impureza 2: 1 h-imidazol -...

IMPUREZA 2: 1 H-Imidazol Rattus Norvergicus TA

APÉNDICE 6

1 / 30Prediction of LD50 for imidazole, LD50 for Rat Trend Analysis

QSAR Toolbox prediction for single chemical

The template of the current report is based on "GUIDANCE DOCUMENT ON THEVALIDATION OF (QUANTITATIVE) STRUCTURE-ACTIVITY RELATIONSHIPS MODELS"published by OECD (September, 2007) and "GUIDANCE ON INFORMATIONREQUIREMENTS AND CHEMICAL SAFETY ASSESSMENT / CHAPTER R.6: QSARS ANDGROUPING OF CHEMICALS" published by ECHA (May, 2008). The report provides information about the target substance, chemical characteristicsused for the grouping, the resulting boundaries of the group of chemicals (applicabilitydomain), the type of data gap filling approach that was applied (read-across, trendanalysis or QSAR models), the predicted result(s) and in the Annex information aboutthe category members or training set and test set chemicals. The chemicals are ordered by the distance to the target substance within thedescriptors space. Only chemicals with experimental data are listed as categorymembers. Depending on the settings selected by the user, detailed information (incl. 2D imageand profiling results) is provided for some chemicals while more limited information(CAS, name, SMILES) is provided for others. If not otherwise specified, the experimental values are reported in bold, recalculatedexperimental values are reported in bold & italic and calculated values are reported inregular font.

QSAR Toolbox 3.2.0.103 TPRF v.3.2.1.32002Database version: 3.5.0/3.1.2


Table of content

Summary 3

1. Target substance

1.1. CAS number 41.2. Other regulatory numbers 4

1.3. Chemical name(s) 41.4. Structural formula 41.5. Structure codes 41.6. Quality of structure identity (CAS/2D quality) 5

2. General information

2.1. Date of report generation 52.2. Report author(s) and contact details 5

3.1. Category definition 53.2. Category justification 83.3. Data matrix 8

3. Category definit ion

4. Prediction

4.1. Defined endpoint (OECD Principle 1) 84.2. Unambiguous algorithm (OECD Principle 2) 84.3. Applicability domain (OECD Principle 3) 94.4. Uncertainty of the prediction (OECD Principle 4) 104.5. Chemical and biological mechanisms (OECD Principle 5) 11

5. Adequacy

5.1. Regulatory purpose 125.2. Approach for regulatory interpretation of the model result 125.3. Outcome 125.4. Conclusion 12

Appendix 1 13

Appendix 2 28

Appendix 3 29

Appendix 4 29

Appendix 5 29

- Category members

- Data matrix

- QMRF

- QMRF, training set

- QMRF, test set

Appendix 6 29 - Additional information from QSAR

Appendix 7 30 - Chemical components



QSAR Toolbox prediction based on trend analysis

Prediction of LD50 for imidazole, LD50 for Rat Trend Analysis

Summary

Toxicity of the target chemical (602 mg/kg) is predicted from category members using trend analysis basedon 11 values within the range 1.53E+03 - 2.00E+03 mg/kg from 11 category members. Category membersare single chemicals or mixtures and are selected based on the profile of the target chemical. Only chemicalshaving experimental data are listed in the category.

The target chemical FALLS within applicability domain of the prediction (see Section 4.3 for details).

The descriptor values for the target chemical and the category members in case they are set oftautomers, set of metabolites or mixtures are calculated using the following rule(s):

1. "log Kow" - taking the weighted average value

The endpoint data used in the prediction is selected from the following database(s):

1. Toxicity Japan MHLW

Below is a summary table for endpoint & descriptor values for the target chemical and the first 10category members. Experimental values from data matrix are presented in bold font. Recalculated endpoint values (ifrequired by selected data usage option in Gap Filling) are presented in italic font. Recalculated endpointvalues based on experimental data only are presented in bold and italic font.

