Registration Dossier

Administrative data

Description of key information

There are no repeated dose toxicity data for dichloro(dimethyl)silane appropriate to assess potential systemic effects, therefore data for the oral route has been read-across from the hydrolysis product, dimethylsilanediol. The key study for repeat dose toxicity via the oral route is a 28-day study in which DMSD was administered to rats at 0, 50, 250 or 500 mg/kg/day. The systemic toxicity NOAEL (No-Observed-Adverse-Effect-Level) for dimethylsilanediol in rats via oral administration was considered to be 250 mg/kg bw/day due to hepatic brown pigment accumulation and associated bile duct hyperplasia and chronic inflammation at 500 mg/kg/day.   For repeat dose toxicity via the inhalation route, there were no effects attributable to treatment when dichloro(dimethyl)silane was administered to rats 5 days/week for 2 weeks at 15 ppm. In a 4-week inhalation study conducted specifically to assess respiratory tract changes and local toxicity, dichloro(dimethyl)silane was administered to rats at 5 or 25 ppm and resulted concentration-related effects in the nasal cavity indicative of a local irritant effect. The local effects noted at 25 ppm were considered to be generally comparable to the group receiving hydrogen chloride at 50 ppm in the same study. In a 90-day inhalation study with hydrogen chloride in rats and mice the No Observed Adverse Effect Concentration (NOAEC) for systemic effects was determined to be 20 ppm (approximately 30 mg/m3) based on decreased body weight following exposure to 50 ppm. No NOAEC for local effects was established as irritant/corrosive effects were observed at all dose levels tested.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
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 (except during exposure)
- Water (e.g. ad libitum): Ad libitum (except during exposure)
- 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 oral 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.
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
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
- Rationale for selecting satellite groups: No satellite groups
- Post-exposure recovery period in satellite groups: No post-exposure recovery period.
Positive control:
None
Observations and examinations performed and frequency:
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 females, feeder weights were taken on days 1, 8, 15, 22 and the day prior to sacrifice.
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes
- How many animals: All males and toxicity group females
- Parameters checked in table 1 were examined.


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At terminal sacrifice
- Animals fasted: Yes
- How many animals: All males and toxicity group females
- Parameters checked in table 1 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: Prior to dosing and during week four of dosing.
- Dose groups that were examined: All males and toxicity group females.
- Battery of functions tested: cage side observations, hand-held observations, open field observations, categorical observations, measurement counts, motor activity.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
Body weight, food consumption, hematology, and clinical chemistry data, and prothrombin times were analysed using a one-way Analysis of Variance (ANOVA) if the data satisfied the requirements of normality of the residuals and homogeneity of variance as determined using a statistical test for normality for homogeneity of variance. If the data do not satisfy the parametric requirements, a Kruskal-Wallis test was used. If the ANOVA or Kruskal-Wallis test was significant (p < 0.05), pair-wise comparisons of the exposed groups to control were made using the Dunnett’s test or a Wilcoxon test, respectively. For variables with multiple measurements across time (motor activity, body weight and food consumption), a repeated measurements ANOVA was performed to determine if a significant time by treatment group interaction exists. Repeated measurements ANOVAs were done using the time (baseline and post-treatment), interval, sex and treatment to look for interactions between the treatment, the time and sex to determine if analysis could be done with the sexes combined. Reproductive parameters with the exception of litter size were analysed using an ANCOVA (Analysis of Covariance) with litter size as the covariate. Litter size was analysed using an ANOVA. Measured continuous Functional Observational Battery (FOB) data were analysed using a combination of ANCOVA with baseline evaluations used as the covariate and repeated measures ANOVA. Categorical FOB data was analysed using the Jonckheere-Terpstra test. Categorical Functional Observational Battery (FOB) data were analysed using the Jonckheere-Terpstra test. This test is used to detect a shift in the categorical observations. Microscopic findings were also analysed using a Cochran-Armitage trend test to indicate an increasing incidence trend with Fischer's Exact tests used to indicate increased incidence over the controls. Clinical signs data were analysed using Mixed Modelling repeated measures.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
For the toxicity group males at 500 mg/kg/day, significant abnormal observations (p<0.01) were noted and included soiling in the abdominal region and urogenital soiling. Urogenital soiling was also significant (p<0.05) in males at 250 mg/kg/day. Soiling of the muzzle was a significant abnormal observation (p<0.02) in the toxicity group females at 500 mg/kg/day. Both abdominal soiling and urogenital soiling were significant abnormal observations (p<0.01) in the reproductive group females at 500 mg/kg/day.
Mortality:
mortality observed, treatment-related
Description (incidence):
All but one animal survived to their scheduled necropsy. The animal that died was euthanised following a dosing injury.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were no statistically significant differences across treatment groups in the mean body weights on any day for any of the three groups: males, toxicity group females, and reproductive toxicity group females. With respect to body weight gain, male group 4 animals had a statistically significant decrease in body weight gain (p<0.05) during week 4. The 500 mg/kg/day male group also had a statistically significant decrease (p<0.02) in total gain from day 1 to 29. For toxicology females there was a statistically significant (p<0.02) in body weight gain during week 3. There were no statistically significant differences in body weight gain for the reproductive females in any of the treatment groups: week 1 and 2 pre-mating, gestational weeks 1, 2, 3 and post-partum day 0 to post-partum day 4. Weight gain for the reproductive females in the three treatment groups was not different from control for the interval from day 1 of study to post-partum day 4.
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 across treatment groups for the reproductive females group or the toxicity female group for any of the measured time periods. In the male group there was a significant difference across treatment groups in week 2, however, there was not a significant difference between control and any of the treatment groups for that week.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
There were no significant differences noted in the other hematology values or hematology differential data across groups for either sex. No toxicological significance is assigned at this time to any statistically identified differences in hematology parameters since the findings were within or slightly below historical control ranges for this laboratory and the findings did not correlate with a pathological outcome.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
There were dose-related decreases in male and female alkaline phosphatase and total bilirubin values as well as a dose related decrease in male aspartate aminotransferease values. No toxicologic significance was assigned to any statistically identified differences in clinical pathology since findings were within or slightly below historical control ranges for this laboratory and the findings did not correlate with a pathological outcome.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
No statistically significant differences between the control and treatment groups in either sex at the treated time point for all the FOB ranked tests, except for an increase in defecation (males) at 500 mg/kg/day at a significance of p <0.05. There was no dose response associated with this effect, nor did it correlate with any change in the other neurobehavioral tests conducted on the same animals. There were no statistically significant differences between either male or female treatment groups and their respective controls for the FOB continuous test and motor activity. There were no treatment-related changes associated with dimethylsilanediol administration on rat neurobiological function as evaluated with FOB and motor activity parameters.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
There were statistically significant differences noted for the following organ weights in toxicity group males; adrenal glands (24% decrease at 500 mg/kg/day at p <0.01), liver (19% increase at 250 and 31% increase at 500 mg/kg/day at p <0.01), testes (12% decrease at 500 mg/kg/day at p <0.01), and thymus (31% decrease at 500 mg/kg/day at p <0.01). There were statistically significant differences for the mean percentage of organ weights relative to body weights for adrenal glands (decrease at p <0.05), liver (increase at 250 and 500 mg/kg/day at p <0.01), and thymus (decrease at p <0.05) for the toxicity group males. There were statistically significant differences noted liver weights in toxicity group females; liver (24% increase at 250 and 61% increase at 500 mg/kg/day at p <0.01). There were statistically significant differences for the mean percentage of organ weights relative to body weights for liver (increase at 250 and 500 mg/kg/day at p <0.01) for the toxicity group females. The increased liver weights in toxicity males and females correlated with the histopathologic finding of centrilobular hyperthrophy. There were no other treatment-related differences in organ weights, absolute and relative (mean %) for toxicity group males and females.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
In the liver, the finding of discoloration (+/- mottled) was observed more commonly in rats of both sexes administered ≥250 mg/kg/day. Liver enlargement was grossly more notable in females administered 500 mg/kg/day. Lung discoloration was more common in male rats administered ≥250 mg/kg/day. Other findings generally occurred singly and were not considered to be attributable to test article administration.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Liver: Males
There were two primary liver findings in male rats. In the liver of male rats, the incidence of centrilobular hypertrophy was significantly increased (p <0.01) in 250 and 500 mg/kg/day groups (8/10 animals in each group) over control. The increased incidence of centrilobular hypertrophy identified correlates with the statistically significant increase in relative liver weight observed for these groups. This is a common effect of xenobiotic administration and is considered an adaptive change.

