Registration Dossier

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Read across.

Data source

Reference
Reference Type:
publication
Title:
Evaluation of 60 Chemicals in a Preliminary Developmental Toxicity Test
Author:
Hardin B.D., Schuler R.L., Burg J.R., Booth G.M., Hazelden K.P., MacKenzie K.M., Piccirillo V.J. and Smith K.N.
Year:
1987
Bibliographic source:
Teratogenesis, Carcinogenesis, and Mutagenesis 7 : 29-48

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Exposure of female pregnant mice for 8 days for gestation day (gd) 6 to 13. Dosages were based on range-finders with non-pregnant mice. Data colleced were limited to daily observations,
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
Aniline
Aniline, p-nitro
Aniline, N,N-dimethyl

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
For dose-finding studies, in general virgin female mice were group housed (five per cage) throughout treatment, and observation periods.
An abbreviated quarantine of about 5 days was applied to approximate that in the reproductive studies. At the end of this quarantine, any animals judged unsuitable for the study were discarded. Remaining mice were weighed and randomly assigned to experimental groups with stratification by body weight.
In the reproductive phases, time-mated (primigravida) mice were received from the vendor on dg 1-3 (vaginal plug = day 0). On gd 6, mice judged unsuitable for the study were discarded. Remaining mice were weighed and randomly assigned to control and experimental groups with stratification by body weight. Mice were singly housed in solid-bottom boxes. Nesting material (Bed-0-Cobs, Sani-chip, San-i-cel, or sterilized white wood shavings) was changed once weekly, but no bedding change was made later than gd 17 to avoid disturbing mice near parturition.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Treatments were administered by gavage using a standard dosing volume of 10 ml/kg body weight. For the reproductive phase, the LD10 predicted on the basis of dose-finding results was the single dose used.
Analytical verification of doses or concentrations:
no
Details on mating procedure:
No details, mice were already pregnant at arrival (gd: 0-2).
Duration of treatment / exposure:
8 days of treatment (gd 6-13)
Frequency of treatment:
Once daily.
Duration of test:
Total duration of the experiment: 17 days (until gd 22)
No. of animals per sex per dose:
Females: 50
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOEL
Effect level:
560 mg/kg bw/day
Based on:
test mat.
Remarks:
Aniline
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOEL
Effect level:
1 200 mg/kg bw/day
Based on:
test mat.
Remarks:
p-nirtoaniline
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOEL
Effect level:
365 mg/kg bw/day
Based on:
test mat.
Remarks:
N,N-dimethylaniline
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOEL
Effect level:
560 mg/kg bw/day
Based on:
test mat.
Remarks:
Aniline
Basis for effect level:
other: developmental toxicity
Dose descriptor:
LOEL
Effect level:
1 200 mg/kg bw/day
Based on:
test mat.
Remarks:
p-nitroaniline
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOEL
Effect level:
365 mg/kg bw/day
Based on:
test mat.
Remarks:
N,N-dimethylaniline
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: See Table 1

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Table 1: Test results

Maternal          Pups         
Substance Dose dead/N B.W. change Viable litters Liveborn % survival Birth  Weight
 (mg/kg/d)  (g) per litter weight (g) gain (g)
Aniline 560 6/50 6.7 25/25 10.3 94 1.5 0.9
p-Nitroaniline 1200 21/50 3.6 11/16 5.0 78 1.5 0.8
N,N-dimethylaniline 365 3/50 8.2 36/37 8.6 98 1.7 1.1
Control (corn-oil) 0/50 9.0 41/41 9.5 99 1.6 1.1
See the original publication for the standard deviations.
Figures in red are significantly different from the respective control values. 

The concentrations tested for Aniline and p-Nitroaniline induced significant effects on maternal body weight, while the concentration tested for p-Nitroaniline induced significant mortality of pups.

Applicant's summary and conclusion

Conclusions:
The no effect levels for embryonal and fetal development of rats exposed in utero to aniline and p-nitroaniline are below concentrations of 560 and 1200 mg/kg bw/d, respectively. The NOEL of N,N-dimethylaniline for teratogenic effects in rats was at 365 mg/kg bw/d.