Registration Dossier

Administrative data

Description of key information

Oral, subacute: OECD 422 in rats:

NOAEL = 150 mg/kg bw/day

There are no sub-chronic repeated dose toxicity data on triethoxy(methyl)silane available, therefore, a testing proposal for a subchronic toxicity study is submitted (OECD 408, oral, rat).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 Oct 2011 - 28 Mar 2012
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose:
reference to same study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
Dams with offspring and pups were terminated on Day 5 post-partum. Litter weights, anogenital distance and nipple retention were not measured. Thyroid hormones of pups were not assessed.
Qualifier:
according to
Guideline:
other: Circular on Test Methods of New Chemical Substances (Japan)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Keep the substance in cool and dark place; tightly closed, in refrigerator (1 - 10°C); fill nitrogen after opening of package.
- Solubility and stability under test conditions: The test substance is stable. The stability was confirmed at the end of exposure using IR spectroscopy.
- Stability of the test substance in the solvent/vehicle: The test substance was determined to be stable for 8 days in the refrigerator and 24 hours at room temperature.
Species:
rat
Strain:
other: Crl:CD (SD)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Atsugi, Japan
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 10 weeks
- Weight at study initiation: 371 - 432 g (males), 223 - 274 g (females)
- Housing: individual animal in cage in steel cages before mating. During mating: one female and one male were kept in the same metal cage. From Day 17 in gestation period to Day 4 in the lactation period: one dam and its pups were kept in the plastic cage with white wood chip as bedding.
- Diet: ad libitum
- Water: tap water ad libitum
- Acclimation period: 2 weeks

DETAILS OF FOOD AND WATER QUALITY:
- Diet: NMF food (Oriental Yeast Co., Ltd., Itabashi-ku, Japan) was provided ad libitum during the acclimation period and throughout the study. Food was removed afternoon/evening prior to necropsy.
- Water: tap water, the quality of water was analysed quarterly.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24
- Humidity (%): 40 - 56
- Air changes (per hr): 10 - 15 times
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 24 Oct to 19 Dec 2011
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Each dosing formulation was prepared every 8 days. The stability of the formulations was determined and concluded to be stable for 8 days in the refrigerator and 24 hours at room temperature. Dosing solutions were prepared by mixing the appropriate amount of the test item and corn oil in a tared container to yield the desired dose levels. Dosing formulations were administered by oral gavage with a flexible stomach tube. The test item was administered at a dose volume of 5 mL/kg bw and was calculated from the most recent body weight. Until administration, stock solution was stored in a dark bottle and in a refrigerator (4 - 8°C).

VEHICLE
- Justification for use and choice of vehicle (if other than water): In a preliminary test, GC and IR was used due to the physical and chemical properties of the test substance, to confirm that the test substance was stable in the corn oil.
- Amount of vehicle (if gavage): 5 mL/kg b.w.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analyses of the dosing formulations were conducted using GC to confirm the concentrations in all dose groups before and at the end of the administration period. The results of dose concentration analyses were determined to be 97.7 - 107.7%. These results were within the acceptable limits (100.0 ± 10.0% of nominal values).

Homogeneity of formulations was not determined.
Duration of treatment / exposure:
Males:
14 days before mating
14 days during mating
14 days after mating

Females:
14 days before mating
27 - 37 days during mating, gestation and lactation period

Males and females of recovery groups:
42 days administration and 14 days post-exposure recovery period
Frequency of treatment:
once daily, 7 days/week
Dose / conc.:
30 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
750 mg/kg bw/day (nominal)
No. of animals per sex per dose:
Male treatment group:
7 (control and 750 mg/kg bw/day)
12 (30 and 150 mg/kg bw/day)

Male recovery group:
5 (control and 750 mg/kg bw/day)

