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Administrative data

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-({4-[bis(2-hydroxyethyl)amino]-2- methylphenyl} diazenyl) -5-nitrobenzonitrile. The study assumed the use of male and female rats in a 24 months toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile is predicted to be 782.171447754 mg/Kg bw/day.

 

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

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:
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 from OECD QSAR Toolbox version 3.4 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.4, 2018
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of the test material: 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile
- IUPAC name: 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile
- Molecular formula: C18H19N5O4
- Molecular weight: 369.38 g/mole
- Substance type: Organic
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
No data
Route of administration:
oral: unspecified
Details on route of administration:
No data
Vehicle:
not specified
Details on oral exposure:
No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
24 months
Frequency of treatment:
Daily
Remarks:
No data
No. of animals per sex per dose:
No data
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data
Observations and examinations performed and frequency:
No data
Sacrifice and pathology:
No data
Other examinations:
No data
Statistics:
No data
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
Details on results:
No data
Dose descriptor:
NOAEL
Effect level:
782.171 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant alterations were noted at the 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 7 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR SN1 OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes by DNA binding by OASIS v.1.4 ONLY

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as 4,4'-Diethylaminoethoxyhexestrol (Hepatotoxicity) Alert OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Alcohol AND Alkyl arenes AND Aromatic amine AND Aryl AND Azo AND Nitrile AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acetal by Organic Functional groups (nested)

Domain logical expression index: "m"

Similarity boundary:Target: Cc1cc(N(CCO)CCO)ccc1N=Nc1ccc(N(=O)=O)cc1C#N
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.492

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.24

Conclusions:
The No Observed Adverse Effect Level (NOAEL) for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile is predicted to be 782.171447754 mg/Kg bw/day.
Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-({4-[bis(2-hydroxyethyl)amino]-2- methylphenyl} diazenyl) -5-nitrobenzonitrile. The study assumed the use of male and female rats in a 24 months toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile is predicted to be 782.171447754 mg/Kg bw/day.

 

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
782 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

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

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: Oral

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of 2-({4-[bis(2-hydroxyethyl) amino]-2-methylphenyl} diazenyl) -5-nitrobenzonitrile. The studies are as mentioned below:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-({4-[bis(2-hydroxyethyl)amino]-2- methylphenyl} diazenyl) -5-nitrobenzonitrile. The study assumed the use of male and female rats in a 24 months toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile is predicted to be 782.171447754 mg/Kg bw/day.

The predicted data is further supported by the data from read across chemicals as mentioned below:

In the NTP report for 60 -70% structurally similar read across chemical, 14 days repeated dose oral toxicity study was performed to determine the toxic nature of HC Yellow 4 (RA CAS no. 59820 -43 -8; IUPAC name: 2-[2-(2-hydroxyethylamino)-5-nitrophenoxy]ethanol) using rats. The test chemical was mixed with feed and dosed to F344/N 5 male and 5 female rats at dose levels of 0, 500, 1000, 2000, 4000 or 8000 mg/Kg bw/day for 14 days. During the study period, the animals were observed for signs of toxicity, death, changes in body weight and feed consumption, and they were subjected to gross and histo-pathology. No deaths were observed and no signs of toxicity attributable to the test chemical administration were noted. The final mean body weights and mean body weight changes of males that received doses of 20,000 ppm (2000 mg/Kg bw/day) and above and females that received doses of10,000 ppm (1000 mg/Kg bw/day) and above were significantly lower than those of the controls. Feed consumption by males that received doses of 20,000 ppm (2000 mg/kg bw/day) or greater and females that received doses of 10,000 ppm (1000 mg/Kg bw/day) or greater was lower than that of the controls during the first week. During the second week, feed consumption by males in the 40,000 ppm (4000 mg/Kg bw/day) dose group was lower than controls; feed consumption by other male and female dose groups was similar to or higher than that of the controls. Because rats that received 40,000 ppm (4000 mg/Kg bw/day) did not gain weight, and the final mean body weights of rats that received 80,000 ppm (8000 mg/kg bw/day) were decreased approximately 30%, it was concluded that the feed consumption values were high and may have included feed scattered by animals searching for unadulterated feed. Significant changes in absolute and relative organ weights were observed but were considered to be secondary to decreases in body weights. Based on these observations made, No observed Adverse effect level (NOAEL) for male rats is considered to be 1000 mg/kg bw and female rats the NOAEL is considered to be 500 mg/Kg bw.

In another data available for the 50 -60% structurally similar read across chemical ( Commission Of The European Communities, 1988), 90 days repeated dose oral toxicity study was performed to determine the toxic nature of Pigment Red 3 (RA CAS no 2425 -85 -6; IUPAC name: 1-(4-Methyl- 2-nitrophenyl azo)-2- naphthol) using rats. The test chemical was mixed with feed and dosed to F344/N 5 male and 5 female rats at dose levels of 0, 125, 250, 500 or 1000 mg/Kg bw/day for 90 days. During the study period, the animals were observed for growth rate, death, hematological parameters and they were subjected to gross and histo-pathology. No deaths were observed and no signs of toxicity attributable to the test chemical administration were noted. No changes in hematological parameters were noted. Slight increases in liver weight were not clearly dose-related. Spleen weight was increased in males of the top-dose group. Microscopy of the six organs examined showed no relevant changes. Based on the observations made and since detailed data is not available, the No observed Adverse effect level (NOAEL) for male and female weanling rats is considered to be 1000 mg/kg bw /day.

Based on the data available for the target chemical and its read across, the test chemical is not likely to be a toxicant as per the criteria mentioned n CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across, the test chemical (CAS no 12236 -25 -8) is not likely to be a toxicant as per the criteria mentioned n CLP regulation.