3,4-dicyanoaniline

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) for 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8) was predicted based on OECD QSAR toolbox 167 mg/kg bw and different studies available on structurally similar read across substances 1,2-Dicyanobenzene (91-15-6) 85 mg/kg bw and 2-methyl-p-phenylenediamine (95-70-5) 102 mg/kg bw. All these studies concluded that the LD50 value is between 50-300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4-aminobenzene-1,2-dicarbonitrile can be classified as category 3 of 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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

Name: 4-aminobenzene-1,2-dicarbonitrile
SMILES:Nc1ccc(C#N)c(C#N)c1
InChI: 1S/C8H5N3/c9-4-6-1-2-8(11)3-7(6)5-10/h1-3H,11H2
Mol. formula: C8H5N3
Molecular Weight: 143.148 g/mole

Species:

rat

Strain:

Wistar

Sex:

male

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

167 mg/kg

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male

Dose descriptor:

LD50

Effect level:

167 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed.

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
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 ( not "k") )  )  and "l" )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and "x" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Phenols and Anilines by Acute aquatic toxicity MOA by OASIS

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (Unhindered) AND Phthalonitriles by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> Direct Acting Epoxides and related OR SN2 >> Direct Acting Epoxides and related >> Epoxides OR SN2 >> SN2 at an sp3 Carbon atom by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as (!Undefined)Group CNHal Lipid Solubility < 4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as (!Undefined)Group CNS Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Group All log Kow < -3.1 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Group CHal Molecular Weight > 370 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.89

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.2

Interpretation of results:

Category 3 based on GHS criteria

Remarks:

Migrated information

Conclusions:

LD50 was estimated to be 167 mg/kg bw, when Wistar male rats were treated with 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8) via oral gavage route.

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 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8). The LD50 was estimated to be 167 mg/kg bw, when Wistar male rats were treated with 4-aminobenzene-1,2-dicarbonitrile via oral gavage route.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

167 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

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, 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in-vivo experiments in rodents, i.e. most commonly in rats for 4-aminobenzene-1,2-dicarbonitrile along with the study available on structurally similar read across substances 1,2-Dicyanobenzene (91-15-6) and 2-methyl-p-phenylenediamine (95-70-5). 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 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8). The LD50 was estimated to be 167 mg/kg bw, when Wistar male rats were treated with 4-aminobenzene-1,2-dicarbonitrile via oral gavage route.

The above study is supported by Ministry of Health, Labour and Welfare, Ministry of the Environment and National Institute of Technology and Evaluation (J-CHECK Japan Chemicals Collaborative Knowledge database, 2010), for the structurally similar read across substance 1,2-Dicyanobenzene (91-15-6). Acute oral toxicity study was conducted in 60 Crj: CD (SD) IGS, SPF male and female rat at the concentration of 0, 30, 60, 120, 240 and 480 mg/kg. The test substance (Purity - 98.7%; Obtained from - Showa Denko K.K., Tokyo, and lot number - CRL-981130) was administered in a 0.5% CMC-Na aqueous solution as volume 5 mL/kg. Mortality and general conditions were observed over 10 days, 30 minutes, 1, 3 and 6 hours on the administration day, once a day for 14 days thereafter. Body weight was measured on days 4, 8, and 15 immediately before administration. Animals were observed for clinical signs. Mortality rate was calculated by the Probit method. At 240 and 480 mg/kg group - All animals were died, At 120 mg/kg group - 4 animals were died, and At 60 mg/kg group - 1 animal was died from 30 minutes to 6 hours after administration. In deceased animals, decline in locomotor activity, convulsions, and stains around the mouth were found in the male and female 120, 240 and 480 mg/kg groups, and in addition to this symptom, the prone position, abnormal vocalization, aberrant tail and cyanosis were observed in male and female 240 And 480 mg/kg group. In the 60 mg/kg group of male, there was only a decline in locomotor activity and walking abnormality. In the female 60 mg / kg group, only convulsions and contamination around the mouth were observed. In the surviving animals, 4 cases of female 60 mg /kg group showed a decline in locomotor activity 6 hours after administration, one of them showed a decrease in locomotor activity and irregular respiration on day 2 which recovered after that.No abnormality was found in body weight of surviving animals. Therefore, LD50 was considered to be 85 mg/kg with 95% confidence limit 50 to 143 mg/kg bw, when Male and female SD rats were treated with 1,2-Dicyanobenzene via oral route.

This study is further supported by Lloyoet al.(Food and Cosmetics Toxicology. Vol. 15, pp. 607-610, 19 April 1977) and U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance 2-methyl-p-phenylenediamine (95-70-5).Acute oral toxicity study was conducted in 20 CFY male and female rat at the concentration of 102 mg/kg. The test substance was administered as 10% Aqueous solution containing 0.05% Na2SO3 to the oral gavage route.In a preliminary range finding study, the freshly prepared solutions or suspensions were administered to groups of 2 male and 2 female rats by oral intubation in a range of dosage volumes, in order to find the approximate median lethal oral dose (LD50). After these preliminary range-finding tests had given a rough approximation of the LD50, larger groups of rats (5 males and 5 females) were used in order to locate the median lethal dose more precisely. A logarithmic dosage interval of 1.6 was used for each material. Rats treated with the vehicle alone served as controls. Mortality and signs of toxicity were observed. Animals were observed for clinical signs and microscopic examination. The LD50 and its 95% confidence limits were calculated from the mortality data either by the method of Litchfield & Wilcoxon (1949) or by that of Weil (1952). 50% mortality was observed in treated rats. Signs of reaction to treatment, observed shortly after dosing included lethargy and piloerection. Other reactions elicited included increased salivation, ataxia, fine body tremors, changes in respiratory rate, dieresis and diarrhoea. Animals that died were examined macroscopically in an attempt to identify the target organs, and animals surviving to the end of the experiment were similarly examined at that time to detect any possible residual damage. There was no microscopic examination of the various tissues and organ systems. Autopsy of the animals that died as a result of treatment revealed changes which, in many cases, included darkening of the liver and kidneys, darkening or pallor of the spleen, haemorrhage of the lungs and intestines, and injection of the intestinal and mesenteric blood vessels. Therefore, LD50 was considered to be 102 mg/kg with 95% confidence limit 69-152 mg/kg bw, when Male and female CFY rats were treated with 2-methyl-p-phenylenediamine via oral gavage route.

Thus, based on the above studies on 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8) and it’s read across substances, it can be concluded that LD50 value is between 50-300 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4-aminobenzene-1,2-dicarbonitrile can be classified as category 3 of acute oral toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 4-aminobenzene-1,2-dicarbonitrile (CAS no: 56765-79-8) and it’s read across substances, it can be concluded that LD50 value is between 50-300 mg/kg bw for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, 4-aminobenzene-1,2-dicarbonitrile can be classified as category 3 for acute oral toxicity.