treatment
- Maternal animals: All surviving animals on day 4 post-partum (toxicity group after 29 days treatment)


GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.


HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table 2 of Section 7.5.1 were prepared for microscopic examination and weighed, respectively.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring on post-partum day 4.

GROSS NECROPSY
- Gross necropsy consisted of an external examination only.

HISTOPATHOLOGY / ORGAN WEIGTHS: Not conducted
Statistics:
See section 7.5.1
Reproductive 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 behaviour of the offspring was recorded.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg/day.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
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.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no differences in the average daily food consumption.
Organ weight findings including organ / body weight ratios:
not examined
Histopathological findings: non-neoplastic:
not examined
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
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, mating and fertility indices.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: hepatic brown pigment accumulation at 500 mg/kg bw/day.

Target system / organ toxicity (P0)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined

Details on results (F1)

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, mating and fertility indices.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
>= 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.

Target system / organ toxicity (F1)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

See Section 7.5.1 for effects on toxicity group males and females in more detail, including results tables for key findings.

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 dichlorodimethylsilane, since this substance hydrolyses rapidly to produce dimethylsilanediol 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, mating, 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.