Female
12 (treatment group)
10 (recovery group)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: dose levels were based on the results of a dose range-finding study, in which animals were orally exposed to 250, 500 and 1000 mg/kg bw/day for 14 days. No deaths occurred in all groups and effects on general clinical signs and body weight were not observed. Males in the 1000 mg/kg bw/day treatment group showed slightly decreased food consumption at the beginning of the study, decreased red blood cell concentration, haemoglobin and haematocrit, increased platelet and total protein, increased liver and thyroid weight and decreased testis weight. Males in 500 mg/kg bw/day showed increased total protein and liver weight. Male in the 250 mg/kg bw/day treatment group showed increased liver weight. Females in the 1000 mg/kg bw/day treatment group showed decreased food consumption during the administration period, increased total protein, increased liver, thyroid and ovary weight. Therefore, 30, 150 and 750 mg/kg bw/day were selected as the dose levels for the main study.
- Post-exposure recovery period in satellite groups: 14 days
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: three times a day

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Males in the treatment and recovery groups and females in the recovery group were obsereved once prior to exposure, once a week during the administration period and recovery period.
Parental females were observed once prior to exposure, once a week during mating period, on gestation days (GD) 1, 7, 14, and 20, and on Day 4 post-partum.

BODY WEIGHT: Yes
- Time schedule for examinations: Males in the treatment and recovery groups and females in the recovery group were weighed on Day 1, 8, 15, 22, 29, 36 and 42 during administration period, on Day 1, 8 and 14 during recovery period, and before termination.
Parental females were weighed on Day 1, 8 and 15 during administration period (non-pregnant animals on Day 22), on GD 0, 7, 14 and 20, on Day 0 and 4 post-partum, and before termination.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal was determined and the mean daily diet consumption was calculated as g food/kg body weight/day: No
- Compound intake was calculated as time-weighted averages from the consumption and body weight gain data: No

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

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination
- Anaesthetic used for blood collection: Yes (isofulfuran)
- Animals fasted: Yes, between 16 to 21 hours before termination
- How many animals: all animals

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination
- Animals fasted: Yes between 16 to 21 hours before termination
- How many animals: all animals

URINALYSIS: Yes
- Time schedule for collection of urine: 24-hour urine was collected on Day 36 and 37 of the administration period for treatment groups, and during Day 8 and Day 9 in recovery period
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Animals were fasted for the first 4 hours. The 4-hour fasted urine samples were obtained and analysed for pH, protein, ketone body, glucose, occult blood, bilirubin, urobilinogen, color, and urine sediment. Urine samples of 20-hour were analysed for osmotic pressure, sodium, potassium and chloride.

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations:
Males in the treatment and recovery groups and females in the recovery group were obsereved once prior to exposure, once a week during the administration and recovery period
Parental females were observed once prior to exposure, once a week during mating period, on GD 1, 7, 14, and 20, and on Day 4 post-partum.
- Dose groups that were examined: 30, 150 and 750 mg/kg bw/day
- Battery of functions tested: Auditory response, approach response, touch response, pupillary reflex, aerial righting reflex, and landing foot splay

IMMUNOLOGY: No

OTHER:
Blood hormone measuring for T3, T4 and TSH at termination. Blood samples taken for clinical chemistry investigations were used to analyze hormone values.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
Brain, pituitary, thyroid, thymus, heart, liver ,spleen, kidney, adrenal, seminal vesicle, prostate, testis, epididymis, ovary, uterus

