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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 OS1600 was determined to be > 99 mg/kg-bw/day since no adverse effects 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 OS1600 was determined to be 170 mg/kg bw/day since no effects were observed on reprotox parameters at the hightes dose tested.

Weight of evidence. Test method OECD 408. GLP study. Based on the read-across approach from the analogue substance OS2200, the NOAEL of OS1600 for effects on reproductive organs was estimated to be >43 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 OS1600 for parental toxicity and toxicity to reproduction were estimated to be 30 mg/kg-bw/day and >99 mg/kg bw/day respectively.
Key result
Dose descriptor:
NOAEL
Remarks:
(parental toxicity)
Effect level:
30 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 subdtance for which the NOAEL was 30 mg/kg-bw/day.
Key result
Dose descriptor:
NOAEL
Remarks:
(reproductive toxicity)
Effect level:
> 99 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.:
99 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 OS1600 was estimated to be >99 mg/kg-bw/day.
Key result
Dose descriptor:
NOAEL
Remarks:
(F1 toxicity)
Generation:
F1
Effect level:
> 99 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:
> 99 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 (OS1600) 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 in, OECD 415, no data on GLP), the NOAEL of OS1600 for parental toxicity was estimated to be 30 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 >99 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 OS1600 for parental toxicity, and F1 and toxicity to reproduction were estimated to be 30 and >99 mg/kg-bw/day respectively.

Endpoint:
reproductive toxicity, other
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
Key result
Dose descriptor:
NOAEL
Remarks:
(reproductive organs)
Effect level:
> 43 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on no effects observed in reproductive organs or tissues (testes, seminal vesicles, ovaries, epididymes, uterus with cervix)
Remarks on result:
other: Based on a read-across from an analogue for which NOAEL > 50 mg/kg bw/day
Key result
Dose descriptor:
NOAEL
Remarks:
(systemic toxicity)
Effect level:
13 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Based on red blood cell rate of turnover resulting in associated changes in the spleen.
Remarks on result:
other: Read-across from an analogue for which NOAEL = 15 mg/kg bw/day.
Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
43 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
spleen
erythrocyte development
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
not specified
Key result
Remarks on result:
not determinable
Remarks:
Repeated dose toxicity study. It provides information on the lack of effects on reproductive organs and tissues, however, the design does not include F1.
Key result
Reproductive effects observed:
no

No effects were observed in the reproductive organs at the highest dose tested (50 mg/kg bw/day): epididymides, ovaries, prostate, seminal vesicles, testes and uterus and cervix.

Conclusions:
Based on the read-across approach, the 90day-NOAEL of the target substance in rats by oral route was 13 mg/kg bw/day in both sexes. No effects were observed in the reproductive organs or tissues up to the highest dose tested (estimated dose of 43 mg/kg bw/day).
Executive summary:

A 13 week repeated dose toxicity test followed by a 4 week recovery period was performed to assess the systemic toxicity of the analogue substance OS 2200 (GLP study). The test was performed in rats by oral gavage, three groups, each comprising then male and ten female rats received OS2200 at dosages of 5, 15 or 50 mg/kg bodyweight/day. It was concluded that the principal action of OS2200 was to affect the red blood cell rate of turnover occurring mainly among animals receiving 50 mg/kg/day, resulting in associated changes in the spleen. A dosage level of 15 mg/kg/day, was considered to be the highest NOAEL for OS 2200 as the changes observed at 5 and 15 mg/kg/day were considered to be minor in nature and had shown full recovery after 4 weeks without treatment. Based on these results, the read-across approach was applied and the 90 days-NOAEL for the target substance OS1600 by oral route in rats was determined to be 13 mg/kg bw/day. No effects were observed in the reproductive organs or tissues up to the highest dose tested (50 mg/kg bw/day). Based on these results, the read-across approach was applied and the 90 days-NOAEL for OS1600 by oral route in rats was determined to be 13 mg/kg bw/day for systemic toxicity and >43 mg/kg bw/day for toxicity in reproductive organs.

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 (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
Key result
Dose descriptor:
NOAEL
Remarks:
(toxicity to reproduction)
Effect level:
170 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects obrserved at the 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:
17 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Basis for effect: 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.:
57 mg/kg bw/day (nominal)
System:
haematopoietic
Organ:
liver
kidney
spleen
erythrocyte development
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified
Key result
Dose descriptor:
NOEL
Remarks:
(toxicity to reproduction)
Generation:
F1
Effect level:
170 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: 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 OS1600 and their molecular weights. The amount of MPKO was estimated using the assumption that 1 mole of the target substance OS1600 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 OS1600 was considered to be 170 mg/kg bw/day since no effects were observed on reproductive screening parameters up to 170 mg/kg bw/day, 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. The results observed in this study showed effects of MPKO assessed by haematology, organ weights and macroscopic appearance at dose levels of 50 mg/kg bw/day and above and microscopic tissue appearance were observed at dose levels of 15 mg/kg bw/day and above. After two weeks off dose complete recovery was seen in many clinical pathology parameters and recovery was in progress but not complete in males for high mean cell haemoglobin level, low mean cell haemoglobin concentration and high mean cell volume and in females low red blood cell counts, high mean cell haemoglobin level and high mean cell volume, organ weights, macroscopic and microscopic appearance. 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 OS1600 was determined to be 17 mg/kg bw/day for systemic toxicity and the NOEL was 170 mg/kg bw/day for toxicity to reproduction.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
99 mg/kg bw/day
Study duration:
subchronic
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
Additional information

