Registration Dossier

Toxicological information

Genetic toxicity: in vitro

Currently viewing:

Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Principles of method if other than guideline:
Model name: A7A-A7E from FDA Genetic toxicity set .Model version: MC4PC version 2.4.1.5
Type of assay:
bacterial reverse mutation assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
a.SMILES: CCOC([S-])=S.[Na+] (Due to the known limitations of used MC4PC software instead of Sodium Ethyl Xanthate its acidic form CCOC(S)=S was used for the model prediction as the closest structural analog).b.InChI: InChI=1/C3H6OS2.Na/c1-2-4-3(5)6;/h2H2,1H3,(H,5,6);/q;+1/p-1c.Other structural representation: noned.Stereochemical features: none

Results and discussion

Test results
Genotoxicity:
negative
Additional information on results:
3.1Endpoint (OECD Principle 1) a.Endpoint: Bacterial Reverse Mutation Test compatible with OECD471 guidanceb.Dependent variable: CASE units (active=30-80, inactive =10-19, marginal 20-29)3.2Algorithm (OECD Principle 2)a.Model or submodel name: A7A-A7E from FDA Genetic toxicity set .b.Model version: MC4PC version 2.4.1.5c.Reference to QMRF: “The corresponding QMRF named ‘MULTICASE A7A,A7B,A7C and A7E FDA Bacterial Reverse Mutation set has been newly compiled”.3.3Applicability domain (OECD principle 3)a.Domains: i.descriptor domain: calculated descriptors (for the acidic form of the test compound, O-ethyl dithiocarbonic acid used in the prediction instead of Sodium Ethyl Xantate, due to a known limitation of used MC4PC software with handling salts. ):ChemicalWater Solubility(log(mol/m3))LogPHuman Intestinal Absorption (%)Molecular Weight(g/mol)Acid (used in QSAR)0.381.1792.26122.21Original Salt5.72*-2.24*81.21144.18**data obtained outside of MC4PC calculationsConclusion: All of these values are within descriptor domain and so the test substance is a candidate for modelling. ii.structural fragment domain : The unknown structural features, which were detected in all test batteries, are typical for xantate moieties. The xantates were not reported a genetoxic in publicly available sources and no component of this product present at levels greater than or equal to 0.1% is identified as probable, possible or confirmed human carcinogen by IARC. The tested substance was reported in NICNAS Priority existing chemical assessment report (1995, Vol.6, 66p) and it was not listed there as genetic toxicant for humans.iii.mechanism domain: N/aiv.metabolic domain; N/ab.Structural analogues: N/a3.4The uncertainty of the prediction (OECD principle 4) The probability that the prediction is accurate is 80% 3.5The chemical and biological mechanisms according to the model underpinning the predicted result (OECD principle 5). N/a4. Adequacy (Optional)4.1Regulatory purpose: REACH registrationApproach for regulatory interpretation of the model result: The RCA reasoning tool, based on the weight of evidence approach, should be applied. This set of rules was developed and refined to assist the U.S. Food and Drug Administration (FDA) in utilizing categorical model predictions in a regulatory setting for drug safety evaluation, since 1998.(Unpublished internal documents, available upon request from the ICSAS office or MultiCASE. See also Matthews EJ, Contrera JF. A new highly specific method for predicting the carcinogenic potential of pharmaceuticals in rodents using enhanced MCASE QSAR-ES software. Regul Toxicol Pharmacol 1998; 28(3):242–264.) According to the RCA rules based evaluation which is summarized in the table above, an alert in order to be relevant and confirmed basing on the weight of evidence approach has to appear in a structurally similar form in more than 2 test modules within a test battery.4.2Outcome: The RCA reasoning system based on the results of MC4PC generated predictions are routinely used the ICSAS office of CDER FDA for the research and regulatory support activities. 4.3Conclusion: . It is concluded that the MultiCASE model/RCA weight of evidence approach is valid for prediction of sodium O-ethyl dithiocarbonate’s effect on genetic toxicity to humans.
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Any other information on results incl. tables

Predicted value (comments):

c:\multicase\mc4pc\fda genetox 2011\job110612.txt

 

 VERSION 2.400

 

 

 

*******************************************************************************

 Now Processing... Sodium Ethyl Xantate                      (Molecule #    1)

*******************************************************************************

 A7A- Mutagenicity - Microbial composite (Sal_Ecoli_Bac) - RCA     #3644 2.40

 ------------------------------------------------------------------------------

 MC calculated Water Solubility is: 0.38 [in log(mol/m**3)]