Endpoint(s)

Acute Toxicity

mg/kg

Descriptor(s)

log Kow

-

0 Target chemical

1 Cat. member No. 1

2 Cat. member No. 2

3 Cat. member No. 3

4 Cat. member No. 4

5 Cat. member No. 5

6 Cat. member No. 6

7 Cat. member No. 7

8 Cat. member No. 8

9 Cat. member No. 910 Cat. member No. 10

- 0.0600

2.00E+03 0.460

2.00E+03 -0.500

2.00E+03 0.920

2.00E+03 1.59

1.53E+03 -2.64

2.00E+03 2.84

2.00E+03 -4.42

2.00E+03 -4.42

2.00E+03 9.07

2.00E+03 12.3



Section 1 Target chemical-

1.1. CAS number:

288-32-4

1.2. Other regulatory numbers:

Not reported

1.3. Chemical name(s):imidazole1h-imidazoleimidazole (solid)imidazole:imidazol

1.4. Structural formula:

NH

N

1.5. Structure codes:

a. SMILES:

C1=CNC=N1

b. Input structure code (if different from SMILES):

Not available

c. Stereochemical features:

Not provided by the user

manually editable field



1.6. Quality of structure identity (CAS/2D quality):

High Quality

Databases:

Aquatic OASISBacterial mutagenicity ISSSTYBiodegradation NITEECHA CHEMECOTOXExperimental pKaEye Irr itation ECETOCGenotoxicity OASISPhys-chem EPISUITE

Section 2 General information-

2.1. Date of report generation:

11.10.2014

2.2. Report author(s) and contact details:

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


Section 3 Category definition and category members-

3.1. Category definit ion:

a. Category hypothesis:

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


b. Applicability domain of the category:

The applicability domain is defined by following scheme



1 2 3

11

NOT

15

A ND

18

A ND

4 5

12

NOT

16

A ND

19

A ND

6

20

A ND

7 8

13

NOT

17

A ND

21

A ND

9 10

14

A ND

22

A ND

1) Referential boundary:

The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer(original)


The target chemical should be classified as No alert found by DNA binding by OASIS v.1.2


The target chemical should be classified as AN2 OR AN2 >> Michael-type addition, quinoidstructures OR AN2 >> Michael-type addition, quinoid structures >> Quinones OR AN2 >>Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-typeaddition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered LactonesOR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation afteraldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalentinteraction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNAIntercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >>Quinones OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >>Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathionedepletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >>Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation ORRadical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA ORRadical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >>Organic Peroxy Compounds OR Radical >> Radical mechanism by ROS formation >>Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >>Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radicalmechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >>Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers andNitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> QuinonesOR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilicattack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attackafter diazoniu ...




The target chemical should be classified as No alert found by DNA binding by OECD


The target chemical should be classified as Acylation OR Acylation >> Isocyanates andIsothiocyanates OR Acylation >> Isocyanates and Isothiocyanates >> Isothiocyanates OR Michaeladdition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >>Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >>Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1>> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >>Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Secondaryaromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2>> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides byDNA binding by OECD


The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer(original)


The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity(Micronucleus) alerts by ISS


The target chemical should be classified as No alert found OR Primary aromatic amine, hydroxylamine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

9) Parametric boundary:

The target chemical should have a value of log Kow which is >= -4.44

10) Parametric boundary:

The target chemical should have a value of log Kow which is <= 14

c. Endpoints covered:



d. Category members:

The list of the category members is available in Appendix 1

The category members shown with respect to the descriptor log Kow

Trend analysis prediction of LD50,making a linear approximation, based on 11 values from 11 analogue chemicals,

Observed target value: N/A, Predicted target value: 602 (244 to 1.48E+03; 95.0%) mg/kg,

Model equation: LD50 = +2.05 (±0.12) +0.0286 (±0.0184) * log Kow, log(1/mol/kg)

log Kow14.013.012.011.010.09.08.07.06.05.04.03.02.01.00.0-1.0-2.0-3.0-4.0-5.0

LD

50

(o

bs

.),

log

(1/m

ol/

kg

)

2.40

2.20

2.00

1.80



3.2. Category justification:

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


3.3. Data matrix:

The data matrix is available in Appendix 2

Section 4 Prediction-

4.1. Defined Endpoint (OECD Principle 1):

a. Endpoint (e.g. Acute toxicity to fish):

XXXXXXXXXXXXXXXXXXXXXXX


b. Dependent variable (e.g. LC50):

XXXXXXXXXXXXXXXXXXXXXXXXX


c. Units:

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


d. Duration:

6 h


e. Species:

Rattus norvegicus


4.2. Unambiguous algorithm (OECD Principle 2):

a. Prediction approach:Trend analysis from category membersExperimental values for the target chemical (if any) were not used in prediction calculations


b. Calculation approach:Linear approximationModel equation:LD50 = +2.05 (±0.12) +0.0286 (±0.0184) * log Kow, log(1/mol/kg)

c. Model name:

Not applicable

d. Model version:

Not applicable

e. Reference to QMRF:

Not applicable

f. Input for prediction (target chemical):

SMILES



g. Descriptor and endpoint values for target chemical (if applicable):

Descriptor(s) log Kow 0.0600

Endpoint (dep. variable) Human Health Hazards#AcuteToxicity

-

h. Additional data eliminations (not determined by domain):

1. By user:

2 value(s) for 1 chemical

The chemical(s) were removed manually by user

Chemical No.1:

CAS: 78-97-7SMILES: CC(O)C#N

EPValue: 31.0 mg/kg

Name(s): 2-hydroxypropanenitr ilelactonitr ilepropanenitrile, 2-hydroxy-

2. By user:

2 value(s) for 1 chemical

The chemical(s) were removed manually by user

Chemical No.1:

CAS: 583-39-1SMILES: S=C1Nc2ccccc2N1

EPValue: 208 mg/kg

Name(s): 2h-benzimidazole-2-thione, 1,3-dihydro-2-mercaptobenzimidazole1,3-dihydro-benzoimidazole-2-thionebenzimidazole-2-thiol1,3-dihydro-2h-benzimidazole-2-thione1,3-dihydrobenzimidazole-2-thione

i. Predicted value (model result):

602 mg/kg

j. Predicted value (comments):



4.3. Applicability domain (OECD Principle 3):

The target chemical FALLS within applicability domain(see Section 3.1.b for detailed description of the domain)



1 2 3

11

NOT

15

A ND

18

A ND

4 5

12

NOT

16

A ND

19

A ND

6

20

A ND

7 8

13

NOT

17

A ND

21

A ND

9 10

14

A ND

22

A ND

4.4. Uncertainty of the prediction (OECD Principle 4): manually editable field

Adequacy of prediction

Model statistic: R2 = 0.579, R2adj = 0.532, s = 0.165

LD50 (obs .), log(1/m ol/kg)2.502.452.402.352.302.252.202.152.102.052.001.951.901.851.801.75

LD

50

(p

red

.),

log

(1/m

ol/

kg

)

2.50

2.40

2.30

2.20

2.10

2.00

1.90

1.80

Adequacy of prediction



95% of Residuals =< 0.294, log(1/mol/kg)

Res iduals , Y - Y.calc0.320.30.280.260.240.220.20.180.160.140.120.10.080.060.040.020

Cu

mu

lati

ve

fre

qu

en

cy

, %

100

90

80

70

60

50

40

30

20

10

0

Cumulative frequency

Prediction range:244 - 1.48E+03, mg/kg (95.0% confidence)

Statistic of the prediction model:N = 11; count of data pointsR2 = 0.579; coefficient of deteminationR2adj = 0.532; adjusted coefficient of deteminationQ2 = 0.390; coefficient of detemination by "leave-one-out" validationSSR = 0.244; sum of squared residualss = 0.165; sample standard deviation of residualsF = 12.4; Fisher functionFa = 7.71; Fisher threshold for statistical significance (95.0% confidence)

4.5. Chemical and biological mechanisms (OECD Principle 5):

Profiling results for the target substance:

DNA binding by OASIS v.1.2

No alert found

DNA binding by OECD

No alert found

Estrogen Receptor Binding

Non binder, without OH or NH2 group

OECD HPV Chemical Categories

Not categorized

Protein binding by OASIS v1.2

No alert found

Protein binding by OECD

No alert found

Protein binding potency

Not possible to classify according to these rules (GSH)

Superfragments

No superfragment

Toxic hazard classification by Cramer (original)



High (Class III)

Toxic hazard classification by Cramer (with extensions)

High (Class III)

US-EPA New Chemical Categories

Not categorized


Comments:


Section 5 Adequacy-

5.1. Regulatory purpose:XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


5.2. Approach for regulatory interpretation of the model result:

XXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXX


5.3. Outcome:Not provided by the user


5.4. Conclusion:




13 / 30Prediction of LD50 for imidazole, LD50 for Rat Trend AnalysisAppendix 1 - Category members



APPENDIX 1 - Category members

From 11 category members, 10 chemicals are reported in more detail,the remaining category members are listed in a table with basic information

1. Cat. member No.1:

1.1. CAS number:

7580-85-0


Not reported

1.3. Chemical name(s):ethanol, 2-(1,1-dimethylethoxy)-2-(t-butoxy)ethanol2-tert-butoxyethanol


SMILES

CC(C)(C)OCCO

CH3

CH3

CH3

O

OH



1.5. Profiling results:


No alert found

DNA binding by OECD

No alert found


Non binder, non cyclic structure


Not categorized


No alert found


No alert found



Superfragments

Has superfragment

OCCOR{*}


High (Class III)


High (Class III)


Ethylene Glycol Ethers

Nonionic Surfactants


2.1. CAS number:

24800-44-0


Not reported



2.3. Chemical name(s):propanol, [(1-methyl-1,2-ethanediyl)bis(oxy)]bis-tr ipropylene glycol[(methylethylene)bis(oxy)]dipropanoltripropylene gycol


SMILES

CC(CO)OCC(C)OCC(C)O

CH3 OH

O

CH3

O

CH3

OH



No alert found

DNA binding by OECD

No alert found




Propylene glycol ethers


No alert found


No alert found



Superfragments

Has superfragment

OC(R{*})COR{*}

OCC(R{*})OR{*}


High (Class III)




High (Class III)


Neutral Organics


3.1. CAS number:

70-55-3


Not reported

3.3. Chemical name(s):

toluene-4-sulfonamide4-methylbenzenesulfonamidep-toluenesulfonamidetoluene-4-sulphonamidebenzenesulfonamide, 4-methyl-


SMILES

Cc1ccc(S(N)(=O)=O)cc1

CH3

S

NH2

O

O



No alert found

DNA binding by OECD

No alert found






Not categorized


No alert found


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized


4.1. CAS number:

95-32-9


Not reported


4-morpholinyl-2-benzothiazole diisulfidebenzothiazole, 2-(4-morpholinyldithio)-2-(4-morpholinyldithio)benzothiazole2-(morpholinodithio)benzothiazolebenzothiazole, 2-(morpholinodithio)-2-(morpholin-4-yldisulfanyl)-1,3-benzothiazole


SMILES

C1CN(SSC2=Nc3ccccc3S2)CCO1



N

S

S

N

S

O



No alert found

DNA binding by OECD

No alert found




Not categorized


SN2

SN2 >> Interchange reaction with sulphur containing compounds

SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfidecompounds


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized




5.1. CAS number:

4189-44-0


Not reported


thiourea dioxidethiourea s,s-dioxidethiourea, s,s-dioxide


SMILES

NC(=N)S(=O)=O

NH2

NH

SH

O

O



No alert found

DNA binding by OECD

No alert found




Not categorized


Nucleophilic addition

Nucleophilic addition >> Addition to carbon-hetero double bonds

Nucleophilic addition >> Addition to carbon-hetero double bonds >> Azomethyme type compounds

SN2

SN2 >> Interchange reaction with sulphur containing compounds



SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfidecompounds


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized


6.1. CAS number:

840-65-3


Not reported

6.3. Chemical name(s):2,6-naphthalenedicarboxylic acid, 2,6-dimethyl esterdimethyl 2,6-naphthalenedicarboxylatedimethyl naphthalene-2,6-dicarboxylate2,6-naphthalenedicarboxylic acid, dimethyl ester2,6-napthalenedicarboxylic acid, dimethyl ester


SMILES

COC(=O)c1ccc2cc(C(=O)OC)ccc2c1



CH3

O

O

O

O

CH3



No alert found

DNA binding by OECD

No alert found




Not categorized


No alert found


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Esters (Acute toxicity)




7.1. CAS number:

13939-25-8


Not reported


triphosphoric acid, aluminum salt (1:1)triphosphoric acid aluminium saltaluminium dihydrogen triphosphatetriphosphoric acid, aluminum salt (1:1)"aluminum [oxido(phosphonatooxy)phosphoryl] phosphatealuminium tripolyphosphate