HISTOPATHOLOGY: Yes
Adrenal, bone, bone marrow, femoral, cerebellum (pons), cerebrum, epididymis, eye, heart, duodenum, jejunum, ileum (Peyer's patch), cecum, colon, rectum, kidney, mesenteric and submandibular lymph nodes, liver, parathyroid, pancreas, pituitary, salivary gland submandibular, sciatic nerve, spleen, stomach, skeletal muscle, femoral, seminal vesicle (coagulating gland), spinal cord, thoracic, testis, thymus, trachea, thyroid, urinary bladder, ovary, uterus, vagina
Statistics:
Barlett test, Dunnett's test, Steel test, F test, Student's t test, Aspin-Welch's t test, Fischer's test
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One male in the 750 mg/kg bw/day treatment group died on Day 12 of administration. Before death, the male showed reddish urine and smudge of lower abdomen on Day 10, decreased spontaneous movement on Day 11, and prone/lateral position and pale skin on Day 12. Reddish urine was also observed in one male in the 750 mg/kg bw/day treatment group on Week 1, 2 and 3.
One female in the 150 mg/kg bw/day treatment group died on Day 1 of the lactation period. However, there was no abnormal general condition reported.
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Treatment groups:
One male in the 750 mg/kg bw/day treatment group died on Day 12 of administration.
One female in the 150 mg/kg bw/day treatment group died on Day 1 post-partum.
All animals in the recovery groups survived the duration of the study.
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1) At the end of administration period
Males in the 750 mg/kg bw/day treatment group showed increased platelet numbers and fibrinogen value and prolonged prothrombin time and activated partial thromboplastin time (APTT). The mode of action is not clear but this could have been caused by the test substance.
Females in the 750 mg/kg bw/day treatment group showed prolonged APTT, decreased relative and absolute neutrophil counts, and increased relative lymphocyte and eosinophil counts. All forementioned changes were considered to be incidental as only a slight change was observed.
Females in the 750 mg/kg bw/day recovery group showed prolonged PT and APTT and increased MCV. Although the relative neutrophil counts were decreased, the absolute counts were not changed. This change was considered to be incidental.
No changes were found in 30 and 150 mg/kg bw/day treatment group in comparison with the control group.
2) At the end of the recovery period
Males in the 750 mg/kg bw/day recovery group showed increased platelet. No changes were observed in females after recovery period in comparison with the control group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1) At the end of the administration period
Males in the 750 mg/kg bw/day treatment group showed increased γ-GTP, decreased total bilirubin, decreased potassium, increased calcium, increased total protein, and decreased A/G ratio. Decreased AST was not considered as a toxicological effect. Total bilirubin was also decreased in males in the 150 mg/kg bw/day treatment group.
Females in the 750 mg/kg bw/day treatment group showed increased γ-GTP, decreased total bilirubin, increased BUN and decreased A/G ratio.
Females in the 750 mg/kg bw/day recovery group showed increased γ-GTP, increased total protein, and decreased A/G ratio. Decreased AST was not considered as a toxicological effect.
No significant changes in clinical biochemistry parameters were observed in the 30 and 150 mg/kg bw/day treatment group compared to the control group.
2) At the end of the recovery period
Males in the 750 mg/kg bw/day recovery group showed decreased total bilirubin. Slight increased albumin was considered as a physiological variation because this change was not observed at the end of the administration period.
Females in the 750 mg/kg bw/day recovery group did not show the any differences when compared with the control group.
Urinalysis findings:
effects observed, non-treatment-related
Description (incidence and severity):
1) At the end of administration period
Yellow urine was observed in 5 males and 3 females in the 750 mg/kg bw/day treatment group. Increased urine volume and decreased osmotic pressure were observed in males in the 150 mg/kg bw/day treatment group. These changes were not dose-depending.
2) At the end of the recovery period
Potassium value was increased in males in the 750 mg/kg bw/day treatment group. This change was regarded to be incidental because it was a slight change and no abnormality was found at the end of the administration.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
1) During administration
Hearing was decreased in the 30 mg/kg bw/day treatment group on week 6 of administration. However, this change was not dose-depending. Since the dead male animal in the 750 mg/kg treatment group was not able to walk on Day 11 of administration, detailed clinical signs were not tested.
Females in the 750 mg/kg bw/day recovery group showed also decreased hearing in Week 1 of administration. This was regarded to be incidental because no changes were found afterward in this group and in females in the treatment group at the same time.

2) During recovery period
The increased hearing in females in the 750 mg/kg bw/day recovery group in Week 1 of recovery period was also regarded to be incidental because no change was observed at other time point and general condition was not abnormal.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
1) At the end of the administration period
Relative and absolute thyroid and liver weight was increased in male and female rats in the 750 mg/kg bw/day treatment group.
Males in the 30 mg/kg bw/day treatment group showed decreased relative and absolute thymus weight and increased absolute heart weight. Males in the 150 mg/kg bw/day treatment group showed decreased relative thymus weight. But these changes were not dose-dependent. Although the relative kidney weight was increased in females in the 750 mg bw/day treatment group, this was regarded to be incidental due to the lack of dose-dependency. Females in the 750 mg/kg bw/day recovery group showed the increased absolute heart weight. This change was also considered to be incidental because the relative weight was not changed.

2) At the end of the recovery period
Males in the 750 mg/kg bw/day recovery group showed increased absolute and relative thyroid and liver weight.
No changes were observed in females of 750 mg/kg bw/day recovery group in comparison with the control group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1) Dead animals
One male in the 750 mg/kg bw/day treatment group showed pale discoloration of skin and all tissues, smudge of lower abdominal fur, enlargement of and dark red foci in the kidney, enlargement of and dark coloration in the liver, dark coloration in the prostate, small thymus, and large urinary bladder. One female in the 150 mg/kg bw/day treatment group showed dark red foci in the kidney and in the forestomach.
2) At the end of the administration period
One male (1/6) in the 750 mg/kg bw/day treatment group showed the enlargement of the kidney. Other slight changes were considered to be incidental.
3) At the end of the recovery period
No changes caused by the test substance were observed in all animals. Other slight changes were considered as incidental.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Exposure of the test material to male and female rats resulted in effects being observed in the following organs: kidney, urinary bladder, liver, and thyroid. In the kidney, there were minimal tubular regeneration (4/6 males in the 750 mg/kg bw/day treatment group), eosinophilic body found in tubular cell (minimal 3/6, mild 1/6 males in the 750 mg/kg bw/day treatment group) and minimal transitional hyperplasia/hypertrophy observed (1/6 males in the 750 mg/kg bw/day treatment group). In the urinary bladder, there was transitional hyperplasia/hypertrophy seen (minimal 2/6 and moderate 1/6 males in the 750 mg/kg bw/day treatment group, minimal 3/12 females in the 750 mg/kg bw/day treatment group). The observed transitional hyperplasia/hypertrophy in male rats in the 30 mg/kg bw/day treatment group was concluded to be not treatment-related effects but instead caused by incidental inflammation of the urinary bladder. In the liver, there was centrilobular hepatocytic hypertrophy observed (minimal 3/6 males in the 750 mg/kg bw/day treatment group, minimal 9/11 and mild 2/12 females in the 750 mg/kg bw/day treatment group, minimal 4/9 females in the 150 mg/kg bw/day treatment group, and minimal 4/6 and mild 1/6 females in the 750 mg/kg bw/day recovery group). In the thyroids, there was hypertrophy in follicular cell (minimal 2/12 males in the 150 mg/kg bw/day treatment group, mild 6/6 males in the 750 mg/kg bw/day treatment group, minimal 10/12 and mild 1/12 females in the 750 mg/kg bw/day treatment group, and minimal 1/5 and mild 4/5 females in the 750 mg/kg bw/day recovery group). The effect observed in the liver is concluded to be associated with induction of drug metabolising enzyme. It is well known that a substance which induces drug metabolising enzyme also promotes metabolism of thyroid hormone and causes hypertrophy of follicular cell through the hypothalamus-hypophysis system as a secondary effect. Effects observed in the transitional epithelium of the kidneys were also noted in the urinary bladder. The mode of action causing this effect was not clear according to this test result. However, the effects on the transitional epithelium in the kidneys and urinary bladder were reversed by the end of the recovery period; these effects were therefore concluded to be reversible.
Histopathological findings: neoplastic:
no effects observed
Details on results:
BODY WEIGHT
There were no statistically significant differences in the mean body weights between controls and test groups.

FOOD CONSUMPTION
There were no statistically significant differences in the mean amount of food consumption between controls and test groups.

HAEMATOLOGY
Decreased ratio and number of neutrophil count in females in the 750 mg/kg bw/day treatment group and decreased ratio of neutrophil count in females in the 750 mg/kg bw/day recovery group was considered to be the toxicological effect of the test substance, but the mode of action is not clear. Increased platelet and fibrinogen, prolonged pro-thrombin time and APTT in males in the 750 mg/kg bw/day treatment group and prolonged pro-thrombin time and APTT in females in the 750 mg/kg bw/day treatment group were also considered as treatment-related effects.

