2-(3-hydroxypropyl)-6-[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione

Endpoint summary

Description of key information

Skin irritation:

The dermal irritation potential of 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating to the skin of New Zealand White rabbits. Based on the estimated result 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Eye irritation:

The ocular irritation potential of 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating into the eyes of Vienna White rabbits. Based on the estimated result 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: extimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione
- Molecular formula: C18H20N2O4
- Molecular weight: 328.366 g/mol
- Smiles notation: c1ccc2C(=O)N(CCCO)C(=O)c3ccc(NCCCO)c1c23
- InChl: 1S/C18H20N2O4/c21-10-2-8-19-15-7-6-14-16-12(15)4-1-5-13(16)17(23)20(18(14)24)9-3-11-22/h1,4-7,19,21-22H,2-3,8-11H2
- Substance type: Organic

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

No data available

Type of coverage:

semiocclusive

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data available

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

No data available

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No skin irritation was observed.

Estimation method: Takes mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 12 - Trans.Metals Zn,Cd,Hg OR Group 14 - Metalloids Si,Ge OR Group 16 - Sulfur S OR Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At OR Group 17 - Halogens I by Chemical elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aromatic Amine Type Compounds by Oncologic Primary Classification

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acrylamide Reactive Functional Groups OR Aldehyde Type Compounds OR Anhydride Type Compounds OR Carbamate Type Compounds OR Lactone Type Reactive Functional Groups OR Not classified by Oncologic Primary Classification

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Aqueous Solubility < 0.1 g/L AND Group CN Molecular Weight > 290 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group CN log Kow > 4.5 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.217

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.5

Interpretation of results:

other: not irritating

Conclusions:

The substance 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating to the skin of New Zealand White rabbits. 

Executive summary:

The dermal irritation potential of 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating to the skin of New Zealand White rabbits. Based on the estimated result 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)can be considered to be not irritating to skin and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione
- Molecular formula: C18H20N2O4
- Molecular weight: 328.366 g/mol
- Smiles notation: c1ccc2C(=O)N(CCCO)C(=O)c3ccc(NCCCO)c1c23
- InChl: 1S/C18H20N2O4/c21-10-2-8-19-15-7-6-14-16-12(15)4-1-5-13(16)17(23)20(18(14)24)9-3-11-22/h1,4-7,19,21-22H,2-3,8-11H2
- Substance type: Organic

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

No data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data available

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no eye irritation was observed in treated animals.

Estimation method: Takes mode value from the 9 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and "k" )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and "q" )  and ("r" and ( not "s") )  )  and ("t" and "u" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Imides (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> N,N-Dialkyldithiocarbamate Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Strong binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents  OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "q"

Similarity boundary:Target: OCCCNc1ccc2c3c1cccc3C(=O)N(CCCO)C2=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg AND Group All Melting Point > 200 C AND Group CN Aqueous Solubility < 0.1 g/L AND Group CN Melting Point > 180 C AND Group CN Molecular Weight > 290 g/mol AND Group CN Vapour Pressure < 0.001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m OR Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.393

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.9

Interpretation of results:

other: not irritating

Conclusions:

The substance 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating into the eyes of Vienna White rabbits.

Executive summary:

The ocular irritation potential of 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)was estimated to be not irritating into the eyes of Vienna White rabbits. Based on the estimated result 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

Various studieshas been investigated for the test chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)to observe the potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) and its structurally similar read across substances1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)andCaffeine (CAS no: 58-08-2) .The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for test chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) .The chemical 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) is estimated to be not irritating to skin of New Zealand White rabbits and thus can be considered as non irritant to skin.

 

 

The OECD SIDS (2000) and U.S. Environmental Protection Agency (2017) conducted skin irritation study ofstructurally similar read across substance 1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4) on six New Zealand White rabbits in order to determine he irritancy potential caused by the chemical under occlusive condition which supports the above result.Duringthetest0.5 ml of the test substance as a finely ground powder moistenedwith water was applied to the shaved dorsal areas of six albino rabbits. The testmaterial was applied to the skin under 1" square gauze patches and held in contact with the skin by means of an occlusive wrap of latex rubber secured by bandaging and elastic tape. The occlusive wrap and gauze patches were removed after 24 hours. Dermal irritation was scored by the Draize Method, and results were recorded 24, 48, 72 and 168 hours after topical application.The Primary Irritation Index was calculated by averaging the mean scores at 24and 72 hours. All animals scored zero (0) at every observation time.Hence the test chemical1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)was considered to beNot irritatingto the skin ofNew Zealand Whiterabbits.

