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EC number: -
CAS number: -
The objective of this study was to obtain initial information on
the toxic potential of test item and on the possible effects of the test
item on reproduction and development when repeatedly administered orally
(by gavage) to rats at doses of 50, 100 and 300 mg/kg bw/day compared to
control animals according to OECD 422. The guideline is designed for use
with the rat, which is the preferred rodent species for toxicity and
reproduction toxicity testing.As
a screening test, it was intended to provide initial informationon
the possible health hazards likely to arise from repeated exposure over
a relatively limited period of time and on the possible effects onmale
and female reproductive performance such as gonadal function, mating
behavior, conception, pregnancy, parturition as well as on development
of the F1 offspring from conception to day 13 post-partum associated
with administration of repeated maternal doses.
Reaction mass of N-butylphthalimide and
n-propylphthalimide and N-sec-butylphthalimide wasadministered
orally (by gavage) once daily at 0 (vehicle only),50, 100
and 300 mg/kg body weight/day(mg/kg
bw/day) doses to four groups ofHsd.Han: of Wistar
ratsconsisting of 12 animals per sex per groupin
concentrations of10, 20 and 60 mg/mLcorresponding
to a 5 mL/kg bw dosing volume.A group of vehicle
(sunflower oil) treated animals (n= 12/sex) served as a control.
The suitability of the chosen vehicle for the test item at the
intended concentrations was analytically verified up front.
Reaction mass of N-butylphthalimide and
n-propylphthalimide and N-sec-butylphthalimide was stable in sunflower
oilin concentrations of ~1 mg/mL
and ~200 mg/mL at room temperature for fourhoursand
in a refrigerator for 3 days.
The concentration of the test item in the
dosing formulations administered to the animals was checked two times
during the study. Reaction mass of N-butylphthalimide and
n-propylphthalimide and N-sec-butylphthalimide concentrations in the
dosing formulations varied within the range between98 % and
107 %of the nominal values and
confirming the proper preparation of the dosing formulations.
All animals of the parent (P) generation were
dosed prior to mating (14 days) and throughout mating. In addition,
males received the test item or vehicle after mating up to the day
before the necropsy (altogether for 47 days). Females were additionally
exposed through the gestation period and up to lactation days 13 - 17,
i.e. up to the day before necropsy (altogether for 51-58 day depending
on the mating day; non-pregnant females were administered for 47 days).
Observations included mortality, clinical
signs, body weight, food consumption, mating, pregnancy and delivery
process, as well as development of offspring.Estrous cycle
was monitored by examining vaginal smears before the treatmentfor
two weeks and for two weeks from the beginning of the treatment period
(two weeks pre-mating period) and during the mating period until
evidence of copulation, and on the day of the necropsy.
The dams were allowed to litter, and rear
their offspring up to day 13 post-partum. Litters were weighed and
offspring were observed for possible abnormalities and were euthanized
on post-natal day 13 or shortly thereafter.
Blood samples were collected for determination of serum levels of
thyroid hormones (T4) from at least two pups per litter (where it was
feasible) on post-natal day 4, from all dams and at least two pups per
litter – if it was feasible – at
termination on post-partum/ post-natal day 13 and from all parent
male animals at termination. Samples of parental male animals and pups
on postnatal day 13 were measured and evaluated.
All parental animals were subjected to gross
pathology one day after the last treatment. The body weight, brain
weight and weight of the testes and epididymides,prostate
and seminal vesicles with coagulating glands as a wholeof
adult male animals were determined. Thyroid gland was preserved from all
adult males and females and one male and
one female pup per litter for the intended
subsequent histopathological examination.
Histopathology examination was performed on
ovaries, uterus, vagina, testes, epididymides, prostate and seminal
vesicles with coagulating gland in the control and high dose groups
(male or female). In addition, these organs were processed
histologically in non-pregnant females and males cohabited with at the
mid dose group.
Five dams and their male mating partners were
randomly selected from each group to examine further signs of toxicity
such as functional observations, hematology, clinical chemistry, gross
necropsy, organ weighing and full histopathology examination.
Full histopathology was performed in dead
male animal at 50 mg/kg bw/day. In addition, uterus with vagina in
single female animals at 50 and 100 mg/kg bw/day, and the thymus in two
male animals at 100 mg/kg
bw/daywere also processed and
evaluated histologically on the basis of macroscopic observations at the
The results of this study were summarized as follows:
no test item related mortality at 50, 100 or 300 mg/kg bw/day groups
during the course of study
animal at 50 mg/kg bw/day died on Day 18 due suffocation. Foamy content
in the trachea and histopathological findings (alveolar emphysema and
edema, congestion in the lungs) refer to para-gastric treatment.
and functional observation
signs of systemic toxicity related to the test item were not detected at
any dose level, neither at the daily nor the detailed weekly clinical
observations nor at the functional observations. The behavior and
physical condition of the animals was not impaired at each dose level
(50, 100 or 300 mg/kg bw/day) during the entire treatment period.
Nuzzling up the bedding material noted for all male animals and
for all female animals at 300 mg/kg bw/day shortly after the
administration from Day 3 up to the last treatment day was not
considered to be toxicologically relevant due to the short duration and
animals showed normal behavior thereafter.
Body weight and body weight gain
The body weight development was not adversely
affected by the test item in male or in female animals at 50, 100 or
300 mg/kg bw/day during the entire treatment period.
The mean daily food consumption was not
affected at 50, 100 or 300 mg/kg bw/day groups in male animals (during
the course of the pre-mating and post mating periods) and in female
animals (during the pre-mating, gestation and lactation periods).
A test item influence on the estrous cycle
was not found at any dose level (50, 100 and 300 mg/kg bw/day).
Reproductive performance and delivery data
The examined parameters of reproductive
ability were comparable in the control and in 50, 100 and 300 mg/kg
bw/day groups (male and female).
There were no toxicologically relevant
differences in the evaluated delivery parameters of dams between the
control and test item treated groups (50, 100 and 300 mg/kg bw/day).
Hematological evaluation did not reveal
adverse test item related changes in the examined parameters at 50, 100
and 300 mg/kg bw/day.
The bile acid concentration was elevated in
female animals at 300 mg/kg bw/day with respect to their control
indicative some disturbances in the enterohepatic circulation or the
The serum thyroid hormone (free T4) level was comparable to their
control in parental male animals and in PN 13 day offspring at 50,100
and 300 mg/kg bw/day.
Macroscopic findings related to the effect of
the test item were not found in male and female animals at 50, 100 and
300 mg/kg bw/day.
There were no test item related changes in
the weights (absolute and relative to body or brain weights) of brain,
testes and epididymides of male animals at any dose level.
The examined organ weights of animals selected for toxicity
examinations were comparable in the control and50,
100 and 300 mg/kg bw/daygroups at the end of the
Histopathological examinations of the
selected organs (ovaries, uterus, vagina, testes,
epididymides, prostate and seminal vesicles with coagulating gland)
did not reveal any test item related changes at 300 mg/kg bw/day.
There were no pathologic changes in the
examined organs or tissues of randomly selected male or female animals
in the control or 300 mg/kg bw/day groups.
on the mortality, clinical signs, body weight development or necropsy
findings were detected in the offspring terminated as scheduled. The
anogenital distance (male and female) or nipple retention (male) were
Under the conditions of the present study,
Reaction mass of N-butylphthalimide and n-propylphthalimide and
N-sec-butylphthalimide administered at 50, 100 or 300 mg/kg bw/day by
oral gavage did not cause signs of systemic toxicity and did not
adversely influence the reproductive performance (gonad function, mating
behavior, conception, parturition) in parental male and female Hsd.Han:
The development of the F1 offspring was
not impaired from birth to post-natal day 13 at any dose level after
repeated oral administration of dams.
Based on these observations the No
Observed Adverse Effect Levels (NOAEL) were determined as follows:
NOAEL for systemic toxicity of male/female
rats: 300 mg/kg bw/day
NOAEL for reproductive performance of
male/ female rats: 300 mg/kg bw/day
NOAEL for F1 Offspring:300 mg/kg bw/day
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