Registration Dossier

Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: 28-day repeated dose oral study with extended histopathology of the sex organs and spermatology
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
August 2011 to March 2012
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study, GLP
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: extended OECD 407 repeated dose study
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
see section on repeated dose toxicity.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
see section on repeated dose toxicity.
Details on mating procedure:
No mating extended histopathology of sex organs.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
see section on repeated dose toxicity.
Duration of treatment / exposure:
28-days
Frequency of treatment:
Daily
Details on study schedule:
see repeated dose toxicity section.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
30 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
300 mg/kg bw
Basis:
actual ingested
Remarks:
Doses / Concentrations:
1000 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
see repeated dose toxcicity section.
Control animals:
yes, concurrent vehicle
Details on study design:
see repeated dose toxcicity section.

Examinations

Parental animals: Observations and examinations:
see repeated dose toxcicity section.
Oestrous cyclicity (parental animals):
not determined
Sperm parameters (parental animals):
Sprem stages and interstitial structure were specifically investigated.
Litter observations:
not applicable
Postmortem examinations (parental animals):
Testes and epididymes preserved in Bouin's fluid. Sections were stained with heamatoxilin/eosin as well as for testes and epididymes with Periodic acid/Schiff's (PAS) stain.
Postmortem examinations (offspring):
not applicable
Statistics:
see repeated dose toxcicity section.
Reproductive indices:
not applicable
Offspring viability indices:
not applicable

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
see repeated dose toxcicity section.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
see repeated dose toxcicity section.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
see repeated dose toxcicity section.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
testes, epididymes and ovary weights not different from controls
Gross pathological findings:
no effects observed
Description (incidence and severity):
No effects on sex organs, other see repeated dose toxcicity section.
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
no effects on sex organs, other see repeated dose toxcicity section.
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: see repeated dose toxcicity section.

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
no effects on completeness of stages, maturation, reabsorption or degeneration
Reproductive performance:
not examined

Details on results (P0)

see repeated dose toxcicity section.
The sperm staging gave the following results: The tet item did not reveal effects on the completeness of stages or cell populations. No inidcation of maturation arrest, resorption of sperm or any degenerative type of effect was observed.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Weight of sex organs, histopathology of sex organs, sperm staging.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Mortality / viability:
not examined
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

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The repeated dose study with an extended histopatholgy of the male sex organs including sperm staging did not reveal any test substance related effects on the sex organs up to the highest dose tested. This indicates that on a screening level ther is no immediate concern for possible effects on fertility.
Executive summary:

In a 28 -day oral gavage study in rats receiving up to 1000 mg/kg bw of the test item per day for 28 consecutive days, no effects on male and female sex organs was observed. The study included an an extended histopatholgy of the male sex organs including sperm staging .No test substance related effects on the sex organs up to the highest dose tested were observed. This indicates that on a screening level there is no immediate concern for possible effects on fertility.