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:
After approval by ECHA
Justification for type of information:
CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION
- Available GLP studies: There are no GLP studies available covering reproductive toxicity information requirements.
- Available non-GLP studies: There are no non-GLP studies available covering reproductive toxicity information requirements.
- Historical human data: There are no historical human data available on reproductive toxicity for the substance.
- (Q)SAR: According to the ECHA Guidance in Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance, there are a large number of potential targets/mechanisms associated with reproductive toxicity which, on the basis of current knowledge, cannot normally be adequately covered by a battery of QSAR models.
- In vitro methods: According to the ECHA Guidance in Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance, The combination of assays in a tiered and/or battery approach may improve predictivity, but the in vivo situation remains more than the sum of the areas modelled by a series of in vitro assays. Therefore, a negative result predicting absence of a particular property for a substance with no supporting information cannot be interpreted as demonstrating the absence of a reproductive hazard with the same confidence as an animal study. A positive result predicting a particular reproductive hazard in a validated in vitro test could provide a justification for the need of further testing beyond the standard information requirement. However, because of limited confidence in this approach at this time, such a result in isolation would not be adequate to support hazard classification.
- Weight of evidence: There are no data available which are sufficient for a weight of evidence approach.
- Grouping and read-across: No substances or a category of substances are known which apply for read-across addressing reproductive toxicity.
- Substance-tailored exposure driven testing: not applicable
- Approaches in addition to above: not applicable
- Other reasons: 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 basic test design of an extended one-generation reproductive toxicity study (test method EU B.56./OECD TG 443 with Cohorts 1A and 1B, without extension of Cohort 1B to include a F2 generation, and without Cohorts 2A, 2B and 3) is a standard information requirement as laid down in column 1 of Section 8.7.3., Annex X. According to Column 2 Annex X of REACH Regulation an extended one-generation reproductive toxicity study does not need to be conducted if:
- the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or
- the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or
- the substance is of low toxicological activity (no evidence of toxicity seen in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure.
None of the points outlined above apply for the test substance. Thus, in order to fulfil information requirements stated in column 1 Annex X of REACH Regulation for substances manufactured or imported in quantities of 1000 tpa or more, an extended one-generation reproductive toxicity study (test method EU B.56./OECD TG 443 with Cohorts 1A and 1B, without extension of Cohort 1B, and without Cohorts 2A, 2B and 3 is proposed.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
The protocol as described in OECD guideline 443 with rats by the oral route is proposed.

Data source

Materials and methods

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

- Premating exposure duration for parental (P0) animals: According to OECD guideline 443
- Basis for dose level selection: According to OECD guideline 443. Available data from a subchronic repeated dose toxicity test (according to OECD 408) and a prenatal developmental toxicity study (according to OECD 414) will be considered.
- Inclusion/exclusion of extension of Cohort 1B: The study design needs to be expanded to include the extension of Cohort 1B to include a F2 generation if:
a) the substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles, and
b) any of the following conditions are met:
* the substance displays genotoxic effects in somatic cell mutagenicity tests in vivo which could lead to classifying it as Mutagen Category 2, or
* there are 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, or
* there are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches.
Since the available data do not trigger the inclusion of extension of cohort 1B, only an extended one-generation reproductive toxicity study (test method EU B.56./OECD TG 443 with Cohorts 1A and 1B, without extension of Cohort 1B to include a F2 generation, and without Cohorts 2A, 2B and 3) is proposed.
- Termination time for F2: Not applicable: As an extension of Cohort 1B is not proposed, no F2 generation is included and the termination time does not need to be determined.
- Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B and/or developmental immunotoxicity Cohort 3
The study design needs to be expanded to include the extension of Cohorts 2A/2B, and/or Cohort 3 if
* existing information on the substance itself derived from relevant available in vivo or non-animal approaches, or
* specific mechanisms/modes of action of the substance with an association to (developmental) neurotoxicity, or
* existing information from studies on effects caused by substances structurally analogous to the substance being studied suggesting such effects or mechanisms/modes of action.
Considering these points, the available data do not trigger an extension to include the extension of Cohort 1B, Cohorts 2A/2B, and/or Cohort 3. Furthermore, assessment of neurobehavior effects (functional observation battery and motor activity assessment) were included in the available OECD 408 study (Triskelion B.V., 2017). Treatment-related findings included sliding with the ventral parts of the head and neck over the bottom of the open field, dyspnoea, grunting respiration, sniffing, piloerection, salivation, serous nasal discharge, low arousal, soft and/or mucoid faces, diarrhoea, soiled perineum and soiled fur. No neurotoxic effects of treatment were observed from motor activity assessment in any of the dose groups during the 30-minute test period. Thus, the OECD 408 study did not indicate neurotoxic potential of the substance.
Therefore, an extended one-generation reproductive toxicity study (test method EU B.56./OECD TG 443 with Cohorts 1A and 1B, without extension of Cohort 1B, and without Cohorts 2A, 2B and 3) is proposed.
- Route of administration: The oral route is proposed because this is a possible route of human exposure. In addition, the dose levels are determined based on the available data from a subchronic repeated dose toxicity test (according to OECD 408) and a prenatal developmental toxicity study (according to OECD 414) in which the animals were also administered via the oral route.

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion