Registration Dossier

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Administrative data

Description of key information

In a study performed according to OECD Test Guideline 413 and in accordance with GLP, Wistar rats were exposed via nose only inhalation to 0, 3.06, 6.94, and 12.1 mg/l (analytical; 0, 3, 7, 12 mg/l nominal) of 1,1,3,3-tetramethyldisiloxane vapour for 6 hours a day, 5 or 6 days a week for 14 weeks, with a 4-week recovery period. A concentration of 12 mg/l was the maximum concentration targeted as this maintains a suitable safety margin below the lower explosive level (LEL) of 3600 ppm (21.2 mg/l). Clinical condition, body weight, food consumption, ophthalmic examination, haematology (peripheral blood), blood chemistry, bronchoalveolar lavage, organ weight, macropathology and histopathology investigations were undertaken. No test item-related adverse effects were observed up to 12.1 mg/l of 1,1,3,3-tetramethyldisiloxane vapour. The NOAEC is therefore concluded to be at least 12.1 mg/l 1,1,3,3-tetramethyldisiloxane vapour.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 Oct 2020 (experimental start date) - 23 Sep 2021 (final report)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (90-Day (Subchronic) Inhalation Toxicity Study
Version / remarks:
Adopted: 25 June 2018
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
RccHan®:WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS UK
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 211-269 g (males), 143-186 g (females)
- Fasting period before study: No
- Housing: Polycarbonate cages with a stainless steel mesh lid, 5 of the same sex per cage
- Diet: Teklad 2014C Diet, ad libitum
- Water: Potable public water, ad libitum
- Acclimation period: 11 days

DETAILS OF FOOD AND WATER QUALITY:
Supplier certificates of analysis provided and reviewed. No specific contaminants were known that may have interfered with or prejudiced the outcome of the study and, therefore, no special assays were performed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 Oct 2020 To: 1-3 Feb 2021 (main), 1-2 Mar 2021 (recovery)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Directed flow nose-only chamber. Atmosphere was generated via a glass sintered vaporizer, with the the test item was supplied to the generator, via a feed line, from a plastic syringe driven at a constant rate by a syringe pump. Breathing quality air provided by in-house compressed air system. Inlet flow: 9 l/min (Groups 2 and 3), 17 l/min (Groups 1 and 4). Extract flow (drawn by in-house vacuum system): 20 l/min (Groups 2 and 3), 27 l/min (Groups 1 4). A length of tubing attached to a T-piece on the extract pipework was left open to draw in balance air. Flow meters calibrated daily, monitored continuously during exposure as part of the system checks (every 30 minutes).

Achieved stability in the syringes (20- and 50-ml) was 5 days at ambient temperature (21C).

TEST ATMOSPHERE
- Brief description of analytical method used: GC analysis
- Samples taken from breathing zone: Yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No test item detected in the Group 1 atmosphere samples. The mean achieved atmosphere concentrations were 102, 99 and 101% of target for Groups 2, 3 and 4, respectively, with little daily variation.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6 hr/d, 5 d/wk to week 13, 6 d/wk for week 14
Dose / conc.:
0 mg/L air (analytical)
Remarks:
No test item detected in the Group 1 atmosphere samples
Dose / conc.:
3.06 mg/L air (analytical)
Remarks:
3 mg/l nominal
Dose / conc.:
6.94 mg/L air (analytical)
Remarks:
7 mg/l nominal
Dose / conc.:
12.1 mg/L air (analytical)
Remarks:
12 mg/l nominal
No. of animals per sex per dose:
10M/10F (main), 10M/10F (recovery, groups 1 and 4)
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on results from a 2 week inhalation dose range finding study in the rat. Concentrations up to 12 mg/l were well tolerated and did not cause any clinical or histopathological changes following 2 weeks of exposure. All concentrations were therefore expected to be tolerated over 13 weeks. A concentration of 12 mg/l was the maximum concentration targeted as this maintains a suitable safety margin below the lower explosive level (LEL) of 3600 ppm (21.2 mg/l).
- Rationale for animal assignment: Random
- Fasting period before blood sampling for clinical biochemistry: Yes, overnight
- Rationale for selecting satellite groups: To assess recovery from any effects in Groups 1 and 4
- Post-exposure recovery period in satellite groups: 4 weeks
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Animals (during acclimatization, exposure period, and recovery) were inspected visually at least twice daily for evidence of ill-health or reaction to treatment.

DETAILED CLINICAL OBSERVATIONS: Yes
* On exposure days, three times daily (pre-exposure, upon return to home cage, as late as possible in working day)
* On non-exposure days during treatment period, twice daily (early in working day, as late as possible in working day)
* A detailed weekly physical examination was performed on each animal to monitor general health.

BODY WEIGHT: Yes
For each animal, recorded one week before treatment commenced, on the day that treatment commenced (Day 1), and twice weekly throughout the study and before necropsy. Group mean weight changes were calculated from the weight changes of individual animals.

FOOD CONSUMPTION: Yes
Weight of food supplied to each cage, amount remaining, and an estimate of amount spilled was recorded for the week before treatment started and for each week throughout the study.

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
The eyes of the animals (pre-treatment: all main and recovery; Week 14: all main Groups 1 and 4) were examined by means of a binocular indirect ophthalmoscope. Prior to each examination, the pupils of each animal were dilated using tropicamide ophthalmic solution (Mydriacyl). As no test item-related changes were observed, the examination was not extended to Groups 2 and 3 in Week 14 or to the recovery animals.

HAEMATOLOGY: Yes
* For all main animals at week 14, peripheral blood samples were collected under anaesthesia after overnight withdrawal of food and prior to dosing. As no test item-related changes were observed, the examination was not extended to the recovery animals.
* For the haematology parameters evaluated, see Table 1 below.
* The analyses were performed using Bayer Advia 120 analyser or a Stago STA Compact Max analyser.
* Blood films (prepared for all samples) were stained (Romanowsky) and examined for abnormalities by light microscopy, in the case of flags from the Advia 120 analyser.

CLINICAL CHEMISTRY: Yes
* For all main animals at week 14 and all recovery animals (Groups 1 and 4) at recovery week 4, blood samples were collected under anaesthesia after overnight withdrawal of food and prior to dosing (where appropriate).
* For the clinical chemistry parameters evaluated, see Table 2 below.
* The analyses were performed using a Roche Cobas 6000 analyser.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF): Yes
* For all main animals and all recovery animals (Groups 1 and 4) after termination, the right lung was used for bronchoalveolar lavage sampling (left lung was processed for histology and light microscopy).
* Cell pellet: A total and differential cell count of the BAL cells was performed using an XT-2000iV. A total and differential count (neutrophils, eosinophils, mononuclear cells (includes monocytes, macrophages) and lymphocytes) were reported as number of cells per animal and the differential cells also as a percentage of the total cell count.
* BALF supernatant: Analysis for lactate dehydrogenase and total protein was conducted using a Roche Cobas 6000.
Sacrifice and pathology:
SACRIFICE:
Animals were sacrificed via an overdose of intraperitoneal pentobarbitone sodium followed by exsanguination.

ORGAN WEIGHTS: Yes
For all main and recovery animals, the organs specified in Table 3 below were weighed at necropsy. For bilateral organs, left and right organs were weighed together, unless specified in Table 3. Organ weights presented both as absolute and as adjusted for terminal body weight.

GROSS PATHOLOGY: Yes
* All main study and recovery animals were subject to a detailed necropsy after termination. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
* For tissues fixed at necropsy, see Table 3 below. Tissues were routinely preserved in 10% Neutral Buffered Formalin. Exceptions: bone marrow smears (air dried, then fixed in methanol), testes (modified Davidson’s fluid), eyes (Davidson’s fluid). As indicated Table 3, the fixed bone marrow smears were retained, but not examined via histopathology (below).

HISTOPATHOLOGY: Yes
* For main animals in Groups 1 and 4, Table 3 below identifies the tissues subject to histopathology.
* For main animals in Groups 2 and 3 and for the recovery animals, only abnormalities were examined.
* Tissue samples were dehydrated, embedded in paraffin wax and sectioned. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required. Sections were stained with haematoxylin and eosin.

