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1 / 27Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysis

QSAR Toolbox prediction for single chemical

T he te mplate of the curre nt r eport is based on " GUIDANCE DOCUMENT ON T HEVALIDA TION OF (QUANTITA TIVE) S TRUCTURE-ACTIV ITY RELAT IONS HIPS MODELS "published by OECD (September, 2007) and "GUIDANCE ON INFORMAT IONREQUIREMENTS A ND CHEMICAL S AFET Y ASSESSMENT / CHAPTER R.6 : QS ARS ANDGROUPING OF CHEMICALS " publ ished by ECHA (Ma y, 2008). The report provides in formation about the ta rget substance , che mica l charac terist icsused for the groupi ng, the resulting boundaries of the group of chem ica ls (appl icabil itydoma i n), the type of data gap fi lling approach that w as app lied (read-across, tr endana lysis or QSAR models), the pre dicted result(s) and in the Anne x informat ion aboutthe categor y membe rs or tr a ining set and test se t chem ica ls. The che mica ls are orde red by the distanc e to the tar get substa nce w ithin thedesc riptors space . Only chemica ls w i th exper imenta l data are listed as categorymembers. Depending on the se ttings sele cted by the user, deta iled i nform ation (incl. 2D ima geand profiling r esults) is provide d for some che mica ls while more lim ited in format ion(CAS , name , SMILES) is provided for othe rs. If not o therw ise specifie d, the exper imenta l va lues ar e reported in bol d, rec a lcula tedexper imenta l va lues are re ported i n bold & ita li c and ca lculated va lues a re re ported 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 substance1.1. 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) 4

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 73.3. Data matrix 7

3. Category definit ion

4. Prediction

4.1. Defined endpoint (OECD Principle 1) 74.2. Unambiguous algorithm (OECD Principle 2) 84.3. Applicability domain (OECD Principle 3) 114.4. Uncertainty of the prediction (OECD Principle 4) 124.5. Chemical and biological mechanisms (OECD Principle 5) 13

5. Adequacy

5.1. Regulatory purpose 145.2. Approach for regulatory interpretation of the model result 145.3. Outcome 145.4. Conclusion 14

Appendix 1 15

Appendix 2 25

Appendix 3 26

Appendix 4 26

Appendix 5 26

- Category members

- Data matrix

- QMRF

- QMRF, training set

- QMRF, test set

Appendix 6 26 - Additional information from QSAR

Appendix 7 27 - Chemical components



QSAR Toolbox prediction based on trend analysis

Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysis

Summary

Toxicity of the target chemical (2.25E+03 mg/kg) is predicted from category members using trend analysisbased on 7 values within the range 2.00E+03 - 2.00E+03 mg/kg from 7 category members. Categorymembers are single chemicals or mixtures and are selected based on the profile of the target chemical. Onlychemicals having 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 categorymembers. 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.

En dpoint ( s)

Acute Toxicity

mg/kg

Descr ip t or (s)

log Kow

-

0 Target chemica l

1 Cat. membe r No . 1







- 2.37

2.00E+03 3.25

2.00E+03 -0.300

2.00E+03 6.08

2.00E+03 -1.77

2.00E+03 7.79

2.00E+03 9.07

2.00E+03 12.3



Section 1 T a rg e t che mica l-

1.1. CAS number:

2524-04-1

1.2. Other regulatory numbers:

Not reported

1.3. Chemical name(s):o,o-diethyl chlorothiophosphateo,o-diethyl phosphorochloridothioatephosphorochloridothioic acid, o,o-diethyl esterethyl phosphorochloridothioate, ((eto)2clps)

1.4. Structural formula:

CH3O

PS

Cl

O

CH3

1.5. Structure codes:

a. SMILES:

CCOP(=S)(Cl)OCC

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

Not available

c. Stereochemical features:

Not provided by the user

manua lly edit able f ie ld

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

High Quality

Da t a bases:

Bacterial mutagenicity ISSSTYECHA CHEMPhys-chem EPISUITE



Section 2 G e n er a l i n fo r m a tio n-

2.1. Date of report generation:

04.11.2014

2.2. Report author(s) and contact details:

Victor Hugo Vázquez ValadezQSAR AnalyticsPafnuncio Padilla 26 Piso 3B. Ciudad Satélite. Naucalpan. Estado de México. 53100+52 58733558


Section 3 C a t e gory d e fi n it io n a nd ca t e gory m e m be rs-

3.1. Category definit ion:

a. Category hypothesis:Las reglas en el perfil del programa Nuevas Sustancias Químicas de la EPA de EE.UU. reproducelas categorías originales citadas en el documento "Programa de Nuevas Sustancias Químicas TSCA(NCP) / Categorías químicos" - un registro oficial de EE.UU. Oficina de EPA de Prevención de laContaminación y Tóxicos.


b. Applicability domain of the category:

The applicability domain is defined by following scheme



1 2 3

9

NOT

12

A ND

14

A ND

4

15

A ND

5 6

10

NOT

13

A ND

16

A ND

7 8

11

A ND

17

A ND

1) Refere ntia l bounda ry:

The target chemical should be classified as Not categorized by US-EPA New Chemical Categories


The target chemical should be classified as No alert found by Protein binding by OASIS v1.2


The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilicaddition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates,Isothiocyanates OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> AmidesOR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electronwithdrawing group OR Michael Addition >> Michael addition on conjugated systems with electronwithdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Additionto carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero doublebonds >> Azomethyme type compounds OR SN2 OR SN2 >> Interchange reaction with sulphurcontaining compounds OR SN2 >> Interchange reaction with sulphur containing compounds >>Thiols and disulfide compounds OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2>> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates OR SN2 >> Nucleophilicsubstitution at sp3 carbon atom >> Alkyl halides OR SN2 >> Nucleophilic substitution at sp3carbon atom >> alpha-Activated haloalkanes OR SNAr OR SNAr >> Nucleophilic aromaticsubstitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromaticsubstitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroarylcompounds by Protein binding by OASIS v1.2


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


The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Phosphorus PAND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 -Halogens F,Cl,Br,I,At by Chemical elements




The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 14 -Metalloids Si,Ge OR Group 15 - Nitrogen N OR Group 17 - Halogens Br by Chemical elements

7) Pa rametric bounda ry:

The target chemical should have a value of log Kow which is >= -1.78

8) Pa rametric bounda ry:

The target chemical should have a value of log Kow which is <= 12.4

c. Endpoints covered:La clasificación de un compuesto químico en una categoría de ECOSAR ™ no expresanecesariamente un peligro acuático. Una vez colocado en una categoría, factores tales como eltamaño molecular y la forma, la solubilidad, la lipofilia, sub-unidades adjuntas, etc. afectarán latoxicidad potencial de una sustancia química. No obstante esta categoría es amplia y nos permitetener una cantidad importante de análogos haciendo más robusto el análisis.


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 7 values from 7 analogue chemicals,

Observed target value: N/A, Predicted target value: 2.25E+03 (1.10E+03 to 4.60E+03; 95.0%) mg/kg,

Model equation: LD50 = +1.81 (±0.16) +0.0495 (±0.0228) * log Kow, log(1/mol/kg)

log Kow12.011.010.09.08.07.06.05.04.03.02.01.00.0-1.0-2.0

LD50

(obs

.), lo

g(1/

mol

/kg)

2.40

2.20

2.00

1.80

3.2. Category justification:



3.3. Data matrix:

The data matrix is available in Appendix 2

Section 4 P r e dict io n-

4.1. Defined Endpoint (OECD Principle 1):



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

Acute toxicity for Rat


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

LD50


c. Units:

mg/kg


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 = +1.81 (±0.16) +0.0495 (±0.0228) * 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 2.37Endpoint (dep. variable) Human Health Hazards#AcuteToxicity

-

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

1. By use r :

1 value for 1 chemical

The chemical(s) were removed manually by user



Che mica l No.1:

CAS: 7782-63-0SMILES: O_O_O_O_O_O_O_O=S1(=O)O{-}.[Fe]{2+}.O{-}1

EPVa lue: 2.00E+03 mg/kg

Name (s): iron(ii) sulfateferrous sulfate heptahydrateiron (ii) sulfate heptahydrate

2. By use r :



Che mica l No.1:




3. By use r :



Che mica l No.1:




4. By use r :

2 value(s) for 1 chemical


Che mica l No.1:

CAS: 7789-12-0SMILES: O_O_O=[Cr](=O)(O{-}.[Na]{+})O{-}.[Cr]{+}(=O)(=O)O{-}.[Na]{+}

EPVa lue: 181 mg/kg

Name (s): sodium dichromate dihydratesodium dichromate dihydrate (vi)chromic acid disodium salt dihydrate

5. By use r :





Che mica l No.1:


EPVa lue: 181 mg/kg


6. By use r :



Che mica l No.1:


EPVa lue: 181 mg/kg


7. By use r :



Che mica l No.1:


EPVa lue: 181 mg/kg


8. By use r :



Che mica l No.1:


EPVa lue: 181 mg/kg


9. By use r :





Che mica l No.1:


EPVa lue: 181 mg/kg


10. By use r :



Che mica l No.1:


EPVa lue: 181 mg/kg


11. By use r :



Che mica l No.1:


EPVa lue: 181 mg/kg


i. Predicted value (model result):

2.25E+03 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

9

NOT

12

A ND

14

A ND

4

15

A ND

5 6

10

NOT

13

A ND

16

A ND

7 8

11

A ND

17

A ND

4.4. Uncertainty of the prediction (OECD Principle 4): manua lly edit able f ie ld

Adequacy of prediction

Model statistic: R2 = 0.862, R2adj = 0.834, s = 0.111

LD50 (obs .), log(1/m ol/kg)2.502.452.402.352.302.252.202.152.102.052.001.951.901.851.801.751.70

LD50

(pre

d.),

log(

1/m

ol/k

g)

2.50

2.40

2.30

2.20

2.10

2.00

1.90

1.80

1.70

Adequacy of predict ion

95% of Residuals =< 0.138, log(1/mol/kg)

Res iduals , Y - Y.calc0.150.140.130.120.110.10.090.080.070.060.050.040.030.020.010

Cum

ulat

ive

freq

uenc

y, %

100

90

80

70

60

50

40

30

20

10

0

Cumulat ive freque ncy



Prediction range:1.10E+03 - 4.60E+03, mg/kg (95.0% confidence) Statistic of the prediction model:N = 7; count of data pointsR2 = 0.862; coefficient of deteminationR2adj = 0.834; adjusted coefficient of deteminationQ2 = 0.698; coefficient of detemination by "leave-one-out" validationSSR = 0.0614; sum of squared residualss = 0.111; sample standard deviation of residualsF = 31.1; Fisher functionFa = 10.6; Fisher threshold for statistical significance (95.0% confidence)

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

Profiling r esult s for t he t a r ge t subs t a nce :

DNA binding by OASIS v.1.2

No alert found

DNA binding by OECD

No alert found

Estrogen Receptor Binding

Non binder, non cyclic structure

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


Co mme nt s :manua lly edit able f ie ld



Section 5 A d e qu a cy-

5.1. Regulatory purpose:Cumplir con los lineamientos para estudios de impurezas en el ambito de los agroquímicos.


5.2. Approach for regulatory interpretation of the model result:Not provided by the user


5.3. Outcome:Not provided by the user


5.4. Conclusion:Not provided by the user



15 / 27Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysisAppendix 1 - Cate gory m embe rs



APPENDIX 1 - Category members

The 7 category members are reported in more detail

1. Ca t . me mb e r No . 1:

1.1. CAS number:

2216-69-5


Not reported

1.3. Chemical name(s):naphthalene, 1-methoxy-1-methoxynaphthalenemethyl 1-naphthyl ether


SMILES

COc1cccc2ccccc12

CH3O



1.5. Profiling results:


No alert found

DNA binding by OECD

No alert found


Non binder, without OH or NH2 group


Not categorized


No alert found


No alert found



Superfragments

No superfragment


High (Class III)


High (Class III)


Not categorized


2.1. CAS number:

77-85-0


Not reported

2.3. Chemical name(s):1,1,1-tris(hydroxymethyl)ethane1,3-propanediol, 2-(hydroxymethyl)-2-methyl-ethylidynetrimethanol2-(hydroxymethyl)-2-methylpropane-1,3-diol




SMILES

CC(CO)(CO)CO

CH3 OH

OHOH



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




3.1. CAS number:

38640-62-9


Not reported

3.3. Chemical name(s):naphthalene, bis(1-methylethyl)-diisopropylnaphthalenebis(1-methylethyl)naphthalene


SMILES

CC(C)c1cccc2ccc(C(C)C)cc12

CH3H3C

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


4.1. CAS number:

115-77-5


Not reported

4.3. Chemical name(s):1,3-propanediol, 2,2-bis(hydroxymethyl)-pentaerythritol2,2-bis(hydroxymethyl)-1,3-propanediolpentaerythritol"""pentaerytritol2,2-bis(hydroxymethyl)propane-1,3-diol2,2-bis(hydroxymethyl)-1,3-propanediol


SMILES

OCC(CO)(CO)CO

OH

OHOH

HO





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


5.1. CAS number:

4390-04-9


Not reported

5.3. Chemical name(s):nonane, 2,2,4,4,6,8,8-heptamethyl-2,2,4,4,6,8,8-heptamethylnonane2,2,4,4,6,8,8-heptamethyl nonanehydrocarbons, c4, 1,3-butadiene-free, polymd., tetraisobutylene fraction, hydrogenated




SMILES

CC(CC(C)(C)C)CC(C)(C)CC(C)(C)C

CH3

CH3H3C

CH3

CH3

CH3

CH3CH3

H3C



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




6.1. CAS number:

26967-76-0


Not reported

6.3. Chemical name(s):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

CH3H3C

OP O

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


7.1. CAS number:

7299-99-2


Not reported

7.3. Chemical name(s):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

O CH3

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


25 / 27Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysisAppendix 2 - Da ta m atr ix



APPENDIX 2 - Data matrix

OMITTED BY THE USER


26 / 27Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysisAppendices 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


27 / 27Prediction of LD50 for o,o-diethyl chlorothiophosphate, IMP 3 for Rat TrendAnalysisAppe ndix 7 - C hemica l components



APPENDIX 7 - Chemical components

NOT APPLICABLE


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