Butan-2-one O,O',O''-(methylsilylidyne)trioxime

Endpoint summary

Description of key information

Acute oral toxicity: Key study: Test according to OECD guideline 401. GLP study. LD50 was determined to be 2463 mg/kg bw.

Acute dermal toxicity: Key study: Test method according to OECD 402. GLP study. LD50 was determined to be > 2000 mg/kg bw.

Acute inhalation toxicity: Data waiving (other justification): According to REACH Annex VIII, column 2, the study was not needed to be performed since the choice for the second routh in addition for the oral route was provided for dermal route.

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:

11 Mar 1986 to 22 Jan 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

yes

Remarks:

(No information on test substance purity)

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Iffa-Credo,France.
- Age at study initiation: 5-7 weeks
- Weight at study initiation: Males: 158-163 g; Females: 138-151 g
- Fasting period before study: Yes
- Housing: groups of five in stainless steel mesh cages.
- Diet: Pelleted complete maintenance diet (UAR, formula "A.D4", UAR, Epinay sur Orge, France), ad libitum
- Water: Softened and filtered drinking water, ad libitum
- Acclimation period: Minimum one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 03.11.1986 To: 17.12.1986

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 2.85 ml/kg

Doses:

1129, 1416, 1782, 2247 (two groups), 2822 mg/kg bw

No. of animals per sex per dose:

Five

Control animals:

other: yes, distilled water

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Mortality and abnormal clinical signs were noted 15 minutes after administration of the test substance, then 1, 2 and 4 hours later and then 14 day recovery period. Body weights were measured on Day -1, Day 1 (immediately before administration), Day 8 and 15.
- Necropsy of survivors performed: yes (and of animals that died).
- Other examinations performed: gross pathology.

Statistics:

The body weight of the animals was evaluated, for each group and each sex, by calculating the mean values, the standard variation and the coefficient of variation to give a statistical appreciation of the homogeneity of the data, and whenever possible, by the Student test to compare each treated group with the control group. The gradient of the mortality curve at the different dose levels enabled an LD50 to be calculated.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 463 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Method of Bliss. The report is not entirely clear, however the upper and lower limits appear to be 95% CL.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 453 mg/kg bw

Based on:

test mat.

Remarks on result:

other: Method of Litchfield & Wilcoxon. The report is not entirely clear, however the upper and lower limits appear to be 95% CL.

Mortality:

See Table 1.

Clinical signs:

other: See Table 1.

Gross pathology:

Discolouration of the spleen.

Table 1: Number of animals that died, time range for mortality, body weight change and overt toxicity.

Dose (mg/kg bw)	Mortality (dead/total)			Time range of deaths (days)	Overt toxicity (numbers affected, where specified in the report)
	Male	Female	Combined
0	0/0	0/0	0/10	-	-
1129	0/0	0/0	0/10	-	Prostration, lethargy, coma (2), piloerection(10), ptosis(4), ataxia. No overt adverse effects on day 2.
1416	0/0	0/0	0/10	-	Prostration, lethargy, coma (3), piloerection(10), ptosis(5), ataxia. No overt adverse effects on day 2.
1782	2/5	0/5	2/10-	2	Prostration, lethargy, coma (6), piloerection(10), ptosis(3), ataxia. No overt adverse effects in surviving animals on day 2.
2247	2/5	2/5	4/10	2	Prostration, lethargy, coma (6), piloerection(10), ptosis(4), ataxia. No overt adverse effects on day 3.
2247	2/5	1/5	3/10	2	Prostration, lethargy, coma (7), piloerection(10). No overt adverse effects in surviving animals on day 3.
2822	4/5	3/5	7/10	2	Either prostration, lethargy or coma (8) in all animals. Some cases of piloerection, lacrimation, clonic convulsions and ataxia. No overt adverse effects in surviving animals on day 3.

 

Interpretation of results:

GHS criteria not met

Remarks:

CLP Implementation

Conclusions:

In an acute oral toxicity study conducted to the now deleted OECD 401 and to GLP (RL 1) the LD50 for butan-2-one O,O',O''-(methylsilylidyne)trioxime was 2463 mg/kg bw in rats. Clinical signs of toxicity at all doses were prostration, lethargy, ptosis, ataxia and coma in several animals. In surviving animals these signs had disappeared by day 2/3.

