Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trimethoxyvinylsilane
EC Number:
220-449-8
EC Name:
Trimethoxyvinylsilane
Cas Number:
2768-02-7
Molecular formula:
C5H12O3Si
IUPAC Name:
trimethoxy(vinyl)silane
Test material form:
liquid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories Japan, Inc., Yokohama, Japan
- Age at study initiation: 9 weeks
- Weight at study initiation: males: 317 - 423 g, females: 250 - 277 g
- Fasting period before study: no fasting period
- Housing: individual in stainless steel cages
- Diet (e.g. ad libitum): CRF-1, pelleted, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 17 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 - 24 °C
- Humidity (%): 41 - 71%
- Air changes (per hr): 12
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared more than once a week. Concentration of stock solution was 200 mg/ml and stored at 4 °C in a refrigerator. The stock solution was diluted with corn oil to achieve the concentration of the dosing solutions.

VEHICLE
- Lot/batch no.: V3T0416 and V4K3008
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Concentration of dosing solution was verified by GC at the study initiation and at the end of the study. The range of concentration was acceptable because it was between 93.6 - 101.2%.
Duration of treatment / exposure:
Male: 14 days before mating, 28 days thereafter (42 days)
Females for repeated dose study: 42 days
Females in mating groups: 14 days before mating, during mating, during resulting pregnancies, 6 days during lactation (44 - 58 days)
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
62.5 mg/kg bw/day (nominal)
Dose / conc.:
250 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
(Males)
6 males/dose
for satellite group: 6 males/dose

(Females for satellite group)
Control, 250 mg/kg b.w., 1000 mg/kg b.w.: 6 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Dose levels were based on the results of a foregoing range finding study, in which animals were orally exposed to 0, 250, 500 and 1000 mg/kg bw/day (Hashima, year not available, 401223P). No mortality was observed in all groups. Reddish urine, decrease in food consumption and occult blood was observed in administered groups. Therefore, 62.5, 250 and 1000 were selected as the dose levels for the main study.

Post-exposure period: Yes, for a sub group of males and females for 14 days

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day during administration period, daily during recovery period, and once before necropsy

DETAILED CLINICAL OBSERVATIONS: Yes (including FOB)
- Time schedule: once before administration, Day 7, 14, 21, 28, 35 and 41 (males)
- Time schedule: once before administration, Day 8 and 15 of administration; Day 1, 8 and 15 of gestation; Day 3 of lactation
- Time schedule: once before administration, Day 8, 15, 22, 29, 36 and 42 (females for satellite group)

BODY WEIGHT: Yes
- Time schedule for examinations: twice a week
Males and satellite females: Day 1, 4, 8, 11, 15, 18, 22, 25, 29, 32, 36, 39 and 42 during administration period, Day 1, 4, 8, 11, 14 and 15 during recovery period
Pregnant females: Day 1, 4, 8, 11, 15 and 18, Day 0, 7, 11 and 21 during gestation, Day 0, 4, 6 and 7 during lactation

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: on day after last administration or after recovery period
- Anaesthetic used for blood collection: Yes (Pentobarbital-Na)
- Animals fasted: Yes
- How many animals: all administered animals
- Parameters checked: RBC, Haemoglobin, Haematocrit, MCV, MCH, MCHC, Platelets, Reticulocytes, PT, APTT, Fibrinogen, WBC, Differential leukocytes: Lymphocyte, Neutrophils, Eosinophils, Basophil, Monocyte

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: on day after last administration or after recovery period
- Animals fasted: Yes
- How many animals: all administered animals
- Parameters checked: AST, ALT, ALP, gamma-GTP, T-protein, Albumin, A/G, T-bilirubin, Urea nitrogen, Creatinine, Glucose, T-cholesterol, Triglycerides, Na, K, Cl, Ca, Inorganic-P

