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Description of key information

Acute toxicity Oral:
The acute oral median lethal dose (LD50) for the test compound 2 biphenylamine in male mice is found to be 1000 mg/kg whereas the LD100 for male and female mice is found to be 10000 mg/kg bw.
Acute toxicity Inhalation:
The chemical biphenyl-2-ylamine has a low vapour pressure of 0.000117 mmHg at 25°C. Also, the particle size distribution was found to be in the range of 106 micron to 150 micron and thus the particulates are not of the inhalable size. Thus exposure by the inhalation route to this chemcal seems highly unlikely. This end point was therefore considered for waiver.
Acute toxicity Dermal:
The median lethal dose (LD50) value of the test substance biphenyl-2-ylamine in rabbits was estimated to be 3328.752929688 mg/kg bw. Considering the CLP Criteria for classification of the substance, it is concluded that biphenyl-2-ylamine is not classified for acute Dermal toxicity to rabbits.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from authoritative source
Qualifier:
according to guideline
Guideline:
other: as below
Principles of method if other than guideline:
Acute oral toxicity study was carried out to assess the effects of 2 biphenylamine on mice.
GLP compliance:
not specified
Test type:
other: no data available
Limit test:
no
Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Center (Frederick, MD)
- Age at study initiation: 6-7 weeks old
- Weight at study initiation: No data available
- Fasting period before study: No data available
- Housing: 2 per cage
- Diet (e.g. ad libitum): Wayne Lab Blox® meal, Allied M ills, Inc. (Chicago, IL). Available ad libitum
- Water (e.g. ad libitum): Available ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.2°-32.2°C.
- Humidity (%): uncontrolled.
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): Fluorescent lighting provided 12 hours per day.
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
- Concentration in vehicle: 1, 10, 100, 1000 and 10,000 mg/Kg bw
- Amount of vehicle (if gavage): No data available
- Justification for choice of vehicle: No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

MAXIMUM DOSE VOLUME APPLIED: No data available

DOSAGE PREPARATION (if unusual): Single preparation

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: No data available
Doses:
1, 10, 100, 1000 and 10,000 mg/Kg bw
No. of animals per sex per dose:
2/sex/dose
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Observed daily for mortality and signs of toxicity; weighed on day 1,7, and 14
- Necropsy of survivors performed: Yes
- Other examinations performed: clinical signs, body weight, Gross pathology
Statistics:
No data available
Sex:
male/female
Dose descriptor:
LD100
Effect level:
10 000 mg/kg bw
Based on:
test mat.
Sex:
male
Dose descriptor:
LD50
Effect level:
1 000 mg/kg bw
Based on:
test mat.
Mortality:
Both animals died at the 10000 mg/kg bw dose level
Clinical signs:
Animals receiving 10000 mg/ kg showed hyperactivity, prostration, and shallow breathing
Body weight:
There was a slight change in body weight of animals at the end of the 14-day observation period.
Gross pathology:
Necropsy showed dark intestinal contents, enlarged lymph nodes, and reddened nasal conchae. Macroscopic examination of animals in the remaining dose groups revealed the presence of enlarged Peyer's patches.
Other findings:
In addition, mice receiving 10mg/kg or 100mg/kg doses had slight opacity in the lens region of the eye
Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) for the test compound 2 biphenylamine in male mice is found to be 1000 mg/kg whereas the LD100 for male and female mice is found to be 10000 mg/kg bw.
Executive summary:

Single dose studies were carried out to test the effects of 2 biphenylamine on male and female mice. The dose concentrations used were 1, 10, 100, 1000 and 10,000 mg/Kg bw.

 

Male and female mice given a single dose of 10 g/kg technical-grade 2-biphenylamine died within 24 hours following administration. Prior to death, these animals showed hyperactivity, prostration, and shallow breathing. Necropsy showed dark intestinal contents, enlarged lymph nodes, and reddened nasal conchae. Macroscopic examination of animals in the remaining dose groups revealed the presence of enlarged Peyer's patches.

In addition, mice receiving 10mg/kg or 100 mg/ kg doses had slight opacity in the lens region of the eye. Mice receiving the 1 g/kg-1000mg/kg dose had mesenteric lymph node enlargement. One mouse in this group died because of a gavage accident. There was a slight change in body weight of animals at the end of the 14-day observation period.

 

Based on the results observed, The acute oral median lethal dose (LD50) for the test compound 2 biphenylamine in male mice is found to be 1000 mg/kg whereas the LD100 for male and female mice is found to be 10000 mg/kg bw.

 

According to the CLP & Harmonized Classification, the test material classifies as an acute toxicant Category 4 chemical.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
1 000 mg/kg bw
Quality of whole database:
Data is of K2 level obtained from NTP Report

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
exposure considerations
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
(Q)SAR
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from QSAR Toolbox version 3.3
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Qualifier:
according to guideline
Guideline:
other: The prediction is done using QSAR Toolbox version 3.3
Principles of method if other than guideline:
The prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: estimation
Species:
rabbit
Strain:
not specified
Sex:
not specified
Type of coverage:
not specified
Vehicle:
unchanged (no vehicle)
Control animals:
not specified
Sex:
not specified
Dose descriptor:
LD50
Effect level:
3 328.753 mg/kg bw
Based on:
test mat.





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 ( not "m") )  )  and "n" )  and ("o" and "p" )  )

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 Aniline AND Aryl AND Biphenyl by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aniline AND Biphenyl AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] AND Aromatic Carbon [C] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Amine AND Aromatic compound AND Primary amine AND Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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: "i"

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: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates, Isothiocyanates  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Ionic interaction OR Ionic interaction >> Substituted guanidines OR Ionic interaction >> Substituted guanidines >> Guanidines 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 on heteroarene sulfenamides OR SN2 >> Nucleophilic substitution on heteroarene sulfenamides >> Heteroarene sulfenamides  by Protein binding by OASIS v1.3

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.17

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.56

Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the QSAR prediction done for acute toxicity of biphenyl-2-ylamine via dermal route, the LD50 value is estimated to be 3328.752929688 mg/kg bw on rabbits. Thus it can be concluded that biphenyl-2-ylamine is not considered to be acutely toxic by the dermal route as per criteria of CLP regulation.
Executive summary:

Based on the QSAR prediction done for acute toxicity of biphenyl-2-ylamine via dermal route, the LD50 value is estimated to be 3328.752929688 mg/kg bw on rabbits. Thus it can be concluded that biphenyl-2-ylamine is not considered to be acutely toxic by the dermal route as per criteria of CLP regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 328.753 mg/kg bw
Quality of whole database:
The median lethal dose (LD50) value of the test substance biphenyl-2-ylamine in rabbits was estimated to be 3328.752929688 mg/kg bw. Considering the CLP Criteria for classification of the substance, it is concluded that biphenyl-2-ylamine is not classified for acute Dermal toxicity to rabbits.

Additional information

Acute toxicity: Oral

Studies of biphenyl-2-ylamine were reviewed for acute oral toxicity from reliable sources having Klimisch rating 2.

Sr. No.

Endpoint name

Value

Units

Species

Source

1.      

LD100

10000

mg/kg of body weight.

Rat

Study report

2.      

LD50

1000

mg/kg of body weight.

Rat

Study report

3.      

LD50

1000

mg/kg of body weight.

Mouse

Study report

4.      

LD50

907.6779

mg/kg of body weight.

Rat

QSAR Predicted data

 

By applying weight of evidence approach to the target chemicalbiphenyl-2-ylamine(CAS No 90-41-5), the majority values are indicative of the chemical likely to cause acute oral toxicity in the Category IV though there are certain values that indicate no toxicity by the oral route. Thus it is concluded thatbiphenyl-2-ylamineis likely to be classified in the oral toxicity category IV.

 

 

Acute toxicity: Inhalation:

The chemical biphenyl-2-ylamine has a low vapour pressure of 0.000117 mmHg at 25°C. Also, the particle size distribution was found to be in the range of 106 micron to 150 micron and thus the particulates are not of the inhalable size. Thus exposure by the inhalation route to this chemcal seems highly unlikely. This end point was therefore considered for waiver.

 

Acute toxicity: Dermal:

The acute toxicity of biphenyl-2-ylamine by dermal route was estimated using QSAR Toolbox version 3.3

The median lethal dose (LD50) value of the test substance biphenyl-2-ylamine in rabbits was estimated to be 3328.752929688 mg/kg bw. Considering the CLP Criteria for classification of the substance, it is concluded that biphenyl-2-ylamine is not classified for acute dermal toxicity to rabbits. 


Justification for selection of acute toxicity – oral endpoint
The acute oral median lethal dose (LD50) for the test compound 2 biphenylamine in male mice is found to be 1000 mg/kg whereas the LD100 for male and female mice is found to be 10000 mg/kg bw.

Justification for selection of acute toxicity – inhalation endpoint
The chemical biphenyl-2-ylamine has a low vapour pressure of 0.000117 mmHg at 25°C. Also, the particle size distribution was found to be in the range of 106 micron to 150 micron and thus the particulates are not of the inhalable size. Thus exposure by the inhalation route to this chemcal seems highly unlikely. This end point was therefore considered for waiver.

Justification for selection of acute toxicity – dermal endpoint
The acute toxicity of biphenyl-2-ylamine by dermal route was estimated using QSAR Toolbox version 3.3

Justification for classification or non-classification

On the basis of available studies, the substance 2 biphenylamine is classified in Acute toxicity category 4 by oral route. This is in agreement with the HArmonized classification of this chemical in the CLP inventory.

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