LIGHT MICROSCOPY: Yes
* For main animals in Groups 1 and 4, Table 3 below identifies the tissues examined via light microscopy.
* For main animals in Groups 2 and 3 and for the recovery animals, only abnormalities were examined.
* Findings were reported as "present" or assigned a severity grade (minimal, slight, moderate, marked or severe).
Statistics:
Summary statistics (e.g., means and standard deviations) were calculated from computer-stored individual raw data. All statistical analyses, also using the individual data, were carried out separately for males and females. The following data types were analysed at each timepoint separately: Body weight (using gains over appropriate study periods), haematology, blood chemistry, organ weights (absolute and adjusted for terminal body weight), and bronchoalveolar lavage data. Group comparisons were made between Group 1 versus Groups 2, 3, and 4. Collectively, the statistical methods used were endpoint specific and included: Bartlett’s test, F1 approximate test, William’s test, Dunnett’s test, t-tests, H1 approximate test, Shirley’s test, Steel’s test, Wilcoxon rank sum tests, Fisher’s exact test, and/or analysis of covariance. Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related clinical signs during the detailed weekly physical examination or in relation to exposures.

Occasional wet fur and red staining were considered to be associated with the method of restraint during exposure.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related but non-adverse effects on body weight gain were observed.

Lower than control mean body weight gain (statistically significant) was seen at 6.94 (females, 0.89X control) and 12.1 mg/l (males, 0.83X control; females, 0.73X control). However, these effects were considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, body weight gain was similar to, or slightly higher than control, for animals previously exposed to 12.1 mg/l.

The lower body weight gain at 3.06 mg/l (females) was considered incidental and not test item-related.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Treatment-related but non-adverse effects on food consumption were observed.

Slightly lower than control food consumption was observed at 12.1 mg/l (both sexes), but was considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, an increase in food consumption was observed for animals previously exposed to 12.1 mg/l when compared with the treatment phase, although consumption remained slightly lower than the concurrent control data.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item-related ophthalmological findings.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item-related changes on haematology parameters in any treated group compared with control.

All differences from control, including those which attained a degree of statistical significance, were consistent with normal variation and considered incidental.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related effects on clinical biochemistry were observed.

Mean triglycerides were statistically significantly higher than control for males exposed to 12.1 mg/l (1.5X control), and higher than control for female groups exposed to 1,1,3,3-tetramethyldisiloxane (up to 1.3X control), although not exposure concentration related. These findings were considered not test item-related due to absence of a microscopic correlate, the small magnitude of changes and, in females, the lack of a exposure concentration relationship. Further, during recovery Week 4, mean triglycerides for animals previously exposed to 12.1 mg/l were within the range of the control data.
Endocrine 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, non-treatment-related
Description (incidence and severity):
There were no test item-related organ weight changes in any treated group compared with control.

All differences from control were consistent with normal variation and considered incidental.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related macroscopic observations were noted.

All macroscopic findings were considered spontaneous and/or incidental.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related microscopic observations were noted.

All microscopic findings were considered spontaneous and/or incidental.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
BRONCHOALVEOLAR LAVAGE:
There were no test item-related changes, for differential cell counts or for total protein and lactate dehydrogenase (LDH), in any treated group compared with control.

For differential cell counts, all other differences from control, including those which attained a degree of statistical significance, were consistent with normal variation and considered incidental.

After 14 weeks, mean total protein was lower than control for males exposed to 12.1 mg/l and higher than control for all 1,1,3,3-tetramethyldisiloxane exposed females. Mean LDH concentrations were higher than control for males exposed to 6.92 mg/l and all 1,1,3,3-tetramethyldisiloxane exposed female groups (not exposure concentration-related). These effects were considered not related to the test item due to the lack of an exposure-concentration relationship and the absence of consistent effects between the sexes. Further, following 4 weeks of recovery for the 12.1 mg/l group, mean LDH for males was lower than control, mean LDH for females was similar to control, and total protein for both sexes was similar to control.
Key result
Dose descriptor:
NOAEC
Effect level:
12.1 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test item-related adverse effects observed up to 12.1 mg/l
Key result
Critical effects observed:
no
Conclusions:
In a study performed according to OECD Test Guideline 413 and in accordance with GLP, Wistar rats were exposed via nose only inhalation to 0, 3.06, 6.94, and 12.1 mg/l (analytical; 0, 3, 7, 12 mg/l nominal) of 1,1,3,3-tetramethyldisiloxane vapour for 6 hours a day, 5 or 6 days a week for 14 weeks, with a 4-week recovery period. Clinical condition, body weight, food consumption, ophthalmic examination, haematology (peripheral blood), blood chemistry, bronchoalveolar lavage, organ weight, macropathology and histopathology investigations were undertaken. No test item-related adverse effects were observed up to 12.1 mg/l of 1,1,3,3-tetramethyldisiloxane vapour. The NOAEC is therefore concluded to be at least 12.1 mg/l 1,1,3,3-tetramethyldisiloxane vapour.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
12 mg/L
Study duration:
subchronic
Species:
rat
Quality of whole database:
Key reliability score 1 study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
15 Oct 2020 (experimental start date) - 23 Sep 2021 (final report)
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 413 (90-Day (Subchronic) Inhalation Toxicity Study
Version / remarks:
Adopted: 25 June 2018
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Wistar
Remarks:
RccHan®:WIST
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Envigo RMS UK
- Females nulliparous and non-pregnant: Yes
- Age at study initiation: 8-9 weeks
- Weight at study initiation: 211-269 g (males), 143-186 g (females)
- Fasting period before study: No
- Housing: Polycarbonate cages with a stainless steel mesh lid, 5 of the same sex per cage
- Diet: Teklad 2014C Diet, ad libitum
- Water: Potable public water, ad libitum
- Acclimation period: 11 days

DETAILS OF FOOD AND WATER QUALITY:
Supplier certificates of analysis provided and reviewed. No specific contaminants were known that may have interfered with or prejudiced the outcome of the study and, therefore, no special assays were performed.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 40-70
- Air changes (per hr): Filtered fresh air which was passed to atmosphere and not recirculated
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 15 Oct 2020 To: 1-3 Feb 2021 (main), 1-2 Mar 2021 (recovery)
Route of administration:
inhalation: vapour
Type of inhalation exposure:
nose only
Vehicle:
air
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
Directed flow nose-only chamber. Atmosphere was generated via a glass sintered vaporizer, with the the test item was supplied to the generator, via a feed line, from a plastic syringe driven at a constant rate by a syringe pump. Breathing quality air provided by in-house compressed air system. Inlet flow: 9 l/min (Groups 2 and 3), 17 l/min (Groups 1 and 4). Extract flow (drawn by in-house vacuum system): 20 l/min (Groups 2 and 3), 27 l/min (Groups 1 4). A length of tubing attached to a T-piece on the extract pipework was left open to draw in balance air. Flow meters calibrated daily, monitored continuously during exposure as part of the system checks (every 30 minutes).

Achieved stability in the syringes (20- and 50-ml) was 5 days at ambient temperature (21C).

TEST ATMOSPHERE
- Brief description of analytical method used: GC analysis
- Samples taken from breathing zone: Yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
No test item detected in the Group 1 atmosphere samples. The mean achieved atmosphere concentrations were 102, 99 and 101% of target for Groups 2, 3 and 4, respectively, with little daily variation.
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6 hr/d, 5 d/wk to week 13, 6 d/wk for week 14
Dose / conc.:
0 mg/L air (analytical)
Remarks:
No test item detected in the Group 1 atmosphere samples
Dose / conc.:
3.06 mg/L air (analytical)
Remarks:
3 mg/l nominal
Dose / conc.:
6.94 mg/L air (analytical)
Remarks:
7 mg/l nominal
Dose / conc.:
12.1 mg/L air (analytical)
Remarks:
12 mg/l nominal
No. of animals per sex per dose:
10M/10F (main), 10M/10F (recovery, groups 1 and 4)
Control animals:
yes
Details on study design:
- Dose selection rationale: Based on results from a 2 week inhalation dose range finding study in the rat. Concentrations up to 12 mg/l were well tolerated and did not cause any clinical or histopathological changes following 2 weeks of exposure. All concentrations were therefore expected to be tolerated over 13 weeks. A concentration of 12 mg/l was the maximum concentration targeted as this maintains a suitable safety margin below the lower explosive level (LEL) of 3600 ppm (21.2 mg/l).
- Rationale for animal assignment: Random
- Fasting period before blood sampling for clinical biochemistry: Yes, overnight
- Rationale for selecting satellite groups: To assess recovery from any effects in Groups 1 and 4
- Post-exposure recovery period in satellite groups: 4 weeks
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
Animals (during acclimatization, exposure period, and recovery) were inspected visually at least twice daily for evidence of ill-health or reaction to treatment.

DETAILED CLINICAL OBSERVATIONS: Yes
* On exposure days, three times daily (pre-exposure, upon return to home cage, as late as possible in working day)
* On non-exposure days during treatment period, twice daily (early in working day, as late as possible in working day)
* A detailed weekly physical examination was performed on each animal to monitor general health.

BODY WEIGHT: Yes
For each animal, recorded one week before treatment commenced, on the day that treatment commenced (Day 1), and twice weekly throughout the study and before necropsy. Group mean weight changes were calculated from the weight changes of individual animals.

FOOD CONSUMPTION: Yes
Weight of food supplied to each cage, amount remaining, and an estimate of amount spilled was recorded for the week before treatment started and for each week throughout the study.

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
The eyes of the animals (pre-treatment: all main and recovery; Week 14: all main Groups 1 and 4) were examined by means of a binocular indirect ophthalmoscope. Prior to each examination, the pupils of each animal were dilated using tropicamide ophthalmic solution (Mydriacyl). As no test item-related changes were observed, the examination was not extended to Groups 2 and 3 in Week 14 or to the recovery animals.

HAEMATOLOGY: Yes
* For all main animals at week 14, peripheral blood samples were collected under anaesthesia after overnight withdrawal of food and prior to dosing. As no test item-related changes were observed, the examination was not extended to the recovery animals.
* For the haematology parameters evaluated, see Table 1 below.
* The analyses were performed using Bayer Advia 120 analyser or a Stago STA Compact Max analyser.
* Blood films (prepared for all samples) were stained (Romanowsky) and examined for abnormalities by light microscopy, in the case of flags from the Advia 120 analyser.

CLINICAL CHEMISTRY: Yes
* For all main animals at week 14 and all recovery animals (Groups 1 and 4) at recovery week 4, blood samples were collected under anaesthesia after overnight withdrawal of food and prior to dosing (where appropriate).
* For the clinical chemistry parameters evaluated, see Table 2 below.
* The analyses were performed using a Roche Cobas 6000 analyser.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No

BRONCHOALVEOLAR LAVAGE FLUID (BALF): Yes
* For all main animals and all recovery animals (Groups 1 and 4) after termination, the right lung was used for bronchoalveolar lavage sampling (left lung was processed for histology and light microscopy).
* Cell pellet: A total and differential cell count of the BAL cells was performed using an XT-2000iV. A total and differential count (neutrophils, eosinophils, mononuclear cells (includes monocytes, macrophages) and lymphocytes) were reported as number of cells per animal and the differential cells also as a percentage of the total cell count.
* BALF supernatant: Analysis for lactate dehydrogenase and total protein was conducted using a Roche Cobas 6000.
Sacrifice and pathology:
SACRIFICE:
Animals were sacrificed via an overdose of intraperitoneal pentobarbitone sodium followed by exsanguination.

ORGAN WEIGHTS: Yes
For all main and recovery animals, the organs specified in Table 3 below were weighed at necropsy. For bilateral organs, left and right organs were weighed together, unless specified in Table 3. Organ weights presented both as absolute and as adjusted for terminal body weight.

