2-Pentanone, 2,2',2''-[O,O',O''-(ethenylsilylidyne)trioxime]

Endpoint summary

Description of key information

Acute toxicity oral: The oral LD50 of OS2600 was determined to be within the range of 1000-2000 mg/kg bw in rats. The LD50 of MPKO, the hydrolysis product of OS2600, was determined to be ca 1133 mg/kg bw in rats.

Acute toxicity dermal: Based on the read-across approach from the analogue substance OS2200, the acute lethal dermal dose to rats of OS2600 was determined to be greater than 1786 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:

experimental study

Adequacy of study:

key study

Study period:

12 April -11 May 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.1100 (Acute Oral Toxicity)

Deviations:

no

Qualifier:

according to guideline

Guideline:

other: Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 12 Nohsan, Notification No 8147, April 2011, including the most recent partial revisions.

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Species:

rat

Strain:

other: Wistar strain, Crl:WI (Han)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany.
- Age at study initiation: Young adult animals (approx. 8 weeks old)
- Weight at study initiation: Body weight variation was within +/- 20% of the sex mean (control group: 152 - 178 grams; 1000 mg/kg group: 147 - 177 grams ; 2000 mg/kg group: 153 - 179 grams).
- Fasting period before study: Animals were deprived of food overnight prior to dosing and until 3-4 hours after administration of the test substance. Water was available ad libitum.
- Housing: Group housing of 3 animals per cage in labeled Macrolon cages
- Diet: Free access to pelleted rodent diet (SM R/M-Z from SSNIFF® Spezialdiäten GmbH, Soest, Germany).
- Water: Free access to tap water.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
Environmental controls for the animal room were set to maintain 18 to 24°C, a relative humidity of 40 to 70%, approximately 15 room air changes/hour, and a 12-hour light/12-hour dark cycle.

IN-LIFE DATES: From: 12 April 2012 to 11 May 2012

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

GAVAGE METHOD: plastic feeding tubes.

Frequency: single dosage, on Day 1.

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.
Dose volume calculated as dose level (g/kg) / density (g/mL).

DOSAGE PREPARATION: The test substance was dosed undiluted as delivered by the sponsor. No correction for purity was made

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Based on anticipated mortality at the next higher dose.

Doses:

1000 mg/kg body weight
2000 mg/kg body weight

No. of animals per sex per dose:

1000 mg/kg: 6 (2 groups of three females in a stepwise manner)
2000 mg/kg: 3

Control animals:

yes

Details on study design:

The toxicity of the test substance was assessed by stepwise treatment of groups of 3 females. The first group was treated at a dose level of 1000 mg/kg. The absence or presence of mortality of animals dosed at one step determined the next step, based on the test procedure defined in the guidelines. The onset, duration and severity of the signs of toxicity were taken into account for determination of the time interval between the dose groups. A concurrent control group was added to the first two treated groups. Thereafter no concurrent control was added.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Twice daily. The time of death was recorded as precisely as possible.
Body weights: Days 1 (pre-administration), 8 and 15 and at death (if found dead after Day 1).
Clinical signs: At periodic intervals on the day of dosing (Day 1) and once daily thereafter, until Day 15.
- Necropsy of survivors performed: on Day 15
- Other examinations performed: bloodsampling on Day 5 and 15 (red blood cell count, reticutolcyte count, hemoglobin level and met-hemoglobin level, organ weights (spleen, kidney and liver) at necropsy, hostopathological examination of the spleen

Statistics:

No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 1 000 - < 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No mortality occurred at 1000 mg/kg and control groups. Two females at 2000 mg/kg (2/3) were found dead on Days 1 or 4.

Clinical signs:

other: No clinical signs were noted in the control animals. Animals at 1000 mg/kg showed lethargy, hunched posture, uncoordinated movements, piloerection, ptosis, slow breathing, and/or watery discharge from the eye on Day 1. Animals at 2000 mg/kg showed lethar

Gross pathology:

Necropsy did not reveal any toxicologically relevant alterations.
A control animal showed pelvic dilation and black nodules in the liver, which are considered incidental findings not related to the test substance. One animal at 2000 mg/kg showed advanced autolysis and the skin of the left region of the head was missing due to cannibalism.

Other findings:

The animals at 1000 mg/kg showed lower red blood cell counts in combination with higher percentage of reticulocytes, compared to the control animals, on Day 5 and 15. A lower level of total hemoglobin was noted on Day 5, which recovered on Day 15. The slight higher met-hemoglobin levels on Day 5 and/or 15 (as compared to the controls) are within the range to be expected for rats of this age and strain.
The surviving animal treated at 2000 mg/kg showed comparable trends in all four parameters.

Liver, spleen and kidney weights of treated animals were considered to be similar to those of control animals.

