Registration Dossier

Administrative data

developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP and appropriate guidelines
Reason / purpose:
reference to same study

Data source

Reference Type:
study report
Report Date:

Materials and methods

Test guidelineopen allclose all
according to
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
according to
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
GLP compliance:
Limit test:

Test material

Details on test material:
Batch No.: 141410
Purity: 99.1%
White to off-white powder
Storage: Dry, cool, well ventilated area

Test animals

other: CD (Crl:CDR (SD)IGS BR) strain of SD origin
Details on test animals and environmental conditions:
Adult virgin female rats from Charles River UK Ltd (male mated with females but not part of the study)
9-10 weeks old at arrival, 10-11 weeks old on date of mating (88 females)
200-268 gr (day of mating)
219-259 gr satellite animals (27 females)
15 room air change/hr
19-25 deg C
RH: 40-70%
12 hr light/12 hr dark cycle
Tap water from public supply
Pelleted laboratory animal diet (UAR VRF-1 certified)
Stage Number of Rats Cage Type Cage flooring
Acclimatisation F (up to 4) TR 18 Stainless steel grid
Mating 1 (M/F) RB3 modified Stainless steel grid
Gestation 1 (F) RB3 modified Stainless steel grid

Administration / exposure

Route of administration:
oral: feed
corn oil
Details on exposure:
see attached document on treatment
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
see attached formulation chemistry
Details on mating procedure:
Females were paired on a one-to-one basis with stock males of the same strain. Each morning following pairing, the trays beneath the cages were checked foe ejected copulation plugs and a vaginal smear was prepared from each female and examined for a presence of spermatozoa. Vaginal smears were prepared and examined even if a copulation plug was present in the vagina. Stock males were returned to the stock male colony once mating had been completed. The day on which a sperm positive vaginal smear or at least three copulation plugs were found was designated Day 0 of gestation.
Duration of treatment / exposure:
1-19 days of gestation
Frequency of treatment:
Dosing regime: 7 days/week
Duration of test:
females were killed on day 20 of gestation
No. of animals per sex per dose:
Number of dams and doses
22 at 0 mg/kg or mg/l
22 at 100 mg/kg or mg/l
22 at 300 mg/kg or mg/l
22 at 1000 mg/kg or mg/l
Details on study design:
See attached document on treament


Maternal examinations:
see attached document on treatment
Ovaries and uterine content:
see attached document on treatment
Fetal examinations:
see attached document on treatment
see attached document on treatment
see attached document on treatment
Historical control data:
see attached document on treatment

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
No deaths occurred in the study and there were no
significant clinical signs recorded. The occurrence of brown
staining and hairloss was recorded for animals in all
groups, including the Controls, and are common consequences
of dosing animals with oily formulations associated with
increased levels of grooming. There were occasional
incidences of increased salivation after dosing, but this
did not appear to be related to dose levels and there were
no other records of reaction to dosing.

Bodyweight and cumulative bodyweight change were unaffected
by treatment with FR-370 at dosages of up to 1000 mg/kg/day
through Days 1-19 of gestation. Comparison of absolute
bodyweight data with adjusted maternal weight and weight
gain (following substraction of the gravid uterine weight
from maternal bodyweight at Day 20), confirmed that
treatment had no adverse effect upon maternal weight.

Foodconsumption by animals receiving FR-370 was similar to
that of concurrent control animals throughout the gestation
period and was not affected by treatment.

There were no macropathological findings at necropsy that
were considered to be related to treatment.

Effect levels (maternal animals)

Dose descriptor:
Effect level:
1 000 mg/kg bw/day (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Effects on fetus - Gross:
All females were pregnant with live young at Day 20 of

There were no adverse effects of treatment on the mean
implantation count, the incidence of pre- or post-
implantation losses or the number of live young. The sex
ratio was similar in all groups and closely matched the
expected 50% incidence of male fetuses.

Litter weight was slightly low at 1000 mg/kg/day with 4/22
females having a placental weight in excess of 0.70 g and an
overall mean value slightly higher than the Control value,
although lower fetal weights were noted at this dosage.
There were no cases of increased litter mean placental
weight in the control group or group receiving 300 mg/kg/day
and only two cases at 100 mg/kg/day. Increased placental
weight appeared to be associated with reduced live litter
size/increased post-implantation loss, but there was no
clear association with treatment and the overall increase in
placental weight at 1000 mg/kg/day was not statistically

Treatment with FR-370 throughout gestation at levels up to
1000 mg/kg/day had no effect on the incidence of major

Effects on fetus - Soft tissue:
Fetuses at 1000 mg/kg/day also showed marginally high
incidence of variation in contralateral eye size, (but at a
frequency similar to that seen in recent studies) and an
increased incidence of partially undescended thymus which
was above recent control levels (See addendum 4). However,
when the range of studies was increased to 25 studies,
including those performed before and after DSV001 (See
addendum 5), recorded incidence at the highest dosage used
(1000 mg/kg/day) was similar to observed maximum levels in
groups in studies receiving a wide range of unrelated
materials and was not considered to represent a treatment
related reaction.

"Partially undescended horn of thymus" is recorded as either
"left, right or bilateral" but for simplicity, reported as
"partially undescended thymus". The observation records a
delay in the normal caudal migration of thymic tissue from
the level of the root of the tongue to the top of the heart.
We know of nothing to suggest that the cranially placed
thymic tissue will not eventually migrate to its normal
location and partially undescended horn of the thymus is not
considered to represent any long term structural damage to
the fetus or a teratogenic event.

There is no evidence to suggest that FR-370 had any
teratogenic potential in the rat.

Effects on fetus - Skeletal:
At 1000 mg/kg/day there was a slight increase in the
incidence of incompletely ossified sternebrae (64% of the
fetuses affected cf 52% of control fetuses), but the
incidence was within the range of values recorded in recent
studies (35% to 70% - See addendum 4) and increases in
groups receiving 100 or 300 mg/kg/day were below concurrent
control value.

Effect levels (fetuses)

Dose descriptor:
Effect level:
300 mg/kg bw/day (nominal)
Basis for effect level:
other: embryotoxicity

Fetal abnormalities

not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

See attached document on results

Applicant's summary and conclusion

The NOAEL determined from this study was1000 mg/kg/day for dams and 300 mg/kg/day for fetuses
Executive summary:

The influence of FR-370 on embryo-fetal survival and

development has been assessed by administring FR-370 by oral

gavage once daily at dosages of 100, 300 and 1000 mg/kg/day

from Day 1 to Day 19 of gestation. The females were killed

on Day 20 of gestation for examination of their uterine

contents and assessed for fetal development.

Treatment had no significant effects upon pregnant female

rats or upon fetal survival, but at 1000 mg/kg/day, fetal

weight was about 5% lower than control and was at the lower

limit, or below recent control mean values. It was

considered that there was little biological significance of

this monir change in fetal weight, in the absnece of

associated generalised changes in skeletal ossification.

Placental weight was slightly high, but neither placental

weight nor litter weight was significantly different from


It was concluded that daily administration of FR-370 by oral

gavage as a suspension in corn oil between Days 1 - 19 of

gestation had no adverse effects on the female rat or on

embryo-fetal survival, growth and development at dose levels

up to 300 mg/kg/day.

At 1000 mg/kg/day maternal treatment was associated with a

slight reduction in fetal growth, but there was no evidence

of any adverse effects upon the mother nor any teratological

effect upon development in utero.

The NOAEL determined from this study was 1000 mg/kg/day for dams and 300 mg/kg/day for the fetuses