Registration Dossier

Administrative data

Description of key information

Key study (sub-acute): Based on the read-across approach from the analogue substance MPKO, the NOAEL after at least 28 days of oral exposure was determined to be 17 mg/kg bw/day for general systemic toxicity.

Key study (sub-chronic): Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for OS1600 was determined to be 13 mg/kg bw/day for general systemic toxicity.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
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 and read-across rationale.
Reason / purpose:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
13 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: red blood cell rate of turnover resulting in associated changes in the spleen.
Remarks on result:
other: Based on a read-across from an analogue substance for which the NOAEL was 15 mg/kg-bw/day.
Key result
Critical effects observed:
not specified
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
Conclusions:
Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for OS1600 was determined to be 13 mg/kg bw/day for general systemic toxicity.
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 by the oral route in rats. 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 the NOAEL for OS 2200. Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for OS1600 was determined to be 13 mg/kg bw/day for general systemic toxicity.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
13 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
OECD guidance study conducted under GLP with a Klimisch score of 1 (since read-across, the Klimisch score is 2). The overall quality of the database was determined to be appropriate for assessment.
System:
haematopoietic

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Key study: Read-across approach from experimental data on the analogue MPKO (RDT 28 days, rats):

The systemic toxic potential and effects on reproduction were assessed in rats following oral administration for at least five weeks with recovery period of 14 days in accordance with OECD Guideline 422 (GLP study). Based on the read-across approach from the experimental data on the analogue substance MPKO, the hydrolysis product of OS1600 (NOAEL = 15 mg/kg bw/day, based on hematological changes associated with red blood cells destruction and associated microscopic findings (discoloration, hemosiderosis and extramedullary hematopoiesis) in spleen, liver or kidneys at dose levels of 50 and 150 mg/kg bw/day), the NOAEL for OS1600 was determined to be 17 mg/kg bw/day for subacute repeated dose toxicity by oral route and the observed adverse effects are expected at an estimated dose levels of 57 and 170 mg/kg bw/day.

Key study: Read-across from experimental data on the analogue OS2200 (RDT 90 days, rats)

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 by the oral route in rats. 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 the NOAEL for OS 2200. Based on the read-across approach from the analogue substance OS2200, the sub-chronic NOAEL for OS1600 was determined to be 13 mg/kg bw/day for general systemic toxicity. Nevertheless, it is important to note the low severity of the observed effect (reductions of haemoglobin less than 10 % without marked organ disfunction) and the absence of persistence of the observed effects (reversibility within 4 weeks recovery-period).

Repeated dose toxicity: via oral route - systemic effects (target organ):

Hematological with associated changes in the spleen.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:

The study with the longest duration (90-days) was chosen.

Justification for classification or non-classification

The 13 weeks-NOAEL (oral, rat) was determined to be 13 mg/kg bw/day based on haematologic changes resulting in associated changes in the spleen observed at an estimated dose of 43 mg/kg bw/day. Nevertheless, given the low severity of this effect (reductions of haemoglobin less than 10 % without marked organ disfunction) and the absence of persistence of the observed effects (reversibility within 4 weeks recovery-period), the substance is not classified for STOT RE according to CLP Regulation (EC) No. 1272/2008.