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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2011
Reliability:
1 (reliable without restriction)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2011
Report Date:
2011

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid, powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: Hypromellose
Duration of treatment / exposure:
From gestation day 6 through lactation day 20 for a total of 36-38 days of dose administration
Frequency of treatment:
Twice daily in equally divided doses (approximately 10 hours apart)
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
50 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes

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:
mortality observed, treatment-related
Description (incidence):
Increased mortality/moribundity at 200 mg/kg/day
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:
effects observed, treatment-related
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

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
ca. 200 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Based on lower body weights in the 200 mg/kg group F1 males and females, a
dosage level of 100 mg/kg/day was considered to be the NOAEL for F1 male and female
systemic toxicity.
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
Sexual maturation:
no effects observed
Anogenital distance (AGD):
no effects observed
Nipple retention in male pups:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Decreased learning performance was noted only for
females in the 200 mg/kg/day group during PND 22 Biel maze testing and there was no effect
noted for females or for males in this group or in any groups during the PND 62 assessment.
Although based on a transient effect in 1 sex, 100 mg/kg/day was considered to be the
NOAEL for F1 neurobehavioral assessment.

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
ca. 100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
developmental neurotoxicity

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Due to the absence of effects on reproductive performance at any dosage
level, a dosage of 200 mg/kg/day was considered to be the NOAEL for F1 reproductive
toxicity
Executive summary:

Three groups of bred female Crl:CD(SD) rats were administered the test item, lacosamide

(SPM 927), twice daily (bid) in 2 equally divided doses given approximately 10 hours apart,

by oral gavage.

Based on F0 clinical findings, mean body weight losses and lower mean body weight gains

and food consumption at 100 and 200 mg/kg/day and increased F0 mortality/moribundity at

200 mg/kg/day, the no-observed-adverse-effect level (NOAEL) for F0 maternal systemic

effects was considered to be 50 mg/kg/day of lacosamide (SPM 927). Based on lower F1

postnatal survival (including total litter loss) and lower birth weights for the 200 mg/kg/day

F1 males and females, the dosage level of 100 mg/kg/day was considered to be the NOAEL

for F1 developmental/neonatal toxicity. Decreased learning performance was noted only for

females in the 200 mg/kg/day group during PND 22 Biel maze testing and there was no effect

noted for females or for males in this group or in any groups during the PND 62 assessment.

Although based on a transient effect in 1 sex, 100 mg/kg/day was considered to be the

NOAEL for F1 neurobehavioral assessment. There were no test item-related macroscopic or

microscopic changes in the F1 animals, including no changes assessed in brain structure as

investigated by sensitive techniques (brain weights and macroscopic and microscopic

evaluations). Based on lower body weights in the 200 mg/kg group F1 males and females, a

dosage level of 100 mg/kg/day was considered to be the NOAEL for F1 male and female

systemic toxicity. Due to the absence of effects on reproductive performance at any dosage

level, a dosage of 200 mg/kg/day was considered to be the NOAEL for F1 reproductive

toxicity and F2 development.

The 50, 100, and 200 mg/kg/day dosage levels correspond to lacosamide AUC0-24 values on

lactation day 10 of 151, 277, and 517 μg*h/mL, respectively.

The study was performed in accordance with the GLP principles.