Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

There are no reproductive toxicity data on dichloro(dimethyl)silane, therefore data from the hydrolysis products, dimethylsilanediol (DMSD) and hydrogen chloride have been used to read-across. In an OECD 422 study with DMSD no adverse effects on reproductive toxicity parameters were observed in rats at oral doses up to 500 mg/kg/day. Limited data indicates that hydrogen chloride would not be expected to contribute to reproductive effects at the doses given.

Link to relevant study records
Reference
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
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
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
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.
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
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.
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: 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.
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.
Critical effects observed:
not specified
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
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.
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.
Critical effects observed:
not specified
Reproductive effects observed:
not specified

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

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.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no reproductive toxicity data on dichloro(dimethyl)silane so good quality data for the hydrolysis products dimethylsilanediol (DMSD) and hydrogen chloride have been used to assess the reproductive toxicity of dichloro(dimethyl)silane. Further details of read-across justification are provided in Section 5.6.3.

Dichloro(dimethyl)silane is very unstable in the presence of water and will rapidly hydrolyse to DMSD and hydrogen chloride (half-life 0.2 minute at pH 4, 0.3 minute at pH 7 and 0.1 minute at pH 9 and 1.5°C) in the presence of moisture. Most if not all of this will have occurred before absorption into the body. Therefore, use of the hydrolysis product data is considered to be appropriate, and there is no need for testing on the substance itself.

In an OECD 422 study in rats conducted by the oral route with DMSD at doses of 0, 50, 250 or 500 mg/kg/day (Dow Corning Corporation, 2009b), no effects were noted on reproductive toxicity parameters and the reproductive No-Observed-Adverse-Effect-Level was defined as 500 mg/kg/day.

Limited data are available regarding the reproductive toxicity in animals following oral, dermal or inhalation exposure to hydrogen chloride or hydrochloric acid, however, protons and chloride ions both exist as normal constituents of body fluid in animals, hence low concentrations of hydrogen chloride appear not to cause adverse effects in animals. Therefore hydrochloric acid would not contribute to any reproductive toxicity effects at the dose levels tested.


Effects on developmental toxicity

Description of key information

There are no reproductive toxicity data on dichloro(dimethyl)silane, therefore data from the hydrolysis products, dimethylsilanediol (DMSD) and hydrogen chloride have been used to read-across. In an OECD 422 study with DMSD no adverse effects on developmental toxicity parameters were observed in rats at oral doses up to 500 mg/kg/day.  In an OECD 414 developmental toxicity study  oral administration of DMSD to pregnant rats at 250, 500 or 1000 mg/kg/day resulted in a maternal Lowest-Observed-Adverse-Effect-Level (LOAEL) of 250 mg/kg/day based on hepatic findings (increased weight, hypertrophy and vacuolation) at all doses. The fetal developmental NOAEL was considered to be 250 mg/kg/day based on lower fetal body weight and increased incidences of fetal malformations and variations at 500 or 1000 mg/kg/day. Limited data indicates that hydrogen chloride would not be expected to contribute to developmental effects at the doses given.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 February 2013 to 9 May 2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Inc., Raleigh, NC, US
- Age at study initiation: approx 79 days
- Housing:stainless steel wire-mesh cages suspended above cage-board
- Diet:PMI Nutrition International, LLC Certified Rodent LabDiet® 5002 (ad libitum):
- Water: municipal water supply (ad libitum):
- Acclimation period: 14 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.1 to 21.3
- Humidity (%): 42.1 to 46.5
- Air changes (per hr): at least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: 19 February 2013 to 28 March 2013
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance formulations were prepared approximately weekly as single formulations for each dose level, divided into aliquots for daily dispensation, and stored refrigerated in plastic bags containing desiccant.


VEHICLE
- Concentration in vehicle: 0, 50, 100 or 200 mg/ml
- Amount of vehicle (if gavage): 5 ml/kg
- Lot/batch no.: 2BD1117, 2BH0747, and 2AJ0197
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Prior to the initiation of dose administration, two sets of duplicate samples for homogeneity determination were collected from the top, middle, and bottom strata of nondosing formulations prepared at 50, 100, and 200 mg/mL. In addition, two sets of duplicate samples for resuspension homogeneity and stability determinations were collected from the top, middle, and bottom strata of an aliquot taken from these same nondosing suspensions following refrigerated storage for 10 days; aliquots were mixed for a minimum of 30 minutes prior to sample collection. Two sets of duplicate samples for concentration analysis were collected from the middle stratum of each dosing formulation (including the control group) from the first and last formulations prepared during the in-life phase. One set of samples from each collection was subjected to the appropriate analyses. The remaining set of samples was stored refrigerated (approximately 2°C to 8°) as back-up. All analyses were conducted by using a validated gas chromatography method with flame ionization detection.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Length of cohabitation: until positive evidence of mating
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
Gestation days 6 to 19
Frequency of treatment:
daily
Duration of test:
until gestational day 20
Dose / conc.:
250 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25 females
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
Dose levels were selected based on results of an OECD 422 study performed with the same test substance. In that study, there were no obvious signs of
reproductive/developmental toxicity at a high-dose level of 500 mg/kg bw/day. Maternal toxicity was limited to higher liver weights and hepatocellular vacuolation. There was a potential for lower body weight gains at 1000 mg/kg bw/day based on a 14-day range-finding study.

The selected route of administration for this study was oral (gavage) because this is a potential route of exposure for humans. Historically, this route has been used extensively for studies of this nature.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily, gestational day 0 to 20

BODY WEIGHT: Yes
- Time schedule for examinations: gestational day 0, 6-20

FOOD CONSUMPTION: Yes
- Time schedule for examinations: gestational day 0, 6-20
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: liver
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: Yes
- Number of late resorptions: Yes
- Other: placentae
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter by Wilson technique, half per litter by midcoronal slice
Statistics:
Analyses were conducted using two-tailed tests (except as noted otherwise) for minimum significance levels of 1% and 5%, comparing each test substance-treated group to the control group. Each mean was presented with the standard deviation, standard error and the number of animals used to calculate the mean.

Maternal body weights (absolute and net), body weight changes (absolute and net), and food consumption, gravid uterine weights, absolute liver weights, numbers of corpora lutea, implantation sites, fetal body weights and viable fetuses were subjected to a parametric one-way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance-treated groups to the control group. In addition, fetal body weights were subjected to a parametric one-way ANCOVA (SAS Institute, Inc., 2002-2008) with litter size as the covariate, to determine intergroup differences. If the ANCOVA revealed significant (p<0.05) intergroup variance, Dunnett’s test (Dunnett, 1964) was used to compare the test article-treated groups to the control group. Mean litter proportions (percent per litter) of prenatal data (viable and nonviable fetuses, early and late resorptions, total resorptions, pre- and postimplantation loss, and fetal sex distribution), total fetal malformations and developmental variations (external, visceral, skeletal, and combined) and each particular external, visceral, and skeletal malformation or variation were subjected to the Kruskal-Wallis nonparametric ANOVA test (Kruskal and Wallis, 1952) to determine intergroup differences. If the ANOVA revealed significant (p<0.05) intergroup variance, Dunn’s test (Dunn, 1964) was used to compare the test substance-treated groups to the control group.
Historical control data:
Yes
Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Low incidences of test substance-related yellow material on the anogenital area was noted in the 500 and 1000 mg/kg bw/day groups. This
finding was noted as early as gestation day 10 or 7 in these respective groups and continuing through gestation day 20. Low incidences of red material around the nose and/or read or clear material around teh mouth were also noted in these groups beginning on gestation day 7 or 6, respectively, through gestation day 20. No findings attributable to treatement noted at 250 mg/kg/day.