GROSS PATHOLOGY: Yes
* All main study and recovery animals were subject to a detailed necropsy after termination. After a review of the history of each animal, a full macroscopic examination of the tissues was performed. All external features and orifices were examined visually. Any abnormality in the appearance or size of any organ and tissue (external and cut surface) was recorded and the required tissue samples preserved in appropriate fixative.
* For tissues fixed at necropsy, see Table 3 below. Tissues were routinely preserved in 10% Neutral Buffered Formalin. Exceptions: bone marrow smears (air dried, then fixed in methanol), testes (modified Davidson’s fluid), eyes (Davidson’s fluid). As indicated Table 3, the fixed bone marrow smears were retained, but not examined via histopathology (below).

HISTOPATHOLOGY: Yes
* For main animals in Groups 1 and 4, Table 3 below identifies the tissues subject to histopathology.
* For main animals in Groups 2 and 3 and for the recovery animals, only abnormalities were examined.
* Tissue samples were dehydrated, embedded in paraffin wax and sectioned. For bilateral organs, sections of both organs were prepared. A single section was prepared from each of the remaining tissues required. Sections were stained with haematoxylin and eosin.

LIGHT MICROSCOPY: Yes
* For main animals in Groups 1 and 4, Table 3 below identifies the tissues examined via light microscopy.
* For main animals in Groups 2 and 3 and for the recovery animals, only abnormalities were examined.
* Findings were reported as "present" or assigned a severity grade (minimal, slight, moderate, marked or severe).
Statistics:
Summary statistics (e.g., means and standard deviations) were calculated from computer-stored individual raw data. All statistical analyses, also using the individual data, were carried out separately for males and females. The following data types were analysed at each timepoint separately: Body weight (using gains over appropriate study periods), haematology, blood chemistry, organ weights (absolute and adjusted for terminal body weight), and bronchoalveolar lavage data. Group comparisons were made between Group 1 versus Groups 2, 3, and 4. Collectively, the statistical methods used were endpoint specific and included: Bartlett’s test, F1 approximate test, William’s test, Dunnett’s test, t-tests, H1 approximate test, Shirley’s test, Steel’s test, Wilcoxon rank sum tests, Fisher’s exact test, and/or analysis of covariance. Significant differences between the groups compared were expressed at the 5% (p<0.05) or 1% (p<0.01) level.
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related clinical signs during the detailed weekly physical examination or in relation to exposures.

Occasional wet fur and red staining were considered to be associated with the method of restraint during exposure.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment-related but non-adverse effects on body weight gain were observed.

Lower than control mean body weight gain (statistically significant) was seen at 6.94 (females, 0.89X control) and 12.1 mg/l (males, 0.83X control; females, 0.73X control). However, these effects were considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, body weight gain was similar to, or slightly higher than control, for animals previously exposed to 12.1 mg/l.

The lower body weight gain at 3.06 mg/l (females) was considered incidental and not test item-related.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Treatment-related but non-adverse effects on food consumption were observed.

Slightly lower than control food consumption was observed at 12.1 mg/l (both sexes), but was considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, an increase in food consumption was observed for animals previously exposed to 12.1 mg/l when compared with the treatment phase, although consumption remained slightly lower than the concurrent control data.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item-related ophthalmological findings.
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test item-related changes on haematology parameters in any treated group compared with control.

All differences from control, including those which attained a degree of statistical significance, were consistent with normal variation and considered incidental.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related effects on clinical biochemistry were observed.

Mean triglycerides were statistically significantly higher than control for males exposed to 12.1 mg/l (1.5X control), and higher than control for female groups exposed to 1,1,3,3-tetramethyldisiloxane (up to 1.3X control), although not exposure concentration related. These findings were considered not test item-related due to absence of a microscopic correlate, the small magnitude of changes and, in females, the lack of a exposure concentration relationship. Further, during recovery Week 4, mean triglycerides for animals previously exposed to 12.1 mg/l were within the range of the control data.
Endocrine 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, non-treatment-related
Description (incidence and severity):
There were no test item-related organ weight changes in any treated group compared with control.

All differences from control were consistent with normal variation and considered incidental.
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related macroscopic observations were noted.

