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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2002
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
test procedure in accordance with national standard methods with acceptable restrictions
Justification for type of information:
Read across, see declaration

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2002
Report date:
2002

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: internal protocol
GLP compliance:
yes (incl. QA statement)
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide
Cas Number:
357336-20-0
Molecular formula:
C11H20N2O2
IUPAC Name:
(2S)-2-[(4R)-2-Oxo-4-propyl-1-pyrrolidinyl]butanamide
Test material form:
solid: particulate/powder

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: suspension in the vehicle l% (w/v) methylcellulose 400cps in sterile pyrogen free water (water for irrigation).
Details on exposure:
The females were dosed twice daily at least 6 hours apart, by oral gavage, from Days 6 to 17 of pregnantcy, inclusive, and received half the daily dose at each administration. The administration was conducted using rubber catheters and disposable plastic syringes. A standard dose volume of 5 mL/kg bodyweight/sub-dose (10 mL/kg bodyweight/day) was given. The dose volume given to each animal was adjusted daily according to the daily bodyweight and dosing was conducted at approximately the same time each day.
Duration of treatment / exposure:
Days 6 to 17 of pregnant y
Frequency of treatment:
The females were dosed twice daily at least 6 hours apart
Doses / concentrationsopen allclose all
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
No. of animals per sex per dose:
6
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
The observations did not persist into the post-dosing period.
There were no clinical signs recorded in the groups receiving 150 or 300 mg/kg/day.
Mortality:
no mortality observed
Description (incidence):
There were no premature deaths during the study.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
here was a dosage-related increase in bodyweight gain, relative to Controls, between Days 6 and 7 of pregnancy (corresponding to Days 1 and 2 of dosing). This change achieved a statistical significance at 300 and 600 mg/kg/day (see Text Table 1). From Day 8 of pregnancy, the maternal bodyweight gain became similar between the Control group and groups receiving ucb 34714. Overall, at the end of the dosing period (Day 18 of pregnancy), there was no noteworthy difference in bodyweight gain between the Control group and groups receiving ucb 34714
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
here was a slight, statistically significant reduction (-9%, relative to Controls) in mean food consumption in the group receiving 600 mg/kg/day, over the period of Days 6 to 9 of pregnancy (corresponding to Days 1 to 4 of dosing) .From Day 9 and until Day 17 of pregnancy, there was no noteworthy difference between the Control group and groups receiving ucb 34714. After cessation of dosing, the food consumption was slightly increased between Days 17 and 20 (approximately +8V0, relative to Controls) in the groups that had received 300 or 600 mg/kg/day. These changes are summarised in Text Table 2. There was no effect of treatment on food consumption in females receiving 150 mg/kg/day.
Food efficiency:
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Immunological findings:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
There was no effect of maternal treatment on the mean number of corpora Iutea or implantations, the extent of post-implantation losses or the number of live foetuses per female in any of the groups receiving ucb 34714 when compared with the Controls.
Pre- and post-implantation loss:
effects observed, treatment-related
Description (incidence and severity):
There was no effect of maternal treatment on the mean number of corpora Iutea or implantations, the extent of post-implantation losses or the number of live foetuses per female in any of the groups receiving ucb 34714 when compared with the Controls.

There was a slight increase in the mean percent pre-implantation loss in the group receiving 600 mg/kg/day (13%), when compared with the Controls (9.3%). This was considered to be due to one female (number 75) which had a very high pre-implantation loss.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not examined
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
not examined
Other effects:
not examined
Details on maternal toxic effects:
In the main study groups, there were four females receiving 150 mg/kg/day which were not pregnant at necropsy (numbers 27, 34, 46 and 47). All other main study females were pregnant with live foetuses. In the satellite groups for toxicokinetic evaluation, one female. receiving 300 mg/kg/day (number 11O)and one receiving 600 mg/kg/day (number 126) were not pregnant at necropsy. All other satellite females were pregnant at necropsy.
There was no effect of maternal treatment on the mean number of corpora Iutea or implantations, the extent of post-implantation losses or the number of live foetuses per female in any of the groups receiving ucb 34714 when compared with the Controls.
There was a slight increase in the mean percent pre-implantation loss in the group receiving 600 mg/kg/day (13%), when compared with the Controls (9.3%). This was considered to be due to one female (number 75) which had a very high pre-implantation loss.

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 300 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
clinical signs

Maternal abnormalities

Key result
Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There was no effect of maternal treatment on the mean foetal, placental or gravid uterus weights or on the percentage of male foetuses in any of the groups receiving ucb 34714 when compared with the Controls.
n the group receiving 600 mg/kg/day there were four foetuses with major abnormalities, compared with no major abnormalities in the Control group. Two of these four abnormal foetuses were from the same litter (female number 75, that had macroscopic findings in the kidneys and a high pre-implantation loss) and had major abnormalities consisting of absent kidneys in one foetus, small kidneys and absence of a uterine horn in the other.
The two remaining abnormal foetuses were from two different litters (female numbers 84 and 94) and major abnormalities consisted of bifid sternum for one foetus and transposition of the aortic and pulmonary arch for the other.
In the groups receiving 150 or 300 mg/kg/day there were single incidence of foetuses with major abnormalities, malrotated hind-limb at 150 and absent kidney at 300mg/kg/day.
There were no treatment-related increases in the incidence of specific minor abnormalities or variants in any group receiving ucb 34714.
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 600 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes

Fetal abnormalities

Key result
Abnormalities:
effects observed, non-treatment-related

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
600 mg/kg bw/day (nominal)
Treatment related:
no
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
no
Relevant for humans:
yes

Applicant's summary and conclusion

Conclusions:
Pregnant females receiving oral doses of 150,300 or 600 mg/kg/day ucb 34714 as two equal daily sub-doses given 6 hours apart during the period of organogenesis, were continuously exposed to the parent compound at all dose levels. After 12 days of treatment, the extent of exposure and trough plasma concentrations (Czdh)were lower than on Day 1. Following single or repeated administration, the rate and extent of exposure increased less than proportionally with the increase in dose. However, the trough plasma levels increased more than proportionally with the increase in dose.
The high dose of 600 mg/kg/day induced clinical signs in the dams (post-dosing salivation and partially closed eyes) as well as a reduction in food consumption during the early stage of pregnancy. There were no noteworthy effects in the darns at the lower doses of 150 or 300 mg/kg/day. The treatment did not induce any effect on pregnancy data or on foetal development.
From the results obtained on this study the maternal ‘No Adverse Effect Level’ (NOAEL) was considered to be 300 mg/kg/day. The foetal/developmental ‘No Adverse Effect Level’ was considered to be 600 mglkgiday.
Executive summary:

Pregnant females receiving oral doses of 150, 300 or 600 mg/kg/day ucb 34714 during organogenesis were continuously exposed to the parent compound at all dose levels. After single and repeated administration of ucb 34714, the rate (Cmax) and extent (AUC (0-24h)) of exposure increased slightly less than proportionally to the dose. This could be related to a dose-dependent limitation in absorption and is consistent with previous reported data from the 4-week toxicity study (7). However, the trough plasma levels (CzJh) increased more than proportionally with the dose. After 12 days administration, the extent of exposure and trough plasma concentrations were lower than on Day 1. These observations, which are also consistent with previous data in non-pregnant rats (7), are possibly related to an increase in the metabolic clearance of ucb 34714.

At 600 mg/kg/day noteworthy maternal effects consisted of salivation and partially closed eyes in all females and a transient decrease in food consumption at the beginning of the treatment period. Salivation occurred immediately after dosing whereas partially closed eyes occurred between 1.25 and 1.5 hours post-dosing. The group mean food consumption was decreased by 9% relative to the Controls during the first three days of the dosing period. During the remaining dosing period, the food consumption was similar between the Control group and the group receiving 600 mg/kg/day. The overall bodyweight gain for the treatment period at 600 mg/kg/day was similar to that of the Controls. The only notable change consisted of a slight and transient increase in bodyweight gain, relative to Controls, between Days 6 and 7 of pregnancy.

At 300 mg/kg/day, the only notable maternal effect was a slight and transient increase in bodyweight gain between Days 6 and 7 of pregnancy. From Day 8, however, the bodyweight gain in this group was similar to that of the Controls. There were no maternal effects at 150 mglkglday.

There were four females receiving 150 mg/kg/day which were found to be not pregnant at necropsy. However, since there was no corresponding decrease in the pregnancy rate in females receiving higher dose levels and all other pregnancy parameters of the group receiving 150 m~kg/day were comparable to the Controls, this was considered not to be related to treatment.

At 600 mg/kg/day, four foetuses presented major abnormalities. However, two of these four abnormal foetuses were from the same litter (female 75) and the findings in both of these foetuses were similar in nature. Female 75 also had a relatively high pre-implantation loss and an abnormal kidney at necropsy. In view of the clustering of the abnormalities in this litter and their similar nature they were considered not to be related to treatment. The major abnormalities in the two remaining foetuses in this group and the two foetuses at lower dose levels (one in each of the groups receiving 150 or 300 mg/kg/day) were disparate in nature and were within the historical control ranges for these abnormalities. Therefore the incidence of major abnormalities in all groups were considered to be unrelated to treatment with ucb 34714.