Registration Dossier

Administrative data

Description of key information

Weight of Evidence: Acute oral toxicity: Based on the read-across apporach from the analogue OS1600, the oral LD50 was determined to be 1540 mg/kg bw.
Weight of Evidence: Acute oral toxicity: Based on the read-across apporach from the analogue OS2600, the oral LD50 was determined to be between 1206 and 2411 mg/kg bw.
Weight of Evidence: Acute toxicity oral: Based on the read-across apporach from the analogue MPKO, the oral LD50 was determined to be 1200 mg/kg bw.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
OS3600 undergoes rapid hydrolysis in aqueous to MPKO and the corresponding silanol. Silanols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to MPKO and their values are comparable. The study has been conducted according to OECD guidance under GLPs.
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 425 (Acute Oral Toxicity: Up-and-Down Procedure)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
up-and-down procedure
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: 9-12 weeks
- Weight at study initiation:
- Fasting period before study: overnight (maximum 20 hours)
- Housing: Individually housed in Macrolon cages (Mill type, height 18 cm.) containing sterilized sawdust and paper as cage enrichment.
- Diet (e.g. ad libitum): ad libitum (SM R/M-Z from SSNIFF Spezialdiaten Gmbh, Soest, Germany
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5 to 21
- Humidity (%): 31-80
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
VEHICLE:
The test substance was dosed undiluted as delivered by the sponsor.

MAXIMUM DOSE VOLUME APPLIED:
2000 mg/kg (2.205 ml/kg) body weight
Doses:
Frequency: Single dosage on Day 1
2000 mg/kg (2.205 mL/kg) body weight
550 mg/kg (0.606 mL/kg) body weight
175 mg/kg (0.1929 mL/kg) body weight
Dose volume calculated as dose level (g/kg)/ spec. gravity.
No. of animals per sex per dose:
Test substance was administered by oral gavage to a female Wistar rat at 2000 mg/kg body weight. In a stepwise procedure 11 additional females were dosed at 175, 550 or 2000 mg/kg body weight. The animals were dosed sequentially one at a time.
Control animals:
no
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Observations daily, body weights on Days 1, 8 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight,organ weights (liver, kidneys and spleen), haematology (in 3 animals)
Statistics:
The LD50 was estimated based on the maximum likelihood by means of the AOT425StatPGM program.
Sex:
female
Dose descriptor:
LD50
Effect level:
1 200 mg/kg bw
Based on:
test mat.
Remarks on result:
other: (read-across from an analogue for which LD50 = 1133 mg/kg bw)
Mortality:
Yes, all at 2000 mg/kg bw (2000 mg/kg bw: 5/5; 550 mg/kg bw: 0/5; 175 mg/kg bw: 0/1).
Clinical signs:
Yes, at all dose groups.
175 mg/kg: Hunched posture.
550 mg/kg: Lethargy, hunched posture, uncoordinated movements, flat posture, laboured respiration, piloerection, salivation..
2000 mg/kg: Lethargy, ventral-lateral recumbency, hunched posture, uncoordinated movements, laboured respiration, rales, piloerection, watery discharge eye, ptosis, hypothermia, salivation.
The surviving animals had recovered from the symptoms between Days 2 and 6.
Body weight:
No effects
Gross pathology:
No macroscopic findings on rats that survived to the scheduled sacrifice. A pale, discolored liver was observed for one rat that was found dead on Day 2.
Other findings:
- Organ weights: Decreased liver weights at 550 mg/kg, decreased spleen weights at >=550 mg/kg, decreased kidney weights at 2000 mg/kg
- Other observations: Haematology showed a slight increase in red blood cells, haemoglobin and haematocrit; a slight increase in red blood cell distribution width, eosinophils and mean corpuscular haemoglobin concentration; and a slight decrease in mean corpuscular volume.

The data matrix is included in the reporting format attached.

The results from the read-across approach are expressed on the basis of the amount of MPKO generated from the hydrolysis reaction of OS3600 and their molecular weights. The amount of MPKO was estimated using the assumption that 1 mole of the target substance OS3600 produces 4 moles of MPKO. No other adaptions are necessary.

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the read-across approach from the analogue MPKO, the oral LD50 for OS3600 in rats was estimated to be 1200 mg/kg bw.
Executive summary:

An acute oral toxicity study was performed on the analogue substance MPKO in accordance with OECD Guideline 425 using the Up and Down procedure (GLP study). Test item was initially administered by oral gavage to a female rat at 2000 mg/kg bw. In a stepwise procedure 11 additional females were dosed at 175, 550 and 2000 mg/kg bw. The animals were dosed sequentially one at a time. All animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15). Animals at 2000 mg/kg bw were found dead. Clinical signs were observed at all doses, from hunched posture at 175 mg/ kg bw to lethargy, uncoordinated movements, laboured respiration, piloerection, discharge eye, ptosis hypothermia and salivation at 2000 mg/kg bw. The surviving animals had recovered from this symptoms by day 6. No effects were observed on the body weight gain. Decreases in weight of the liver (550 and 2000 mg/kg bw), kidneys (2000 mg/kg bw) and the spleen (550 and 2000 mg/kg bw) were noted. Haematology showed a slight increase in red blood cells, haemoglobin and haematocrit; a slight increase in red blood cell distribution width, eosinophils and mean corpuscular haemoglobin concentration; and a slight decrease in mean corpuscular volume. No macroscopic abnormalities were observed. The LD50 in rats was determined to be ca. 1133 mg/kg bw and within the range of 300 -2000 mg/kg bw. Based on these results, the read-across approach was applied and the oral LD50 for OS3600 was determined to be 1200 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 200 mg/kg bw
Quality of whole database:
The study is a GLP compliant and has a Klimisch score 2 (read-across from an endpoint with Klimisch score 1)

Additional information

Acute toxicity oral:

Weight of evidence: Read-across approach from experimental data on the analogue OS1600:

An acute oral toxicity study was performed on the analogue substance OS1600 according to OECD Guideline 425 (GLP study). Based on the obtained results (LD50 ca. 1234 mg/kg bw, hematological effects observed), the read-across approach was applied and the oral LD50 in rats for the substance OS3600 was determined to be ca 1540 mg/kg bw.

Weight of evidence: Read-across approach from experimental data on the analogue OS2600:

The acute oral toxicity study was performed on the analogue OS2600 in accordance with OECD Guideline 423 (GLP study). Based on the obtained results (LD50 within the range of 1000-2000 mg/kg bw and haematology parameters affected by treatment at 1000 mg/kg and 2000 mg/kg), the read-across approach was applied and the oral LD50 in rats for the substance OS3600 was determined to be between 1206 and 2411 mg/kg bw.

Weight of evidence: Read-across approach from experimental data on the analogue MPKO:

An acute oral toxicity study was performed with MPKO, the hydrolysis product of OS3600, in the rat in accordance with OECD Guideline 425 (GLP study). The LD50 in rats was determined to be ca. 1133 mg/kg bw and within the range of 300 -2000 mg/kg bw. Effects on haematology parameters were observed. Based on the read-across approach, the oral LD50 in rats for OS3600 was estimated to be 1200 mg/kg bw.


Justification for selection of acute toxicity – oral endpoint
The lowest LD50 value was chosen.

Justification for classification or non-classification

Based on the available data, the substance is classified as Acute Toxicity Category 4, H302 in accordance with CLP Regulation (EC) no. 1272/2008 since the acute toxicity value (oral) expressed as LD50 is between 300 and 2000 mg/kg bw.