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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20.04.1999 to 10.02.2000
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
full histopathology of required tissues was not carried out.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2000
Report date:
2000

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
EC Number:
260-350-7
EC Name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
Cas Number:
56706-10-6
Molecular formula:
C18H42O6S2Si2
IUPAC Name:
4,4,13,13-tetraethoxy-3,14-dioxa-8,9-dithia-4,13-disilahexadecane
Constituent 2
Reference substance name:
S2
IUPAC Name:
S2

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 Japan
- Age at study initiation: Five weeks.
- Weight at study initiation: Males: 139.5-162.9 g. Females: 119.6-144.0 g.
- Fasting period before study:
- Housing: Individually in hanging stainless steel cage with wire mesh floor.
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: yes, but period not stated.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: From: 17.06.1999 To: 29.07.1999

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test substance was weighed accurately and dissolved with olive oil to make a 10 %w/v solution from which the 2.0, 0.4 and 0.08 % w/v solutions were prepared. 10 and 2.0 %w/v solutions were prepared weekly, and the 0.4 and 0.08 % w/v were prepared prior to use.


VEHICLE
- Justification for use and choice of vehicle (if other than water): No data.
- Concentration in vehicle: 10, 2.0, 0.4 and 0.08 %w/v.
- Amount of vehicle (if gavage): No data
- Lot/batch no. (if required): 004RRA
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
28 days (plus a 14 day recovery period with no treatment for the high dose group)
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
8 mg/kg bw/day (actual dose received)
Dose / conc.:
40 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
Six
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Based on the results of a 14 day preliminary study.
- Rationale for animal assignment (if not random): Random
- Rationale for selecting satellite groups: No data
- Post-exposure recovery period in satellite groups: yes, vehicle only and high dose group recovery groups.
- Section schedule rationale (if not random): No data
Positive control:
None

Examinations

Observations and examinations performed and frequency:
The day of the initiation of dosing was defined as Day 1, and the day before as Day -1. The week of the initiation of the dosing period was defined as Week 1. Also, the next day of the final dosing was defined as Recovery day 1, and the week of the initiation of the recovery period as Recovery week 1.
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least daily.


DETAILED CLINICAL OBSERVATIONS: No data


BODY WEIGHT: Yes
- Time schedule for examinations: Before dosing on Day -2, then on Days 1, 3, 8, 12, 17, 21, 26 and 28, and during the recovery period on Days 1, 5, 10 and 14. Plus immediately before necropsy for calculation of relative organ weights.


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


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: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: At the termination of dosing and at the end of the recovery period.
- Anaesthetic used for blood collection: Yes (ether).
- Animals fasted: Yes, overnight (16-20 hours).
- How many animals: All survivors.
- Parameters checked in table 1 were examined. In addition a myelogram was performed as haematological abnormalities were noted in the preliminary toxicity study. Thin bone marrow smears were prepared from the left femurs in the first three animals of each group at the terminal necropsy of the dosing and recovery periods, and examined in the 1000 mg/kg and vehicle control groups on the terminal necropsy of the dosing period. Parameters examined were: myerobrasts, promyelocytes, myelocytes, metamyelocytes, stab neutrophils, segmented neutrophils, eosinophils, basophils, lymphocytes, plasmacytes, megakaryocytes, retoperitheliums, mastocytes, monocytes, proerythroblasts, basoerythroblasts, polychromatic erythroblasts, neuerythroblasts, and myeloblast series/erythroblasts series (M/E ratio).


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: At the termination of dosing and at the end of the recovery period.
- Animals fasted: Yes, overnight (16-20 hours).
- How many animals: All survivors.
- Parameters checked in table 1 were examined.


URINALYSIS: Yes
- Time schedule for collection of urine: At termination of the dosing and recovery periods.
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 1 were examined.


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table 2)
HISTOPATHOLOGY: Yes (see table 2)
Statistics:
Data regarding body weights, food intakes, haematology, clinical chemistry, urinalysis and organ weights were analysed using the Bartlett's test for homogeneity of variance. If the variances were homogeneous at a significance level of 5%, one way analysis of variance was performed. If there was a significant difference in this analysis, the difference between the vehicle group and each of the treatment groups was analysed by the Dunnett's test (equal number of data). If the variances were not homogeneous the Kruskal-Wallis's test was used. If there was a significant difference in this analysis, the difference between the vehicle control group and each of the treatment groups was analysed by the nonparametric Dunnett's test (equal number of data).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
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
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
effects observed, treatment-related
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: During the dosing period salivation was observed in males of the vehicle control group (8/12), 8 mg/kg bw/day group (3/6), 40 mg/kg bw/day group (5/6), 200 mg/kg bw/day group (6/6) and 1000 mg/kg bw/day group (12/12). In females the salivation was observed in the vehicle control group (4/12), 8 mg/kg bw/day group (3/6), 40 mg/kg bw/day group (3/6), 200 mg/kg bw/day group (5/6) and 1000 mg/kg bw/day group (12/12). Staining around the nose and mouth was observed in 3/12 males and 1/12 females in the high dose group. Hair loss was also observed in the high dose males (2/12). These clinical signs were not observed in the recovery period. Salivation is commonly observed in gavage studies.


BODY WEIGHT AND WEIGHT GAIN: There were no abnormalities in either the dosing or recovery periods.


FOOD CONSUMPTION: There were no abnormalities in either the dosing or recovery periods.


HAEMATOLOGY: There were no abnormalities in males. At termination of dosing there was a decrease in red blood cell count, and an increase in activated thromboplastin time in high dose females. At the end of the recovery period an increase in red blood cell count and a decrease in mean corpuscular haemoglobin was noted in the high dose group.


CLINICAL CHEMISTRY: At the end of the dosing period there was an increase in calcium level in the high dose group males. In high dose females there were increases in GPT and gamma-GTP activities, total cholesterol, total protein, albumin levels, and a decrease in alkaline phosphatase activity. There was also a tendency towards increased GPT activity due to an increase in one animal of the 200 mg/kg bw/day. There were no such findings at the end of the recovery period.


URINALYSIS: There was a tendency towards increased ketone bodies in the high dose groups for males and females, and the 200 mg/kg bw/day group for females at the end of the dosing period. There were no such findings at the end of the recovery period.


ORGAN WEIGHTS: Small testes were observed in one male of the vehicle control group at the end of the recovery period, but these were not analysed statistically as they were considered to be a malformation. In males at termination of dosing, increases in relative liver weights were noted in the 200 and 1000 mg/kg bw/day groups. Decreased absolute testis weights were noted in the 8 and 40 mg/kg bw/day groups, and decreased relative kidney weights were noted in the 200 mg/kg bw/day group. In females there was an increase in absolute liver weight in the 200 mg/kg bw/day group, and an increase in absolute and relative liver weights in the 1000 mg/kg bw/day group. There were no such findings at the end of the recovery period.


GROSS PATHOLOGY: At the end of the dosing period males had enlargement (2/6) of the liver and loss of hair (1/6) in the highest dose group. Females of the highest dose group (4/6) had liver enlargement. At the termination of the recovery period no abnormalities were observed in females, but there was one male of the vehicle control group that had small testes.


HISTOPATHOLOGY: NON-NEOPLASTIC: Table 3 summaries the histopathology findings.

Effect levels

Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table 3: Incidence of selected pathologies

Parameter

n=6/sex

Dose level (mg/kg bw/day)

Control

8

40

200

1000

Recovery control

Recovery 1000

Liver enlargement

M

0

0

0

0

2

0

0

F

0

0

0

0

4

0

0

Testes - small

M

0

0

0

0

0

1

0

F

-

-

-

-

-

-

-

Skin - Loss of hair

M

0

0

0

0

1

0

0

F

0

0

0

0

0

0

0

Liver – Centrilobular hypertrophy of hepatocytes

M

0

-

-

-

4/6 (+)

0

0

F

0

-

-

-

3/6 (+)

0

0

Centrilobular lipid droplets of hepatocytes

M

0

-

-

0

0

0

0

F

0

-

-

3/6 (+)

0

0

0

Disseminated microgranuloma

M

1/6 (+)

-

-

1/6 (+)

0

1/6 (+)

0

F

0

-

-

0

2/6 (+)

1/6 (+)

0

Periportal lipid droplets of hepatocytes

M

1/6 (+)

-

-

0

0

0

0

F

1/6 (+), 1/6(++)

-

-

1/6 (±), 2/6 (+)

3/6 (+), 2/6 (++)

0

0

Periportal microgranuloma

M

0

-

-

0

0

0

0

F

1/6 (++)

-

-

1/6 (+)

2/6 (+)

0

0

Single cell necrosis of hepatocytes

M

0

-

-

0

0

0

1/6 (+)

F

0

-

-

0

0

0

2/6 (+)

Kidney – Basophilic tubules

M

0

-

-

0

4/6 (+)

0

1/6 (±), 2/6 (+)

F

0

-

-

0

1/6 (±)

0

1/6 (±), 2/6 (+)

Increased eosinophilic bodies

M

0

-

-

0

0

0

2/6 (±)

F

0

-

-

0

0

0

0

Increased hyaline droplets

M

0

-

-

0

1/6 (± ), 1/6 (+)

0

3/6 (±)

F

0

-

-

0

0

0

0

Subcapsular solitary cyst

M

1/6 (+)

-

-

0

0

0

0

F

0

-

-

0

0

0

0

Testes – diffuse atrophy of seminiferous tubules

M

-

-

-

-

-

1/1 (+++)

-

F

-

-

-

-

-

-

-

Leydig cell hyperplasia

M

-

-

-

-

-

1/1 (++)

-

F

-

-

-

-

-

-

-

Skin – scab formation

M

-

-

-

-

1/1 (+)

-

-

F

-

-

-

-

1/1

-

-

± very slight, + slight, ++ moderate, +++ severe

Applicant's summary and conclusion

Conclusions:
In a well conducted and documented 28-day repeated dose oral gavage study (reliability score 1) conducted according to OECD 407 and GLP, the NOAEL for Si-75 was 200 mg/kg bw/day in rats. This was based on histopathological changes in the liver and kidney.
Executive summary:

In a 28-day repeated dose oral toxicity study Si-75 was administered to Sprague-Dawley rats (6/sex/dose) by oral gavage for 28 consecutive days. Si-75 was administered in olive oil at doses of 0 (vehicle only), 8, 40, 200 and 1000 mg/kg bw/day. Separate recovery groups (14 days) were provided for the control and highest dose groups. There were no deaths and no abnormalities in clinical signs, body weights and food intakes during the dosing period. In haematological examinations at the termination of the dosing period, a decrease in red blood cell count and an increase in activated partial thromboplastine time were noted in high dose females. In blood chemical examinations at the termination of the dosing period, increases in calcium level of males, GPT and gamma-GTP activities, total cholesterol, total protein and albumin levels of females were noted in the high dose groups. A decrease in alkaline phosphatase activity was noted in the high dose females. In urinalysis at the termination of the dosing period, urinary ketone bodies showed increases in the high dose males and the 200 mg/kg bw/day and high dose females. Increases in liver weights were noted in the 200 and 1000 mg/kg bw/day males and females. In addition, enlargement of the liver and centrilobular hypertrophy were observed in high dose males and females. Periportal lipid droplets of the hepatocytes were noted in high dose females. Basophilic tubules in the kidney were noted in the high dose males and females. Increased hyaline droplets in the kidney were noted in high dose males. In the recovery period, basophilic tubules in the kidneys of males and females, and increased hyaline droplets in the kidney of males remained in the high dose groups. Other treatment-related changes were not observed at the end of the recovery period. Based on the histopathological changes, i.e. centrilobular hypertrophy of the hepatocytes and basophilic tubules in the kidneys in high dose males and females, hyaline droplets in the kidney in high dose males, and periportal lipid droplets of the hepatocytes in high dose females the NOAEL was concluded to be 200 mg/kg bw/day.