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

Endpoint summary

Description of key information

Acute toxicity: oral

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of 2-(3-hydroxypropyl)-6- [(3-hydroxy propyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) in rat by the oral route. 50% mortality observed at 2956.76 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of 2-(3-hydroxypropyl)-6-[(3-hydroxy propyl)amino]-1H- benz[de]isoquinoline-1,3(2H)-dione in rat was estimated to be 2956.76 mg/kg b.wt.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

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:

Prediction is done using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: refer below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data available

Doses:

No data available

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Sex:

not specified

Dose descriptor:

LD50

Effect level:

2 956.76 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed

Mortality:

50% mortality observed at 2956.76 mg/kg bw in treated rats.

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 5 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 "l" )  and "m" )  and ("n" and "o" )  )

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 OR AN2 >> Schiff base formation >> Dicarbonyl compounds 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 >> Coumarins 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) >> Coumarins 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, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives 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 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline 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 SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 by Estrogen Receptor Binding

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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 >> Carbamates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> beta-Lactams  OR SN2 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: "k"

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: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.158

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.51

Interpretation of results:

other: not classified based on CLP criteria

Conclusions:

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of 2-(3-hydroxypropyl)-6-[(3-hydroxy propyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) in rat by the oral route. 50% mortality observed at 2956.76 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of 2-(3-hydroxypropyl)-6-[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione in rat was estimated to be 2956.76 mg/kg b.wt.

Executive summary:

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) in rat by the oral route. 50% mortality observed at 2956.76 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of 2-(3-hydroxypropyl)-6-[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione in rat was estimated to be 2956.76 mg/kg b.wt. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that 2-(3-hydroxypropyl)-6- [(3-hydroxy propyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) does not exhibit acute toxicity via the oral route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 956.76 mg/kg bw

Quality of whole database:

The data is Klimicsh 2 and from OECD QSAR toolbox version 3.3 (2017).

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Various studies including predicted results from the validated model and experimental study has been investigated for acute oral toxicity to a greater or lesser extent for the test chemical 2-(3-hydroxypropyl) -6 -[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) along with its structurally similar read across substance 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0).The predicted data for target chemical 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) has been compared with the experimental data (in vivo experiments in rodents i.e. most commonly in rats and mice) for read across substance. The studies are summarized as below:

 

The acute toxicity study was predicted using OECD QSAR toolbox version 3.3 (2017); to evaluate the toxic effects of administration of 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) in rat by the oral route. 50% mortality observed at 2956.76 mg/kg bw in treated rats. Therefore, the acute oral median lethal dose (LD50) of 2-(3-hydroxypropyl)-6-[(3-hydroxypropyl)amino]-1H- benz[de]isoquinoline-1,3(2H)- dione in rat was estimated to be 2956.76 mg/kg b.wt.

 

Similarly based on the prediction done by using the Danish (Q)SAR Database, the acute toxicity study was estimated to evaluate the toxic effects of administration of 2-(3-hydroxypropyl)-6-[(3-hydroxypropyl) amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821 -24 -6) in rat by the oral route. 50% mortality observed at 3600.0 mg/kg/day in treated rats. Therefore, the acute oral median lethal dose (LD50) of 2-(3-hydroxypropyl)-6-[(3-hydroxypropyl) amino]-1H-benz[de]isoquinoline-1,3(2H)-dione in rat was estimated to be 3600.0 mg/kg/day.

 

The above study is supported by the experimental study conducted by Efimov , et al. (1986) (United States Patent Document. #4598081), in which the toxicity of 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) was examined by way of experiment performed on rats. Mature animals both male and female, weighting 180 to 220 g (rats) were used for said experiment. 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) was administered perorally. The drug was introduced in the form of a starch suspension through a gastric tube. A total of 36 rats were used in the experiment. Rats were given dosages of 3000 mg/kg bw to 6000 mg/kg bw. The animals were kept under observation for 5 days. The symptoms of the acute lethal poisoning by 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) was characterized by flaccidity, hypodynamia, and lower respiration rhythm. Only a few animals showed a short-time initial excitation. 6-8 hours later the animals laid down on the side, their condition became comatose, followed by death. That is the animals died slowly, as a rule, during the first 24-26 hours. Doses of up to 3000 mg/kg bw caused no deaths but 2 animals died at 3500 mg/kg bw, 1 animal died at 4000 mg/kg bw, 3 animals died at 4500 mg/kg bw, 4 animals died at 5000 mg/kg bw, 4 animals died at 5500 mg/kg bw and 5 animals died at 6000 mg/kg bw. Thus, the acute oral median lethal dose (LD50) of 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) in rat was observed to be 4000 (3030 to 5280) mg/kg b.wt. Therefore, according to CLP criteria for acute toxicity rating for the chemicals, it infers that 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) does not exhibit acute toxicity via the oral route.

 

Similarly, the experimental study conducted by Efimov , et al. (1986) (United States Patent Document. #4598081), in which the toxicity of 1,3-dioxo-1H-benz (de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) was examined by way of experiment performed on white mice. Mature animals both male and female, weighting 18 to 22 g (white mice) were used for said experiment. 1,3-dioxo-1H-benz(de)isoquinoline -2(3H) butyric acid (Isodibut) was administered perorally. The drug was introduced in the form of a starch suspension through a gastric tube. A total of 51 mice were used in the experiment. Mice were treated with 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) at the dosages of 1260, 1500, 2000, 3500, 3750, 4000, 4500, 4750, 5000 and 5250 mg/kg bw orally. The animals were kept under observation for 5 days. The symptoms of the acute lethal poisoning by 1,3-dioxo- 1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) was characterized by flaccidity, hypodynamia, and lower respiration rhythm. Only a few animals showed a short-time initial excitation. 6-8 hours later the animals laid down on the side, their condition became comatose, followed by death. It was observed that 3 animals died at 3750 mg/kg bw, 2 animals at 4000 mg/kg bw, 4 animals at 4500 mg/kg bw, 5 animals at 4750 mg/kg bw, 3 animals at 5000 mg/kg bw and 5 animals died at 5250 mg/kg bw. Thus, the acute oral median lethal dose (LD50) of 1,3-dioxo-1H-benz(de)is oquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) in mice was observed to be 3700 mg/kg b.wt. Therefore, according to CLP criteria for acute toxicity rating for the chemicals, it infers that 1,3-dioxo-1H-benz(de)isoquino line-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0) does not exhibit acute toxicity via the oral route.

 

So, based on the above mentioned studies for target substance 2-(3-hydroxypropyl)-6 -[(3-hydroxy propyl)amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) and the read across substance 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909-96-0), the median lethal dose (LD50) value was found to be in the range of 2956.76 mg/kg b.wt to 4000.0 mg/kg/day. Thus,on the basis of these LD50 value and by comparing these studies with the criteria of CLP regulation, it infers that the test substance 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl)amino]-1H-benz [de]isoquinoline- 1,3(2H)-dione (CAS No. 52821-24-6) does not classify as an acute oral toxicant.

Justification for classification or non-classification

Based on the above mentioned studies on 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl) amino]-1H-benz[de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) and to its read across substance 1,3-dioxo-1H-benz(de)isoquinoline-2(3H) butyric acid (Isodibut) (CAS No. 88909 -96 -0), it can be found that LD50 oral value is greater than 2000 mg/kg b.wt. Thus, according to CLP regulation, it infers that the test substance 2-(3-hydroxypropyl)-6 -[(3-hydroxypropyl)amino]-1H-benz [de]isoquinoline-1,3(2H)-dione (CAS No. 52821-24-6) does not classify as an acute oral toxicant.