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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Short description of key information:

Key study: Based on the read-across approach from experimental data (Test method EPA OTS 798.4700) on analogue butanone oxime, the NOAEL for reproductive and postnatal toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in a two-generation study was estimated to be > 213.81 mg/kg/day for rats.

 

Link to relevant study records

Reference

Endpoint:

two-generation reproductive toxicity

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

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not examined

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Based on the experimental results on the analogue where adult toxicity was observed in both generations and both sexes at all doses (LOAEL for parental toxicity = 10 mg/kg bw/day, basis for effect: hematopoiesis and hemosiderosis in spleens and livers), the read-across approach was applied and the LOAEL for parental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 10.69 mg/kg bw/da

Key result

Dose descriptor:

LOAEL

Remarks:

(parental toxicity)

Effect level:

10.69 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (Based on read-across approach from analogue substance butanone oxime) (Basis for effect: hematopoiesis and hemosiderosis in spleens and livers of P and F1 males and females).

Remarks on result:

other: Generation: other: (P and F1)

Key result

Dose descriptor:

NOAEL

Remarks:

(reproductive and postnatal toxicity)

Effect level:

> 213.81 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (Based on read-across approach from analogue substance butanone oxime) (Basis for effect: no effects at highest dose tested).

Remarks on result:

other: Generation: (F1 and F2)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Based on the experimental results on the analogue where no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity was observed at the highest dose (NOAEL for reprotox > 200 mg/kg bw/day), the read-across approach was applied and the NOAEL for reproduction and postanatal toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be > 213.81 mg/kg bw/day.

Key result

Dose descriptor:

LOAEL

Generation:

F1

Effect level:

10.69 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (Based on read-across approach from analogue substance butanone oxime) (Basis for effect: hematopoiesis and hemosiderosis in spleens and livers of P and F1 males and females).

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 213.81 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (Based on read-across approach from analogue substance butanone oxime) (Basis for effect: no effects at highest dose tested).

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

> 231.81 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: (Based on read-across approach from analogue substance butanone oxime) (Basis for effect: no effects at highest dose tested).

Reproductive effects observed:

not specified

Conclusions:

Based on the read-across approach from experimental results on analogue butanone oxime, the LOAEL for parental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 10.69 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 213.81 mg/kg bw/day.

Executive summary:

A two-generation study was performed on the analogue substance butanone oxime on CD (Sprague-Dawley) rats according to EPA OTS 798.4700 up to 200 mg/kg bw/day. Based on the experimental results on the analogue where adult toxicity was observed in both generations and both sexes at all doses (LOAEL for parental toxicity = 10 mg/kg bw/day, basis for effect: hematopoiesis and hemosiderosis in spleens and livers) and where no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity was observed at the highest dose (NOAEL for reprotox > 200 mg/kg bw/day), the read-across approach was applied and the LOAEL for parental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 10.69 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 213.81 mg/kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

213.81 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Two studies available on an analogue substance (screening study and two-generation study), of which screening study has Klimisch score = 1 and the two-generation study has a Klimisch score = 2. The overall quality of the database was determined as appropriate for assessment.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Read-across from experimental results on analogue substance butanone oxime:

Key study: A two-generation study was performed on the analogue substance butanone oxime on CD (Sprague-Dawley) rats according to EPA OTS 798.4700 up to 200 mg/kg bw/day. Based on the experimental results on the analogue where adult toxicity was observed in both generations and both sexes at all doses (LOAEL for parental toxicity = 10 mg/kg bw/day, basis for effect: hematopoiesis and hemosiderosis in spleens and livers) and where no evidence of reproductive organ or mammary gland pathology or of reproductive or postnatal toxicity was observed at the highest dose (NOAEL for reprotox > 200 mg/kg bw/day), the read-across approach was applied and the LOAEL for parental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 10.69 mg/kg bw/day and the NOAEL for reproduction and postanatal toxicity was estimated to be > 213.81 mg/kg bw/day.

 

Supporting study: A preliminary reproductive toxicity screening test (test method similar to OECD 422) was performed in rats on the analogue substance butanone oxime up to 100 mg/kg/day. In terms of reproductive/developmental toxicity, delivery index in the 100 mg/kg group showed significant decrease compared with the control group value. With regard to the neonates, no adverse effects of the analogue substance were observed in any groups. NOELs for reproductive/developmental toxicity were considered to be 100 and 30 mg/kg/day for males and females from F0 respectively, and 100 mg/kg/day for the F1 generation. Based on these results, the read-across was applied and the NOEL for reproductive/developmental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 106.90 and 32.07 mg/kg/day for males and females from F0 respectively and 115.34 mg/kg/day the F1 generation. In reference to the repeat dose toxicity, based on the experimental results obtained on the analogue substance where congestion and deposits were seen in the spleen at 10 mg/kg/day in both sexes (NOEL for parental toxicity <10 mg/kg/day), the read-across approach was performed and the NOEL for parental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be <10.69 mg/kg/day.

 

Justification for selection of Effect on fertility via oral route:

One two-generation study available (key study).

Effects on developmental toxicity

Description of key information

Key study: Based on the read-across approach from experimental results (Test method EPA OTS 798.4900) on analogue butanone oxime where no treatment-related gestational effects, malformations or developmental variations were observed, the NOAEL for developmental toxicity of butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was determined to be > 641.43 mg/kg bw/day in rats.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

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

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Based on the experimental results on the analogue substance where the LOAEL for maternal toxicity was determined to be 60 mg/kg bw/day (basis for effect: enlarged spleens), the read-across approach was applied and the LOAEL for maternal toxicity for Butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 64.14 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

> 641.43 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

(analogue substance)

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

LOAEL

Effect level:

64.14 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

(analogue substance)

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Based on the experimental results on the analogue substance where the NOAEL for developmental toxicity was determined to be >600 mg/kg bw/day (basis for effect: no effects were observed), the read-across approach was applied and the NOAEL for developmental toxicity for Butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be >641.43 mg/kg bw/day.

Key result

Dose descriptor:

NOAEL

Effect level:

> 641.43 mg/kg bw/day (actual dose received)

Based on:

test mat.

Remarks:

(analogue substance)

Sex:

male/female

Basis for effect level:

other: Developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

Based on the read-across approach from experimental results on analogue butanone oxime, the LOAEL for maternal toxicity for Butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rats was estimated to be 64.14 mg/kg bw/day and the NOAEL for developmental toxicity >641.43 mg/kg bw/day.

Executive summary:

A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in Sprague-Dawley rats according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the LOAEL for maternal toxicity was determined to be 60 mg/kg bw/day (basis for effect: enlarged spleens) and the NOAEL for developmental toxicity was determined to be >600 mg/kg bw/day (basis for effect: no effects were observed), the read-across approach was applied and the LOAEL for maternal toxicity for Butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 64.14 mg/kg bw/day and the NOAEL for developmental toxicity >641.43 mg/kg bw/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

641.43 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Two studies available on an analogue substance for developmental toxicity with Klimisch scores = 2 and 3. The overall quality of the database was determined as appropriate for assessment.

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Read-across from experimental results on analogue substance butanone oxime:

Key study: A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in Sprague-Dawley rats according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the LOAEL for maternal toxicity was determined to be 60 mg/kg bw/day (basis for effect: enlarged spleens) and the NOAEL for developmental toxicity was determined to be >600 mg/kg bw/day (basis for effect: no effects were observed), the read-across approach was applied and the LOAEL for maternal toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was estimated to be 64.14 mg/kg bw/day and the NOAEL for developmental toxicity >641.43 mg/kg bw/day.

Supporting study: A Prenatal Developmental Toxicity Test was performed on the analogue substance butanone oxime up to 600 mg/kg bw/day in New Zealand White rabbits according to EPA OTS 798.4900. Based on the experimental results on the analogue substance where the NOAEL for maternal toxicity was determined to be 24 mg/kg bw/day, the read-across approach was applied and the NOAEL for maternal toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rabbits was estimated to be 25.66 mg/kg bw/day. In reference to the developmental toxicity, in the study performed on analogue butanone oxime only 6 rabbits produced litters due to an excessive maternal mortality and abortions at the 40 mg/kg dose level. The NOAEL for developmental toxicity was determined to be 24 mg/kg bw/day (basis for effect: a decrease in the mean number of viable fetuses and an increase in the number of early resorptions). Based on these results, the NOAEL for developmental toxicity for butan-2-one O,O',O'',O'''-silanetetrayltetraoxime in rabbits was estimated to be 25.66 mg/kg bw/day. Nevertheless, the severe maternal toxicity and limited number of litters precluded a full assessment of developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:

The study performed in rats was chosen due to its higher quality (key study).

Justification for classification or non-classification

Based on the available information on toxicity to reproduction and developmental toxicity, butan-2-one O,O',O'',O'''-silanetetrayltetraoxime was considered to be negative for toxicity to reproduction, and therefore the substance is not classified in accordance with CLP Regulation (EC) No 1272/2008.