Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Type of information:
migrated information: read-across based on grouping of substances (category approach)
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 using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Data source

Reference
Reference Type:
other: Predicted data
Title:
[R]: 752 mg/kg bw/day (actual dose received); Estimation for NOAEL for CAS 52320-66-8
Author:
Sustainability Support Services (Europe) AB
Year:
2018
Bibliographic source:
OECD QSAR Toolbox prediction Ver. 3.3; using categorisation and read across approach considering nearest 5 substances with Log Kow as the descriptor

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: as below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide
SMILES:CCOc1ccc(NC(=O)C(C(C)=O)N=Nc2ccc(Cl)cc2N(=O)=O)cc1
InChI:1S/C18H17ClN4O5/c1-3-28-14-7-5-13(6-8-14)20-18(25)17(11(2)24)22-21-15-9-4-12(19)10-16(15)23(26)27/h4-10,17H,3H2,1-2H3,(H,20,25)/b22-21+
Molecular Formula: C18H17ClN4O5
Molecular Weight: 404.808 g/mole

Test animals

Species:
rat
Strain:
Wistar
Details on species / strain selection:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
not specified

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Remarks on MMAD:
not specified
Vehicle:
not specified
Details on exposure:
not specified
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 32 days, Female about 7 weeks
Frequency of treatment:
once daily
Details on study schedule:
not specified
Doses / concentrations
Dose / conc.:
752 mg/kg bw/day
No. of animals per sex per dose:
11
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified

Examinations

Parental animals: Observations and examinations:
not specified
Oestrous cyclicity (parental animals):
not specified
Sperm parameters (parental animals):
not specified
Litter observations:
not specified
Postmortem examinations (parental animals):
not specified
Postmortem examinations (offspring):
not specified
Statistics:
not specified
Reproductive indices:
not specified
Offspring viability indices:
not specified

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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 / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
752 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reproductive performance
Remarks on result:
other: No effect observed

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
no effects observed
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
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
other: not specified
Generation:
other: not specified
Based on:
not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Any other information on results incl. tables

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Amides by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> N-substituted aromatic amides by DPRA Cysteine peptide depletion

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential AND NO2-alkyl/NO2-benzene derivatives (8b) by DART scheme v.1.0

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Polyhalogenated benzene derivatives (8c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Similarity boundary:Target: CCOc1ccc(NC(=O)C(C(C)=O)N=Nc2ccc(Cl)cc2N(=O)=O)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Similarity boundary:Target: CCOc1ccc(NC(=O)C(C(C)=O)N=Nc2ccc(Cl)cc2N(=O)=O)cc1
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkylarylether AND Aromatic compound AND Aryl chloride AND Aryl halide AND Carbonyl compound AND Carboxylic acid amide AND Carboxylic acid sec. amide AND Ether AND Halogen derivative AND Ketone AND Nitro compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Carboxylic acid by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.57

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.21

Applicant's summary and conclusion

Conclusions:
NOAEL was estimated to be 752 mg/kg bw when rats were orally exposed with 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide .
Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide. The NOAEL was estimated to be 752 mg/kg bw when rats were orally exposed with 2-[(E)-2-(4-chloro-2-nitrophenyl)diazen-1-yl]-N-(4-ethoxyphenyl)-3-oxobutanamide .