Registration Dossier

Administrative data

Description of key information

There are no sub-chronic repeated dose toxicity data for the registered substance, 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8). Therefore, data are read-across from the structural analogue, [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 10217-34-2).

In the key sub-chronic toxicity study in rats for the analogue [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 10217-34-2), conducted according to OECD Test Guideline 408 and in compliance with GLP, the NOAEL was concluded to be 1000 mg/kg bw/day (NOTOX, 1998).  

This result is supported by a 28-day repeated dose oral toxicity study for the registered substance, 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8), which was conducted according to OECD Test Guideline 407 and in compliance with GLP. No adverse effects were seen at the highest dose tested and the NOAEL was concluded to be 1000 mg/kg bw/day (Dow Corning Corporation, 1981).

In a subacute inhalation repeated dose toxicity study with the registered substance, 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8), conducted according to a protocol similar to OECD Test Guideline 412 and in compliance to GLP, a NOAEC of 0.225 mg/l was concluded. Following nine exposures to an aerosol of 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8) (target concentrations 0, 75, 225 and 750 mg/m3) over a two week period there were no adverse effects found in rats. However, 5/10 males and 1/10 female rats died between day three and five of dosing when exposed to a concentration of 0.75 mg/l. The animals appeared to have died from exhaustion due to malnutrition (Dow Corning Corporation, 1982).

There is also a repeated inhalation study for the hydrolysate of 3-(2,3-epoxypropoxy)propyltrimethoxysilane (No CAS available), which tested a single concentration of 0.119 mg/l for 28 days. A NOAEC could not be established as significant reductions in body weight (11% decrease in absolute body weight and 29% reduction in body weight gain) were observed at this concentration. The study was conducted to investigate the potential for induction of laryngeal granulomas and therefore did not include haematology, clinical chemistry or urinalysis investigations. There was no adverse pathology (BRRC, 1991).

There are no reliable dermal studies available.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1997-09-04 through 1997-12-12
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Qualifier:
according to
Guideline:
EU Method B.26 (Sub-Chronic Oral Toxicity Test: Repeated Dose 90-Day Oral Toxicity Study in Rodents)
Qualifier:
according to
Guideline:
other: EPA 40 CFR, Part 798 "Health Effects Testing Guidelines:, 1989-07-01, Section 798.2650 Oral Toxicity
GLP compliance:
yes (incl. certificate)
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 6 weeks
- Housing: Group housing of 5 animals per sex per cage in stainless steel suspended cages with wire mesh floors from the day of arrival until start of the pre-test. Single housing of rats in Macrolon MIII cages with sterilised sawdust provided as bedding from start of the pre-test onwards.
- Diet (e.g. ad libitum): ad libitum standard pelleted laboratory animal dies (Carfil Quality BVBA, Oud-Turnhout, Belgium)
- Water (e.g. ad libitum): ad libitum tap water
- Acclimation period: At least 5 days before start of treatment under laboratory conditions.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 50
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 hours dark/12 hours light
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
Oral gavage, using a stainless steel stomach tube or rubber catheter. Formulations were places on a magnetic stirrer during dosing.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Duplicate samples of Week 1 formulations were analysed to check homogeneity (highest and lowest concentrations; samples taken at the top, middle and bottom of the container) and accuracy of preparation (all concentrations). Also, duplicate samples of formulations prepared during Weeks 4 and 13 were analysed to check accuracy of preparation (all concentrations). Total number of samples was 32. Test substance formulations in polyethylene glycol formed a homogeneous suspension at the concentrations tested. Analysis of the accuracy of dose preparations of Groups 2, 3 and 4 revealed overall mean values of 102, 102 and 102% of nominal when values of peaks 1 and 2 were combined. This was considered to represent an acceptable level of accuracy for formulations of this type.
Duration of treatment / exposure:
90 days
Frequency of treatment:
Once daily, 7 days/week
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10 males/10 females per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Dose selection rationale: Dose levels were based on the results of a prior 28-day oral toxicity study in the rat.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS/DETAILED CLINICAL OBSERVATIONS: Yes
Mortality/Viability were examined twice daily.
Clinical signs were observed at least twice daily at the time of dosing as well as 1-2 hours post-dosing from Day 1 onwards. The time of onset, degree and duration were recorded. Observations included, but were not limited to, changes in skin and fur, eyes and mucous membranes, respiratory, circulatory, autonomic and central nervous systems, somatomotor activity and behaviour pattern. All symptoms were recorded according to fixed scales. Only the absence/presence of signs were recorded.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly, beginning 1 week prior to test substance administration and just prior to scheduled necropsy.

