Registration Dossier

Administrative data

Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Octene, hydroformylation products, high boiling

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION [please address all points below]:
- Available GLP studies: none for this endpoint
- Available non-GLP studies: None for this endpoint
- Historical human data: None for this endpoint
- (Q)SAR: not applicable to address all parameters assessed in an EOGRTS
- In vitro methods: none available to address all parameters assessed in an EOGRTS
- Weight of evidence: available studies (OECD 414, rep. dose) do not address all required parameters. Consequently, data are insufficient for a WoE approach
- Grouping and read-across: complex UVCB mixture, no suitable analoque available, for which the required data exist

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- The substance is not classified for mutagenicity, carcinogenicity, or reproductive toxicity. Even though toxicity is low (i.e., no human relevant effects up to limit dose in the existing studies), systemic resoption occurs, as seen by adaptive effects after repeated exposure and rat specific a2µ nephropathy. Consequently, the waiving criteria in Reach Annex X, column 2 do not apply to this substance.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- According to Reach Annex X, column 2, extension to the F2 generation is required, if the substance is genotoxic or is suspected to cause endocrine disruptions. All tests for genotoxicity were negative. There were no effects on reproductive organs or function, estrous cycle or sperm parameters in a 90-day repeated dose toxicity study and a teratogenicity study up to the limit dose of 1000mg/kg. Additionally, there were no hints that the steady state for the internal exposure takes exceptionally long to be reached. Consequently, none of the criteria to extent the study to the F2 generation are met.
- After repeated exposure for up to 90-days, the only adverse effect was a male rat specific a2µ nephropathy, which is not relevant for humans. This includes that FOB results were similar to control animals, and except for an increase in liver metabolism and a related enhanced excretion rate of bilirubin, all blood and clinical chemical parameters were unaltered. In the absence of any hints for effects on the immune system or CNS, neither cohorts 2A/2B nor cohort 3 are required.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Version / remarks:
basic design
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS:

- Premating exposure duration for parental (P0) animals: 2 weeks. No longer premating exposure is deemed necessary due to the absence of effects on sperm parameters or estrous cycle in a 90-day rep. dose toxicity study.
- Basis for dose level selection: Final dose selection will be performed based on a range finding study comparable to OECD 422. All former studies were performed up to the limit dose of 1000mg/kg. Adverse effects were limited to a2µ nephropathy in male rats.
- Inclusion/exclusion of extension of Cohort 1B
According to Reach Annex X, column 2, extension to the F2 generation is required, if the substance is genotoxic or is suspected to cause endocrine disruptions. All tests for genotoxicity were negative. There were no effects on reproductive organs or function, estrous cycle or sperm parameters in a 90-day repeated dose toxicity study and a teratogenicity study up to the limit dose of 1000mg/kg. Additionally, there were no hints that the steady state for the internal exposure takes exceptionally long to be reached. Consequently, none of the criteria to extent the study to the F2 generation are met.
- Inclusion/exclusion of Cohorts 2A and 2B and Cohort 3:
After repeated exposure for up to 90-days, the only adverse effect was a male rat specific a2µ nephropathy, which is not relevant for humans. This includes that FOB results were similar to control animals, and except for an increase in liver metabolism and a related enhanced excretion rate of bilirubin, all blood and clinical chemical parameters were unaltered. In the absence of any hints for effects on the immune system or CNS, neither cohorts 2A/2B nor cohort 3 are required.
- Route of administration: oral

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Oxooel 9N
- Analytical purity: 100%
- Lot/batch No.: 93932509TO
- Storage condition of test material: Room temperature, N2-atmosphere

Test animals

Species:
rat

Results and discussion

Applicant's summary and conclusion