N2-acetyl-N-benzyl-O-methyl-L-serinamide

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Study period:

2011

Reliability:

1 (reliable without restriction)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Sprague-Dawley

Sex:

female

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)

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

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: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

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

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

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:

no effects observed

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

Key result

Reproductive effects observed:

no

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.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2011

Reliability:

1 (reliable without restriction)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Version / remarks:

Oral (BID Gavage) Pre- and
Postnatal Development Study in Sprague Dawley Rats

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Crj: CD(SD)

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)

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

Maternal examinations:

In the 200 mg/kg/day group, 2 females were euthanized in extremis on gestation days 10 and
23 and 1 female was found dead on lactation day 8. In addition, 8 females in this group had
total litter loss during lactation days 0-5. Relevant clinical findings observed for these
females prior to death/euthanasia at approximately 1 hour following each daily dose. These findings consisted primarily of
behavior-related findings (prostration, hunched posture, hindlimbs splayed, rocking, lurching,
or swaying while ambulating, impaired use of hindlimbs, and body drags [abdomen touches
surface]) and body pale, body cool to touch, and red and/or clear material around the nose
and/or mouth and were noted 4-17 days prior to death/euthanasia/total litter loss. Due to
mortality observed in the 200 mg/kg/day group animals assigned to the pre- and postnatal
phase, 7 dams and their litters in the 200 mg/kg/day group previously assigned to the
toxicokinetic phase were transferred to the main study phase on lactation day 8 or 9. With the
exception of 1, 2, and 2 females in the control, 50, and 200 mg/kg/day groups, respectively,
that failed to deliver, all other females survived to lactation day 21.
Test item-related excreta-related findings of light brown and yellow feces and/or decreased
defecation were observed for females that were found dead, euthanized in extremis, with total
litter loss, failed to deliver, or that survived to the scheduled necropsy in the 50, 100, and
200 mg/kg/day groups at the daily examinations beginning as early as gestation day 7 and
generally continuing through lactation day 7; the decreased defecation correlated with the
reduced body weight gains and food consumption noted for these females. Test item-related
clinical findings, including behavior-related findings (prostration, rocking, lurching, or
swaying while ambulating, hunched posture, hindlimbs splayed, body drags [abdomen makes
contact with surface], impaired use of hindlimbs), body cool to touch, body pale, red and/or
clear material around the nose and/or mouth, dilated pupils were observed in the
200 mg/kg/day group approximately 1 hour following each daily dose administration
generally during gestation day 6 through lactation day 20.

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Mean body weight losses and lower mean body weight gains
and food consumption at 100 and 200 mg/kg/day

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

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

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

no effects observed

Changes in number of pregnant:

no effects observed

Other effects:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

ca. 50 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

Fetal body weight changes:

no effects observed

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

Key result

Dose descriptor:

NOAEL

Effect level:

>= 200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: decreased learning

Key result

Developmental effects observed:

no

Lowest effective dose / conc.:

200 mg/kg bw/day

Treatment related:

yes

Conclusions:

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.

Executive summary:

In the 200 mg/kg/day group, 2 females were euthanized in extremis on gestation days 10 and

23, 8 females had total litter loss during lactation days 0-5, and 1 female was found dead on

lactation day 8. It was therefore decided to transfer 7 dams and their litters that were

originally assigned to the toxicokinetic phase to the main study phase, in order to retain

enough animals in the high-dose group. The transfer was done on lactation day 8 or 9. Test

item-related clinical findings were observed for females in the 200 mg/kg/day group that were

found dead, euthanized in extremis, with total litter loss, failed to deliver, or that survived to

the scheduled necropsy. These findings included behavior-related findings (prostration,

rocking, lurching, or swaying while ambulating, hunched posture, hindlimbs splayed, body

drags, impaired use of hindlimbs), body cool to touch, body pale, red and/or clear material

around the nose and/or mouth, and dilated pupils were noted approximately 1 hour following

each daily dose administration generally throughout the treatment period. In addition, test

item-related, non-adverse excreta-related findings (light brown and/or yellow feces and

decreased defecation) were observed in the 50, 100, and 200 mg/kg/day groups at the daily

examinations generally throughout the gestation treatment period until lactation day 7.

The pregnancy rates in the control, 50, 100, and 200 mg/kg/day groups were unaffected by

test item administration.

In the 100 and 200 mg/kg/day F0 groups, mean body weight losses (4 g and 16 g, respectively,

during gestation days 6-9), lower mean body weight gains (13.3% and 41.6%, respectively,

during gestation days 6-20), lower mean body weights on gestation day 20 (5.0% and 12.6%,

respectively), and lower mean food consumption (13.0% and 34.8% during gestation

days 6-20) were measured over the gestation period compared to the control group. The

decrements in mean body weights generally continued through lactation day 4 in the

200 mg/kg/day group F0 females (up to 8.4%); mean body weights in the 100 mg/kg/day

group F0 females were similar to the control group during lactation. No effects on mean food

consumption were noted in the 100 and 200 mg/kg/day groups during lactation. In the

50 mg/kg/day group, test item-related, lower mean maternal body weight gain (80%) with

corresponding reduced mean food consumption (23.8%) were only noted during the first

3 days of test item administration (gestation days 6-9). This transient decrement in food

consumption early in gestation was sufficient to result in lower mean food consumption in the

50 mg/kg/day group when the entire gestation treatment period was evaluated. However,

mean body weight and body weight gain and food consumption in this group was similar to

the control group for the remainder of the gestation (gestation day 9 onwards) and lactation

treatment periods; therefore, the initial decrement in mean body weight gain and food

consumption noted in the 50 mg/kg/day group was considered to be test item-related but not

adverse.