FOOD CONSUMPTION: Weekly, beginning 1 week prior to test substance administration.

WATER CONSUMPTION: Subjective appraisal was maintained during the study, but no quantitative investigation introduced as no effect was suspected.

OPHTHALMOSCOPIC EXAMINATION: Both eyes were examined following installation of tropicamide solution (5 mg/ml for all animals at pre-test and all animals at Week 13.

CLINICAL LABORATORY INVESTIGATIONS: Blood samples were collected under light ether anaesthesia immediately prior to post mortem examination. The animals were fasted overnight before blood sampling, but water was provided. Blood samples were drawn from the retro-orbital sinus of all rats/sex/group and collected into tubes prepared with EDTA for haematological parameters (0.6 mL), with citrate for clotting tests (1 mL) and untreated tubes for clinical biochemistry parameters (>2 mL) Blood sampling was conducted prior to treatment, at 30 days of treatment and prior to sacrifice at 90 days of treatment.

HAEMATOLOGY: The following haematology parameters were determined from blood prepared with EDTA as an anti-coagulant: RBC count; HB; HCT; MCV; MCH; MCHC; platelet count; RDW; WBC; and differential leucocyte count SEG, EO, BASO, LYMPH & MONO. PT and PTT were determined from blood prepared with citrate as the anti-coagulant.

CLINICAL CHEMISTRY: Clinical biochemistry parameters determined from serum included ALAT/GPT; ASAT/GOT; BILI T.; CHOLEST. T., TRIGL.; Creatinine; Glucose; Urea; PROTEIN T.; ALBUMIN; GLOBULIN; A/G RATIO; ALP; Sodium; Potassium; Chloride; Calcium; and INORG. PHOSPH.
Sacrifice and pathology:
GROSS PATHOLOGY: Examinations included: adrenal glands; aorta; brain; caecum; cervix; colon; duodenum; epididymides; eyes with optic nerve and Harderian gland; female mammary gland area; femur including knee joint; heart; ileum; jejunum; kidneys; liver; lung; lymph nodes; oesophagus; ovaries; pancreas; pituitary gland; prostate gland; rectum; salivary glands; sciatic nerve; seminal vesicles; skeletal muscle; skin; spinal cord; spleen; sternum with bone marrow; stomach; testes; thyroid including parathyroid; trachea; urinary bladder; uterus; vagina; and all gross lesions, tissue masses and tumours.

ORGAN WEIGHTS: Organ weights were recorded for adrenal glands; brain; heart; kidneys; liver; lungs; ovaries; spleen; and testes.

HISTOPATHOLOGY: Slides of all tissues collected at the scheduled sacrifice from all animals of the control and the highest dose group, as well as from all animals of all dose groups which died spontaneously, all gross lesions, lungs, livers and kidneys of all animals (all dose groups) were examined by a pathologist.
Statistics:
Univariate one-way ANOVA was used to assess the significance of intergroup differences.
If the variables could be assumed to follow a normal distribution, the Dunnett-test (many-to-one t-test) based on a pooled variance estimate was applied for the comparison of the treated groups and the control groups for each sex.
The Steel-test (many-to-one rank test) was applied when the data could not be assumed to follow a normal distribution.
The exact Fisher-test was applied to the ophthalmoscopic observations.
All tests were two-sided and in all cases p<0.05 was accepted as the lowest level of significance.
Group means were calculated for continuous data and medians were calculated for discrete data (scores) in the summary tables.
Test statistics were calculated on the basis of exact values for means and pooled variances. Individual values, means and standard deviations may have been rounded off before printing. Therefore, two groups may display the same printed means for a given parameter, yet display different test statistics values.
Clinical signs:
no effects observed
Description (incidence and severity):
There were no clinical signs of toxicity or behavioural changes over the 90-day observation period that were considered to be relevant to treatment.

Excessive salivation was observed in control and treated animals in a dose-related manner immediately after dosing. In the majority of animals, this finding was not observed 1-2 hours post-dosing. Excessive salivation is often noted in rats of this age and strain following oral gavage and considered to be related to multiple intra-oesophageal intubation and/or the taste of the test substance. Therefore, this finding was considered not to be a sign of systemic toxicity.

Other findings that were noted did not show a dose-response relationship and included piloerection, rales, brown staining of the forelegs, head and shoulders, red staining around the eye, nose and periorbital region, diarrhoea, blinking eye and black discoloration of the skin. These findings were considered to be within the normal range of biological variation for rats of this age and strain and are not test material related.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One control male died after dosing on Day 3 and another control male died prior to dosing on the same day. One male receiving 500 mg/kg/day died prior to dosing on Day 5. The control male which died after dosing did not exhibit any clinical signs prior to death. At necropsy, haemorrhagic fluid was noted in the thoracic cavity. The control male which died on Day 3 prior to dosing showed hunched posture and piloerection and at necropsy findings were noted in the pancreas, kidneys, urinary bladder, epididymides, prostate, spleen and thymus. The 500 mg/kg/day-dosed male which died on Day 5 showed laboured respiration prior to death, but no macroscopic findings were noted at necropsy.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No statistically significant differences were noted in body weights and body weight gain of treated animals versus controls. Body weights and body weight gain of treated animals remained in the same range as controls over the 90-day study period. Slightly low values for body weight and body weight gain were recorded for control and treated males on Day 29. This was due to overnight fasting of these animals prior to blood sampling.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
There were no differences in food consumption before or after allowance for body weight between treated and control animals. Slightly low values for food consumption were recorded for control and treated males over Days 22-29. This was also due to overnight fasting of these animals prior to blood sampling.
Food efficiency:
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related ophthalmology findings at pretest and Week 13. Anterior synechia was noted in one male of the 100 mg/kg/day group at pre-test, and corneal opacity with vascularization was seen in one male of the 500 mg/kg/day group in Week 13. Both findings were considered to be within the normal range of variation for rats of this age and strain and no toxicological relevance was attached to these observations.
Haematological findings:
no effects observed
Description (incidence and severity):
At pretest no statistically significant differences were noted between animals assigned to the control and treatment groups.

After 30 days of treatment, red blood count, haemoglobin, haematocrit and mean corpuscular haemoglobin concentration values were slightly decreased in females in the 1,000 mg/kg/day dose group. Mean corpuscular haemoglobin concentration was also decreased in females receiving 100 and 500 mg/kg/day. In addition, total white blood cell count was decreased in females receiving 1,000 mg/kg/day. However, none of these parameters showed a clear dose-response, and the control values were slightly high in comparison with the historical data. Therefore, the toxicological relevance of these decreases is doubted.

After 13 weeks of treatment, red blood cell count and haematocrit values were slightly decreased in females of the 1,000 mg/kg/day dose group and mean corpuscular haemoglobin concentration was increased in females of this dose group. Partial thromboplastin time was slightly increased in females receiving 500 and 1,000 mg/kg/day.

Other minor statistically significant differences arising between control and treated animals after 30 days and 13 weeks of treatment were considered to have arisen by chance and in the absence of a dose-response relationship considered not to represent a change in biological significance.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
At pre-test, sodium, chloride and calcium were slightly lower and urea slightly higher in males assigned to the treatment groups in comparison with animals of the control group. In females of the treatment groups, triglycerides and calcium were lower and sodium higher compared to control values. The values were considered to have resulted from slightly high or low control values but remained within the range of historical data that can be expected for untreated animals of this age and strain.

After 30 days of treatment, there were no differences noted between control and treated animals that were related to treatment with the test substance. Statistically significant changes noted in all dose groups did not exhibit a clear dose-dependent relationship and/or were considered to have resulted from slightly high (calcium, aspartate aminotransferase activity) or low control values (glucose).

