Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Cross-reference
Reason / purpose for cross-reference:
data waiving: supporting information
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 May 2017 - 10 November 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
29 July 2016
Deviations:
not applicable
GLP compliance:
yes (incl. QA statement)
Remarks:
Date of inspection: 05/12/2016, Date of issue: 15/03/2017
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: Sponsor / 440038-285
- Expiration date of the lot/batch: 15 March 2019
- Purity test date: no data


STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Refrigerated (2 to 8°C) in darkness
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: stable


TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: none

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl:CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River (UK) Ltd
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation:
Males: 69 to 76 days old.
Females: 83 to 90 days old

- Weight at study initiation:
Males: 333 to 387 g.
Females: 239 to 302 g.

- Fasting period before study: NO DATA
- Housing:
Cages comprised of a polycarbonate body with a stainless steel mesh lid; changed at appropriate intervals.
Solid (polycarbonate) bottom cages were used during the acclimatization, pre-pairing, treatment, gestation, littering and lactation periods.
Grid bottomed cages were used during pairing. These were suspended above absorbent paper which was changed daily during pairing.

- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period:
Males: six days before commencement of treatment.
Females: 20 days before commencement of treatment.


DETAILS OF FOOD AND WATER QUALITY:
DIET
SDS VRF1 Certified pelleted diet.
A sample (100g) of each batch of diet used was retained within Pharmacy (frozen -10 to -30ºC) until finalization of the report. Samples were discarded after finalization of the report.
The diet contained no added antibiotic or other chemotherapeutic or prophylactic agent.

WATER
Potable water from the public supply via polycarbonate bottles with sipper tubes. Bottles were changed at appropriate intervals.

Certificates of analysis for the diet are scrutinized and approved before any batch of diet was released for use. Certificates of analysis were routinely provided by the water supplier.

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

Route of administration:
oral: gavage
Details on route of administration:
Route: Oral gavage using a suitably graduated syringe and a rubber catheter inserted via the mouth.
Treated at: constant doses in mg/kg/day.
Volume dose: 5 mL/kg body weight.
Individual dose volume: Calculated from the most recently recorded scheduled body weight.
Control (Group 1): vehicle at the same volume dose as treated groups.
Frequency: Once daily at approximately the same time each day.
Formulation: A daily record of the usage of formulation was maintained based on weights. This balance was compared with the expected usage as a check of correct administration. No significant discrepancy was found.
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Justification for use and choice of vehicle (if other than water): substance insoluble in water
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of each formulation prepared for administration in Week 1 (for each treatment group) and on Day 10 to 12 of lactation (females only) were analyzed for achieved concentration of the test item.
See Attachment 1 for full analytical methods.
The analytical procedure was successfully validated with respect to specificity of chromatographic analysis, limits of detection and quantification, linearity of detector response, repeatability, method accuracy and precision. The homogeneity and stability was confirmed for 3-(3,3,3-Trimethyl-1,1- bis((trimethylsilyl)oxy)disiloxanyl) propyl methacrylate in Corn Oil formulations at nominal concentrations of Low nominal concentration mg/mL and High nominal concentration mg/mL during distribution between the bottles, during magnetic stirring for 2 hours, ambient temperature storage for 1 day and refrigerated storage for up to 15 days. The mean concentrations of 3-[3,3,3trimethyl-1,1bis[(trimethylsiyl)oxy] dissiloxanyl] propyl methacrylate in test formulations analyzed for the study were within ±3% of nominal concentrations, confirming accurate formulation.
Duration of treatment / exposure:
Males Two weeks before pairing up to necropsy after a minimum of five weeks of treatment.
Females Two weeks before pairing, then throughout pairing and gestation until Day 13 of lactation.
Animals of the F1 generation were not dosed.
Frequency of treatment:
Once daily at approximately the same time each day.
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: doses were selected on the basis of a range finding study (linked to this endpoint)
Positive control:
No
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were inspected visually at least twice daily for evidence of ill-health or reaction to treatment. Cages were inspected daily for evidence of animal ill-health amongst the occupant(s). Any deviation from normal was recorded at the time in respect of nature and severity, date and time of onset, duration and progress of the observed condition, as appropriate.
During the acclimatization period, observations of the animals and their cages were recorded at least once per day.


DETAILED CLINICAL OBSERVATIONS: Yes
Before treatment commenced and during each week of treatment and on Days 0, 7, 14 and 20 after mating and Days 1, 6 and 12 of lactation, detailed physical examination and arena observations were performed on each animal. On each occasion, the examinations were performed at approximately the same time of day (before dosing during the treatment period), by an observer unaware of the experimental group identities. “Blind” recording was not possible for animals during pairing or for females after mating and during lactation, for logistical reasons, therefore observations were made on these occasions without “blinding”.
After removal from the home cage, animals were assessed for physical condition and behavior during handling and after being placed in a standard arena. Any deviation from normal was recorded with respect to the nature and, where appropriate, degree of severity. Particular attention was paid to possible signs of neurotoxicity, such as convulsions, tremor and abnormalities of gait or behavior.
Findings were either reported as "present" or assigned a severity grade - slight, moderate or marked.


BODY WEIGHT: Yes
- Time schedule for examinations:
The weight of animals was recorded as follows:
F0 males: Weekly during acclimatization. Before dosing on the day that treatment commenced (Day 0) and weekly thereafter. On the day of necropsy.
F0 females: Weekly during acclimatization. Before dosing on the day that treatment commenced (Day 0) and weekly before pairing.Days 0, 7, 14 and 20 after mating. Day 1, 4, 7 and 13 of lactation. On the day of necropsy.


FOOD CONSUMPTION:
The weight of food supplied to each cage and an estimate of any spilled was recorded as follows:
F0 animals: Weekly, from the day that treatment commenced. Food consumption was not recorded for males and females during the period when paired for mating (Week 3), but recommenced for males in Week 4. For females after mating food consumption was performed to match the body weight recording:
Days 0-6, 7-13 and 14-19 after mating
Days 1-3, 4-6 and 7-12 of lactation.
From these records the mean daily consumption per animal (g/animal/day) was calculated for each relevant phase.


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: Not specified


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At termination.
- Anaesthetic used for blood collection: Yes (isoflurate)
- Animals fasted: No
- How many animals: The five lowest numbered surviving males and the first five lactating females with a surviving litter per group.
- The following paramters were checked:

Hematocrit (Hct)*
Hemoglobin concentration (Hb)
Erythrocyte count (RBC)
Absolute reticulocyte count (Retic)
Mean cell hemoglobin (MCH)*
Mean cell hemoglobin concentration (MCHC)*
Mean cell volume (MCV)
Red cell distribution width (RDW)
Total leucocyte count (WBC)
Differential leucocyte count:
Neutrophils (N)
Lymphocytes (L)
Eosinophils (E)
Basophils (B)
Monocytes (M)
Large unstained cells (LUC)
Platelet count (Plt)

* Derived value calculated in ClinAxys

Blood film (prepared for all samples) - Romanowsky stain, examined for abnormalities by light microscopy, in the case of flags from the Advia 120 analyzer. Confirmation or a written description from the blood film was made where appropriate.
Additional blood samples (nominally 0.5 mL) were taken into tubes containing citrate anticoagulant and examined using a Stago STA Compact Max analyzer and appropriate reagent in respect of:
Prothrombin time (PT) - using IL PT Fibrinogen reagent.
Activated partial thromboplastin time (APTT) - using IL APTT reagent.



CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: No
- How many animals: The five lowest numbered surviving males and the first five lactating females with a surviving litter per group.
- The following parameters were checked:

Alkaline phosphatase (ALP)
Alanine aminotransferase (ALT)
Aspartate aminotransferase (AST)
Total bilirubin (Bili)
Bile acids (Bi Ac)
Urea
Creatinine (Creat)
Glucose (Gluc)
Total cholesterol (Chol)
Triglycerides (Trig)
Sodium (Na)
Potassium (K)
Chloride (Cl)
Calcium (Ca)
Inorganic phosphorus (Phos)
Total protein (Total Prot)
Albumin (Alb)
Globulin (Glob)

Albumin/globulin ratio (A/G Ratio) was calculated from total protein concentration and analyzed albumin concentration.


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: Yes
- Battery of functions tested:
Sensory Reactivity and Grip Strength
Sensory reactivity and grip strength assessments were performed (before dosing) on the five lowest numbered surviving males in each group during Week 5 of treatment and on the first five lactating females in each group at Day 7-9 of lactation. Animals were tested by an observer who was unaware of the treatment group to which each animal belonged. Before the start of observations, male cage labels showing the treatment group were replaced by labels stating only the study, animal and cage numbers. For females, animals were moved into individual cages prior to transport to the testing room. The cage labels on these individual cages showed only the study and animal number. Animals were not necessarily all tested on the same day, but the numbers of animals and the times of testing were balanced across the groups as far as possible on each day of testing.
The following measurements, reflexes and responses were recorded:
Approach response
A blunt probe was brought towards the animal’s head until it was close to the animal’s nose (but not touching the whiskers). The animal’s reaction was recorded as:
1 No reaction or ignores probe/walks past probe
2 Normal awareness and reaction e.g. approaches and/or sniffs probe
3 Active avoidance, abnormally fearful or aggressive reaction
Pinna reflex
The inside of one ear was touched lightly with a nylon filament and the reaction recorded as:
1 No response
2 Normal response e.g. ear twitches/flattens or animal shakes its head
3 Abnormally fearful or aggressive response

Auditory startle reflex
The animal’s response to a sudden sharp noise was assessed and scored as:
1 No response
2 Weak response e.g. ear twitch only
3 Normal response e.g. obvious flinch or startle
4 Exaggerated response e.g. all feet off floor

Tail pinch response
The animal’s tail was pinched sharply with forceps approximately one third from the tip and the response graded as:
1 No response
2 Weak response e.g. turns around slowly or weak vocalization without moving away
3 Normal response e.g. jumps forward or turns around sharply, usually with vocalization
4 Exaggerated response e.g. excessive vocalization, body movement or aggression

Grip strength
Forelimb and hindlimb grip strength was measured using Mecmesin Basic Force Gauges. Three trials were performed.
At any point during the observations, additional comments were made as free text where considered appropriate.
Motor Activity
During Week 5 of treatment for males and at Day 7-9 of lactation for females, the motor activity of the five lowest numbered surviving males and the first five lactating females in each group was measured (before dosing) using a Rodent Activity Monitoring System (Version 2.0.6), with hardware supplied by Pearson Technical Services and software developed and maintained by Envigo.
Animals were tested individually in clear polycarbonate cages and motor activity was measured by counting infra-red beam breaks over ten 6-minute intervals (one hour total). Ten beams were set at two height levels (five low and five high) to detect cage floor and rearing activity respectively. Animals were not all necessarily tested on the same day, but the numbers of animals and the times of testing were balanced across the groups as far as possible on each day of testing.


IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 1)
HISTOPATHOLOGY: Yes (see table 1)
Other examinations:
Examinations relating to reproductive toxicity, including thyroid hormone sampling on offspring, were also performed (see IUCLID Section 7.8)
Statistics:
Statistical analyses were performed on the majority of data presented and results of these tests, whether significant or non-significant, are presented on the relevant tables. For some parameters, including estrous cycles before treatment, pre coital interval, gestation index and stage of estrous cycle at termination, the similarity of the data was such that analyses were not considered to be necessary.
All statistical analyses were carried out separately for males and females using the individual animal as the basic experimental unit. For litter/fetal findings the litter was taken as the treated unit and the basis for statistical analysis and biological significance was assessed with relevance to the severity of the anomaly and the incidence of the finding within the background control population.
The following data types were analyzed at each timepoint separately:
Grip strength and motor activity
Body weight, using absolute weights and gains over appropriate study periods
Food consumption, over appropriate study periods during gestation and lactation
Hematology and blood chemistry
Estrous cycles during treatment
Gestation length
Litter size, survival indices and sex ratio
Ano-genital distance, adjusted for Day 1 pup body weight
Organ weights, both absolute and adjusted for terminal body weight
Clinical signs:
no effects observed
Description (incidence and severity):
No test item-related changes in general clinical condition were observed following treatment with 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate.
Mortality:
mortality observed, treatment-related
Description (incidence):
Group 4 male No. 3 receiving 1000 mg/kg/day was killed for welfare reasons on Day 32 of treatment due to underactivity and reduced body temperature and had shown signs of incoordination and abnormal gait. Gross abnormalities were observed in the skin (scabs), liver (pale and dark areas), spleen (enlarged), mesenteric lymph nodes (dark), pancreatic lymph nodes (dark and enlarged), testes (dark areas), eyes (dark areas) and meninges of the brain (thickened). At microscopic examination, vacuolated macrophage aggregates/inflammation and hepatocyte necrosis considered to be test item-related were seen in the liver. Myeloid cell leukemia was also seen in most tissues (lungs, liver, and kidneys) and was considered as a factor contributory to death, though not related to treatment.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test item-related changes in bodyweight and bodyweight gain were observed following treatment with 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test item-related changes in food consumption were observed following treatment with 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Hematology investigations after 5 weeks of treatment revealed males at 200 mg/kg/day and males and females at 500 and 1000 mg/kg/day had lower than Control hematocrit and hemoglobin concentrations, with dose responses evident in males. Males receiving 200, 500 and 1000 mg/kg/day had higher than Control reticulocytes.
Males at 500 or 1000 mg/kg/day and females at 200, 500 and 1000 mg/kg/day had lower than Control red cell distribution width with a dose response evident in both sexes. Mean cell volume was also lower than Control in all treated groups and both sexes although no dose response was apparent.
Total leucocyte count was dose-dependently increased in all treated groups of males and increased in treated females as a result of increased neutrophils and/or lymphocytes when compared with Control.
All inter-group differences, including those attaining statistical significance, were minor, confined to one sex or lacked dose-relationship and were therefore attributed to normal biological variation.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
The biochemical examination of the blood plasma performed after five weeks of treatment for males and on Day 14 of lactation for females indicated revealed no test-item related changes.
All inter-group differences, including those attaining statistical significance, were minor, confined to one sex or lacked dose-relationship and were therefore attributed to normal biological variation.
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Sensory reactivity and grip strength:
The sensory reactivity observations conducted during Week 5 of treatment for males and Day 7-9 of lactation for females revealed no findings which were considered treatment related in animals receiving 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate at doses of 200, 500 and 1000 mg/kg/day.

