Registration Dossier

Administrative data

developmental toxicity
Type of information:
other: hydrolysis product
Adequacy of study:
other information
1 (reliable without restriction)

Data source

Reference Type:
review article or handbook

Materials and methods

Test guideline
according to
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:

Test material

Details on test material:

Test animals


Administration / exposure

Route of administration:
oral: gavage
Duration of treatment / exposure:
6d through 19 post coitum
Frequency of treatment:
Duration of test:
No. of animals per sex per dose:
25 time-mated female rats per dose

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:
Effect level:
60 mg/kg bw/day

Results (fetuses)

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables


Only pregnant dams or pregnant dams sacrificed at schedule were used for calculations. Animals which were totally or partially excluded were: 3 non-pregnant control animals; one non-pregnant animal from each dose group. No mortality was seen in any of the groups.

Low dose, 20 mg/kg bw/d:

No substance related effects seen.

Intermediate dose, 60 mg/kg bw/d:

No substance related effects seen, except slight but significant decrease of body weight gain on d 6-8 p.c.

High dose, 180 mg/kg bw/d:

Clinical data:

Transient salivation was noted in 6/25 animals during days 15-19 p.c. starting few minutes after dosing and lasting 15

to 20 min. Vaginal hemorrhage on d 20 was noted in one animal.

Salivation was regarded to be treatment related due to bad taste or local affection of the upper digestive tract, but was not assessed as an adverse or toxic effect.

Food intake, body weights:

Food intake was significantly reduced (-13% compared to controls) during a period at the beginning of treatment on d 6-8 p.c. Body weight gain was also statistically reduced compared to controls on d 6-8 p.c. (-45%) and d 17-20 p.c. (-34%). However, at the end of the treatment period body weight was comparable in all groups.

Findings were regarded as being substance-induced and reflecting direct adverse effects on dams (d 6-8) and on fetuses (d 17-20; resorptions, lowered fetal body weight).

Corrected body weight gain was comparable in all dose groups.

Terminal examination of dams:

Uterus weight was significantly reduced (-26% vs. controls). Significantly increased postimplantation loss (43% vs 8% in controls) was due to late resorptions. 3/24 females resorbed all implants during the last treatment days and had no live fetuses at termination. The number of live fetuses per litter was significantly reduced. Additionally the number of live male fetuses per litter was significantly reduced.

Examination of fetuses

Sex distribution was comparable to control animals in all treatment groups. In high dose animals, placental weight was increased (+22% vs. control), whereas mean fetal body weight was reduced (-14%, both sexes combined).

External malformations (anasarca and/or cleft palate) were significantly increased in high dose fetuses (13/132 fetuses; ca. 10%) in 7/21 litters (=33%), i.e. 9% versus 0% affected fetuses/litter in the control group.

Soft tissue variations (dilated renal pelvis and ureter) were statistically significantly increased compared with controls (27.1% vs. 6.4%).

Skeletal malformations (shortened scapula, bent radius/ulna, malpositioned and bipartite sternebra) were significantly increased; noted in 7/73 fetuses (=9.6%) in 5/21 litters (=24%), i.e. 7.8% vs. 1.1% affected fetuses/litter in the control group. Also, significant increase of several skeletal variations (mainly delays in the ossification process) was noted (98.4% affected fetuses/litter in high dose group vs. 91.1% in control group).

Applicant's summary and conclusion

Maternal toxicity was noted exclusively at 180 mg/kg bw/d as
substantiated by significantly reduced food intake at initiation of treatment and impaired body weight gains on days 6-8 p.c.. No signs of maternal toxicity were seen at 60
mg/kg bw/d and below.
Fetal development was adversely affected at 180 mg/kg bw/d as
substantiated by the high rate of late resorptions (3/24 animals showing complete resorption) which resulted in an elevated postimplantation loss and reduced fetal body weights.
At 180 mg/kg bw/d selective teratogenicity was indicated by increased occurrence of external and skeletal malformations and variations of which anasarca, cleft palate, shortened scapula, and incomplete or delayed ossifications were the most prominent. No increases were noted at 20 or 60 mg/kg bw/d.
Based on these findings NOAEL for maternal toxicity and for
prenatal developmental toxicity is 60 mg/kg/d