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
Remarks:
Provisional testing proposal, intended to be reviewed; also see "justification for type of information".
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS
This is a provisional testing proposal, subject to review/withdrawal during the consultation phase, since information may be retrieved allowing to address this endpoint without additional animal testing. Testing proposal was triggered for formal reasons.

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out : Bis-(a,a-dimethyl)peroxide (dicumyl peroxide), CAS No. 80-43-3
- Name of the substance for which the testing proposal will be used: As above

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Available GLP studies : None for REACH Annex IX/X, point 8.7.3
- Available non-GLP studies : None for REACH Annex IX/X, point 8.7.3
- Historical human data: None identified
- (Q)SAR: Not applicable for reproductive toxicity
- In vitro methods : Not applicable for reproductive toxicity
- Weight of evidence : Not applicable due to absence of studies covering this endpoint
- Grouping and read-across: Not considered suitable
- Substance-tailored exposure driven testing: Not applicable
- Approaches in addition to above: Not known
- 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:
- Not applicable

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design/methodology proposed: An extended one-generation reproduction toxicity study with bis-(a,a-dimethyl)peroxide is proposed to be performed according to OECD TG 443 and in compliance with GLP pending approval by ECHA. Details on study design and inclusion/exclusion of cohorts are provided in section "justification for study design".

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:
- Pre-mating exposure duration for parental (P0) animals : Male and female P0 animals are proposed to be treated with the test substance for 10 weeks prior to mating. This procedure ensures exposure at all stages of spermatogenesis and folliculogenesis before mating in order to be able to evaluate any potential adverse effect on fertility.
- Basis for dose level selection : Results from previously performed studies like repeated dose toxicity and relevant data from prenatal developmental toxicity testing in the species of interest (rat) will be taken into account in order to select a dose that induces some toxicity, but not severe suffering or mortality. Accordingly, it will be possible to assess whether the substance causes adverse effects on reproduction or whether these effects are secondary to systemic toxicity.

- Inclusion/exclusion of extension of cohort 1B and termination time for F2 : The registrant does not propose extension of cohort 1B to the F2 generation because none of the conditions that trigger the inclusion of this cohort are fulfilled according to chapter R.7a: Endpoint specific guidance, Version 6.0, and REACH Annex X:
a)
"The substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles":
- The substance is not intended to be used by consumers or professionals and therefore significant exposure of these populations is not expected; the substance is exclusively used in industrial premises.

b)
"The substance displays genotoxic effects in somatic cell mutagenicity tests in vivowhich could lead to classifying it as Mutagen Category 2":
- The substance is not classified as mutagenic category 1A, 1B or 2. There were no signs of genotoxic effects in any of the relevant assays performed in vitro or in vivo.

"There are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches."
- There were no indications for modes of action related to endocrine disruption from in vivo studies or non-animal approaches.

"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”:
- The substance is not considered PBT/vPvB. The toxicokinetic behaviour of similar substances (dibenzoyl peroxide) suggests rapid clearance from systemic circulation and it can therefore be expected that dicumyl peroxide will not show potential for accumulation. The NOAELs/LOAELs of subchronic studies are in a similar range and are not more than 3 times lower than the NOAEL/LOAELfrom a subacute study. Overall, there are no indications that the internal dose for the substance will reach a steady state in the test animals only after an extended exposure.

- Inclusion/exclusion of developmental neurotoxicity cohorts 2A and 2B and developmental immunotoxicity cohort 3 : The registrant does not propose inclusion of cohorts 2A, 2B and 3 because, based on the available data, there are no particular concerns for effects on developmental neurotoxicity or developmental immunotoxicity. Therefore, inclusion of these additional cohorts does not seem justified.
- Route of administration : Oral, consistent with available repeated dose toxicity studies
- Other considerations, e.g. on choice of species, strain, vehicle and number of animals: None

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion