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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction:

Since no significant changes were noted relating to effects on reproductive toxicity in rats, the No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 520 mg/Kg bw/day.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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 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. The supporting QMRF report has been attached

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

Dermal irritation (if dermal study):

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

520 mg/kg bw/day

Based on:

test mat.

Sex:

not specified

Basis for effect level:

reproductive performance

other: no significant changes were noted at mentioned dose level

Critical effects observed:

not specified

Remarks on result:

other: Not specified

Critical effects observed:

not specified

Reproductive effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 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 ( not "i") )  )  and "j" )  and "k" )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

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 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: "g"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR No alert found OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD

Domain logical expression index: "h"

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: "i"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> Substituted 1-Alken-3-ones (MA) by Protein binding potency

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Similarity boundary:Target: CCCCNc1ccc2c3c1cccc3C(=O)N(CCCC)C2=O
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Amineptine (Hepatotoxicity) Alert OR Oxyphenistain (Hepatotoxicity) Alert OR Perhexiline (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.37

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.04

Conclusions:

Since no significant changes were noted relating to effects on reproductive toxicity in rats, the No Observed Adverse Effect Level (NOAEL) for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 520 mg/Kg bw/day.

Executive summary:

Toxicity to reproduction 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 relating to effects on reproductive toxicity, the No Observed Adverse Effect Level for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 520 mg/Kg bw/day.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

520 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is of k2 reliability and is predicted from OECD QSAR toolbox.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Toxicity to reproduction:

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 toxicity to reproductionity endpoint and are represented here as weight of evidence approach:

Toxicity to reproduction 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 relating to effects on reproductive toxicity, the No Observed Adverse Effect Level for 2-butyl-6-(butylamino)-1H-benzo[de]isoquinoline-1,3(2H)-dione is estimated to be 520 mg/Kg bw/day.

 

The structurally related substance 2-methyl-1H-isoindole-1,3(2H)-dione (CAS 550-77-4) administered by gavage once daily at 0, 50, 150, and 600 mg/kg/day to parental F0 CD® (SD) rats, 10/sex/group, through prebreed, mating, gestation, and lactation and direct dosing to F1 offspring from weaning to scheduled sacrifice, resulted in adult F0 parental toxicity at 600 mg/kg/day, which was more severe in females than in males (Cited in HPVIS database). Toxicity was present in F0 females at 600 mg/kg/day was expressed as periparturtional demise in 4 of the 10 pregnant females and reduced total and live litter size at birth. There was F1 offspring toxicity observed postnatally, expressed as reduced pup body weights per litter during lactation in both sexes, and centrilobular hepatocellular hypertrophy in F1 males and females at 600 mg/kg/day, and hyaline droplets in the kidneys of the F1 adult males at 600 mg/kg/day. In addition, F1 postweanlings exhibited reduced body weights at 150 and 600 mg/kg/day for females and at 50, 150, and 600 mg/kg/day for males. Acquisition of puberty in F1 males was significantly delayed at 50, 150, and 600 mg/kg/day and in F1 females at 600 mg/kg/day, associated with reduced body weights during the postwean retention period at all 3 doses for F1 males and at the top dose for F1 females.The F0 male and female systemic No observable adverse effect level (NOAEL) was 150 mg/kg/day. The F1 male systemic NOAEL was less than 50 mg/kg/day, and the F1 female systemic NOAEL was 50 mg/kg/day (both due to reduced body weights at higher doses). The NOAELs for F0 reproductive toxicity were at or above 600 mg/kg/day for males and 150 mg/kg/day for females (due to periparturitional demise and to reduced total implants/litter and reduced total and live litter sizes at birth at 600 mg/kg/day). The NOAELs for F1 offspring toxicity were less than 50 mg/kg/day for males (due to reduced postweaning body weights and delays in acquisition of puberty at all the doses) and at 50 mg/kg/day for females (due to reduced postwean body weights at 150 and 600 mg/k g/day and delay in acquisition of puberty at 600 mg/kg/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 does not exhibit toxicity to reproduction.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

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 does not exhibit toxicity to reproduction.