5 Replies Latest reply on Oct 10, 2018 1:49 PM by 956039

    Multifunctional acrylates profile (and related endpoint specific alerts) and BfR inclusion rules

    956039 New User

      I was wondering if I can get an explanation as to why a chemical with Multifunctional acrylates profile is not detected by the skin irritation/corrosion BfR rule Esters including acrylic and methacrylic esters in the Toolbox. The chemical SMILE in the toolbox is C=CC(=O)OCCOCCOCCOCCOC(=O)C=C. The acrylic group in the similar chemical COCCOC(=O)C=C (like other two with data in the ECETOC eye irritation database)is captured by the inclusion rule.

       

      Also: where can I find the explanation about the meaning of the MMAS in the Toolbox.

       

      Thank you

      Julija

        • Re: Multifunctional acrylates profile (and related endpoint specific alerts) and BfR inclusion rules
          1006501 New User

          Dear Julija,

          You can get an explanation for each category in the Literature tab (Figure 1). There you can see the structural alerts which are coded by using the SMARTS language.

          Figure 1

           

          The structural alert for Acrylic and methacrylic esters is defined to capture chemicals that have alkyl, arylalkyl or aryl group bonded to the acrylate moiety. The chemical with CAS 17831-71-9 (corresponding to the first SMILES) does not meet these criteria (Figure 2).

          Figure 2

           

          The second chemical (CAS 3121-61-7) is mapped by the structural query used to represent the Ethyleneglycolethers category (Figure 3).

          Figure 3.

           

          The first chemical (CAS 17831-71-9) does not meet this rule because of the presence of second acrylic fragment. If you remove it, then the chemical will be captured by the same category (Ethyleneglycolethers) (Figure 4).

           

          Figure 4

           

          In summary: the profiling results are correct in the way the structural alerts are coded.

           

           

          MMAS means Modified Maximum Average Score. No additional information is available in Toolbox.  The MMAS is described in the paper by Bagley, et.al. (1992):

          Bagley D. M., Botham P. A., Gardner J. R., Holland G., Kreiling R., Lewis R. W., Stringer D. A. and Walker A. P. (1992) Eye irritation: reference chemicals data bank. Toxicology in Vitro 6, 487-491.

           

           

           

          Kind regards,

          Darina

            • Re: Multifunctional acrylates profile (and related endpoint specific alerts) and BfR inclusion rules
              956039 New User

              Thank you Darina,

              I am wondering if an acrylic group is specifically excluded oritt is just not included in the definition for the R moieties in the Acrylic and methacrylic esters alert,  based on 'training' set of chemicals used to derive the BfR inclusion rules?

               

              Interestingly when I run a QSAR to fill data gap on skin/eye irritation on the first chemical (not detecting inclusion rules for eye or skin irritation) I get a positive result for eye irritation. Obviously the choice to run the QSAR was not a hypothesis driven choice based on profiling of the chemical, but I did it.  How can I explain  the positive result with the prediction  referenced as follows: QSAR result /Toolbox and SAR/QSAR /BfR eye irritation/corrosion.

               

               

               

              The reference to BfR eye irritation/corrosion does not lead to the profiling scheme,  but even if I went to it,  I cannot explain this result based on the alerts there. How can I figure out what is the mechanistic explanation? What combination or rules/considerations (metabolism?) or maybe predictions from the Danish QSAR database (which I don't see in the Toolbox now). Can you help?

               

              I was also wondering whether inclusion of the ESTOFF database (ref 61 in Gerner,et al.,  (2000). D ATLA 28, 11–28. ) or other databases used as validation references or example all ECVAM and ICCVAM databases in the Toolbox would be possible or useful? I see the ECVAM genotoxicity and carcinogenicity database already included.

               

              In terms of background explanation for MMAS it would be really useful to have an explanation of the code within the tool as an explain or about function.

               

              Thank you very much for your patience and consideration.

              Julija

                • Re: Multifunctional acrylates profile (and related endpoint specific alerts) and BfR inclusion rules
                  1006501 New User

                  Dear Julija,

                  The BfR models are based on the corresponding profilers for inclusion and exclusion rules. Currently there is a problem with the predicted results for the chemicals where any of the parameters used in the exclusion rules could not be calculated. For such chemicals you will see “Undefined” profiling result. In this case, lipid solubility of the analyzed chemical is not available (see the figure below).

                  Unfortunately, I am not aware on how exactly the structural boundaries in Inclusion rules profilers are defined and which are the used training set chemicals. More details on the skin/eye irritation/corrosion categories could be get by the authors of the profiles/(Q)SARs.

                  Regarding importing of new databases in Toolbox – there is a specific procedure of donation and approval of a database before its inclusion to the official Toolbox package. The procedure also includes pre-processing of raw data in order to establish if it is suitable for import into Toolbox as well as to provide a sense of how the new data would fit into the current endpoint tree. One of the main advantages of importing of new databases to the Toolbox lies in the ability to combine more data going into data gap filling.

                   

                  Kind regards,
                  Darina