Mean maternal body weight gains in the 1000 mg/kg bw/day group were similar to the control group during gestation days 6-12. Significantly (p<0.05) lower mean body weight gains were noted in this group during gestation days 12-15 (27.8%) and 15-20 (13.7%) compared to the control group. As a result, mean body weight gain in the 1000 mg/kg bw/day group was lower than the control group when the entire treatment period (9.6%; gestation days 6-20) was evaluated. Mean gravid uterine weight in the 1000 mg/kg bw/day group was slightly lower (8.5%) than the control group. The lower mean body weight gain late in gestation and lower mean gravid uterine weight in this group were attributed to the lower mean fetal body weight and slightly lower mean number of viable fetuses and were not considered to be evidence of maternal toxicity. Lower mean food consumption was noted in the 1000 mg/kg bw/day group throughout the gestation treatment period (days 6-20).

Mean liver weights in the 250, 500, and 1000 mg/kg bw/day groups were 20.2%, 35.7% and 65.6% higher, respectively, than the control group value. Test substance-related microscopic findings were noted in the liver of the 250, 500, and 1000 mg/kg bw/day groups. Centrilobular hypertrophy was considered an adaptive response. Periportal vacuolation, characterized by primarily macrovesicular change, was morphologically consistent with lipid accumulation. Although hepatocellular lipid accumulation may be an adaptive response, in this study the vacuolation was considered an adverse finding at ≥250 mg/kg bw/day due to the increased incidence and severity in the test substance-treated groups, along with the increases in liver weight.

Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Abnormalities:
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
A higher mean litter proportion of postimplantation loss (primarily due to a higher incidence of late resorptions), with a corresponding lower mean litter proportion of viable fetuses was noted in the 1000 mg/kg bw/day group. Statistically significant lower mean fetal body weights were observed in all test substance-treated groups. Although the mean fetal body weight in the 250 mg/kg bw/day group was only 5.3% lower than the concurrent control group value (0.2 g less) and within the range of thehistorical control data, the difference from the concurrent control group was statistically significant when analyzed using both an analysis of variance (ANOVA; p<0.05) and an analysis of covariance (ANCOVA; p<0.01) with litter size as the covariate. However, these methods assume litter size is unaffected by treatment.

The lower mean fetal weights in these groups coincided with increased incidences of skeletal variations in a dose-related manner related to lesser degree of ossification and bent ribs or limb bones (see below). Mean fetal sex ratios in all test substance-treated groups and intrauterine survival in the 250 and 500 mg/kg bw/day groups were unaffected by maternal test substance administration.

Test substance-related adverse effects on fetal morphology were noted in all test substance-treated groups, with some of the findings interpreted as test substance-related having incidences in the 250 and 500 mg/kg bw/day groups being within the range of the historical control data and some of the findings only represent 1 fetus in the group, and consisted of the following:

- External malformations (fetal anasarca, localized fetal edema, tarsal flexure, and cleft palate) were noted at 1000 mg/kg bw/day.
- Visceral malformations (retroesophageal, right-sided, or coarctation of the aortic arch and absent cartilaginous rings of the trachea) were noted at 1000 mg/kg bw/day; one fetus in the 500 mg/kg bw/day group also had a retroesophageal aortic arch.
- Skeletal malformations consisted of costal cartilage anomaly (500 and 1000 mg/kg bw/day), bent scapula (500 and 1000 mg/kg bw/day; statistically significant at 1000 mg/kg bw/day), and bent limb bone(s) and sternoschisis (1000 mg/kg bw/day).
- Visceral developmental variations consisted of small thyroid gland(s) (250 mg/kg bw/day and higher), pale spleen (500 mg/kg bw/day and higher), and major blood vessel variations and pale or swollen liver (1000 mg/kg bw/day). One of the fetuses in the 1000 mg/kg bw/day group with a swollen liver also had white areas in the liver.

