2-octadecyl-1H-thioxantheno[2,1,9-def]isoquinoline-1,3(2H)-dione

Endpoint summary

Description of key information

1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-  is non toxic by oral and dermal route. 

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:

other: Data is from QSAR Toolbox 3.4.

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

equivalent or similar to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Acute oral toxicity study of 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- in rats

GLP compliance:

not specified

Test type:

other: No data

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:

other: Oral

Vehicle:

not specified

Details on oral exposure:

Duration of test: 24 hours

Doses:

5931.255371094 mg/kg bw

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:

5 931.255 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality observed

Mortality:

50 % mortality observed 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" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and "j" )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Biphenyl AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Imide AND Naphtalene AND Quinolone/ Quinolinedione/ Isoquinolinedione AND Sulfide by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives AND SN1 AND SN1 >> Alkylation after metabolically formed carbenium ion species AND SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives AND SN2 AND SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation AND SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, NH2 group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Extremely reactive (GSH) OR Extremely reactive (GSH) >> Benzoquinones (MA) OR Highly reactive (GSH) OR Highly reactive (GSH) >> 3-Alken-2-ones (MA) OR Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) OR Moderately reactive (GSH) >> Substituted 1-Alken-3-ones (MA) OR Slightly reactive (GSH) OR Slightly reactive (GSH) >> Methacrylates (MA) OR Slightly reactive (GSH) >> Substituted haloacetamides (SN2) OR Slightly reactive (GSH) >> Tiglates (MA) by Protein binding potency

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Similarity boundary:Target: CCCCCCCCCCCCCCCCCCN1C(=O)c2ccc3c4c2c(ccc4-c2ccccc2S3)C1=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Stable form by Tautomers unstable

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Enol form OR Imine form - 1,3-H shift OR Keto form (5-membered heteroarenes) - 1,3-H shift by Tautomers unstable

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acrylamide Reactive Functional Groups OR Acrylate Reactive Functional Groups OR Alpha- and beta-Haloether Reactive Functional Groups OR Aromatic Amine Type Compounds OR Carbamate Type Compounds OR Halogenated Aromatic Hydrocarbon Type Compounds OR Phenol Type Compounds by Oncologic Primary Classification

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated carbonyls OR Hydrazine by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Alpha aryloxy substituted acetic acid (9c) OR Known precedent reproductive and developmental toxic potential OR Not covered by current version of the decision tree OR Organophosphorus compounds (1b) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aliphatic Amines OR Esters (Acute toxicity) OR Esters (Chronic toxicity) OR Neutral Organics by US-EPA New Chemical Categories

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 9.79

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 15

Interpretation of results:

not classified

Conclusions:

Estimated LD50 was considered to be 5931.255371094 mg/kg bw when rats were treated with 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- orally for 24 hours.

Executive summary:

Acute oral toxicity was estimated by using QSAR Toolbox 3.4 in rats by using1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-in the concentration of 5931.255371094 mg/kg bw orally. 50% mortality was observed in treated rats. Therefore, estimated LD50 was considered to be 5931.255371094 mg/kg bw when rats were treated with1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-orally for 24 hours.  

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

5 931.255 mg/kg bw

Quality of whole database:

Data is from QSAR Toolbox 3.4

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from QSAR Toolbox 3.4

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

equivalent or similar to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Acute dermal toxicity study of 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- in rabbits

GLP compliance:

not specified

Test type:

other: No data

Limit test:

no

Species:

rabbit

Strain:

other: albino

Sex:

male

Details on test animals or test system and environmental conditions:

5 male albino rabbits (avg. wt 2492 g) were used.

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

No data available

Duration of exposure:

14 days

Doses:

4632.437988281 mg/kg bw

No. of animals per sex per dose:

5 male

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male

Dose descriptor:

LD50

Effect level:

4 632.438 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50 % mortality observed

Mortality:

50 % mortality observed was observed in treated rabbits

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" or "d" )  and "e" )  and "f" )  and "g" )  and ("h" and ( not "i") )  )  and ("j" and "k" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Biphenyl AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND Imide AND Naphtalene AND Quinolone/ Quinolinedione/ Isoquinolinedione AND Sulfide by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives AND SN1 AND SN1 >> Alkylation after metabolically formed carbenium ion species AND SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives AND SN2 AND SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation AND SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Iminium Ion Formation AND SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines by DNA binding by OECD

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group 12 - Trans.Metals Zn,Cd,Hg OR Group 17 - Halogens Br OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 6.1

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 15.3

Interpretation of results:

not classified

Conclusions:

Estimated LD50 was considered to be 4632.437988281 mg/kg bw when rabbits were treated with 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- dermally for 14 days.

Executive summary:

Acute dermal toxicity was estimated by using QSAR Toolbox 3.4 in rabbits by using 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-in the concentration of 4632.437988281mg/kg bw dermally. 50% mortality was observed in treated rabbits. Therefore, estimated LD50 was considered to be 4632.437988281 mg/kg bw when rabbits were treated with1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-dermally for 14 days.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 632.438 mg/kg bw

Quality of whole database:

Data is from QSAR Toolbox 3.4

Additional information

Acute oral toxicity:

Data available for target1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-(CAS no 27870-92-4) and it’s read across 2-Heptadecyl-4,5-dihydro-1H-imidazole (CAS no95-19-2) and Dimethyl palmitamine (CAS no 112-69-6) for acute oral toxicity are summarized as below 

Based on the prediction done by QSAR Toolbox 3.4 (2016), acute oral toxicity was estimated in rats by using1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-in the concentration of 5931.255371094 mg/kg bw orally. 50% mortality was observed in treated rats. Therefore, estimated LD50 was considered to be 5931.255371094 mg/kg bw when rats were treated with1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-orally for 24 hours.  