Additionally, there was minimal to moderate brown pigment accumulation in and around bile ducts, with associated bile duct hyperplasia and chronic inflammation in 9/10 high-dose males. Under polarised light some pigment accumulations show birefringence. The finding was split into three components and recorded as 1) brown pigment, 2) periportal chronic inflammation, and 3) bile duct hyperplasia associated with brown pigment accumulation. The severity of the inflammatory and bile duct hyperplasia components generally closely matched the pigment accumulation. The brown pigment was not observed in control animals, at lower dose levels, or in female rats. Periportal chronic inflammation (9/10 animals), hyperplasia in the bile ducts associated with brown pigment accumulation (8/10 animals), and brown pigment accumulation (9/10 animals) showed significant increase in incidence (p<0.01) over control only in the 500 mg/kg/day group. For these microscopic findings in the liver, there were no significant shifts in severity across treatment groups.

Females:
In the liver, the incidence of centrilobular hypertrophy was significantly increased (p <0.01) in the 250 and 500 mg/kg/day female toxicity groups. The increased incidence of centrilobular hypertrophy identified correlates with the statistically significant increase in relative liver weight observed for these groups. This is a common effect of xenobiotic administration and is considered an adaptive change.

For liver periportal vacuolization, only the 500 mg/kg/day toxicity female group was significantly (p <0.02) increased in incidence over the control group. Comparison of the graded animals only showed a significant increase in severity grade across treatment groups for liver vacuolization in females. It is generally but not universally held that this finding in and of itself is not considered adverse unless severe.

Thyroid Gland:
Both the 250 and 500 mg/kg/day male toxicity groups (8/10 and 9/10 animals, respectively) had significantly increased incidence (p <0.01) of thyroid gland follicular hypertrophy than did the control group and the comparison of the graded animals showed a significant increase in severity grade across treatment groups. Hypertrophy of the thyroid follicular epithelium is a common secondary response to increased thyroid hormone catabolism due to up-regulation of hepatic microsomal enzymes in response to xenobiotic administration. The rat is particularly sensitive to this effect due to the species’ lack of a protective carrier protein, thyroid binding globulin.

Prostate Gland
The 500 mg/kg/day group had a statistically significant increase in incidence (p <0.05) in chronic inflammation of the prostate gland over that seen in the control group. Chronic inflammation of the prostate gland is a fairly common spontaneous finding. This finding is not considered to be attributable to test article administration, particularly since the two most severe instances occurred in rats administered 0 and 50 mg/kg/day

Lung
In the lungs of males rats, there was an increasing trend in the observed incidence of pulmonary histiocytosis (aggregates of foamy macrophages). For histocytosis in the lungs there were no pair wise significant differences between any treated group and control. This is a very common spontaneous finding and there was no clear increase in severity associated with dosage. This finding is not considered to be attributable to test article administration.
Histopathological findings: neoplastic:
not examined
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: Based on hepatic brown pigment at 500 mg/kg bw/day
Critical effects observed:
not specified

Table 3: Absolute and relative organ weights of males and toxicity group females

 

Males

Females

DAILY DOSE
(mg/kg bw/day)

0

50

250

500

0

50

250

500

NUMBER OF ANIMALS

 10

 10

10 

10 

 10

 10

10 

 10

BODY WEIGHT MEAN (g)a

430.83

421.51

420.22

401.2

259.56

256.32

257.99

254.47

BRAIN

 

 

 

 

 

 

 

 

Absolute Weighta

g

1.99

1.97

1.99 

1.97 

1.93

1.92 

1.90 

1.92 

ADRENALS

 

 

 

 

 

 

 

 

Absolute Weighta

g

0.05935*

0.05482

0.05601

0.04514** 

0.071

0.068 

0.072 

0.068 

EPIDIDYMIDES

 

 

 

 

Absolute Weighta

g

1.2160

1.1929

1.1653

1.1224

n.a.b

n.a.b

n.a.b

n.a.b

HEART

 

 

 

 

 

 

 

 

Absolute Weighta

g

1.36 

1.29 

1.34 

1.25 

 0.88

0.85 

0.86 

0.87 

KIDNEYS

 

 

 

 

 

 

 

 

Absolute Weighta

g

2.84

2.86

3.02

2.85

 1.76

1.79 

1.80 

1.74 

LIVER

 

 

 

 

 

 

 

 

Absolute Weighta

g

12.4102*

12.7829

14.8119**

16.2321**

7.4828**

7.4317

9.2845**

12.0684**

PROSTATE GLAND

Absolute Weighta

g

0.8422

0.8371

8244

0.7347

n.a.b

n.a.b

n.a.b

n.a.b

SEMINAL VESICLES

Absolute Weighta

g

1.8543

1.5639

1.7048

1.7136

n.a.b

n.a.b

n.a.b

n.a.b

SPLEEN

 