 MC calculated Log(Octanol/Water) Partition Coef.is: 1.17

 Molecule satisfies the rule of 5 (bioavailable)

 MC Calculated Human Intestinal Absorption is: 92.3%

** WARNING ** The following functionalities are UNKNOWN to me:

      *** SH -CS -O -

       *** CS -O -CH2-

 

MULTICASE-3 Prediction

----------------------

** The molecule does not contain any known biophore

 ** The results are QUESTIONABLE due to the

               presence of UNKNOWN functionalities **

 

 CONCLUSIONS:

 ------------

 ** The projected Mutagenicity activity is  10.0    CASE units **

 ** The compound is presumed to be INACTIVE **

 ** The probability that this molecule is Mutagenicity is   22% **-

 

 RCA CONCLUSIONS:

 -------------------------

 RCA Expert Call: Negative Coverage: 2w

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

 

 

 

*******************************************************************************

 Now Processing... Sodium Ethyl Xantate

*******************************************************************************

 A7B- Mutagenicity - Salmonella t. 5-strains            - RCA     #3535 2.40

 ------------------------------------------------------------------------------

 MC calculated Water Solubility is: 0.38 [in log(mol/m**3)]

 MC calculated Log(Octanol/Water) Partition Coef.is: 1.17

 Molecule satisfies the rule of 5 (bioavailable)

 MC Calculated Human Intestinal Absorption is: 92.3%

** WARNING ** The following functionalities are UNKNOWN to me:

      *** SH -CS -O -

       *** CS -O -CH2-

 

MULTICASE-3 Prediction

----------------------

** The molecule does not contain any known biophore

 ** The results are QUESTIONABLE due to the

               presence of UNKNOWN functionalities **

 

 CONCLUSIONS:

 ------------

 ** The projected Mutagenicity activity is  10.0    CASE units **

 ** The compound is presumed to be INACTIVE **

 ** The probability that this molecule is Mutagenicity is   22% **-

 

 RCA CONCLUSIONS:

 -------------------------

 RCA Expert Call: Negative Coverage: 2w

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

 

 

 

*******************************************************************************

 Now Processing... Sodium Ethyl Xantate

*******************************************************************************

 A7C- Mutagenicity - E.coli composite                   - RCA     # 527 2.40

 ------------------------------------------------------------------------------

 MC calculated Water Solubility is: 0.38 [in log(mol/m**3)]

 MC calculated Log(Octanol/Water) Partition Coef.is: 1.17

 Molecule satisfies the rule of 5 (bioavailable)

 MC Calculated Human Intestinal Absorption is: 92.3%

** WARNING ** The following functionalities are UNKNOWN to me:

      *** SH -CS -O -

       *** CS -O -CH2-

 

MULTICASE-3 Prediction

----------------------

** The molecule does not contain any known biophore

    However,

 The UNKNOWN fragment : CS -O -

 is similar to the biophore : CS -N -

    The molecule might therefore be active and should be tested experimentally

 

 CONCLUSIONS:

 ------------

 ** The projected Mutagenicity activity is  10.0    CASE units **

 ** The compound is presumed to be INACTIVE **

 ** The probability that this molecule is Mutagenicity is   22% **-

 ** The results are INCONCLUSIVE

 

 RCA CONCLUSIONS:

 -------------------------

 RCA Expert Call: Negative Coverage: 2w

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

 

 

 

*******************************************************************************

 Now Processing... Sodium Ethyl Xantate

*******************************************************************************

 A7D- Mutagenicity - E.coli WP strains                  - RCA     # 280 2.40

 ------------------------------------------------------------------------------

 MC calculated Water Solubility is: 0.38 [in log(mol/m**3)]

 MC calculated Log(Octanol/Water) Partition Coef.is: 1.17

 Molecule satisfies the rule of 5 (bioavailable)

 MC Calculated Human Intestinal Absorption is: 92.3%

** WARNING ** The following functionalities are UNKNOWN to me:

      *** SH -CS -O -

       *** CS -O -CH2-

 

MULTICASE-3 Prediction

----------------------

** The molecule does not contain any known biophore

 ** The results are QUESTIONABLE due to the

               presence of UNKNOWN functionalities **

 

 CONCLUSIONS:

 ------------

 ** The projected Mutagenicity activity is  10.0    CASE units **

 ** The compound is presumed to be INACTIVE **

 ** The probability that this molecule is Mutagenicity is   21% **-

 

 RCA CONCLUSIONS:

 -------------------------

 RCA Expert Call: Negative Coverage: 2w

HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH

The Test is Done.

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):negativeThe tested molecule does not contain any confirmed alerts and is assumed to be inactive.