Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study published in peer-reviewed journal.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Groups of 24 mated female rats were exposed to concentrations of 0, 125, 500, and 2000 mg/kg bw/d of test substance by oral gavage during days 6-15 of gestation. On day 20 of gestation, the animals were sacrificed and the uterine contents examined. Pups were removed by caesarean section and soft tissue and skeletal examinations performed.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Composition of test material, percentage of components: <1% C9, 16% C10, 43% C11, 40% C12, 1% C13, <1% C14; avg C11.26
- Analytical purity: 98.5

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 7 nights, if female was still not pregnant, she was moved to another male for an additional 7 nights, and then to a third male if needed
- Proof of pregnancy: vaginal plug or sperm in vaginal smear referred to as day 0 of pregnancy
- After successful mating each pregnant female was caged (how): individually
Duration of treatment / exposure:
days 6-15 of gestation
Frequency of treatment:
daily
Duration of test:
section on 20th of gestation
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 125, 500, 2000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
24 mated females rats/dose and control groups
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


BODY WEIGHT: Yes
- Time schedule for examinations: days 0, 6, 10, 12, 15, and 20 of gestation

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: complete post-mortem examination

Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of live and dead fetuses, sex of fetuses
Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Statistics:
Nair, RS, Auletta, CS, Schroeder, RE, and Johannsen, FR (1990). Chronic toxicity, oncogenic potential, and reproductive toxicity of p-nitroaniline in rats. Fundam. Appl. Toxicol. 15, 607-621.
Indices:
incidence of fetuses and litters with malformations and resorption sites

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Mean body weight gains were significantly decreased since the 10th day of gestation in the 2000 mg/kg bw/d group (p <= 0.01) and from the 12th to 15th day of gestation in the 500 mg/kg bw/d group; compensatory increases of weight gains occurred in the posttreatment period in these groups; food consumption was significantly reduced during treatment (p <= 0.01) and significantly increased after treatment in the 500 mg/kg bw/d (p <= 0.005) and 2000 mg/kg bw/d groups (p 0= 0.01).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEL
Effect level:
500 mg/kg bw/day
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
No treatment related increases in soft tissue malformations and variations were found; the incidence of fetuses with at least one ossification variation was significantly increased in the 2000 mg/kg/ bw/d group (p0.05): main variations were incomplete ossification of several cranial bones and vertebral elements and in addition in the 500 mg/kg bw/d group the incidence of rudimentary rib structures; a significant decrease of those variations in the 125 mg/kg bw/d group was not considered treatment related (p <= 0.05).

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
125 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

Incidence of Fetal Skeletal Alterations

Dose (mg/kg/day)

0

125

500

2000

Rudimentary ribs

20 (14)

15 (10)

48 (18)

52 (20)

Total fetuses (litters) with variations

82 (21)

54 (22)

82 (23)

106 (22)

% fetuses (litters) with variations

57.3 (91.3)

41.9 (95.7)

57.2 (100)

79.7 (100)

Applicant's summary and conclusion

Conclusions:
LAB was not classified as a teratogen by the authors.
Executive summary:

This study examined the potential developmental toxicity of the test substance. Groups of 24 mated female rats were exposed to concentrations of 0, 125, 500, and 2000 mg/kg bw/d of test substance by oral gavage during days 6-15 of gestation. On day 20 of gestation, the animals were sacrificed and the uterine contents examined. Pups were removed by caesarean section and soft tissue and skeletal examinations performed. The LOAEL for maternal toxicity was 500 mg/kg bw/day based on reduced body weight gain. The NOAEL for maternal toxicity was 125 mg/kg bw/day. The LOAEL for embryotoxicity was also 500 mg/kg bw/day based on increased incidence of incomplete ossification. The NOAEL for embryotoxicity was also 125 mg/kg bw/day. Since no embryotoxicity was seen at doses that were not toxic to the maternal animals, the test substance is not classified as teratogenic.