Registration Dossier

Administrative data

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

Referenceopen allclose all

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:
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.

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:
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.

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:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Reason / purpose:
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

Referenceopen allclose all

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:
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.

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:
data waiving: supporting information
Reason / purpose:
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.