After 13 weeks of treatment, urea values were increased in males receiving 1,000 mg/kg/day. Other values in treated animals after 13 weeks achieving a level of statistical significance when compared to controls were considered to have arisen as a result of slightly high (total bilirubin, cholesterol, aspartate aminotransferase activity, total protein, calcium) or low control values (creatinine, sodium) and in the absence of a treatment-related distribution or corroborative findings in the opposite sex, considered to be of no toxicological significance.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Organ weights and relative organ weights of treated animals were considered to be similar to those of control animals. Decreased absolute lung weights recorded in animals receiving 1000 mg/kg/day were considered to have resulted from slightly high control values and not to represent a sign of toxicity.
Gross pathological findings:
no effects observed
Description (incidence and severity):
Macroscopic observations at necropsy did not reveal any alterations that were considered to have arisen as a result of treatment. The few macroscopic findings noted were unremarkable and did not distinguish treated animals from the controls. A subcutaneous nodule in the genital region was seen in a single animal of the 100 mg/kg/day dose group and its histopathological correlate is discussed below. All findings were considered to be within the range of biological variation for rats of this age and strain and not to represent a change in toxicological significance.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no microscopic findings noted that were considered to be treatment-related. Mammary adenocarcinoma was the microscopic correlate to the subcutaneous nodule noted at necropsy in one animal of the 100 mg/kg/day dose group. This was an early occurrence of a common spontaneous neoplasm and was not related to treatment with the test article. From the tissues examined, a definitive cause of death for the three unscheduled decedents could not be determined. All microscopic findings recorded were considered to be spontaneous in nature and within the range of background morphological alterations encountered in Wistar rats of this age and strain. They occurred at similar incidences and severity in both control and treated groups.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed.
Critical effects observed:
no
Conclusions:
In this oral 90-day repeated dose toxicity study, conducted on male and female Wistar rats using appropriate test guideline and in compliance with GLP, treatment with Silane, Triethoxy [2-(7-OxaBicyclo[4.1.0]Hept-3yl)Ethyl]- for 90 days produced only minimal changes that were not accompanied by any evidence of organ dysfunction. Based on these results, a No Observed Adverse Effect Level (NOAEL) of 1000 mg/kg bw/day was concluded for repeated dose oral exposure to Silane, Triethoxy [2-(7-OxaBicyclo[4.1.0]Hept-3yl)Ethyl]-.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subchronic
Species:
rat

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:
supporting study
Study period:
14.08.1989 to 08.09.1989
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
The restrictions were that only one dose and males were tested, and limited examinations were performed, i.e. no haematology, biochemistry or urinalysis. However, this study was performed primarily to investigate effects on the larynx.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
only one concentration used, only males, limited examinations, i.e. no haematology, biochemistry or urinalysis.
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, NY.
- Age at study initiation: 41 days 
- Weight at study initiation: 131.2 + 9.0 grams
- Fasting period before study: No data
- Housing: 1/2 per cage in stainless steel, wire-mesh cages.
- Diet (e.g. ad libitum): Ad libitum (except during exposure period)
- Water (e.g. ad libitum): Ad libitum (except during exposure period)
- Acclimation period: Two days


ENVIRONMENTAL CONDITIONS
- Temperature (°F): 62-70 (17-21°C)
- Humidity (%): 45-77
- Air flow: 300l/min (13.5 changes/min)
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 14.08.1989 to 08.09.1989
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: MMAD was 2.93 (±1.71) microns
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: The inhalation chambers used in the study were constructed of stainless steel with glass windows for animal observations, with a volume of approximately 1300 litres.
- Method of holding animals in test chamber: Free
- Source: No data
- Method of conditioning air: No data
- System of generating particulates/aerosols: A 2% TMSPGE-hydrolysate solution was prepared daily and was metered from a piston pump into an atomizer fitted with a liquid nozzle and an air nozzle.  The atomizer was inserted into the top of the inhalation chamber turret where the liquid aerosol was dispersed throughout the chamber by filtered chamber supply air.  The operating pressure of the atomizer used to generate the TMSPGE-hydrolysate was 20 psig.
- Temperature, humidity, pressure in air chamber: 18.5-19.9oC, 84.9-93.8%
- Air flow rate: 300 L/min
- Air change rate: 13.5/min
- Method of particle size determination: The particle size distribution was measured using a TSI Aerodynamic Particle Sizer and a 20:1 diluter.  These determinations were made once a day for the duration of the study.  The data collected were analysed by probit analysis to obtain the mass median aerodynamic diameter (MMAD) and the geometric standard deviation (sg).   
- Treatment of exhaust air: No data


TEST ATMOSPHERE
- Brief description of analytical method used: Chamber concentrations of TMSPGE-hydrolysate were determined by gravimetric methods. Four samples were obtained from the TMSPGE-hydrolysate aerosol exposure chamber each day.  The nominal concentration was calculated daily by dividing the total amount of material delivered to the chamber by the total airflow rate. 
- Samples taken from breathing zone: No data

      
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Chamber concentrations of TMSPGE-hydrolysate were determined by gravimetric methods. Four samples were obtained from the TMSPGE-hydrolysate aerosol exposure chamber each day.  The nominal concentration was calculated daily by dividing the total amount of material delivered to the chamber by the total airflow rate. 
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
Five days per week for three weeks followed by four days of exposure during the fourth week for a total of 19 exposures over a 4-week period
Dose / conc.:
119 mg/m³ air (analytical)
Dose / conc.:
150 mg/m³ air (nominal)
No. of animals per sex per dose:
15 males
Control animals:
yes
Details on study design:
- Dose selection rationale: No data
- Rationale for selecting satellite groups: Five of the 15 test and control animals were assigned to a satellite group for ultrastructural evaluation of the larynges. However, this was not performed.
- Post-exposure recovery period in satellite groups: None
Positive control:
None
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
The rats were observed daily during exposure and observations were recorded on a group basis. Preceding and following each exposure, observations were recorded for animals exhibiting overt clinical signs. At the time of body weight collection and just preceding necropsy, detailed observations were performed on all animals.  On non-exposure days, animals were observed once a day for overt clinical signs and mortality.


DETAILED CLINICAL OBSERVATIONS: No


BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were measured prior to initiation of the first exposure, weekly and immediately prior to sacrifice.  


FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No


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: No


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Males: days -4 and 11; females: days -5 and 10
- Dose groups that were examined: Control and test.


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
Ten animals of the test material hydrolysate treated and control groups were sacrificed on the day following the 19th exposure. A complete necropsy was performed on these animals and the following tissues were fixed in 10% neutral buffered formalin for histologic evaluation: gross lesions, larynx, lungs, trachea, nasal turbinates and kidneys. The remaining two rats from the control group were subjected to a complete necropsy and perfusion-fixed with 5% methanol-free EM grade formaldehyde.  The perfusion-fixation was performed to allow comparison of these control rats with rats from another silane group that was also perfusion-fixed.  The larynges from these two rats were then further immersion-fixed in 2% glutaraldehyde.  Other organs, including brain, spinal cord, and peripheral nerves, were taken from these control animals and processed for light microscopic evaluation.
Other examinations:
The satellite group (5 test material hydrolysate treated and 5 control animals) was sacrificed on the day following the 18th exposure. The larynges of three control animals and five test material hydrolysate treated animals were taken and immersion-fixed in 2% glutaraldehyde for possible electron microscopic examination. 
Statistics:
The data for continuous, parametric variables were intercompared for the exposure and control groups by use of Levene's test for homogeneity of variances and by t-tests. If Levene's test indicated homogeneous variances, the groups were compared by pooled variance t-tests.  If Levene's test indicated heterogeneous variances, the groups were compared by separate variance t-test. Frequency data were compared using Fisher's exact tests.  All statistical tests, except the frequency comparisons, were performed using BDMP Statistical Software (Dixon, 1985). The frequency data tests are described in Biometry (Sokal and Rohlf, 1969). The probability value of p < 0.05 (two-tailed) was used as the critical level of significance for all tests.
Clinical signs:
no effects observed
Description (incidence and severity):
No mortality or exposure-related clinical signs were observed during the study.
Mortality:
no mortality observed
Description (incidence):
No mortality or exposure-related clinical signs were observed during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Decreases in absolute body weight and/or body weight gain were observed for the test material hydrolysate treated animals during each week of the study.  At the end of the study the percent decrease in mean body weight of the test material hydrolysate exposed group compared to the control group was 11%. At the end of the study the percent decrease in mean body weight gain of the test material hydrolysate exposed group compared to the control group was 29%.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
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:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
No adverse findings.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No abnormal findings.
Histopathological findings: neoplastic:
not examined
Dose descriptor:
NOAEC
Basis for effect level:
other: No NOAEC was identified.
Remarks on result:
not determinable
Critical effects observed:
not specified

