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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Remarks:
14-day dose range-finding study
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
11 February 2019 to 08 April 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:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
14-day dose range-finding study
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

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: 309 – 361 g; females: 189 – 215 g
- Fasting period before study: no
- Housing: The animals were kept in groups of 2 animals / sex / group / cage in IVC cages (type III, polysulphone cages) on Altromin saw fibre bedding
- Diet (e.g. ad libitum): Free access to Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: at least 5 days

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C
- Humidity (%): 55%
- Air changes (per hr): 10x/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 formulation were prepared freshly on each administration day before the administration procedure and administered directly after its preparation. The vehicle was also used as control item.


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.
The test item was dissolved in dried and de-acidified corn oil.
- Concentration in vehicle:
- Amount of vehicle (if gavage):
- Lot/batch no. (if required): M4CG5257
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, 7 days a week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (actual dose received)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
200 mg/kg bw/day (actual dose received)
Dose / conc.:
25 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
24 animals (12 males and 12 females) were used for the study (2 male and 2 female animals per group).
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose for the first dose groups were selected in consultation with the sponsor prior to the start of the study. The remaining doses were selected sequentially in consultation with the sponsor during the course of the treatment period of this study. The treatment was started with 50 mg/kg bw/day and 100 mg/kg bw/day. In case of no effects at a particular dose level, the dose levels for the remaining groups were increased stepwise one dose level at a time until effects are seen. Tested feasible doses were at 200, 25 and 300 mg/kg bw/day. Before starting dosing with a new higher 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: overnight
- Rationale for selecting satellite groups: not applicable
- Post-exposure recovery period in satellite groups: not applicable
- Section schedule rationale (if not random): not applicable
Positive control:
not used

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: All animals were observed for clinical signs during the entire treatment period of 14 days.
General clinical observations were made at least once a day, approximately at the same time each day and considering the peak period of anticipated effects after dosing. The health condition of the animals was recorded. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

BODY WEIGHT: Yes
- Time schedule for examinations: Body weight was recorded 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 cage.

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
- Parameters checked in table [No.2] were examined.

Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see tables 3 and 4)

HISTOPATHOLOGY: Yes (see tables 3 and 4)
Other examinations:
Not specified

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Treatment with the test item did not cause any adverse clinical signs in males and females up to 300 mg/kg bw/day.
Clinical signs like moving the bedding was observed at 200 mg/kg bw/day (animal no. 7 during days 11-14) and 300 mg/kg bw/day (animal no. 11 & 12 during days 8-14 and 12-14 respectively) in males and at 300 mg/kg bw/day (animal no. 23 & 24 during days 8-14) in females. These clinical signs are considered to be a local reaction to the test item administration at post dose observation and not considered to be an adverse systemic toxicity signs.
Nasal discharge, swellings/masses and moderate piloerection were observed at 200 mg/kg bw/day on days 2-4. These clinical signs are considered to be an incidental finding.
Mortality:
no mortality observed
Description (incidence):
No mortality occurred in the control or any of the dose groups during the treatment period. All the animals survived till scheduled day of necropsy.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Treatment did not show any adverse effect on the body weight and body weight change in any of the groups tested up to 200 mg/kg bw/day during the study period and there were slight reduction in body weight or body weight change at 300 mg/kg bw/day in both male and female during days 1-14 and not comparable to control body weight.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
During the treatment days 1-8, there were slight reduction in food consumption at 50 mg/kg bw/day (deviation from control: 20%) and 100 mg/kg bw/day (deviation from control: 15%) and during days 8-14 in 200 mg/kg bw/day (deviation from control: 15%) in males. In females, there was reduction in food consumption during days 1-8 at 200 mg/kg/ bw/day (deviation from control: 23%). However, mean food consumption from treatment day 1 to 14 was shown to be comparable up to 300 mg/kg bw/day when compared to control both in males and females.
Food efficiency:
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Description (incidence and severity):
Mean WBC levels were moderately decreased in males of group 2 (50 mg/kg bw/day, deviation from control: 62 %) and in group 3 (100 mg/kg bw/day, deviation from control: 69 %). Slightly lower mean PLT in group 6 (300 mg/kg bw/day, deviation from control: 16 %) was observed when compared to control group.
Mean WBC levels were highly increased in females of group 4 (200 mg/kg bw/day, deviation from control: 86 %), in group 5 (25 mg/kg bw/day, deviation from control: 77 %) and group 6 (300 mg/kg bw/day, deviation from control: 98 %). Slightly higher mean PLT in group 4 (200 mg/kg bw/day, deviation from control: 26 %) and 6 (300 mg/kg bw/day, deviation from control: 24 %) was observed when compared to the corresponding control group.
Treatment with the test item had no dose-dependent effect on haematology parameters of males and females in any of the test item-treated groups. Differences between test item-treated males or females and their respective controls showed no dose-dependency or consistency and thus were not considered toxicologically relevant.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
Treatment with the test item had no dose-dependent effect on clinical biochemistry parameters in any of the test item-treated groups.
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 males and females treated with the test item and their respective control groups.
Differences between test item-treated females and control animals in mean weight of uterus and ovaries were not considered toxicologically relevant as female reproductive organs undergo variable changes depending on the stage of the estrous cycle.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Test item-related gross lesions were noted in the stomach at 200 and 300 mg/kg bw/day. Gross lesions in the stomach consisted of white (cranial) focus and few (2-6) yellow (0.1 cm in diameter) in animal no. 7, 8 of males and in animal no. 19, 20 (200 mg/kg bw/day), 23 and 24 (300 mg/kg bw/day) of females.
The spleen was enlarged in male no. 8 at 200 mg/kg bw/day.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Stomach
Induced inflammatory and degenerative lesions were noted in animals from 25 mg/kg/day onwards.
Both males at 25 mg/kg bw/day and one animal per sex at 50 mg/kg bw/day were affected by inflammation in the glandular stomach submucosa. In addition, one female at 50 mg/kg bw/day was affected by an acute inflammation in the forestomach submucosa and another male was affected by squamous hyperplasia in the forestomach.
The forestomach submucosa inflammation increased in incidence and severity in animals from 100 mg/kg bw/day onwards that was associated with squamous hyperplasia and increased incidence and severity of the forestomach.
From 200 mg/kg bw/day onwards, there were single cases of glandular stomach erosion, glandular stomach degeneration, forestomach ulceration, and single cases of serosal inflammation. The serosal inflammation is indicative for ulcerative perforation.
There were no further findings that distinguished controls from test item-treated animals.
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
LOAEL
Effect level:
25 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:
not specified

Applicant's summary and conclusion

Conclusions:
A 14-day non-GLP dose range-finding study was conducted with trichloro(octyl)silane (CAS No. 5283-66-9) based on guideline OECD 407 but modified to realise a staggered dose selection depending on substance related effects. Additional histopathology examinations were performed for precise NOAEL justification, but a NOAEL could not be determined. In the study test item-related gross lesions were noted in the stomach at ≥ 25 mg/kg bw/day and these were evident during histopathological examination. At the microscopic examination, inflammatory and degenerative lesions were noted in animals from 25 mg/kg/day onwards. Based on the data generated from this dose range finding study, dose levels of 5, 10, 25 mg/kg bw/day are suggested for the subsequent main study with the test item.