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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2010
Report Date:
2010

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPPTS 870.3550 (Reproduction/Developmental Toxicity Screen)
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Lupranol VP 9236
- Content: 99.9 g/100g
- Physical state: liqiud (viscous)/colorless, clear
- Molecular weight: 280 g/mol

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS
The test substance was applied as a solution. To prepare the solution, the appropriate amount of test substance was weighed out depending on the desired concentration. Then the vehicle (drinking water) was filled up to the desired volume, subsequently mixed using a magnetic stirrer. The test-substance preparations were prepared daily.
The daily volume administered was 10 ml/kg of body weight.
Details on mating procedure:
MATING PROCEDURES:
Each of the male and female animals was mated overnight in a 1 : 1 ratio for a maximum of 2 weeks. Throughout the mating period, each female animal was paired with a predetermined male animal from the same dose group. The animals were paired by placing the female in the cage of the male mating partner from about 4.00 p.m. until 7.00 - 9.00 a.m. of the following morning. Deviations from the specified times were possible on weekends and public holidays and were reported in the raw data. A vaginal smear was prepared after each mating and examined for sperm. If sperm was detected, pairing of the animals was discontinued. The day on which sperm was detected was denoted "day 0" and the following day "day 1" post coitum.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The stability of the test substance in drinking water for a period of up to 4 hours at room temperature was verified.
Frequency of treatment:
Daily
Details on study schedule:
The test substance was administered orally via gavage to the F0 generation parental animals daily, at approximately at the same time in the morning(exception: no administration to animals being in labor). The treatment lasted up to one day prior to sacrifice. The animals of the control group were treated in the same way with the vehicle only (drinking water). The calculation of the volume administered was generally based on the most recent
individual body weights. At least 13 days after the beginning of treatment, males and females from the same dose group were mated overnight in a ratio of 1:1 (see details on mating procedure). All F0 males were sacrificed under Isoflurane anesthesia on study day 35 followed by necropsy. The females were allowed to litter and rear their pups until day 4 after parturition. F0 females were sacrificed under Isoflurane anesthesia on study day 49/56 followed by necropsy.
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:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Doses were selected according to a preceding subacute rat study were the same doses were applied over 4 weeks by gavage.

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
A cageside examination was conducted daily before and about 1 hour after application for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. Abnormalities and changes were documented for each animal.

The littering and lactation behavior of the dams was generally evaluated in the mornings in combination with the daily clinical inspection of the dams. Only particular findings (e.g., animal could not litter, umbilical cord not cut) were documented on an individual dam basis.
On weekdays (except public holidays) the littering behavior of the dams was inspected in the afternoons in addition to the evaluations in the mornings.
The day of littering was considered to be the 24-hour period from about 3.00 p.m. of one day until about 3.00 p.m. of the following day.

BODY WEIGHT: Yes
In general, the body weight of the male and female parental animals was determined once a week at the same time of the day (in the morning).
The body weight change of the animals was calculated from these results.
The following exceptions are notable for the female animals:
• During the mating period the parental females were weighed on the day of positive evidence of sperm (day 0 post coitum) and on days 7, 14 and 20 post coitum.
• Females with litter were weighed on the day of parturition (day 0 post partum) and on day4 post partum.

FOOD CONSUMPTION: Yes
Generally, food consumption was determined once a week (in a period of 7 or 6 days resp.) for male and female parental animals, with the following exceptions:
• Food consumption was not determined during the mating period (male and female F0
animals).
• Food consumption of the F0 females with evidence of sperm was determined on days 0,
7, 14 and 20 post coitum.
• Food consumption of F0 females, which gave birth to a litter was determined on days 0
and 4 post partum.
Food consumption was not determined in females without positive evidence of sperm (during the mating period of dams used in parallel) and females without litter (during the lactation period of dams used in parallel).

WATER CONSUMPTION : No
Sperm parameters (parental animals):
The following parameters were determined:
• sperm motility
• sperm morphology
• sperm head count (cauda epididymis)
• sperm head count (testis)
Sperm motility examinations and the preparation of the specimens for sperm morphology were carried out in a randomized sequence. Sperm morphology and sperm head count (cauda epididymis and testis) were evaluated forthe control and highest dose group, only.
Litter observations:
Pup number and status of delivery; pup viability/mortality; sex ratio, pup clinical observations, pup body weight data
Postmortem examinations (parental animals):
Gross pathological examination:
- Gross pathological examination was performed for all females and males at necrosy.
HISTOPATHOLOGY / ORGAN WEIGHTS
- Organ weights: Testes, Epididymides, Ovaries
- The following organs were fixed: all gross lesions, pituitary gland, prostate gland, seminal vesicles with coagulation glands, uterus, oviducts, cervix uteri, vagina, left testis, left epididymis, ovaries
Histopathological examination: all gross lesions, left testis, lefr epididymis, ovaries (all animals of the control and high dose group)
Postmortem examinations (offspring):
All surviving pups (after sacrifice on day 4 post partum by means of CO2), all stillborn pups and those pups that died before schedule, were examined externally, eviscerated and their organs were assessed macroscopically. All pups without any notable findings or abnormalities were discarded after their macroscopic evaluation.
Reproductive indices:
Reproductive indices:
- female and male mating index
- male and female fertility index
- gestation index
Offspring viability indices:
live birth index
post implantation loss
sex ratio

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed

Reproductive function / performance (P0)

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

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: general, systemic toxicity
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: reproductive performance and fertility

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: developmental toxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

Under the conditions of this reproduction/developmental toxicity screening test (OECD TG 421, gavage) the NOAEL (no observed adverse effect level) for reproductive performance and fertility is 1000 mg/kg body weight/day for the F0 parental rats. The NOAEL for general, systemic toxicity of the test substance was 1000 mg/kg body weight/day for the F0 parental animals. The NOAEL for developmental toxicity in the F1 progeny of the test-substance treated groups was found to be 1000 mg/kg body weight/day.