Registration Dossier

Administrative data

Description of key information

Groups of 10 male and 10 female F344/N rats and B6C3F1 mcie were administered 0, 10, 20, 40, 80, or 160 mg m-chloroaniline per kilogram body weight in dilute hydrochloric acid by gavage 5 days a week for 13 weeks. Animals were evaluated for hematology, clinical chemistry, histopathology, and reproductive system effects.
Groups of 16 mal Crl:CD rats were exposed head-only, 6 hrs/day, 5 days/week, for 2 weeks to either 6, 30 or 50 ppm( = ca. 31.8, 159 or 265 mg/m³) m-chloroaniline. A control group was simultaneously exposed to air only. Animals were evaluated for clinical and histopathological lesions following 10 exposures and after a 14-day recovery period.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Reason / purpose:
reference to same study
Reference:
Composition 0
Composition 0
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Principles of method if other than guideline:
Groups of 10 male and 10 female F344/N rats were administered 0, 10, 20, 40, 80, or 160 mg m-chloroaniline per kilogram body weight in dilute hydrochloric acid by gavage 5 days a week for 13 weeks. Animals were evaluated for hematology, clinical chemistry, histopathology, and reproductive system effects.
GLP compliance:
yes
Test material information:
Composition 1
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Route of administration:
oral: gavage
Vehicle:
other: 1 M hydrochloric acid
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days a week for 13 weeks
Remarks:
Doses / Concentrations:
0, 10, 20, 40, 80, or 160 mg m-chloroaniline per kilogram body weight
Basis:
actual ingested
No. of animals per sex per dose:
10 male and 10 female rats/dose
Control animals:
yes, concurrent vehicle
Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Hematotoxicity
Critical effects observed:
not specified

The hematopoietic system was the target of m-chloroaniline in rats. One female rat in the 160 mg/kg m-chloroaniline group during week 12, possibly secondary to methemoglobinemia. The final mean body weights and weight gains of male rats in the highest dose group were significantly less than those of the respective controls. Clinical findings of toxicity included a transient bluish discoloration of the genital and footpad regions in rats administered m-chloroaniline; these effects occurred primarily in the 80 and 160 mg/kg groups. Methemoglobin concentrations were increased in dosed rats and resulted in a secondary anemia; the severity of the anemia increased with increasing dose. Microscopic lesions considered related to chemical administration in included hemosiderin pigmentation in the bone marrow, kidney, liver, and spleen; hematopoiesis in the liver and spleen; and erythroid cell hyperplasia in the bone marrow. These lesions reflected the response to hemolytic anemia and methemoglobinemia induced by chloroanilines.

Executive summary:

Groups of 10 male and 10 female F344/N rats were administered 0, 10, 20, 40, 80, or 160 mg m-chloroaniline per kilogram body weight in dilute hydrochloric acid by gavage 5 days a week for 13 weeks. Animals were evaluated for hematology, clinical chemistry, histopathology, and reproductive system effects.

The hematopoietic system was the target of m-chloroaniline in rats. One female rat in the 160 mg/kg m-chloroaniline group during week 12, possibly secondary to methemoglobinemia. The final mean body weights and weight gains of male rats in the highest dose group were significantly less than those of the respective controls. Clinical findings of toxicity included a transient bluish discoloration of the genital and footpad regions in rats administered m-chloroaniline; these effects occurred primarily in the 80 and 160 mg/kg groups. Methemoglobin concentrations were increased in dosed rats and resulted in a secondary anemia; the severity of the anemia increased with increasing dose. Microscopic lesions considered related to chemical administration in included hemosiderin pigmentation in the bone marrow, kidney, liver, and spleen; hematopoiesis in the liver and spleen; and erythroid cell hyperplasia in the bone marrow. These lesions reflected the response to hemolytic anemia and methemoglobinemia induced by chloroanilines.

The LOAEL is 10 mg/kg bw in this study.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
10 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Guideline study according OECD 408

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: secondary literature
Reference:
Composition 0
Principles of method if other than guideline:
Groups of 16 mal Crl:CD rats were exposed head-only, 6 hrs/day, 5 days/week, for 2 weeks to either 6, 30 or 50 ppm( = ca. 31.8, 159 or 265 mg/m³) m-chloroaniline. A control group was simultaneously exposed to air only. Animals were evaluated for clinical and histopathological lesions following 10 exposures and after a 14-day recovery period.
GLP compliance:
no
Test material information:
Composition 1
Species:
rat
Strain:
Crj: CD(SD)
Sex:
male
Route of administration:
other: vapour/aerosol
Type of inhalation exposure:
head only
Vehicle:
air
Remarks on MMAD:
MMAD / GSD: no data
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
2 weeks
Frequency of treatment:
6 hrs/day, 5 days/week, for 2 weeks
Remarks:
Doses / Concentrations:
6, 30 or 50 ppm( = ca. 31.8, 159 or 265 mg/m³) m-chloroaniline
Basis:
nominal conc.
No. of animals per sex per dose:
16 animals/dose
Control animals:
yes, concurrent vehicle
Dose descriptor:
LOAEC
Effect level:
32 mg/L air (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: extramedullary hematopoesis, hemosiderin deposits in spleen, methemoglobinemia
Critical effects observed:
not specified

During and immediately following exposure, rats in the 30 and 50 ppm dose groups were slight to moderately cyanotic. Slight increase in body weights were observed in all test groups during exposure and recovery.

Clinical pathological examinations revealed a dose-dependent effect of m-chloroaniline on several hematologic parameters. Decrease in erythrocyte count, hemoglobin content, and hematocrit and increase in leucocytes, immature erythrocytes, mean cell volume and mean cell hemoglobin resulted from 10 exposures to all exposure levels.

Pathologic examinations revealed dose-dependent microscopic changes in hematopoetic tissues consistent with the development of hemolytic anemia and subsequent extramodullary hematopoesis.

Executive summary:

Groups of 16 mal Crl:CD rats were exposed head-only, 6 hrs/day, 5 days/week, for 2 weeks to either 6, 30 or 50 ppm( = ca. 31.8, 159 or 265 mg/m³) m-chloroaniline. A control group was simultaneously exposed to air only. animals were evaluated for clinical and histopathological lesions following 10 exposures and after a 14-day recovery period.

During and immediately following exposure, rats in the 30 and 50 ppm dose groups were slight to moderately cyanotic. Slight increase in body weights were observed in all test groups during exposure and recovery.

Clinical pathological examinations revealed a dose-dependent effect of m-chloroaniline on several hematologic parameters. Decrease in erythrocyte count, hemoglobin content, and hematocrit and increase in leucocytes, immature erythrocytes, mean cell volume and mean cell hemoglobin resulted from 10 exposures to all exposure levels.

Pathologic examinations revealed dose-dependent microscopic changes in hematopoetic tissues consistent with the development of hemolytic anemia and subsequent extramodullary hematopoesis.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEC
32 mg/m³
Study duration:
subacute
Species:
rat
Quality of whole database:
secondary literature - therefore reliability 4

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

Additional information

In the subchronic oral gavage study, the hematopoietic system was the target of m-chloroaniline in rats and mice. Methemoglobin concentrations were increased in dosed rats and mice studies and resulted in a secondary anemia; the severity of the anemia increased with increasing dose. Microscopic lesions considered related to chemical administration in rats and mice included hemosiderin pigmentation in the bone marrow, kidney, liver, and spleen; hematopoiesis in the liver and spleen; and erythroid cell hyperplasia in the bone marrow. These lesions reflected the response to hemolytic anemia and methemoglobinemia induced by the chloroanilines. In both studies the LOAEL is 10 mg/kg bw (lowest applied dose).

In the subacute inhalation study, during and immediately following exposure, rats in the 30 and 50 ppm dose groups were slight to moderately cyanotic. Clinical pathological examinations revealed a dose-dependent effect of m-chloroaniline on several hematologic parameters. Decrease in erythrocyte count, hemoglobin content, and hematocrit and increase in leucocytes, immature erythrocytes, mean cell volume and mean cell hemoglobin resulted from 10 exposures to all exposure levels. Pathologic examinations revealed dose-dependent microscopic changes in hematopoetic tissues consistent with the development of hemolytic anemia and subsequent extramodullary hematopoesis. The LOAEL was 32 mg/m³ (lowest applied dose).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
2 valid guideline studies on rats and mice conducted by the same test laboratory are available. m-chloroaniline has the same pattern of toxicity in rats and mice - but rats rats are more sensitive towards the test substance than mice.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
only repeated dose results from a secondary soucre for inhalation is available

Repeated dose toxicity: via oral route - systemic effects (target organ) cardiovascular / hematological: other

Repeated dose toxicity: inhalation - systemic effects (target organ) cardiovascular / hematological: other

Justification for classification or non-classification

In the 90-day oral gavage studies in rats and mice, the hematopoietic system was the target of m-chloroaniline. Hematotoxicity occured at all doses (LOAEL = 10 mg/kg bw).

In the 14 day inhalation study in rats, clinical pathological examinations revealed a dose-dependent effect of m-chloroaniline on several hematologic parameters. Pathologic examinations revealed dose-dependent microscopic changes in hematopoetic tissues consistent with the development of hemolytic anemia and subsequent extramodullary hematopoesis. Hematotoxicity occured at all doses (LOAEL = 32 mg/m³).

Based on these results, a classification as R48/23 (GHS: STOT RE 1; H372) is justified.