 

The above results were further supported by experimental study performed by OECD SIDS (2007) forstructurally similar read across substanceCaffeine (CAS no: 58-08-2) on two male and one female White Vienna rabbits according to OECD Guide-line 404 "Acute Dermal Irritation/Corrosion".About 500 mg of theCaffeine(a 50% (w/w) aqueous formulation) was applied for 4 hours under semiocclusive conditions. After 4 hours, the application patches were removed, and the application sites were washed with water and Lutrol/water (1/1). The skin was scored at 30-60 minutes after removal of the patches and at 24, 48, and 72 h. No signs of irritation were observed and the irritation indices (erythema and edema) were 0 in each animal at each reading time. Hence the chemicalCaffeine (CAS no: 58-08-2)was observed to be non irritant to the skin ofWhite Vienna rabbits.

 

 

Thus on the basis of available data for thetarget chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) and its structurally similar read across substances1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)andCaffeine (CAS no: 58-08-2),it can be concluded thatchemical 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

 

 

Eye irritation:

In different studies,the test chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)has been investigated for potential for ocular irritationto a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) and its structurally similar read across substances1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)andCaffeine (CAS no: 58-08-2) .The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the eye irritation potential was estimated for test chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) .The chemical 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) is estimated to be not irritating to eye of Vienna White rabbits and thus can be considered as non irritant to eye.

 

 

The OECD SIDS (2000) and U.S. Environmental Protection Agency (2017) conducted an eye irritation study ofstructurally similar read across substance 1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4) on six New Zealand White rabbits in order to determine the irritancy potential caused by the chemical which supports the above result.Duringthetest100.0 mg of the undiluted test substance as a finely ground powder was applied to one eye of six albino rabbits. The other eye was not treated and served as a control. The cornea, iris and conjuntivae were examined immediately after treatment, and then at intervals of 10 minutes, 1 hour, and at 24, 48, 72 and 168 hours. The Draize Method was used for scoring eye irritation.The average Draize score for 24, 48 and 72 hours was calculated for each animal and then averaged over the six animals. The average Draize score was 1.3 on scale from 0-110. Since there was no evidence of eye irritation at 48 hours in any of the animals, the chemical 1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)was considered to benot irritatingto the eye ofNew Zealand Whiterabbits.

 

 

The above results were further supported by experimental study performed by OECD SIDS (2007) forstructurally similar read across substanceCaffeine (CAS no: 58-08-2) on two male and one female White Vienna rabbits according to OECD Guide-line 405 "Acute Eye Irritation/Corrosion"About One tenth millilitre (bulk volume; ca. 56 mg) of the test substance was instilled into the right conjunctival sac of each rabbits. The treated eyes were not washed. The eyes were scored at 1, 24, 48, and 72 h and at 8 days post instillation. Slight corneal opacity was found in all 3 rabbits at 24h and in 1 rabbit at day 8. Slight to well-defined conjunctival redness was present in all 3 rabbits at 24h (grad 2) and in 1 rabbit at day 8; slight to moderate conjunctival swelling was found in 1 rabbits at up to 48 hours. No iritis was observed. Mean irritation indices were 0.9 (corneal opacity), 0.0 (iritis), 1.6 (conjunctival erythema), and 0.6 (conjunctival edema). On the basis of observed scores, the chemicalCaffeine (CAS no: 58-08-2)was considered to be non irritant to the eyes ofWhite Vienna rabbits.

 

 

Thus on the basis of available data for thetarget chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) and its structurally similar read across substances1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)andCaffeine (CAS no: 58-08-2),it can be concluded thatchemical 3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) is unable to cause eye irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

 

Justification for classification or non-classification

The skin and eye irritation potential of test chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6) and its structurally similar read across substances1,4-benzenediamine, N-(1-methylethyl)-N'-phenyl (CAS no: 101-72-4)andCaffeine (CAS no: 58-08-2)were observed in various studies. The results obtained from these studies indicate that the chemical3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dioneis unlikely to cause skin and eye irritation. Hence3-(3-hydroxypropyl)-8-[(3-hydroxypropyl)amino]-3-azatricyclo[7.3.1.0⁵,¹³]trideca-1(13),5,7,9,11-pentaene-2,4-dione (CAS No: 52821-24-6)can be classified under the category “Not Classified” for skin and eye as per CLP.