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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study planned
Justification for type of information:
Testing proposal Prenatal Developmental Toxicity Study on a rodent species (OECD 414)

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 1,6-hexanediyl-bis-carbamic acid-bis[2-[2-(1-ethylpentyl)-3-oxazolidinyl]-ethyl]-ester (Incozol EH)

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 this substance covering the endpoint of prenatal developmental toxicity
- Available non-GLP studies: There are no non-GLP studies available for this substance covering the endpoint of prenatal developmental toxicity
- Historical human data: There are no historical human data available on prenatal developmental toxicity for the substance.
- (Q)SAR: (Q)SAR approaches are currently not well fitted-for-purpose for reproductive toxicity and consequently no firm recommendations can be made concerning their routine use in a testing strategy in this area (ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R 7a: Endpoint specific guidance, 2017).
- In vitro methods: There are no in vitro methods available to cover the endpoint of prenatal developmental toxicity
- Weight of evidence: There is no data available which is sufficient for a weight of evidence approach.
- Grouping and read-across: There are no substances which apply for read across addressing prenatal developmental toxicity

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 fully registered according to REACH Annex VII and will be updated according to REACH Annex IX. Therefore, a study on developmental toxicity in one species is legally required. Furthermore, none of the adaption options from Annex IX, 8.7, column 2 are applicable for the substance, as the substance is not a genotoxic carcinogen, germ cell mutagen or known to cause developmental toxicity and is therefore classified as a reproductive toxicant Category 1 or 2 according to CLP. Although the substance shows low bioavailability, toxicological activity and hydrolyses immediately after contact with water, it must be considered for developmental toxicity testing as due to human exposure according to its intended use, its hydrolysis products can be absorbed systemically after oral exposure.

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
Details on study design / methodology proposed:
Based on the legal requirements, a Prenatal Developmental Toxicity Study on one species according to OECD guideline 414 is proposed to assess the effects of the test substance on growth, survival, maintenance of pregnancy of maternal animals and effects on resorptions, fetal deaths, fetal growth, morphological variations and malformations of a rodents offspring.
This study is the test system proposed in Annex X, 8.7, column 1 and in the ECHA Guidance on Information Requirements and Chemical Safety Assessment, Chapter R 7a: Endpoint specific guidance, 2017. Under consideration of the substance properties, it is regarded to be the appropriate test system to investigate the potential to induce prenatal developmental toxicity, i.e., substances or their metabolites (hydrolysis products) that become readily systemically available upon ingestion. Furthermore, historical control data are available for various tissues. The test substance is proposed to be administered orally by gavage to rats as the proposed rodent species according to OECD guideline 414. As a reliable sub-chronic 28-day repeated dose toxicity study according to OECD guideline 407 is available in rats, doses will be based on this study data.
Based on the results of the available sub-chronic study in rats, the maximum recommended dose of 1000 mg/kg bw/day will be used as the high dose. Two additional doses (separated by a factor of 2 to 4) are proposed. Based on the available sub-chronic study and on the underlying solubility studies propylene glycol and 1,2-propane diol can be used as a vehicle. Details will be defined in the study protocol.
A sufficient number of female rats per dose or control groups to reach a minimum of 20 animals with implantation sites at necropsy will be chosen and is proposed. The test chemical is intended to be administered daily to pregnant animals by gavage, at least from implantation to one day prior to the day of scheduled killing. Shortly before caesarean section, the females will be killed, the uterine contents are examined, and the fetuses are evaluated for fetal deaths, sex, body weight, AGD, soft tissue and skeletal changes. Dams will be observed during the treatment period, weighted, and examined post-mortem. These examinations will include macroscopical structural abnormalities, weight of thyroid glands and uteri, histopathological assessment of thyroid gland and uteri, number of corpora lutea and degree of resorption.

This Testing Proposal is concurrently submitted for EU REACH and UK REACH.

Data source

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
(E)-N-{6-[(E)-({2-[2-(heptan-3-yl)-1,3-oxazolidin-3-yl]ethoxy}(hydroxy)methylidene)amino]hexyl}{2-[2-(heptan-3-yl)-1,3-oxazolidin-3-yl]ethoxy}carboximidic acid
EC Number:
925-259-5
Cas Number:
140921-24-0
Molecular formula:
C32H62N4O6
IUPAC Name:
(E)-N-{6-[(E)-({2-[2-(heptan-3-yl)-1,3-oxazolidin-3-yl]ethoxy}(hydroxy)methylidene)amino]hexyl}{2-[2-(heptan-3-yl)-1,3-oxazolidin-3-yl]ethoxy}carboximidic acid

Test animals

Species:
rat

Administration / exposure

Route of administration:
oral: gavage

Results and discussion

Applicant's summary and conclusion

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