CLINICAL CHEMISTRY
Decreased potassium levels was considered to be in the physiological range as changes in urine volume and diarrhea were not observed. BUN was also not considered to be treatment-related because no impairment was found in the kidneys. Increased total protein was correlated to induction of drug metabolising enzyme in theliver. Increased calcium levels was regarded as a secondary effect of increased total protein, but the mode of action was not clear. Due to the lack of impairment in the livers, increased gamma GTP was considered to be not toxicological significant. Changes in the total bilirubin levels was also considered to be not toxicological significant, because these changes were only slight.

URIANALYST
Yellow urine was considered to be a treatment related effect, because there were histopathological changes in the kidneys and bladder.

ORGAN WEIGHTS
There were statistically significant differences observed in absolute organ weights in males compared to controls. Thyroids (increase at 750 mg/kg bw/day treatment group), thymus (decrease at 30 mg/kg bw/day treatment group), heart (increase at 30 mg/kg bw/day treatment group), and liver (increase at 750 mg/kg bw/day treatment group).
There were statistically significant differences in the mean percentage of organ weights relative to body weights for males: thyroids (increase at 750 mg/kg bw/day treatment group), thymus (decrease at 30 and 150 mg/kg bw/day treatment group), and liver (increase at 750 mg/kg bw/day treatment group).
There were statistically significant differences noted for absolute organ weights in females compared to controls; thyroids (increase at treatment and recovery 750 mg/kg bw/day group), heart (increase at 750 mg/kg bw/day recovery group), and liver (increase at 750 mg/kg bw/day treatment and recovery groups).
There were statistically significant differences for the mean percentage of organ weights relative to body weights for thyroids (increase at 750 mg/kg bw/day treatment and recovery groups), liver (increase at 750 mg/kg bw/day treatment and recovery groups), and kidneys (increase at 750 mg/kg bw/day treatment group) in females.
However, the changes were reversed by the end of the recovery period. These effects could be considered to be reversible.

GROSS PATHOLOGY
Effects attributable to test article administration in males occurred in the liver, kidney, prostate, thymus, bladder, and skin. In females test material-related effects were observed in the kidney and forestomach.

HISTOPATHOLOGY: NON-NEOPLASTIC
Exposure of the rats (male and female) to the test material resulted in effects being observed in the following organs: kidney, urinary bladder, liver, and thyroid. In the kidney, there were minimal tubular regeneration (4/6 males in the 750 mg/kg bw/day treatment group), eosinophilic body found in tubular cell (minimal 3/6, mild 1/6 males in the 750 mg/kg bw/day treatment group) and minimal transitional hyperplasia/hypertrophy observed (1/6 males in the 750 mg/kg bw/day treatment group). In the urinary bladder, there was transitional hyperplasia/hypertrophy seen (minimal 2/6 and moderate 1/6 males in the 750 mg/kg bw/day treatment group, 3/12 females in the 750 mg/kg bw/day treatment group). The observed transitional hyperplasia/hypertrophy in male rats in the 30 mg/kg bw/day treatment group was concluded not to be a treatment-related effects but instead caused by incidental inflammation of the urinary bladder. In the liver, there was centrilobular hepatocytic hypertrophy observed (minimal 3/6 males in the 750 mg/kg bw/day treatment group, minimal 9/11 and mild 2/12 females in the 750 mg/kg bw/day treatment group, minimal 4/9 females in the 150 mg/kg bw/day treatment group, and minimal 4/6 and mild 1/6 females in the 750 mg/kg bw/day recovery group). In the thyroids, there was hypertrophy in follicular cell (minimal 2/12 males in the 150 mg/kg bw/day treatment group, mild 6/6 males in the 750 mg/kg bw/day treatment group, minimal 10/12 and mild 1/12 females in the 750 mg/kg bw/day treatment group, and minimal 1/5 and mild 4/5 females in the 750 mg/kg bw/day recovery group). The effect observed in the liver is concluded to be associated with induction of drug metabolising enzyme. It is well known that a substance which induces drug metabolising enzyme also promotes metabolism of thyroid hormone and causes hypertrophy of follicular cell through the hypothalamus-hypophysis system as a secondary effect. Effects observed in the transitional epithelium of the kidneys were also noted in the urinary bladder. The mode of action causing this effect was not clear according to this test result. However, the effects on the transitional epithelium in the kidneys and urinary bladder were reversed by the end of the recovery period; these effects were therefore concluded to be reversible.