Mean F0 gestation lengths and the process or parturition were not affected by test item

administration at any dosage level. No test item-related macroscopic findings were noted at

the F0 necropsy; mean numbers of implantation sites and unaccounted-for sites in the 50, 100,

and 200 mg/kg/day groups were similar to the control group.

Lower mean live litter size and mean F1 postnatal survival (including total litter loss) was

noted in the 200 mg/kg/day group. Lower mean body weight gains were noted in the

200 mg/kg/day F1 pups through PND 7, resulting in lower (up to 13.8% for males and

13.5% for females) mean body weights throughout the pre-weaning period. No test

item-related effects on the number of F1 pups born, the percentages of males at birth, the

general physical condition of the F1 pups at any dosage level, live litter size, F1 postnatal

survival, body weights, or body weight gains in the 50 and 100 mg/kg/day groups were noted.

No macroscopic findings that could be attributed to F0 maternal test item administration were

noted at any dosage level at the necropsy of F1 pups that were found dead, euthanized

in extremis or due to death of the dam, or at the scheduled necropsy on PND 21.

There were no effects on the ages of attainment of surface righting response, pinnal

detachment, incisor eruption, eye opening, balanopreputial separation, and vaginal patency at

any dosage level. No consistent dose-related trends were noted when detailed clinical

observation data were evaluated for PND 21 and 61.

In the 200 mg/kg/day group, the F1 females only exhibited transient decreased learning

performances in the Path B of the Biel maze assessments on PND 22. This effect was not

observed on PND 62, and it was therefore concluded that there were no persistent effects on

learning ability. There were no effects of F0 maternal test item administration observed on

locomotor activity and auditory startle responsiveness in the 50, 100, and 200 mg/kg/day

males and females, and learning and memory assessments in the F1 males and females in the

50 and 100 mg/kg/day groups and F1 males in the 200 mg/kg/day group.

There were no deaths or clinical findings in the F1 generation following weaning that could be

attributed to administration of the test item to the F0 females. Decrements in mean F1 body

weights noted for the 200 mg/kg/day group during the pre-weaning period continued to the

post-weaning period. Lower mean F1 body weights were noted for the 200 mg/kg/day group

males and females during the entire generation (males) or pre-mating period (females). Mean

body weight gain in the 200 mg/kg/day group males was lower than the control group during

PND 28-35 but was generally similar throughout the remainder of the F1 generation; mean

body weight gain in the 200 mg/kg/day group females was similar to the control group during

the pre-mating period. Mean F1 body weights and body weight gains for the 50 mg/kg/day

males and females and the 100 mg/kg/day group males and females during the post-weaning

period were unaffected by F0 maternal test item administration. Mean F1 gestation and

lactation body weight gains were similar to the control group in all test item-treated group.

However, the decrements in mean body weights continued generally throughout gestation in

the 200 mg/kg/day group and during lactation days 1-4 in the 200 mg/kg/day group. No

effects on mean body weights were noted in the 50 and 100 mg/kg/day group F1 females

during gestation or lactation.

There were no effects of F0 maternal test item administration on F1 reproductive performance,

gestation length, the process of parturition, macroscopic findings, or the mean numbers of

corpora lutea, implantation sites and unaccounted-for sites.

Lower mean final body weights were noted in the 200 mg/kg/day F1 males and females at the

scheduled necropsies on PND 72 and lactation day 10. There were no test item-related

macroscopic or microscopic changes in the central or peripheral nervous system or in the

pituitary (examined in males only), kidney, liver, lung, and heart in the F1 animals that were

exposed to the test item in utero and via maternal milk.

There were no effects of F0 maternal test item administration on the mean number of F2 pups

born, viability on PND 0, percentage of males at birth, postnatal survival, physical condition,

body weights, body weight gains, or necropsy findings of F2 pups that were found dead or

euthanized in extremis.

Control animals were not exposed to SPM 927 or it major metabolite, SPM 12809. Treated

F0 females were continuously exposed to both the parent compound and its major metabolite.

The extent of exposure to the metabolite represented 20% to 35% of the extent of exposure to

the parent compound throughout the study. The test item was rapidly absorbed. The

exposure – dose relationship was approximately proportional. The exposure to the parent

compound was higher at gestation day 18 compared to the first day of dosing and lactation

day 10. The exposure to the major metabolite was lower at the first day of treatment than on

gestation day 18 or lactation day 10. The F1 pups were exposed to lacosamide (SPM 927) and

to its major metabolite (SPM 12809) at all dose levels and the plasma concentrations were

similar in both genders. The exposure of the F1 pups to both parent compound and its

metabolite represented 6% to 8% of the exposure of the lactating F0 females, whatever the

dose.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available