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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
EAC3 undergoes rapid hydrolysis in aqueous to acetone oxime and the corresponding ethylsilanetriol. Silanetriols undergo continuous condensation reactions to produce higher molecular weight siloxanes which are considered biologically unavailable. Therefore, the observed toxicity is likely due to the acetone oxime and their values are comparable. Moreover, the analogue methyl isobutyl ketoxime, which shares the same functional groups with acetone oxime, also has comparable values for the relevant molecular properties and they are toxicologically equivalent.
Reason / purpose for cross-reference:
reference to other study
Principles of method if other than guideline:
Read-across approach from experimental data (test method equivalent to OECD Guideline 415, no data on GLP) on an analogue substance.
GLP compliance:
no
Limit test:
no
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
(at an estimated dose of 79.13 mg/kg bw/day)
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
(at an estimated dose of 79.13 mg/kg bw/day)
Other effects:
no effects observed
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Based on the experimental results on the analogue substance MIBKO in rats, where the NOAEL for parental toxicity was determined to be 30 mg/kg bw/day based on histological effects on the spleen and where the NOAEL for toxicity to reproduction was > 100 mg/kg bw/day since no adverse effects were observed at the highest dose, the read-across was applied and the NOAEL of EAC3 for parental toxicity and toxicity to reproduction were estimated to be 23.74 and >79.13 mg/kg bw/day respectively.
Dose descriptor:
NOAEL
Remarks:
(parental toxicity)
Effect level:
23.74 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(analogue substance)
Sex:
male/female
Basis for effect level:
other: (Read-across approach from an analogue) (Based on histological effects on the spleen)
Dose descriptor:
NOAEL
Remarks:
(reproductive toxicity)
Effect level:
> 79.13 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(analogue substance)
Sex:
male/female
Basis for effect level:
other: (Read-across approach from an analogue) (Based on no effects at the highest dose tested)
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
no effects observed
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 substance MIBKO in rats, where the NOAEL for F1 and developmental parameters was determined to be >100 mg/kg bw/day since no adverse effects were observed at the highest dose, the read-across was applied and the NOAEL of EAC3 was estimated to be >79.13 mg/kg bw/day.
Dose descriptor:
NOAEL
Remarks:
(F1 toxicity)
Generation:
F1
Effect level:
> 79.13 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(analogue substance)
Sex:
male/female
Basis for effect level:
other: (Read-across approach from an analogue) (Based on no effects at the highest dose tested)
Dose descriptor:
NOAEL
Remarks:
(developmental and sexual maturation)
Generation:
F1
Effect level:
> 79.13 mg/kg bw/day (nominal)
Based on:
test mat.
Remarks:
(analogue substance)
Sex:
male/female
Basis for effect level:
other: (Based on no effects at the highest dose tested)
Reproductive effects observed:
not specified

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

Conclusions:
Based on the read-across approach from experimental data on the analogue substance MIBKO (a one-generation reproduction study in, OECD 415, no data on GLP), the NOAEL for parental toxicity was estimated to be 23.74 mg/kg bw/day (based on histological effects on the spleen) and the NOAEL for the F1 generation and reproductive toxicity was estimated to be >79.13 mg/kg bw/day (based on no effects on reproduction or developmental parameters or in the F1 pups).
Executive summary:

Based on the experimental data from the one-generation reproduction study on the analogue substance MIBKO in rats, where the NOAEL for parental toxicity was determined to be 30 mg/kg bw/day based on histological effects on the spleen and where the NOAEL for F1 and toxicity to reproduction was > 100 mg/kg bw/day based on no effects on reproductive or developmental parameters or in the F1 pups at the highest dose, the read-across was applied and the NOAEL of EAC3 for parental toxicity, and F1 and toxicity to reproduction were estimated to be 23.74 and >79.13 mg/kg bw/day respectively.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
79.13 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
One-generation toxicity study is available on analogue substances, with a Klimish score = 1. Moreover, as supporting studies, three repeated dose toxicity tests are in place (Klimish score = 2) where effects on reproductive organs were observed. The overall quality of the database was determined as appropriate for assessment.
Additional information

Key study Read-across from experimental data on analogue substance MIBKO:

A one-generation reproduction study was performed according to OECD guideline 415 with methyl isobutyl ketoxime (MIBKO) in Sprague-Dawley rats. No adverse effects were observed in any of the reproductive or developmental parameters or in the F1 pups. The toxicity profile includes symptoms of minimal to moderate hemosiderosis and minimal congestion in the spleens at 100 mg/kg bw/day males and females. The NOAEL for parental toxicity in the F0 generation was considered to be 30 mg/kg bw/day based on histological effects on the spleen. The minor changes observed in male kidneys at 30 mg/kg bw/day was not considered to be significant. The NOAEL for the F1 generation and reproductive toxicity was considered to be >100 mg/kg bw/day based on no effects observed at the highest dose. Based on these results the read-across was applied and the NOAEL of EAC3 for parental toxicity and the NOAEL for F1 generation and toxicity to reproduction were estimated to be 23.74 and >79.13 mg/kg bw/day respectively.

Supporting study: Read-across from experimental data on analogue substance Wasox-VMAC2:

A 28 days oral repeated dose toxicity test was performed on the analogue substance Wasox-VMAC2 according to OECD Guideline 407 and GLP. The NOEL was determined to be 20 mg/kg bw/day in rats since effects on erythrocyte parameters and extramedullary hematopoiesis in the spleen were observed. Based on these results, the read-across was applied and the 28 days NOEL for oral exposure in rats was estimated to be 15.99 mg/kg bw/day under the test conditions. No effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 159.85 mg/kg bw/day).

Supporting study: Read-across from experimental data on analogue substance Wasox-MMAC2:

A 28 days oral repeated dose toxicity test was performed on the analogue substance Wasox-MMAC2 according to OECD Guideline 407 and GLP. The NOEL was determined to be 20 mg/kg bw/day in rats since effects on erythrocyte related parameters, liver and spleen weight changes, haematopoiesis in the spleen and hypercellularity in the bone marrow were observed. Based on these results, the read-across was applied and the 28 days NOEL for oral exposure in rats was estimated to be 16.54 mg/kg bw/day under the test conditions. No effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 165.37 mg/kg bw/day).

Supporting study: Read-across from experimental data on analogue substance MIBKO:

A 90 days oral repeated dose toxicity test was performed on the analogue substance MIBKO according to OECD Guideline 408 and GLP. The NOAEL was determined to be 15 mg/kg bw/day in rats since effects on red blood cells, resulting in associated changes in the spleen were observed. Based on these results, the read-across was applied and the 90 days NOAEL for oral exposure in rats was estimated to be 11.87 mg/kg bw/day under the test conditions. No effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 39.57 mg/kg bw/day).

Two-generation reproduction study:

In accordance with Column 1 of REACH Annex IX, the two-generation reproductive toxicity study does not need to be conducted since the no effects were observed on reproduction and development parameters in the one-generation toxicity study. Moreover, the 90-day and 28-day repeated dose toxicity studies do not indicate adverse effects on reproductive organs or tissues.


Short description of key information:
Key study: Based on the read-across approach from experimental data on the analogue substance MIBKO (a one-generation reproduction study in, OECD 415, no data on GLP), the NOAEL for the F1 generation and reproductive toxicity was estimated to be >79.13 mg/kg bw/day (based on no effects on reproduction or developmental parameters or in the F1 pups).
Supporting study: Based on the read-across approach from experimental data on analogue substance Wasox-VMAC2 (OECD Guideline 407, GLP study), no effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 159.85 mg/kg bw/day).
Supporting study: Based on the read-across approach from experimental data on analogue substance Wasox-MMAC2 (OECD Guideline 407, GLP study), no effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 165.37mg/kg bw/day).
Supporting study: Based on the read-across approach from experimental data on analogue substance MIBKO (OECD Guideline 408, GLP study),no effects were observed in the reproductive organs or tissues up to the highest dose tested (an estimated dose of 39.57 mg/kg bw/day).
Two-generation reproduction study: Data waiving (other justification): In accordance with Column 1 of REACH Annex IX, the two-generation reproductive toxicity study does not need to be conducted since the no effects were observed on reproduction and development parameters in the one-generation toxicity study. Moreover, the 90-day and 28-day repeated dose toxicity studies do not indicate adverse effects on reproductive organs or tissues.

Justification for selection of Effect on fertility via oral route:
One-generation study is available.

Effects on developmental toxicity

Description of key information
Data waiving (study scientifically unjustified): The pre-natal developmental toxicity study does not need to be conducted since no effects were observed on F1 generation regarding both developmental parameters and sexual maturation in the one-generation toxicity study.
Additional information

Data waiving (study scientifically unjustified): The pre-natal developmental toxicity study does not need to be conducted since no effects were observed on F1 generation regarding both developmental parameters and sexual maturation in the one-generation toxicity study.

Justification for classification or non-classification

Based on the available information on toxicity to reproduction and developmental toxicity, 2 -propanone, 2,2',2''-[O,O',O''-(ethylsilylidyne)trioxime 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.

Additional information