4-isopropylaniline

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels

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 exposure:

as required ba the respective guideline

Details on mating procedure:

12 pairs were successfully mated

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 oral gavage

Details on study schedule:

as required by the respective guideline

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 ba the respective guideline

Positive control:

no

Examinations

Parental animals: Observations and examinations:

clinical signs and mortailty
body weight development, food consumption. hematology and coagulation, blood chemistry data

Oestrous cyclicity (parental animals):

duration of estrous cycle

Sperm parameters (parental animals):

no data

Litter observations:

No. of total pups born, No of total live pups born, sex ratio, No of total live pups on day 4, No of total dead pups born

Postmortem examinations (parental animals):

relative and absolute organ weights, histological findings are reported

Postmortem examinations (offspring):

no data

Statistics:

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

Reproductive indices:

copulation index, fertility index, gestation index, implantation index, delivery index

Offspring viability indices:

live birth index, viability index on day 4

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Details on results (P0)

---REPEAT DOSE TOXICITY
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: increase of methaemoglobin at 20 mg/kg or more
HCT, HGB, RBC and MCHC decreased and MCV, MCH, PLT and RC increased at 60 mg/kg
ORGAN WEIGHTS
Spleen weight increases at 60 mg/kg in males and at 20 or more mg/kg in females
Liver weight increases in males at 20 or more mg/kg, in females at 60 mg/kg
GROSS PATHOLOGY
Blackening and enlargement of spleen at 20 or more mg/kg 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.

---REPRODUCTIVEand DEVELOPMENTAL TOXICITY

In terms of reproductive toxicity no adverse effects were observed inestrous cycle, copulation and fertility results, findings for delivery and duration of gestation period in any treatment groups.
With regard to the effects on neonates, body weights of pups in both sexes and viability on day 4 of lactation in the 60 mg/kg bw -group were decreased

Effect levels (P0)

1

Dose descriptor:

NOAEL

Remarks:

for reproductive ability of parents

Effect level:

60 mg/kg bw/day (nominal)

Sex:

male/female

2

Dose descriptor:

other: NOAEL (general toxicity)

Effect level:

6 mg/kg bw/day

Sex:

male/female

Basis for effect level:

other: see respective section of repeated dose toxicity

Results: F1 generation

General toxicity (F1)

Clinical signs:

not specified

Mortality / viability:

not specified

Body weight and weight changes:

effects observed, treatment-related

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Details on results (F1)

With regard to the effects on neonates, body weights of pups in both sexes and viability on day 4 of lactation in the 60 mg/kg group were decreased.

Effect levels (F1)

Dose descriptor:

NOAEL

Remarks:

for developmental toxicity

Generation:

F1

Effect level:

20 mg/kg bw/day (nominal)

Sex:

male/female

Basis for effect level:

other: based on decreased viability on day 4 and body weights at 60 mg/kg bw

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

p-Isopropylanilin was studied for oral toxicity in rats in an OECD 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.In terms of reproductive toxicity no adverse effects were observed in estrous cycle, copulation and fertility results, findings for delivery and duration of gestation period in any treatment groups.With regard to the effects on neonates, body weights of pups in both sexes and viability on day 4 of lactation in the 60 mg/kg bw -group were decreased

Thus, the NOAEL (general toxicity )= 6 mg/kg bw/day; NOAEL(fertility)= 60 mg/kg bw/day; NOAEL(offspring)= 20 mg/kg bw/day