Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
extended one-generation reproductive toxicity - with F2 generation and developmental neurotoxicity (Cohorts 1A, 1B with extension, 2A and 2B)
Data waiving:
other justification
Justification for data waiving:
other:
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
Extended One Generation Reproductive Toxicity Study (EOGRTS) OECD 443 including Cohorts 1A and 1B with extension to include an F2 generation with the addition of Cohort 2; exclusion of Cohort 3 per ECHA decision letter.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: Alcohols, C9-11-branched

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
Based on the available toxicity data, it is unlikely that the substance identified as Alcohols, C9-11-branched would have any effect on fertility, however, the existing information do not meet the criteria established by ECHA for providing an adaptation to fulfill the information requirement under REACH.
The information submitted here is a non-confidential summary of the efforts that have been undertaken to justify the submission of a testing proposal and which are described in greater detail in the document attached to the dossier.

- Available GLP studies
While assessing the endpoint of “reproductive toxicity”, there are 3 elements which need to be evaluated from different sources of data:
1. Reproductive toxicity was assessed in a 90-day repeat-dose toxicity test.
A repeated dose 90-day oral gavage toxicity study in rats (OECD 408) on the registered substance found no adverse test substance-related histological effects on reproductive organs (i.e., cervix, epididymides, ovaries with oviducts, prostate with coagulating glands, seminal vesicles, testes, uterus, vagina) or organ weights (uterus, testes, prostate with seminal vesicles and coagulating glands, ovaries with oviducts, and epididymides [total and cauda]) up to and including a dose of 1,000 mg/kg/d. Additionally, no test-substance adverse findings were observed for spermatogenesis parameters (i.e., sperm production rate, motility/viability, and morphology) in adult male rats, nor were any test-substance adverse impacts on any phase of the estrous cycle (estrus, diestrus, proestrus) observed in adult female rats. Thus, no impacts to reproductive organs, either by weight or in onset of pathological changes, are expected to be observed due to test substance administration.

2. Developmental toxicity will be assessed in a prenatal developmental toxicity test.

A prenatal developmental toxicity test (OECD 414) battery including palatability and rangefinder studies in rat with the test substance was initiated on 05-Mar-2020 and results will be reported by 21-Dec-2020.

3. Fertility (e.g. mating, pregnancy, influence of gestational exposures), which can be fully assessed in multi-generational studies with equivalent information provided by reproductive studies of other designs (e.g. a combination of 1-generation reproductive toxicity studies combined with repeat-dose studies that evaluate spermatogenesis in males and all 4 stages of the estrus cycle in females).
Currently, no available GLP studies for reproductive (OECD 415, 416, or 443) toxicity are available for the substance. Existing GLP study data does not meet the standard to fill the information requirement, as information on reproduction is missing.
- Available non-GLP studies:
No data available
- Historical human data
Relevant epidemiological data on Alcohols, C9-11-branched (EC # 271-360-6) does not exist.
- (Q)SAR
QSAR methods were not employed, as the registered substance is part of a closely related group of substances with structural similarity, made by the same manufacturing process, and have similar toxicological properties as analogs with sufficient similarity to provide scientifically supportable read-across.
- In vitro methods
In vitro testing covering mutagenicity and genotoxicity using read-across to closely related alcohols (Alcohols, C9-11-iso-, C10-rich (EC #271-234-0) and Alcohols, C11-14-iso-, C13-rich (EC #271-235-6) are included in the dossier, and include five different genetic toxicity guideline study designs assessing six different endpoints for genetic toxicity: mammalian cell micronucleus, bacterial reverse mutation assay, mammalian cell gene mutation (OECD 487, OECD 471, OECD 490 on Alcohols, C11-14-iso-, C13-rich, respectively) and mammalian chromosomal aberration, mammalian gene cell mutation, and bacterial reverse mutation assay (OECD 473, OECD 476, and OECD 471 on Alcohols, C9-11-iso-, C10-rich, respectively). Negative results for all assays listed here indicate genotoxicity is not expected. Thus, waiver of the reproductive endpoint based on known genotoxicity, carcinogenicity, or mutagenicity is not appropriate.
- Weight of evidence
The existing data does not support a weight of evidence approach to fill data gaps for this endpoint.
- Grouping and read-across
Grouping and read across was not deemed appropriate for this endpoint, as the appropriate type of reproductive data is not available on the closely related group of products with structural similarity, made by the same manufacturing process, that have similar toxicological properties. Details are provided in the attached read across analysis document.
- Substance-tailored exposure driven testing
A substance-tailored exposure based waiver cannot be applied as a DNEL cannot be derived according to Annex XI, 3.2 (a)(ii), footnote 1 “For the purpose of subparagraph 3.2(a)(ii), without prejudice to column 2 of Section 8.7 of Annexes IX and X, a DNEL derived from a screening test for reproductive/developmental toxicity shall not be considered appropriate to omit a prenatal developmental toxicity study or a two-generation reproductive toxicity study. For the purpose of subparagraph 3.2(a)(ii), without prejudice to column 2 of section 8.6 of Annexes IX and X, a DNEL derived from a 28-day repeated dose toxicity study shall not be considered appropriate to omit a 90-day repeated dose toxicity study.”
- Approaches in addition to above [if applicable]
Not applicable
- Other reasons [if applicable]
Not applicable

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:
- An acceptable column 2 adaptation for reproductive toxicity study could not be formulated.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Additional details on study decision and testing proposal justification are provided in the attached testing proposal document.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Justification for study design:
Please see attached proposal for detailed study design justification, including supporting data and rationale.

Test material

Constituent 1
Chemical structure
Reference substance name:
Isoundecan-1-ol
EC Number:
257-376-6
EC Name:
Isoundecan-1-ol
Cas Number:
51750-47-1
Molecular formula:
C11H24O
IUPAC Name:
3,5 dimethyl nonanol-1

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Analytical verification of doses or concentrations:
yes

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion