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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions. No data on vehicle for gavage. Limited details on test substance and examinations.
Justification for type of information:
refer to category justification provided in IUCLID section 13

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2007

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
yes
Remarks:
no data on vehicle for gavage; limited details on test substance and examinations
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Hsd: Sprague–Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: (P) 12 weeks
- Housing: in groups of 5 per sex per cage
- Diet: laboratory rodent diet (Altromin MT pelleted diet, A. Rieper, Bolzano, Italy), ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 55 ± 10
- Air changes (per hr): 15-20
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
Dose volumes are calculated according to individual body weight on the first day of treatment and adjusted for body weight at weekly intervals.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: approx. 3 days (mean pre-coital period) up to 20 days
- Proof of pregnancy: vaginal plug and/or vaginal smear
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
(P) Males and females: 2 weeks before pairing and continuously thereafter, up to the day before sacrifice (study day 53, day 4 post partum)
Frequency of treatment:
daily, 7 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
300 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: clinical signs were recorded daily throughout the study.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: all animals were examined on arrival. Examinations of dams and litters took place on Day 4 post-partum.

BODY WEIGHT: Yes
- Time schedule for examinations: body weight was determined on the first day of treatment with the test material and in weekly intervals thereafter.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption: Yes, not further specified

OTHER:
- Prostate weight, testes, weight, epididymides weight, seminal vesicle weight and gestation period were determined
Oestrous cyclicity (parental animals):
Vaginal smears are taken daily for 14 days prior to pairing and each morning during the pairing period to detect marked anomalies of the estrous cycle and to determine the median pre-coital interval.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: testis weight, epididymis weight, seminal vesicle weight
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, presence of gross anomalies, weight gain, food consumption, physical or behavioural abnormalities, other: implantation per litter, mean litter weights, mean pup weights, pre-birth loss

GROSS EXAMINATION OF DEAD PUPS:
yes, for external and internal abnormalities; possible cause of death was not determined for pups born or found dead
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals on Day 53 (on Day 4 post partum)
- Maternal animals: All surviving animals on Day 53 (on Day 4 post partum)
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 4 days of age.
- These animals were subjected to postmortem examinations (macroscopic examination).
Statistics:
Mean values and standard deviations of the following parameters were calculated:
- litter weights at birth and sacrifice
- absolute and relative organ weights of testes, epididymis, seminal vesicles and prostate
- pre-coital intervals
- total litter size, sex ratio (%)
- implantation/litter
- gestation period
- pre-birth loss/litter (number and %)
Reproductive indices:
female: copulation or fertility index, pregnancy rates, copulatory intervals
males: fertility index

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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:
not examined
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:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
No clinical signs were observed during the whole study period.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
No effects on body weights were noted during the study.

TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)
No effects on food consumption were observed during the experimental period.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No effects on estrous cycle were reported.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No treatment-related effects on absolute and relative weights of testis and epididymis were observed at any dose level.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
In males and females, no substance-related effects on fertility index were observed. A slight, but not significant decrease in copulatory index was observed in females receiving the high dose (1000 mg/kg bw/d). One female in the mid-dose group and two females in the high-dose group did not mate until day 10 and were mated with another male afterwards. One female in the high dose group did not mate after a period of 20 days.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No effects on relative and absolute weights of testis, epididymis, and seminal vesicles were observed between test substance-treated and control animals. A marginal reduction in absolute and relative prostate weights in all treated males compared to the control group was noted. In the low dose group (100 mg/kg bw/d) a significant reduction in the weights of prostate were observed. Due to the absence of dose-dependency, this effect was not considered to be biologically significant.

GROSS PATHOLOGY (PARENTAL ANIMALS)
No substance-related effects were seen at macroscopic examination.

Effect levels (P0)

open allclose all
Key result
Dose descriptor:
NOAEL
Remarks:
systemic toxicity
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no treatment-related effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Remarks:
reproductive toxicity
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects on male and female reproductive organs and performance
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (P0)

Key result
Critical effects observed:
no

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:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)
No effects on mean litter weights and sex ratios were observed between the F1 generations of treated and control animals. Some slight, but not significant variations in pre-birth loss were seen in the high-dose group compared to controls.

CLINICAL SIGNS (OFFSPRING)
No treatment-related clinical signs were observed in pre-weaning pups.

BODY WEIGHT (OFFSPRING)
No differences in the mean litter weight on Day 0 (birth) and Day 4 (sacrifice) were noted in treated and control groups.

GROSS PATHOLOGY (OFFSPRING)
Necropsy did not reveal any substance-related effects in decedent or F1 pups.

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Remarks:
embryo/fetotoxicity
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse effects on embryo/fetotoxicity
Remarks on result:
not determinable due to absence of adverse toxic effects

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
A reproduction/developmental toxicity screening test performed according to OECD 421 with the test material did not result in any adverse effect on maternal/reproductive/embryo-/fetotoxicity. Thus, a NOAEL (maternal/reproduction/embryo-/fetotoxicity) of ≥1000 mg/kg bw/day was derived.