The following skeletal developmental variations were also noted in the indicated test substance-treated groups and generally corresponded to the test substance-related lower mean fetal weights at all dose levels.
- A lower incidence of cervical centrum no. 1 ossified (250, 500, and 1000 mg/kg bw/day); higher incidences of bent ribs and 14th rudimentary rib(s) (250 mg/kg bw/day and higher); higher incidences of pubis unossified and 27 presacral vertebrae (250 mg/kg bw/day and higher); and higher incidences of reduced ossification of the rib(s) (500 mg/kg bw/day and higher).
- Higher incidences of sternebra(e) nos. 5 and/or 6 unossified (500 and 1000 mg/kg bw/day); higher incidences of 7th cervical rib(s), reduced ossification of the vertebral arches, and sternebra(e) nos. 1, 2, 3, and/or 4 unossified (500 and 1000 mg/kg bw/day); and higher incidences of unco-ossified vertebral centra and reduced ossification of the skull and rib(s) (500 and 1000 mg/kg bw/day).
- Higher incidences of vertebral centra unossified, metacarpals and/or metatarsals unossified, entire sternum unossified, and 14th full rib(s), (1000 mg/kg bw/day).
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Increased incidence of fetal variations and malformations and lower fetal weight at 500 and 1000 mg/kg/day.
Abnormalities:
not specified
Developmental effects observed:
not specified

Table - Incidence of Selected Histopathologic Findings,
                       Gestation Day 20 Scheduled Necropsy

 

Females

Dosage (mg/kg bw/day):

0

250

500

1000

 

 

 

 

 

Livera

25

25

25

25

  Hypertrophy, hepatocellular, centrilobular

0

25

24

23

      Minimal

-

1

9

0

      Mild

-

23

15

18

      Moderate

-

1

0

5

 

 

 

 

 

  Vacuolation, hepatocellular, periportal

14

21

24

22

      Minimal

6

15

12

5

      Mild

8

5

11

13

      Moderate

-

1

1

4

a - Number of tissues examined from each group.

Table - Mean Litter Proportions of Test Substance-Related External
Malformations (% per Litter)

Finding

0
mg/kg bw/day

250
mg/kg bw/day

500
mg/kg bw/day

1000 mg/kg bw/day

HC Mean (Range)

Fetal Anasarca

0.0

0.0

0.0

4.3 

0.0 (0.0-1.3)

Localized Fetal Edema

0.0

0.0

0.0

0.9

0.0 (0.0-0.9)

Tarsal Flexurea

0.0

0.0

0.0

0.6

0.0 (0.0-0.3)

Cleft Palate

0.0

0.0

0.0

0.3

0.0 (0.0-0.3)

a- Noted as Carpal and/or Tarsal Flexure on Tables
Values are bolded for findings considered to be test substance-related

Table - Mean Litter Proportions of Test Substance-Related Visceral
Malformations (% per Litter)

Finding

0
mg/kg bw/day

250
mg/kg bw/day

500
mg/kg bw/day

1000 mg/kg bw/day

HC Mean (Range)

Retroesophageal Aortic
    Arch

0.0

0.0

0.3

1.4

0.0 (0.0-0.3)

Coarctation of the Aortic
    Arch

0.0

0.0

0.0

1.4

Not observed

Trachea- Absent
    Cartilaginous Rings

0.0

0.0

0.0

1.3

Not observed

Right-Sided Aortic Arch

0.0

0.0

0.0

0.3

0.0 (0.0-0.2)

Values are bolded for findings considered to be test substance-related.

