4-isopropylaniline

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

experimental study

Adequacy of study:

other information

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Original study report is not available but available documentation is sufficient for assessment

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-isopropylaniline

EC Number:

202-797-2

EC Name:

4-isopropylaniline

Cas Number:

99-88-7

Molecular formula:

C9H13N

IUPAC Name:

4-(propan-2-yl)aniline

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): 4-(1-Methylethyl)aniline
- Analytical purity: 99.27 wt%

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

as required by respective guideline

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 48 days
Females: from 14 days before mating to day 3 of lactation (approximately 39 days)

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 6, 20 and 60 mg/kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

as required by the respective guideline

Positive control:

no

Examinations

Observations and examinations performed and frequency:

clinical signs and mortailty
body weight development, food consumption. hematology and coagulation, blood chemistry data
copulation index, fertility index, estrous cycle, gestation index, delivery index

Sacrifice and pathology:

Males were killed at day 48, females on day 4 of lactation
relative and absolute organ weights, histological findings are reported

Other examinations:

findings of delivery in dams and observations of their pups

Statistics:

according to S. Gad and CS Weil: Statistics and experimental design for toxicologists, Telford Press, New Jersey, 1986, pp 43-45

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

effects observed, treatment-related

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

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

Details on results:

CLINICAL SIGNS AND MORTALITY
1 female was found dead in the 60 mg/kg group at day 25 (?) of gestation.
Anemic eyeballs and salivation were observed in the 20 mg/kg or more groups in both sexes and pallor in the 60 mg/kg group was noted in females during gestation period.

BODY WEIGHT AND WEIGHT GAIN
Decrease in the 20 mg/kg or more groups in males and in the 60 mg/kg group in females during gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Decrease of food consumption in the 60 mg/kg group in males during the early administration period

HAEMATOLOGY
Males:significant increase in methaemoglobin at 20 mg/kg or more
HCT, HGB, RBC and MCHC significantly decreased and MCV, MCH, PLT and RC significantly increased at 60 mg/kg

ORGAN WEIGHTS (relative, significant)
males: Spleen weight increases significantly at 60 mg/kg and liver and kidneys at 20 or more mg/kg bw
females: Liver weight increases at 60 mg/kg bw and spleen at 20 mg/kg bw or more

GROSS PATHOLOGY
Blackening and enlargement of spleen at 20 mg/kg bw or more in both sexes.

HISTOPATHOLOGY: NON-NEOPLASTIC
Increases of hematopoiesis in bone marrow, congestion, deposits of pigment and extramedullary hematopoiesis in the spleen at 20 or more mg/kg in both sexes. Extramedullary hematopoiesis in the liver at 60 mg/kg in males and 20 or more mg/kg in females.
Deposits of pigment and hypertrophy of hepatocytes in both sexes at 60 mg/kg.

for effects on reproduction : see the respective section

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

6 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

LOAEL

Effect level:

20 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: clinical signs of toxicity, reduction of body weight, organ weight increases and hematological changes were observed in the group dosed with 20 mg/kg bodyweight.

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

p-Isopropylanilin was studied for oral toxicity in rats in an OECD (422) combined repeat dose reproductive /developmental toxicity screening test at doses of 0, 6, 20, and 60 mg/kg bw/day. With regard to general toxicity the NOAEL was 6 mg/kg bw/day based on clinical signs of toxicity, reduction of body weight, organ weight increases and hematological changes which were observed in the groups dosed with 20 mg/kg bodyweight or more.