 

 

 

 

 

 

 

Absolute Weighta

g

0.73 

0.72

0.73 

0.64 

 0.54

0.57 

0.53 

0.52 

TESTES

 

 

 

 

Absolute Weighta

g

3.4618**

3.5100

3.3643

3.0551**

n.a.b

n.a.b

n.a.b

n.a.b

THYMUS

 

 

 

 

 

 

 

 

Absolute Weighta

g

0.4265**

0.4256

0.3509

0.2935**

 0.42

0.44 

0.37 

0.33 

OVARIES

 

 

 

 

Absolute Weighta

g

n.a.b

n.a.b

n.a.b

n.a.b

 0.133

0.134 

0.128 

0.142 

UTERUS

 

 

 

 

Absolute Weighta

 

n.a.b

n.a.b

n.a.b

n.a.b

0.42 

0.44 

0.37 

0.33 

a Group means at the end of terminal necropsy are shown.

b n.a. = not applicable

* p0.05, ** p0.01 (one-way analysis of variance)

Table 4: Incidence of selected pathologies

Parameter

n=5/sex

Dose level (mg/kg bw/day)

Control

61

305

1221

 

Liver: centrilobular hypertrophy

M

0+++

1

8+++

8+++

 

F

0+++

0

8+++

10+++

 

Liver: chronic multifocal inflammation

M

9

8

8

1

 

F

7

9

6

4

 

Liver: Periportal chronic inflammation

M

0+++

0

0

9+++

 

Liver: periportal hepatocellular vacuolation

F

5+++***

4

7

10++

 

Liver: bile duct hyperplasia

M

0+++

0

0

8+++

 

F

-

-

-

-

 

Liver: brown pigment

M

0+++

0

0

9+++

 

F

-

-

-

-

 

Prostate gland: chronic inflammation

M

2+*

6

5

7+

 

F

-

-

-

-

 

Prostate gland: single cell necrosis

M

1

0

0

1

 

F

-

-

-

-

 

Thyroid gland: follicular hypertrophy

M

1+++*

0

8+++

9+++

 

F

0

0

0

1

 

+ indicate a significant trend by the Cochran-Armitage Test across treatment groups (in the control column) or between control and treatment group by Fischer’s Exact Test with p values of +0.05, ++0.02 and +++0.01. * indicate a significant shift in grade across treatment groups (in the control column) with p values of *0.05, **0.02 and ***0.01.

See attachments for result tables.

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 based on hepatic brown pigment at 500 mg/kg bw/day. It is considered appropriate to use this result as the basis for general systemic 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) dichloro(methyl)silane was administered by oral gavage in corn oil for 28 (toxicity group females) or 29 (males) days to 10 rats/sex/group (exception, female 50 mg/kg group where N=9) at 0, 50, 250 or 500 mg/kg/day.  A single group of males was used for both the toxicity and reproductive phases of the study.  Reproductive group females were treated (10 rats/dose group) for 14 days prior to the mating period, during the mating period and through post-partum day 3. Clinical observations were performed daily immediately following exposure.  Body weight measurements were performed weekly.  All animals received a detailed physical examination once before the first dose (to allow for within-subject comparisons), and weekly thereafter. Additional body weights on reproductive females were obtained on gestational days (GD) 0, 7, 14, and 20, within 24 hours of parturition, and on post-partum day four. Individual food consumption was recorded at least weekly, except during the cohabitation period. Functional observational battery (FOB) and motor activity evaluations were performed on males and toxicity group females once prior to initiation of exposures and during the 4th week of exposure.  Blood samples for hematology and serum chemistry evaluations were collected at the scheduled necropsy from males and toxicity group females. Complete necropsies were performed on the males and the toxicity group females and selected organs were weighed. Microscopic examination was performed on protocol specified tissues on all toxicity group animals from the control and 500 mg/kg/day dose groups. Target tissues examined from the low- and mid-dose levels included liver, lung, prostate gland and thyroid gland from male rats and liver and lung from female rats. 

Mating was initiated after the first two weeks of exposure by pairing reproductive group females with males of the same treatment group until positive evidence of mating was obtained. Reproductive and developmental parameters evaluated included evidence of mating, pregnancy, duration of gestation, mean litter size, mean live litter size, mean litter weight, and mean ratio of live births/litter size. Dams and pups were euthanized on post-partum day 4 and examined for external gross lesions. The number of corpora lutea, and the number of uterine implantation sites were determined for all reproductive group females.

Oral gavage administration of dimethylsilanediol to male and female Sprague-Dawley rats at concentrations of up to 500 mg/kg/day for 28 (toxicity females) or 29 (males) consecutive days was generally well tolerated. For the toxicity group males at 250 and 500 mg/kg/day significant soiling was observed (abdominal region and urogenital soiling).  Soiling of the muzzle was a significant abnormal observation in the toxicity group females at 500 mg/kg/day. Both abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg/day. 

There were no statistically significant differences across exposure groups in the mean body weights on any day for toxicity group females and reproductive toxicity group females. In the male group there was a significant difference across treatment groups in week 2, however, there was not a significant difference between control and any of the treatment groups for that week. With respect to body weight gain, male group 4 animals had a significant decrease in body weight gain during week 4 and in total gain from day 1 to 29. For toxicology females there was significant decrease in body weight gain during week 3. 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 between control and treatment groups for the reproductive females group or the toxicity male and female groups for any of the measured time periods. There were no significant differences of toxicological significance between the control and treatment groups in either sex for the FOB ranked tests. There were no significant differences between either male or female treatment groups and their respective controls for the FOB continuous test and motor activity. There were no treatment-related changes associated administration on rat neurobiological function as evaluated with FOB and motor activity parameters. The significant changes that were noted in hematological parameters and prothrombin times for toxicity group males and females were within or slightly below historical control values. The significant changes that were noted in clinical chemistry parameters for toxicity group males and females were within or slightly below historical control values. The increased liver weights in toxicity males and females at 250 and 500 mg/kg/day correlated with the histopathologic finding of centrilobular hyperthrophy. There were no other treatment-related differences in organ weights, absolute and relative for toxicity group males and females. 

