N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP study, comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine

EC Number:

212-344-0

EC Name:

N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine

Cas Number:

793-24-8

Molecular formula:

C18H24N2

IUPAC Name:

N1-(4-methylpentan-2-yl)-N4-phenylbenzene-1,4-diamine

Details on test material:

Santoflex 13, purity: 100%

Test animals

Species:

rat

Strain:

Sprague-Dawley

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

yes

Details on mating procedure:

positve mating was confirmed by the presence of a copulatory plug

Duration of treatment / exposure:

GD 6 - 15

Frequency of treatment:

once daily

Duration of test:

study termination on gestation day 20

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

Sex: female
Duration of test: sacrifice on GD 20

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

50 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

LOAEL

Effect level:

100 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Mortality:

Survival was 100% in all study groups.

No abortions or premature deliveries occurred during the study period. The pregnancy rate was 80% in the control group and 92% in the other study groups.

Clinical signs:

Clinical signs which could be related to test article administration occurred during the treatment period in the mid and high dose groups. These observations consisted of salivation prior to dosing, soft stool, diarrhea, green fecal discoloration and green staining of the anogenital fur. The incidence of the findings was dose-related in the 100 and 250 mg/kg/day groups.

Soft stool, salivation prior to dosing and clear wet material around the mouth were each observed in one animal on one day during the treatment period in the low dose group. These clinical signs cannot be attributed to administration of the test compound in the 50 mg/kg/day group on the basis of this incidence.

BODY WEIGHTS

Maternal body weights and maternal body weight gain were comparable between the control, low and high dose groups.

In the 100 mg/kg/day group, mean body weights were slightly increased on gestation days 12, 16 and 20, and mean body weight gains were slightly to moderately increased during gestation days 9-12, 16-20, 6-16 and 0-20. The mean values were statistically significant when compared with the control group. These differences were probably due to an unusually large litter size in this group, a condition which was not related to SANTOFLEX 13 administration.

FOOD CONSUMPTION

Mean food consumption, evaluated as g/animal/day and g/kg/day, was comparable between the low dose group and the vehicle control group throughout the study.

In the mid dose group, food consumption was increased with statistical significance during gestation days 9-12 and 16-20 (g/animal/day). This effect corresponds to the body weight increase noted at this dose level and is considered due to an unusually large litter size.

In the 250 mg/kg/day group, mean food consumption was decreased during the first three days of treatment when compared to the vehicle control group; evaluated as g/kg/day this decrease was statistically significant. During the remainder of the treatment period (gestation days 9-12 and 12-16) food consumption was slightly increased when compared to the control group although none of the values were statistically significant during these intervals. After the treatment period (gestation days 16-20), food intake in the 250 mg/kg/day group was significantly increased when evaluated as g/animal/day and g/kg/day.

PATHOLOGY

No morphopathological changes which could be attributed to the administration of SANTOFLEX 13 were observed in any of the treated animals. Rough and firm spleen was noted in one animal in the 100 mg/kg/day group. This type of lesion is not unusual for rats of this strain and age.

GESTATION DAY 20 CESAREAN SECTION DATA

No differences which could be associated with the administration of SANTOFLEX 13 were observed between the control and the treated groups with respect to numbers of viable fetuses, early and late resorptions, fetal sex ratio and fetal weights. A significant increase (p < 0.05) in the mean numbers of viable fetuses, implantation sites and corpora lutea occurred in the 100 mg/kg/day group when compared with the control group. Since ovulation and implantation occur prior to treatment, these differences were not related to SANTOFLEX 13 administration.

FETAL MORPHOLOGICAL EVALUATION

The type of malformations occurring in this study and their frequency were not indicative of a teratogenic response. One fetus in the control group had a diaphragmatic hernia. Two fetuses from two litters in the 100 mg/kg/day group were malformed. The defects observed in this group included one instance of unilateral microphthalmia and one fetus with multiple anomalies. No fetal malformations were observed in the 250 mg/kg/day group.

Small numerical increases (non-statistically significant) in the incidence of a number of skeletal variations were noted in the treated groups. These included an increase in the percentage of fetuses with sternebrae no. 5 and/or 6 unossified and malaligned sternebrae (100 and 250 mg/kg/day groups), sternebrae no. 1, 2, 3 and/or 4 unossified and 27 presacral vertebrae (50, 100 and 250 mg/kg/day groups) and 7th cervical ribs (250 mg/kg/day group). These are common developmental variations in this species and all have been observed to occur with similar incidence in the historical data. The remaining developmental variations occurred with similar frequency between the control group and the treated groups.