In a ChemIDplus Toxnet Database (2016) for read across, acute oral toxicity was given for rats by using 2-Heptadecyl-4,5-dihydro-1H-imidazole in the concentration of 3800 mg/kg bw orally. 50 % mortality observed in treated rats. Therefore, LD50 was considered to be 3800 mg/kg bw when rats were treated with 2-Heptadecyl-4,5-dihydro-1H-imidazole orally.

In a ChemIDplus Toxnet Database (2016) for read across, acute oral toxicity was given for mice by using Dimethyl palmitamine in the concentration of 3000 mg/kg bw orally. 50 % mortality observed in treated mice. Therefore, LD50 was considered to be3000 mg/kg bw when mice were treated with Dimethyl palmitamine orally. 

In a US EPA High Production Volume Information System (HPVIS) (2016) for read across, acute oral toxicity was evaluated in Sprague-Dawley male and female rats by using 1-Hexadecanamine, N, N-dimethyl- orally in the concentration of 2000 mg/kg bw in Arachis oil B.P. and observed for 14 days. No 50 % mortality was observed in treated rats. Three male rats died prior to scheduled sacrifice on days 1, 3 and 8, and one female died on day 2. Hunched posture, piloerection, lethargy and decreased respiratory rate were observed in one female at one and four hours post dose and increased salivation also was observed in this female at one hour post dose. Hunched posture, piloerection and lethargy, and occasional or isolated signs of ptosis, diarrhea, emaciation and red/brown staining around the snout and eyes were observed in surviving rats during the 14 day observation period. All surviving rats appeared normal by day 13. In one surviving male and female decrease in body weight during the first week was observation. All surviving rats showed body weight gain over the second week of the observation period. Red lungs, dark liver and kidneys, with hemorrhage of the gastric mucosa and small intestines, and incidents of hemorrhage of the nonglandular epithelium of the stomach and large intestine were observed in died rats. No gross pathological abnormalities were observed in rats that survived the 14-day, post-dose observation period. Therefore, LD50 was considered to be > 2000 mg/kg bw when Sprague-Dawley male and female rats were treated with 1-Hexadecanamine, N, N-dimethyl- orally.

Thus, based on weight of evidence for target1h-thioxantheno[2,1,9-def]isoquinoline-1,3 (2h)-dione, 2-octadecyl-(CAS no 27870-92-4) and it’s read across 2-Heptadecyl-4,5-dihydro-1H-imidazole (CAS no95-19-2) and Dimethyl palmitamine (CAS no 112-69-6) for acute oral toxicity is likely to be non hazardous as per the CPL criteria of classification.

 Acute dermal toxicity:

Data available for target1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-(CAS no 27870-92-4) and it’s read across 2-Heptadecyl-4,5-dihydro-1H-imidazole (CAS no95-19-2) and Dimethyl palmitamine (CAS no 112-69-6) for acute oral toxicity are summarized as below 

Based on the prediction done by QSAR Toolbox 3.4 (2016), acute dermal toxicity was estimated in rabbits by using1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-in the concentration of 4632.437988281mg/kg bw dermally. 50% mortality was observed in treated rabbits. Therefore, estimated LD50 was considered to be 4632.437988281 mg/kg bw when rabbits were treated with1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl-dermally for 14 days.

In a US EPA High Production Volume Information System (HPVIS) (2016) for read across, acute dermal toxicity was evaluated in New Zealand White rabbits by using 1-Hexadecanamine, N, N-dimethyl- dermally and observed for 14 days. At 4400 mg/kg bw., between 24 and 48 hours post dose, rabbit became extremely weak, lethargic and in a moribund state. These rabbits died within the next few hours. At 2200 and 3300 mg/kg bw, rabbits survived until study termination eventually showed signs of recovery. No signs of toxicity were observed in the rabbits during the first six hours following test substance administration. Rabbits in all dose groups showed signs of generalized weakness and lassitude, and did not eat or drink 24 hours post dose. Signs of slight transient erythema, and appeared dried, leathery and wrinkly were also observed in treated rabbits. At 2200 and 3300 mg/kg bw, hair loss and considerable decrease in body weight was observed in treated rabbits. No significant gross pathological changes were observed in treated rabbits. Therefore, LD50 was considered to be 2359.5 mg/kg bw (95% confidence limits = 1705 to 3355 mg/kg bw) when New Zealand White rabbits were treated with 1-Hexadecanamine, N, N-dimethyl- dermally.

Thus, based on weight of evidence for target1h-thioxantheno[2,1,9-def]isoquinoline-1,3 (2h)-dione, 2-octadecyl-(CAS no 27870-92-4) and it’s read across Dimethyl palmitamine (CAS no 112-69-6) for acute dermal toxicity is likely to be non hazardous as per the CPL criteria of classification.

Justification for selection of acute toxicity – oral endpoint
Estimated LD50 was considered to be 5931.255371094 mg/kg bw when rats were treated with 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- orally for 24 hours.

Justification for selection of acute toxicity – dermal endpoint
estimated LD50 was considered to be 4632.437988281 mg/kg bw when rabbits were treated with 1h-thioxantheno[2,1,9-def]isoquinoline-1,3(2h)-dione, 2-octadecyl- dermally for 14 days.

Justification for classification or non-classification

Based on weight of evidence for target 1h-thioxantheno[2,1,9-def]isoquinoline-1,3 (2h)-dione, 2-octadecyl-(CAS no 27870-92-4) and it’s read across 2-Heptadecyl-4,5-dihydro-1H-imidazole (CAS no 95-19-2) and Dimethyl palmitamine (CAS no 112-69-6) for acute oral and dermal toxicity is likely to be non hazardous as per the CPL criteria of classification.

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