There were three primary effects of the test article observed in the liver, including centrilobular hypertrophy in both sexes, periportal hepatocellular vacuolation (microvesicular lipidosis, females only), and brown pigment accumulation (males only) which was accompanied by chronic inflammation and bile duct hyperplasia. Centrilobular hypertrophy is considered an adaptive change. Hepatic lipidosis, unless severe, is generally considered non-adverse. Hepatic brown pigment is considered an adverse effect. Follicular cell hypertrophy was observed in the thyroid gland of mid- and high-dose male rats. This may reflect an adaptive secondary effect and adverse in the rat, but the mechanism is generally not applicable to species with significant levels of thyroid binding globulin (Capen, et al., 2002). Lung (males and females) and prostate gland were considered possible target tissues; however, further examination and inclusion of animals from the mid- and low-dose groups did not support this interpretation. 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. 

Based on the results of this study, the systemic toxicity NOAEL (No-Observed-Adverse-Effect-Level) for dimethylsilanediol in rats via oral administration in corn oil is considered to be 250 mg/kg/day based on hepatic brown pigment accumulation at 500 mg/kg bw/day.  In the absence of adverse effects on reproductive or developmental parameters in this study, a NOAEL of 500 mg/kg/day is assigned for reproductive and developmental toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
250 mg/kg bw/day
Study duration:
subacute
Species:
rat
System:
gastrointestinal tract
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February to March 2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study conducted to a design based on an appropriate guideline but with fewer animals and fewer parameters evaluated, and in compliance with GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
: Six animals per sex per group, only two test substance exposure levels tested, clinical pathology parameters not investigated and only respiratory tract tissues and gross lesions examined microscopically.
Principles of method if other than guideline:
Establish potential effect on respiratory tract and compare with hydrogen chloride.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (US)
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 266 to 329g males, 182 to 220g females
- Fasting period before study: no
- Housing: individually in wire mesh cages
- Diet (ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002
- Water (ad libitum): Reverse osmosis-treated tap water
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 to 22.1
- Humidity (%): 32.5 to 43.8
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 25 February 2014 To: 21 March 2014
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: not applicable.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 205-L polycarbonate whole-body inhalation exposure chambers, with polyvinyl chloride (PVC) dispersion and exhaust tubes and ethylene propylene diene monomer (EPDM) seals
- Method of holding animals in test chamber: plastic nose-only exposure restraint tubes
- Source of air: facility breathing quality, in-house compressed air source
- Method of conditioning air: HEPA- and charcoal-filtered, temperature- and humidity-controlled source
- System of generating DCDMS vapour: the vapour generators consisted of a sealable 4-neck reaction flask (1000 mL) maintained at room temperature. DCDMS from the original container was transferred to a smaller secondary vial that was placed into the flask after the lid was removed from the vial. Using a Coilhose Pneumatics regulator and a digital mass flowmeter, nitrogen was metered to 1 port of the reaction flask to act as a carrier gas for the test substance vapour. A second port was used as an outlet for delivery of DCDMS vapour to a tee fitting where dilution nitrogen was added. Dilution nitrogen flow was controlled using a Coilhose Pneumatics regulator and a digital mass flowmeter. Test substance vapour was directed to the exposure chamber inlet where it mixed with humidified dilution supply air.
- System of generating HCl vapour: A generation bag was prepared by diluting 1400 mL of neat HCl gas in 22 L of nitrogen or by diluting 350 mL of neat HCl in 5.5 L of nitrogen. The generation bag was placed in a 130-L stainless steel and glass whole body chamber. Compressed air was added to create a positive pressure within the generation chamber and to force the HCl gas mixture from the generation bag through 40 inches of ⅛-inch Teflon line to the exposure chamber. Compressed air delivery to the generation chamber was controlled using a Coilhose Pneumatics regulator equipped with a needle valve. The test atmosphere from the generation bag was metered to the exposure chamber using a Gilmont rotameter-type flowmeter. Dilution nitrogen was added prior to the chamber inlet using a Coilhose Pneumatics regulator with metering using a Top-Trak digital mass flow meter. The nitrogen and HCl gas mixture was mixed with chamber supply air at the chamber inlet.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 72L/minute
- Air change rate: approximately 21 per hour
- Treatment of exhaust air: facility exhaust system, which consisted of charcoal- and HEPA-filtration

TEST ATMOSPHERE
- Brief description of DCDMS analytical method used: Gas chromatograph with flame ionisation detector (GC-FID)
- DCDMS Samples taken from breathing zone: yes
- Brief description of HCl analytical method used: Gas chromatograph with halogen-specific detector (GC-XSD)
- DCDMS Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysed concentrations were determined at specified intervals using the following chromatographic methods. For DCDMS generation/exposure systems, pre-dilution samples were collected from the test substance vapour delivery line to the exposure chamber prior to the chamber inlet (where the vapour was diluted with humidified supply air). Analysed concentrations of DCDMS vapour in nitrogen were determined at approximately 30-minute intervals by a gas chromatograph with flame ionization detector (GC-FID#2). The DCDMS vapour concentrations prior to dilution with supply air were targeted at 100 ppm and 500 ppm for Chambers 3 and 4, respectively. These target vapour concentrations in nitrogen were determined based on a 20x dilution factor with supply air to obtain the desired chamber exposure concentration (5 and 25 ppm, respectively). Chamber samples from within the DCDMS exposure chambers and the control chamber were collected from the approximate animal breathing zone of each chamber and analyzed using an additional gas chromatograph with flame ionization detector (GC-FID#1). For the 2 DCDMS chambers, samples were collected at approximately hourly intervals. The DCDMS vapour concentrations within these exposure chambers (following dilution with humidified air) represented the residual parent compound (portion remaining that had not undergone hydrolysis). For the filtered air control chamber, samples were collected one time during each exposure using a Tedlar gas bag and appropriate sample pump.

For the HCl gas and high concentration DCDMS chambers samples for determination of total chlorine content were collected from the approximate animal-breathing zone within the exposure chambers and were analysed using a gas chromatograph with halogen specific detector (GC#1-XSD). Samples were analysed approximately hourly for the HCl chamber and once daily for the high concentration DCDMS chamber.
Duration of treatment / exposure:
6 hours and 13 minutes
Frequency of treatment:
5/days/week for 4 weeks
Dose / conc.:
5.3 ppm (nominal)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
25 ppm (nominal)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
0.83 ppm (analytical)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
2.6 ppm (analytical)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
50 ppm (nominal)
Remarks:
hydrogen chloride
Dose / conc.:
49 ppm (analytical)
Remarks:
hydrogen chloride
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in a previous 90-day inhalation study, administration of 50 ppm hydrogen chloride resulted in an increased incidence of generally minimal effects in the nasal cavity, thus the same concentration was selected to produce similar effects. As dichloro(dimethyl)silane liberates 2 molar equivalents of HCl upon hydrolysis, 25 ppm dichloro(dimethyl)silane was selected as an equivalent concentration. The lower dichloro(dimethyl)silane concentration was selected to be equivalent to the reported HCl NOAEC.
Positive control:
Hydrogen chloride
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: during exposure and approximately 1 hour after exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice pre-study, weekly during study period and on day of scheduled necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: daily during first week, twice during second week, then weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: weekly

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
ORGAN WEIGHTS: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Statistics:
All statistical tests were performed using WTDMS™ unless otherwise noted. 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 by sex.

