2,4-xylidine

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1983

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: None-guideline study following a scientifically sound study design (mechanistic study) with sufficient study reporting.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1983

Materials and methods

Test guideline

Test guideline 1

Qualifier:

no guideline available

Test guideline 2

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

yes

Remarks:

only males tested, 20 day study

Principles of method if other than guideline:

Method as described in Short et al., see reference.
The study was designed to provide a histopathologic evaluation of specific target organs following oral administration of the test substance for either 5, 10 or 20 days. Each rat in the 8 treatment groups and the group of controls were gavaged once daily. Each group contained 30 rats and all groups began treatment on the same day. The materials were administered orally via gavage needle without vehivle at 25 % of the estimated oral LD50. 10 rats out of each group were sacrificed at 5 days (after 5 consecutive doses). Ten more were sacrificed at 10 days, and the final at 10 and 20 days, following continual daily dosing.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,4-xylidine

EC Number:

202-440-0

EC Name:

2,4-xylidine

Cas Number:

95-68-1

Molecular formula:

C8H11N

IUPAC Name:

2,4-dimethylaniline

Details on test material:

Source: Aldrich Chemical Co.
Purity: 98.7 %

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

- nine weeks of age
- 10d acclimation period
- 2 rats per cage
- 12hr light-cycle
- 72°F +/-2°F
- Purina rat chow and water were supplied ad libitum

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

The study was designed to provide a histopathologic evaluation of specific target organs following oral administration of the test substance for either 5, 10 or 20 days. Each rat in the 8 treatment groups and the group of controls were gavaged once daily. Each group contained 30 rats and all groups began treatment on the same day. The materials were administered orally via gavage needle without vehicle at 25 % (117 mg/kg bw/d) of the estimated oral LD50 (467 mg/kg bw). 10 rats out of each group were sacrificed at 5 days (after 5 consecutive doses). Ten more were sacrificed at 10 days, and the final at 10 and 20 days, following continual daily dosing.

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

5, 10 or 20 days

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
117mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

30 rats per substance, 10 sacrificed after 5d, 10 sacrificed after 10d and 10 sacrificed after 20d of expousre

Control animals:

yes, sham-exposed

Details on study design:

please refer to "Details on exposure"

Positive control:

no data

Examinations

Observations and examinations performed and frequency:

Daily observations of general health, estimates of food and water consumption, and body weights during acclimation and treatemt period

Sacrifice and pathology:

- 10 rats at day 5
- 10 rats at day 10
- 10 rats at day 20
- Exsanguination via cardiac puncture after being rendered unconcious in an atmosphere of CO2
- Liver, spleen, thyroid, urinary bladder and kidneys were removed, trimmed of fat, weighed and fixed in neutral buffered 10% formalin, as well as samples of trachea and esophagues
- Bone marrow impressions were made from a cross section of femur
- Histological sections were prepared and stained by hematoxylin and eosin by conventional methods
- Sections of liver, spleen and kidney were also stained with Prussian Blue for confirmation of hemosiderin scoring

Other examinations:

none

Statistics:

no data

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

thinness and rough hair

Mortality:

mortality observed, treatment-related

Description (incidence):

thinness and rough hair

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

depressed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

severely depressed

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

increased kidney and liver weight

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

mild tracheitis

Histopathological findings: neoplastic:

not specified

Details on results:

- 2 dead rats after 10d of dosing and 1 dead rat after 20d of dosing
- clinical signs comprised: thinness, rough hair coat

- body weight decreased
- spleen to body weight rations were increased, w/o specific changes in spleen weights
- liver weights and liver to body weight ratio was increased
- kidney weights were unchanged, with a slight increase in kidney to body weight ratio

- histopathological lesions: mild tracheitis, probably due to the administration procedure

- slight congestion of the spleen
- slight hemosiderosis in spleen

- toxic hepatopathy with extensive cloudy swelling, diffuse hepatocellular necrosis, early periacinar connective tissue proliferation, biliary hyperplasia, and periacinar vacuolar degeneration

Effect levels

Dose descriptor:

NOAEL

Effect level:

< 117 mg/kg bw/day (actual dose received)

Sex:

male

Basis for effect level:

other: changes in body weight and organs

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

Rats treated with 2,4 -Dimethylaniline had a toxic hepatopathy characterized by extensive cloudy swelling deffisue hepatocellular necrosis, early periacinar connective tissue proliferation, biliary hyperplasia, and periacinar vacuolar degeneration as described in article. In addition there were secret island of periacinar vacuolar degeneration that appeared as small islands of lipoid cells.

Applicant's summary and conclusion

Conclusions:

From the results presented in this publication a NOAEL for 2,4-Dimethylaniline is < 117 mg/kg bw/d based on severe hepatic effects.

Executive summary:

The study was designed to provide a histopathologic evaluation of specific target organs following oral administration of the test substance for either 5, 10 or 20 days. Each rat in the 8 treatment groups and the group of controls were gavaged once daily. Each group contained 30 rats and all groups began treatment on the same day. The materials were administered orally via gavage needle without vehicle at 25 % (117 mg/kg bw/d) of the estimated oral LD50 (467 mg/kg bw). 10 rats out of each group were sacrificed at 5 days (after 5 consecutive doses). Ten more were sacrificed at 10 days, and the final at 10 and 20 days, following continual daily dosing.

The following effects were observed:

2 dead rats after 10d of dosing and 1 dead rat after 20d of dosing

- clinical signs comprised: thinness, rough hair coat

- body weight decreased

- spleen to body weight rations were increased, w/o specific changes in spleen weights

- liver weights and liver to body weight ratio was increased

- kidney weights were unchanged, with a slight increase in kidney to body weight ratio

- histopathological lesions: mild tracheitis, probably due to the administration procedure

- slight congestion of the spleen

- slight hemosiderosis in spleen

- toxic hepatopathy with extensive cloudy swelling, diffuse hepatocellular necrosis, early periacinar connective tissue proliferation, biliary hyperplasia, and periacinar vacuolar degeneration.