HORMONE VALUES:
In the 750 mg/kg bw/day treatment group, males showed increased TSH. Decreased T4 and increased TSH were observed in females in the 750 mg/kg bw/day treatment and recovery groups, respectively. These changes were considered to be caused by induction of drug metabolism system in the liver. However, the direct effect of the test item on the thyroids is not clear.
Dose descriptor:
NOAEL
Effect level:
150 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: based on transitional epithelial cell hyperplasia in the kidney and urinary bladder of male rats and transitional epithelial cell hyperplasia in the urinary bladder in female rats observed in the 750 mg/kg bw dose group.
Critical effects observed:
not specified

Table 1. Haematology

Dose

mg/kg

No.

 

Male (end of administration)

Male (end of recovery)

 

 

 

Platelet

X10000/µL

PT

s

APTT

s

Fibrinogen

mg/dL

Platelet

X10000/µL

0

7

Mean

S.D.

97.0

7.4

15.7

2.4

24.5

4.5

276

43

111.5

4.6

30

5

Mean

S.D.

95.4

12.5

15.2

2.8

23.9

2.6

279

33

-

150

5

Mean

S.D.

105.7

7.6

15.6

2.1

23.4

2.2

283

20

-

750

6

5 a)

Mean

S.D.

121.4**

19.1 D

31.1**

9.1 ST

45.4**

9.9 ST

362**

62 D

129.2**

4.8 T

 

 

 

Female (lactation day 5)

 

 

 

APTT

S

Differential leukocyte counts (%)

Lymph.

Differential leukocyte counts (%)

Neut.

Differential leukocyte counts (%)

Eosino.

Differential leukocyte counts (100/µL)

Neut.

0

12

Mean

S.D.

16.0

2.1

57.9

5.7

38.5

5.5

0.5

0.3

42.1

7.9

30

5

Mean

S.D.

15.6

1.5

58.5

8.0

38.1

7.8

0.7

0.4

44.7

9.9

150

5

Mean

S.D.

16.5

2.5

63.3

4.0

33.0

4.7

0.7

0.2

33.4

6.9

750

12

Mean

S.D.

19.8**

2.4 D

65.9*

9.2 D

30.1

9.4 D

0.9**

0.4D

29.3*

12.8

 

 

 

Female satellite group (end of administration)

 

 

 

MCV

fL

PT

s

APTT

s

Differential leukocyte counts (%)

Neut.

0

5

Mean

S.D.

48.8

1.0

12.2

0.6

17.5

3.5

20.5

2.7

750

5

Mean

S.D.

50.3*

0.8 T

13.8*

1.1 T

25.8*

4.7

14.8*

4.0 T

*: p<0.05; **: p<0.01

D: Dunnett’s test, ST: Steel’s test, T: Student’s t-test,

a)     Number of animals was 5 at the end of recovery

Table 2 Clinical chemistry

Dose

mg/kg

No.

 

Male (end of administration)

 

 

 

AST (GOT)

IU/L

γ-GTP

IU/L

T. bilirubin

mg/dL

K

mmol/L

Ca

mg/L

TP

g/dL

A/G

0

7

Mean

S.D.

74

16

1

1

0.1

0.0

4.6

0.3

9.4

0.4

5.6

0.3

1.24

0.10

30

5

Mean

S.D.

59

2

1

0

0.1

0.0

4.5

0.2

9.4

0.3

5.6

0.2

1.19

0.10

150

5

Mean

S.D.

64

11

1

0

0.0*

0.0 ST

4.7

0.3

9.5

0.3

5.8

0.2

1.18

0.15

750

6

Mean

S.D.

