Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In this study, treatment of female rats with MK-0217 at a dose

level of 5 mg/kg/day was associated with protracted parturition,

and the same physical signs of toxicity, including dystocia, that

was observed in late gestation in two other studies of MK-0217 in

pregnant female rats at doses ranging from 5-15 mg/kg/day.

Pregnant rats in late gestation and lactation mobilize calcium

from the skeletal system in response to the increased demands for

this mineral by the rapidly developing fetuses and pups (Garner

et 21., J. Bone & Min. Res., J: 319, 1988). Treatment of female

rats with MK-0217 at high doses (25 mg/kg/day) for 15 days prior

to mating through Day 19 of gestation caused severe hypocalcemia

, a condition likely attributable to this drug being an inhibitor of calcium mobilization from the bone.

The physical signs of toxicity observed in the current study and in

the previous study were very likely a consequence

of hypocalcemia.

Based on the physical signs of toxicity, including dystocia, in

FO females and deaths of Fl pups, the no-effect dose level in

this study was 1.25 mg/kg/day.

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
15-5-1989 to 28-6-1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Purity was 99.3 percent as determined by HPLC analysis.
Dosing concentrations as well as the
stability of MK-0217 in vehicle (deionized water)
were confirmed by chemical analyses
as being satisfactory.
Species:
rat
Strain:
Sprague-Dawley
Details on species / strain selection:
Crl:CD (SD) BR
Sex:
female
Details on test animals and environmental conditions:
Source: Charles River Breeding Laboratories, Wilmington, MA
Age of Females at Beginning of Study: 10 weeks
Starting Weight Range (grams): 190-260
Identification Method: FO: ear notches, dye marking

Environmental Conditions:
During the pre-breeding, gestational, and lactational
periods, females were singly housed.
Up to Day 15 of gestation, the females were in hanging metal cages;
thereafter,plastic boxes for delivery were used.
Bedding in the plastic boxes consisted of wooden chips
(Beta chips, Northeastern Products Corp., Warrensburg, NY).
All FO females were housed at a temperature of 20-27c.
Timed lighting provided a12-hour light/12-hour dark cycle.
All rats had free access to Purina Certified Rodent Chow #5502 and tap water
throughout the study.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deionised
Details on mating procedure:
In the afternoon of the 15th day of treatment, the
females were placed with untreated males of the same
strain, one female with one male.
The female rats
were removed from the cages of the males after mating
was confirmed by the presence of a seminal plug in
the cage pan or vagina. The day a plug was found was
considered Day 0 of gestation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
MK-0217: Purity was 99.3 percent as determined by
HPLC analysis. Dosing concentrations as well as the
stability of MK-0217 in vehicle (deionized water)
were confirmed by chemical analyses
as being satisfactory
Duration of treatment / exposure:
Drug administration was once daily starting at 2
weeks prior to cohabitation for mating (15 doses in
all), during cohabitation, and through Day 20 of
gestation.
Frequency of treatment:
daily
Details on study schedule:
There were originally 30 FO females randomly
assigned to each group.
As soon as 23 females in
each group mated, they were selected for continuation
in the study. This was done to ensure that all
litter deliveries would start within as short a span
of days as possible.
The remainder of the females
were then sacrificed by C0
2
c- 624
gas inhalation and
discarded after a gross examination of the thoracic,
abdominal and pelvic viscera.
Dose / conc.:
0 mg/kg bw/day (nominal)
Dose / conc.:
0.5 mg/kg bw/day (actual dose received)
Dose / conc.:
1.25 mg/kg bw/day (actual dose received)
Dose / conc.:
5 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
30 reduced to 23 after mating
Control animals:
yes, concurrent vehicle
Details on study design:
The high dose, 5 mg/kg/day, was chosen because in a
previous oral fertility study of MK-0217 in female
rats this dosage was the minimum dosage tested and
was associated with dystocia. The mid
and low doses were selected to determine a dose level
which would not be associated with dystocia.
Parental animals: Observations and examinations:
Physical Signs:
FO females were examined daily for physical signs from
initiation of the study to sacrifice. Examinations for
postdosing signs were conducted 1 to 5 hours after each
treatment.
Body Weights:
Body weights of FO females were recorded as follows:
premating Days 1, 8 and 15; gestational Days 0, 6, 12,
16, 18, 20 and (if needed) 24; and on lactation Day 0.

Reproductive Performance and Fertility:
The following were recorded or calculated to evaluate
reproductive performance and status: average time to
mating (mean day of mating), incidence of pregnancy,
implants per female, parturition behavior,
postimplantation survival, date and time of delivery
(length of gestation), incidence of pregnant FO females
with live pups, and numbers of live and dead pups
delivered. Parturition behavior was observed on weekdays
on gestational Days 21 through 23 at 7:30 a.m., 10:30
a.m., 1:30 p.m. and 4:30p.m. On gestational Day 24 and
on weekends, the observations were made at 7:30 a.m. and
10:30 a.m.

The following were examined to determine if they should be
used as a covariate for the indicated parameter:
Body weights of FO females on prebreeding Day 1 (for
possible effects on body weight gains during prebreeding Days
1 to 15).
Number of live Fl pups/litter and length of the gestational
period of the FO females (for possible effects of pup body
weights on postnatal Day 0.

Parameters Analyzed:
( 1) FOFemales:
(a)Body WeightChanges: Premating: Days1 to 15
Oestrous cyclicity (parental animals):
Not examined
Sperm parameters (parental animals):
Not examined
Litter observations:
On postnatal Day 0 (day of delivery) the pups were counted,
weighed, externally examined, and sexed. On postnatal Days 3
to 5, all pups were sacrificed by C02 gas inhalation and
discarded without further examination.

Postmortem examinations (parental animals):
On postpartum Days 3 to 5, the FO females which
delivered were killed by C02
gas inhalation and had gross examinations performed by a pathologist on the thoracic,
abdominal, and pelvic viscera.
The numbers of uterine metria! glands were recorded.
These examination were also performed on the early death females.
Gross examination of unmated females was described earlier.
One nonpregnant control female was sacrificed on Day 24
of presumed gestation and grossly examined as above.
Postmortem examinations (offspring):
not examined
Statistics:
In statistically analyzing selected data, statistical
significance at P <= 0.05 was based on trend analysis after
rankit transformation.
The trend analysis determined if there was a significant (P <= 0.05) trend with increasing
dosage including all treatment groups. If there was a
significant (P <= 0.05) trend, data from the high dose group
was excluded and the trend test was repeated.
This process was repeated until the trend test was not significant
(P > 0.05).
The highest dosage level with no significant
(P > 0.05) trend was designated the NOSTASOT (no statistical
significance of trend)

Reproductive indices:
incidence of pregnancy,
implants
per female,
parturition behavior,
postimplantation survival, date and time of delivery
(length of gestation), incidence of pregnant FO females
with live pups,
Offspring viability indices:
numbers of live and dead pups
delivered.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Physical signs related to treatment were observed in 3
pregnant FO females in the 5 mg/kg/day group. Tremors
and labored breathing were observed in female 89-4167 in
this group on gestational Day 21 and the animal was
sacrificed as moribund on the same day. Female 89-4169
in the same group displayed the same above-described
physical signs on gestational Day 21 and was found dead
the morning of the next day. The third female in the
high dose group (89-4172) showed protracted parturition
(lasting from approximately 7:30a.m. to 1:30 p.m.).
There were no treatment-related signs in the other
drug-treated groups.
Female 1189-4101 in the low dose
group had a prolonged delivery, but since this was not
observed in the mid-dose group, it was not considered
treatment-related.
Mortality:
mortality observed, treatment-related
Description (incidence):
Tremors
and labored breathing were observed in female 89-4167 in
this group on gestational Day 21 and the animal was
sacrificed as moribund on the same day. Female 89-4169
in the same group displayed the same above-described
physical signs on gestational Day 21 and was found dead
the morning of the next day.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
There were no treatment-related effects on mean body
weight gains of FO females.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not examined
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
There was treatment-related protracted parturition in
the previously-illentioned high dose female (89-4172), but
there were no treatment-related effects on reproductive
performance or status as measured by mean day of mating,
incidence of pregnancy, length of gestation, numbers of
implants/female, or numbers of FO females with live
pups.
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1.25 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
reproductive performance
Clinical signs:
no effects observed
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The female in the high dose group which had protracted
parturition (89-4172) had a litter of 2 dead pups and 12
live. The death of these 2 pups was considered related
to treatment
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects on pup body
weights.
In the 5 mg/kg/day group, the postnatal Day 0 mean body
weight of Fl female pups was 6% less than that of the
control group and the difference was statistically
significant (P i 0.05). The mean Day 0 body weight of Fl
male pups was 4% less than that of controls, but this
difference was not statistically significant (P > 0.05).
The slight decreases in Day 0 body weights of the high
dose Fl pups, as compared to controls, were scattered
rather evenly throughout this group although in one
litter (89-4181) the pups were exceptionally small on Day
0, with body weights ranging from 4.0 to 5.0 grams.
Since the decrements in mean Fl pup body weights at
5 mg/kg/day were very small, and since in a previous oral
fertility study of MK-0217 in female rats (TT ii89-708-0)
the mean Fl male and female pup weights in the
5 mg/kg/day group on Day 0 were comparable to those of
the controls, the slight decreases in mean pup body
weights in the current study were not considered
treatment-related.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
Other effects:
not examined
Behaviour (functional findings):
not examined
Developmental immunotoxicity:
not examined
Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
5 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
yes
Conclusions:
In this study, treatment of female rats with MK-0217 at a dose
level of 5 mg/kg/day was associated with protracted parturition,
and the same physical signs of toxicity, including dystocia, that
was observed in late gestation in two other studies of MK-0217 in
pregnant female rats at doses ranging from 5-15 mg/kg/day.
Pregnant rats in late gestation and lactation mobilize calcium
from the skeletal system in response to the increased demands for
this mineral by the rapidly developing fetuses and pups (Garner
et 21., J. Bone & Min. Res., J: 319, 1988). Treatment of female
rats with MK-0217 at high doses (25 mg/kg/day) for 15 days prior
to mating through Day 19 of gestation caused severe hypocalcemia
, a condition likely attributable to this drug being an inhibitor of calcium mobilization from the bone.
The physical signs of toxicity observed in the current study and in
the previous study were very likely a consequence
of hypocalcemia.
Based on the physical signs of toxicity, including dystocia, in
FO females and deaths of Fl pups, the no-effect dose level in
this study was 1.25 mg/kg/day.
Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
1.25 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
two studies are avaialble, both conducted according to established scientific principles and GLP
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

Description of key information

In the 10.0 and 25.0 mg/kg/day groups maternal toxicity was evidenced by decreases in mean maternal body weight gain and

mean food consumption during the treatment period of Days 6-17 of gestation. Developmental toxicity was observed in the 25.0

mg/kg/day group as evidenced by decreased fetal weights, increased numbers of litters and fetuses with sites of

incomplete ossification as well as increased number of sites of incomplete ossification and hypoplastic rib.

Developmental toxicity was evidenced in the 10.0 mg/kg/day group by increases in the number of litters and fetuses with sites of incomplete ossification as well as number of sites of incomplete ossification.

There was no treatment-related maternal or developmental toxicity at the 5.0 mg/kg/day dose.

The NOAEL for developmental toxicity is 5 mg/kg bw/day and the NOAEL for Maternal Toxicity (body weight reduction) is 5 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
13-3-1989 to 6-4-1989
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
dosing from GD6 to 17
GLP compliance:
yes
Limit test:
no
Specific details on test material used for the study:
Lot Number: L-670,452-00SY-008
Puritv: 98.6% by titration
Factor: 1.33
Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl CD (SD) BR
Details on test animals and environmental conditions:
Source: Charles River Breeding Laboratories, Wilmington, Massachusetts Age at Initiation:
Approximately 12 weeks
Weight Range at Initiation: 203-281 grams
Identification Method: Ear notches

Environmental Conditions:
a. Housing:
Females were housed singly in wire mesh bottom cages;
room temperature at 20• to 27•c; room lights were set
with a timer for a 12-hour light and 12-hour dark cycle.
b. Diet:
The rats had free access to Purina Certified Rodent
Chow 1!5002 and tap water.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
deinonised
Details on exposure:
Preparation of Test Article:
Solutions of MK-0217 in vehicle were prepared daily.
Control Article: Deionized water
Dosing Volume: 5 ml/kg based on most recent body weight.
Concentrations 1,2 and 5 mg/ml
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Drug Assays and Stability:
Samples of the dosing solutions were collected during
the first and second weeks of dosing and were assayed
for concentration. All dosing samples for the 25.0 and
10.0 mg/kg/day groups were within acceptable limits (not
less than 90% of desired concentration). The first week
sample of the 5.0 mg/kg/day group was also within
acceptable limits but the analysis of sample for the
second week of this dose group did not achieve the
desired concentration being 54.9% (duplicate 54. 7%) of
the desired concentration). This is considered an
individual dilution error in the 5.0 mg/kg/day group on
a single day of dosing and not a systematic error in
drug preparation. The compound has been shown to be
stable in this vehicle under the conditions of the study.
Details on mating procedure:
Each female was housed with 1 untreated male of the
same strain. Females were selected for study when daily
examination revealed the presence of copulatory plugs
below the cage floor. The day of finding the plug(s)
was considered Day 0 of gestation.
Duration of treatment / exposure:
Dosing through Gestation Days 6 to 17
Frequency of treatment:
Daily
Dose / conc.:
5 mg/kg bw/day (actual dose received)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
25 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
25 (twenty five)
Control animals:
yes, concurrent vehicle
Details on study design:
Females were assigned to the following groups based on
a computer-generated list of random permutations of 5*:
Treatment Groups Number of Females Per Group
Control 25
MK-0217 at:
5.0 mg/kg/day 25
10.0 mg/kg/day 25
25.0 mg/kg/day 25

*The fifth group was comprised of substitution animals.
Maternal examinations:
Physical Signs:
Females were observed for physical signs once daily on Day
0 and during Days 6-20 of gestation and 1-5 hours post
dosing.

Maternal Body Weights:
Recorded on Days 0, 6, 8, 10, 12, 14, 16, 18 and 20 of
gestation.

Food Consumption:
Measured for all animals on Days 3-5, 6-8, 9-11, 12-14,
15-17 and 18-20 of gestation.

Necropsy:
A gross examination of thoracic, pelvic and abdominal
viscera was done on all sacrificed females.
Ovaries and uterine content:
All females were sacrificed on Day 20 of gestation by C0
2
asphyxiation. The uterus of each female was examined to
determine reproductive status (pregnant or non-pregnant).
The number of corpora lutea was counted.
Fetal examinations:
Females sacrificed on Day 20 of gestation were assigned a
code number so that litters could be examined without
knowledge of treatment groups. The order of examination was
determined by
a
computer-generated list of random
permutations of 4.
Implants were counted, classified as
live fetus, dead fetus or resorption.
All fetuses were
weighed and examined externally. Every third fetus in each
litter and all externally malformed and dead fetus were
given a visceral examination by dissection. The heads of
these fetuses were fixed in Bouin's solution and later
examined by free-hand coronal sections.
All fetuses were
fixed, cleared, and stained with alizarin red for subsequent
skeletal examination.
Statistics:
Statistical analyses were based on analysis of variance or
covariance using a least significant different procedure
after normalizing for nonparametric data by a rankit method
. Results were considered to be statistically significant if P ~ 0.05.
Indices:
Maternal body weight changes between Days 6 and 18, 18
and 20, and 6 and 20 of gestation (adjusted for Day 6
body weight where appropriate)
 03Z4QL
 
-10-
b. Percent preimplantation loss (litter mean)
c. Implants per pregnant female
d. (Resorptions + dead fetuses)/implants (litter mean)
e. Live fetus per pregnant female
f. Live fetal weight (litter mean, adjusted for time of
sacrifice)
g. Fetuses per litter with incomplete ossification of any
site.
h. Fetuses per
litter affected with hypoplastic
rib.
i.
Fetuses per litter with
incomplete ossification
of
pelvic bone.
j.
Fetuses per litter with
incomplete ossification of
sternebra.
k. Number of litters affected with incomplete ossification.
1. Average number of ossified sacrocaudal vertebrae per
fetus per litter.
m. Total number of live fetuses per litter.
n. Average female fetal weight per litter.
o. Average male fetal weight per litter.
Historical control data:
Not reported
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
First signs of rales were noted on Day 15 of gestation.
They were observed in 7/25 animals in the 25 .Q mg/kg/day
group, 5/25 on a single day and 2/25 animals for 2 days. It
 is unlikely that the rales observed in these animals are
related to treatment as rales were not observed 1 to 5 hours
post dosing and were not observed in a previous oral range­
finding study in pregnant rats given MK-0217
at 25.0 mg/kg/day on Day 6 through 16 of gestation. There
were no other treatment-related signs.
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Description (incidence):
There were no deaths or abortions during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
During the treatment period (Days 6-18 of gestation) there
were significant (P ~ 0.05) dose-related decreases in mean
materoal body weight gain compared to controls of 9. 5'% and
25.0'% in the 10.0 and 25.0 mg/kg/day dose groups,
respectively. There were no significant effects of
treatment on mean materoal body weight gain in the post
dosing period of Days 18 to 20 of gestation. From Days 6 to
20 of gestation the 10.0 and 25.0 mg/kg/day groups had a
significant (P ~ 0.05) decrease in mean materoal body weight
gain of 8.4 and 21'%, respectively. The mean materoal body
weight gains of the 5.0 mg/kg/day group were not
significantly different from controls.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
In the 25.0 mg/kg/day group average materoal food
consumption was decreased 18.5'% on Days 9-11 of gestation,
17.9'% on Days 12-14 of gestation, 10.3'% on Days 15-17 of
gestation and 12.9'% on Days 18-20 of gestation. In the 10.0
mg/kg/day group food consumption was slightly decreased by
9. 7% on Days 18-20 of gestation.
These decreases in food average consumption are considered treatment related. There
was no effect of treatment on food consumption in the 5.0
mg/kg/day group.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
One female (#89-0384) in the 25.0 mg/kg/day group had
distended intestines which is considered treatment-related
as it has been observed in a previous 3-month oral toxicity
study (TT #89-008-0) in rats dosed at 30 mg/kg/day. There
were no other treatment-related findings.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
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
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Details on maternal toxic effects:
During the treatment period (Days 6-18 of gestation) there were significant (P ~ 0.05) dose-related decreases in mean materoal body weight gain compared to controls of 9. 5'% and 25.0'% in the 10.0 and 25.0 mg/kg/day dose groups, respectively. From Days 6 to 20 of gestation the 10.0 and 25.0 mg/kg/day groups had a significant (P ~ 0.05) decrease in mean materoal body weight gain of 8.4 and 21'%, respectively.
Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
Abnormalities:
no effects observed
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
There was a significant (P ~ 0.05) treatment-related
decrease in mean male live fetal weight of 6.6% in the 25.0
mg/kg/day group. There was a slight but not statistically
significant decrease (5.5%) in mean female live fetal weight
in the 25.0 mg/kg/day group which is also considered
treatment-related. One litter (Female #89-0384) in the 25.0
mg/kg/day group had a severe depression in live fetal
weight.
The mean live fetal weight of this litter was
decreased 50.2% in males (53.4% below control weights) and
55.9% in females (58.3% below control weights) below the
mean live fetal weight for this dose group. This female had
signs of maternal toxicity and gross findings at necropsy as
discussed below. There were no effects of treatment on mean
fetal weights in the 5.0 and 10.0 mg/kg/day group.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined
Reduction in number of live offspring:
not examined
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were no treatment-related effects observed on
external or visceral examination. One fetus in the 10.0
mg/kg/day group (#89-0359-03) had multiple cranial facial
malformations (micrognathia, cleft lip and palate,
aglossia). One fetus in the 25.0 mg/kg/day group had a tail
malformation. The findings in these 2 fetuses are
considered single incidental events not related to
treatment.
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
There was a slight but not statistically significant increase in the numbers of fetuses/litter with hypoplastic
rib in the 25.0 mg/kg/day group which is considered treatment related.
There was an increased incidence of fetuses with wavy rib in the 5.0 mg/kg/day group (7 fetuses
in treated group vs. 1 in control). Six of the 7 fetuses with wavy rib were in 1 litter (#89-0340) which had he highest number of sites of incomplete ossification for
the dose group and were at the low end of the fetal weight range for this group. The increased number of wavy rib in
this litter is considered to be associated with decreased skeletal maturity due to lower fetal weight.
There is no dose response for wavy rib and this increase in the 5.0 mg/kg/day group is not considered treatment related. Two
fetuses from 1 litter (#89-0398) in 25.0 mg/kg/day group had vertebral malformations (1 cervical vertebral malformation
and 1 missing vertebra) which are considered unrelated to treatment. There were no other treatment-related effects on
skeletal malformations or variations.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One fetus in the 5.0 and 25.0 mg/kg/day group had a distended ureter.
This common variation is not considered treatment related.
One fetus in the control group had a ventricular septal defect in the heart and one
25.0 mg/kg/day fetus had a cerebral ventricular enlarge-
ment. This single malformation in the treated group is
considered a single incidental finding and not treatment
related.
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
5 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
fetal/pup body weight changes
skeletal malformations
Key result
Abnormalities:
effects observed, treatment-related
Localisation:
skeletal: skull
skeletal: sternum
skeletal: vertebra
skeletal: pelvic girdle
Description (incidence and severity):
54.2% and 56% of litter with sites of incomplete ossificaiton at 10 and 25 mg/kg/day respectively.
10.5% and 16% of fetuses with sites of incomplete ossificaiton at 10 and 25 mg/kg/day respectively.
11% fetuses with incomplete ossified sternebra at 25mg/kg/day
7.5% of fetuses with ossified sacrocaudal vertebra at 25 mg/kg/day.
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
yes