URINALYSIS: Yes
- Time schedule for collection of urine: on Day 2 and 37 in fasted males, Day 3 and 38 in non-fasted males, Day 2 during administration period and Day 5 of lactation in fasted females, Day 3 during administration period and Day 6 of lactation in non-fasted females, after recovery period in females
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes/No
- Parameters checked: Colour, pH, Protein, Glucose, Ketone body, Bilirubin, Occult blood, Urobilinogen, Urinary sediments, Epithelial cells, Erythrocytes, Leukocytes, Casts, Crystals
Sacrifice and pathology:
ORGAN WEIGHT: Yes: Brain, pituitary, thyroids, thymus, heart, liver, spleen, kidney, adrenals, testes, epididymides, ovaries, uterus, lung
GROSS PATHOLOGY: Yes: heart, lung, trachea, liver, pancreas, sublingual gland, submandibular gland, oesophagus, stomach, duodenum, jejunum, ileum, cecum, colon, rectum, thymus, spleen, submandibuar lymph node, mesentric lympha node, kidney, urinary bladder, testis, epididymis, seminal vesicle, prostate, ovary, uterus, pituitary, adrenal, thyroid, parathyroid, cerebrum, cerebellum, medulla oblongata, spinal code, sciatic nerve, eyeball, Harderian gland, bone (sternum or femur), and mammary gland
HISTOPATHOLOGY: Yes: heart, lung, trachea, liver, pancreas, sublingual gland, submandibular gland, oesophagus, stomach, duodenum, jejunum, ileum. cecum. colon, rectum, thymus, spleen, submandibuar lymph node, mesentric lympha node, kidney, urinary bladder, urethra, ovary, uterus, pituitary, adrenal, thyroid, parathyroid, cerebrum, cerebellum, medulla oblongata, spinal code, sciatic nerve, eyeball, Harderian gland, bone (sternum or femur), bone marrow (sternum or femur), and mammary gland
Statistics:
Bartlett test, Dunnett test, chi-square test, Cochran-Armitage test

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: mortality occurred
Transient salivation, soiled hair, a decrease in locomotor activity, reddish urine, hypothermia, perioral smudges, perianal soiling, diarrhoea, bradypnea, and piloerection were noted in the dying animals. Transient salivation, soiled hair and reddish urine were noted in the surviving males and females of the 1000 and 250 mg/kg groups.
Mortality:
mortality observed, treatment-related
Description (incidence):
1000 mg/kg bw/day: mortality occurred
Two males and 1 female from the 1000 mg/kg bw/day group died on Day 16 and 17 of males and Day 8 of female.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: reduced body weight
Low body weights were noted in males on Day 4 to 42 during administration period and Day 1 and 4 during recovery period. No changes were detected in females during administration period and recovery period.

Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was decreased on Day 2 in males of 62.5 and 250 mg/kg bw/day group and on Day 2, 5 and 9 of males in 1000 mg/kg bw/day. Males in 62.5 mg/kg bw/day group and 250 mg/kg bw/day group showed more food consumption on Day 9 and 5, respectively. Increased food consumption was also observed in males of 1000 mg/kg bw/day on Day 5, 9 and 12 in recovery period. These increase was not observed as a toxicity effect of the test item, since no change was observed in body weight.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: reduced Hb concentration
Decreased red blood cell counts, haemoglobin concentrations, hematocrit, MCV, and MCH and increased fibrinogen concentrations were noted in males of the 1000 mg/kg bw/day group after administration period. Prolonged APTT was observed in males of 62.5 mg/kg after recovery period. This change was no regarded as a tox effect of the test item due to lack of dose-responsibility. Red blood cell counts, haemoblobin, hematocrit were decreased and reticulocytes were increased in males administered with 1000 mg/kg bw/day. Besides, decreased fibrinogen were observed in 250 and 1000 mg/kg administered males. However, this change disappeared after recovery period. This change was not caused by the test item.

Lower hematocrit in females of the 1000 and 250 mg/kg bw/day groups, and decreased haemoglobin concentrations and prolonged APTT in females of the 1000 mg/kg bw/day group were also noted after administration period. Decreased MCV and MCH was detected in females of 250 mg/kg bw/day after recovery period. Decreased MCV, MCH, MCHC and RBC were also observed in females of 1000 mg/kg bw/day group.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: TP reduced in males/females
Increased CL was observed in males of 62.5 mg/kg bw/day after administration period. However, dose- responsibility was not noted. Low total protein, albumin, A/G ratios, and potassium, and high g-GTP, urea nitrogen, and creatinine were noted in males of the 1000 mg/kg bw/day group after administration period. The change of g-GTP was not caused by the test item because no changes of liver was detected by the histopathological findings. Lower AST was detected in males of 250 and 1000 mg/kg bw/day after administration period but this was not regarded as a tox effect of the test item.