All macroscopic findings were considered spontaneous and/or incidental.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
No test item-related microscopic observations were noted.

All microscopic findings were considered spontaneous and/or incidental.
Histopathological findings: neoplastic:
not examined
Other effects:
effects observed, non-treatment-related
Description (incidence and severity):
BRONCHOALVEOLAR LAVAGE:
There were no test item-related changes, for differential cell counts or for total protein and lactate dehydrogenase (LDH), in any treated group compared with control.

For differential cell counts, all other differences from control, including those which attained a degree of statistical significance, were consistent with normal variation and considered incidental.

After 14 weeks, mean total protein was lower than control for males exposed to 12.1 mg/l and higher than control for all 1,1,3,3-tetramethyldisiloxane exposed females. Mean LDH concentrations were higher than control for males exposed to 6.92 mg/l and all 1,1,3,3-tetramethyldisiloxane exposed female groups (not exposure concentration-related). These effects were considered not related to the test item due to the lack of an exposure-concentration relationship and the absence of consistent effects between the sexes. Further, following 4 weeks of recovery for the 12.1 mg/l group, mean LDH for males was lower than control, mean LDH for females was similar to control, and total protein for both sexes was similar to control.
Key result
Dose descriptor:
NOAEC
Effect level:
12.1 mg/L air (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No test item-related adverse effects observed up to 12.1 mg/l
Key result
Critical effects observed:
no
Conclusions:
In a study performed according to OECD Test Guideline 413 and in accordance with GLP, Wistar rats were exposed via nose only inhalation to 0, 3.06, 6.94, and 12.1 mg/l (analytical; 0, 3, 7, 12 mg/l nominal) of 1,1,3,3-tetramethyldisiloxane vapour for 6 hours a day, 5 or 6 days a week for 14 weeks, with a 4-week recovery period. Clinical condition, body weight, food consumption, ophthalmic examination, haematology (peripheral blood), blood chemistry, bronchoalveolar lavage, organ weight, macropathology and histopathology investigations were undertaken. No test item-related adverse effects were observed up to 12.1 mg/l of 1,1,3,3-tetramethyldisiloxane vapour. The NOAEC is therefore concluded to be at least 12.1 mg/l 1,1,3,3-tetramethyldisiloxane vapour.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEC
12 mg/L
Study duration:
subchronic
Species:
rat
Quality of whole database:
Key reliability score 1 study available

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

Repeated dose inhalation data for 1,1,3,3-tetramethyldisiloxane are presented. In addition, data for the final hydrolysis product, dimethylsilanediol (CAS No 1066-42-8 / EC No. 213-915-7), are included in the dossier to allow risk characterisation for humans exposed via the environment.

 

1,1,3,3-Tetramethyldisiloxane was evaluated in a study conducted according to OECD Test Guideline 413 and in compliance with GLP (Labcorp Early Development Laboratories, 2021, reliability score 1). Wistar Han rats were exposed via nose only inhalation to 0, 3.06, 6.94, and 12.1 mg/l (analytical; 0, 3, 7, 12 mg/l nominal) of 1,1,3,3-tetramethyldisiloxane vapour for 6 hours a day, 5 days a week for weeks 1 through 13, with 6 days of exposure for week 14 and a 4-week recovery period. A concentration of 12 mg/l was the maximum concentration targeted as this maintains a suitable safety margin below the lower explosive level (LEL) of 3600 ppm (21.2 mg/l). The main study included 10 rats per sex per exposure group, with 10 rats per sex also included in the recovery (0 and 12.1 mg/l) groups. Observations and examinations were conducted per OECD Test Guideline 413, including clinical condition, body weight, food consumption, ophthalmic examination, haematology (peripheral blood), blood chemistry, bronchoalveolar lavage, organ weight, macropathology and histopathology.

 

No test item-related adverse findings were observed. As discussed below, two results (lower mean body weight gain at 6.94 mg/l and 12.1 mg/l, and lower food consumption at 12.1 mg/l) were identified as related to treatment with 1,1,3,3-tetramethyldisiloxane, but were considered non-adverse in nature.

