Registration Dossier

Administrative data

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
Reference:
Composition 0
Qualifier:
according to
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
Test material information:
Composition 1
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
Estrous 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
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous 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.