Weight of evidence:

1. Test method OECD 415. GLP Study: Read-across from experimental data on the analogue substance methyl isobutyl ketoxime (MIBKO): A one-generation study was performed on the analogue substance MIBKO on Sprague-Dawley rats according to OECD guideline 415. No adverse effects were observed in any of the reproductive or developmental parameters or in the F1 pups. The toxicity profile included 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 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 OS1600 for parental toxicity, and F1 and toxicity to reproduction were estimated to be 30 and >99 mg/kg-bw/day respectively.

2.Test method OECD 422. GLP study: Read-across from experimental data on the analogue substance MPKO: The systemic toxic potential and effects on reproduction of the analogue MPKO were assessed in rats following oral administration for at least five weeks in accordance with OECD Guideline 422 (GLP study). Based on the read-across approach from the analogue substance MPKO, the hydrolysis product of OS1600 (NOEL = 150 mg/kg bw/day since no adverse effects observed on the reproductive screening parameters at the highest dose level), the NOEL for OS1600 was determined to be 170 mg/kg bw/day for reproductive toxicity in rats.

3. Test method OECD 408. GLP study: Read-across from experimental data on analogue substance OS2200: A 90 days oral repeated dose toxicity test was performed on the analogue substance OS2200 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 (oral) for OS1600 in rats was estimated to be 13 mg/kg- bw/day under the test conditions. No effects were observed in the reproductive organs or tissues (testes, seminal vesicles, ovaries, epididymides, uterus with cervix) up to the highest dose tested (an estimated dose of 43 mg/kg-bw/day).

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.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Reason / purpose:
data waiving: supporting information
Reason / purpose:
data waiving: supporting information
Abnormalities:
not specified
Developmental effects observed:
not specified
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 (Klimish =1) is available.
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
See attached reporting format.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
(parental systemic toxicity)
Effect level:
17 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 an estimated dose levels of 58 mg/kg bw/day and above.
Remarks on result:
other: 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:
170 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: There were no effects on any of the developmental endpoints assessed.
Remarks on result:
other: 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 OS1600 and their molecular weights. The amount of MPKO was estimated using the assumption that 1 mole of the target substance OS1600 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 OS1600 was considered to be 170 mg/kg bw/day since no effects were observed on the developmental screening parameters up to 170 mg/kg bw/day, 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. The results observed in this study showed effects of MPKO assessed by haematology, organ weights and macroscopic appearance at dose levels of 50 mg/kg bw/day and above and microscopic tissue appearance were observed at dose levels of 15 mg/kg bw/day and above. After two weeks off dose complete recovery was seen in many clinical pathology parameters and recovery was in progress but not complete in males for high mean cell haemoglobin level, low mean cell haemoglobin concentration and high mean cell volume and in females low red blood cell counts, high mean cell haemoglobin level and high mean cell volume, organ weights, macroscopic and microscopic appearance. 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 OS1600 was determined to be 17 mg/kg bw/day for systemic toxicity and 170 mg/kg bw/day for toxicity to reproduction.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
99 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
The studies available (screening study and one generation toxicity study), of which screening study has Klimisch score=2 (read-across) and the one generation study has Klimish score=2. The overall quality of the database is therefore high.
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

Weight of evidence:

1. Test method OECD 415. GLP Study: Read-across from experimental data on the analogue substance methyl isobutyl ketoxime (MIBKO): A one-generation study was performed on the analogue substance MIBKO on Sprague-Dawley rats according to OECD guideline 415. No adverse effects were observed in any of the reproductive or developmental parameters or in the F1 pups. 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 OS1600 for developmental effects was estimated to be > 99 mg/kg-bw/day.

2. Test method OECD 422. GLP study: Based on the read-across approach from the analogue substance MPKO, the NOEL for OS1600 was determined to be 170 mg/kg bw/day since no effects were observed on screening developmental parameters at the highest dose tested.

Justification for classification or non-classification

Based on the available results, the substance OS1600 is not classified in accordance with CLP Regulation (EC) no. 1272/2008 since no adverse effects were observed on reproductive and/or developmental parameters.