4,4'-Methylene-bis-(3-chloro-2,6-diethylaniline)

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
ECHA considers registration dossiers for substances > 100 tpa as technically complete even if they do not contain the results of a screening study for reproductive/developmental toxicity if:
- a 90-day subchronic toxicity study is available
- if the dossier contains either the results of, or a testing proposal for a prenatal developmental toxicity study
As a subchronic 90-day oral toxicity study is already available and a developmental/teratogenicity is planned to be conducted, the reprotoxicity screening study is waived.

Reproductive effects observed:

not specified

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study planned

Justification for type of information:

TESTING PROPOSAL ON VERTEBRATE ANIMALS
This substance has been notified as new chemical substance und the previous European chemicals legislation (ELINCS). A standard data set was provided at that time. In addition, a 90-day repeated oral toxicity study was conducted for a planned Food Contact registration. The standard Annex 8 data requirements consist of a reproduction toxicity screening test. However, as a 90-day oral toxicity study is already available and the 100 tpa tonnage threshold was exceeded, the registrant suggest to conduct a developmental toxicity / teratogenicity on rats (according to OECD 414) to fulfill the Annex 9 data requirements of the REACH-regulations. If a subchronic 90-day oral toxicity study is already available, a developmental / teratogenicity test is preferred instead of a reprotoxicity screening study according to OECD 421 or 422.

NON-CONFIDENTIAL NAME OF SUBSTANCE ON WHICH TESTING IS SUGGESTED TO BE CARRIED OUT:
- 4,4'-Methylene-bis-(3-chloro-2,6-diethylaniline)
- EC-Number: 402-130-7
- CAS-Number: 106246-33-7

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]:

1. AVAILABLE GLP-STUDIES:
Complete study package (GLP) of ELINCS-notification dossier incl. prolonged oral toxicity studies on rats over 28 and 90 days; no information about reproductive or developmental toxicity available, as those endpoints were not required at time of notification/registration. All studies are of good quality (Klimisch 1), GLP-compliant and conducted according to OECD- and/OR EU-testing methods.

2. SUITABLE ALTERNATIVE OR (Q)SAR TESTING METHODS:
Suitable (in-vitro) testing or QSAR-methods are not available

3. AVAILABLE NON-GLP STUDIES:
Non-GLP studies on developmental toxicity/teratogeniciy are not available

4. HISTORICAL HUMAN DATA
Historical human data are not availalable

5. GROUPING/READ-ACROSS APPROACH:
A possible read-across approach to the following structurally similar substance (same chemical structure, but without Cl-atoms) was initially taken into consideration:
Non-Confidential Name of possible Read-Across Substance:
- 4,4'-Methylenebis[2,6-diethylaniline]
- EC number: 237-185-4
- CAS number: 13680-35-8
- Registered by same applicant
For this substance, an annex 9 REACH-data set incl. OECD 414 on rats is already available and a study on a second species (rabbit) is currently ongoing. However, a comparison of all results and toxicity endpoints of source and target substances showed, that the two chemicals are not that similar as expected and have a rather different toxicity profile with deviating solubility properties in water and n-octanol:
- Different phys-chem characteristics: CAS 106246-33-7 is ca. 20-fold less soluble in water than the read-accross candidate CAS 13680-35-8), and has a much higher Log Pow; although both would be characterised as of low water-solubility and high lipophilicity.
- The substance in question (CAS 106246-33-7) is classified for oral acute toxicity (LD50 < 2000 mg/kg), whereas the possible read-accross substance (CAS 13680-35-8) is not (LD50 > 5000 mg/kg)
- While the main target organ in the subchronic studies appears the same, liver, the histopathology is different.
Finally, we came to the conclusion, that the criteria for sameness are not fulfilled and therefore, a read-accross to CAS number 13680-35-8 is not possible. As consequence, we suggest to conduct an OECD 414 with 4,4'-Methylene-bis-(3-chloro-2,6-diethylaniline) (EC-Number: 402-130-7 / CAS-Number: 106246-33-7)

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Species:

rat

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available (further information necessary)

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available