Body weight, body weight change, food consumption, and organ weight data were subjected to a parametric one way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance treated groups to the control group. The positive control data were evaluated using the 2-sample t-test (Sokal and Rohlf, 1981) and compared to the vehicle control group.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Higher mean adrenal gland weights were noted in the 25 ppm dichloro(dimethyl)silane group males and females, lower mean thymus weights were noted in the 25 ppm DCDMS group females, and lower mean spleen weights were noted in the 5 and 25 ppm dichloro(dimethyl)silane and 50 ppm HCl group females.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic changes were observed within nasal cavity levels I through III in the dichloro(dimethyl)silane and HCl-exposed males and females.

Histologic changes in the dichloro(dimethyl)silane and HCl-exposed animals were mainly confined to the anterior nasal cavity and included squamous epithelial hyperplasia, hyperkeratosis, interstitial edema, mucous cell hyperplasia, degeneration of the respiratory epithelium, and subacute inflammation. The most prominent changes were observed in nasal cavity level I, the nasal vestibule, in which squamous epithelial hyperplasia and hyperkeratosis were observed in both test substance-exposed groups and the 50 ppm HCl gas-exposed group, and interstitial edema was observed in the 25 ppm dichloro(dimethyl)silane-exposed group males and females (as well as a single 50 ppm HCl-exposed female). Squamous epithelial hyperplasia was also observed in nasal level II. Changes in nasal levels II and III generally were observed at a higher incidence and severity in the HCl-exposed animals when compared with the dichloro(dimethyl)silane-exposed animals, and included mucous cell hyperplasia and degeneration of respiratory epithelium. The respiratory epithelial degeneration was mainly observed in the 50 ppm HCl group animals (aside from a single 25 ppm dichloro(dimethyl)silane group male). Subacute inflammation was also observed in nasal levels II and III. It was observed at a similar incidence and severity in the 25 ppm DCDMS group males when compared with the 50 ppm HCl group males. However, it was observed in the majority of 50 ppm HCl group females but not in any 25 ppm DCDMS females.

Only interstitial edema in nasal level I and subacute inflammation in males, primarily in nasal level III, had higher incidences in the 25 ppm dichloro(dimethyl)silane group compared to the 50 ppm HCl group. The remaining nasal cavity findings were either predominantly observed in the 50 ppm HCl group (degeneration of the respiratory epithelium and subacute inflammation in females), were observed at a slightly higher incidence in the 50 ppm HCl group (squamous epithelial hyperplasia and mucous cell hyperplasia), or were observed at a similar incidence in both groups (hyperkeratosis).

Overall, the histopathology observations in the nasal cavity did not suggest greater irritant effects for the 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group.

Mild acute inflammation was observed in the larynx of a single 25 ppm DCDMS exposed male and a single 50 ppm HCl-exposed male
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEC
Sex:
male/female
Basis for effect level:
other: local irritant effects noted in the nasal cavity at both 5 and 25 ppm (26 or 132 mg/m3) DCDMS. Similar findings recorded for 50 ppm HCl, which were generally comparable in incidence and severity to 25 ppm DCDMS.
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Critical effects observed:
not specified
Conclusions:
Inhalation administration of dichloro(dimethyl)silane at targeted concentrations of 5 or 25 ppm, or hydrogen chloride at 50 ppm, to rats for 5 days per week for 4 weeks, resulted in subacute inflammation, hyperplasia and/or hyperkeratosis of the squamous epithelium and mucous cell hyperplasia of the respiratory epithelium in the anterior nasal cavity. Exposure to 25 ppm dichloro(dimethyl)silane or 50 ppm hydrogen chloride was also associated with interstitial edema and respiratory epithelial degeneration within the anterior nasal cavity and acute inflammation in the larynx. Generally the incidence and severity of effects were similar in the 25 ppm dichloro(dimethyl)silane and 50 ppm hydrogen chloride groups. Overall, the histopathology observations in the nasal cavity did not suggest a greater irritant effect for the 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February to March 2014
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Study conducted to a design based on an appropriate guideline but with fewer animals and fewer parameters evaluated, and in compliance with GLP.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
: Six animals per sex per group, only two test substance exposure levels tested, clinical pathology parameters not investigated and only respiratory tract tissues and gross lesions examined microscopically.
Principles of method if other than guideline:
Establish potential effect on respiratory tract and compare with hydrogen chloride.
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River (US)
- Age at study initiation: approximately 8 weeks
- Weight at study initiation: 266 to 329g males, 182 to 220g females
- Fasting period before study: no
- Housing: individually in wire mesh cages
- Diet (ad libitum): PMI Nutrition International, LLC Certified Rodent LabDiet® 5002
- Water (ad libitum): Reverse osmosis-treated tap water
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21.0 to 22.1
- Humidity (%): 32.5 to 43.8
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 25 February 2014 To: 21 March 2014
Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: not applicable.
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 205-L polycarbonate whole-body inhalation exposure chambers, with polyvinyl chloride (PVC) dispersion and exhaust tubes and ethylene propylene diene monomer (EPDM) seals
- Method of holding animals in test chamber: plastic nose-only exposure restraint tubes
- Source of air: facility breathing quality, in-house compressed air source
- Method of conditioning air: HEPA- and charcoal-filtered, temperature- and humidity-controlled source
- System of generating DCDMS vapour: the vapour generators consisted of a sealable 4-neck reaction flask (1000 mL) maintained at room temperature. DCDMS from the original container was transferred to a smaller secondary vial that was placed into the flask after the lid was removed from the vial. Using a Coilhose Pneumatics regulator and a digital mass flowmeter, nitrogen was metered to 1 port of the reaction flask to act as a carrier gas for the test substance vapour. A second port was used as an outlet for delivery of DCDMS vapour to a tee fitting where dilution nitrogen was added. Dilution nitrogen flow was controlled using a Coilhose Pneumatics regulator and a digital mass flowmeter. Test substance vapour was directed to the exposure chamber inlet where it mixed with humidified dilution supply air.
- System of generating HCl vapour: A generation bag was prepared by diluting 1400 mL of neat HCl gas in 22 L of nitrogen or by diluting 350 mL of neat HCl in 5.5 L of nitrogen. The generation bag was placed in a 130-L stainless steel and glass whole body chamber. Compressed air was added to create a positive pressure within the generation chamber and to force the HCl gas mixture from the generation bag through 40 inches of ⅛-inch Teflon line to the exposure chamber. Compressed air delivery to the generation chamber was controlled using a Coilhose Pneumatics regulator equipped with a needle valve. The test atmosphere from the generation bag was metered to the exposure chamber using a Gilmont rotameter-type flowmeter. Dilution nitrogen was added prior to the chamber inlet using a Coilhose Pneumatics regulator with metering using a Top-Trak digital mass flow meter. The nitrogen and HCl gas mixture was mixed with chamber supply air at the chamber inlet.
- Temperature, humidity, pressure in air chamber:
- Air flow rate: 72L/minute
- Air change rate: approximately 21 per hour
- Treatment of exhaust air: facility exhaust system, which consisted of charcoal- and HEPA-filtration

TEST ATMOSPHERE
- Brief description of DCDMS analytical method used: Gas chromatograph with flame ionisation detector (GC-FID)
- DCDMS Samples taken from breathing zone: yes
- Brief description of HCl analytical method used: Gas chromatograph with halogen-specific detector (GC-XSD)
- DCDMS Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysed concentrations were determined at specified intervals using the following chromatographic methods. For DCDMS generation/exposure systems, pre-dilution samples were collected from the test substance vapour delivery line to the exposure chamber prior to the chamber inlet (where the vapour was diluted with humidified supply air). Analysed concentrations of DCDMS vapour in nitrogen were determined at approximately 30-minute intervals by a gas chromatograph with flame ionization detector (GC-FID#2). The DCDMS vapour concentrations prior to dilution with supply air were targeted at 100 ppm and 500 ppm for Chambers 3 and 4, respectively. These target vapour concentrations in nitrogen were determined based on a 20x dilution factor with supply air to obtain the desired chamber exposure concentration (5 and 25 ppm, respectively). Chamber samples from within the DCDMS exposure chambers and the control chamber were collected from the approximate animal breathing zone of each chamber and analyzed using an additional gas chromatograph with flame ionization detector (GC-FID#1). For the 2 DCDMS chambers, samples were collected at approximately hourly intervals. The DCDMS vapour concentrations within these exposure chambers (following dilution with humidified air) represented the residual parent compound (portion remaining that had not undergone hydrolysis). For the filtered air control chamber, samples were collected one time during each exposure using a Tedlar gas bag and appropriate sample pump.

For the HCl gas and high concentration DCDMS chambers samples for determination of total chlorine content were collected from the approximate animal-breathing zone within the exposure chambers and were analysed using a gas chromatograph with halogen specific detector (GC#1-XSD). Samples were analysed approximately hourly for the HCl chamber and once daily for the high concentration DCDMS chamber.
Duration of treatment / exposure:
6 hours and 13 minutes
Frequency of treatment:
5/days/week for 4 weeks
Dose / conc.:
5.3 ppm (nominal)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
25 ppm (nominal)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
0.83 ppm (analytical)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
2.6 ppm (analytical)
Remarks:
dichloro(dimethyl)silane
Dose / conc.:
50 ppm (nominal)
Remarks:
hydrogen chloride
Dose / conc.:
49 ppm (analytical)
Remarks:
hydrogen chloride
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: in a previous 90-day inhalation study, administration of 50 ppm hydrogen chloride resulted in an increased incidence of generally minimal effects in the nasal cavity, thus the same concentration was selected to produce similar effects. As dichloro(dimethyl)silane liberates 2 molar equivalents of HCl upon hydrolysis, 25 ppm dichloro(dimethyl)silane was selected as an equivalent concentration. The lower dichloro(dimethyl)silane concentration was selected to be equivalent to the reported HCl NOAEC.
Positive control:
Hydrogen chloride
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: during exposure and approximately 1 hour after exposure

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: twice pre-study, weekly during study period and on day of scheduled necropsy

BODY WEIGHT: Yes
- Time schedule for examinations: daily during first week, twice during second week, then weekly

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule: weekly

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table)
ORGAN WEIGHTS: Yes (see table)
HISTOPATHOLOGY: Yes (see table)
Statistics:
All statistical tests were performed using WTDMS™ unless otherwise noted. 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 by sex.

Body weight, body weight change, food consumption, and organ weight data were subjected to a parametric one way ANOVA (Snedecor and Cochran, 1980) to determine intergroup differences. If the ANOVA revealed statistically significant (p<0.05) intergroup variance, Dunnett's test (Dunnett, 1964) was used to compare the test substance treated groups to the control group. The positive control data were evaluated using the 2-sample t-test (Sokal and Rohlf, 1981) and compared to the vehicle control group.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Higher mean adrenal gland weights were noted in the 25 ppm dichloro(dimethyl)silane group males and females, lower mean thymus weights were noted in the 25 ppm DCDMS group females, and lower mean spleen weights were noted in the 5 and 25 ppm dichloro(dimethyl)silane and 50 ppm HCl group females.
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Histopathologic changes were observed within nasal cavity levels I through III in the dichloro(dimethyl)silane and HCl-exposed males and females.

Histologic changes in the dichloro(dimethyl)silane and HCl-exposed animals were mainly confined to the anterior nasal cavity and included squamous epithelial hyperplasia, hyperkeratosis, interstitial edema, mucous cell hyperplasia, degeneration of the respiratory epithelium, and subacute inflammation. The most prominent changes were observed in nasal cavity level I, the nasal vestibule, in which squamous epithelial hyperplasia and hyperkeratosis were observed in both test substance-exposed groups and the 50 ppm HCl gas-exposed group, and interstitial edema was observed in the 25 ppm dichloro(dimethyl)silane-exposed group males and females (as well as a single 50 ppm HCl-exposed female). Squamous epithelial hyperplasia was also observed in nasal level II. Changes in nasal levels II and III generally were observed at a higher incidence and severity in the HCl-exposed animals when compared with the dichloro(dimethyl)silane-exposed animals, and included mucous cell hyperplasia and degeneration of respiratory epithelium. The respiratory epithelial degeneration was mainly observed in the 50 ppm HCl group animals (aside from a single 25 ppm dichloro(dimethyl)silane group male). Subacute inflammation was also observed in nasal levels II and III. It was observed at a similar incidence and severity in the 25 ppm DCDMS group males when compared with the 50 ppm HCl group males. However, it was observed in the majority of 50 ppm HCl group females but not in any 25 ppm DCDMS females.

Only interstitial edema in nasal level I and subacute inflammation in males, primarily in nasal level III, had higher incidences in the 25 ppm dichloro(dimethyl)silane group compared to the 50 ppm HCl group. The remaining nasal cavity findings were either predominantly observed in the 50 ppm HCl group (degeneration of the respiratory epithelium and subacute inflammation in females), were observed at a slightly higher incidence in the 50 ppm HCl group (squamous epithelial hyperplasia and mucous cell hyperplasia), or were observed at a similar incidence in both groups (hyperkeratosis).

Overall, the histopathology observations in the nasal cavity did not suggest greater irritant effects for the 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group.

Mild acute inflammation was observed in the larynx of a single 25 ppm DCDMS exposed male and a single 50 ppm HCl-exposed male
Histopathological findings: neoplastic:
no effects observed
Dose descriptor:
NOAEC
Sex:
male/female
Basis for effect level:
other: local irritant effects noted in the nasal cavity at both 5 and 25 ppm (26 or 132 mg/m3) DCDMS. Similar findings recorded for 50 ppm HCl, which were generally comparable in incidence and severity to 25 ppm DCDMS.
Remarks on result:
not determinable
Remarks:
no NOAEC identified
Critical effects observed:
not specified
Conclusions:
Inhalation administration of dichloro(dimethyl)silane at targeted concentrations of 5 or 25 ppm, or hydrogen chloride at 50 ppm, to rats for 5 days per week for 4 weeks, resulted in subacute inflammation, hyperplasia and/or hyperkeratosis of the squamous epithelium and mucous cell hyperplasia of the respiratory epithelium in the anterior nasal cavity. Exposure to 25 ppm dichloro(dimethyl)silane or 50 ppm hydrogen chloride was also associated with interstitial edema and respiratory epithelial degeneration within the anterior nasal cavity and acute inflammation in the larynx. Generally the incidence and severity of effects were similar in the 25 ppm dichloro(dimethyl)silane and 50 ppm hydrogen chloride groups. Overall, the histopathology observations in the nasal cavity did not suggest a greater irritant effect for the 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group.

Endpoint conclusion
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The only available repeat dose data for dichloro(dimethyl)silane is a 4-week inhalation study designed to investigate and compare the local effects of dichloro(dimethyl)silane and hydrogen chloride (WIL, 2014). Therefore good quality data for the hydrolysis products dimethylsilanediol (DMSD) and hydrogen chloride have been used to assess the general systemic toxicity of dichloro(dimethyl)silane.

It is considered not to be either ethical or technically feasible to perform repeated dose toxicity testing with dichloro(dimethyl)silane by any route of exposure at toxicologically relevant doses or concentrations due to its known corrosive properties. Following repeated oral dosing, the corrosive nature of the product could affect the lining of the stomach, giving rise to hyperplasia and a subsequent reduced food intake. This would make the interpretation of any systemic findings difficult. A guideline-compliant repeated-dose inhalation study should elicit systemic toxicity at the highest test concentration. Since the local corrosive effects of dichloro(dimethyl)silane would be significant a valid inhalation study according to the relevant guidelines is technically not feasible. It is also unlikely that any systemic effects would be seen at dose levels made sufficiently low (25 ppm) to prevent the known corrosive effects and/or distress in the test species. This is confirmed by the 28-day inhalation study with dichloro(dimethyl)silane (WIL, 2014) in which there were no effects of treatment on clinical signs, body weight or food consumption that would indicate a systemic effect. Furthermore, in this study histopathology indicates that the effects in the upper respiratory tract are similar to HCl. In accordance with the decision of the MSC and ECHA it is therefore concluded that HCl will dominate the inhalation toxicity profile of dichloro(dimethyl)silane and further repeated dose toxicity testing is not necessary.

With regard to the dermal route, due to the known corrosive effects of dichloro(dimethyl)silane, appropriate H-phrases and P-statements are included in the labelling, meaning that repeated skin contact can be excluded.

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. As has been demonstrated by the acute toxicity and irritation/corrosion data, there would also be additional corrosive local effects from hydrogen chloride if dichloro(dimethyl)silane were to be administered.

Data obtained via the oral route for DMSD are therefore considered appropriate for read-across to dichloro(dimethyl)silane with respect to systemic effects.

Local effects from the other hydrolysis product, hydrogen chloride are addressed by good quality data for that substance (Toxigenics Inc, 1983) and the 4 -week DCDMS study (WIL, 2014).

Local corrosive effects of dichloro(dimethyl)silane can be assessed qualitatively or quantitatively by considering the amount of hydrogen chloride produced by hydrolysis

Dimethylsilanediol

An OECD 422 study has been conducted with DMSD (Dow Corning Corporation, 2009b) in which rats were given oral doses of 0, 50, 250 or 500 mg/kg/day for 28/29 days by oral gavage. Administration of DMSD was generally well tolerated with soiling of the muzzle the only significant abnormal observation which was recorded for females at 500 mg/kg/day. Increased liver weights at 250 and 500 mg/kg bw/day correlated with the histopathological finding of centrilobular hypertrophy. There were three primary effects of DMSD observed in the liver, including centrilobular hypertrophy in both sexes, periportal hepatocellular vacuolation (microvesicular lipidosis, females only), and brown pigment accumulation in and around the bile ducts (males only) which was accompanied by chronic inflammation and bile duct hyperplasia. Under polarised light some pigment accumulations show birefringence, but this finding was not consistent in size or between animals.

Centrilobular hypertrophy is considered an adaptive change. Hepatic lipidosis, unless severe, is generally considered non-adverse. The hepatic brown pigment accumulation and associated bile duct hyperplasia and chronic inflammation were considered an adverse effect. Follicular cell hypertrophy was observed in the thyroid gland of 250 and 500 mg/kg/day male rats and may reflect an adaptive secondary effect and considered adverse in the rat, but the mechanism is generally not applicable to species with significant levels of thyroid binding globulin (Capen, et al., 2002). Lung (males and females) and prostate gland were considered possible target tissues; however, further examination and inclusion of animals from the mid- and low-dose groups did not support this interpretation.

Based on the results of this study, the systemic toxicity NOAEL (No-Observed-Adverse-Effect-Level) for dimethylsilanediol in rats via oral administration was considered to be 250 mg/kg/day due to hepatic brown pigment accumulation and associated bile duct hyperplasia and chronic inflammation at 500 mg/kg/day.

