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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2004
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: NTP study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
not applicable
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Pharmaceutical grade Dapsone

Test animals

Species:
mouse
Strain:
CD-1
Details on test animals and environmental conditions:
Time - mated mice (CD-1) Swiss albino were dosed by gavage.
Mice were kept in groups in stainless-steel containers at 22 degree C

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5 %
Details on exposure:
Doses of 0, 50, 100, 200 mg/kg bw were applied by gavage divided in two portions: one half in the morning, one half in the evening. as for Humans.
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
no data
Details on mating procedure:
no data
Duration of treatment / exposure:
Gestation days 6-15 , necropsy at day 17
Frequency of treatment:
daily (morning and evening)
Duration of test:
17 days
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
200
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
100
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
50
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0
Basis:
nominal conc.
No. of animals per sex per dose:
20-21 only females
Control animals:
yes, concurrent vehicle
Details on study design:
Timed-mated mice (20-21 per group) were monitored at regular intervals for clinical signs of toxicity, feed consumption, and body weight. At necropsy (gd 17), the following observations were made: clinical condition; maternal body, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of prenatal deaths (resorptions and/or dead fetuses) and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal).
The study was performed in two replicates.

Examinations

Maternal examinations:
Timed-mated mice (20-21 per group) were monitored at regular intervals for clinical signs of toxicity, feed consumption, and body weight. At necropsy (gd 17), the following observations were made: clinical condition; maternal body, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of prenatal deaths (resorptions and/or dead fetuses) and live fetuses were recorded. Live fetuses were weighed, sexed, and examined for morphological anomalies (external, visceral, and skeletal). The study was performed in two replicates.
Ovaries and uterine content:
yes
Fetal examinations:
yes
Statistics:
no data
Indices:
yes
Historical control data:
no data

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
For dapsone alone, maternal mortality (10%) was noted at the high dose, but otherwise clinical observations were unremarkable. At scheduled necropsy (gd 17), gross findings included enlarged spleens in 1, 12, 13 or 17 dams in the control through high dose groups, respectively. Maternal body weight, weight change, and gravid uterine weight were each reduced at the highest dose of dapsone (200 mg/kg/day). As noted during the pre-treatment period, there was a tendency for dapsone groups to consume more feed than the controls. Consistent with this observation, maternal feed consumption was usually at or above controls for subsequent measurement periods. The exception to this pattern was a significant reduction in maternal relative feed consumption at the highest dose of dapsone at the beginning of the treatment period (gd 6 to 9).

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
ca. 200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
Indices of prenatal mortality appeared to be elevated at the highest dose of dapsone (e.g., 16% resorbed implantation sites vs. 2% for controls). Some indices of prenatal mortality reached statistical significance and effects tended to be more severe in the second replicate. Fetal body weights (male, female or both) were significantly reduced by 25% at the highest dose of dapsone. Altered incidences of fetal morphological anomalies (malformations or variations) were noted, but patterns of effects varied across replicates.

Effect levels (fetuses)

Remarks on result:
not measured/tested

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Variations and malformations in Dapsone treated embryos were not statistically significant as they were distributed unevenly over all dose groups.

Applicant's summary and conclusion

Conclusions:
Dapsone is not teratogenic in CD-1 Swiss albino mice.
Executive summary:

Based on the NTP-study conducted, Dapsone is not teratogenic in CD-1 Swiss albino mice.