There were no treatment-related findings in the spleens of the 1000 mg/kg treated rats.
No direct cause of death at 2000 mg/kg could be established from the examined sections of the spleen.
There was a treatment related microscopic finding in the 2000 mg/kg treated rats. Atrophy of the white and red pulp of the spleen was noted at minimal degree in the one surviving female and at moderate degree in one female (found dead on Day 4).
The remainder of the recorded microscopic findings in the spleen were all within the normal range of background alterations encountered in rats of this age and strain and therefore not regarded as test article related.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

In an acute oral toxicity study with female rats, the LD50 was determined to be between 1000 and 2000 mg/kg bw.

Executive summary:

The acute oral toxicity study was performed in accordance with OECD Guideline 423 and EU Method B1 tris. Initially, OS 2600 was administered by oral gavage to 3 female Wistar rats at 1000 mg/kg body weight. In a stepwise procedure additional groups of females were dosed at 1000 and 2000 mg/kg body weight. Concurrent control groups were added in the first two treatment groups. All animals were subjected to daily observations and weekly determination of body weight. Blood samples were taken from all surviving animals on Day 5 and prior to necropsy. Macroscopic examination was performed on the day of death or after terminal sacrifice (Day 15). Histopathology examination was performed on the spleen. No mortality occurred at 1000 mg/kg and control groups. Two females at 2000 mg/kg (2/3) were found dead on Days 1 or 4 and therefore, the oral LD50 value of OS 2600 in Wistar rats was established to be within the range of 1000-2000 mg/kg body weight. Haematology parameters were affected by treatment at a dose level of 1000 mg/kg, and the same trend was noted at 2000 mg/kg. The following findings were included: lower red blood cell count, higher reticulocyte percentage and lower haemoglobin levels. These findings were not accompanied by treatment related morphological changes in the spleen at 1000 mg/kg. Two animals at 2000 mg/kg (one surviving and one which died on Day 4) showed atrophy of the white and red pulp of the spleen at microscopic examination.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 000 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has a Klimisch score 1.

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across from an analogue substance for which a guideline study (KIimish = 1) is available.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached reporting format and read-across rationale.

Reason / purpose for cross-reference:

read-across source

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 1 786 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Based on a read-across from an analogue for which LD50 > 2000 mg/kg bw

The data matrix is included in the reporting format attached.

The results from the read-across approach are expressed (calculated) on the basis of the molecular weight of OS2600 and OS2200 since the basic structures of the target and source substances are the same. No other adaptation is necessary.

Interpretation of results:

not classified

Remarks:

Criteria used for interpretation of results: EU

Conclusions:

Based on the read-across approach from the analogue substance OS2200, the dermal LD50 of OS2600 was determined to be greater than 1786 mg/kg bw.

Executive summary:

An acute dermal toxicity study was performed on the analogue substance OS2200 according to EU Method B.3. A group of ten rats (five males and five females) was given a single dermal application of the test substance, as supplied, at a dose level of 2000 mg/kg bw. All animals were killed and examined macroscopically on Day 15, the end of the observation period. There were no deaths and no signs of systemic reaction to treatment. Sites of application showed no irritation or other dermal changes. In comparison with historical data from the Department of Industrial Toxicology of HRC, slightly low bodyweight gains were recorded for one male and three females on Day 8. All other rats achieved satisfactory bodyweight gains throughout the study. No abnormalities were recorded at the macroscopic examination on Day 15. The LD50 of the analogue OS220 was therefore > 2000 mg/kg bw. Based on these results, the read-across approach was applied and the dermal LD50 of OS2600 was determined to be > 1786 mg/kg bw.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

1 786 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has a Klimisch score 1 (since read-across, the Klimisch score is 2).

Additional information

Acute toxicity oral:

Key study: The acute oral toxicity study was performed in accordance with OECD Guideline 423 (GLP study). The oral LD50 value for OS2600 was established to be within the range of 1000-2000 mg/kg body weight. Haematology parameters were affected by treatment at a dose level of 1000 mg/kg, and the same trend was noted at 2000 mg/kg.

Supporting study: An acute oral toxicity study was performed with MPKO, the hydrolysis product of OS2600, in the rat in accordance with OECD Guideline 425 using the Up and Down procedure (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.

Acute toxicity dermal:

Key study: Read-across approach from experimental data on the analogue substance OS2200: An acute dermal toxicity study was performed on the analogue substance OS2200 according to EU Method B.3 (GLP study). Based on the experimental results obtained with the analogue substance OS2200 (LD50 > 2000 mg/kg bw, with no signs of systemic reaction to treatment and no abnormalities at the macroscopic examination), the acute lethal dermal dose (LD50) to rats for OS2600 was determined to be > 1786 mg/kg bw.

Justification for classification or non-classification

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