N-(2-ethoxyphenyl)-N'-(2-ethylphenyl)oxamide

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

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 adequate and reliable documentation / justification

Remarks:

The Leadscope Model Applier contains both statistical-based QSAR models as well as expert rule-based alerts satisfying the ICH M7 requirement for having the two specified technologies.

Justification for type of information:

1. SOFTWARE :Leadscope Model Applier
2. MODEL (incl. version number) Version 1.7, October 2013
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :see attcahed report for details
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
See attached QMRF
5. APPLICABILITY DOMAIN
See attached study report
6. ADEQUACY OF THE RESULT
See attached study report for details

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

no guideline followed

Guideline:

other: Leadscope Model Applier

Principles of method if other than guideline:

Leadscope Model Applier

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-(2-ethoxyphenyl)-N'-(2-ethylphenyl)oxamide

EC Number:

245-950-9

EC Name:

N-(2-ethoxyphenyl)-N'-(2-ethylphenyl)oxamide

Cas Number:

23949-66-8

Molecular formula:

C18H20N2O3

IUPAC Name:

N-(2-ethoxyphenyl)-N'-(2-ethylphenyl)ethanediamide

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): N-(2-Ethoxyphenyl)-N'-(2-ethylphenyl)ethanediamide

Test animals

Species:

rat

Strain:

not specified

Administration / exposure

Route of administration:

other: QSAR prediction

Vehicle:

other: QSAR prediction

Analytical verification of doses or concentrations:

no

Details on mating procedure:

Not applicable - QSAR prediction

Duration of treatment / exposure:

Not applicable - QSAR prediction

Frequency of treatment:

Not applicable - QSAR prediction

Duration of test:

Not applicable - QSAR prediction

Doses / concentrations

Remarks:

Doses / Concentrations:
Not applicable - QSAR prediction
Basis:
other:

No. of animals per sex per dose:

Not applicable - QSAR prediction

Control animals:

other: Not applicable - QSAR prediction

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

LOEL

Effect level:

ca. 110 mg/kg bw/day

Based on:

other: Not applicable - QSAR prediction

Basis for effect level:

other: other:

2

Dose descriptor:

NOEL

Effect level:

> 110 mg/kg bw/day

Based on:

other: Not applicable - QSAR prediction

Basis for effect level:

other: other:

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Remark: Not applicable - QSAR prediction

Effect levels (fetuses)

Dose descriptor:

LOEL

Effect level:

ca. 110 mg/kg bw/day

Based on:

other: not applicable for Qsar prediction

Sex:

not specified

Basis for effect level:

changes in litter size and weights

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

The predictions of reproductive toxicity on male and female rats are illustrated in Table 1.

Leadscope Suite, model and submodel	Leadscope Prediction call	Leadscope Positive Prediction probability	Prediction reliability parameters
			Model Fragment Count	30% Similarity Training Neighbours Count	Reliability assessment
Reproductive toxicity – Rat male	NEGATIVE	0.28	12	4	MODERATE RELIABLE
Reproductive toxicity – Rat female	NEGATIVE	0.14	10	4	RELIABLE

Table 1: Leadscope prediction of reproductive toxicity on male and female rats. 

 

In the case of the target chemical, the male reproductive toxicity prediction is moderately reliable since 12 model fragment counts were identified and 4 training structures were identified being similar to the target chemical. In more details the prediction is evaluated to be moderately reliable since 2 out of the four mostly similar structures found in the training set, i.e. Cilostazol and Carteolol, are characterized by consistent experimental data, being all of them negative for reproductive toxicity on male rats, while the other 2 structures, i.e. Phenacetin and nitro-p-acetophenetidide, 3-, are positive for reproductive toxicity on male rats. Thus, Leadscope predicted NEGATIVE for reproductive toxicity on male rats and the prediction has to be considered moderately reliable.

 

In the case of the target chemical, the female reproductive toxicity prediction is reliable since 10 model fragment counts were identified and 4 training structures were identified being similar to the target chemical. In more details the prediction is evaluated to be reliable since all the four mostly similar structures found in the training set, i.e. Phenacetin, Cilostazol, Carteolol and Ethoxzolamide are characterized by consistent experimental data, being all of them negative for reproductive toxicity on female rats. Thus, Leadscope predicted NEGATIVE for reproductive toxicity on female rats and the prediction has to be considered reliable.

Applicant's summary and conclusion

Conclusions:

Leadscope QSAR models predicted the target chemical as possesing NEGATIVE reproductive toxicity on male and female rats.

Executive summary:

The S-IN (2013) study was designed to generate estimated in silico (non-testing) reproductive toxicity data for the target chemical to be used for its regulatory assessment.

The reproductive toxicity on rat male and female of the investigated target chemical was predicted by QSAR models. The predictions were evaluated in terms of their reliability, as required by OECD principles for the validation, for regulatory purposes, of (Quantitative) Structure-Activity Relationship Models QSAR. Leadscope QSAR models predicted the target chemical as NEGATIVE both on male and female rats.

Two different in silico approaches, i.e. the read-across approach and QSAR model predictions, were combined and used in a consensus assessment to enhance the reliability of the predictions. In fact, if the QSAR prediction is consistent with that of the read-across, it further supports the result of the read-across. On the contrary, the inconsistency between the two predictions is extremely useful to identify special cases that might need further analysis and more discussion.

The two in silico approaches were in agreement further supporting the reliability of the predictions.