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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:
supporting study
Study period:
29 November 2018 to 04 February 2019
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:
2019
Report Date:
2019

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The aim of this 14-day dose-range finding study was to provide a basis for the selection of dose levels to be used in prenatal developmental toxicity study via oral (gavage) route. The dose-range finding study was 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
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
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, tightly closed, overlaid with protective gas (argon), protected from moisture
- Stability under test conditions: stable
- Solubility and stability of the test substance in the solvent/vehicle: stable and soluble in corn oil
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: n/a

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Females (if applicable) nulliparous and non-pregnant: yes
- Age at study initiation: 12-13 weeks old
- Weight at study initiation: males: 323 – 381 g; females: 207 – 245 g
- Fasting period before study: no
- Housing: The animals were kept in groups of 2 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 five days

DETAILS OF FOOD AND WATER QUALITY:

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

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test item was weighed into a tared plastic vial on a suitable precision balance and the vehicle was added to give the appropriate final concentration of the test item. The formulation was alternately vortexed and/or stirred until visual homogeneity was achieved.

VEHICLE
- Justification for use and choice of vehicle (if other than water): The vehicle was selected in consultation with the sponsor based on the test item’s characteristics
- Concentration in vehicle: 0, 12.5, 25, 62.5, 125, 43.75 mg/mL
- Amount of vehicle (if gavage): not specified
- Lot/batch no. (if required): NKCD1021
- Purity: not specified
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
A dose formulation analysis was not performed in this study.
Duration of treatment / exposure:
14 days
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Remarks:
Group 1
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Remarks:
Group 2
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Remarks:
Group 3
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Remarks:
Group 4
Dose / conc.:
500 mg/kg bw/day (actual dose received)
Remarks:
Group 5
Dose / conc.:
175 mg/kg bw/day (actual dose received)
Remarks:
Group 6
No. of animals per sex per dose:
2 male and 2 female per group
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The doses for dose groups 2 and 3 and the control group (group 1) were selected in consultation with the sponsor prior to the start of the study. The remaining doses were selected in consultation with the sponsor in the course of the treatment period of this study. The treatment was started with 50 and 100 mg/kg bw/day, respectively. In case of no effects at particular dose levels the dose of remaining groups was increased stepwise until effects were seen. Before starting dosing with a new dose level at least 3 treatments per animal and dose group were made.
- Rationale for animal assignment (if not random): random
- Fasting period before blood sampling for clinical biochemistry: yes, overnight fasting
- Rationale for selecting satellite groups: n/a
- Post-exposure recovery period in satellite groups: no recovery period
- Section schedule rationale (if not random): n/a
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day
- Cage side observations included: morbidity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made at least once a day

BODY WEIGHT: Yes
- Time schedule for examinations: once before assignment to the experimental groups and on study days 1, 3, 6, 8, 11 and 14 during the treatment period as well as on the day of necropsy

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Food consumption was measured on study days 1, 8 and 14 for each animal.

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): No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment
- Anaesthetic used for blood collection: No
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment
- Animals fasted: Yes
- How many animals: all animals
- Parameters checked in table [No.1] were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see table No 2)

HISTOPATHOLOGY: Yes (see table No 2)
Statistics:
Toxicology and pathology data were captured either on paper according to appropriate SOPs or using the validated computerised system Ascentos® System (version 1.3.4, Pathology Data Systems Ltd.).

