Registration Dossier

Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

Currently viewing:

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2001
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2005
Report date:
2005

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Oral developmental and perinatal/postnatal reproductive toxicity study in rats, including postnatal reproductive toxicity in rats with behavioral and functional evaluation. Pregnant females dosed daily throughout gestation and postpartum.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Dapsone
EC Number:
201-248-4
EC Name:
Dapsone
Cas Number:
80-08-0
Molecular formula:
C12H12N2O2S
IUPAC Name:
4,4'-sulfonyldianiline
Test material form:
solid
Details on test material:
Dapsone (16 tablets, 25 mg each)a was used to prepare the suspensions. The tablets were ground to powder using a mortar and pestle, and
then two suspensions were prepared.
Specific details on test material used for the study:
USP Lot #01110D

Test animals

Species:
rat
Strain:
Crj: CD(SD)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Analytical verification of doses or concentrations:
not specified
Frequency of treatment:
Daily
Duration of test:
F0 animals were sacrificed on day 28 post partum
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
3 mg/kg bw/day
Dose / conc.:
12 mg/kg bw/day
Dose / conc.:
30 mg/kg bw/day
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle

Examinations

Maternal examinations:
Body weights, food consumption, clinical signs and duration of gestation. Gross necropsy following weaning.
Litter size, pup viability and nursing behaviour.
Fetal examinations:
F1 animals were evaluated for performance in a water filled M maze for overt coordination, swimming ability, learning and memory.
F1 males were monitored for the age of preputial separation and F1 females were monitored for the age of vaginal opening.

F1 animals were observed for changes in mating behaviour. F1 males testes and epididymides were weighed. F1 females were exhamined for numbers of corpora lutea, implantation sites and viable fetuses. F2 fetuses were weighed and examined for gross external alterations.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One high dose female was found dead during lactation. No other unscheduled deaths.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Significantly reduced in high dose group over the period of gestation. Mean body weight tended to be reduced in high dose females during the lactation perod.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Mirrored body weight effects.
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Reduced mean implantations at 75 mg/kg/d.
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
The mean number of stillborn pups per litter was significantly higher with increased exposure to dapsone.
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
12 mg/kg bw/day
Basis for effect level:
body weight and weight gain
food consumption and compound intake

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
The mean number of stillborn pups per litter was significanty higher with increased exposure to dapsone but no effects were observed on pup viability post partum.
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

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
30 mg/kg bw/day
Basis for effect level:
other: No effects observed in the abscence of maternal toxicity

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Treatment of pregnant rats resulted in maternal toxicity, but not effects on physical or behavioural development were noted in the offspring.
All clinical signs were considered incidental, body weight gain was significantly reduced in high dose females and food consumption mirrored body weight observations.
There was no effect of treatment on the duration of the destation period, the number of rats that delivered or the number of dams with pups dying post partum. The number of stillborn pips per litter was increased but only in the presence of effects on maternal body weight and food consumption. No effects were noted on pup viability postpartum.
Executive summary:

An oral gavage developmental and perinatal/postnatal reproduction toxicity study in rats, including a postnatal behavioural/functional evaluation, was conduced in groups of 25 female rats with dose levels of 0, 3, 12 and 30 mg/kg/d. F0 females were administered the test articles daily from gestation day 7 (seventh day following confirmed mating) through day 27 postpartum. F0 animals were sacrificed on day 28 postpartum. 25 F1 animals of each gender (pups of F0 animals) were selected on day 28 postpartum. At approximately 90 days of age the F1 animals were cohabited for up to 21 days with an F1 animal of the opposite gender and from a different litter. F1 males were sacrificed at the conclusion of the cohabitation period. F1 females were sacrificed on gestation day 21 and c-sectioned.


Body weight, clinical signs and food consumption were monitored daily. F0 animals were monitored for duration of gestation, litter size, pup viability and nursing behaviour. Gross necropsy was performed. F1 animals were evaluated on approx. day 70 postpartum for performance in a water filled M maze for overt coordination, swimming ability, learning and memory. F1 males were monitored for the age of preputial separation and F1 females observed for age of vaginal opening. F1 animals were observed for changes in mating behaviour. Reproductive organs were weighed and F1 females were observed for numbers of corpora lutea, implantation sites and viable fetuses. F2 females were weighed and examined for gross external alterations.


Little toxicity was overserved under the conditions of the study, although mean body weight gain was significantly reduced in high-dose F0 females over the period of gestation, indicating that a sufficiently high level of exposure was achieved for the data to be valid. The mean number of stillborn pups was slightly but statistically significantly higher in high dose treatment groups than control. No effects were observed on pup viability, physical development, behaviour, learning ability or reproduction.