 

Treatment-related but non-adverse effects on mean body weight gain were observed. Lower than control mean body weight gain (statistically significant) was seen at 6.94 (females, 0.89X control) and 12.1 mg/l (males, 0.83X control; females, 0.73X control). However, these effects were considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, body weight gain was similar to, or slightly higher than, control, for animals previously exposed to 12.1mg/l.

 

For food consumption, treatment-related but non-adverse effects were seen. Slightly lower than control food consumption was observed at 12.1 mg/l (both sexes) but was considered non-adverse due to the small magnitude of changes and noted recovery. Following the 4-week recovery period, an increase in food consumption was observed for animals previously exposed to 12.1 mg/l when compared with the treatment phase, although consumption remained slightly lower than the concurrent control data.

 

In the absence of test item-related adverse effects, the systemic toxicity NOAEC for 1,1,3,3-tetramethyldisiloxane in this study was considered to be at least 12.1 mg/l vapour, the highest exposure concentration tested.

 

In a 14-day range finding inhalation study (Covance Laboratories limited, 2021, reliability score 2; GLP compliance not claimed, but study generally followed GLP principles), Wistar rats were exposed via nose-only inhalation to 0, 2.86, 7.34, and 10.8 mg/l (analytical; 0, 3, 7, 12 mg/l nominal) of 1,1,3,3-tetramethyldisiloxane vapour for 6 hours a day, 5 days a week for 2 weeks. Examinations included: Clinical condition, body weight, food consumption, organ weight, macropathology and histopathology. 1,1,3,3-tetramethyldisiloxane vapor was well tolerated, with no clinical reactions or respiratory tract pathology. Based on the absence of test item-related effects in the study, the 14-day systemic toxicity NOAEC for 1,1,3,3-tetramethyldisiloxane was considered to be at least 10.8 mg/l vapour. The results of this study were used in the dose selection for the OECD Test Guideline 413 study.

 

In the supporting combined repeated dose toxicity study with the reproduction / developmental toxicity screening test with the final hydrolysis product dimethylsilanediol, conducted according to OECD Test Guideline 422 and in compliance with GLP, dimethylsilanediol 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 bw/day (Dow Corning Corporation, 2009).  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. 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. Observations and examinations were conducted per OECD Test Guideline 422, including (as relevant to repeated dose toxicity) clinical observations, detailed physical examination, body weight, food consumption, functional observational battery (FOB) and motor activity, haematology, serum chemistry, necropsy, organ weight measurement, and microscopic examination.  

 

Oral gavage administration of dimethylsilanediol was generally well tolerated in the rat. Significant findings included clinical signs, effects on body weight gain (males and toxicity females), and effects on the liver (organ weight and pathology). For almost all other endpoints, there were no significant differences in any of the treatment groups as compared to the study controls. For haematology and serum chemistry, the noted significant changes (toxicity males and females) from study controls were within or slightly below historical control values.

 

For clinical signs in the toxicity group males at 250 and 500 mg/kg bw/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 bw/day. Both abdominal soiling and urogenital soiling were significant abnormal observations in the reproductive group females at 500 mg/kg bw/day.  

 

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.

 

In the liver, increased liver weights in toxicity males and females at 250 and 500 mg/kg bw/day correlated with the histopathologic finding of centrilobular hypertrophy. Based on liver pathology, there were three primary effects of the test article, including centrilobular hypertrophy in both sexes, periportal hepatocellular vacuolation (microvascular 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.

 

Other considered pathology included the thyroid gland, lung, and prostate gland. 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.  

 

Based on the results of this study, the systemic toxicity NOAEL for the final hydrolysis product dimethylsilanediol in rats via oral administration in corn oil was considered to be 250 mg/kg bw/day, based on liver effects (brown pigment accumulation in males and vacuolation in females) at 500 mg/kg bw/day. 

Justification for classification or non-classification

Based on the available repeated dose inhalation data for 1,1,3,3-tetramethyldisiloxane, this substance is not classified for specific target organ toxicity through repeated or prolonged exposure according to Regulation (EC) No. 1272/2008.