Butan-2-one O,O',O'',O'''-silanetetrayltetraoxime

Endpoint summary

Description of key information

Key study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 333.54 ppm (26.73 and 32.07 mg/kg bw/day for males and females respectively).

Supporting study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one-O,O',O''-(methylsilanetriyl)oxime for 13 weeks repeated dose toxicity by oral route in mice was estimated to be 720.89 ppm (126.88 mg/kg bw/day) for males and 1441.79 ppm (392.17 mg/kg bw/day) for females.

Key study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOEL for butan-2-one-O,O',O''-(methylsilanetriyl)oxime for 28 days repeated dose toxicity by oral route in rats was estimated to be 4.61 mg/kg/day.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
The target substance TOS is an oxime silane that undergoes rapid hydrolysis in aqueous to MEKO and the corresponding silanol. At the same time, silanols undergo continuous condensation reaction to produce higher molecular weight siloxanes which are in the molecular weight range large enough to be considered biologically unavailable. Therefore, the toxicity of TOS is due to the hydrolysis product MEKO and their values are comparable.
See attached reporting format.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

(males and females at >=2672.61)

Mortality:

mortality observed, treatment-related

Description (incidence):

(males and females at >=2672.61)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

(males at >=1336.30 ppm, females at >=2672.61 ppm)

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

no effects observed

Description (incidence and severity):

(not significant)

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

(males and females at >= 333.54 ppm)

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

(males at >= 333.54 ppm, females at >=668.15 ppm)

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

(males and females at >=668.15 ppm)

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

(males and females at >= 668.15 ppm)

Histopathological findings: neoplastic:

no effects observed

Details on results:

Based on experimental results obtained with the analogue substance butanone oxime in rats after 13 weeks oral administration where the NOAEL for erythrotoxicity was 312 ppm and the NOAEL for olfactory epithelium degeneration was 1250 ppm, the read-across approach was applied and the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 333.54 ppm for erythrotoxicity and 1336.30 ppm for olfactory epithelium degeneration.

Key result

Dose descriptor:

NOAEL

Remarks:

(erythrotoxicity)

Effect level:

333.54 ppm

Based on:

test mat.

Remarks:

(analogue subtance)

Sex:

male/female

Basis for effect level:

other: (based on read-across approach from experimental data on analogue butanone oxime) (basis for effect: anemia)

Key result

Dose descriptor:

NOAEL

Remarks:

(nose)

Effect level:

1 336.3 ppm

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (based on read-across approach from experimental data on analogue butatone oxime) (basis for effect: olfactory epithelium degeneration)

Key result

Critical effects observed:

not specified

The concentrations used in the study on the analogue substance and the read-across approch estimation are as follows:

 

Unit	Sex	MEKO	TOS
ppm	Male/female	312,00	333,54
		625,00	668,15
		1250,00	1336,30
		2500,00	2672,61
		5000,00	5345,21
mg/kg bw/day	Male	25,00	26,73
		50,00	53,45
		100,00	106,90
		175,00	187,08
		280,00	299,33
mg/kg bw/day	Female	30,00	32,07
		65,00	69,49
		120,00	128,29
		215,00	229,84
		335,00	358,13

 

 

Conclusions:

Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 333.54 ppm (26.73 and 32.07 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1336.30 ppm (106.90 and 128.29 mg/kg bw/day for males and females respectively) for olfactory epithelium degeneration.

Executive summary:

A 90 days repeated dose toxicity test was performed on analogue substance butanone oxime in accordance with an equivalent method to OECD Guideline 408. After 13 weeks oral administration of analogue MEKO to rats up to 5000 ppm (up to 280 mg/kg bw/day in males and up to 335 mg/kg/bw/day), the NOAEL for erythrotoxicity was determined to be 312 ppm (25 and 30 mg/kg bw/day in males and females respectively) and the NOAEL for olfactory epithelium degeneration was determined to be 1250 ppm (100 and 120 mg/kg bw/day in males and females respectively).

Based on these results, the read-across approach was applied and the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 333.54 ppm (26.73 and 32.07 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1336.30 ppm (106.90 and 128.29 mg/kg bw/day for males and females respectively) f or olfactory epithelium degeneration.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

26.73 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Three studies are available on an analogue substance (two 90d and a 28 day repeated dose toxicity studies) with a Klimisch score = 1. The overall quality of the database was determined as appropriate for assessment.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

ORAL Repeated dose toxicity study:

Key study: Read-across from experimental data on analogue butatone oxime: 90 days oral repeated dose toxicity study in rats (test method similar to OECD 408):

In the study performed on analogue butatone onxime, groups of 10 rats per sex were given drinking water containing 0, 312, 625, 1250, 2500, or 5000 ppm (25, 50, 100, 175, 175, 280 mg/kg bw/day in males and 30, 65, 120, 215, 335 mg/kg bw/day in females) of test item. All rats survived until the end of the study. NOAEL for the most sensitive parameter (erythrotoxicity) for rats after 90 days of exposure to butanone oxime was determined to be 312 ppm (25 mg/kg bw/day males and 30 mg/kg bw/day females). Based on these results, the read-across approach was applied and the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 333.54 ppm (26.73 mg/kg bw/day in males and 32.07 mg/kg bw/day in females).

Supporting study: Read-across from experimental data on analogue substance butanone oxime: 90 days oral repeated dose toxicity study in mice (test method similar to OECD 408):

In the study performed on analogue butanone oxime, groups of 10 mice per sex were given drinking water containing 0 (control), 625, 1,250, 2,500, 5,000, or 10,000 ppm (110, 200, 515, 755, 1330 mg/kg bw/day in males and 145, 340, 630, 1010 and 3170 mg/kg bw/day in females) of test substance. All mice survived until the end of the study. The NOAEL after 90 days of exposure to butanone oxime based on the most sensitive parameter was determined to be 625 ppm (110 mg/kg bw/day) for male mice (basis for effect: hyperplasia of the urinary bladder transitional epithelium) and 1250 ppm (635 mg/kg bw/day) for female mice (basis for effect: infiltration of inflammatory cells into the underlying submucosa in the urinary bladder and degeneration of the olfactoy epithelium). Based on these results, the read-across approach was applied and the NOAEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 668.15 ppm (117.59 mg/kg bw/day) for males and 1336.30 ppm (363.47 mg/kg bw/day) for females.

Key study: Read-across from experimental data on analogue substance butanone oxime: 28 days oral repeated dose toxicity study in rats (test method similar to OECD 407):

In the study performed by the Japanese authorities, 7 rats per sex and per dose were orally exposed to the analogue substance butanone oxime at 0 (control), 4, 20 and 100 mg/kg bw/day doses during 28 days. The NOEL for repeat dose toxicity for both males and females was considered to be both 4 mg/kg/day (basis for effect: effects on erythrocyte series, spleen weight increase, hemosiderin granules in the liver (only in females)). Based on these results, the read-across approach was applied and the NOEL for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 4.28 mg/kg bw/day.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The study with the longest duration (90-days) performed and lowest NOAEL was chosen.

Justification for classification or non-classification

Based on available data and in accordance with CLP Regulation (EC) No 1272/2008, the substance butan-2-one O,O',O'',O'''-silanetetrayltetraoxime is classified as STOT Rep. Exp. 2 since the ignificant toxic effects were observed in a 90-day repeated-dose study (oral) conducted in experimental animals within value ranges 10 -100 mg/kg bw/day.