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

Endpoint summary

Description of key information

Key study: Test method EEC B7, OECD 407. GLP study. Based on the observation of a dose-related regenerative anemia in the 150 and 300 mg/kg/day males and females the NOAEL following 28-day oral administration of test substance to rats.
Key study: Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 433.93 ppm (34.77 and 41.72 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 13 weeks repeated dose toxicity by oral route in mice was estimated to be 869 ppm (152.99 mg/kg bw/day) for males and 1738.50 ppm (472.87 mg/kg bw/day) for females.

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:

migrated 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: see 'Remark'

Remarks:

2-butanone-O,O',O''- (phenylsilylidyne)trioxime undergoes rapid hydrolysis in aqueous to butanone oxime and the corresponding silanol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to butanone oxime and their values are comparable.

Reason / purpose for cross-reference:

reference to other study

Principles of method if other than guideline:

Read-across approach from experimental data (test method similar to OECD Guideline 408, GLP study) on an analogue substance.

GLP compliance:

no

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

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

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

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

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

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 the 2-butanone-O,O',O''-(phenylsilylidyne)trioxime was estimated to be 433.93 ppm for erythrotoxicity and 1738.50 ppm for olfactory epithelium degeneration.

Dose descriptor:

NOAEL

Remarks:

(erythrotoxicity)

Effect level:

433.93 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)

Dose descriptor:

NOAEL

Remarks:

(nose)

Effect level:

1 738.5 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)

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	POS
ppm rats	Male/female	312,00	433,93
		625,00	869,25
		1250,00	1738,50
		2500,00	3477,00
		5000,00	6954,01
mg/kg bw/day	Male	25,00	34,77
		50,00	69,54
		100,00	139,08
		175,00	243,39
		280,00	389,42
mg/kg bw/day	Female	30,00	41,72
		65,00	90,40
		120,00	166,90
		215,00	299,02
		335,00	465,92

Meko = Butanone oxime

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

See "Data Matrix" and "Reporting Format" attached.

Conclusions:

Based on the read-across approach from experimental results on analogue butanone oxime, the NOAEL for 2-butanone-O,O',O''-(phenylsilylidyne)trioxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 433.93 ppm (34.77 and 41.72 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1738.50 ppm (139.08 and 166.90 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 2-butanone-O,O',O''-(phenylsilylidyne)trioxime for 13 weeks repeated dose toxicity by oral route in rats was estimated to be 433.93 ppm (34.77 and 41.72 mg/kg bw/day for males and females respectively) for erythrotoxicity and 1738.50 ppm (139.08 and 166.90 mg/kg bw/day for males and females respectively) f or olfactory epithelium degeneration.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

34.77 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The key study on the analogue substance is GLP compliant and of high quality (Klimisch score = 1). The overall quality of the database was determined as appropriate for assessment.

Additional information

Key study: Experimental results (RDT oral 28 days, rats)

A 28 days repeated dose toxicity test was performed with the test substance in accordance with EEC method B7 and OECD guideline 407. Test item was administered orally, by gavage, to rats up to 300 mg/kg bw/day for 28 consecutive days followed by a 14 -day recovery phase. Oral administration of test substance for 28 consecutive days produced a dose-related anemia. This was supported by changes in several hematology parameters including decreased in the 150 and 300 mg/kg bw/day doses. Enlarged, blackish-purple spleens were observed at 150 and 300 mg/kg bw/day and persisted to the end of the recovery phase in the 300 mg/kg bw/day dose animals. Histologically, the spleen of the 300 mg/kg bw/day dose animals was noted to have extramedullary hematopoiesis and accumulations hemosiderin. Hepatic changes were also noted and consisted of multiple, scattered foci of extramedullary hematopoiesis within sinusoids and numerous hemosiderin laden macrophages (Kupffer cells) lining sinusoids. Based on the observation of a dose-related regenerative anemia in the 150 and 300 mg/kg/day males and females the NOAEL following 28-day oral administration of test substance to rats.

Key study: Read-across from experimental data on analogue butatone oxime (RDT 90 oral days, rats)

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 was estimated to be 433.93 ppm (34.77 and 41.72 mg/kg bw/day for males and females respectively).

Supporting study: Read-across from experimental data on analogue substance butanone oxime (RDT oral 90 days, mice)

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 was estimated to be 869 ppm (152.99 mg/kg bw/day) for males and 1738.50 ppm (472.87 mg/kg bw/day) for females.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study with the longest duration (90-days) was chosen (key study).

Justification for classification or non-classification

Based on available data and in accordance with CLP Regulation (EC) No 1272/2008, the substance is classified as STOT Rep. Exp. 2 (target organ: red blood cells) since significant toxic effects were observed in a 90-day repeated-dose study (oral) conducted in experimental animals within value ranges of 10 -100 mg/kg bw/day.