Table - Mean Litter Proportions of Test Substance-Related Visceral
Developmental Variations (% per Litter)

Finding

0
mg/kg bw/day

250
mg/kg bw/day

500
mg/kg bw/day

1000 mg/kg bw/day

HC Mean (Range)

Major Blood Vessel
   Variation

0.0

1.8

0.6

4.7

0.1 (0.0-0.8)

Thyroid Gland(s)- Small

0.0

0.3

0.5

0.8

Not observed

Spleen- Pale

0.0

0.0

0.6

5.6

0.0 (0.0-0.6)

Liver- Swollen

0.0

0.0

0.0

0.6

0.0 (0.0-0.3)

Liver- Pale

0.0

0.0

0.0

0.5

0.0 (0.0-0.3)

Values are bolded for findings considered to be test substance-related.

Table - Mean Litter Proportions of Test Substance-Related Skeletal
Malformations (% per Litter)

Finding

0
mg/kg bw/day

250
mg/kg bw/day

500
mg/kg bw/day

1000 mg/kg bw/day

HC Mean (Range)

Bent Scapula

0.0

0.0

3.7

17.8**

0.0 (0.0-0.3)

Bent Limb Bone(s)

0.0

0.0

0.0

6.1

0.0 (0.0-0.3)

Costal Cartilage Anomaly

0.0

0.2

0.8

8.3

0.0 (0.0-0.3)

Sternoschisis

0.0

0.3

0.0

0.8

0.0 (0.0-0.6)

Values are bolded for findings considered to be test substance-related.
** = Significantly different from the concurrent control group at p<0.01.

Table - Mean Litter Proportions of Test Substance-Related Skeletal
Variations (% per Litter)

Finding

0
mg/kg bw/day

250
mg/kg bw/day

500
mg/kg bw/day

1000 mg/kg bw/day

HC Mean (Range)

Cervical Centrum No. 1
   Ossified

19.1

0.3**

0.3**

0.0**

20.2 (6.6-35.8)

Bent Rib(s)

0.0

3.7

31.0**

56.9**

0.2 (0.0-2.1)

Sternebra(e) Nos. 5 and/or 6
   Unossified

11.0

10.4

26.7*

44.1**

6.4 (0.2-26.1)

14th Rudimentary Rib(s)

13.1

27.5

37.9**

44.7**

7.1 (0.0-18.9)

Pubis Unossified

0.0

2.4

8.1

13.0**

0.1 (0.0-2.3)

7th Cervical Rib(s)

2.3

3.5

8.4

21.2**

0.8 (0.0-3.7)

Reduced Ossification of
   the Skull

0.3

0.9

2.1

7.6

0.1 (0.0-1.0)

Reduced Ossification of
   the Vertebral Arches

0.3

0.9

2.1

17.1**

0.1 (0.0-1.3)

Sternebra(e) Nos. 1, 2, 3,
   and/or 4 Unossified

0.2

0.3

4.2

11.8**

0.2 (0.0-1.5)

Unco-Ossified Vertebral
   Centra

0.0

0.0

0.9

3.6

0.0 (0.0-0.5)

27 Presacral Vertebrae

0.2

4.1

6.1

14.0**

0.2 (0.0-1.8)

Vertebral Centra
   Unossified

0.0

0.0

0.0

2.7

0.0 (0.0-0.4)

Metacarpal(s) and/or
   Metatarsals Unossified

0.0

0.0

0.0

1.3

Not observed

Entire Sternum Unossified

0.0

0.0

0.0

4.6

0.0 (0.0-0.4)

Reduced Ossification of the
   Rib(s)

0.0

0.6

1.8

1.5

0.0 (0.0-1.2)

14th Full Rib(s)

0.0

1.5

0.3

1.4

0.1 (0.0-0.9)

Values are bolded for findings considered to be test substance-related.
* = Significantly different from the concurrent control group at p<0.05.

** = Significantly different from the concurrent control group at p<0.01.

Table - Results of additional statistical analysis: Number of dams (N), mean litter size, mean fetal weight (Analysis 1) and litter weight (Analysis 3) by DMSD dose. Relative differences to controls and p-values from linear regression on categories of dose.

