2-Pentanone, 2,2',2''-[O,O',O''-(ethenylsilylidyne)trioxime]

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Weight of evidence: Test method OECD 415. GLP study. Based on the read-across approach from the analogue substance MIBKO, the NOAEL for OS2600 was determined to be > 103 mg/kg-bw/day since no adverseeffects were observed in any of the reproductive or developmental parameters or in the F1 pups.

Weight of evidence. Test method OECD 422. GLP study. Based on the read-across approach from the analogue substance MPKO, the NOEL of OS2600 was determined to be 175 mg/kg bw/day since no effects were observed on reprotox parameters at the hightes dose tested.

Moreover: Test method OECD 408. GLP study. Based on the read-across approach from the analogue substance OS2200, the NOAEL of OS2600 for effects on reproductive organs was estimated to be >134 mg/kg bw/day since no effects were observed on the reproductive organs at the highest tested dose.

Link to relevant study records

Reference

Reference 1

Endpoint:

one-generation reproductive toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across from an analogue substance for which a guideline study (Klimish =1) is available.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached reporting format and read-across rationale.

Reason / purpose for cross-reference:

read-across source

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 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 OS2600 for parental toxicity and toxicity to reproduction were estimated to be 31 mg/kg-bw/day and >103 mg/kg bw/day respectively.

Key result

Dose descriptor:

NOAEL

Remarks:

(parental toxicity)

Effect level:

31 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: Based on a read-across form an analogue substance for which the NOAEL was 30 mg/kg-bw/day.

Key result

Dose descriptor:

NOAEL

Remarks:

(reproductive toxicity)

Effect level:

> 103 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Based on no effects at the highest dose tested

Remarks on result:

other: Based on a read-across from analogue substance for which the NOAEL was 100 mg/kg-bw/day.

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

103 mg/kg bw/day (nominal)

System:

haematopoietic

Organ:

spleen

Treatment related:

yes

Dose response relationship:

no

Relevant for humans:

not specified

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 OS2600 was estimated to be >103 mg/kg-bw/day.

Key result

Dose descriptor:

NOAEL

Remarks:

(F1 toxicity)

Generation:

F1

Effect level:

> 103 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects at the highest dose tested.

Remarks on result:

other: Based on a read-across form an analogue substance for which the NOAEL was 100 mg/kg-bw/day.

Key result

Dose descriptor:

NOAEL

Remarks:

(developmental and sexual maturation)

Generation:

F1

Effect level:

> 103 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effects at the highest dose tested.

Remarks on result:

other: Based on a read-across form an analogue substance for which the NOAEL was 100 mg/kg-bw/day.

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

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

The read-across approach from experimental results with the supporting substance MIBKO are expressed (calculated) as the estimated toxicity based on molecular weights and the estimated amount of oxime generated from the hydrolysis reaction. The amount of oxime generated was estimated using the assumption that 1 mole of test material (OS2600) produces 3 moles of MPKO, and thus, an estimated quantity of 3 moles of MIBKO.

Conclusions:

Based on the read-across approach from experimental data on the analogue substance MIBKO (a one-generation reproduction study, OECD 415), the NOAEL of OS2600 for parental toxicity was estimated to be 31 mg/kg bw/day (based on histological effects on the spleen) and the NOAEL for the F1 generation and reproductive toxicity (P and F1) was estimated to be >103 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 OS200 for parental toxicity, and F1 and toxicity to reproduction were estimated to be 31 and >103 mg/kg-bw/day respectively.

Reference 2

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Read-across from an analogue substance for which a guideline study (KIimish = 1) is available.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached reporting format and read-across rationale.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

(Toxicity to reproduction)

Effect level:

175 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects observed at highest dose tested.

Remarks on result:

other: Based on a read-across from an analogue for which NOAEL = 150 mg/kg bw/day

Key result

Dose descriptor:

NOAEL

Remarks:

(systemic toxicity)

Effect level:

18 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Red blood cell destruction with associated findings in the spleen, liver or kidneys at an estimated dose levels of 58 mg/kg bw/day and above.

Remarks on result:

other: Based on a read-across from an analogue for which NOAEL = 15 mg/kg bw/day

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

58 mg/kg bw/day (nominal)

System:

haematopoietic

Organ:

blood

kidney

liver

spleen

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Key result

Dose descriptor:

NOEL

Remarks:

Toxicity to reproduction and development

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no effects on any of the reproductive parameters or developmental endpoints evaluated.

Remarks on result:

other: Based on a read-across from an analogue for which NOEL = 150 mg/kg bw/day

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

The data matrix is included in the reporting format attached.