Decreased total protein and increased A/G ratio was detected in males of 1000 mg/kg bw/day after recovery period. Increased chloride was noted in males of 1000 mg/kg bw/day after recovery period but this was not caused by the test item due to the range of background data (106.4 ± 1.9 mEq/l). Inorganic phosphate was increased in same group. This change was not considered as a tox effect of the test item, since this was not observed after administration period.

Low total protein and triglycerides in females of the 1000 mg/kg bw/day group were noted after administration period, and a tendency for high g-GTP in females of the 1000 and 250 mg/kg bw/day groups was observed. The decrease in t-bilirubin was not considered as a tox effect of the test item in females of 1000 mg/kg after administration period. Decreased in total protein was observed in females of 1000 mg/kg bw/day after recovery period. Increased ALP and Cl observed in females of 1000 mg/kg bw/day was not caused by the test item, since this data was similar to the background data of this test facility (ALP: 242.7 ± 1012.4 IU/l, Cl: 107.7 ± 2.1 mEq/l).
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: occurrence of blood and epithelial cells
Males on Day 2 before administration: increased volume and decreased specific gravity, occult blood positive, epithelial cells and erythrocytes were noted in 1000 mg/kg bw/day. 250 mg/kg bw/day groups showed occult blood and erythrocytes.
Females on Day 2 before administration: increased volume and decreased specific gravity, occult blood positive, erythrocytes and leukocytes were noted in 1000 mg/kg bw/day. 250 mg/kg bw/day groups showed occult blood and erythrocytes.
Males on Day 3 after administration: 250 mg/kg bw/day groups showed white turbidity, occult blood and erythrocytes. White turbidity, occult blood, erythrocytes and leukocytes were observed in 1000 mg/kg bw/day.
Females on Day 3 after administration: 250 mg/kg bw/day groups showed white turbidity, occult blood and erythrocytes. White turbidity, occult blood, erythrocytes and epithelial cells were observed in 1000 mg/kg bw/day.
Males on Day 37 before administration: Decreased specific gravity, occult blood, epithelial cells, erythrocytes and leucocytes were observed in 1000 mg/kg bw/day.
Females on last day before administration: Epithelial cells were observed in 250 mg/kg bw/day and erythrocytes and leucocytes were observed in 1000 mg/kg bw/day.
Males on Day 37 after administration: 250 mg/kg bw/day groups showed white turbidity, erythrocytes and leucocytes. White turbidity, occult blood, erythrocytes and leucocytes were observed in 1000 mg/kg bw/day.
Females on last day after administration: Leucocytes were found in 1000 mg/kg bw/day.
Males and females after recovery period: No changes were observed.
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
Salivation was observed in males and females of 1000 mg/kg bw/day after administration. Ease of removal from cage was decreased in 250 mg/kg bw/day but this was observed before administration. Salivation was observed in 1000 mg/kg bw/day. No changes were noted in both sexes regarding sensory response and grip strength. Increased spontaneous motor activity was noted in males 250 mg/kg bw/day but this was not regarded as a specific toxic effect due to lack of dose response. No change of spontaneous motor activity was reported in females.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
reduced thymus weight (females, all dose groups)
Body weight of males in 1000 mg/kg bw/day after administration period was increased. Decrease in absolute weight of thymus, increase in absolute weight of kidney, increase in relative weight of spleen, kidney and adrenals were observed in males of 1000 mg/kg bw/day after administration period. In same group, decrease in absolute weight of pituitary was also observed but this was not caused by the test item, since no change was detected in its relative weight. Absolute weight of brain was also increased. However, this change was not regarded as compound-related effect but caused by the difference of body weight.
No changes in body weight were detected in females after administration groups. Relative weight of thymus was decreased in females of 62.5 and 250 mg/kg. Decreased absolute weight of thymus, decreased relative weight of thymus and increased relative weight of liver were observed in females after administration period.
No changes of body weight was detected in males after recovery period. Decreased absolute weight of pituitary and increased relative weight of heart was observed in males in 62.5 mg/kg bw/day. However, these changes were not considered as a toxic effect of the test item, since there was no dose-response. Absolute weight of kidney was increased in males of 250 mg/kg bw/day but this was not caused by the test item due to lack of dose dependency. Relative weight of kidney was increased in males. Absolute weight of pituitary was also decreased. This was not caused by the test item because no change was detected in relative weight.
No changes of body weight were found in females after recovery period. Increased absolute and relative weight of uterus were observed in 250 and 1000 mg/kg bw/day after recovery period. However, these changes were not caused by the test item since no changes were observed after administration period. Furthermore, these data was similar to the background data of the test facility (absolute weight: 672 mg, relative weight: 229 mg (%)).
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
1000 mg/kg bw/day: kidney enlargement
Two dead male animals in 1000 mg/kg bw/day showed atrophy of thymus and spleen. One dead male animal in 1000 mg/kg bw/day showed enlargement of kidneys and dark read glandular mucosa were noted in males of the 1000 mg/kg bw/day group. Enlargement of kidney was observed in four males in 1000 mg/kg bw/day after administration period. Atrophy of spleen was observed in one male of control group after recovery period.
One dead female showed atrophy of thymus and spleen in 1000 mg/kg bw/day. One female in 1000 mg/kg bw/day showed the enlargement of kidney. This was related to hydronephrotic kidney which was observed by histopathological examination and accidentally occurred. No abnormalities were found in females after recovery period.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
250 mg/kg bw/day: hyperplasia (urinary bladder)
In dead males in 1000 mg/kg bw/day, two animals showed postmortal change in whole organs and tissues. One dead male showed vacuolization of lamina propria in jejunum, one male showed hyperplasia of transitional epithelium in kidney, two males showed slight hyperplasia of transitional epithelium in urinary bladder, two males showed hyperplasia of transitional epithelium in urethra, one animal showed atrophy of seminiferous tubule in testis and one animal showed cell debris in lumen in epididymis.