52*

6 ST

2*

1 D

0.0**

0.0 ST

4.2*

0.2 D

10.0*

0.3 D

6.0*

0.2 D

1.06*

0.10 D

 

 

 

Female (lactation day 5)

 

 

 

γ-GTP

IU/L

T. bilirubin

mg/dL

BUN

mg/dL

A/G

0

12

Mean

S.D.

1

1

0.1

0.1

12

2

1.25

0.06

30

5

Mean

S.D.

1

0

0.1

0.1

13

1

1.28

0.12

150

5

Mean

S.D.

1

1

0.1

0.1

12

3

1.26

0.18

750

12

Mean

S.D.

3**

1 ST

0.0*

0.0 ST

17**

3 D

1.12**

0.07 D

 

 

 

Female (Satellite, end of administration)

 

 

 

γ-GTP

IU/L

ALP

IU/L

TP

g/dL

A/G

0

5

Mean

S.D.

1

0

203

33

6.3

0.3

1.40

0.15

750

5

Mean

S.D.

2**

1 T

156*

27 T

6.8*

0.3 T

1.19*

0.08 T

 

 

 

Male (end of recovery)

 

 

 

T. bilirubin

mg/dL

Albumin

g/dL

0

5

Mean

S.D.

0.1

0.0

3.0

0.1

750

5

Mean

S.D.

0.0**

0.0 T

3.2 **

0.1 T

*: p<0.05; **: p<0.01

D: Dunnett’s test, ST: Steel’s test, T: Student’s t-test,

 

Table 3. Hormone

Dose mg/kg

 

Male (end of administration)

Female (lactation day 5)

Female (satellite, end of administration)

Male (end of recovery)

 

 

No.

TSH

ng/mL

No.

T4

µg/dL

No.

TSH

ng/mL

No

T4

µg/dL

0

Mean

S.D.

7

5.61

4.62

12

3.6

1.1

5

3.10

2.13

5

4.0

1.0

30

Mean

S.D.

5

4.04

2.13

5

3.1

0.8

-

-

-

-

150

Mean

S.D.

5

10.62

10.55

5

2.8

0.9

-

-

-

-

750

Mean

S.D.

6

17.03*

14.39 ST

12

2.6*

0.8 D

5

8.32*

3.68 T

5

5.7 *

1.0 T

*: p<0.05

-: not performed

D: Dunnett’s test, ST: Steel’s test, T: Student’s t-test,

 

Table 4. Organ weight

Dose

 

Male (end of administration)

mg/kg

 

Thyroid (R+L)

Thymus

Heart

Liver

 

 

Absolute

mg

Relative

mg/100 g BW

Absolute

mg

Relative

mg/100 g BW

Absolute

mg

Absolute

mg

Relative

mg/100 g BW

0

No.

Mean

S.D.

7

24.2

3.1

7

4.9

0.7

7

341

100

7

67

12

7

1.36

0.14

7

12.81

2.19

7

2.56

0.18

30

No.

Mean

S.D.

12

22.9

3.7

12

4.6

0.7

12

251*

68 D

12

50*

13 D

12

1.50*

0.12 D

12

13.22

1.59

12

2.62

0.19

150

No.

Mean

S.D.

12

23.6

3.8

12

4.6

0.7

12

267

74

12

52*

13 D

12

1.46

0.10

12

13.97

1.29

12

2.72

0.15

750

No.

Mean

S.D.

6

30.5*

6.5 D

6

6.1*

1.3 D

6

296

53

6

60

10

6

1.38

0.04

6

18.53**

0.87 D

6

3.73**

0.26 D

 

 

Female (lactation day 5)

 

 

Thyroid (R+L)

Liver

Kidney (R+L)

 

 

Absolute

mg

Relative

mg/100 g BW

Absolute

mg

Relative

mg/100 g BW

Relative

mg/100 g BW

0

No.

Mean

S.D.

12

15.8

2.8

12

5.2

0.9

12

9.84

0.92

12

3.25

0.27

12

0.64

0.05

30

No.

