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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: Effect on the fertility of male rats
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2000
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Information is available from the pre-approval review of Aczote (a cream containing 5% dapsone for use against acne) by U.S. FDA.

Data source

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

Materials and methods

Principles of method if other than guideline:
Treatment of males only. Fertility effects on females have been studied separately
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid - liquid: suspension
Details on test material:
Dapsone plus 180 mg/kg/day diethylene glycol monoethylether

Test animals

Species:
rat
Strain:
other: Rat/Crl:CD(SD)IGS BR VAF/Plus
Sex:
male

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on exposure:
The study was conducted in two stages, with an initial study that involved dosages of 0, 12, 30 and 75 mg/kg/day, and a second study that involved exposures at 0, 0.5, 2 and 12 mg/kg/day. Therefore there were two groups which received 0 mg/kg/day (vehicle control group) and two groups which received 12 mg/kg/day.
Details on mating procedure:
Only males were treated. Untreated females were used to confirm male reproductive potential.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
F0 males were dosed with the test material 63 days prior to cohabitation with untreated females and continued through the day prior to sacrifice
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0
Basis:
actual ingested
mg/kg bw/day
Remarks:
Doses / Concentrations:
0.5
Basis:
actual ingested
mg/kg bw/day
Remarks:
Doses / Concentrations:
3
Basis:
actual ingested
mg/kg bw/day
Remarks:
Doses / Concentrations:
12
Basis:
actual ingested
mg/kg bw/day
Remarks:
Doses / Concentrations:
30
Basis:
actual ingested
mg/kg bw/day
No. of animals per sex per dose:
25 males (treated) and 25 females (untreated)
Control animals:
yes, concurrent vehicle
Positive control:
none

Examinations

Parental animals: Observations and examinations:
F0 male rats observed for viability and clinical signes twice daily. Body weight was recorded daily. F0 females were nonitred for body weight and clinical signs on gestation days 0, 7, 10 and 13. All F0 females were sacrificed on gestation day 13, cesarian sectioned, gross necropsied, and the numbers of corpora lutea, implantation sites, and viable and non-viable embryos was recorded. Following Completion of the cohabitation period, F1 males wer subjected to gross necropsy, the reproductive organs (each testis, each epididymidis, seminal vesicles and prostate) weighted, and sperm concentration and motility were evaluated.
Oestrous cyclicity (parental animals):
Females were not treated
Sperm parameters (parental animals):
Concentration and motility
Postmortem examinations (parental animals):
Gross pathology of males
Postmortem examinations (offspring):
not performed in this study
Statistics:
yes
Reproductive indices:
yes
Offspring viability indices:
yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Pale or blue extremities, salvation, poor grooming. Incidence proportional to exposure
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
BW gain significantly reduced > 75 mg/kg/day.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
BW gain significantly reduced > 75 mg/kg/day.
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Other effects:
not examined
Description (incidence and severity):
Test substance intake: gavage

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Description (incidence and severity):
only males treated
Reproductive function: sperm measures:
effects observed, treatment-related
Description (incidence and severity):
motility: Effects above 75 mg/kg/day; sperm number: no effect

Details on results (P0)

Number of implantation sites in females and viable embryos significantly reduced if males were treated >12 mg/kg/day, presumably due to the numbers or effectiveness of sperm.

Effect levels (P0)

Key result
Dose descriptor:
NOAEL
Effect level:
>= 0.5 - < 3 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: Effect is on the number of motile sperm

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
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

Details on results (F1)

Only male fertility tested.

Effect levels (F1)

Remarks on result:
not measured/tested

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dapsone impaired fertility in male rats at high doses. This was evident from reductions in fertility index (numbers of rats pregnant/number of rats mated), reduced sperm motility (percentage of observed sperm that were motile), and reduced numbers of implantations and viable embryos in the females that did become pregnant. Statistically significant reductions in percentage of motile sperm were observed at exposures of 3 mg/kg/day and above. 0.5 mg/kg/day was the apparent NOAEL in this study, although a non-significant trend toward a reduction in the percentage of motile sperm may have been apparent.
Executive summary:

In this study, male rats were treated for 63 days prior cohabitation with untreated females. Dapsone at high doses impaired fertility in male rats. This was evident from reductions in fertility index (numbers of rats pregnant/number of rats mated), reduced sperm motility (percentage of observed sperm that were motile), and reduced numbers of implantations and viable embryos in the females that did become pregnant. Statistically significant reductions in percentage of motile sperm were observed at exposures of 3 mg/kg/day and above. 0.5 mg/kg/day was the apparent NOAEL in this study, although a non-significant trend toward a reduction in the percentage of motile sperm may have been apparent.