2-butanone-O,O',O''-(phenylsilylidyne)trioxime

Endpoint summary

Description of key information

Acute toxicity, oral. Key study: Test method EPA OTS 798.1175 (similar to OECD guideline 401). GLP study. The acute oral LD50 in the rat was determined to be greater than 2000 mglkg. The 100 mg/kg dose group was considered to be NOAEL since  toxicity was observed in rats dosed at 2000 mg/kg and 500 mg/kg as expressed by adverse clinical signs and significant body weight decreases. 
Acute toxicity, dermal: Key study: Test method EEC B3, OECD 402. GLP study. The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

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

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Test method according to EPA OTS 798, similar to OECD 401. GLP study.

Qualifier:

according to guideline

Guideline:

EPA OTS 798.1175 (Acute Oral Toxicity)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes

Test type:

fixed dose procedure

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source:Charles River Laboratories, Inc., Portage, Michigan.
- Age at study initiation: young adult
- Weight at study initiation: 200-300g
- Fasting period before study: overnight
- Housing: The animals were housed individually in suspended stainless steel cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21.5-23.5 ºC (71-74ºF)
- Humidity: 39-53 %
- Air changes (per hr): 10-15 air changes/hour
- Photoperiod: 12-hour light/l2-hour dark cycle

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 1.98 mL/kg

DOSAGE PREPARATION (if unusual): Individual doses were calculated based on the animal's fasted (day 0) body weight.

RATIONALE FOR DOSE SELECTION: A range findint study was performed exposing one rat per sex per dose to 100, 500, 1000, 2000 and 3000 mg/Kg. Clinical observation, body weights and gross necropsy were analysed. The range-finding data indicated that the test article produced mortality at the highest tested dose level of 3000 mglkg level in females, but did not produce mortality at that level in the males.

Doses:

100, 500, 2000 mg/kg

No. of animals per sex per dose:

5 males and 5 females per dose.

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: two times on study day 0 (postdose) and daily thereafter (days 1-14).
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight, gross necropsy, organ weights, histopathohlogy
Organ weights: Heart, Kidneys (paired), Liver, Spleen, Testes (paired), Brain.
Retained tissues: Heart, Kidneys (paired), Liver, Spleen, Testes (paired), Brain, Femur (bone marrow), Ovaries, Thymus.

Statistics:

Since the LD50 values could not be reliably calculated based on the mortality response, the LD50 was estimated based on the observed data.
Body weights, body weight gains and organ weights were analyzed by one-way analysis of variance.

Preliminary study:

A. Range-Finding Study
1. Dosing
On day -1, the animals chosen for the range-finding study were weighed and fasted overnight. On day 0, the test article was administered orally as a single dose using a ball tipped stainless steel gavage needle attached to a syringe at the following levels: 100, 500, 1000, 20000, 3000 mg/kg.
Number of animals per sex per dose: 1 male, 1 female per dose.
2. Clinical Observations
The range-finding animals were observed for mortality on day 0 (post-dose) and on days 1-7. A general healthlmortality check was performed twice daily (in the morning and in the afternoon).
3. Body Weights
Individual body weights were obtained for the range-finding animals prior to fasting (day -1) and prior to dosing on day 0.
4. Gross Necropsy
All range-finding animals which died spontaneously during the study or were euthanized by carbon dioxide inhalation at study termination (day 7) were removed from study. No necropsy was performed.
The range-finding data indicated that the test article produced mortality at the highest tested dose level of 3000 mglkg level in females, but did not produce mortality at that level in the males.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

The only mortality occurred on study day 1 at 2000 mgl/kg bw.

Clinical signs:

other: The most notable clinical abnormalities observed during the study included prostration, decreased activity, wobbly gait, rigidity upon handling, breathing abnormalities, urine stain, decreased defecation, partially closed eyelids and dark material around

Gross pathology:

Gross internal findings observed in the animal that died included abnormal content in the trachea, digestive tract and urinary bladder, reddened mucosa in the small intestine, mottled lungs, stained mucosa in the stomach, and dark red foci on the thymus. Significant gross internal findings observed at necropsy on study day 14 included blackish-purple spleens in the animals dosed at 500 and 2000 mglkg. Significant gross internal findings observed at necropsy on study day 14 included blackish-purple spleens in the animals dosed at 500 and 2000 mg/kg. Statistically significant increases in spleen weight relative to final body weight were observed for males dosed at 500 and 2000 mg/kg.

Other findings:

Organ weights: Statistical differences in absolute spleen weight were observed in the males dosed at 500 mg/kg. Although not statistically different, there was also an increase for the animals dosed at 2000 mg/kg. Statistically significant increases in spleen weight relative to final body weight were observed for males dosed at 500 and 2000 mg/kg. Increases in spleen weight relative to final body weight, while greater in females dosed at 500 and 2000 mg/kg, were not statistically significant. No other statistically significant differences were observed.

Under the conditions of this test, the acute oral LD50 in the rat was determined to be greater than 2000 mgl/kg. However, toxicity was observed in rats dosed at 2000 mgkg and 500 mgl/kg as expressed by adverse clinical signs and significant body weight decreases. The 100 mgl/kg dose group was considered to be NOAEL.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The LD50 of test item was determined to be greater than 2000 mg/kg. 

Executive summary:

This study was performed to assess the short-term toxicity of test item in Sprague-Dawley rats when administered by gavage as a single oral dose according to EPA OTS EPA OTS 798.1175. This study is intended to provide information on the potential health hazards of the test article with respect to oral exposure. Under the conditions of this test, the acute oral LD50 in the rat was determined to be greater than 2000 mglkg. However, toxicity was observed in rats dosed at 2000 mg/kg and 500 mg/kg as expressed by adverse clinical signs and significant body weight decreases. The 100 mg/kg dose group was considered to be NOAEL.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 001 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has Klimisch score 1. The overall quality of the database was determined as appropriate for assessment.

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:

experimental study

Adequacy of study:

key study

Study period:

1999-02-23 to 1999-03-09

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: According to EEC method B3 and OECD guidleline 402 with GLP.

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

yes

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Spague Dawley CD obtained fiom Harlan U.K. Ltd., Bicester, Oxon, England.
- Age at study initiation: eight to eleven weeks
- Weight at study initiation: 219 to 242 g
- Fasting period before study:
- Housing: Individually in stainless steel metal cages (20cm high x 39cm wide x 39cm long) until Day 3 when they were returned to group housing.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 18-22 ºC
- Humidity: 28- 52 %
- Photoperiod: time switch to provide 12 hours of artificial light (0700 - 1900 hours) in each 24-hour period.

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorso lumbar region, equivalent approximately to 10% of the total body weight.
- % coverage: Treatment area (50mm x 50mm) was covered with porous gauze with a non-irritating dressing
- Type of wrap if used: Further covered by a waterproof dressing encircled firmly around the trunk of the animal.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Washed with warm water (38ºC) and blotted dry with absorbent paper.
- Time after start of exposure: 24 hours

TEST MATERIAL:
- Amount(s) applied (volume or weight with unit): 1.947 mL/kg bw
- Concentration (if solution): Administered as supplied.

Duration of exposure:

24 h

Doses:

2000 mg/kg

No. of animals per sex per dose:

5 rats per sex and per dose.

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Animals were observed soon after dosing and at frequent intervals for the remainder of Day 1. On subsequent days animals were observed on at least two occasions during the day. Bodyweight of each rat was recorded on days 1 (prior to dosing), 8 and 15.
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, dermal responses (using the scoring system according to the guidelines), body weight, macroscopic pathology (opening the thoracic and abdominal cavities)

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

There were no deaths throughout the study.

Clinical signs:

other: There was no evidence of a systemic response in any animal throughout the study.

Gross pathology:

No macroscopic abnormalities were observed for animals killed at study termination.

Other findings:

Dermal responses: No treatment related dermal reactions were seen in any animal during the study.

The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mgkg bodyweight.

Interpretation of results:

not classified

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Executive summary:

The study was designed to assess the toxicity of the test item following a single dermal administration to the rat according to EEC method B3 and OECD guideline 402. Five rats per sex rats were exposed by topical application (dorso lumbar region) to 2000 mg/kg bw under occlusive conditions. After 24 hours of exposure the treated area was washed with water. No treatment related dermal reactions were seen in any animal during the study. No deaths and no evidence of a systemic response in any animal throughout the study. The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 001 mg/kg bw

Quality of whole database:

The study is a GLP compliant and has Klimisch score 1. The overall quality of the database was determined as appropriate for assessment.

Additional information

Acute toxicity, oral: Key study: An acute oral toxicity test was performed with the test substance according to EPA OTS 798.1175 (similar to OECD guideline 401). Five Sprague-Dawley rats were exposed up to a single oral dose of 2000 mg/kg bw. The acute oral LD50 in the rat was determined to be greater than 2000 mglkg. However, toxicity was observed in rats dosed at 2000 mg/kg and 500 mg/kg as expressed by adverse clinical signs and significant body weight decreases. The 100 mg/kg dose group was considered to be NOAEL.

Acute toxicity, dermal: Key study: An acute dermal toxiciy test with the test substance was performed according to EEC method B3 and OECD guideline 402. Five Sprague-Dawley rats per sex rats were exposed by topical application to 2000 mg/kg bw under occlusive conditions for 24 hours. The acute lethal dermal dose to rats was demonstrated to be greater than 2000 mg/kg bodyweight.

Acute toxicity, inhalation: Data waiving (other justification): According to REACH Annex VIII, column 2: In addition to the oral route, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided. The information is provided for dermal route.

Justification for selection of acute toxicity – oral endpoint
Only one study available.

Justification for selection of acute toxicity – inhalation endpoint
According to REACH Annex VIII, column 2: In addition to the oral route, for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route need be provided. The information is provided for dermal route.

Justification for selection of acute toxicity – dermal endpoint
Only one study available.

Justification for classification or non-classification

Based on the available data on oral and dermal acute toxicity (LD50 > 2000 mg/kg bw), the test substance is not classified for acute toxicity according to CLP Regulation (EC) No 1272/2008.