One death occurred in females in 1000 mg/kg bw/day. The dead animal showed moderate postmortal change in whole organs and tissues, slight cellular infiltration of heart, slight hyperplasia of transitional epithelium in kidney and slight hyperplasia of transitional epithelium in urinary bladder. However, these observed changes in dead males and female were not marked. Death was caused by deteriorating general conditions by the test substance.

Histopathological findings after administration and recovery phase are listed in Tables.

On histopathological examination, hyperplasia of transitional epithelium in the urinary bladder was noted in males at all doses. The effect seemed to be substance-related and followed a dose-response relationship. The incidence of hyperplasia in the 250 and 1000 mg/kg bw/day groups was statistically significantly increased up to the end of the recovery period, although a slight decrease (mild to slight) in severity was observed from end of administration period to the end of the recovery period. Hyperplasia that was observed in 2/6 male rats of the 62.5 mg/kg bw/day group after the administration period seemed to be treatment-related, as there were no incidences in the control group; hyperplasia was not observed in the urinary bladder of females in the 62.5 mg/kg bw/day group. In general, hyperplasia in the urinary tract/bladder is not a typical spontaneous lesion, but simple hyperplasia may also occur in untreated animals. Often it is a secondary effect provoked by inflammation or physical damage. The effects observed in males at 62.5 mg/kg bw/day were not evaluated as adverse, as the incidence was not increased statistically significantly and the severity of the effect was stated as "slight". In addition the effects were fully reversible within the recovery period.
Histopathological findings: neoplastic:
no effects observed

Effect levels

Dose descriptor:
NOAEL
Effect level:
62.5 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic

Target system / organ toxicity

Critical effects observed:
yes
Lowest effective dose / conc.:
250 mg/kg bw/day (actual dose received)
System:
urinary
Organ:
bladder
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

Table 1: Body weights of male and female rats of the administration and recovery period.

Group

Control

Test substance

mg/kg

0

62.5

250

1000

Number of males

12

12

12

12

Days of administration

 

 

 

 

1

399±13

399±15

400±15

400±15

11

430±16

417±14

420±23

392±27**

22

456±18

446±20

447±27

417±21**

32

491±21

481±21

479±26

440±22**

42

516±26

498±27

496±28

447±13**

 

 

 

 

 

Number of males

6

6

6

6

Days of recovery

 

 

 

 

1

518±29

511±34

508±25

449±16**

4

524±30

516±36

518±23

472±24*

8

531±30

527±38

528±22

489±26

14

542±32

536±38

541±26

511±35

 

 

 

 

 

 

 

 

 

 

Number of females

6

 

6

6

Days of administration

 

 

 

 

1

266±10

 

264±8

266±10

42

331±25

 

313±9

317±27

Number of females

6

 

6

6

Days of recovery

 

 

 

 

1

328±26

 

314±13

316±26

14

340±25

 

329±16

334±19

 

 

 

 

 

 

 

 

 

 

Significantly different from control group (*: p<0.05; **: p<0.01)

Table 2: Haematology results of male and female rats after the administration period.