The results from the read-across approach are expressed on the basis of the amount of MPKO generated from the hydrolysis reaction of OS2600 and their molecular weights. The amount of MPKO was estimated using the assumption that 1 mole of the target substance OS2600 produces 3 moles of MPKO. No other adaptions are necessary.

Conclusions:

Based on the read-across approach from the analogue substance MPKO, the NOEL for OS2600 was considered to be 175 mg/kg bw/day since no effects were observed on reproductive screening parameters up to the highest dose tested.

Executive summary:

The systemic toxic potential and effects on reproduction were assessed in rats following oral administration of the analogue substance MPKO for at least five weeks in accordance with OECD Guideline 422. There were no adverse effects of treatment on the reproductive/developmental screening parameters assessed at least 150 mg/kg/day. The NOAEL for MPKO was considered to be 15 mg/kg bw/day for general systemic toxicity. The NOEL for reproductive and developmental screening parameters was considered to be 150 mg/kg bw/day. Based on these results, the read-across approach was applied, and the NOAEL for OS2600 was determined to be 18 mg/kg bw/day for systemic toxicity and 175 mg/kg bw/day for toxicity to reproduction.

Reference 3

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

the extended one-generation reproductive toxicity study does not need to be conducted because there are no results from available repeated dose toxicity studies that indicate adverse effects on reproductive organs or tissues, or reveal other concerns in relation with reproductive toxicity

Justification for type of information:

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

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

103 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The studies available are a screening study, a one-generation study and a subchronic repeated dose toxicity. The screening study has Klimisch score=2 (read-across from a Klimish 1 study), the one-generation study has Klimisch score=2 (read-across from a Klimish 1 study) and the subchronic repeated dose study has Klimish score =2 (read-across from a Klimish 1 study). The overall quality of the database is therefore high.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Data waiving: 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. Moreover, no developmental toxicity was observed in the "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test" up to the highest tested dose.

Key study: Test method OECD 422. GLP study: Based on the read-across approach from the analogue substance MPKO, the hydrolysis product of OS2600 (NOEL = 150 mg/kg bw/day since no adverse effects observed on the developmental screening parameters at the highest dose level), the NOEL for OS2600 was determined to be 175 mg/kg bw/day for developmental toxicity in rats.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of 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: Read-across from an analogue substance for which a guideline study (KIimish = 1) is available.

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached reporting format and read-across rationale.

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

(parental systemic toxicity)

Effect level:

18 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: Red blood cell destruction with associated findings in the spleen, liver or kidneys at dose levels of 50 mg/kg bw/day and above.

Remarks on result:

other: Based on a read-across from an analogue for which NOAEL = 15 mg/kg bw/day

Key result

Abnormalities:

no effects observed

Key result

Dose descriptor:

NOEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no effects on any of the developmental endpoints assessed.

Remarks on result:

other: Based on a read-across from an analogue for which NOEL = 150 mg/kg bw /day.

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

The data matrix is included in the reporting format attached.

The results from the read-across approach are expressed on the basis of the amount of MPKO generated from the hydrolysis reaction of OS2600 and their molecular weights. The amount of MPKO was estimated using the assumption that 1 mole of the target substance OS2600 produces 3 moles of MPKO. No other adaptions are necessary.

Conclusions:

Based on the read-across approach from the analogue substance MPKO, the NOEL for OS2600 was considered to be 175 mg/kg bw/day since no effects were observed on the developmental screening parameters up to the highest dose tested.

Executive summary:

The systemic toxic potential and effects on reproduction were assessed in rats following oral administration of the analogue substance MPKO for at least five weeks in accordance with OECD Guideline 422. There were no adverse effects of treatment on the reproductive/developmental screening parameters assessed at least 150 mg/kg/day. The NOAEL for MPKO was considered to be 15 mg/kg bw/day for general systemic toxicity. The NOEL for reproductive and developmental screening parameters was considered to be 150 mg/kg bw/day. Based on these results, the read-across approach was applied, and the NOAEL for OS2600 was determined to be 18 mg/kg bw/day for systemic toxicity and 175 mg/kg bw/day for toxicity to reproduction.

Reference 2

Endpoint:

developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
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. Moreover, no developmental toxicity was observed in the "Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test" up to the highest tested dose.

Reason / purpose for cross-reference:

data waiving: supporting information

Reason / purpose for cross-reference:

data waiving: supporting information

Abnormalities:

not specified

Developmental effects observed:

not specified

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

175 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is GLP compliant with a Klimisch score of 1 (since read-across, the Klimisch score is 2).

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on the available data, OS2600 is not classified in accordance with CLP Regulation (EC) no. 1272/2008 since no adverse effects were observed on reproductive and/or developmental parameters both in P and F1 generations.