Registration Dossier
Registration Dossier
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 305-230-8 | CAS number: 94350-12-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- From 11 December 2017 to 18 March 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 018
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- 2016
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Saccharomyces cerevisiae, lysate
- EC Number:
- 305-230-8
- EC Name:
- Saccharomyces cerevisiae, lysate
- Cas Number:
- 94350-12-6
- IUPAC Name:
- Saccharomyces cerevisiae, lysate
- Test material form:
- solid: particulate/powder
- Remarks:
- light beige
- Details on test material:
- - Source and lot/batch No.of test material:
supplied by the sponsor, batch no. AC17F00560
- Expiration date of the lot/batch: February 2019
- Purity test date: 30 June 2017
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: supplied by the Sponsor, batch no. AC17F00560
- Expiration date of the lot/batch: 28 February 2019
- Purity test date: 30 June 2017
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Controlled room temperature (15-25ºC, ≤70% Relative Humidity); as the powder was hygroscopic, it should be stored appropriately (in a tightly closed container).
- Stability under test conditions: Stable under the test conditions
- Solubility and stability of the test substance in the solvent/vehicle: All test item formulation samples were found to be homogeneous. Formulations were considered to be adequately stable under the study conditions.
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: not applicable
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test item was formulated in the vehicle (as a visibly stable homogenous suspension). Formulations were prepared daily (fresh prior to administration to animals) at appropriate concentrations (according to the dose level and treatment volume selected)
- Preliminary purification step (if any): not applicable
- Final dilution of a dissolved solid, stock liquid or gel: 0, 20, 60, 200 mg/mL
- Final preparation of a solid: The calculated amount of test item was added into a beaker, then it was filled up with the vehicle up to the calculated final volume. The mixture was mixed vigorously by a magnetic stirrer to make a homogenous formulation and was kept mixed until the end of treatment.
FORM AS APPLIED IN THE TEST (if different from that of starting material)
In formulation in vehicle
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- The rat is regarded as a suitable species for toxicology and reproduction toxicology studies. Wistar rat was selected due to experience with this strain of rat in toxicity and reproduction toxicity studies and known fertility. The same strain was used for the Dose Range Finding study
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: Young adult rats, approximately 12 weeks old at start and 14 weeks old at mating.
- Weight at study initiation: Young adult rats, approximately 12 weeks old at start and 14 weeks old at mating.
- Fasting period before study: No fasting period
- Housing: Type II polycarbonate
- Diet (e.g. ad libitum): ssniff® SM R/M “Autoclavable complete diet for rats and mice – breeding and maintenance” ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: 13 days
DETAILS OF FOOD AND WATER QUALITY: The food was considered not to contain any contaminants that could reasonably be expected to affect the purpose or integrity of the study. Water quality control analysis was performed at least once every three months and microbiological assessment is performed monthly.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.5-25.4°C
- Humidity (%): 21-48%
- Air changes (per hr): 15-20 air exchanges per hour
- Photoperiod (hrs dark / hrs light): 12h/12h
IN-LIFE DATES: From: 30 November 2017 To:24 January 2018
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- - PREPARATION OF DOSING SOLUTIONS:
:
The test item was formulated in the vehicle (as a visibly stable homogenous suspension). Formulations were prepared daily (fresh prior to administration to animals) at appropriate concentrations (according to the dose level and treatment volume selected)
- VEHICLE
- Justification for use and choice of vehicle (if other than water): Based on the available information provided by the Sponsor as well as results of two studies performed at the Test Facility, distilled water was selected as vehicle for this study in agreement with the Sponsor. The same vehicle was used in the Dose Range Finding study
- Concentration in vehicle: 0, 20, 60 and 200 mg/mL
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): Distilled water
Manufacturer: Hungaro-Gal Ltd.
Batch number: 8130917
- Purity: pure - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The results of the dose formulation analysis was performed using a UV spectrophotometric method. Samples were collected three times during the study. Samples were kept on ice and analysed within the stability period. The measured test item concentrations of the individual test item containing dose formulations varied between 96.7% and 104.4% of their nominal concentrations, the mean values were in the 98.2-103.8% range. No test item was detected in the control samples. These results were within the acceptable ranges (90% - 110%) and were considered suitable for the study purposes. All test item formulation samples were found to be homogeneous. Formulations were considered to be adequately stable under the study conditions.
- Duration of treatment / exposure:
- Male and female Wistar rats were treated for 2 weeks pre-mating and then during the mating / post-mating periods. This was 28 days in total for males. Females were treated throughout gestation and up to and including postpartum/lactation day (63 days)
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- 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:
- 12 animals per sex per dose were used
- Control animals:
- yes
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose levels were selected based on available data, including the results of an acute oral toxicity study in rats (according to OECD No. 423) performed at the Test Facility and a 7-day repeated Dose Range Finding (DRF) study in the rat performed at the Test Facility with the aim of inducing toxic effects but ideally no death or suffering at the highest dose, up to a limit of 1000 mg/kg/day, and a NOAEL at the lowest dose
- Rationale for animal assignment (if not random): All adult/parental (P) male and female animals were sorted according to body weight by computer and divided into weight ranges on the day of start of treatment. There were an equal number of animals from each weight group randomly assigned to each dose group to ensure that animals of all test groups were as nearly as practicable of a uniform weight. This process was controlled by the computer software PROVANTIS v.9, to verify the homogeneity/variability between/within the groups. Males and females were randomised separately.
- Rationale for selecting satellite groups: no satellite group
- Post-exposure recovery period in satellite groups: no satellite group
- Section schedule rationale (if not random): according to OECD No. 422 guideline
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice daily
- Cage side observations checked: Animals were inspected for signs of morbidity and mortality.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule and parameters checked: More detailed examinations were performed once before the first exposure (to allow for within-subject comparisons), then at least weekly, in the morning or before treatment. These observations were performed outside the home cage in a standard arena, at similar day times as practical. The animals were monitored for changes in skin, fur, eyes, mucous membranes, occurrence of secretions and excretions, and autonomic activity (e.g. lachrymation, 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. self-mutilation, walking backwards) were also recorded. Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
BODY WEIGHT: Yes
- Time schedule for examinations: All adult animals were weighed with an accuracy of 1 g for randomisation purposes, then at least weekly during the pre-exposure period, on Day 0, afterwards at least weekly and at termination.
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: No : g/animal/day
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: All animals selected for blood sampling were fasted (overnight period of food deprivation, after the litter had been culled). Blood samples were collected by cardiac puncture under pentobarbital anaesthesia, immediately prior to scheduled necropsy.
For terminal blood sampling in all selected animals (5 males and 5 females/group),
3 samples were taken from each animal: one for haematology (in tubes with K3-EDTA as anticoagulant, 1.6 mg/mL blood), one for blood clotting times (in tubes with sodium citrate as anticoagulant) and one to obtain serum (in tubes with no anticoagulant) for clinical chemistry.
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: Yes
- How many animals: 40 animals
- Parameters checked in table 1 were examined.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
All animals selected for blood sampling were fasted (overnight period of food deprivation, after the litter had been culled). Blood samples were collected by cardiac puncture under pentobarbital anaesthesia, immediately prior to scheduled necropsy.
For terminal blood sampling in all selected animals (5 males and 5 females/group),
3 samples were taken from each animal: one for haematology (in tubes with K3-EDTA as anticoagulant, 1.6 mg/mL blood), one for blood clotting times (in tubes with sodium citrate as anticoagulant) and one to obtain serum (in tubes with no anticoagulant) for clinical chemistry.
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: Yes
- How many animals: 40 animals
- Parameters checked in table 2 were examined.
URINALYSIS: Yes / No / Not specified
- Time schedule for collection of urine: Urine sampling was performed prior to necropsy by placing the selected animals in metabolic cages for approximately 16 hours
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table 3 were examined.
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: last exposure week (Day 22-23 for males and PPD8-9 for females)
- Dose groups that were examined: 5 animals per sex per group were examined
- Battery of functions tested: sensory activity ; grip strength ; motor activity
other: Parameters including body position, locomotor activity, respiration rate, respiration type, piloerection, head searching compulsive biting or licking, circling, upright walking, retropulsion, jumping, exophthalmos, twitches, clonic convulsions, tonic convulsions, tremor, startle, transfer arousal, spatial locomotion, gait, posture, limb position, finger approach, finger withdrawal, touch escape response, diarrhoea, diuresis, visual placing, grip strength, body tone, corneal reflex, pinna, toe pinch, grasping reflex, positional struggle, skin, mucous membrane colour, salivation, palpebral closure, lachrymation, limb tone, abdominal tone, tail pinch, righting reflex, and/or vocalisation were evaluated using a scoring system
Assessment of potential test item related neurotoxicity was performed during the last exposure week (males on Day 22-23; females on PPD8-9). Selected animals (5 per sex per group) were subjected to the functional observation battery including quantitative assessment of grip strength and measurement of landing foot splay and fore/hind limb grip strength.Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity was conducted and the general physical condition and behaviour of animals were tested. A modified Irwin test was performed Parameters including body position, locomotor activity, respiration rate, respiration type, piloerection, head searching compulsive biting or licking, circling, upright walking, retropulsion, jumping, exophthalmos, twitches, clonic convulsions, tonic convulsions, tremor, startle, transfer arousal, spatial locomotion, gait, posture, limb position, finger approach, finger withdrawal, touch escape response, diarrhoea, diuresis, visual placing, grip strength, body tone, corneal reflex, pinna, toe pinch, grasping reflex, positional struggle, skin, mucous membrane colour, salivation, palpebral closure, lachrymation, limb tone, abdominal tone, tail pinch, righting reflex, and/or vocalisation were evaluated using a scoring system, where score “0” was given when the behaviour or reaction of the animal was considered normal, and -1 or -2, or +1 and +2 was given if the response was less than or more than expected in an untreated animal. Locomotor activity assessment was conducted using Automatic Monitoring System of rat locomotor activity SMART v. 2.5 (Harvard Apparatus, Germany). Locomotor activity was monitored by placing each animal individually into an open-field of
50 x 50 cm for a 1-hour observation time; a DVD recording of activity/movement was made. A recording was made for a duration of 60 minutes, under dim-light and undisturbed conditions for each evaluated animal. The DVD was analysed with “SMART” software after all recordings were made, to produce the appropriate parameters. The data from all groups was evaluated for distance travelled in 5-minute segments of the 1 hour. The data from the 5-minute segments were presented graphically with the intention of showing plateau activity in controls, and comparing the treatment groups.
During micoscopic evaluation, special attention was paid to the central and peripheral nervous system tissues for any evidence of neurotoxicity
IMMUNOLOGY: During micoscopic evaluation, special attention was paid to the organ weight, appearance and histopathology of immune-system tissues for any evidence of immunotoxicity (spleen, thymus, lymph nodes and bone marrow).
OTHER: For thyroid hormone analysis, blood samples were taken by cardiac puncture or venepuncture into tubes containing K3-EDTA as anticoagulant from all adult males at termination. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
At termination, the adult rats were euthanized under pentobarbital anaesthesia, followed by exsanguination.
Gross necropsy was performed on all animals. After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed macroscopically. Any abnormality was recorded with details of the location, colour, shape and size, as appropriate. Special attention was paid to the organs of the reproductive system.
HISTOPATHOLOGY: Yes (see table 4) - Other examinations:
- This study was performed according to OECD TG 422 method. Hence, additional parameters were evaluated as reproductive functions and organs and pups (detailed in the section 7.8.1 Toxicity to reproduction)
- Statistics:
- The statistical evaluation of data was performed with the program package SPSS PC+4.0 or SAS v9.2.
In case of the SPSS PC+4.0 software, the heterogeneity of variance between groups was checked by Bartlett's test. Where no significant heterogeneity was detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was significant, then Duncan's Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorow-Smirnow test. In the case of non-normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was applied. If a positive result was detected, the inter-group comparisons were performed using Mann-Whitney U-test. The Chi-squared test was used for non-continuous data. In case of the SAS v9.2 software the normality and heterogeneity of variance between groups was checked by Shapiro-Wilk and Levene tests. Where both tests showed no significant heterogeneity, an Anova / Ancova test was carried out. If the obtained result was positive, Dunnett’s test was used to assess the significance of inter-group differences; identifying differences of <0.05 or <0.01.
If either of the Shapiro-Wilk or Levene tests showed significance on the data, a Kruskal-Wallis analysis of variance was used after Rank Transformation. If there was a positive result, the inter-group comparisons were performed using Dunn test. For non-continuous data, the Cochran-Armitage test for trend was applied and the Chi-squared test was used for differences relative to control.
For pathology data, Chi-squared test was used to check for overall similarity of the relative frequencies, the system then checked the significance against a 0.05 value and also performed pairwise tests of the treatment groups versus the control group. The Fisher’s Exact Test was performed replacing the Chi-squared test if the group size was <5.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- No clinical signs were observed during the study.
- Mortality:
- no mortality observed
- Description (incidence):
- No mortality was observed in the study.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No test item effect on body weight or body weight gain was detected during the study. There were no statistically significant variations in body weight or body weight gain values in the test item treated groups of either sex when compared to the control at any occasion. The measured values were within the range commonly recorded for this strain and age. The slight increased total body weight gain value of the High dose females compared to control (calculated for the entire period of the study) was without statistical significance and without dose response, thus it was not considered as a test item related effect.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- There were no test item related differences in the mean daily food consumption in any test item treated group when compared to the controls. The measured values were within the normal range for this strain and age. Occasional statistically significant differences were regarded as incidental and of no toxicological significance.
- Haematological findings:
- no effects observed
- Description (incidence and severity):
- When compared to the controls, there were no statistically significant differences or biologically relevant test item related changes in males and females of the test item treated groups. The relative amount of eosinophil leukocytes showed relatively large percentage differences in the test item treated groups when compared to control due to the low absolute values which is normal for this parameter. However, opposite trends were seen in males and females, there was no statistical significance and the observed values were within the historical control range. Thus, these differences were considered as animal variability, not being a test item related effect. No statistically significant changes were recorded for any other haematology or coagulation parameters in the test item treated males and females.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no significant changes or biologically relevant effects on the serum chemistry that could be ascribed to the test item administration. A relatively large percentage difference for Aspartate Aminotransferase (AST) activity was detected in test item treated females when compared to control, without a statistical difference. An apparent dose response was observed in females only, but the difference did not gain statistical significance in any dose groups. No similar trend was seen in males and all the observed values were within the historical control range. Thus the differences seen in females were considered as not being related to test item treatment. No statistically significant changes were recorded for any other parameters in the test item treated males and females.
- Urinalysis findings:
- no effects observed
- Description (incidence and severity):
- No test item related changes were recorded in any of the test item treated groups when compared to the control.
Higher urine volume was collected in the test item treated females when compared to the control, slightly higher volume was also detected in High dose males. However, none of the observed values were statistically significant when compared to the relevant control data, and were within the historical control range. All the individual values obtained in this study were considered to be normal based on the detailed comparison of both sets (the collected urine volume is usually highly variable as indicated by the historical control data). Therefore, the numerical differences were not considered to reflect a test item related effect. This fact was confirmed by the lack of any supporting evidence of any changes in these animals (clinical chemistry or other urinary analysis parameters). - Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no test item related effects in the neurological assessment as there were no observed differences in animal behaviour, general physical condition or in the reactions to different types of stimuli in the control or test item treated groups (summary of results is seen in Table 6). No statistically significant or biologically relevant differences were noted during the assessment of landing foot splay test or grip strength.
- Immunological findings:
- no effects observed
- Description (incidence and severity):
- Basic indication of immunological effects were observed during microscopic examination, no effects were reported.
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- No test item related effects on organ weights were observed in any dose groups (males and females). Terminal body weights of test item treated animals (males and females) were not significantly different from control animals. There were no statistically significant differences or toxicological relevant changes in organ weights (including thyroid weight) of any test item treated dose groups (males and females) when compared to control data. Thus, no test item effect on organ weights were concluded.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No test item-related macroscopic findings were noted at necropsy.
The following incidental or background findings were seen in the terminally euthanized animals. Dilated right kidney pelvis was seen in one Control male (#1002). Focal discoloration (paleness) of right kidney was observed in one Mid dose male (#3010). Discoloured liver (pale, diffuse discoloration) in one Mid dose female (#3506). Dark red multifocal discoloration of left lobe of lung was recorded in one Control female (#1507). Small left seminal vesicle (with coagulating gland) was recorded in one Mid dose male (#3010). Small testis (right) was detected in a Low dose male (#2008), soft testis (left) was noted in one Control male (#1010). Adrenal gland on the left side was not presented in one control male (#1003). - Neuropathological findings:
- no effects observed
- Description (incidence and severity):
- There were no test item related effects in the neurological assessment as there were no observed differences in animal behaviour, general physical condition or in the reactions to different types of stimuli in the control or test item treated groups.
No statistically significant or biologically relevant differences were noted during the assessment of landing foot splay test or grip strength. In case of locomotor activity measurements (SMART), all dose groups of males and females had a normal locomotor activity ; in all cases the initial activity was high, with generally a reduced activity in the 5-minute periods to an approximate plateau by about 20-30 minutes. There was no statistical significance between the test item treated animals and the relevant control groups when evaluating the total travelled distance (period of 0-60 minutes). - Histopathological findings: non-neoplastic:
- no effects observed
- Description (incidence and severity):
- There were no test item related microscopic changes up to dose level of 1000 mg/kg bw/day.
Other changes were seen in control and treated animals without meaningful differences in severity and incidence, and were considered to be incidental or a common background. These included slight bilateral vacuolation of the adrenal gland cortex in one Control male. In the oesophagus, focal / multifocal cellular degeneration of cells necrosis two Control males and one High dose male and focal / multifocal infiltration of inflammatory cells were presented in one Control female. Focal / multifocal infiltration of inflammatory cells were presented in the heart myocardium of two Control males. Unilateral / bilateral renal pelvic dilatation was also recorded for two Control males and one High dose male. - Other effects:
- no effects observed
- Description (incidence and severity):
- No effect of test item was observed in the study based on the results of thyroid hormone analysis and thyroid gland weights.
Effect levels
- Key result
- 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: Overall observations
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Table 5:Selected body weight parameters of parental animals
Parameters |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Male, Body weight on Day 27 (g) |
541.1 |
535.7 |
539.8 |
546.1 |
NS |
difference(%) |
-1.0 |
-0.2 |
0.9 |
|
|
Male, Body weight gain Day 0-27 (g) |
61.6 |
55.8 |
59.1 |
65.7 |
NS |
difference(%) |
-9.5 |
-4.1 |
6.6 |
|
|
Female, Body weight on GD20 (g) |
436.1 |
445.5 |
429.0 |
430.5 |
NS |
difference(%) |
2.2 |
-1.6 |
-1.3 |
|
|
Female, Body weight on PPD13 (g) |
352.7 |
363.1 |
362.4 |
366.8 |
NS |
difference(%) |
3.0 |
2.0 |
4.0 |
|
|
Female, Body weight gain Day 0-PPD13 (g) |
75.0 |
85.6 |
84.2 |
88.5 |
NS |
difference(%) |
14.1 |
12.2 |
18.1 |
|
Notes: Data (group mean values, n=12) were rounded to one decimal place.
NS: Statistically not significant when compared to control
Table 6:Summary of selected FOB and SMART parameters
Parameters |
Dose groups |
|
|
||||
Control |
Low dose |
Mid dose |
High dose |
|
|||
Males |
|
||||||
Landing foot splay, mm (hind paws) |
97.1 |
98.0 |
89.9 |
94.4 |
NS |
||
HC range: 26-129 |
difference(%) |
1.0 |
-7.4 |
-2.7 |
|
||
Grip-strength, g (forelimbs) |
1961.1 |
1873.4 |
1733.3 |
1788.3 |
NS |
||
HC range: 1100.0-2332.9 |
difference(%) |
-4.5 |
-11.6 |
-8.8 |
|
||
Grip-strength, g (hind limbs) |
1036.1 |
1028.9 |
805.8 |
950.3 |
NS |
||
HC range: 483.3-1377.6 |
difference(%) |
-0.7 |
-22.2 |
-8.3 |
|
||
Total travelled distance (cm) |
7206.3 |
7417.6 |
7304.1 |
7754.7 |
NS |
||
HC range |
difference(%) |
2.9 |
1.4 |
7.6 |
|
||
Females |
|
||||||
Landing foot splay, mm (hind paws) |
76.6 |
72.1 |
81.3 |
92.0 |
NS |
||
HC range: 35-108 |
difference(%) |
-5.9 |
6.1 |
20.1 |
|
||
Grip-strength, g (forelimbs) |
1355.1 |
1533.9 |
1494.3 |
1540.6 |
NS |
||
HC range: 795.1-1935.1 |
difference(%) |
13.2 |
10.3 |
13.7 |
|
||
Grip-strength, g (hind limbs) |
743.5 |
846.5 |
827.7 |
759.1 |
NS |
||
HC range: 391.7-1265.4 |
difference(%) |
13.9 |
11.3 |
2.1 |
|
||
Total travelled distance (cm) |
5749.0 |
6162.6 |
5071.7 |
6830.9 |
|
||
HC range: |
difference(%) |
7.2 |
-11.8 |
18.8 |
NS |
||
Notes: Data (group mean values, n=5) are rounded to one digit or to whole number.
Total travelled distance of 0-60 minutes was calculated. HC: Historical control
NS: Statistically not significant when compared to the control.
Table 7:Summary ofselected haematology parameters
Parameters |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Males |
|||||
Relative amount of Eosinophils (%) |
1.42 |
1.68 |
2.64 |
2.04 |
NS |
HC range: 0.00-3.90 |
difference(%) |
18.3 |
85.9 |
43.7 |
|
Females |
|
||||
Relative amount of Eosinophils (%) |
2.64 |
1.18 |
1.24 |
1.02 |
NS |
HC range: 0.30-9.60 |
difference(%) |
-55.3 |
-53.0 |
-61.4 |
|
Notes: Data (group mean values, n=5) were rounded to two decimal places. HC: Historical control.
NS: Statistically not significant compared to control
Table 8:Summary of selected clinical chemistry parameters
Parameters |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Males |
|||||
AST (GOT) activity (U/L) |
191.4 |
124.2 |
156.2 |
175.6 |
NS |
HC range: 93-628 |
difference(%) |
-35.1 |
-18.4 |
-8.3 |
|
Females |
|
||||
AST (GOT) activity (U/L) |
232.6 |
261.0 |
307.8 |
368.8 |
NS |
HC range: 89-533 |
difference(%) |
12.2 |
32.3 |
58.6 |
|
Notes: Data (group mean values, n=5) were rounded to one decimal place. HC: Historical control.
AST (GOT): Aspartate Aminotransferase (GlutamicOxaloaceticTransaminase)
NS: Statistically not significant compared to control
Table 9:Summary of selected urinary analysis parameters
Parameters |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Males |
|||||
Volume (mL) |
9.4 |
9.3 |
10.6 |
12.1 |
NS |
HC range: 1.0-51.0 |
difference(%) |
-1.1 |
12.8 |
28.7 |
|
Females |
|
||||
Volume (mL) |
7.4 |
12.0 |
12.8 |
10.8 |
NS |
HC range: 0.8-32.0 |
difference(%) |
62.2 |
73.0 |
45.9 |
|
Notes: Data (group mean values, n=5) were rounded to one decimal place. HC: Historical control.
NS: Statistically not significant compared to control
Table 10:Organ weight data
Organ weight |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Males |
|
||||
Terminal body weight, g |
516.3 |
514.3 |
518.3 |
522.5 |
NS |
(difference%) |
-0.4 |
0.4 |
1.2 |
|
|
Thyroid(absolute), g |
0.0195 |
0.0188 |
0.0188 |
0.0189 |
NS |
(difference%) |
-3.8 |
-3.8 |
-3.0 |
|
|
Thyroid (relative to body), % |
0.00590 |
0.00551 |
0.00559 |
0.00557 |
NS |
(difference%) |
-6.7 |
-5.2 |
-5.6 |
|
|
Females |
|
||||
Females Terminal body weight, g |
332.3 |
340.6 |
335.9 |
341.2 |
NS |
(difference%) |
2.5 |
1.1 |
2.7 |
|
|
Thyroid(absolute), g |
0.0247 |
0.0282 |
0.0306 |
0.0260 |
NS |
(difference%) |
14.2 |
24.0 |
5.4 |
|
|
Thyroid (relative to body), % |
0.00476 |
0.00547 |
0.00593 |
0.00497 |
NS |
(difference%) |
14.9 |
24.5 |
4.4 |
|
Notes: Data (group mean values, n=12) were rounded to one decimal place. Thyroid and parathyroid weights were measured together. NS: Statistically not significant compared to control
Table 11:Selected parameters related to thyroid hormone levels
Parameters |
Dose groups |
|
|||
Control |
Low dose |
Mid dose |
High dose |
|
|
Parental males |
|
||||
Number of evaluated males |
12 |
12 |
12 |
12 |
|
T4 concentration(ng/mL) |
42.16 |
41.78 |
41.78 |
43.41 |
NS |
Thyroid gland weights (g) |
0.0247 |
0.0282 |
0.0306 |
0.0260 |
NS |
Thyroid gland / body weight (%) |
0.0048 |
0.0055 |
0.0059 |
0.0050 |
NS |
PND13 pups |
|
||||
Number of evaluated litters |
12 |
12 |
12 |
12 |
|
T4 concentration(ng/mL) |
41.33 |
42.52 |
40.72 |
42.25 |
NS |
Thyroid gland weights (g) |
0.0053 |
0.0062** |
0.0063** |
0.0057 |
DN |
Thyroid gland / body weight (%) |
1.965 |
2.180 |
2.097 |
2.025 |
NS |
Notes: Data (group mean values) were rounded to two or four decimal places. Thyroid and parathyroid weights were measured together. Thyroid gland weight for one male and one female pup per litter were determined except of litter #2511 where no male pup survived until PND13. Pups blood were pooled for T4 (thyroxin) determination. Historical control range for T4 was 23.6-61.6 ng/mL (parental males) and 34.3-60.7 ng/mL (PND13 pups).
Statistical significance compared to control: * = p<0.05, ** = p<0.01
DN: Duncan’s Multiple range test; NS: Statistically not significant compared to control
Applicant's summary and conclusion
- Conclusions:
- Under the experimental conditions of the study, daily administration of Saccharomyces cerevisiae, lysate test item by oral gavage to Wistar rats at dose levels of 100, 300 or 1000 mg/kg bw/day (Low, Mid and High dose groups, respectively) during the treatment period of this study did not result in test item related mortality, clinical signs, or significant changes in body weight / body weight gain, food consumption, haematology, clinical chemistry or urinalysis parameters. No test item related effect was detected during neurotoxicity assessment. No test item-related macroscopic or microscopic findings were recorded in any of the dose groups at necropsy or during histopathology evaluation. In conclusion, under the conditions of this study, the No Observed Adverse Effect Level (NOAEL) for Saccharomyces cerevisiae, lysate was considered to be 1000 mg/kg bw/day for the female and male parental (adult) generation.
- Executive summary:
The purpose of this GLP-compliant Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test in the Rats was to obtain information on the toxicity of Saccharomyces cerevisiae, lysate test item following repeated daily administration by oral gavage to Wistar rats according to OECD TG 422 method.
Male and female Wistar rats were treated for 2 weeks pre-mating and then during the mating / post-mating periods. This was 28 days in total for males. Females were treated throughout gestation and up to and including postpartum/lactation day (63 days). Parameters measured during the study included signs of morbidity and mortality twice daily, detailed observation of clinical signs daily or weekly, neurological assessment, weekly body weight and food consumption, and clinical pathology evaluation, including haematology, coagulation, clinical chemistry and urinalysis. Neurological assessment of functional observation battery (including the measurements of the landing foot splay and grip strength) and measurement of locomotor activity was performed during the last week of the treatment. At termination, necropsy with macroscopic examination was performed. Weights of selected organs were recorded and representative tissues / organs were sampled and preserved in appropriate fixatives from the adult animals. The thyroxine (T4) levels in the adult males was also assessed.
Under the experimental conditions of the study, with daily administration of Saccharomyces cerevisiae, lysate test item by oral gavage to Wistar rats at dose levels of 100, 300 or 1000 mg/kg bw/day (Low, Mid and High dose groups, respectively) no mortality, clinical signs, or significant changes in body weight / body weight gain, food consumption, haematology, clinical chemistry or urinalysis parameters were observed. No test item related effect was detected during neurotoxicity assessment. No test item-related macroscopic or microscopic findings were recorded in any of the dose groups at necropsy or during histopathology evaluation. In conclusion, under the conditions of this study, the No Observed Adverse Effect Level (NOAEL) for Saccharomyces cerevisiae, lysate was considered to be 1000 mg/kg bw/day for the female and male parental (adult) generation according to CLP criteria.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.

EU Privacy Disclaimer
This website uses cookies to ensure you get the best experience on our websites.