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Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.1
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
2 year
Control animals:
not specified
Clinical signs:
no effects observed
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:
127 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No clinical signs of toxicity were reported.
Remarks on result:
other: not specified
Critical effects observed:
not specified
Organ:
not specified
Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified
Key result
Dose descriptor:
dose level:
Generation:
other: not specified
Based on:
other: not specified
Sex:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
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 ("g" and "h" )  )

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 Aromatic heterocyclic halide AND Aryl AND Aryl halide by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aniline AND Aromatic heterocyclic halide AND Aryl halide 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 Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] 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 Aryl chloride AND Aryl halide AND Halogen derivative 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 Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.62

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.02

Conclusions:
The oral administration of 3-chloroaniline to male/female Sprague-Dawley rat ,at a dose level of 127 mg/kg bw/day (actual dose received).No clinical signs of toxicity were reported.
Thus the NOAEL for reproductive toxicity study was considered to be 127 mg/kg bw/day (actual dose received).
Executive summary:

The oral administration of 3-chloroaniline to male/female Sprague-Dawley rat ,at a dose level of 127 mg/kg bw/day (actual dose received).No clinical signs of toxicity were reported.

Thus the NOAEL for reproductive toxicity study was considered to be 127 mg/kg bw/day (actual dose received).

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
127 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from QSAR model considered by OECD.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Toxicity to reproduction

WoE Summary of 108-42-9 for toxicity to reproduction

Based on the various studies available with Klimish rating 2 and 4 for the target as well as the read across substances for CAS: 108-42-9 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results are summarized as follows

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

NOAEL

 

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

Rat

Oral

No clinical signs of toxicity were reported.

Predicted data for target chemical (108-42-9)

2

NOAEL

 

25 mg/kg bw

Rat

Oral

No statistically significant or toxicologically relevant adverse effects on any of the maternal reproductive parameters studied were observed in the 25 mg/kg dose groups.

Data from study report for RA CAS:95-76-1

 

LOAEL

125 mg/kg bw

The test article did, however, produce a slight (though not statistically, significant) increase in absorptions and consequently in post-implantation loss at 125 mg/kg.

3.

NOAEL

 

 

10 mg/kg bw/day

 

Rat

Oral

No effects observed on clinical signs , mortality , body weight , food consumption as well as gross and histopathology.

Data from study report for RA CAS:108-45-2

 

LOAEL

 

 

90 mg/kg bw/day

 

 

 

Effects observed on the following parameters that were examined :Clinical signs, mortality, body weight, food consumption, reproductive performance, Gross and histopathology.

Based on the studies summarized in the above table it can be observed that the endpoint low observed effect value (LOAEL) varies from 90 mg/kg bw/day to 125 mg/kg bw as well as no effect value (NOAEL) varies from 10 mg/kg bw/day to 127 mg/kg bw/day (actual dose received) based on the data from prediction as well as publication for target & read across substance. The effect observed on the above doses are-

·        Produce a slight (though not statistically, significant) increase in absorptions and consequently in post-implantation loss.

·        Effects observed on clinical signs, mortality, body weight, food consumption, reproductive performance, Gross and histopathology.

·        No clinical signs of toxicity were reported.

·        No statistically significant or toxicologically relevant adverse effects on any of the maternal reproductive parameters studied were observed in the 25 mg/kg dose groups.

·        No effects observed on clinical signs , mortality , body weight , food consumption as well as gross and histopathology.

Thus based on the above results it can be concluded that the substance CAS: 108-42-9 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since low effective dose value (LOAEL) is higher than 90 mg/kg bw/day thus based on this value it can be concluded that substance CAS: 108-42-9 is considered to be not toxic to reproduction below the dose level of 90 mg/kg bw/day. Also there are no known evidence of adverse effect on reproduction to human of CAS: 108-42-9.

Short description of key information:

From the various data available and adopting the weight of evidence approach, it has been concluded that 3-Chloroaniline is not likely to have reprotoxic effects within the dose levels mentioned in the respective end points.

Justification for selection of Effect on fertility via oral route:

The oral administration of 3-chloroaniline to male/female Sprague-Dawley rat ,at a dose level of 127 mg/kg bw/day (actual dose received).No clinical signs of toxicity were reported.

Thus the NOAEL for reproductive toxicity study was considered to be 127 mg/kg bw/day (actual dose received).

Effects on developmental toxicity

Description of key information

From the various data available and adopting the weight of evidence approach, it has been concluded that 3-chloroaniline is not likely to have teratogenic effects.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.1
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
Sex : female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
day 6 - 15 of gestation
Frequency of treatment:
daily
Control animals:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no data
Dose descriptor:
other: not specified
Based on:
not specified
Basis for effect level:
other: not specified
Remarks on result:
other: not specified
Abnormalities:
not specified
Localisation:
not specified
Description (incidence and severity):
not specified
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Fetal weight decreased
Dose descriptor:
LOAEL
Effect level:
130 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: fetotoxicity
Remarks on result:
other: not specified
Abnormalities:
not specified
Localisation:
other: not specified
Description (incidence and severity):
not specified
Developmental effects observed:
not specified
Treatment related:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL,LOAEL,LOAEC
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 ("g" and "h" )  )

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 Aromatic heterocyclic halide AND Aryl AND Aryl halide by Organic functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aniline AND Aromatic heterocyclic halide AND Aryl halide 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 Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] 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 Aryl chloride AND Aryl halide AND Halogen derivative 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 Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.705

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.02

Conclusions:
The oral administration of 3-chloroaniline to female Sprague-Dawley rat by gavage,at a dose level of 130 mg/kg bw/day (actual dose received),resulted in a decreased fetal weight.Thus the LOAEL(lowest observed adverse effect level) for fetotoxicity study was considered to be 130 mg/kg bw/day (actual dose received),it is regarded that at concentrations lower than 130 mg/kg bw/day (actual dose received) there will be no fetotoxicity when administered orally.
Executive summary:

The oral administration of 3-chloroaniline to female Sprague-Dawley rat by gavage,at a dose level of 130 mg/kg bw/day (actual dose received),resulted in a decreased fetal weight.Thus the LOAEL(lowest observed adverse effect level) for fetotoxicity study was considered to be 130 mg/kg bw/day (actual dose received),it is regarded that at concentrations lower than 130 mg/kg bw/day (actual dose received) there will be no fetotoxicity when administered orally.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LOAEL
130 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from QSAR model considered by OECD.
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

WoE Summary of 108-42-9 for developmental toxicity

Based on the various studies available with Klimish rating 2 and 4 for the target as well as the read across substances for CAS: 108-42-9 based on the category approach of organic functional group along with similar mechanistic approach and having structural similarities defined by QSAR toolbox. This data is combined with the prediction done using the QSAR toolbox for the target chemical based on similar category approach, the results are summarized as follows

Sr. No

End point

Value

Species

Route

Effects

Remarks

1

LOAEL(fetotoxicity)

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

Sprague-Dawley, rat

Oral(gavage)

Foetal weight decreased

Predicted data for target chemical (108-42-9 )

2

End point not reported

(Teratogenicity study)

-

Human

No effects observed.

Predicted data for target chemical (108-42-9 )

3

NOAEL (Maternal toxicity)

 

 

 

 

 

 

 

 

LOAEL (teratogenicity)

25 mg/kg

 

 

 

 

 

 

 

 

125 mg/kg

 

Charles River CrI:CD BR, rat

Oral(gavage)

No statistically significant or toxicologically relevant adverse effects on any of the maternal reproductive or embryotoxicity parameters studied.

 

 

 

A significant delay in ossification of a few skeletal elements of the fetuses in this high-dose group was observed.      

 

Data from study report for RA CAS : 95-76-1

4

TDLo - Lowest published toxic dose (developmental toxicity)

375 mg/kg

Rat

intraperitoneal

Fetal death observed.

Data from publication for RA CAS : 108-45-2

5.

LOAEL (maternal toxicity)

 

 

 

 

 

 

LOAEL (teratogenicity)

90 mg/kg bw/day

 

 

 

 

 

90 mg/kg bw/day

 

Rat

oral: gavage

Effects observed on the following parameters that were examined :Clinical signs, mortality, body weight, food consumption ,reproductive performance, gross and histopathology.

A smaller number of litters with living fetuses, lower placental weight, fewer living fetuses/litter, lower body weight of a living fetus, more total resorption,a higher number of dead fetuses, a higher percentage of dams with minor changed fetuses, a greater incidence of fetuses with minor malformations was observed.

Data from study report for RA CAS : 108-45-2

 

Based on the studies summarized in the above table with various routes it can be observed that the low observed effect level (LOAEL) varies from 90 mg/kg bw/day to 130 mg/kg bw/day (actual dose received) and the lowest published toxic dose is 375 mg/kg based on the data from prediction as well as publication for target &read across substance. The effect observed on the above doses are-

·        Fetal weight decreased.

·        A significant delay in ossification of a few skeletal elements of the fetuses in this high-dose group was observed.     

·        Fetal death observed.

·        A smaller number of litters with living fetuses, lower placental weight, fewer living foetuses /litter, lower body weight of a living fetus, more total resorption, a higher number of dead fetuses, a higher percentage of dams with minor changed fetuses, a greater incidence of fetuses with minor malformations was observed.

Thus based on the above results it can be concluded that substance CAS: 108-42-9 is expected to show the similar toxicological effect based on the effects observed on the other category members. Since low effective dose value (LOAEL) is higher than 90 mg/kg bw/day thus based on this value it can be concluded that substance CAS: 108-42-9 is considered to be not toxic to teratogenic effects below the dose level of 90 mg/kg bw/day. Also there are no known evidence of adverse effect on reproduction to human of CAS: 108-42-9.

 

Justification for selection of Effect on developmental toxicity: via oral route:

The oral administration of 3-chloroaniline to female Sprague-Dawley rat by gavage,at a dose level of 130 mg/kg bw/day (actual dose received),resulted in a decreased fetal weight.Thus the LOAEL(lowest observed adverse effect level) for fetotoxicity study was considered to be 130 mg/kg bw/day (actual dose received),it is regarded that at concentrations lower than 130 mg/kg bw/day (actual dose received) there will be no fetotoxicity when administered orally.

Justification for classification or non-classification

From the NOAEL and LOAEL values obtained for 3-Chloroaniline for toxicity to reproduction as well as developmental toxicity, it is considered that the chemical does not qualify for classification as a reproductive or developmental toxicant.

Additional information