Motor activity:
Motor activity conducted during Week 5 of treatment for males and Day 7-9 of lactation for females revealed no findings which were considered treatment related in animals receiving
3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate at doses of 200, 500 and 1000 mg/kg/day.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
When compared with controls, the adjusted mean liver and spleen weights were statistically significantly high in males treated at 200, 500 and 1000 mg/kg/day with a dose-response.
Liver weights were also increased in females at 200, 500 and 1000 mg/kg/day when compared to Control, although no statistical significance was attained, nor was a dose response evident.
All other organ weights were unaffected by treatment.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Liver: Pale areas were seen in liver of both sexes given 200 and 1000 mg/kg/day and in males given 500 mg/kg/day.
Skin: Scabs were seen on the skin of males in all treatment groups.
The incidence and distribution of all other findings were considered to be incidental and unrelated to the test item.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Test item-related changes were seen in the liver and mesenteric lymph nodes.
Liver: Hepatocyte hypertrophy, vacuolated macrophage aggregates associated with or without inflammation, inflammation and necrosis were seen in the liver of males and females given 1000 mg/kg/day. Similar findings were seen in some males given 200 or 500 mg/kg/day.
Mesenteric lymph nodes: Vacuolated macrophage aggregates were seen in males and females given 1000 mg/kg/day.
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Description (incidence and severity):
Findings of an Uncertain Relationship to Treatment
Skin: Epidermal erosion and/or scabs, usually accompanied by hyperplasia, dermal/subcutaneous inflammation and/ or dermal haemorrhage were seen in males of all treatment groups. These findings were present on additional sections of skin presented because of abnormalities identified at necropsy (scabs). No histopathological changes were seen in the routine skin samples. Due to the anatomical distribution of findings (side of the face) and absence in treated females, these findings were considered to be of uncertain relationship to treatment.
Details on results:
The oral administration of 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate to parental Crl:CD(SD) rats at dose levels of 200, 500 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after five weeks of treatment and females on Day 14 of lactation was generally well tolerated.
Group 4 male No. 3 receiving 1000 mg/kg/day was killed for welfare reasons on Day 32 of treatment due to underactivity and reduced body temperature and had shown signs of incoordination and abnormal gait. Myeloid cell leukaemia was seen in most tissues (lungs, liver, and kidneys) and was considered as a factor contributory to death, though not related to treatment.
There were no treatment related findings observed at the detailed physical examination and grip strength, motor activity, bodyweights and food consumption were all unaffected by treatment.
Macropathology revealed pale areas of the liver which correlated with hepatocyte hypertrophy, vacuolated macrophage aggregates associated with or without inflammation, inflammation and necrosis seen in the liver of males and females given 1000 mg/kg/day. Similar findings were also seen in some males given 200 or 500 mg/kg/day. Vacuolated macrophage aggregates were seen in in the mesenteric lymph nodes in males and females given 1000 mg/kg/day. Epidermal erosion and/or scabs, usually accompanied by hyperplasia, dermal/subcutaneous inflammation and/ or dermal haemorrhage were seen in males of all treatment groups; however the findings presented an uncertain relationship to treatment.
Mean adjusted spleen weights were statistically significantly high in all groups of treated males with a dose response apparent, but there were no supporting microscopic pathology changes in the spleen so a relationship to treatment was considered unlikely.
The study design also included an assessment of endocrine disruptor relevant endpoints. This objective was met by including the measurement of the hormone thyroxine (T4) in adult males and in offspring at Day 13 of age, by evaluating changes in adult organ weight and gross organ pathology of endocrine-sensitive organs and, because some developmental stages (e.g. gestational and neo-natal) are particularly sensitive to endocrine effects, an external examination of all offspring, measurement of the ano-genital distance of offspring on Day 1 of age and nipple counts for male offspring on Day 13 of age. T4 levels were considered unaffected by treatment in F0 males and F1 offspring on Day 13 of age and no significant changes were identified at the microscopic examination of thyroid, adrenal and pituitary glands and the reproductive organs. All offspring were macroscopically normal; in particular no effects were seen on the external genitalia. Ano-genital distances and male nipple counts were not adversely affected by treatment. It was therefore concluded that, in the context of this study, 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate showed no evidence of being an endocrine disruptor.
Key result
Dose descriptor:
LOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology
Critical effects observed:
yes
Lowest effective dose / conc.:
200 mg/kg bw/day (actual dose received)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Table 2.Summary of findings in the liver of animals killed after 5 weeks of treatment

Group/sex

1M

2M

3M

4M

1F

2F

3F

4F

Dose (mg/kg/day)

0

200

500

1000

0

200

500

1000

Pale area(s)

0

1

3

6

0

1

0

2

Number of tissues examined

10

10

10

10

10

10

10

10

 

Table 3. Summary of findings in the skin of animals killed after 5 weeks of treatment

Group/sex

1M

2M

3M

4M

1F

2F

3F

4F

Dose (mg/kg/day)

0

200

500

1000

0

200

500

1000

Scab(s)

0

1

2

5

0

0

0

0

Number of tissues examined

10

10

10

10

10

10

10

10

 

Table 4. Summary of treatment related findings in the liver of animals killed after
5 weeks of treatment

Group/sex

1M

2M

3M

4M*

1F

2F

3F

4F

Dose (mg/kg/day)

0

200

500

1000

0

200

500

1000

Hypertrophy, Hepatocyte

 

 

 

 

 

 

 

 

Minimal

0

1

2

0

0

0

0

0

Slight

0

0

1

6

0

0

0

5

Total

0

1

3

6

0

0

0

5

Aggregates, Macrophage, Vacuolated/Inflammation

 

 

 

 

 

 

 

 

Minimal

0

0

0

1

0

0

0

3

Slight

0

0

1

3

0

0

0

1

Moderate

0

0

0

3

0

0

0

1

Total

0

0

1

7

0

0

0

5

Inflammation

 

 

 

 

 

 

 

 

Minimal

0

1

3

1

0

0

0

2

Slight

0

0

0

4

0

0

0

0

Moderate

0

0

0

0

0

0

0

1

Total

0

1

3

5

0

0

0

3

Group/sex

1M

2M

3M

4M*

1F

2F

3F

4F

Dose (mg/kg/day)

0

200

500

1000

0

200

500

1000

Necrosis, Hepatocyte, Focal

 

 

 

 

 

 

 

 

Minimal

0

1

2

2

0

0

0

4

Slight

0

0

1

4

0

0

0

0

Moderate

0

0

0

0

0

0

0

1

Total

0

1

3

6

0

0

0

5

 

 

 

 

 

 

 

 

 

Number of tissues examined

5

1

3

7

5

1

0

6

* includes animal no 3 killed prematurely

Table 5. Summary of treatment related findings in the mesenteric lymph nodes of animals killed after 5 weeks of treatment

Group/sex

1M

2M

3M

4M*

1F

2F

3F

4F

Dose (mg/kg/day)

0

200

500

1000

0

200

500

1000

Aggregates, Macrophage, Vacuolated

 

 

 

 

 

 

 

 

Minimal

0

0

0

3

0

0

0

0

Slight

0

0

0

1

0

0

0

3

Moderate

0

0

0

1

0

0

0

2

Total

0

0

0

5

0

0

0

5

 

 

 

 

 

 

 

 

 

Number of tissues examined

5

0

0

6

5

0

0

5

* includes animal no 3 killed prematurely

Table 6. Summary of findings of an uncertain relationship to treatment in the skin after 5 weeks of treatment

Group/sex

1M

2M

3M

4M*

Dose (mg/kg/day)

0

200

500

1000

Erosion, Epidermal

 

 

 

 

Minimal

0

1

2

3

Moderate

0

0

0

1

Total

0

1

2

4

Scab(s)

 

 

 

 

Minimal

0

1

1

0

Slight

0

0

0

1

Moderate

0

0

0

1

Total

0

1

1

2

Hyperplasia, Epidermal

 

 

 

 

Minimal

0

0

0

1

Slight

0

0

0

2

Total

0

0

0

3

Inflammation, Dermal/Subcutis

 

 

 

 

Minimal

0

0

0

1

Slight

0

1

0

1

Total

0

1

0

2

Haemorrhage, Dermal

 

 

 

 

Minimal

0

0

1

2

Total

0

0

1

2

 

 

 

 

 

Number of tissues examined

5

1

2

7

* includes animal no 3 killed prematurely

Full results are attached in Attachment 2.

Conclusions:
It was concluded that the oral administration of 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate to parental Crl:CD(SD) rats at dose levels of 200, 500 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after five weeks of treatment and females on Day 14 of lactation was generally well tolerated, however hepatocyte hypertrophy, vacuolated macrophage aggregates associated with or without inflammation, inflammation and necrosis were seen in the liver of males and females given 1000 mg/kg/day. Similar findings were also seen in some males given 200 or 500 mg/kg/day.

The no-observed adverse-effect level (NOAEL) of 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate for systemic toxicity was concluded to be < 200 mg/kg/day.
Executive summary:

Summary

The purpose of this study was the assessment of general systemic toxic potential in Crl:CD(SD) rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of 3-(3,3,3-Trimethyl-1,1-bis((trimethylsilyl)oxy)disiloxanyl)propyl methacrylate by oral gavage administration for at least five weeks.

Three groups of ten male and ten female rats received3-(3,3,3-Trimethyl-1,1-bis((trimethylsilyl)oxy)disiloxanyl)propyl methacrylateat doses of 200, 500 or 1000 mg/kg/day by oral gavage administration. Males were treated daily for two weeks before pairing, up to necropsy after a minimum of five consecutive weeks. Females were treated daily for two weeks before pairing, throughout pairing, gestation and until Day 13 of lactation. Females were allowed to litter, rear their offspring and were killed on Day 14 of lactation. The F1 generation received no direct administration of the test item; any exposure was in utero or via the milk. A similarly constituted Control group received the vehicle, corn oil, at the same volume dose as treated groups.

During the study, clinical condition, detailed physical examination and arena observations, sensory reactivity observations, grip strength, motor activity, body weight, food consumption, hematology (peripheral blood), blood chemistry, thyroid hormone analysis, estrous cycles, pre-coital interval, mating performance, fertility, gestation length, organ weight and macroscopic pathology and histopathology investigations were undertaken.

Results

There were no treatment related findings observed at the detailed physical examination and grip strength, motor activity, bodyweights and food consumption were all unaffected by treatment.

Hematology investigations after 5 weeks of treatment revealed males at 200 mg/kg/day and males and females at 500 and 1000 mg/kg/day had lower than Control hematocrit and hemoglobin concentrations, with dose responses evident in males. Males receiving 200, 500 and 1000 mg/kg/day had higher than Control reticulocytes. Males at 500 and 1000 mg/kg/day and females at 200, 500 and 1000 mg/kg/day had lower than Control red cell distribution width with a dose response evident in both sexes. Mean cell volume was also lower than Control in all groups and both sexes although no dose response was apparent. Total leucocyte count was dose-dependently increased in males and increased in females as a result of increased neutrophils and lymphocytes when compared with Control.

When compared with controls, the adjusted mean liver and spleen weights were statistically significantly high in males treated at 200, 500 and 1000 mg/kg/day with a dose-response.Liver weights were also increased in females at 200, 500 and 1000 mg/kg/day when compared to Control, although no statistical significance was attained, nor was a dose‑response evident.

Pale areas were seen in liver of both sexes given 200 and 1000 mg/kg/day and in males given 500 mg/kg/day. Hepatocyte hypertrophy, vacuolated macrophage aggregates associated with or without inflammation, inflammation and necrosis were seen in the liver of males and females given 1000 mg/kg/day. Similar findings were seen in some males given 200 or 500 mg/kg/day.

Conclusion

It was concluded that the oral administration of3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate to parental Crl:CD(SD) rats at dose levels of 200, 500 or 1000 mg/kg/day for two weeks before pairing, during pairing and then up to termination of the males after five weeks of treatment and females on Day 14 of lactation was generally well tolerated, however hepatocyte hypertrophy, vacuolated macrophage aggregates associated with or without inflammation, inflammation and necrosis were seen in the liver of males and females given 1000 mg/kg/day. Similar findings were also seen in some males given 200 or 500 mg/kg/day

The no-observed adverse-effect level (NOAEL) of 3-[3,3,3-trimethyl-1,1-bis[(trimethylsiyl)oxy]dissiloxanyl]propyl methacrylate for systemic toxicity was concluded to be < 200 mg/kg/day.

Data source

Materials and methods

Results and discussion

Applicant's summary and conclusion