No NOAEC identified

Table 1 - Individual body weight (grams), males group for 0 mg/m3

  Week 0 Week 1 Week 2 Week 3 Week 4
Animal 1  114.4 123.2 151.8 178.2 199.5
Animal 2  123.7 134.7 165.3 193.4 213.2
Animal 3 119.5 130.3 158.6 186.8 208.3
Animal 4 123.7 136.9 167.0 194.3 -
Animal 5 125.8 136.0 160.0 184.3 200.2
Animal 6 121.7 129.8 151.7 169.7 188.9
Animal 7 127.5 136.5 163.2 183.7 -
Animal 8 130.1 140.8 164.9 188.6 200.8
Animal 9 137.3 148.6 179.8 207.3 -
Animal 10 132.7 141.1 165.1 106.3 -
Animal 11 138.7 145.0 179.2 208.1 228.4
Animal 12 132.8 140.9 163.9 186.4 211.5
Animal 13 141.4 154.2 190.5 219.5 -
Animal 14 143.9 158.0 195.8 225.9 247.4
Animal 15 153.9 104.8 200.1 231.0 253.4
           
Mean  131.1 141.4 170.5 196.2 215.1
St. dev. 10.5 11.2 15.1 18.1 21.4
M 15.0 15.0 15.0 15.0 10.0

Table 2 - Individual body weight (grams), males with 150 mg/m3

  Week 0 Week 1 Week 2 Week 3 Week 4
Animal 1  117.4 123.2 143.1 154.7 176.9
Animal 2  132.6 120.2 142.7 160.1 177.6
Animal 3 121.8 126.2 139.4 153 166.8
Animal 4 127.7 132.1 150.2 168.1 -
Animal 5 123.9 128.7 149.7 173.8 -
Animal 6 131.1 137.6 163.3 186.3 202.1
Animal 7 131.8 135.7 160.4 180.5 -
Animal 8 131.9 138.2 157.8 178.5 192.3
Animal 9 133.7 139.8 163.4 180 193.6
Animal 10 134.4 140.4 152..9 165.7 182.4
Animal 11 132.3 138.3 154.3 175.1 193.2
Animal 12 138.5 146.6 188.4 187.9 -
Animal 13 138.8 145.1 171.6 195.9 212.3
Animal 14 145 152.5 173.9 196 213.7
Animal 15 138.3 145.5 163.9 186.5 -
 
Mean  131.4 137.3 156.9 178.8 191.3
St. dev. 7.52 0.32 10.54 12.73 15.47
M 15 15 15 15 10

Please see attached documents for all gained result tables.

Conclusions:
In a four-week repeated inhalation study (reliability score 2) conducted using a protocol similar to OECD 412 (with restrictions) and GLP, rats were exposed to an aerosol of 3-glycidoxypropyltrimethoxysilane hydrolysate at a concentration of 119 mg/m3. Significant reductions in body weight gain were observed and therefore the NOAEC was <119 mg/m3. There was no evidence of laryngeal granuloma formation.
Executive summary:

In a four-week repeated inhalation study (reliability score 2) conducted using a protocol similar to OECD 412 (with restrictions) and GLP, rats were exposed to an aerosol of 3-glycidoxypropyltrimethoxysilane hydrolysate at a concentration of 119 mg/m3. Significant reductions in body weight gain were observed and therefore the NOAEC was <119 mg/m3. There was no evidence of laryngeal granuloma formation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEC
119 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

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

There are no sub-chronic repeated dose toxicity data for the registered substance, 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8). Therefore, data are read-across from the structural analogue, [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 10217-34-2).

The key 90-day repeated dose oral toxicity study with the analogue substance [2-(3,4-epoxycyclohexyl)ethyl]triethoxysilane (CAS 10217-34-2) was conducted according to OECD Test Guideline 408, and in compliance with GLP (NOTOX, 1998). The NOAEL was reported to be 1,000 mg/kg bw/day. Ten animals per sex were dosed with 0, 100, 500 and 1000 mg/kg bw/day. There were no test material related deaths, clinical findings or notable haematological changes. Slightly increased serum urea levels were recorded in males of the 1,000 mg/kg bw/day dose group at pre-test and after 13 weeks of treatment. There was no evidence of organ dysfunction in the organs examined. The only change noted below a dose of 1,000 mg/kg bw/day was an increase in partial thromboplastin time at 500 mg/kg/day, but in the absence of other relevant findings, a connection with treatment was considered to be unlikely (NOTOX, 1998).

The NOAEL for 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8) was reported to be =1000 mg/kg bw/day in rat in a good quality, 28-day repeated dose oral toxicity study conducted according to OECD Test Guideline 407 (Dow Corning Corporation, 1981). The restriction of the study was no post-exposure observation period. Ten animals per sex were dosed with 40, 400 and 1000 mg/kg bw/day. There were no test-substance related mortalities. One 40 mg/kg bw/day male and two 1000 mg/kg bw/day males died during the course of the study, which was reported to be due to dosing trauma. No effects on food consumption or body weights were reported. The haematological, blood biochemical or urinalysis parameters were all within normal range. No abnormal findings were made at necropsy and there were no test substance related effects on organ weights (Dow Corning Corporation, 1981).

The NOAEC for 3-(2,3-epoxypropoxy)propyltrimethoxysilane (CAS 2530-83-8) was reported to be 225 mg/m3 (aerosol) in rat in a good quality, 14-day repeated dose inhalation toxicity study conducted according to OECD Test Guideline 412 and in compliance to GLP (Dow Corning Corporation, 1982). The target concentrations aimed for were 0, 75, 225 and 750 mg/m3. Deaths occurred only at 750 mg/m3 (5 males and one female), with no concomitant acute tissue toxicity. The animals are reported to have succumbed to inanition (exhaustion due to lack of nutrition). Nasal discharge, dry and moist rales and body weight depression were reported in a dose response pattern. The body weight depression was evident only at high dose. No histopathological evidence of a systemic or localized respiratory tract effect was evident in response to treatment. No post-exposure period was included in the study, instead the rats were necropsied on the day after the end of exposure (Dow Corning Corporation, 1982).

In a 28-day repeated dose inhalation toxicity study with the hydrolysis product of 3-(2,3-epoxypropoxy)propyltrimethoxysilane, reported as

3-glycidoxypropyltrimethoxysilane hydrolysate (no CAS available) the NOAEC was reported to be <119 mg/m3. The study was conducted using a protocol similar to OECD Test Guideline 412 and in compliance with GLP (BRRC, 1991). Fifteen male rats were exposed to an aerosol of 3-glycidoxypropyltrimethoxysilane hydrolysate (no CAS available) at a concentration of 119 mg/m3, with significant reductions in body weight gain and the resultant extrapolation of a NOAEC of <119 mg/m3. The restrictions of the study were only one dose and males were tested, and the performance of limited examinations, i.e. no haematology, biochemistry or urinalysis. The study was performed primarily to investigate effects on the larynx, with no evidence of laryngeal granuloma formation. The study was conducted according to an appropriate OECD test guideline with acceptable restrictions. The restrictions were that only one dose level and males were tested, and limited examinations were performed, i.e. no haematology, biochemistry or urinalysis. The study was performed primarily to investigate effects on the larynx.

Justification for classification or non-classification

Based on the available data, 3-(2,3-epoxypropoxy)propyltrimethoxysilane does not require classification for target organ toxicity following oral or inhalation exposure according to Regulation (EC) No 1272/2008.