2-[[4-[bis(2-hydroxyethyl)amino]-o-tolyl]azo]-5-nitrobenzonitrile

Endpoint summary

Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity, LD50 value was predicted based on OECD QSAR toolbox for target substance 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) was estimated to be 4055.47mg/kg bw and for different studies available on the structurally similar read across substance 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1) was considered to be 10000mg/kg bw and Disperse Red 17(3179-89-3) was considered to be >2000mg/kg bw. All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) can be Not classified for acute oral toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute 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 v3.4 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4, 2018

GLP compliance:

not specified

Test type:

other:

Limit test:

no

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:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

No data available

Doses:

4055.47 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male/female

Dose descriptor:

LD50

Effect level:

4 055.47 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

No data available

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides OR Acylation >> Acylation involving an activated (glucuronidated) ester group OR Acylation >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group >> Arenesulfonamides OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR AN2 OR AN2 >> Michael addition to activated double bonds OR AN2 >> Michael addition to activated double bonds >> alpha,beta-Unsaturated Carbonyls and Related Compounds OR AN2 >> Michael type addition to activated double bond of pyrimidine bases OR AN2 >> Michael type addition to activated double bond of pyrimidine bases >> Pyrimidines and Purines OR AN2 >> Michael-type addition to quinoid structures  OR AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides OR AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines OR AN2 >> Nucleophilic addition at polarized N-functional double bond OR AN2 >> Nucleophilic addition at polarized N-functional double bond >> Arenesulfonamides OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases >> Pyrimidines and Purines OR Michael addition OR Michael addition >> Michae addition on quinoide type compounds OR Michael addition >> Michae addition on quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Activated electrophilic ethenylarenes  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.4

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

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 Alkali Earth OR Halogens by Groups of elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "m"

Similarity boundary:Target: Cc1cc(N(CCO)CCO)ccc1N=Nc1ccc(N(=O)=O)cc1C#N
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Similarity boundary:Target: Cc1cc(N(CCO)CCO)ccc1N=Nc1ccc(N(=O)=O)cc1C#N
Threshold=60%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Nitrobenzenes (Testicular toxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.02

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.37

Interpretation of results:

other: Not classified

Conclusions:

LD50 value was estimated to be 4055.47 mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) by orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8). LD50 value was estimated to be 4055.47 mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) by orally.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 055.47 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2018)

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute Oral Toxicity: 

In different studies, 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) has been investigated for acute oral toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) along with the study available on the structurally similar read across substance 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1) and Disperse Red 17(3179-89-3). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8). LD50 value was estimated to be 4055.47 mg/kg bw. When male and female Sprague-Dawley rats were exposed with 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) by orally.

In another experimental study conducted by U.S .National library of medicine (ChemID plus A TOXNET DATABASE.2017) for the structurally similar read across substance 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1). Acute oral toxicity study was done in mouse using 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1). No mortality was observed at dose 10000mg/kg bw.Hence LD50 was considered to be >10000mg/kg body weight. When mouse was treated with 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1)orally.

In another experimental study conducted by European Commission (CCP (Scientific Committee on Consumer Products), Opinion on Disperse Red 17, 16 December 2008) for the structurally similar read across substance Disperse Red 17(3179-89-3).Acute oral toxicity study was done in 5 male and 5 female Sprague Dawley using Disperse Red 17(3179-89-3). The test material dissolved in water and administered by oral gavage route in dose concentration 2000 mg /kg bw. The dose was selected on the basis of preliminary study. All the animals were observed 1, 2and 4 hours after dosing and thereafter daily for 14 days. Body weights were recorded on days 1, 8 and 15 of the study. Macroscopic examination of main organs was performed after autopsy. No histological examinations were performed.

No mortality was observed at dose 2000mg/kg bw. The only clinical sign was a pink discoloration of the skin, apparent from 1 hour to 7 days after dosing. Body weight gain was considered normal for the age and strain of rat. At autopsy an orange coloration of the mammary tissue and /or abdominal fat, attributed to the staining properties of the substance and not considered to be a toxic effect. The distribution and persistence of staining indicates that the substance has the potential to accumulate, at least at the high dose used in this acute study.HenceLD50 was considered to be>2000mg/kg body weight. When male and female rats were treated with Disperse Red 17(3179-89-3) orally.

Thus, based on the above studies on 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) and it’s structurally similar read across substances 3-[[4-[(2-chloro-4-nitrophenyl)azo]phenyl]ethylamino]propiononitrile(40880-51-1) and Disperse Red 17(3179-89-3). it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) can be not classified for acute oral toxicity.

 

 

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation 2-({4-[bis(2-hydroxyethyl)amino]-2-methylphenyl}diazenyl)-5-nitrobenzonitrile (12236-25-8) can be not classified for acute oral toxicity.