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Toxicological information

Toxicity to reproduction

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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:
As per timings provided in ECHA final decision
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
According to REACH regulation Annex IX the conduct of a EOGRTS is required to cover the endpoint toxicity to reproduction.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 2,2',6,6'-Tetrabromo-4,4'-isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION
- Available GLP studies: no studies available to cover this endpoint
- Available non-GLP studies: no studies available
- Historical human data: no data available
- (Q)SAR: No adequate QSAR model is available to fulfill this information requirement.
- In vitro methods: Currently no validated and accepted in vitro methods are available to cover this endpoint. It is currently not possible, with in vitro models, to account for the influence of the complex processes of absorption, distribution in the body, metabolism and excretion that occur in the whole animal, which will affect the toxic properties of the test substance.
- Weight of evidence: No adequate data are available, neither for the target substance, nor for related substances, to cover this endpoint.
- Grouping and read-across: The substance is a UVCB substance, and no adequate alternative substance with data suitable for read-across purposes is available.
- Substance-tailored exposure driven testing [if applicable]: Based on use conditions, exposure cannot be completely excluded.
- Approaches in addition to above [if applicable]: n.a.
- Other reasons [if applicable]: n.a.

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:

Column 2 of Annex IX states that the reproductive toxicity studies do not need to be performed 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 these conditions are met by the substance: The substance is not classified for carcinogenicity or mutagenicity. Furthermore, the substance was shown to be systemically available as demonstrated by findings reported in the 28 d repeated dose toxicity study. Therefore, the above listed column 2 adaptions cannot be applied.


FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed: The proposed study design is in accordance with the OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study). The oral route of exposure is selected based on the physico-chemical properties of the substance. Rat is the preferred species according to OECD TG 443.

Data source

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
GLP compliance:
yes
Justification for study design:
SPECIFICATION OF STUDY DESIGN FOR EXTENDED ONE-GENERATION REPRODUCTION TOXICITY STUDY WITH JUSTIFICATIONS [please address all points below]:

- Premating exposure duration for parental (P0) animals
A ten-week premating exposure duration to cover the full spermatogenesis and folliculogenesis before mating is proposed as detailed in ECHA's Endpoint specific guidance R.7a.

- Basis for dose level selection
Dose levels will be based on the results of the proposed OECD Guideline 408 and OECD Guideline 414 studies. The highest dose level will be selected with the aim to induce some toxicity in male and female animals.

- Inclusion/exclusion of extension of Cohort 1B / Inclusion/exclusion of developmental neurotoxicity Cohorts 2A and 2B / Inclusion/exclusion of developmental immunotoxicity Cohort 3
Currently the available data do not trigger any of the additional cohorts. Nevertheless, depending on the outcome of the proposed OECD Guideline 408 and OECD Guideline 414 studies the iclusion of additional cohorts may be reconsidered.
REACH specifies that the extension of cohort 1B to include the F2 generation shall be proposed by the registrant or may be required by the Agency 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.”

The substance is not genotoxic. There are so far neither indications, that a steady state is reached only after extended exposure, nor indications of endocrine disrupting modes of action. Thus, the triggers for the extension of cohort 1B to include the F2 generation are not met.

“An Extended One-Generation Reproductive Toxicity Study including cohorts 2A/2B (developmental neurotoxicity) and/or cohort 3 (developmental immunotoxicity) shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41, in case of particular concerns on (developmental) neurotoxicity or (developmental) immunotoxicity justified by any of the following:
— existing information on the substance itself derived from relevant available in vivo or non-animal approaches (e.g. abnormalities of the CNS, evidence of adverse effects on the nervous or immune system in studies on adult animals or animals exposed prenatally), or
— specific mechanisms/modes of action of the substance with an association to (developmental) neurotoxicity and/or (developmental) immunotoxicity (e.g. cholinesterase inhibition or relevant changes in thyroidal hormone levels associated to adverse effects), or
— existing information on effects caused by substances structurally analogous to the substance being studied, suggesting such effects or mechanisms/modes of action.”

No particular concern for (developmental) neurotoxicity is evident from the available data. In the available 28 d repeated dose toxicity study no toxicologically significant changes in the behavioural parameters, sensory reactivity and functional performance were noted. Thus, the triggers for the inclusion of Cohort 2A and 2B are not met.
No particular concern for (developmental) immunotoxicity is evident from the available data. Thus, the triggers for the inclusion of Cohort 3 are not met.

- Route of administration
The oral route of exposure is selected based on the physico-chemical properties of the substance.

- Other considerations, e.g. on choice of species, strain, vehicle and number of animals [if applicable]
Rat is the preferred species according to OECD TG 443.

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
impurity
Type:
impurity
Test material form:
solid

Test animals

Species:
rat

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion