Registration Dossier

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:
after ECHA's final decision, depending on laboratory capacity
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: Reaction products of pentaerythritol, propoxylated and 1-chloro-2,3-epoxypropane with hydrogen sulfide

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 for the endpoint toxicity to reproduction
- Available non-GLP studies: there are no non-GLP studies available for the endpoint toxicity to reproduction
- Historical human data: there are no historical human data that can be considered acceptable for this higher tier toxicity endpoint.
- (Q)SAR: Although (Q)SAR programmes include several endpoints that are related to toxicity to reproduction, these (Q)SAR endpoints do not cover all endpoints that need to be investigated for the endpoint reproductive toxicity. In some cases (Q)SAR for this endpoint can be useful as a first indication for possible reproductive toxicity; however absence of structural alerts is considered not acceptable to replace further studies for this toxicity endpoint, neither for registration nor for classification purposes.
According to ECHA Practical Guide on alternatives to animal testing (July 2016) ECHA’s experience of using adaptations to address standard information requirements reveals that there are no simple (Q)SAR solutions for complex health endpoints such as reproductive toxicity.
- In vitro methods: there are no reliable in vitro tests available that can be considered for the endpoint reproductive toxicity that sufficiently cover the endpoint for risk assessment and classification purposes
- Weight of evidence: there is no relevant information available that can be used in a WoE to cover the endpoint reproductive toxicity for registration and classification purposes.
- Grouping and read-across: there are currently no structures known (and that also have reliable data on reproductive toxicity) that can be used for grouping or read-across, and which is acceptable for registration and classification purposes.

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 specific rules for adaptation from column 1 as given in column 2 are not met, as the available data do not demonstrate that the substance is a genotoxic carcinogen or germ cell mutagen. The available data are indicative for systemic absorption, whereas data demonstrating adverse effect on fertility meeting the criteria for classification as Repr Cat 1 or 2 (with adequate data to support risk assessment). According to Column 1 and Column 2 of Regulation (EC) No 1907/2006 concerning REACH an extended one-generation toxicity study (OECD 443), basic test design (cohorts 1A and 1B without extension to include a F2 generation) needs to be performed in case the available repeated dose toxicity studies (e. g. 90- day study) indicate adverse effects on reproductive organs or tissues or reveal other concerns in relation with reproductive toxicity. No treatmentrelated effects were observed on all sexual organ weights, estrous cycle length and number, and sperm motility, count and percentage of abnormal
sperms in a reliable 90-day repeated dose toxicity study in rat. The weight of the thyroid gland was increased in females and slight/minimal follicular hypertrophy/hyperplasia was seen in males and females at 1000 mg/kg bw/day and in males at 250 mg/kg bw/day also follicular hypertrophy/hyperplasia was seen. Hormones made in the thyroid gland are involved in the regulation of T-lymphocyte development and growth. The extended one generation study is proposed to contain the developmental immunotoxicity cohort (DIT) due to the thyroid effects observed in the 90-day study. The reproduction-developmental screening study is waived, based on testing proposals for an extended one-generation toxicity study (OECD 443) and a developmental toxicity study (OECD 414) for ANNEX IX registration.

Data source

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: OECD 443, including DIT cohort
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; according to guideline
- Basis for dose level selection: all available information from toxicity studies and when necessary a dose range finding study
- Exclusion of extension of Cohort 1B
- Termination time for F2: according to guideline
- Exclusion of developmental neurotoxicity Cohorts 2A and 2B
- Inclusion of developmental immunotoxicity Cohort 3
- Route of administration: oral

Test material

Constituent 1
Reference substance name:
Reaction products of pentaerythritol, propoxylated and 1-chloro-2,3-epoxypropane with hydrogen sulfide
EC Number:
701-196-7
Cas Number:
72244-98-5
Molecular formula:
not applicable
IUPAC Name:
Reaction products of pentaerythritol, propoxylated and 1-chloro-2,3-epoxypropane with hydrogen sulfide

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion