Registration Dossier

Toxicological information

Repeated dose toxicity: oral

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
No start date given. Study completed on 03.06.2004.
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004
Reference Type:
study report
Title:
Unnamed
Year:
2006
Report Date:
2006

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
This is a screening study.
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc, North Carolina, USA
- Age at study initiation: Minimum of nine weeks
- Weight at study initiation: Males: 285-304 g; Females: 214-239 g
- Fasting period before study: No
- Housing: Individually in suspended wire-mesh cages
- Diet (e.g. ad libitum): Ad libitum
- Water (e.g. ad libitum): Ad libitum
- Acclimation period: Five days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 39-67
- Air changes (per hr): 10-15
- 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: Not required - given neat.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
Seven days
Frequency of treatment:
Daily (seven days/week)
Doses / concentrationsopen allclose all
Dose / conc.:
20 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
500 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:
Five
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: None stated

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: At least once daily for mortality, morbidity and moribundity. At least once daily for general clinical observations.

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights recorded on study days one and four prior to dosing and study day eight prior to scheduled necropsy.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No. Feeder weights were recorded on study day one prior to dosing and on the day of scheduled euthanasia, unscheduled euthanasia, or the day that an animal was found dead. Food consumption was calculated from these initial and final feeder weights.

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: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals found dead or euthanised (scheduled or unscheduled) on study were subjected to a complete, detailed gross necropsy, which included examination of external surface of the body, all orifices, and the cranial, thoracic and abdominal cavities and their contents.

HISTOPATHOLOGY: No
Statistics:
Group mean body weight and food consumption were processed. Analysis of variance was performed on the mean body weight, mean body weight gain, and food consumption data for males and females.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
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
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY: Animals in the 0, 20 and 100 mg/kg bw/day dose groups were dosed once daily for seven days and necropsied on the day after the last dose. Animals in the 500 and 1000 mg/kg bw/day groups received 3 or 4 administered doses depending on the circumstances (unscheduled deaths/euthanasia). One 500 mg/kg bw/day group female was found dead on study day 4. One 1000 mg/kg bw/day group male died shortly after on study day 4. Two 1000 mg/kg bw/day group males, one 500 mg/kg bw/day group female, and two 1000 mg/kg bw/day group females were identified for unscheduled euthanasia prior to the dosing period on study day 4, and as such did not receive a dose on day 4.

Except for the occasional salivation during/shortly after dosing the animals in the 20 mg/kg bw/day group appeared normal. In the 100 mg/kg bw/day group, animals appeared normal, except that the salivation during or shortly after dosing was more prominent along with the observation that the saliva occasionally appeared to contain blood. Animals in the 500 mg/kg bw/day were often not normal when assessed approximately one hour after dosing. Signs were primarily abnormal posture, vocalising upon handling, rales, porphyrin staining, and soiling. Only one occurrence of normal was observed for animals in the 1000 mg/kg bw/day group. Similar signs were observed as for the 500 mg/kg bw/day. A bloody discharge from the penis/vulva was observed in this dose group following administration on day 1. This observation was not made again.

BODY WEIGHT AND WEIGHT GAIN: Animals in the 500 and 1000 mg/kg bw/day groups had marked body weight loss. Body weight gain was reduced in the 100 mg/kg bw/day group

FOOD CONSUMPTION: Food consumption was reduced in the 100 mg/kg bw/day group, but was normal in the low dose group.

GROSS PATHOLOGY: Macroscopic findings at necropsy on day 4 for the 500 and 1000 mg/kg bw/day groups revealed severe lesions (ulceration/erosions) to the oesophagus and stomach. These lesions were consistent in appearance and location with deposition of a corrosive material. The known moisture sensitivity of this test substance and associated liberation of acetic acid suggests that acetic acid liberation at the site of dose administration is responsible for these lesions. Thickening of the oesophageal wall and minor glandular stomach ulceration was observed in many of the 100 mg/kg bw/day dose group animals, along with minimal glandular stomach erosion present in two if the low dose females.

Effect levels

Dose descriptor:
LOAEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: occasional salivation during/shortly after dosing the animals

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
In a seven-day range-finding study conducted to determine appropriate doses for administration in an OECD TG 422 study, and was therefore not conducted to a guideline or to GLP (reliability score 2). In this study a NOAEL could not be determined for triacetoxyethylsilane due to the corrosive effects of this substance on the oesophagus and stomach. On the basis of this result it is concluded that it is not feasible to conduct the OECD TG 422 study, which is in agreement with the decision of the US EPA.