Registration Dossier

Administrative data

Endpoint:
screening for reproductive / 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:
guideline study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2008
Report Date:
2008

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
not specified
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
rat
Strain:
Crj: CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: Until copulation confirmed
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males: 14 days before mating until sacrifice (pre-mating and mating periods; 32 days total)
Females: 14 days before mating until the third day after delivery (pre-mating, mating and gestation periods)
Male: 43 days; Female: 40-53 days
Frequency of treatment:
Daily
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In female animals, reduced body weight gain during late pregnancy and lactation periods was found in the groups treated with 300 mg/kg bw/day dose and higher.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
. Fertility index at 1000 mg/kg bw/day was sifnificantly decreased. The implantation index and the number of pups born were significantly reduced in the groups treated with 300 mg/kg bw/day and higher. The reduction in the number of live pups in the 1000 mg/kg bw/day group was observed on postnatal days (PNDs) 0 and 4.

Details on results (P0)

Male animals were sacrificed and necropsied on Day 43, and the testis, epididymis, ventral prostate and seminal vesicle were collected. Testis and epididymis were weighed. All females delivered were sacrificed and necropsied on PND 4, and the ovary, uterus and vagina were collected.
No abnormalities were observed in delivery and lactation conditions, and the treatment also did not change a gestation length and the indices of birth rate, live birth rate and viability on PND 4. In addition, it did not affect indices of development and growth of the offspring, such as sex ratio and body weight on PND 0, 4, and body morphology.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
other: Implantation index.
Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male
Basis for effect level:
reproductive performance

Target system / organ toxicity (P0)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day (actual dose received)
System:
female reproductive system
Organ:
uterus
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
not specified

Results: P1 (second parental generation)

General toxicity (P1)

Histopathological findings: neoplastic:
not examined

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
not examined

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
gross pathology

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
yes
Lowest effective dose / conc.:
100 mg/kg bw/day
Treatment related:
yes
Relation to other toxic effects:
reproductive effects in the absence of other toxic effects
Dose response relationship:
yes
Relevant for humans:
not specified

Any other information on results incl. tables

With regard to reproductive toxicity, a decrease in the implantation index and the number of pups was noted in the groups treated with 300 mg/kg bw/day dose and higher. In male animals, histopathological examination found no abnormalities in the testis. However, a significant increase in the number of cauda epididymal lumen with decreased number of spermatozoa and slightly increased cell debris was observed in the epididymis of the 1000 mg/kg bw/day group.

Applicant's summary and conclusion

Conclusions:
There are two effects being displayed in this study. Firstly the reproductive performance/implantation in females with treatment related adverse effects at 300 mg/kg bw and above. The other effect is in the male sex organs at 1000 mg/kg bw. However the NOAEL 100 mg/kg bw is based on the effects seen in females.