4,4'-Isopropylidenediphenol, ethoxylated

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Type of information:

experimental study planned

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS
[Please provide information for all of the points below. The information should be specific to the endpoint for which testing is proposed. Note that for testing proposals addressing testing on vertebrate animals under the REACH Regulation this document will be published on the ECHA website along with the third party consultation on the testing proposal(s).]

NON-CONFIDENTIAL NAME OF SUBSTANCE:
- Name of the substance on which testing is proposed to be carried out:
4,4'-Isopropylidenediphenol, 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 [please address all points below]:
- Available GLP studies:
The potential of 4,4'-Isopropylidenediphenol, ethoxylated to induce genotoxic effects was tested in a suitable in vitro test battery, conducted under GLP. The target substance was tested negative in a bacterial reverse gene mutation test conducted according to OECD 471 and in a In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene according to OECD 490. In an in vitro micronucleus test (OECD 487), 4,4'-Isopropylidenediphenol, ethoxylated did induce chromosomal damage. No additional GLP studies were identified on 4,4'-Isopropylidenediphenol, ethoxylated to comply with the requirements outlined in Annex IX of REACH regarding the Mammalian Erythrocyte Micronucleus Test.

- Available non-GLP studies:
No non-GLP studies were identified on 4,4'-Isopropylidenediphenol, ethoxylated to comply with the requirements outlined in Annex IX of REACH regarding the Mammalian Erythrocyte Micronucleus Test.

- Historical human/control data
No historical human/control data were identified on 4,4'-Isopropylidenediphenol, ethoxylated to comply with the requirements outlined in Annex IX of REACH regarding the Mammalian Erythrocyte Micronucleus Test.


- (Q)SAR
The outcome of a QSAR assessment will not overrule the positive results of an in vitro micronucleus test.

- In vitro methods
Further in vitro testing will not be sufficient to provide information to draw conclusion on this endpoint.

- Weight of evidence
There is not sufficient data available on 4,4'-Isopropylidenediphenol, 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 the toxicity to reproduction potential of the substance.


- Grouping and read-across:
No further experimental data on potential analogues are available.

- Substance-tailored exposure driven testing [if applicable]
Omitting testing based on absence or no significant exposure is not applicable for the substance based on the available exposure scenarios.


- Approaches in addition to above [if applicable]
Not applicable

- Other reasons [if applicable]
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:
- In accordance to ANNEX IX of the REACH Regulation 1907/2006, column 2, "If there is a positive result in any of the in vitro genotoxicity studies in Annex VII or VIII and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant."

According to ECHA R7a Guidance Table R.7.7-5, in case of a negative bacterial mutagenicity and a positive cytogenic assay, adequate somatic cell in vivo test to investigate structural or numerical chromosome aberrations should be selected. Hence, it is necessary to propose an appropriate in vivo somatic cell genotoxicity test (OECD 474).

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:
- Details on study design / methodology proposed [if relevant]
According to ECHA R7a Guidance Table R.7.7-5, "If systemic availability cannot be ascertained reliably, it should be investigated before progressing to in vivo tests". For the test substance, blood parameter changes observed in the repeat dose oral toxicity study would suggest that absorption does take place orally. In acute oral exposures, only mild systemic effects reported at extremely high dose. For example, at 5000 mg/kg bw 5/10 females died within 48 hours. In addition, at acute exposures of 3200-6400 mg/kg bw, Immediately after administration quiet behaviour, reddened eyes, staggering, compulsive mastication, salivation, scrubby fur were observed and the male rats showed squatting posture and irregular respiration, whereas the females showed abdominal-lateral-back position, apathy and wet fur. Overall, evidence suggest that absorption of test substance takes place. However, no data in mice is available. Hence, a dose range finding study is proposed.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Version / remarks:

July 29, 2016

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of assay:

mammalian erythrocyte micronucleus test

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 will be representative of the boundary composition shared and agree by each registrant.

Test animals

Species:

mouse

Administration / exposure

Route of administration:

oral: gavage

Details on exposure:

Single dose. The animals will be sacrificed 24 and 48 hours after treatment.

Applicant's summary and conclusion

Executive summary:

The potential of 4,4'-Isopropylidenediphenol, ethoxylated to induce genotoxic effects was tested in a suitable in vitro test battery, conducted under GLP. The target substance was tested negative in a bacterial reverse gene mutation test conducted according to OECD 471 and in a In Vitro Mammalian Cell Gene Mutation Tests Using the Thymidine Kinase Gene according to OECD 490. In an in vitro micronucleus test (OECD 487), 4,4'-Isopropylidenediphenol, ethoxylated did induce chromosomal damage. No additional GLP studies were identified on 4,4'-Isopropylidenediphenol, ethoxylated to comply with the requirements outlined in Annex IX of REACH regarding the Mammalian Erythrocyte Micronucleus Test.

In accordance to ANNEX IX of the REACH Regulation 1907/2006, column 2, "If there is a positive result in any of the in vitro genotoxicity studies in Annex VII or VIII and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant."

According to ECHA R7a Guidance Table R.7.7-5, in case of a negative bacterial mutagenicity and a positive cytogenic assay, adequate somatic cell in vivo test to investigate structural or numerical chromosome aberrations should be selected. Hence, it is necessary to propose an appropriate in vivo somatic cell genotoxicity test (OECD 474)