2-butyl-6-(butylamino)-1H-benz[de]isoquinoline-1,3(2H)-dione

Endpoint summary

Description of key information

Repeated dose toxicity: oral
The No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione in rats is estimated to be 994 mg/Kg bw/day after repeated exposure via oral route.

Repeated dose toxicity: inhalation
According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione, which is reported as 0.00000000141 Pa. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 106 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical 12-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal
The acute toxicity value for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

other information

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 predicted by OECD QSAR Toolbox version 3.4. The supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as mentioned below

Principles of method if other than guideline:

Data is predicted by OECD QSAR Toolbox version 3.4.

GLP compliance:

not specified

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Analytical verification of doses or concentrations:

not specified

Remarks:

not specified

Control animals:

not specified

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

994 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: no significant changes were noted at mentioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and "h" )  and "i" )  and "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 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 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Secondary aromatic amine 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 Imides by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Allyl esters (Hepatotoxicity) Rank A OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "h"

Similarity boundary:Target: CCCCNc1ccc2c3c1cccc3C(=O)N(CCCC)C2=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

Similarity boundary:Target: CCCCNc1ccc2c3c1cccc3C(=O)N(CCCC)C2=O
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Similarity boundary:Target: CCCCNc1ccc2c3c1cccc3C(=O)N(CCCC)C2=O
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as N-methylol derivatives by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.722

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.59

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione in rats is estimated to be 994 mg/Kg bw/day after repeated exposure via oral route.

Executive summary:

Repeated dose oral toxicity was evaluated for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione using SSS QSAR prediction database. The study assumed the use of rats in a subacute study. Since no significant changes were noted, the No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 994 mg/Kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

994 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is of K2 reliability and predicted from OECD QSAR toolbox.

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: dermal

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: oral
Predicted data for the substance 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione and its read across substance were reviewed for Repeated dose oral toxicity endpoint and are represented here as weight of evidence approach:

Repeated dose oral toxicity was evaluated for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione using SSS QSAR prediction database. The study assumed the use of rats in a subacute study. Since no significant changes were noted, the No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 994 mg/Kg bw/day.

Groups of 10 rats /sex were fed structurally related substance 2-methyl-1H-isoindole-1,3(2H)-dione (CAS 550-77-4)at levels of 0, 0.25, 0.5 and 1.0% (as cited in HPVIS document). All rats were observed for mortality twice each day. Clinical signs and body weights were recorded at initiation and weekly thereafter. Food consumption was recorded weekly. After 30 days of treatment, all surviving rats were fasted overnight and weighed prior to terminal sacrifice and necropsy. At necropsy the liver and kidneys were weighed. The following tissues were saved from all animals: brain, pituitary, thoracic spinal cord, eyes, salivary glands (mandibular), stomach, trachea, thymus esophagus, heart, spleen, adrenals, pancreas, duodenum, jejunum, ileum, colon, cecum, mesenteric lymph node, urinary bladder, testes with epididymides and prostate (males), ovaries and uterus (females), femur, bone marrow (costochondral junction), lungs, liver, kidneys, thyroid (with parathyroids), skeletal muscle, and all gross lesions. Microscopic evaluation was conducted on sections of the lungs, liver, brain and kidneys from rats of all treatment groups. A necropsy also was performed on all rats that were sacrificed in extremis or were found dead during the study. One male rat in the 0.25% group died on Day 26 of the study. Statistically significant decreases in body weight of both male and female rats in the 0.5 and 1.0% groups (6% and 18% lower than controls for males and 4% and 11% lower than control for females, respectively) were noted during the fourth week of exposure. Mean food consumption values of the treated male and female rats were lower than control at some measurement periods, but the food consumption value for the male rats in the 1.0% group during the final week of exposure was the only statistically significant decrease noted. Mean compound consumption for the male rats in the 0.25, 0.50 and 1.0% groups ranged from 146 to 203 mg/kg/day, 330 to 403 mg/kg/day and 685 to 815 mg/kg/day, respectively. The mean compound consumption for the female rats in the 0.25, 0.5 and 1.0% groups range from 197 to 226 mg/kg/day, 409 to 573 mg/kg/day and 921 to 1100 mg/kg/day, respectively. The gross pathology revealed no treatment-related effects in any PI-treated group. Mean liver relative to terminal body weight was increased for both sexes and mean kidney weight relative to terminal body weight was increased for males at 1.0%. Microscopic evaluation revealed compound-related findings of centrilobular to diffuse hepatocellular enlargement in rats of both sexes in the 0.5 and 1.0% treatment groups. In addition, the severity of chronic progressive nephropathy was increased slightly in the male rats in the 1.0% group. There were no compound-related findings present in the tissues examined from the male or female rats in the 0.25% group.  Thus, the No observed adverse effect level (NOAEL) for the substance2-methyl-1H-isoindole-1,3(2H)-dione is determined to be 250 mg/kg bw/day.

Considering above data and by applying weight of evidence approach it can be concluded that the substance 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is not toxic on Repeated exposure via oral route and is considered to not classified as per CLP regulation.

Repeated dose toxicity: inhalation
According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione, which is reported as 0.00000000141 Pa. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 106 micrometer which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical 12-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is highly unlikely. Therefore this study is considered for waiver.

Repeated dose toxicity: dermal
The acute toxicity value for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione (as provided in section 7.2.3) is >2000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Justification for classification or non-classification

Considering above data and by applying weight of evidence approach it can be concluded that the substance 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is not toxic on Repeated exposure via oral route and is considered to not classified as per CLP regulation.