Dose

/

mg/kg/day

N

Mean
Litter Size

Mean Fetal
Weight

 / g

Relative Difference
Mean Fetal Weight*

/ %

Relative Difference
Mean Fetal Weight*

P -Value

Litter Weight

/ g

Relative Difference
Litter Weight*

/ %

Relative Difference
Litter Weight*

P-Value

0

25

14.2

3.83

0.00

-

54.47

0.00

-

250

25

15.2

3.64

-4.91

.0037

55.38

1.67

.7029

500

25

14.3

3.44

-10.14

<0.0001

48.91

-10.21

.0218

1000

25

13.2

2.92

-23.82

<0.0001

38.84

-28.70

<0.0001

*reference: dose = 0 mg/kg/day

See attachments for result tables.

Conclusions:
Oral administration of dimethylsilanediol to pregnant rats at 250, 500 or 1000 mg/kg/day resulted in a maternal No-Observed-Adverse-Effect-Level (NOAEL) of < 250 mg/kg/day based on hepatic findings (increased weight, hypertrophy and vacuolation) at all doses.

The fetal developmental NOAEL was considered to be 250 mg/kg/day based on lower fetal body weight and increased incidences of fetal malformations and variations at 500 or 1000 mg/kg/day.
Executive summary:

Administration of dimethylsilanediol to pregnant rats at doses of 250, 500 or 1000 mg/kg/day resulted in a maternal No-Observed-Adverse-Effect-Level (NOAEL) of less than 250 mg/kg/day based on higher mean liver weights and corresponding microscopic findings of hepatocellular hypertrophy and periportal hepatocellular vacuolation at all doses.

A higher mean litter proportion of post implantation loss, with a corresponding lower mean litter proportion of viable fetuses, was considered attributable to treatment and adverse in the 1000 mg/kg bw/day group.

Mean fetal body weights at the three doses were 5.3%, 10.5%, and 23.7% lower, respectively, than the concurrent control group and these differences were statitically significant at all doses when analysed by ANOVA or ANCOVA. However, these statistical methods assume litter size is unaffected by treatment. The mean fetal weight in the 250 mg/kg bw/day group was within the historical control data range and was only 0.2 g lower than the concurrent control group mean. Furthermore, litter size can be affected by treatment so additional statistical analysis of the fetal weight data using an appropriate statistical method specific for this type of data, which takes litter size into account (Morfeld, 2013), demonstrated that fetal weight at 250 mg/kg/day was comparable with control and not statistically significant and therefore unaffected by treatment at this dose.

Fetal malformations were noted in the 500 and 1000 mg/kg bw/day groups, but not in the 250 mg/kg bw/day group. Fetal variations were recorded in all dose groups with some visceral (small thyroid gland) and skeletal variations in the 250 mg/kg bw/day group showing a dose-response relationship. However, many of the fetal variations noted in the 250 mg/kg/day group were either recorded at an incidence that was not statistically significant and/or within the historical control incidence. Furthermore, as many, but not all, of these variations (skeletal developmental delays) correlate with fetal body weight, and fetal body weight was not affected by treatment, then the variations noted at the low dose of 250 mg/kg/day are also considered not to be attributable to treatment.

Therefore, the NOAEL for prenatal developmental toxicity was considered to be 250 mg/kg/day.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

There are no developmental toxicity data on dichloro(dimethyl)silane so good quality data for the hydrolysis products dimethylsilanediol (DMSD) and hydrogen chloride have been used to assess the developmental toxicity of dichloro(dimethyl)silane. Further details of read-across justification are provided in Section 5.6.3.

Dichloro(dimethyl)silane is very unstable in the presence of water and will rapidly hydrolyse to DMSD and hydrogen chloride (half-life 0.2 minute at pH 4, 0.3 minute at pH 7 and 0.1 minute at pH 9 and 1.5°C) in the presence of moisture. Most if not all of this will have occurred before absorption into the body. Therefore, use of the hydrolysis product data is considered to be appropriate, and there is no need for testing on the substance itself.