Group

Control

Test substance

mg/kg

0

62.5

250

1000

Number of males

6

6

6

5

At termination of administration period

 

 

 

 

RBC (104/µl)

836±43

829±34

813±32

755±59*

HGB (g/dl)

15.4±0.9

15.3±0.6

14.9±0.5

13.3±1.1**

HCT (%)

45.5±2.4

45.4±1.8

44.2±2.0

39.5±3.6**

MCV (fl)

54.5±1.5

54.7±1.1

54.4±0.8

52.3±1.6*

MCH (pg)

18.4±0.6

18.5±0.4

18.4±0.2

17.7±0.4*

MCHC (g/dl)

33.9±0.4

33.7±0.4

33.8±0.5

33.7±0.4

PLT (104/µl)

94.1±9.3

92.6±2.3

96.1±14.1

95.1±9.2

RET (‰)

26±5

23±4

27±4

23±5

PT (sec.)

16.1±1.9

18.0±2.3

16.6±2.4

16.1±1.9

APTT (sec.)

22±1.4

23.5±2.0

21.1±2.1

21.8±2.0

Fbg (mg/dl)

210.6±10.5

223.2±13.3

210.8±17.8

263.4±8.4**

WBC (10²/µl)

72±18

55±5

68±18

102±35

 

 

 

 

 

Number of females

6

6

6

6

At termination of administration period

 

 

 

 

RBC (104/µl)

714±25

725±11

687±36

697±33

HGB (g/dl)

14.3±0.5

14.3±0.5

13.8±0.4

13.5±0.6*

HCT (%)

42.1±1.1

41.6±1.4

39.9±1.6*

39.5±1.5*

MCV (fl)

59±2.4

57.4±2.1

58.1±1.4

56.7±1.0

MCH (pg)

20.1±0.8

19.7±0.8

20±0.7

19.3±0.4

MCHC (g/dl)

34.1±0.4

34.3±0.2

34.5±0.5

34±0.6

PLT (104/µl)

103.3±6.0

101±7.5

105.8±8.5

95.2±15

RET (‰)

56±12

53±12

60±12

62±24

PT (sec.)

13.8±0.4

13.8±0.3

14.1±0.4

13.6±0.6

APTT (sec.)

17.3±0.8

18±0.6

18.4±1.1

18.8±0.7**

Fbg (mg/dl)

210.4±18.6

214.6±16.2

237.5±57.6

189.2±7.3

WBC (10²/µl)

52±15

52±6

53±18

48±9

Significantly different from control group (*: p<0.05; **: p<0.01)

Table 3: Organ weights of male and female rats after the administration period.

Group

Control

Test substance

mg/kg

0

62.5

250

1000

Number of males

6

6

6

5

At termination of administration period

 

 

 

 

Body weight (g)

496±24

474±13

469±33

422±18**

Brain (g)

2.08±0.08

2.11±0.09

2.08±0.07

2.07±0.05

(g%)

0.42±0.03

0.44±0.03

0.45±0.03

0.49±0.02**

Pituitary (mg)

13.9±0.7

14.3±1.4

13±0.7

11.8±1.2**

(mg%)

2.8±0.2

3±0.3

2.8±0.2

2.8±0.3

Thymus (mg)

287±43

241±43

323±41

189±38**

(mg%)

58±8

51±10

69±9

45±10

Spleen (mg)

777±99

752±115

723±136

832±136

(mg%)

156±16

159±25

154±23

196±25*

Kidney (g)

3.14±0.25

3.14±0.36

3.1±0.18

4.27±0.99*

(g%)

0.63±0.03

0.66±0.06

0.66±0.05

1.01±0.25**

Adrenals (mg)

55.4±7.7

60.3±7.4

60.6±4.4

61.1±4.9

(mg%)

11.2±1.6

12.7±1.5

13±1.3

14.5±1.7**

 

 

 

 

 

Number of females

12

11

11

10

Body weight (g)

302±17

312±18

311±19

286±19

Thymus (mg)

307±56

256±66

247±60

170±52**

(mg%)

103±22

82±19*

80±21*

59±16**

Liver (g)

9.48±0.78

10.01±0.65

10.11±0.99

9.86±0.87

(g%)

3.14±0.17

3.21±0.16

3.25±0.19

3.44±0.19**

Significantly different from control group (*: p<0.05; **: p<0.01)


 

Table 4: Organ weights of male and female rats after the recovery period.

