4,4'-Isopropylidenediphenol, ethoxylated

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study planned

Remarks:

Study is underway with LabCorp (previously Covance). Due to unforeseen issues the completion of this study has been delayed. Please refer to letter attached to this dossier

Study period:

2021

Justification for type of information:

Justification for type of information - Testing Proposal for Developmental toxicity teratogenicity

TESTING PROPOSAL ON VERTEBRATE ANIMALS

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out: 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2).

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 GLP studies were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Available non-GLP studies: No non-GLP studies were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Historical human data: No historical human data were identified on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- (Q)SAR: According to ECHA Endpoint Specific Guidance Chapter R.7a, considering the large number of potential targets and mechanisms associated with reproductive toxicity, this endpoint cannot be adequately covered by a battery of QSAR models. QSAR models could only be used to identify likely mode of actions for toxicity to reproduction and there is currently no (Q)SAR model allowing to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of a substance.
- In vitro methods: According to ECHA Endpoint Specific Guidance Chapter R.7a, there is currently no in vitro method accepted for regulatory use to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of a substance. In vitro testing can only be used in order to identify potential targets and mechanisms associated with reproductive toxicity, but in vivo situation is considered to be more than the sum of the areas modelled by a series of in vitro assays.
- Weight of evidence: There is not sufficient data available on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) and read-across substances that could be used in a weight-of-evidence approach in order to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.
- Grouping and read-across: The substance 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) (CAS 37353-75-6 / EC 500-097-4) was identified as a potential read-across substance for 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated). Both substances are UVCB whose constituents are 4,4-isopropylidenediphenol with various degrees of ethoxylation or propoxylation. These constituents have a mean chain length comprised between 1 and 4.5 ethoxy or propoxy groups. A GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test was performed on both substances according to OECD Testing Guideline 422 using Sprague-Dawley rats. Maternal toxicity was observed in animals treated with 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) during the Dose-Range Finding study performed at up to 1,000 mg/kg bw/d, along with developmental findings with a decrease of pup body weights observed at 500 mg/kg/day during the main study. As for the 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated), a significant bodyweight reduction was observed in animals treated at 1,000 mg/kg bw/d during the main study, while no significant treatment-related developmental effects were observed in pups from parents exposed at up to 1,000 mg/kg bw/d. It can be concluded from these results that 4,4'-Isopropylidenediphenol, propoxylated (1 – 4.5 moles propoxylated) can be expected to be more toxic to reproduction than 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) and therefore cannot be considered as a suitable read-across substance in order to comply with the requirements outlined in Annex IX of REACH regarding the Developmental toxicity / teratogenicity of the substance.

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:
- In accordance to Annex IX of REACH, Column 2, a Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure studies does need to be conducted as:
—4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to be a genotoxic carcinogen.
— 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to be a germ cell mutagen.
— Available data suggests that systemic absorption occurs following an exposure to 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) by the oral route.
—4,4- isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to have adverse effects on fertility, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage fertility (H360F).
—4,4- isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) is not known to cause developmental toxicity, meeting the criteria for classification as toxic for reproduction category 1A or 1B: May damage the unborn child (H360D).

ADDITIONAL INFORMATION
4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2) has been added to the definitive CO-RAP list and will be evaluated in 2020 by the French MSCA. The evaluating MSCA may want to comment on the study design required for the purpose of the evaluation of the developmental toxicity / teratogenicity of the substance. Therefore, it is proposed to wait for Final CO-RAP Decision on 4,4-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated) (EC 500-082-2) before performing this test in order to avoid the potential duplication of any unnecessary animal testing.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not applicable

Test material

Test material information

1

Reference substance name:

4,4'-Isopropylidenediphenol, ethoxylated

EC Number:

500-082-2

EC Name:

4,4'-Isopropylidenediphenol, ethoxylated

Cas Number:

32492-61-8

Molecular formula:

C15H16O2.(C2H5O)n.(C2H5O)m sum of n+m: >1 - <4.5 moles EO

IUPAC Name:

2-[4-[2-[4-(2-hydroxyethoxy)phenyl]propan-2-yl]phenoxy]ethanol

Test material form:

liquid: viscous

Details on test material:

Chemical name : 4,4'-isopropylidenediphenol, ethoxylated (1 – 4.5 moles ethoxylated)
EC number : 500-082-2

Based on the qualitative and quantitative information on the composition, the sample used are representative of the boundary composition shared and agree by each registrant.

Test animals

Species:

rat

Strain:

Crj: CD(SD)