Dichloro(dimethyl)silane

In a short term repeated dose inhaled study in rats (which did not meet current guideline requirements) conducted with dichloro(dimethyl)silane (Dow Corning Corporation, 1993) in which a concentration of 15 ppm was administered 5 days/week for 2 weeks there were no treatment-related effects noted.

In a 4-week repeated dose study (WIL, 2014) inhalation administration of dichloro(dimethyl)silane at targeted concentrations of 5 or 25 ppm (26 or 132 mg/m3) or hydrogen chloride at 50 ppm to rats for 5 days per week for 4 weeks resulted in subacute inflammation, hyperplasia and/or hyperkeratosis of the squamous epithelium and mucous cell hyperplasia of the respiratory epithelium in the anterior nasal cavity. Exposure to 25 ppm (132 mg/m3) dichloro(dimethyl)silane or 50 ppm hydrogen chloride was also associated with interstitial edema and respiratory epithelial degeneration within the anterior nasal cavity and acute inflammation in the larynx. Generally the incidence and severity of effects were similar in the 25 ppm dichloro(dimethyl)silane and 50 ppm hydrogen chloride groups. The incidence and severity of the effects in the hydrogen chloride exposed group were generally comparable to those noted in the 90-day inhalation study with hydrogen chloride (Toxigenics, 1983). Overall, the histopathology observations in the nasal cavity did not suggest a greater irritant effect for the 25 ppm dichloro(dimethyl)silane group compared with the 50 ppm HCl group.

Hydrogen Chloride

In a 90-day repeated dose inhalation study in rats and mice (Toxigenics, 1983), 31 males and 21 females of each species/strain were exposed to test concentrations of 0, 10, 20 and 50 ppm hydrogen chloride gas (HCl). Treatment was whole-body exposure for six hour per day, 5 days per week. Fifteen males and 10 females from each group were sacrificed after four exposures and the nasal turbinates, trachea, lung and gross lesions were examined microscopically. In general, all animals in the high dose group showed adverse findings after 4-days exposure.

One female high dose mouse was found dead on study day 12, and four low dose male mice were found dead on study day 92. In addition, one high dose female mouse was sacrificedin extremis on study day 20. One high dose female Sprague-Dawley rat was found dead on study day 4. However, the study authors noted that the deaths did not appear to be related to exposure to HCl. Clinical signs were consistent with the irritant/corrosive properties of HCl (appendage, tail or lip injury in the form of toe missing/swollen/open/gelatinous, scabbed/deformed/lesion, crusty nose, tissue mass, mouth injury, scabbed nose, crusty muzzle, red stained fur, nasal discharge, crusty eye, poor coat quality); some of the observed injuries may have been mechanical and not related to test material exposure.

Ninety days exposure to 50 ppm HCl resulted in decreased body weights in all four strains after four exposures. Following 90 days of exposure B6C3F1 male and female mice and male Sprague-Dawley rats exposed to 50 ppm had biologically significant decreases in body weight.

After four days of exposure there were statistically significant decreases in food consumption for high dose male Sprague-Dawley rats and male Fischer 344 rats. After 90 days high dose mice had the largest reduction in food consumption. The rats did not show a consistent reduction in food consumption that could be deemed exposure-related.

There were no treatment-related effects on the haematology, clinical chemistry or urinalysis parameters that were examined.

Decreased liver weights were observed in high dose male and female mice and Fischer 344 female rats. The authors noted that this might have been due to the overall reduced body weights.

Animals exposed to all concentrations of HCl had minimal to mild rhinitis, which occurred in the anterior portion of the nasal cavity and was dose and time related. Mice also developed varying degrees of cheilitis with accumulations of haemosiderin-laden macrophages involving the perioral tissues at 50 ppm. At all exposure concentrations mice developed oesinophilic globules in epithelial cells lining the nasal turbinates after 90 days of exposure. The No Observed Adverse Effect Concentration (NOAEC) for systemic effects was determined to be 20 ppm (approximately 30 mg/m3) based on decreased body weight following exposure to 50 ppm. No NOAEC for local effects was established as irritant/corrosive effects were observed at all dose levels tested.

Similar local effects were noted for the group administered HCl in the 4 -week dichloro(dimethyl)silane inhalation study (WIL, 2014).

READ-ACROSS JUSTIFICATION

To reduce animal testing REACH recommends to make use of a read-across approach where appropriate based on the high accordance in properties relevant for the specific endpoint. In the case of repeated dose toxicity and reproductive toxicity relevant properties are structural similarity as well as physical-chemical and basic toxicological parameters in the same range. In the following paragraphs the read-across approach for dichloro(dimethyl)silane is evaluated point by point. Further details are given in a supporting report (PFA 2013) attached in Section 13 of the IUCLID dataset.

Read-across hypothesis

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. As has been demonstrated by the acute toxicity and irritation/corrosion data, and the 28 -day repeated dose inhalation studythere would also be additional corrosive local effects from HCl if dichloro(dimethyl)silane were to be administered.

Local corrosive effects of dichloro(dimethyl)silane attributed to the presence of HCl can be assessed qualitatively or quantitatively by considering the amount of HCl produced by hydrolysis.

Discussion of repeated systemic toxicity of the non-silanol hydrolysis product Hydrochloric acid

In a 90 -day repeated dose inhalation study with HCL (Toxigenics, 1983) no serious adverse systemic effects were observed in rats and mice exposed up to 50 ppm (approximately 70 mg/m3) for 6 hours per day, 5 days per week. The only significant adverse finding relating to systemic toxicity was decreased body weight at the highest dose level. Local effects on the nasal turbinates of rats and mice mice were observed at all dose levels tested (10, 20 and 50 ppm). Testing with HCl at higher test concentrations is neither ethically nor technically feasible since severe corrosive effects would lead to discomfort and distress in the test animals. It is considered that the apparent systemic effects at 50 ppm in the study were most likely secondary to local corrosive effects at this dose level.

Folllowing uptake of HCl, hydrogen and chloride ions will enter the body’s natural homeostatic processes and significant systemic effects are unlikely.

Conclusion

Read across for systemic effects from the dimethylsilanediol key 28-day repeat dose oral study is considered to be valid. Inhalation studies show that systemic effects of dichloro(dimethyl)silane are not as marked and also that the levels of HCl generated at the doses used would not result in significant systemic effects.


Justification for classification or non-classification

Based on the available data for dichloro(dimethyl)silane and read-across data from hydrolysis products dimethylsilanediol and hydrogen chloride, dichloro(dimethyl)silane does not require classification for target organ toxicity according to Regulation (EC) No 1272/2008.