Group

Control

Test substance

mg/kg

0

62.5

250

1000

Number of males

6

6

6

5

At termination of recovery period

 

 

 

 

Body weight (g)

519±29

513±36

514±23

483±33

Pituitary (mg)

17.3±1.1

15±1.3*

16.1±2.3

14.9±1*

(mg%)

3.3±0.2

2.9±0.4

3.1±0.5

3.1±0.2

Heart (g)

1.46±0.14

1.61±0.14

1.49±0.08

1.48±0.07

(g%)

0.28±0.02

0.31±0.02*

0.29±0.02

0.31±0.02

Kidney (g)

3.08±0.13

3.33±0.18

3.36±0.25*

3.28±0.13

(g%)

0.6±0.04

0.65±0.05

0.65±0.03

0.68±0.04**

 

 

 

 

 

Number of females

6

0

6

6

Body weight (g)

319±22

 

309±13

311±18

Uterus (mg)

543±32

 

753±186*

734±97*

(mg%)

171±17

 

243±54**

236±30*

Significantly different from control group (*: p<0.05; **: p<0.01)

 

Table 5: Histopathological findings of male and female rats after the administration and recovery period.

Group

Control

Test substance

mg/kg

0

62.5

250

1000

Number of males

6

6

6

5

After administration period/recovery period

 

 

 

 

Duodenum, vacuolization, lamina propria

0/0

0/0

1 (slight)/ 1 (slight)

3 (slight)*/2 (slight-mild)

Ileum, vacuolization, lamina propria

0/0

0/0

1 (slight)/0

5 (mild)**/ 5 (mild)**

Mesenteric lymph node, vacuolization simus

0/0

0/0

0/0

2 (slight)/4 (slight)**

Kidney, hyperplasia, transitional epithelium

0/0

0/0

0

5 (mild)**

Pyelonephritis

0/0

0/0

0

5 (mild-moderate)**

Regeneration, urinary tubule

0/0

1 (slight)/0

0/0

0/5 (slight-mild)**

Urinary bladder, hyperplasia, transitional epithelium

0/0

2 (slight)/0

6 (slight-mild)**/ 5 (slight)**

5 (mild)**/ 5 (slight)**

Urethra, hyperplasia, transitional epithelium

0/0

0/0

0/0

4 (slight-mild)**/0

 

 

 

 

 

Number of females

6

6

6

6

Duodenum, vacuolization, lamina propria

0/0

0/-

1 (slight)/0

2 (slight-mild)/5 (slight)**

Jejunum, vacuolization, lamina propria

0/0

0/-

0/0

6 (mild)**/ 6 (mild)**

Mesenteric lymph node, vacuolization simus

0/0

0/-

0/0

3 (slight-mild)*/ 3 (slight)*

Kidney, hyperplasia, transitional epithelium

0/0

0/-

0/0

3 (slight-mild)*/ 3 (slight)*

Regeneration, urinary tubule

0/0

0/-

0/0

3 (slight)*/ 4 (slight)*

Urinary bladder, hyperplasia, transitional epithelium

0/0

0/-

6 (slight-mild)**/ 6 (slight-mild)**

6 (mild)**/6 (slight-mild)**

Urethra, hyperplasia, transitional epithelium

 

 

 

 

Significantly different from control group (*: p<0.05; **: p<0.01)


 

Applicant's summary and conclusion

Conclusions:
In a reliable study conducted according to OECD Test Guideline 422 and in compliance with GLP, administration of trimethoxy(vinyl)silane at a dose of 62.5 mg/kg bw/day did not lead to organ damage including irreversible morphological effects permanently impairing the function of the organ/tissue (reversibility after recovery period). Also, no other effects such as necrosis or other cell death were reported, which could contribute to the degeneration of the metabolically-functional tissue. The No Observed Adverse Effect Level (NOAEL) was therefore determined to be 62.5 mg/kg bw/day. The Lowest Observed Adverse Effect Level (LOAEL) was set to 250 mg/kg bw/day, based on the histopathological changes in the urinary bladder observed in all animals (males and females) at this dose level.