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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:
1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study
Cross-reference
Reason / purpose:
read-across source

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Crj: CD(SD)

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
unchanged (no vehicle)
Details on exposure:
Treatment by gavage commenced on Day 15 of pregnancy and continued
daily up to Day 21 post partum. The animals were sacrificed on Day
post partum.
Dosage volumes were calculated for individual animals on Day 15 of
pregnancy and adjusted according to bodyweight within 24 hours of
delivery of litters.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Samples of dose solutions were
taken once (from formulations prepared for use on the first day of
treatment) for analysis by the Sponsor. Results are presented as
Addendum 6.
Details on mating procedure:
Sexually mature (8-10 weeks
weight range 200-220 g) Specific
Pathogen Free female rats (Crl: CD (SD) BR VAF/Plus strain) which were
time-mated to identified males of the same strain, were ordered from Charles
River UK Ltd., Manston Road, Margate, Kent. The day of mating, as judged by
the appearance of sperm in the vaginal smear or by the presence of a vaginal
plug, was considered as Day O of pregnancy.
A total of 45 time-mated females were delivered, weight range on
arrival was 186 - 260 g. An additional 5 animals were ordered for health
check purposes.
On arrival all animals were examined for abnormalities and for signs of
overt ill health. Those designated as health check animals were killed
within 24 hours after arrival at HRC and subjected to routine macroscopic
examination. Any abnormalities seen were processed immediately and examined
microscopically. Lungs, liver, kidneys, spleen and heart were preserved in
fixative, but not processed further. Their health status was considered
satisfactory (see Addendum 1).
The remaining animals were weighed on arrival and assigned a temporary
individual identification (by tail mark). They were weighed on Day 7 and
Day 13 of pregnancy when 32 (weight range 286 - 374 g) were assigned to ‘our
groups, each of 8 animals, by computerised stratified randomisation to give
approximately equal initial group mean bodyweights. The computerised
allocation was examined to ensure an acceptable distribution of the males to
which females were mated. Following allocation, the animals were earmarked
to give individual identification. Prior to the commencement of treatment,
all animals were inspected by a Veterinary Officer and considered to be of
satisfactory health status for the study. Excess animals were discarded
once
21°C
treatment had commenced
Duration of treatment / exposure:
Treatment by gavage commenced on Day 15 of pregnancy and continued
daily up to Day 21 post partum. The animals were sacrificed on Day
post partum.
Dosage volumes were calculated for individual animals on Day 15 of
pregnancy and adjusted according to bodyweight within 24 hours of
delivery of litters.
Frequency of treatment:
Daily
Duration of test:
Day 15 of pregnancy and continued daily up to Day 21 post partum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
70 mg/kg bw/day
Dose / conc.:
350 mg/kg bw/day
Dose / conc.:
1 800 mg/kg bw/day
No. of animals per sex per dose:
8 per dose
Control animals:
yes

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Description (incidence and severity):
Parent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Dermal irritation (if dermal study):
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Mortality:
no mortality observed
Description (incidence):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Body weight and weight changes:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Food efficiency:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Ophthalmological findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Haematological findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Urinalysis findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Behaviour (functional findings):
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Immunological findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Gross pathological findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Neuropathological findings:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Other effects:
no effects observed

Maternal developmental toxicity

Number of abortions:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Early or late resorptions:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Dead fetuses:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Other effects:
no effects observed
Description (incidence and severity):
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney
Details on maternal toxic effects:
arent females treated at 1800 mg/kg/day and, to a lesser extent, at
350 mg/kg/day showed post-dose salivation. No signs of reaction to
treatment were noted at 70 mg/kg/day. There were no obvious
treatment–related systemic effects on other maternal parameters as
assessed by water and food consumption, bodyweight change, duration of
pregnancy, macroscopic post mortem findings or liver and kidney

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 75 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Changes in sex ratio:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
External malformations:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Skeletal malformations:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Visceral malformations:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings
Other effects:
no effects observed
Description (incidence and severity):
Treatment of the parent female had no noticeable adverse effect on
litter parameters from birth to weaning, macroscopic post mortem
findings of offspring or absolute liver and kidney weights of
weanlings

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 1 800 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: highest dose no effect

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Within the context of this study the no effect level for observable
maternal response was 70 mg/kg/day while the no effect level for pre– and
post natal development was 1800 mg/kg/day.
Since 1800 mg/kg/day provides a multiple of 100 to 200 of the
anticipated human dose, it is considered that this dosage is suitable as a
high dosage for the main study.
Executive summary:

In this preliminary assessment of the effect of ucb L059, a CNS agent,

on the pregnant rat and her offspring during the peri– and post natal

period, dosages of O (Control), 70, 350 and 1800 mg/kg/day were

administered daily by gavage to females from Day 15 of pregnancy

through to weaning.

Females were allowed to litter and rear their young to weaning when

they were sacrificed and subjected to macroscopic post mortem

examination.

2. Parent females treated at 1800 mg/kg/day and, to a lesser extent, at

350 mg/kg/day showed post-dose salivation. No signs of reaction to

treatment were noted at 70 mg/kg/day. There were no obvious

treatment–related systemic effects on other maternal parameters as

assessed by water and food consumption, bodyweight change, duration of

pregnancy, macroscopic post mortem findings or liver and kidney

weights.

3. Treatment of the parent female had no noticeable adverse effect on

litter parameters from birth to weaning, macroscopic post mortem

findings of offspring or absolute liver and kidney weights of

weanlings.

Conclusion

Within the context of this study the no effect level for observable

maternal response was 70 mg/kg/day while the no effect level for pre– and

post natal development was 1800 mg/kg/day.

Since 1800 mg/kg/day provides a multiple of 100 to 200 of the

anticipated human dose, it is considered that this dosage is suitable as a

high dosage for the main study. The lower dosages will also be identical to

those employed in this preliminary study.

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