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Toxicological information

Acute Toxicity: oral

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Administrative data

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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
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

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- Name of test material (as cited in study report): 2-pentanone oxime (methyl propyl ketoxime)
- Molecular formula (if other than submission substance): C5H11NO
- Molecular weight (if other than submission substance): 101.15
- Smiles notation (if other than submission substance): C\C(CCC)=N\O
- InChl (if other than submission substance): Mixture of all possible stereoisomers
- Structural formula attached as image file (if other than submission substance): see Fig.

Test animals

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

Administration / exposure

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.

Results and discussion

Effect levels
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.

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.