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Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
7-day dose range-finding study
Type of information:
experimental study
Remarks:
Supporting evidence of corrosivity
Adequacy of study:
key study
Study period:
24th May 2017 to 8th June 2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The aim of this regulation driven 7-day dose-range finding study was to provide a basis for the selection of low dose levels to be used in repeated dose oral (gavage) toxicity study. The dose-range finding study and the full repeated dose study were planned to assess the possible health hazards, in particular local corrosive effects, which could arise from repeated exposure of trichloro(propyl)silane via oral administration to rats. Therefore, macroscopic and microscopic examinations of the animals were limited to the respiratory and gastrointestinal tracts.
GLP compliance:
no
Remarks:
a 7-day dose-range finding study was to provide a basis for the selection of low dose levels to be used in repeated dose oral (gavage) toxicity study.
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Trichloro(propyl)silane
EC Number:
205-489-6
EC Name:
Trichloro(propyl)silane
Cas Number:
141-57-1
Molecular formula:
C3H7Cl3Si
IUPAC Name:
trichloro(propyl)silane
Test material form:
liquid
Specific details on test material used for the study:
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: room temperature, stored under an Argon atmosphere to avoid hydrolysis
- Stability under test conditions: not specified
- Solubility and stability of the test substance in the solvent/vehicle: The test item was used as provided by the sponsor.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was used as provided by the sponsor
- Preliminary purification step (if any): none
- Final dilution of a dissolved solid, stock liquid or gel: not applicable
- Final preparation of a solid: not applicable

Test animals

Species:
rat
Strain:
other: Wistar Crl:WI(Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 12 weeks old
- Weight at study initiation: males: 327 – 349 g; females: 213 – 241 g
- Fasting period before study: no
- Housing: The animals were kept in groups of 5 animals / sex / group / cage in IVC cages
- Diet (e.g. ad libitum): Altromin 1324 maintenance diet for rats and mice, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least 5 days

DETAILS OF FOOD AND WATER QUALITY: Certificates of food, water and bedding are filed for two years at BSL Munich and afterwards archived at Eurofins Munich

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3 °C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: Control group: 0.101 ml/kg bw, low-dose group: 0.025 m/kg bw, mid-dose group: 0.050 ml/kg bw, high-dose group: 0.101 ml/kg bw. The application v
olume was calculated based on the density of 1.19 g/ml of the test item. The test item was applied undiluted due to the high instability of the test item in the presence of water.
For each animal the individual dosing volume was calculated on the basis of the body weight most recently measured.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
7-day treatment was planned, but the animals were treated for 2 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day (nominal)
Remarks:
The lowest possible dose based on the minimum volume of neat test substance that can be dosed.
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
120 mg/kg bw/day (nominal)
No. of animals per sex per dose:
3 males and 3 females per dose per group (except low dose); 5 males and 5 females for low dose group.
Control animals:
yes
Details on study design:
- Dose selection rationale:
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: satellite groups not used
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): random
Positive control:
not used

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once a day, approximately at the same time each day. Twice daily all animals were observed for morbidity and mortality.
- Cage side observations checked in table included: mortality, morbidity, general clinical observations

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: on study days 1 and 4 prior to dosing, and was planned for study day 7 prior to the scheduled necropsy

FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes, on study days 1 prior to dosing and was also planned for the days of scheduled euthanasia

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Not applicable

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (See table 1) Detailed gross necropsy which included careful examination of the external surface of the body, all orifices and the cranial, thoracic and abdominal cavities and their contents. All macroscopic findings were recorded and organs showing gross abnormalities were preserved in neutral buffered formalin. Gross necropsy of all animals including decedent animals, without organ weights, were performed. At necropsy, special attention was paid to the gastrointestinal tract. The gastrointestinal tract was opened with scissors and cleaned with water to examine inner surfaces macroscopically for corrosive effects.
All animals intercurrently sacrificed were subjected to a gross necropsy.

HISTOPATHOLOGY: Yes (See table 1)
Statistics:
Toxicology and pathology data were captured either on paper according to appropriate SOPs or using the validated computerised system Ascentos® System

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Moving the bedding, moderate to marked salivation and nasal discharge were noted directly after dosing in test animals. These signs represent typical signs of local reactions and were equally distributed among the dose groups in terms of incidence and severity. In addition stress-related effects such as piloerection, vocalization and chromodacryorrhea were recorded. Severe clinical findings such as moderate to marked reduced spontaneous activity, abnormal breathing, half eyelid-closure, slight wasp waist and hunched posture were also observed. All presented clinical signs were not recorded in control animals.
Mortality:
mortality observed, treatment-related
Description (incidence):
All 22 animals of the test item-treated groups were euthanised in a moribund condition for animal welfare reasons by study day 2. Two males had to be sacrificed on the first day of the study. All animals of the control groups survived until the scheduled sacrifice on day 8. Therefore, the mortality is considered to be related to the test item.
Body weight and weight changes:
not examined
Description (incidence and severity):
Body weight of animals of test item-treated groups could only be determined on study day 1 and no body weight gain could be determined during the treatment period as animals were sacrificed on study day 1 or 2.
On study day 1 mean values of body weight measurements in the dose groups were comparable to the control group in both males and females.
Food consumption and compound intake (if feeding study):
not examined
Description (incidence and severity):
No effects of trichloro(propyl)silane on food consumption could be determined during the treatment period of the male and female dose groups when compared to the respective controls as animals were sacrificed on study day 1 or 2.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
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:
effects observed, treatment-related
Description (incidence and severity):
Erosions/ulcers concerning the complete stomach could be found in 6/10 animals of the low dose (LD) group, in 3/6 of the middle dose (MD) group and in all animals (6/6) of the high dose (HD) group. In addition, in 3 other animals foci and foamy contents could be observed (one each from low, mid and high dose groups). Moreover, a solid content was found in the esophagus of animals 13 (HD, male) and 25 (MD, female).
In 5/10 LD animals a discoloration of the esophagus was detected. 4/6 MD animals as well as 5/6 HD animals exhibited fluid/foam filled esophagi with two of the MD animals showing discoloration in addition.
The lungs of female 21 (LD group) were fluid filled and those of male 13 (HD group) had red discoloration.
Only two animals of the LD group (males 6 and 7) exhibited no macroscopic findings.
The abovementioned findings correlated with histopathological observations as outlined below. None of the presented macroscopic findings were recorded in control animals and were therefore considered to be related to the test item formulation.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Esophagus:
- inflammatory and/or degenerative lesions in all test item-treated animals.
- hyperacute lesions: mucosal degeneration (coagulation necrosis)
- acute inflammation in one low dose female.
- necrotizing inflammation in remaining animals in single case associated with ulceration and esophageal perforation
Trachea:
- acute inflammation or necrotizing inflammation in a few animals throughout all test item-treated groups.
Lungs:
- multifocal peribronchiolar inflammation was recorded in the lungs of one high dose animal affecting mainly the alveoli connecting the terminal end sacs associated with bronchiolar epithelium degeneration
- deposition of cellular detritus associated with degenerated epithelium in one mid dose animal
Stomach:
- inflammatory and degenerative lesions affected both the forestomach and the glandular stomach, consisting of inflammation and ulceration
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

Key result
Dose descriptor:
LOAEL
Effect level:
ca. 30 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
gross pathology
histopathology: neoplastic
mortality
Remarks on result:
other: no NOAEL could be determined as animals were sacrificed prior to completion of the study.

Target system / organ toxicity

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
30 mg/kg bw/day (actual dose received)
System:
respiratory system: upper respiratory tract
Organ:
oesophagus
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Table 1: Mortality data

Males

Males

Males

Males

Females

Females

Females

Females

Group

Animal No.

Number of Application

Time after last application

(h:min)

Group

Animal No.

Number of Application

Time after last application (h:min)

2

4

2

06:42

2

18

1

18:24

2

5

2

06:20

2

19

2

06:23

2

6

2

06:46

2

20

2

06:49

2

7

2

06:39

2

21

2

06:53

2

8

2

06:49

2

22

2

06:54

3

9

1

1: 58

3

23

1

18:07

3

10

2

02:38

3

24

2

02:55

3

11

2

01:41

3

25

1

18:19

4

12

2

02:40

4

26

2

02:54

4

13

1

02:13

4

27

2

02:53

4

14

2

01:44

4

28

2

02:34

Table2: Incidence and mean severity of lesions in esophagus

Dose (mg/kg)

Control

Control

30 mg/kg

30 mg/kg

60 mg/kg

60 mg/kg

120 mg/kg

120 mg/kg

Total Animals/Sex

Affected / Mean Severity

(3) M

(3) F

(4) M*

(5) F

(3) M

(3) F

(3) M

(3) F

Food in lumen

0

0

0

1

2

0

2

0

Degeneration, mucosal

0

0

0

0

2/3.5

1/4.0

3/4.7

1/3.0

Inflammation, acute

0

0

0

1/1.0

0

0

0

0

Inflammation, necrotizing

0

0

4/2.8

4/3.3

1/3.0

2/2.5

0

2/4.0

Table3: Incidence and mean severity of lesions in trachea

Dose (mg/kg)

Control

Control

30 mg/kg

30 mg/kg

60 mg/kg

60 mg/kg

120 mg/kg

120 mg/kg

Total Animals/Sex

Affected / Mean Severity

(3) M

(3) F

(5) M

(5) F

(3) M

(3) F

(3) M

(3) F

Inflammation, acute

0

0

1/1.0

1/2.0

0

1/2.0

0

2/1.0

Inflammation, necrotizing

0

0

0

1/3.0

1/3.0

1/1.0

1/2.0

0

Table4: Incidence and mean severity of lesions in lung

Dose (mg/kg)

Control

Control

30 mg/kg

30 mg/kg

60 mg/kg

60 mg/kg

120 mg/kg

120 mg/kg

Total Animals/Sex

Affected / Mean Severity

(3) M

(3) F

(5) M

(5) F

(3) M

(3) F

(3) M

(3) F

Inflammation, peribronch.

0

0

0

0

0

0

1/2.0

0

Degeneration, bronchiolar

epithelium

0

0

0

0

0

1/1.0

1/1.0

0

Detritus intrabronchial

0

0

0

0

0

1/2.0

1/2.0

0

Table5: Incidence and mean severity of lesions in stomach

Dose (mg/kg)

Control

Control

30 mg/kg

30 mg/kg

60 mg/kg

60 mg/kg

120 mg/kg

120 mg/kg

Total Animals/Sex

Affected / Mean Severity

(3) M

(3) F

(5) M

(5) F

(3) M

(3) F

(3) M

(3) F

Inflammation, forestomach

0

0

0

0

0

1/2.0

0

0

Erosion, glandular stomach

0

0

0

0

1/2.0

0

0

0

Ulceration, forestomach/

Glandular stomach

0

0

1/3.0

0

1/3.0

0

2/3.5

0

Ulceration, glandular

stomach

0

0

2/1.5

2/2.0

0

1/3.0

1/3.0

3/2.0

Table6: Time of death after last application and related major pathology

Group

Males

Animal No.

Time after last application

(h:min)

Number of Applications

Main Findings

2

4

06:42

2

Necrotizing inflammation in esophagus, Stomach ulceration

2

5

06:20

2

Necrotizing inflammation in esophagus, Stomach ulceration

2

6

06:46

2

Necrotizing inflammation in esophagus

2

7

06:39

2

Necrotizing inflammation in esophagus

2

8

06:49

2

Stomach ulceration

3

9

1: 58

1

Mucosal degeneration in esophagus

3

10

02:38

2

Necrotizing inflammation in esophagus, Stomach ulceration

3

11

01:41

2

Mucosal degeneration in esophagus

Necrotizing inflammation in trachea

4

12

02:40

2

Mucosal degeneration in esophagusStomach ulceration

4

13

02:13

1

Mucosal degeneration in esophagus,Stomach ulceration

4

14

01:44

2

Mucosal degeneration in esophagusNecrotizing inflammation in trachea

Stomach ulceration

Table7: Time of death after last application and related major pathology

Group

Females

Animal No.

Time after last application

(h:min)

Number of Applications

Main Findings

2

18

18:24

1

Necrotizing inflammation in esophagus, Stomach ulceration

2

19

06:23

2

Necrotizing inflammation in esophagus

Necrotizing inflammation in trachea

2

20

06:49

2

Necrotizing inflammation in esophagus

2

21

06:53

2

Necrotizing inflammation in esophagus

2

22

06:54

2

Stomach ulceration

3

23

18:07

1

Necrotizing inflammation in esophagus

Necrotizing inflammation in trachea

3

24

02:55

2

Necrotizing inflammation in esophagus

Stomach inflammation

3

25

18:19

1

Mucosal degeneration in esophagus

Stomach ulceration

4

26

02:54

2

Mucosal degeneration in esophagus,Stomach ulceration

4

27

02:53

2

Necrotizing inflammation in esophagus,

Stomach ulceration

4

28

02:34

2

Necrotizing inflammation in esophagusStomach ulceration

Applicant's summary and conclusion

Conclusions:
Trichloro(propyl)silane was tested in a regulatory driven 7-day dose range-finding study (non-GLP) in order to determine the feasibility of dosing chlorosilanes (at low doses to avoid corrosive effects) in repeated dose oral toxicity tests. In this study a NOAEL could not be determined due to the corrosive effects of the test substance on the gastrointestinal and respiratory tracts. All animals administered the tests substance were sacrificed on study day 2 due to ethic reasons. The findings at pathology and histophathology showed signs of corrosion which was considered to be related to the hydrolysis product hydrocloric acid.