SMILES

OP(O)(=O)OP1(=O)OP2(=O)O{-}.[Al]{3+}(.O{-}1).O{-}2

OHP

OHO

O

P

OO

P OO-

Al+++

O-

O-



No alert found

DNA binding by OECD

No alert found




Not categorized


No alert found


No alert found





Superfragments

No superfragment


High (Class III)


High (Class III)


Aluminum Compounds

Phosphates, Inorganic


8.1. CAS number:

13939-25-8


Not reported


triphosphoric acid, aluminum salt (1:1)aluminum dihydrogen tr iphosphatetriphosphoric acid, aluminium salt (1:1)


SMILES

OP1(=O)OP2(=O)OP(O)(=O)O{-}.[Al]{3+}(.O{-}1).O{-}2

OH

PO

O

PO

OP

OHO

O-

Al+++

O-

O-



No alert found

DNA binding by OECD



No alert found




Not categorized


No alert found


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Aluminum Compounds

Phosphates, Inorganic


9.1. CAS number:

26967-76-0


Not reported


tris(p-cumenyl)phosphatetris(p-isopropylphenyl)phosphatetris(isopropylphenyl) phosphatetris[2-(propan-2-yl)phenyl] phosphatephenol, (1-methylethyl)-, phosphate (3:1)


SMILES

CC(C)c1ccccc1OP(=O)(Oc1ccccc1C(C)C)Oc1ccccc1C(C)C



CH3

H3C

O

PO

O

H3C

CH3

O

CH3

CH3



No alert found

DNA binding by OECD

No alert found




Not categorized


No alert found


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized




10.1. CAS number:

7299-99-2


Not reported


hexanoic acid, 2-ethyl-, 1,1'-[2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]-1,3-propanediyl] esterpentaerythritol tetra(2-ethylhexanoate)2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]propane-1,3-diyl bis(2-ethylhexanoate)hexanoic acid, 2-ethyl-, 2,2-bis[[(2-ethyl-1-oxohexyl)oxy]methyl]-1,3-propanediyl esterhexanoic acid, 2-ethyl-, 2,2-bis (2-ethyl-1-oxohexyl)oxy methyl -1,3-propanediyl esterhexanoic acid, 2-ethyl-, 2,2-bis (2-ethyl-1-oxohexyl)oxy methyl -1,3-propanediyl ester3-[(2-ethylhexanoyl)oxy]-2,2-bis{[(2-ethylhexanoyl)oxy]methyl}propyl 2-ethylhexanoatepentaerythritol tetraisooctanoate3-[(2-ethylhexanoyl)oxy]-2,2-bis{[(2-ethylhexanoyl)oxy]methyl}propyl 2-ethylhexanoate (non-preferredname)


SMILES

CCCCC(CC)C(=O)OCC(COC(=O)C(CC)CCCC)(COC(=O)C(CC)CCCC)COC(=O)C(CC)CCCC

CH3CH3

O

O

O

O

CH3CH3

O

OCH3

CH3

O

OH3C

H3C



No alert found

DNA binding by OECD

No alert found


Non binder, MW>500


Not categorized


No alert found




No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized

Chemical(s) No. 11 - 11 are reported below:

No. CAS Chem. name SMILES

11 110-30-5 octadecanamide,n,n'-1,2-ethanediylbis-

CCCCCCCCCCCCCCCCCC(=O)NCCNC(=O)CCCCCCCCCCCCCCCCC


28 / 30Prediction of LD50 for imidazole, LD50 for Rat Trend AnalysisAppendix 2 - Data matrix



APPENDIX 2 - Data matrix

OMITTED BY THE USER


29 / 30Prediction of LD50 for imidazole, LD50 for Rat Trend AnalysisAppendices 3, 4, 5, 6 - QMRF



APPENDIX 3 - QMRF

NOT APPLICABLE

APPENDIX 4 - QMRF, training set chemicals

APPENDIX 5 - QMRF, test set chemicals

APPENDIX 6 - Additional information from (Q)SAR


30 / 30Prediction of LD50 for imidazole, LD50 for Rat Trend AnalysisAppendix 7 - Chemical components



APPENDIX 7 - Chemical components

NOT APPLICABLE


impureza 2: 1 h-imidazol -...

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