Registration Dossier

Administrative data

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

EC 259-048-8 is not expected to cause genotoxicity based on a weight of evidence evaluating the dialkyl dithiophosphate ester functionality. This is supported by the following assessment:

 

1.      Read across from the alkyl zinc dialkyldithiophosphate (ZDDP) category

 

Alkyl ZDDPs contain the same core functional group as EC 259-048-8 with the only difference being they have an alkyl chain instead of an alkaryl. As such, applying this data is a conservative approach to evaluating the potential genotoxicity of EC 259-048-8, which is a larger and bulkier molecule. Therefore, it is expected to have decreased bioavailability and reactivity compared to the analog substances. EC 259-048-8 also contains tetrapropenyl phenol (also known as Phenol, dodecyl-, branched; TPP; EC Number 310-154-4) as an impurity. TPP is not mutagenic or genotoxic as demonstrated by the test data for this substance, which can be found in the registration dossier for this material.

 

Multiple genotoxicity data points demonstrating lack of genotoxic potentail are available for the alkyl ZDDP category. This includes bacterial mutation (in vitro Ames); mammalian mutation (in vitro mouse lymphoma assay); and clastogenicity and aneugenicity (in vivo mouse micronucleus test). The OECD 474in vivomouse micronucleus study covers the requirement for the OECD 473in vtirochromosomal aberration test. The alkyl ZDDP category justification and data summary is attached in section 13 of this dossier – this document provides an overview of the substances that contain genotoxicity data.

 

It should be noted that CAS 2215-35-2, a 1,3-dimethylbutyl ZDDP, was negative in an Ames gene mutation assay but gave equivocal results in a mammalian cell gene mutation assay (TK+/- mouse lymphoma assay). However, the study was non-GLP, performed using a non-standard cell line (BALB/3T3 A31) and gene locus (ouabain resistance), and had only two surviving dose levels. The mutant frequencies observed at these dose levels showed no clear relationship to achieved toxicity and therefore the study is considered to be unreliable.

 

This is supported by additional investigations testing zinc chloride and a calcium analog of a ZDDP. Zinc chloride showed high degree of cytotoxicity (the total growth ranged from 2% to 61%) and positive results for mutagenicity. These results are consistent with previous studies which demonstrated that the zinc ion caused the cytotoxicity and mutagenicity in similarly cultured mammalian cell systems (Amakeret al., 1979). Calcium dialkyl dithiophosphate did not exhibit mutagenicity and relative higher cell viability was obtained (the total growth ranged from 17% to 74%). Taken together, the data suggest the dialkyldithiophosphate portion of the ZDDP molecule is non-mutagenic. The zinc subcomponent is likely the causative agent under these specific test conditions. However, since zinc is not classified as carcinogen, the weight of evidence suggests that zinc is not a mutagen.

 

These supporting studies are provided in the REACH registration dossier as is the genotoxicity data on EC 224-235-5, which is the closest alkyl ZDDP analog (based on molecular weight).  

 

2.      QSAR

 

To further evaluate the genotoxicity potential, modeling using OASIS TIMES v.2.28.1.4 was conducted with the following

 

·        In vivomicronucleus v.11.11

·        In vitroMammalian Chromosome Aberration S9 activated v.15.15

·        Ames mutagenicity S9 activated v.15.15

 

All 3 models predicted the parent compound and the metabolites as negative. The dialky dithiophosphate ester (without Zn) was the molecule modeled; it was in the model’s parametric domain and 71% (micronucleus) or 77.4% (Ames and chromosomal aberration) was inside the structural fragment domain. Each model prediction is summarized in the dossier with the QPRF attached.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Justification for classification or non-classification

No evidence of mutagenic or genotoxic potential based on QSAR modeling and based on read across to structural analogs with the same functional groups.