Details on Maternal Toxicity (decreased weight gain ), laparotomy data and summary of fetal abnomalities are appended as attachments.

Conclusions:
In the 10.0 and 25.0 mg/kg/day groups maternal toxicity was
evidenced by decreases in mean maternal body weight gain and
mean food consumption during the treatment period of Days 6-17
of gestation. Developmental toxicity was observed in the 25.0
mg/kg/day group as evidenced by decreased fetal weights,
increased numbers of litters and fetuses with sites of
incomplete ossification as well as increased number of sites of
incomplete ossification and hypoplastic rib.
Developmental toxicity was evidenced in the 10.0 mg/kg/day group by increases
in the number of litters and fetuses with sites of incomplete ossification as
well as number of sites of incomplete ossification.
There was no treatment-related maternal or developmental
toxicity at the 5.0 mg/kg/day dose.
The NOAEL for developmental toxicity is 5 mg/kg bw/day and the NOAEL for Maternal Toxicity (body weight reduction) is 5 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
5 mg/kg bw/day
Study duration:
subacute
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

Justification for classification or non-classification

In the developmental study, treatment with 10.0 and 25.0 mg/kg/day resulted in slight maternal toxicity which was evidenced by decreases in mean maternal body weight gain and mean food consumption during the treatment period of Days 6-17 of gestation. Developmental toxicity was observed in the 25.0 mg/kg/day group as evidenced by decreased fetal weights, increased numbers of litters and fetuses with sites of incomplete ossification as well as increased number of sites of incomplete ossification and hypoplastic rib.

Developmental toxicity was evidenced in the 10.0 mg/kg/day group by increases in the number of litters and fetuses with sites of incomplete ossification as well as number of sites of incomplete ossification.

There was no treatment-related maternal or developmental toxicity at the 5.0 mg/kg/day dose.

The NOAEL for developmental toxicity is 5 mg/kg bw/day and the NOAEL for Maternal Toxicity (body weight gain reduction) is 5 mg/kg bw/day.

The incidence of maternal toxicity ( reduction in body weight gain and food consumption) is not considered sufficient to negate the fetal effects observed (significant and extensive incomplete ossification) across the studies conducted. Consequently , it is considered appropriate to classify the substance as Reproductive Toxicity Category 2 for development (H361d).