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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2012-08-29 - 2013-04-24
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Species:
rat
Strain:
other: Crl: CD(SD)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories,Research Models and Services, Germany GmbH, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: Males/females: Both 59 days
- Weight at study initiation: Males: 272.2 g to 299.9 g, Females: 210.4 g to 233.6 g


- Fasting period before study: 16 hours
- Housing: kept individually in MAKROLON cages (type III plus)
- Diet (e.g. ad libitum): Commercial ssniff® R/M-H V1534 (ssniff Spezialdiäten GmbH, 59494 Soest, Germany; served as food ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22°C ± 3°C
- Humidity (%): 55% ± 15%
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hours light / 12 hours dark
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg b.w./day
Details on mating procedure:
Sexually mature male and female rats were randomly paired for mating. Mating
was monogamous: 1 male and 1 female animal were placed in one cage during the
dark period. The female was placed with the same male until pregnancy had occurred
or 2 weeks had elapsed. Each morning the females were examined for the
presence of sperm or a vaginal plug. If findings were negative, mating was repeated.
The day of conception (day 0 of gestation) was considered to be the day
on which sperm was found. In case pairing was unsuccessful, re-mating of females
with proven males of the same group was considered. This procedure was
repeated until at least 8 pregnant dams were available for each group.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
For the analysis of the test item-vehicle mixtures samples of approx. 2 x 1 mL
were taken at the following time points and stored at ≤ minus 20°C until analysis
at LPT:
Start of treatment period Concentration and stability
Immediately after preparation of the test itemvehicle
mixtures as well as 8 and 24 hours after
storage of the test item preparations at room
temperature:
3 samples/dose level group (groups 2 to 4)
Number of samples: 3 x 3 = 9
Homogeneity
At start of administration, during (middle) administration
and before administration to the
last animal of each dose level group:
3 samples/dose level group (groups 2 to 4).
Number of samples: 3 x 3 = 9
End of treatment period Concentration
During treatment with the test item always before
administration to the last animal/dose level
group:
1 sample/dose level group (groups 2 to 4).
Number of samples: TD 26 (1 x 3) = 3
Number of samples: TD 39 (1 x 3) = 3
Sum of all samples: 24
Sum of all aliquots: 48
The samples were labelled with the study number, test item, test species, type of
sample, aliquot number, concentration, test day, sampling time and date.
Duration of treatment / exposure:
Males
The daily administration of the test item started
two weeks before mating and lasted until the
day before sacrifice (considering a minimum total
dosing period of at least 28 days).
Females
The daily administration of the test item started
two weeks before mating and lasted up to at
least day 3 of lactation.
Frequency of treatment:
once daily
Details on study schedule:
- Age at mating of the mated animals in the study: 10-11 week
Remarks:
Doses / Concentrations:
0 mg/kg bodyweight/day (control)
Basis:
actual ingested
Remarks:
Doses / Concentrations:
60 mg/kg bodyweight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
200 mg/kg bodyweight/day
Basis:
actual ingested
Remarks:
Doses / Concentrations:
600 mg/kg bodyweight/day
Basis:
actual ingested
No. of animals per sex per dose:
80 animals (40 male and 40 female rats),
10 animals/sex/group.
A sufficient number to grant at least 8 pregnant
females per group for evaluation of the F0 generation
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: See supporting study: 14-DAY DOSE-RANGE-FINDING STUDY OF IBP1-Na (DANAFLOATTM 245) BY ORAL ADMINISTRATION TO RATS
Parental animals: Observations and examinations:
AGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Cageside observations included skin/fur, eyes, mucous membranes, respiratory
and circulatory systems, somatomotor activity and behaviour patterns. The
onset, intensity and duration of any signs observed were recorded.
Individual animals were observed before and after dosing at each time of dosing for
any signs of behavioural changes, reaction to treatment or illness.
In addition, animals were checked regularly throughout the working day from 7:00
a.m. to 3:45 p.m. On Saturdays and Sundays animals were checked regularly from
7:00 a.m. to 11:00 a.m. with a final check performed at approximately 3:30 p.m.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least daily, The frequency was increased when signs of toxicity were observed.
Additionally, once before the first exposure (to allow within-subject comparisons)
and once a week thereafter, detailed clinical observations were made in all animals
outside the home cage in a standard arena and at the same time, each time preferably
by observers unaware of the treatment. Signs noted included changes in
skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and
autonomic activity (e.g. lacrimation, piloerection, pupil size, and unusual respiratory
pattern). Changes in gait, posture and response to handling as well as the
presence of clonic or tonic movements, stereotypies (e.g. excessive grooming,
repetitive circling), difficult or prolonged parturition or bizarre behaviour (e.g. selfmutilation,
walking backwards) were also recorded.
Dated and signed records of appearance, change, and disappearance of clinical
signs were maintained on clinical history sheets for individual animals.

BODY WEIGHT: Yes
- Time schedule for examinations: Males and females were weighed on the first day of dosing, weekly thereafter and
at termination of the study. During gestation, females were weighed on days 0, 7,
14 and 20 and within 24 hours of parturition (day 1 post-partum) and day 4 postpartum.
Body weights were recorded individually for each adult animal.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: daily
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No test item-related premature death was noted
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
The histopathological examination revealed test item related changes in the forestomach from male and female rats of the intermediate and the high dose group (200 and 600 mg IBP1-Na/kg b.w./day) in form of hyperplasia and hyperkeratosis of the squamous ce
Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: General health parameters
Key result
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Reproductive parameters
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
In the high dose group the mean litter weight of the male and female pups was decreased by 5.6% on lactation day 1 and by 9.6% on lactation day 4 (without statistical significance). No noticeable differences were noted for the total litter weight
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: General health parameters
Reproductive effects observed:
not specified
Conclusions:
The aim of the experiment was to obtain information on possible effects of the test item IBP1-Na on reproduction and/or development according to OECD guideline 422. The test item was administered orally to rats at dose levels of 60, 200 or 600 mg IBP1-Na/kg b.w./day.
The application started two weeks before mating on test day one and ended on the day or one day before sacrifice. Day of sacrifice was on test day 38 for the male rats and between lactation day 4 and 5 for the female rats.

Effects on the parental generation
No test item-related premature death was noted.
At the intermediate and the high dose level (200 and 600 mg IBP1-Na/kg b.w./day) a slight to extreme salivation was noted in nearly all animals, with a higher incidence at the high dose level. Piloerection and an increased water consumption were noted for a few animals of the intermediate and the high dose group.
The neurological screening revealed a reduction for the hindlimb grip strength of the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day).
A slight reduction in body weight was noted until the end of the study on test day 38 for the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day). Body weight at autopsy was reduced accordingly.
Examination of the haematological and biochemical parameters revealed statistically significant changes in the male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day), which were considered as to be test item-related.
Macroscopic inspection at autopsy revealed test item related changes in the cardiac part of the stomach from 3 male animals of the intermediate dose group (200 mg IBP1-Na/kg b.w./day) and in the cardiac part of the stomach from 1 female animal of the high dose group (600 mg IBP1-Na/kg b.w./day).
Examination of the organ weights revealed a slightly statistically significant increase in the relative liver weight of the male rats of the high dose group (600 mg IBP1-Na/kg b.w./day).
The histopathological examination revealed test item related changes in the forestomach from male and female rats of the intermediate and the high dose group (200 and 600 mg IBP1-Na/kg b.w./day) in form of hyperplasia and hyperkeratosis of the squamous cell epithelium, infiltration with neutrophilic granulocytes, granulation tissue and ulcerations.

Additionally, a test item-related centrilobullar hepatocellular hypertrophy was noted In the liver from male and female animals of the high dose group (600 mg IBP1-Na/kg b.w./day).

Effects on reproduction parameters and organs
No test item-related influence was noted on the reproduction parameters and organs in any treatment group.
The qualitative sperm staging revealed no test item-related spermatogenic changes.

Effects on the development of the F1 offspring (pups)
A non-statistically significant reduction in mean litter weight of approximately 6% to 9% was noted on lactation day 1 and 4 for the male and female pups of the high dose group (600 mg IBP1-Na/kg b.w./day), which is regarded to be test item-related.
No test item related influence was noted on the survival rate of the pups.

The following no-observed-effect levels were established for systemic effects:
Effects on the F0-generation
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.

Effects on reproduction
NOAEL (no-observed-adverse-effect level): 200 mg IBP1-Na/kg b.w./day, p.o.

Remark: The test solution contains NaOH due to the production method.
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for selection of Effect on fertility via oral route:

Effects on developmental toxicity

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2016-2017
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes (incl. QA statement)
Limit test:
no
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Batch No.of test material:0001021592
- Expiration date of the lot/batch:December 11th, 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature, protected from light
- Stability under test conditions: Stable
- Solubility and stability of the test substance in the solvent/vehicle: Stable
Species:
rat
Strain:
Wistar
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, 97633 Sulzfeld, Germany
- Age at study initiation: 12-13 weeks
- Weight at study initiation:
Body weight before
the start of pairing:
males: 349 – 381 g (mean: 366.67 g, ± 20% = 293.34 – 440.01 g)
females: 180 - 236 g (mean: 204.17 g, ± 20% = 163.34 – 245.01 g)
- Housing: - Full barrier in an air-conditioned room
- Diet (e.g. ad libitum): - Free access to Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum): - Free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control, microbiological controls at regular intervals)
- Acclimation period: minimum 5 days

DETAILS OF FOOD AND WATER QUALITY:
- Diet (e.g. ad libitum): - Free access to Altromin 1324 maintenance diet for rats and mice
- Water (e.g. ad libitum):- Free access to tap water, sulphur acidified to a pH of approximately 2.8 (drinking water, municipal residue control
ENVIRONMENTAL CONDITIONS
- Temperature (°C):22 ± 3 °C
- Humidity (%): 55 ± 10 %
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: To:
Delivery of Animals: 03 March 2016
Acclimatisation Period: 03 - 08 March 2016
Experimental Starting Date: 08 March 2016
Experimental Completion Date: 08 July 2016
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

VEHICLE
- Justification for use and choice of vehicle (if other than water): water used
- Concentration in vehicle: 0 23,5, 117,6 and 313,7 mg/l
- Amount of vehicle (if gavage): 5 mL/kg body weight
- Lot/batch no. (if required):
Name: aqua ad iniectabilia
Manufacturer: AlleMan Pharma
Batch No.: 503424
Physical State: liquid
Storage Conditions: at room temperature
Expiry Date: 28/02/2018

- Purity: pure
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The assessment of homogeneity as well as a determination of the nominal concentration of the test item in the vehicle was performed at various intervals using a validated analytic method (BSL Munich study no. 156096).
Samples for analysis of concentration analysis of the active ingredient within the vehicle (nominal concentration) were taken in the first and last week of the study for all doses, including controls (8 samples in total). Samples for homogeneity were taken from the top, middle and bottom of the high dose and low dose preparation. Samples were taken in the first and last week of the study (12 samples in total).
Each sample was retained in duplicates (sample A, sample B, each at least 5 mL). The A- sample were analysed at Eurofins Munich. The procedures followed for the study sample analysis were mentioned in a phase plan (BSL Munich study no. 156108) that was amended to the study plan. The B-samples were retained at -15 to -35°C at BSL Munich until the analysis had been performed, and discarded after completion of the final study report. Analytical results are reported in the appendix of the present report (Appendix 3).
Concentration results were considered acceptable if sample concentration results are within or equal to ± 10% of theoretical concentration. For homogeneity, the criteria for acceptability were a relative standard deviation (RSD) of concentrations of ≤10% for each group.
Details on mating procedure:
Mating was performed using a ratio of 1:2 (male to female). Females were paired for cohabitation in batches in order to control the number of animals for terminal sacrifice on a particular day. At the subsequent morning and the next morning onwards, the vaginal smear of each female was checked to confirm the pregnancy. The day on which sperms were observed in the vaginal smear was considered as gestation day ‘0’. Mated females were assigned in an unbiased manner to the control and treatment groups ensuring that group mean body weights were comparable with each other. Each animal was assigned an unique identification number. After obtaining a sufficient number of sperm positive females, the remaining females and males were discarded without any observations.
Duration of treatment / exposure:
The pregnant females were treated with the test item formulation or vehicle on 7 days per week between gestation day 5 until gestation day 19.
Frequency of treatment:
Daily, between gestation day 5 and gestation day 19.
Duration of test:
Until gestation day 20
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control group, group name C
Dose / conc.:
60 mg/kg bw/day (nominal)
Remarks:
Lowest dosage group, group name LD
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Medium dosage group, group name MD
Dose / conc.:
800 mg/kg bw/day (nominal)
Remarks:
High dosage group, group name HD
No. of animals per sex per dose:
The control group had 23 sperm positive females, the LD group had 29 sperm positive females and the MD and HD groups each had 24 sperm positive females. However, at necropsy, the number of gravid females was 21 of 23 in the control group, 21 of 29 in the LD group, 20 of 24 in the MD group and 20 of 24 in the HD group.
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day, approximately at the same time each day at 30 min after dosing. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: General clinical observations were made once a day, approximately at the same time each day at 30 min after dosing. Twice daily all animals were observed for morbidity and mortality except on weekends and public holidays when observations were made once daily.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed once before initiation of pairing to ensure that the body weights are within + 20% variation.
The sperm positive females were weighed during gestations days 0, 5, 8, 11, 14, 17 and 20. Males were not weighed in this study except once before initiation of pairing.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
Food consumption of sperm positive females was measured on gestations days 5, 8, 11, 14, 17 and 20.
Food consumption was not measured for males during the entire study or for both males and females during the mating period

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: At the time of termination, the dam (presumed pregnant female) was examined macroscopically for any structural abnormalities or pathological changes, which may have influenced the pregnancy. Immediately after the termination, the uteri were removed and the pregnancy status of the dams was confirmed. Uteri that appear non-gravid were further examined by staining with 10 % ammonium sulphide solution to confirm the non-pregnant status.
Each gravid uterus with the cervix was weighed. The number of corpora lutea was counted for pregnant animals. The uterine contents were examined for embryonic or fetal deaths as well as the number of viable fetuses. The degree of resorption (late and early) was confirmed in order to help estimate the relative time of death of the conceptus. The position and number of fetuses in each uterine horn was also recorded.


OTHER:
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [/ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]
Craniofacial examination of the heads of the fetuses used for the soft tissue examination were performed for internal structure including the eyes, brain, nasal passage and tongue by razor blade serial sectioning
technique.
Fetuses scheduled for skeletal examination were eviscerated and the entire litter was transferred into separate(?) plastic bottles containing 95% ethanol. These fetuses were processed using the Alizarin red staining technique. After fixation in 95% ethanol, the fetuses were macerated with a 1% aqueous potassium hydroxide solution for 1 day and transferred to an Alizarin red solution (0.0025% in 1% aqueous potassium hydroxide) for 1 day. After that, the fetuses were again transferred to 1 % KOH. Alizarin stained fetuses were then cleared and dehydrated in a solution containing 2 parts of 70% ethanol, 2 parts of glycerin and one part of benzyl alcohol for 1 day and finally preserved in a 1:1 solution of 70 % ethanol and glycerin.
The stained fetuses were examined under the stereomicroscope, the skull was examined for size, shape and degree of ossification of nasal, parietal, interparietal, supraoccipital, exoccipital, lacrimal, zygomatic (malar), squamosal (temporal), premaxillary, maxillary, basisphenoid, hyoid and tympanic ring (annulus). Similarly, the vertebral centres, ribs and sternal centres were also examined for size, shape and counted for the number of ossification centers. The cervical, thoracic, lumbar, sacral, caudal vertebrae were observed for the ossification of centers and arches. Pelvic girdles, fore limbs and hind limbs were examined for the development of the bones. Any deviation from the normal development was recorded for each fetus.

- Head examinations: Yes: [all per litter / half per litter / #? per litter ] / No / No data
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The observation of moving the bedding started with the onset of treatment in MD and HD group animals. Few animals of LD group also showed moving the bedding from GD 12. This behavior was seen immediately post dose administration, was transient and is considered to be a local and non-specific reaction.
Abnormal breathing was observed in 1 of 24 females of MD group and 4 of 24 females of HD group; alopecia was observed in 3 of 29 females of LD group and 1 of 24 females of HD group; crust formation was observed in 1 of 24 females of HD group; piloerection was observed in 4 of 24 females of HD group; salivation was observed in 2 of 29 females of LD group, 1 of 24 females of MD group and 1 of 24 females of HD group. The clinical signs alopecia and salivation in test item treated groups did not show dose dependency and occurred sporadically in single animals. The abnormal breathing was transient, occurred sporadically and was limited to 4 of 24 animals. Therefore, these clinical findings were not considered to be adverse or treatment-related.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects on body weight and body weight gain in test-item treated groups compared to the controls. HD animals showed statistically significantly lower weight gain or body weight loss between GD 5-8 however all animals recovered quickly and between GD 8-11 there was a higher weight gain in the HD group compared to the corresponding control. These changes were transient and are not considered to be an adverse effect of test-item treatment.
There were no statistically significant differences in the mean terminal body weights and mean adjusted maternal body weights in test-item treated groups compared to the corresponding control group.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
There was no adverse effects on food consumption during the treatment period in test-item treated groups compared to the control. There was statistically significantly lower food consumption between GD 5-8 in the HD group compared to the corresponding control however all animals recovered quickly and showed food consumption values similar to controls from GD 8 and onwards. This transient change was not considered to be an adverse effect of test-item treatment.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
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:
effects observed, non-treatment-related
Description (incidence and severity):
There were no adverse macroscopic findings in test-item treated group animals. In the LD group there were observations of a cyst on the ovary (1 of 29 females), extra growth in fat tissue (1 of 29 females), and fluid filled and distended uterus (2 of 29 females). In the MD group there was one observation of a fluid filled ovary (1 of 24 females). These findings occurred in a limited number of females and without dose dependency. Therefore, these findings are not considered to be related to test-item treatment.
Neuropathological findings:
no effects observed
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects of test-item treatment on prenatal parameters including the number of corpora lutea, number of implantation sites, number of live fetuses and number of resorptions (early and late), number of male and female fetuses, sex ratio and percent pre- and post-implantation losses. Statistically significantly higher mean resorptions (early and total) occurred in the MD group (1.45) compared to the control group (0.48). This finding was not dose dependent and therefore, is not assumed to be related to test-item treatment
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
There were no effects of test-item treatment on prenatal parameters including the number of corpora lutea, number of implantation sites, number of live fetuses and number of resorptions (early and late), number of male and female fetuses, sex ratio and percent pre- and post-implantation losses. Statistically significantly higher mean resorptions (early and total) occurred in the MD group (1.45) compared to the control group (0.48). This finding was not dose dependent and therefore, is not assumed to be related to test-item treatment
Dead fetuses:
effects observed, non-treatment-related
Description (incidence and severity):
The finding of 8 dead fetuses in female no. 79 of the HD group was an isolated incidence and is not considered to be a treatment-related effect. The adjusted body weight of this animals was significantly lower compared to the other animals in the group, and the food consumption was reduced from gd 17-20 during which period the animal lost weight
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
act. ingr.
Basis for effect level:
behaviour (functional findings)
body weight and weight gain
changes in number of pregnant
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
effects on pregnancy duration
food consumption and compound intake
gross pathology
mortality
number of abortions
pre and post implantation loss
total litter losses by resorption
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were slightly higher incidences of incomplete ossification of supraoccipital bones in MD (30%) and HD (35%) compared to control (23.81%); and slightly higher incidences of full 14th rib (right sided) in MD (10%) and HD (10%) group compared to control (4.76%). In addition, in the HD group there was a higher incidence of misshapen 6th sternebrum (10% in HD and 0% in control); a higher incidence of extra ossification sites at vertebral lumbar arch(es) (10% in HD group and 0% in control); a higher incidence of unossified forelimb metacarpals (63.16% in HD group (and 28.57% in control); a higher incidence of pelvic caudal bone (Bilateral) shift (25% in HD and 19.05% in control) a higher incidence of cervical 7th rudimentary rib (bilateral) (15% in HD (and 4.76% in control); and a higher incidence of cervical 7th rudimentary rib (left) (15% in HD group and 9.52% in control).
Higher incidences of cervical 7th rudimentary rib (right) were noted in LD (14.29%) and HD (10%) groups compared to control (4.76%).
The incidences of all of these observations in the test-item treated groups were without statistical significance, without dose dependency and/or were within the historical control data range, except for the misshapen 6th sternebrum in HD group, for which the incidence was outside the historical control data range (0% to 4.55%). The misshapened sternebrae is a malformation, but considering that only 3 of 112 fetuses were affected, and in the complete absence of any other indication of treatment-related fetal effects within the group, the finding was not considered to be related to the test item, but rather a coincidental finding.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
There were a range of visceral observations in control and test item treated groups. Most of the observations were noted in single animals and none occurred at statistically significantly higher incidences in test- item treated groups when compared to the corresponding control group. There were higher litter incidences of dilated ureter (bilateral) in MD (30%) and HD (30%) groups compared to control (23.81%) without statistical significance and these were within the historical control data range (see Appendix 4). Therefore, this finding was not an adverse effect of test-item treatment
Other effects:
not specified
Key result
Dose descriptor:
NOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
act. ingr.
Sex:
not specified
Basis for effect level:
reduction in number of live offspring
changes in sex ratio
fetal/pup body weight changes
changes in litter size and weights
changes in postnatal survival
external malformations
skeletal malformations
visceral malformations
Key result
Abnormalities:
no effects observed
Localisation:
external: cranium
external: ear
external: eye
external: face
external: limb
external: paw
external: tail
external: trunk
external: anogenital distance
external: anus
external: genital tubercle
external: large intestine
external: thorax
external: umbilicus
external: pelvic region
skeletal: skull
skeletal: skull, fontanelles
skeletal: skull sutures
skeletal: clavicle
skeletal: scapule
skeletal: forelimb
skeletal: sternum
skeletal: rib
skeletal: supernumerary rib
skeletal: vertebra
skeletal: pelvic girdle
skeletal: hindlimb
visceral/soft tissue: integumentary
visceral/soft tissue: gastrointestinal tract
visceral/soft tissue: hepatobiliary
visceral/soft tissue: urinary
visceral/soft tissue: cardiovascular
visceral/soft tissue: heamatopoietic
visceral/soft tissue: immune system
visceral/soft tissue: musculoskeletal system
visceral/soft tissue: nervous system
visceral/soft tissue: central nervous system
visceral/soft tissue: peripheral nervous system
visceral/soft tissue: somatic nervous system
visceral/soft tissue: autonomic nervous system
visceral/soft tissue: endocrine system
visceral/soft tissue: respiratory system
visceral/soft tissue: male reproductive system
visceral/soft tissue: female reproductive system
visceral/soft tissue: eye
visceral/soft tissue: ear
other:
Key result
Developmental effects observed:
no
Conclusions:
On the basis of this prenatal developmental toxicity study in Wistar pregnant female rats with IBP1-Na at dose levels of 60, 300, and 800 mg/ kg body weight/ day administered on gestation days 5 to 19, the following conclusions can be made:
There were no observed effects on maternal animals of test-item treated groups compared to the corresponding control group. There were no treatment-related adverse effects on embryo-fetal development. Thus, the NOAEL for the maternal toxicity and embryo-fetal developmental toxicity is 800 mg/ kg body weight/ day.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
800 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for selection of Effect on developmental toxicity: via oral route:

Justification for classification or non-classification

Additional information