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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
not relevant
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1992
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:
1992
Report Date:
1992

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no

Test material

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

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
water
Details on exposure:
In this assessment of the effect of ucb L059, a CNS agent, on the
fertility and general reproductive performance of the rat, dosages of O
(Control), 70, 350 and 1800 mg/kg were administered once per day by
gavage. Thirty parent males per group were dosed for 9 weeks prior to
pairing and through to termination. Thirty females per group were
dosed for 2 weeks prior to pairing and through to termination either on
Day 20 of pregnancy or after rearing their young to weaning.
On Day 21 post partum, 12 male and 12 female offspring per group were
selected to form the basis of an F1 generation in which general and
behavioral development, and reproductive capacity were assessed.
Apart from possible exposure in utero and/or through the mothers’ milk,
F1 generation animals received n—o direct treatment.
Details on mating procedure:
During the mating
female in plastic
At the end of the
UCB 389/911362
period, rats were housed on the basis of one male to one
breeding cages (North Kent Plastics, RM-2 type).
mating period the males were rehoused with their former
cagemates in metal cages (Bowman@) and the females were housed in
individual breeding cages (North Kent Plastics, RM-2 type) prior to
sacrifice of selected animals on Day 20 of pregnancy or for the birth and
rearing of young of remaining females.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see ADDENDUM 7 testreport
Duration of treatment / exposure:
dosages of O
(Control), 70, 350 and 1800 mg/kg were administered once per day by
gavage. Thirty parent males per group were dosed for 9 weeks prior to
pairing and through to termination. Thirty females per group were
dosed for 2 weeks prior to pairing and through to termination either on
Day 20 of pregnancy or after rearing their young to weaning.
On Day 21 post partum, 12 male and 12 female offspring per group were
selected to form the basis of an F1 generation in which general and
behavioral development, and reproductive capacity were assessed.
Apart from possible exposure in utero and/or through the mothers’ milk,
F1 generation animals received n—o direct treatment.
Frequency of treatment:
Parent males per group were dosed for 9 weeks prior to pairing and through to termination
Females per group were dosed for 2 weeks prior to pairing and through to termination
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:
30
Control animals:
yes
yes, plain diet

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

It is concluded that, whilst the mating performance and fertility of FO
adult animals was unaffected by treatment at dosages up to 1800 mg/kg/day

Effect levels (P0)

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:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
food efficiency
water consumption and compound intake
ophthalmological examination
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
neuropathology
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
effects on the offspring were apparent at 350 and 1800 mg/kg/day. The no
effect level for the general and behavioral development of their offspring
was 70 mg/kg/day.

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Liver, kidney
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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:
effects observed, treatment-related
Description (incidence and severity):
Kidney
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Liver, kidney
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Liver, kidney
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Liver, kidney
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 75 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs

Target system / organ toxicity (F1)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
75 mg/kg bw/day (nominal)
Organ:
kidney
liver
Treatment related:
yes
Dose response relationship:
not specified
Relevant for humans:
yes

Overall reproductive toxicity

Key result
Reproductive effects observed:
no
Lowest effective dose / conc.:
70 mg/kg bw/day
Treatment related:
yes

Applicant's summary and conclusion

Conclusions:
It is concluded that, whilst the mating performance and fertility of F0 adult animals was unaffected by treatment at dosages up to 1800 mg/kg/day,
effects on their offspring were apparent at 350 and 1800 mg/kg/day. The no effect level for the general and behavioral development of their offspring
was 70 mg/kg/day.
Executive summary:

This report describes an experiment performed to assess the effect of

ucb L059, a CNS agent, on fertility and general reproductive performance of

the rat and on post natal development and reproductive capacity of the F1

offspring when administered by gavage to FO males and females.

Dosages of O (Control), 70, 350 and 1800 mg/kg/day were chosen based on the

results of a one year oral toxicity study in the rat using these dosages

(UCB/227). In this study (UCB/227) no effect was seen on bodyweight or food

intake, there were post-dose clinical signs of salivation and “paddling” of

forepaws and lethargy at 1800 and 350 mg/kg/day only. The liver and kidneys

were identified as target organs with rats given 70 mg/kg/day being

essentially unaffected. The oral route was chosen by the Sponsor, this

being the intended route of human exposure.

A single batch of ucb L059 was used for this study (designated 901; received

in these laboratories 8 August 1990, 28 November 1990 and 13 March 1991;

purity 99.9%, with an expiry date of June 1995). The test material was

supplied as a white crystalline powder which was stored at room temperature

in the dark. A certificate of analysis is presented as Addendum 6. Samples

of dose solutions were taken on three occasions for analysis of achieved

concentration. Results of these analyses performed by the Sponsor are

presented as Addendum 7.