Executive summary:

An acute oral toxicity study was conducted according to the OECD guideline 401 under GLP conditions. Five Sprague Dawley rats per sexe were exposed to 1129, 1416, 1782, 2247 (two groups), 2822 mg/kg bw test substance by oral gavage. Control animals were administered distilled water. Mortality and abnormal clinical signs were noted 15 minutes after administration of the test substance, then 1, 2 and 4 hours later and then 14 day recovery period. Body weights were measured on Day -1, Day 1 (immediately before administration), Day 8 and 15. Necropsy was performed at day 15 to survivors and to animals which died. Clinical signs of toxicity at all doses were prostration, lethargy, ptosis, ataxia and coma in several animals. In surviving animals these signs had disappeared by day 2/3, reduced body weight gain was observed at high doses, discolouration of the spleen was observed macroscopically.  The oral LD50 was determined as 2463 mg/kg-bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 463 mg/kg bw

Quality of whole database:

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

05 Nov - 26 Nov 1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Deviations:

no

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: Iffa-Crédo, FRANCE
- Age at study initiation: 5-7 wk
- Weight at study initiation: 188-201 g (m); 167-177 g (f)
- Housing: single housing in suspended stainless steel cage
- Diet : standard diet, ad libitum
- Water: drinking water, ad libitum
- Acclimation period: 1 wk

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±3
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: apparently from: 1986-11-05 To: 1986-11-20

Type of coverage:

semiocclusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: 10%
- % coverage: 10%
- Type of wrap if used: bandage (adhesive perforated tape)

REMOVAL OF TEST SUBSTANCE
- Washing: wiped with gauze
- Time after start of exposure: 24 h

TEST MATERIAL
- Amount(s) applied: 2000 mg/kg bw (2.02 ml/kg bw)
- Concentration: neat

Duration of exposure:

24 h

Doses:

Definitive study: 2000 mg/kg bw
Preliminary study: 1000, 2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

yes

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observations at 15 min; 1, 2 and 4 h; then daily till day 14. Weights weekly.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Bliss; Litchfield & Wilcoxon mentioned. None required.

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: No mortality occurred up to 2000 mg/kg bw.

Mortality:

None

Clinical signs:

other: No clinical, behavioural or local (dermal) effects.

Gross pathology:

No treatment related effect.

Interpretation of results:

GHS criteria not met

Remarks:

CLP Implementation.

Conclusions:

A reliable limit study conducted in compliance with a standard guideline and in accordance with GLP, identified an LD50 of > 2000 mg/kg bw in male and female rats. No local effects were reported.

Executive summary:

An acute dermal toxicity study was performed with the test subtance according to OECD guideline 402. According to the results of a preliminary study, a group five rats per sex was given a single dermal application of the test substance at a dose level of 2000 mg/kg bw, the application site (10 %) was covered by a semiocclusive patch for 24 hours. Clinical observations were made at 15 min, 1, 2 and 4 h then daily until day 14 after the removal of the test substance, weights were measured weekly. 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. No abnormalities were recorded at the macroscopic examination on Day 15. Based on the results the LD50 for the test substance in rats was determined to be greater than 2000 mg/kg bw.

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 quality of the database was determined as appropriate for assessment.

Additional information

Acute oral toxicity:

Key study: In an acute oral toxicity study conducted to the now deleted OECD 401 and to GLP (RL 1) the LD50 for Butan-2-one O,O',O''-(methylsilanetriyl)oxime was 2463 mg/kg bw in rats. Clinical signs of toxicity at all doses were prostration, lethargy, ptosis, ataxia and coma in several animals. In surviving animals these signs had disappeared by day 2/3.

Supporting study: An acute oral study was performed with a method similar to OECD Guideline 401 (GLP study) in F344 rats and the LD50 was stimated to be ~ 2500 mg/kg. Dose-related anemia was found at all dose levels 14 days after dosing and the spleen microscopically showed extramedullary hematopoiesis and hemosiderin deposition consistent with a hemolytic event.

Acute dermal toxicity:

Key study: A limit study conducted in compliance with a standard guideline and in accordance with GLP, identified a LD50 for butan-2-one O,O',O''-(methylsilanetriyl)oxime of > 2000 mg/kg bw in male and female rats.

Acute inhalation toxicity:

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. This information is provided for dermal route.

Justification for selection of acute toxicity – oral endpoint

The study with highest reliability.

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. This 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 butan-2-one O,O',O''-(methysilanetriyl)oxime is not classified for acute toxicity according to CLP Regulation (EC) No 1272/2008.