3-chloroaniline

Endpoint summary

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.

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