In an OECD 422 study in rats conducted by the oral route with DMSD at doses of 0, 50, 250 or 500 mg/kg/day (Dow Corning Corporation, 2009b), no effects were noted on developmental toxicity parameters and the developmental No-Observed-Adverse-Effect-Level was defined as 500 mg/kg/day. An OECD 414 developmental toxicity study conducted by the oral route with DMSD at doses of 0, 250, 500 or 1000 mg/kg/day (WIL Research, 2014) resulted in a maternal Lowest-Observed-Adverse-Effect-Level (LOAEL) of 250 mg/kg/day based on higher mean liver weights and corresponding microscopic findings of hepatocellular hypertrophy and periportal hepatocellular vacuolation at all doses, a maternal NOAEL was not defined.

A higher mean litter proportion of post implantation loss, with a corresponding lower mean litter proportion of viable fetuses, was considered attributable to treatment and adverse in the 1000 mg/kg bw/day group. Mean fetal body weights at the three doses were 5.3%, 10.5%, and 23.7% lower, respectively, than the concurrent control group and these differences were statistically significant at all doses when analysed by ANOVA or ANCOVA. However, these statistical methods assume litter size is unaffected by treatment. The mean fetal weight in the 250 mg/kg bw/day group was within the historical control data range and was only 0.2 g lower than the concurrent control group mean. Furthermore, litter size can be affected by treatment so additional statistical analysis of the fetal weight data using an appropriate statistical method specific for this type of data, which takes litter size into account (Morfeld, 2014), demonstrated that fetal weight at 250 mg/kg/day was comparable with control and not statistically significant and therefore unaffected by treatment at this dose. Fetal malformations were noted in the 500 and 1000 mg/kg bw/day groups, but not in the 250 mg/kg bw/day group. Fetal variations were recorded in all dose groups with some visceral (small thyroid gland) and skeletal variations in the 250 mg/kg bw/day group showing a dose-response relationship. However, many of the fetal variations noted in the 250 mg/kg/day group were either recorded at an incidence that was not statistically significant and/or within the historical control incidence. Furthermore, as many, but not all, of these variations (skeletal developmental delays) correlate with fetal body weight, and fetal body weight was not affected by treatment, then the variations noted at the low dose of 250 mg/kg/day are also considered not to be attributable to treatment. It is important to note that 1) malformations are alterations in fetal morphology that are expected to be permanent and to interfere with the function or viability of the organism, and 2) variations are alterations that are transient, do not interfere with the function or viability of the organism, and are often seen in control animals. Based on the fact that variations are not considered adverse the variations recorded in the OECD 414 test on DMSD should not be considered as adverse findings and the lowest dose of 250 mg/kg bw/day is the NOAEL based on reduced fetal body weight and malformations at the mid and high doses.

Limited data are available regarding the development in animals following oral, dermal or inhalation exposure to hydrogen chloride or hydrochloric acid, however, protons and chloride ions both exist as normal constituents of body fluid in animals, hence low concentrations of hydrogen chloride appear not to cause adverse effects in animals. Therefore hydrochloric acid would not contribute to any developmental toxicity effects at the dose levels tested.


Justification for classification or non-classification

Based on the available data, dichloro(dimethoxy)silane (DCDMS) does not require classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008.

DCDMS is a corrosive material. It is unlikely that exposure to DCDMS will be high enough to trigger a systemic effect in absence of severe damage to the respiratory tract or gastro-intestinal tract. Acute local effects are protecting against systemic effect. The lowest Dimethylsilanediol dose to trigger a reproductive effect in the prenatal development test are in the range above 250 mg/kg bw. It would convert to a inhalation concentration of above 330 mg/m3 of HCl. This figure is well above the OEL of HCl which is 8 mg/m3 and which has been set to protect again irritation effect.