Mean

S.D.

12

16.6

2.6

12

5.3

0.9

12

10.23

0.49

12

3.26

0.17

12

0.68

0.04

150

No.

Mean

S.D.

9

16.5

2.8

9

5.3

0.9

9

10.46

1.76

9

3.32

0.31

9

0.66

0.06

750

No.

Mean

S.D.

12

21.0**

3.1 D

12

6.9**

0.9 D

12

12.66**

1.09 ST

12

4.13**

0.24 D

12

0.70*

0.07 D

 

 

Female (Satellite group, end of administration)

 

 

Thyroid (R+L)

Heart

Liver

 

 

Absolute

mg

Relative

mg/100 g BW

Absolute

mg

Absolute

mg

Relative

mg/100 g BW

0

No.

Mean

S.D.

5

13.4

1.5

5

5.0

0.6

5

0.87

0.05

5

7.05

0.67

5

2.60

0.14

750

No.

Mean

S.D.

5

19.9**

1.9 T

5

7.3**

1.1 T

5

0.98**

0.03 T

5

11.36**

1.48 T

5

4.10**

0.27 T

 

 

Male (end of recovery)

 

 

 

Thyroid (R+L)

 

 

 

Absolute

mg

Relative

mg/100 g BW

 

0

No.

Mean

S.D.

5

21.0

2.7

5

4.0

0.5

 

750

No.

Mean

S.D.

5

28.3**

4.0 T

5

5.4*

0.8 T

 

Conclusions:
Based on the results of this study, the NOAEL for systemic toxicity was determined to be 150 mg/kg bw/day based on transitional epithelial cell hyperplasia in the kidney and urinary bladder of male rats and transitional epithelial cell hyperplasia in the urinary bladder in female rats observed in the 750 mg/kg bw dose group.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
150 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The study was conducted in accordance with an appropriate OECD test guideline with acceptable restrictions and in compliance with GLP and is therefore considered to be reliability 2.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no 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

Studies were chosen as key when the available study was of relevance and sufficient quality for classification, labelling and risk assessment. No adequate information about specific organ toxicity after sub-chronic repeated exposure is available for triethoxy(methyl)silane (CAS 2031-67-6). In order to satisfy the requirements of REACH Annex IX, Column 1, 8.6.2 further data are necessary to fully cover this endpoint. A test proposal for a subchronic toxicity study (OECD 408, rat, oral route) is being submitted for triethoxy(methyl)silane (CAS 2031 -67 -6).  The study will be conducted after a decision on the requirement to carry out the proposed test has been taken in accordance with the procedure laid down in Regulation (EC) 1907/2006, and a deadline to submit the information required has been set by ECHA. Approximately 12 months will be needed to perform the study and finalise the study report.

To conduct a quantitative risk assessment, the sub-acute data on the registered substance triethoxy(methyl)silane (CAS 2031 -67 -6) was used as an interim measure.  

Sub-acute:

A key OECD 422 combined repeated dose/reproductive and developmental screening study is available by the oral route for triethoxy(methyl)silane. Male and female rats were treated with 30, 150 and 750 mg/kg bw/day of triethoxy)methyl)silane. Exposure to triethoxy(methyl)silane was associated with mortality of one male rat in the 750 mg/kg bw/day and one female rat in the 150 mg/kg bw/day dose groups, respectively. Histomorphological changes such as transitional epithelial cell hyperplasia in the kidney and urinary bladder of male rats and transitional epithelial cell hyperplasia in the urinary bladder in female rats were observed in the 750 mg/kg bw dose group. In the 150 mg/kg bw/day dose group, hypertrophy of follicular cell in the thyroid of male rats and centrilobular hepatocyte hypertrophy in female rats were considered as an adaptive response caused by induction of drug metabolising enzymes. Therefore, the NOAEL was determined to be 150 mg/kg bw/day and the LOAEL to be 750 mg/kg bw/day (METI, 2012). 

Justification for classification or non-classification

The available data on repeated dose toxicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 and are therefore conclusive but not sufficient for classification of the registered substance.