Registration Dossier

Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19-07-2009 to 03-02-2010
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
up-and-down procedure
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: RccHan: WIST
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Laboratories B.V. 5961 AD Horst, The Netherlands.
- Age at study initiation: 10 weeks
- Weight at study initiation: 175.9 – 204.7 g
- Fasting period before study: Overnight fasting period prior to intubation.
- Housing: Individually in Makrolon type-3 cages with standard softwood bedding (‘Lignocel’ J. Rettenmaier & Söhne GmbH&CoKG, Rosenberg, Germany, imported by Provimi Kliba AG, 4303 Kaiseraugst, Switzerland) during treatment and observation.
- Diet : Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, as libtum (except for the overnight fasting period prior to intubation and approximately 3-4 hours post dose).
- Water :Community tap water from Füllinsdorf, ad libitum.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30-70
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 19-08-2009 To:14-10-2009

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
VEHICLE
- Justification for choice of vehicle:To prevent hydrolysis of the test substance in contact with moisture/water.

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg bw
.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Limit dose
Doses:
2000 and 550 mg/kg bw
No. of animals per sex per dose:
4 females - 2000 mg/kg bw and 3 females - 550 mg/kg bw.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:The animals were examined daily during the acclimatisation period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs once during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2 to 15. Mortality/ viability was recorded once during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2 to 15. Body weights were recorded on day -1 (prior to removal of food), day 1 (prior to administration) and on day 8 and 15. All animals were examined macroscopically after death whether they died spontaneously or were killed in extremis, as well as at the end of the study.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights, histopathology.
Statistics:
The statistical programme (AOT 425 STAT Pgm) version: 1.0,2001 was used.

Results and discussion

Effect levels
Sex:
female
Dose descriptor:
LD50
Effect level:
1 049 mg/kg bw
Based on:
test mat.
95% CL:
>= 550 - <= 2 000
Remarks on result:
other: based on an assumed sigma of 0.5.
Mortality:
500 mg/kg bw - No mortality occurred during the study period.
2000 mg/kg bw – All 4 animals died spontaneously or had to be killed in extremis due to the relevant clinical signs observed including an excessive body weight loss in the three sacrificed animals. The severe body weight loss (over 20 %) required the sacrifice of the animals.

Clinical signs:
500 mg/kg bw – No clinical signs were observed in the three treated females (No. 2, 4 and 6) within the first 30 minutes on test day 1. One (No.6) of these animals showed no clinical signs during the entire study. The two other animals were observed with slightly ruffled fur and slight sedation at the 1- and 5- hour readings. The slightly ruffled fur persisted in one (No.4) of these animals on test days 2 and 3. These two animals showed no additional clinical signs during the remainder of the study.

2000 mg/kg bw – Clinical signs were within the first 30 minutes and generally persisted until death occurred. Slight to moderate reffled fur, hunched posture, slight to moderate sedation, tachypnea, bradypnea, labored to deep respiration, slight to moderate poor coordination, cyanosis, red serious rhinorrhea, general bad state of health (weakness) and body weight loss.
Body weight:
500 mg/kg bw – The body weights were within the range commonly recorded for this strain and age.
2000 mg/kg bw – The animals showed a loss of body weight ( -21 % for animal No.7 and -24.6 % for animal No.3 and 5) between the day of treatment (= day 1; fasting period was on day, between test day -1 and test day 1) and the day of sacrifice (test day 4, 5 or 6). No body weight was recorded following the spontaneous death of the first animal treated at 2000 mg/kg on test day 1 and found dead on test day 2.
Gross pathology:
500 mg/kg bw – Necropsy and macroscopic examination revealed no substance-related findings.
2000 mg/kg bw – Light red congested lungs and black brown stomach distended with gas in animal No.1 dosed at 2000 mg/kg bw (which died spontaneously), tan discoloration of kidneys in animal No.3 (killed in extremis) and spleen reduced in size as well as distended stomach in animal No.7 (killed in extremis). Animal No.5 (killed in extremis) showed no macroscopic findings at the unscheduled necropsy .

Applicant's summary and conclusion

Interpretation of results:
other: CLP/EU GHS criteria are met, Category 4 classification required according to Regulations (EC) No 1272/2008.
Conclusions:
In an acute oral toxicity study conducted according to OECD 425 and to GLP, the median lethal dose of trimethoxyphenylsilane after single oral administration to female rats observed over a period of 14 days, is: LD50 (female rats)= 1049 mg/kg bw (based on an assumed sigma of 0.5).