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
Study period:
Study period to be confirmed following consideration and approval of the testing proposal by ECHA.
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
S-(3-(triethoxysilyl)propyl)octanethioate
S-[3-(triethoxysilyl)propyl]octanethioate
CAS 220727-26-4
EC 436-690-9

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:

- Available GLP studies
The available GLP studies for the substance (28-day study, 90-day study, pre-natal developmental toxicity study in the rat) are not sufficient to meet the REACH Annex X data requirement for reproductive toxicity.

- Available non-GLP studies
No non-GLP studies relevant to the REACH Annex X data requirement for reproductive toxicity are available

- Historical human data
No relevant historical human data are available for this endpoint.

- (Q)SAR
(Q)SAR methods are not sufficiently validated and are not considered to be sufficiently robust to meet the REACH Annex X data requirement for reproductive toxicity.

- In vitro methods
No in vitro data are available. Current in vitro methods are not sufficiently validated and are not considered to be sufficiently robust to meet the REACH Annex X data requirement for reproductive toxicity.

- Weight of evidence
The available toxicological dataset for the substance (repeated dose 28-day and 90-day studies in the rat; rat pre-natal developmental toxicity study) do not indicate any potential for reproductive toxicity. There is no indication of any effects on the organs or tissues of the male or female reproductive tracts, and no indication of an endocrine mode of action. However, these data are not sufficiently robust to meet the REACH Annex X data requirement for reproductive toxicity.

- Grouping and read-across
Substances sufficiently similar for the purposes of read-across or grouping are not identified.

- Substance-tailored exposure driven testing
Not applicable.

- Approaches in addition to above
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:
The substance is not known to have an adverse effect on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B.
The substance is not known to be a genotoxic carcinogen and appropriate risk management measures implemented.
The substance is not known to be a germ cell mutagen and appropriate risk management measures implemented.
The substance does not meet the definition of ‘low toxicological activity’ (no evidence of toxicity seen in any of the tests available). Furthermore it is predicted that systemic absorption occurs via relevant routes of exposure, and there is the potential for significant human exposure.
The available toxicological dataset for the substance (repeated dose 28-day and 90-day studies in the rat; rat pre-natal developmental toxicity study) do not indicate any potential for reproductive toxicity. There is no indication of any effects on the organs or tissues of the male or female reproductive tracts, and no indication of an endocrine mode of action. However, these data are not sufficiently robust to meet the REACH Annex X data requirement for reproductive toxicity.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
An EOGRTS is proposed with the substance in the rat, using the oral route of exposure. The ‘basic’ study deign (with a 10-week pre-mating period) is proposed in the absence of any specific concerns or triggers necessitating mating of the F1B cohort, or inclusion of the developmental neurotoxicity cohorts (Cohorts 2A, 2B) or developmental immunotoxicity cohort (Cohort 3). The highest dose level to be used in the study will be selected on the basis of the existing toxicological dataset, in order to demonstrate evidence of parental toxicity.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Version / remarks:
Current version (28 July 2011)
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS:
- Premating exposure duration for parental (P0) animals
A pre-mating exposure period of 10 weeks will be used for parental (P0) animals, in order to cover one complete cycle of spermatogenesis.

- Basis for dose level selection
Dose levels for the EOGRTS will be selected in consultation with the CRO on the basis of the existing toxicity data (28-day, 90-day and prenatal developmental toxicity studies in the rat), and any additional range-finding data considered necessary. The dose levels will be selected in order to demonstrate some parental toxicity at the high dose level, and a clear NOAEL at the low dose level. The intermediate dose level will be selected on the basis of appropriate dose spacing.

- Inclusion/exclusion of extension of Cohort 1B
It is not proposed to include mating of the F1B cohort to produce the F2 generation. While the substance has uses leading to significant exposure of consumers or professionals, the substance does not display genotoxic effects in somatic cell mutagenicity tests, which could lead to classifying it as Mutagen Category 2. Additionally, there are no indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure. Furthermore, there are no indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies.

- Termination time for F2
Not applicable: it is not proposed to include mating of the F1B cohort to produce the F2 generation.

- Exclusion of developmental neurotoxicity Cohorts 2A and 2B
The existing dataset does not indicate any particular concerns on (developmental) neurotoxicity. Specifically, there is no indication from relevant available in vivo or non-animal approaches (e.g. abnormalities of the CNS, evidence of adverse effects on the nervous system in studies on adult animals or animals exposed prenatally). Additionally, there is no evidence for specific mechanisms or modes of action of the substance with an association to (developmental) neurotoxicity (e.g. cholinesterase inhibition or relevant changes in thyroidal hormone levels associated with adverse effects). Furthermore, existing information on effects caused by substances struc¬turally analogous to the substance do not suggest such effects or mechanisms/modes of action.

- Exclusion of developmental immunotoxicity Cohort 3
The existing dataset does not indicate any particular concerns on (developmental) immunotoxicity. Specifically, there is no indication from relevant available in vivo or non-animal approaches (e.g. abnormalities of the CNS, evidence of adverse effects on the immune system in studies on adult animals or animals exposed prenatally). Additionally, there is no evidence for specific mechanisms or modes of action of the substance with an association to (developmental) immunotoxicity. Furthermore, existing information on effects caused by substances struc¬turally analogous to the substance do not suggest such effects or mechanisms/modes of action.

- Route of administration
The oral route of administration is proposed. Based on the hydrolytic instability of the test material, dietary administration is not a suitable route; gavage dosing is therefore proposed.

- Other considerations, e.g. on choice of species, strain, vehicle and number of animals
The study is proposed in the rat. The choice of strain will be guided by the experience and availability of background data at the CRO, and the strain (Wistar) used in the existing toxicity studies. The choice of vehicle will be guided by the experience of the CRO, solubility properties of the test material, compatibility with the test material, and the vehicle (dehydrated peanut oil) used. Group size will be in line with the recommendations of the test guideline.

Test material

Test animals

Species:
rat
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Applicant's summary and conclusion