Biphenyl-2-ylamine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

No compound related effects were observed, the no observed adverse effect level (NOAEL) for test material biphenyl-2-ylamine in rats was found to be 850 mg/kg bw/day (actual dose received).

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

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

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

not specified

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

not specified

Details on exposure:

no data

Details on mating procedure:

no data

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

52 days

Frequency of treatment:

daily

Remarks:

Doses / Concentrations:
597, 850, 1000 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

10

Control animals:

yes

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

850 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: No efffect on organ weight

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Reproductive effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 6 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 ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and ("s" and "t" )  )

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 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Quinones 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 ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones 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 diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines 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 attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups 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 >> Sulfanilic acid derivatives 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 alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Ac-SN2 OR Ac-SN2 >> Acylation involving an activated (glucuronidated) carboxamide group OR Ac-SN2 >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amines OR Ac-SN2 >> Direct acylation involving a leaving group OR Ac-SN2 >> Direct acylation involving a leaving group >> Carboxylic Acid Amines OR AN2 OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Carboxylic Acid Amines OR AN2 >> Shiff base formation with carbonyl compounds OR AN2 >> Shiff base formation with carbonyl compounds >> Pyrazolone and Pyrazolidine Derivatives by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR SN2 OR SN2 >> Nucleophilic substitution on heteroarene sulfenamides OR SN2 >> Nucleophilic substitution on heteroarene sulfenamides >> Heteroarene sulfenamides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Not categorized by OECD HPV Chemical Categories

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Diarylide yellow pigments OR Hydrotrope surfactants by OECD HPV Chemical Categories

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.19

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.31

Conclusions:

Since no compound related effects were observed, the no observed adverse effect level (NOAEL) for test material biphenyl-2-ylamine in rats was found to be 850 mg/kg bw/day (actual dose received).

Executive summary:

The reproductive toxicity of biphenyl-2-ylamine to rats was estimated using QSAR Toolboox version 3.3

Since no compound related effects were observed, the no observed adverse effect level (NOAEL) for test material biphenyl-2-ylamine in rats was found to be 850 mg/kg bw/day (actual dose received).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

850 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

K2 Predicted data.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Studies for reproductive toxicity from QSAR predicted data and reliable sources having Klimisch rating 2 were reviewed for the read across substance.

The summary of the results are presented below:

Sr. No	End point	Value	Species	Route	Effects	Remarks
1.	NOAEL	850 mg/kg bw/day (actual dose received).	Rat	Oral-Gavage	No effect on organ weight	Predicted Data for CAS: 90-41-5
2.	NOAEL	428 mg/ kg bw/ d	Mouse	Oral: feed	No effect on survival, clinical signs, body weight, food consumption, gross pathology and histopathology	Experimental data for RA CAS: 2185-92-4
3.	NOAEL	50 mg/ kg bw/ d (male)             150 mg/ kg bw/ d (female)	Rat	Oral: feed	No adverse effect on survival, clinical sign, Body weight, Food consumption, gross pathology of testes and Histopathology     No adverse effect on survival, clinical sign, Body weight, Food consumption and Histopathology of reproductive organs	Experimental data for RA CAS: 2185-92-4

 

Based on the studies summarized in the above table it can be observed that NOAEL value varies from 50 to 428 mg/Kg bw/ d. in rats and mice. The effects observed on these doses was listed as follows:

·        No effect on organ weight

·        No effect on survival, clinical signs, body weight, food consumption, gross pathology and histopathology

·        No adverse effect on survival, clinical sign, Body weight, Food consumption, gross pathology of testes and histopathology of reproductive organs.

 

Since from the QSAR predcted data for target chemical indicates no effective dose value (NOAEL) is850 mg/kg bw/day (actual dose received)thus based on this value it can be concluded that substance is considered to be not toxic to reproduction via oral route for the above mentioned dose.

Short description of key information:
The reproductive toxicity of biphenyl-2-ylamine to rats was estimated using QSAR Toolboox version 3.3
Since no compound related effects were observed, the no observed adverse effect level (NOAEL) for test material biphenyl-2-ylamine in rats was found to be 850 mg/kg bw/day (actual dose received).

Justification for selection of Effect on fertility via oral route:
Data is from QSAR Toolbox Version 3.3

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Toxicity to reproduction: other studies

Additional information

The reproductive toxicity of biphenyl-2-ylamine to rats was estimated using QSAR Toolboox version 3.3

Since no compound related effects were observed, the no observed adverse effect level (NOAEL) for test material biphenyl-2-ylamine in rats was found to be 850 mg/kg bw/day (actual dose received).

Justification for classification or non-classification

Based on the available studies for the read across substance, it is expected that the target chemical is not likely to exhibit reproductive toxicity.