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Treatment with trichloro(propyl)silane caused marked clinical signs in males and females of group 5 (500 mg/kg bw/day). Male animal no. 10, which was found dead on study day 2, was seen with moderate piloerection and moving the bedding after treatment on day 1. The second male animal in group 5 (animal no. 9) showed moderate piloerection, slightly reduced spontaneous activity, prone position, half eyelid closure, hypothermia and emesis/vomitus before the animal was sacrificed in moribund condition. Clinical signs of both female animals in group 5 were slightly, moderately or severely reduced spontaneous activity, slight to moderate piloerection, ataxia, slow movements, lacrimation, hypothermia, red urine (animal no. 21) and for animal no. 22 prone position, hunched posture, moderate wasp waist, dehydration, half eye lid closure and severely increased salivation.
Severely reduced spontaneous activity in close relation after test item treatment on days 6 to 8 was observed for one male of group 4 (250 mg/kg bw/day) and slight piloerection was noted on two days during the first week of treatment in all males of group 3 (100 mg/kg bw/day).
Moving the bedding was noted in animals of groups 2, 3, 4 and 6 (50 - 250 mg/kg bw/day) and increased salivation in groups 6 and 4 (175 - 250 mg/kg bw/day) on several treatment days.
Clinical findings like moving the bedding or increased salivation, which were noted in animals of all dose groups on several days were considered to be due to discomfort caused by a local reaction to trichloro(propyl)silane.
Mortality:
mortality observed, treatment-related
Description (incidence):
On the second day of treatment, 1/2 males and 2/2 females of group 5 (500 mg/kg/day) were euthanized in a moribund condition. One animal at 500 mg/kg/day was found dead on treatment day 2. Inflammatory lesions of the stomach were considered to be the cause of mortality. All remaining animals survived until the scheduled sacrifice
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Mean body weight of the male control group, group 2 (50 mg/kg bw/day) and 3 (100 mg/kg bw/day) increased throughout the study period. A slight decrease was found for group 6 (175 mg/kg bw/day) within the first three treatment days. Mean weight of group 4 (250 mg/kg bw/day) showed a tendency towards a decrease during the treatment period and was slightly lower at the end of treatment when compared to start of treatment.
For female control and dose groups 2, 3, 4 (50, 100 and 250 mg/kg bw/day) and 6 (175 mg/kg bw/day), mean body weight showed an increase from day 1 to the end of treatment on day 14.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Males of dose groups 4 (250 mg/kg bw/day) and 6 (175 mg/kg bw/day) showed a tendency towards a slightly lower mean food consumption when compared to the control group - more prominently in group 4 (between 11 and 17 % below controls). Mean food consumption in males of dose groups 2 and 3 (50 - 100 mg/kg bw/day) and in females of all dose groups were comparable to the control group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Mean haematology values of all male and female dose groups were comparable to mean values of the control group and no adverse effect was seen.
The slightly and dose dependently increased mean platelet count (PLT) value in females dose groups was not considered to be of toxicological relevance.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Treatment with trichloro(propyl)silane had no effects on parameters of clinical biochemistry of males and females in any of the test item-treated groups, which were considered toxicologically relevant.
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
Mean organ weights showed no dose-dependent differences between male and female dose groups when compared to respective control group.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
For male animals in group 5 (500 mg/kg bw/day), which were sacrificed or were found dead on day 2, macroscopic findings were noted mainly in gastrointestinal organs. The findings were abnormal coloured oesophagus or stomach with bloody content and focal haemorrhage at duodenum and ileum. Abnormal colouration (yellow or spotted) was recorded for liver or pancreas and gelatinous content was found in the urinary bladder of animal no. 9.
General observation recorded for animal no. 22 in female group 5 (500 mg/kg bw/day) was yellow fluid content and for animal no. 21 the stomach was seen with blood, focal haemorrhage and cyst at the wall. Yellow coloured or spotted liver, pancreas and kidneys were additionally seen in this group.
For animals in group 4 (250 mg/kg bw/day), findings like swollen gastric wall and white coloured ulceration at the fundic area and bloody red surface were noted. Necropsy findings in group 6 (175 mg/kg bw/day) were mainly spotted coloured stomach and white ulceration at the gastric wall
At macroscopic assessment no findings at any organ was noted for male and female control group and dose groups 2 and 3 (50 – 100 mg/kg bw/day) and females of group 6 (175 mg/kg bw/day).
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Findings at histopathological evaluation were mainly seen in organs of the gastrointestinal tract.
In single cases (one male each from groups 50 and 175 mg/kg bw/day and one female of group 250 mg/kg bw/day), inflammation in the esophagus was noted.
Induced inflammatory and degenerative lesions of stomach were noted in animals from all dose levels.
At 50 mg/kg bw/day, there were inflammatory and degenerative lesions in the stomach consisting of epithelial degeneration in the forestomach, glandular stomach erosion, forestomach ulcerations and inflammation, and in one case inflammation in the serosa (peritonitis). A reactive change was noted by the epithelial hyperplasia in the forestomach and increased hyperkeratosis of the forestomach epithelium in animals from this group.
At 100 mg/kg bw/day, the findings were similar but appeared at a higher severity. They consisted of forestomach inflammation, glandular stomach inflammation and squamous hyperplasia with increased epithelial hyperkeratosis.
At higher dose levels (175 to 500 mg/kg bw/day), erosive and ulcerative lesions in the glandular stomach and forestomach in association with inflammation dominated the picture of lesions. Namely, serosa inflammation (i.e., peritonitis) was present in most animals. In most group 5 animals, there was also a mucosa atrophy.
Inflammatory intestinal lesions appeared in some cases at 250 mg/kg bw/day. They consisted of erosion and inflammation. More cases were noted at 500 mg/kg bw/day. In single cases in group 5 (500 mg/kg bw/day), the lesions were associated with mucosal atrophy in various intestinal segments.
Additionally, in one male of group 5 (500 mg/kg bw/day), there was slight multifocal coagulated hepatocellular necrosis. There were no further findings that distinguished controls from test item-treated animals.
Histopathological findings: neoplastic:
not examined
Other effects:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks on result:
not determinable
Dose descriptor:
LOAEL
Effect level:
50 mg/kg bw/day (actual dose received)
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.:
50 mg/kg bw/day (actual dose received)
System:
gastrointestinal tract
Organ:
stomach
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

Table3: Incidence of test item-related gross lesions

Dose (mg/kg bw/day)

0

0

50

50

100

100

250

250

500

500

175

175

Number of Animals

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

Stomach, mass

0

0

0

0

0

0

1

0

0

0

0

0

Stomach, cyst, wall

0

0

0

0

0

0

0

0

0

1

0

0

Stomach, ulcerated

0

0

0

0

0

0

2

2

0

0

1

0

Stomach, swollen wall

0

0

0

0

0

0

2

2

0

0

0

0

Stomach, hemorrhage

0

0

0

0

0

0

0

0

2

1

 0

0

Stomach, content blood

0

0

0

0

0

0

0

0

2

1

 0

0

Stomach, abnormal

color/foci

0

0

0

0

0

0

1

0

0

0

1

0

Duodenum, hemorrhage

0

0

0

0

0

0

0

0

1

0

0

0

Ileum, content blood

0

0

0

0

0

0

0

0

1

0

0

0

Abdominal cavity fluid

0

0

0

0

0

0

0

0

1

0

0

0

Liver yellow

0

0

0

0

0

0

0

0

1

0

0

0

Table4: Relevant Findings in Esophagus

Dose (mg/kg

bw/day)

0

0

50

50

100

100

250

250

500

500

175

175

Total Animals/Sex

Affected / Mean

Severity

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

Inflammation

0

0

1/1.0

0

0

0

0

1/3.0

0

0

1/1.0

0

Table5: Relevant Findings in Stomach

Dose (mg/kg

bw/day)

0

0

50

50

100

100

250

250

500

500

175

175

Total Animals/Sex

Affected / Mean

Severity

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

Hyperkeratosis

0

0

0

1/1.0

2/2.0

2/1.5

1/2.0

2/2.0

0

0

2/2.0

2/2.0

Degeneration, epithelium, forestomach

0

0

1/1.0

0

0

1/1.0

0

1/2.0

0

2/2.5

0

0

Erosion, glandular stomach

0

0

1/1.0

0

0

0

0

0

2/2.5

2/2.5

0

1/1.0

Ulceration, forestomach

0

0

1/1.0

0

0

0

1/3.0

2/1.5

0

0

1/2.0

1/1.0

Ulceration,

glandular stom.

0

0

0

0

0

0

0

0

1/3.0

1/2.0

0

0

Inflammation, forestomach

0

0

1/1.0

2/1.0

2/2.5

2/2.0

2/2.0

2/3.0

0

2/2.5

2/2.5

2/2.5

Inflammation, glandular stom.

0

0

0

0

1/1.0

0

1/2.0

0

2/2.5

2/2.5

1/1.0

0

Inflammation, serosa

0

0

1/1.0

0

0

0

1/2.0

2/2.0

1/2.0

2/1.5

1/1.0

1/2.0

Hyperplasia, squamous

0

0

2/1.5

2/2.0

2/3.0

2/3.0

2/3.0

2/3.5

0

0

2/3.0

2/3.0

Mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

2/2.5

0

0

Table6: Relevant Findings in Intestine

Dose (mg/kg

bw/day)

0

0

50

50

100

100

250

250

500

500

175

175

Total Animals/Sex

Affected / Mean

Severity

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

(2)M

(2) F

Duodenum: erosion

0

0

0

0

0

0

1/2.0

0

1/2.0

0

0

0

Duodenum:

inflammation

0

0

0

0

0

0

0

0

1/1.0

1/1.0

0

0

Duodenum: mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Jejunum:

erosion

0

0

0

0

0

0

1/1.0

0

 0

0

0

0

Jejunum: mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Ileum: erosion

0

0

0

0

0

0

0

0

1/3.0

0

0

0

Ileum:

inflammation

0

0

0

0

0

0

0

0

1/1.0

0

0

0

Ileum:

mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Cecum:

inflammation

0

0

0

0

0

0

1/1.0

0

0

0

0

0

Cecum:

mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Colon:

mucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Rectum:

ucosal atrophy

0

0

0

0

0

0

0

0

1/3.0

1/1.0

0

0

Applicant's summary and conclusion

Conclusions:
In the dose range-finding study, which was not conducted according to a guideline or GLP, a NOAEL was not concluded. In the study test item-related gross lesions were noted in the gastrointestinal organs at ≥ 175 mg/kg bw/day and these were evident during histopathological examination. At the microscopic examination, specific findings were found, starting at the dose of 50 mg/kg bw/day. These findings included inflammatory and degenerative lesions which consisted of erosions, inflammation, hyperplasia, ulceration, hyperkeratosis and mucosa atrophy.