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EC number: 419-740-4 | CAS number: 137658-79-8 CGL 1545
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Jun 2014- Jan 2015
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 015
- Report date:
- 2015
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 22 Jan 2001
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Remarks:
- Landesamt für Umwelt, Wasserwirtschaft und Gewerbeaufsicht, Kaiser-Friedrich-Straße 7, 55116 Mainz
- Limit test:
- no
Test material
- Reference substance name:
- Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane
- EC Number:
- 410-560-1
- EC Name:
- Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxyphenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane
- Molecular formula:
- C28 H28 N3 O4 + C12 H25 / C13 H27 (represents two main components)
- IUPAC Name:
- Reaction products of 2-(4,6-bis(2,4-dimethylphenyl)-1,3,5-triazin-2-yl)-5-hydroxy phenol with ((C10-16, rich in C12-13 alkyloxy)methyl)oxyrane
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Lot/batch No.of test material: 0008577537
- Expiration date of the lot/batch: 01 Jul 2015
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature
- Stability under test conditions: Guaranteed by the manufacturer
- Stability in the vehicle: Analytical verifications of the stability of the test substance in corn oil at room temperature over a period of 8 days had been verified prior to the start of the study. Given that test substance is completely miscible with corn oil Ph. Eur./DAB, solutions are considered to be homogenous without further analysis.
- Solubility and stability of the test substance in the solvent/vehicle: The test substance was completely miscible with corn oil
TREATMENT OF TEST MATERIAL PRIOR TO TESTING
For the test substance preparations, the test substance was heated up to 72 °C before exposure solution preperation
FORM AS APPLIED IN THE TEST (if different from that of starting material) : Liquid
OTHER SPECIFICS:
- Physical state/Appearance: Solid/ slightly yellow
Test animals
- Species:
- rat
- Strain:
- Wistar
- Remarks:
- Crl:WI[Han]
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-12 weeks
- Housing: single housing
- Diet (e.g. ad libitum): ad libitum; ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland.
- Water (e.g. ad libitum): ad libitum; potable tap water bottles
- Acclimation period: six days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 2014-06-23 To: 2014-08-04
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: For the test substance preparation, the test substance was heated up to 72°C. Thereafter the specific amount of test substance was weighed, topped up with corn oil in a calibrated beaker and intensely mixed with a magnetic stirrer (70°C) until it was completely dissolved.
VEHICLE
- Justification for use and choice of vehicle (if other than water): Test item is insoluble in water
- Concentration in vehicle: Adjusted to amount of vehicle
- Amount of vehicle (if gavage): 4ml/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The results of the analysis of the oily test substance preparations confirmed the correctness of the prepared concentrations. The analytical values of the samples corresponded to the expected values within the limits of the analytical method, i.e. were always above 90% and below 110% of the nominal concentrations
- Details on mating procedure:
- - Impregnation procedure: The animals were paired by the breeder (“time-mated”)
- Proof of pregnancy: Detection of vaginal plug/sperm - Duration of treatment / exposure:
- 14 days
- Frequency of treatment:
- daily
- Duration of test:
- GD 6-19 / 14 days
Doses / concentrationsopen allclose all
- Dose / conc.:
- 60 mg/kg bw/day (nominal)
- Remarks:
- as low-dose level
- Dose / conc.:
- 200 mg/kg bw/day (nominal)
- Remarks:
- as mid-dose level
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- as high mid-dose level
- Dose / conc.:
- 600 mg/kg bw/day (nominal)
- Remarks:
- as high-dose level
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: A GLP-compliant range finding study was conducted (dosing 300 mg/kg bw/d and 1000 mg/kg bw/d for 14 d)
- As scheduled in the study plan, the high-dose level for this study was 600 mg/kg body weight/day which was intended to be administered to test group 3. Because of a mistake, an incorrect dose level was applied to test group 3; the actually administered dose was 300 mg/kg bw/d throughout the entire study. Therefore, an additional dose group of 600 mg/kg bw/d (test group 5) and a control group (test group 4) were added to the study to cover the dose range as originally specified in the study plan.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Clinical symptoms were checked twice daily from Mondays to Fridays and once daily on Saturdays, Sundays and public holidays (GO 0 to 20).
DETAILED CLINICAL OBSERVATIONS: A cage-side examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of overt toxicity. If such signs occurred, the animals were examined several times daily (GD 0-20).
Food Consumption: The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.
BODY WEIGHT: Yes
- Time schedule for examinations: GO 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20. Furthermore, the corrected body weight gain was calculated after terminal sacrifice (terminal body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6).
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day: GD 20.
- Organs examined: uterus of the dams (weight, number of corpora lutea, number and distribution of implantation sites); fetuses (gross pathology, soft tissue examination, skeletal examination) - 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
- Other: Site of implantations in the uterus - Fetal examinations:
- - External examinations: Yes: [all per litter ]
- Soft tissue examinations: Yes: [ half per litter ]
- Skeletal examinations: Yes: [ half per litter ]
Examinations of the fetuses after dissection from the uterus:
At necropsy each fetus was weighed, sexed, and external tissues and all orifices were examined macroscopically. The sex was determined by observing the distance between the anus and the base of the genitalia. Furthermore, the viability of the fetuses and the condition of placentae, umbilical cords, fetal membranes, and fluids were examined. The placentas were weighed and their individual weights were recorded. Thereafter, the fetuses were sacrificed by a subcutaneous injection of pentobarbital (Narcoren®; dose: 0.1 mL/fetus). After these examinations, approximately one half of the fetuses per dam were eviscerated, skinned and fixed in ethanol; the other half were placed in Harrison’s fluid for fixation.
Soft tissue examination of the fetuses:
The fetuses fixed in Harrison’s fluid were examined for any visceral findings according to the method of BARROW and TAYLOR. After this examination these fetuses were discarded.
Skeletal examination of the fetuses:
The skeletons of the fetuses fixed in ethanol were stained according to a modified method of KIMMEL and TRAMMELL. Thereafter, the skeletons of these fetuses were examined under a stereomicroscope. After this examination the stained fetal skeletons were archived individually.
Evaluation criteria for assessing the fetuses:
In the present study the glossary of WISE et al. (1997) and its updated version of MAKRIS et al. (2009) was essentially used to describe findings in fetal morphology. Classification of these findings was based on the terms and definitions proposed by CHAHOUD et al. (1999) and SOLECKI et al. (2001, 2003):
Malformation
A permanent structural change that is likely to adversely affect the survival or health.
Variation
A change that also occurs in the fetuses of control animals and/or is unlikely to adversely affect the survival or health. This includes delays in growth or morphogenesis that have otherwise followed a normal pattern of development. The term "unclassified observation" was used for those fetal findings, which could not be classified as malformations or variations. All fetal findings were listed in tables according to these classifications. - Statistics:
- DUNNETT's test:
Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of preimplantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
FISHER'S EXACT test (onesided):
Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings
WILCOXON-test (one-sided):
Proportions of fetuses with malformations, variations and/or unclassified observations in each litter - Indices:
- sex ratio
- Historical control data:
- yes, period over 4 years
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- Two females of the high-dose group (600 mg/kg bw/d) showed transient salivation at two occasions during the treatment period (GD 14 and GD 17). Salivation persisted in the respective animals only for some minutes after daily gavage dosing (i.e. up to 10 minutes). Such transient salivation shortly after dosing most likely reflects a reaction of the animals to the taste and smell of the test substance. It is not considered to be a sign of systemic toxicity.
- Mortality:
- no mortality observed
- Description (incidence):
- There were no substance-related or spontaneous mortalities in any test group (0, 60, 200, 300 or 600 mg/kg bw/d)
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- The high-dose of the test substance (600 mg/kg bw/d) caused a decrease in body weight gain as well as a significant decrease in the corrected (net) body weight gain. The corrected body weight gain (terminal body weight on GD 20 minus weight of the
unopened uterus minus body weight on GD 6) was statistically significantly lower (about 18% below concurrent control) in test group 5 (600 mg/kg bw/d).
The corrected body weight gain of test groups 1-3 (60, 200 and 300 mg/kg bw/d) revealed no difference of any biological relevance to the concurrent control group. - Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- In comparison to the respective concurrent control group, the mean food consumption of the high-dose dams (test group 5 - 600 mg/kg bw/d) was slightly, but statistically significantly decreased on GD 10-13 and GD 15-17. If calculated for the entire treatment period (GD 6-19) or study period (GD 0-20), the high-dose dams consumed -6% or -4% less food than the concurrent control group (test group 4).
The mean food consumption of the dams in test groups 1, 2 and 3 (60, 200 and 300 mg/kg bw/d) was generally comparable to the concurrent control throughout the entire study period.
This includes the statistically significantly increased mean food consumption value in test group 2 during pre-treatment on GD 3-6. - 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):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Description (incidence and severity):
- The mean gravid uterus weights of the animals of test groups 1, 2, 3 and 5 (60, 200, 300 and 600 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the concurrent control groups revealed no dose-dependency and were assessed to be without biological relevance.
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- No necropsy findings which could be attributed to the test substance were seen in any dam.
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- not specified
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related and/or biologically relevant differences between the test groups 0-5 (0, 60, 200, 300, 0 and 600 mg/kg bw/d) in the postimplantation loss.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related and/or biologically relevant differences between the test groups 0-5 (0, 60, 200, 300, 0 and 600 mg/kg bw/d) in the number of resorptions
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related and/or biologically relevant differences between the test groups 0-5 (0, 60, 200, 300, 0 and 600 mg/kg bw/d) in the number of viable fetuses.
- Changes in pregnancy duration:
- not specified
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related and/or biologically relevant differences between the test groups 0-5 (0, 60, 200, 300, 0 and 600 mg/kg bw/d) in conception rate.
- Other effects:
- no effects observed
- Description (incidence and severity):
- There were no test substance-related and/or biologically relevant differences between the test groups 0-5 (0, 60, 200, 300, 0 and 600 mg/kg bw/d) in the mean number of corpora lutea and implantation sites.
- Details on maternal toxic effects:
- Maternal toxic effects: Yes. Remark: Body weight gain at 600 mg/kg bw 82 % of control group
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 300 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The mean fetal weights of test groups 1, 2, 3 and 5 (60, 200, 300 and 600 mg/kg bw/d) were not influenced by the test substance and did not show any biologically relevant differences in comparison to the concurrent control groups.
- Reduction in number of live offspring:
- not examined
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- The apparent skew in the sex distribution of live fetuses in test group 5 (significantly more males than females) is a consequence of a similar skew in the concurrent control group 4 which is almost exactly the reversed image of group 5 (more females than males).
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- External malformations were recorded for one control fetus (0 mg/kg bw/d), this fetus had associated skeletal findings. The total incidence of external malformations in treated animals did not differ significantly from the concurrent control group and was comparable to the historical control data.
One external variation, i.e. limb hyperextension, was detected in test group 2 (200 mg/kg bw/d). This single case was considered to be incidental and not related to treatment.
Two unclassified external observations, i.e. polyhydramnios and placentae fused, were recorded for two fetuses of test group 2 (200 mg/kg bw/d). These findings were not considered to be biologically relevant. - Skeletal malformations:
- no effects observed
- Description (incidence and severity):
- Some skeletal malformations were detected in test groups 0, 2 and 3 (0, 200 and 300 mg/kg bw/d) affecting the skull, sternum, vertebral column (with or without involving the ribs) and humerus. One control fetus of test group 0 showed multiple skeletal malformations and had associated external findings. All these findings were single cases, most of them can be found in the historical control data. An association with the treatment is not assumed.
Additionally, some isolated cartilage findings without impact on the respective bone structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, the vertebral column, the sternum and ribs and did not show any relation to dosing. However, the incidence of notched cartilage between basisphenoid and basioccipital was significantly increased in test group 2 (200 mg/kg bw/d) and the incidence of branched rib cartilage was significantly increased in test group 1 (60 mg/kg bw/d). However, this findings showed no dose-dependency and were therefore assessed to be without biological relevance. - Visceral malformations:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- Fetal soft tissue variations
Three soft tissue variations were detected, i.e. short innominate, dilated renal pelvis and dilated ureter. These variations were neither significantly different from the concurrent control nor dose-dependently present. Therefore, they were not considered to be biologically relevant
Weight of the placentae
The mean placental weights of test groups 1, 2, 3 and 5 (60, 200, 300 and 600 mg/kg bw/d) were comparable to the concurrent control groups. The statistically significantly higher mean placental weights of test group 2 were well within the historical control range (0.47 g [0.35 g - 0.99 g] and therefore were assessed to be of no biological relevance. - Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects: No effects
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 600 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: abscence of adverse effects for the tested doses
Fetal abnormalities
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Developmental effects observed:
- no
Any other information on results incl. tables
Tab. 2: Mean maternal body weight change during gestation
group 0 - 0 mg/kg bw | group 1 - 60 mg/ kg bw | group 2 - 200 mg/kg bw | group 3 - 300 mg/kg bw | group 4 - 0 mg/kg bw | group 5 - 600 mg/kg bw | |
days 6 - 6 | 31.0 g | 31.5 g | 33.8 g | 31.7 g | 34.7 g | 31.2 g * |
days 6 - 19 | 83.5g | 83.7 g | 83.7 g | 80.7 g | 87.6 g | 79.4 g * |
days 0 - 20 | 126.7 g | 128.0 g | 130.9 g | 125.7 g | 135.9 g | 124.8 g * |
Dunnett-test, two-sided, * p< = 0.05
Tab. 3: Individual fetal external malformations
test group | Dam No, Fetus No, Sex | Findings |
0 (0 mg/kg bw) | 4, 07, male | short trunk, thread-like tail |
1 (60 mg/kg bw) | none | |
2 (200 mg/kg bw) | none | |
3 (300 mg/kg bw) | none | |
4 (0 mg/kg bw) | none | |
5 (600 mg/kg bw) | none |
Tab. 4: Total fetal external variations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter |
N | 23 | 25 | 25 | 25 | 25 | 24 |
Fetuses |
N | 228 | 253 | 229 | 249 | 263 | 255 |
Fetal incidence |
N (%) | 0.0 | 0.0 | 1 (0.4) | 0.0 | 0.0 | 0.0 |
Litter incidence |
N (%) | 0.0 | 0.0 | 1 (4.0) | 0.0 | 0.0 | 0.0 |
Affected fetuses/litter |
Mean % | 0.0 | 0.0 | 4.0 | 0.0 | 0.0 | 0.0 |
Tab. 5: Total external unclassified observations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter |
N | 23 | 25 | 25 | 25 | 25 | 24 |
Fetuses |
N | 228 | 253 | 229 | 249 | 263 | 255 |
Fetal incidence |
N (%) | 0.0 | 0.0 | 2 (0.9) | 0.0 | 0.0 | 0.0 |
Litter incidence |
N (%) | 0.0 | 0.0 | 2 (8.0) | 0.0 | 0.0 | 0.0 |
Affected fetuses/litter | Mean % | 0.0 | 0.0 | 4.4 | 0.0 | 0.0 | 0.0 |
Tab. 6: Total fetal soft tissue variations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter Fetuses | N N | 23 109 | 25 121 | 25 107 | 25 119 | 25 127 | 24 121 |
fetal incidence | N (%) | 6 (5.5) | 3 (2.5) | 3 (2.8) | 4 (3.4) | 5 (3.9) | 2 (1.7) |
litter incidence | N (%) | 6 (26) | 3 (12) | 2 (8.3) | 4 (16) | 5 (20) | 2 (8.3) |
affected fetuses / litter | mean % | 5.4 | 3.0 | 2.2 | 3.4 | 3.7 | 2.1 |
Tab. 7: Individual fetal skeletal malformations
test group | Dam No, Fetus No, Sex | Findings |
0 (0 mg/kg bw) | 4, 07, male | fetus with multiple skeletal malformations |
1 (60 mg/kg bw) | none | |
2 (200 mg/kg bw) | 72-10 F 72-12 M | shortened humerus shortened humerus |
3 (300 mg/kg bw) | 89-05 F93-10 F | misshapen basioccipital, severely malformed vertebralcolumn and/or ribs, cleft sternumshortened humerus |
4 (0 mg/kg bw) | none | |
5 (600 mg/kg bw) | none |
Tab. 8: Total fetal skeletal malformations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter Fetuses | N N | 23 119 | 25 132 | 25 122 | 25 130 | 25 136 | 24 134 |
fetal incidence | N (%) | 1 (0.8) | 0.0 | 2 (1.6) | 2 (1.5) | 0.0 | 0.0 |
litter incidence | N (%) | 1 (4.3) | 0.0 | 1 (4.0) | 2 (8.0) | 0.0 | 0.0 |
affected fetuses / litter | mean % | 0.9 | 0.0 | 1.3 | 1.6 | 0.0 | 0.0 |
Tab. 9: Total fetal skeletal variations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter Fetuses | N N | 23 119 | 25 132 | 25 122 | 25 130 | 25 136 | 24 134 |
fetal incidence | N (%) | 116 (97) | 128 (97) | 120 (98) | 126 (97) | 134 (99) | 134 (100) |
litter incidence | N (%) | 23 (100) | 25 (100) | 25 (100) | 25 (100) | 25 (100) | 24 (100) |
affected fetuses / litter | mean % | 97.4 | 97.1 | 98.5 | 96.9 | 98.5 | 100.0 |
Tab. 10: Occurrence of statistically significantly increased fetal skeletal variations (expressed as mean percentage of affected fetuses/litter)
For a better overview, all skeletal variations with statistically significant differences between the control and the treated groups were compiled in the table below. All incidences were expressed on a fetus per litter basis and any statistically significant differences, which were outside historical control ranges were marked in bold and italics types.
Finding | group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | HCDMean %(range) |
Incomplete ossification of parietal; unchanged cartilage |
9.2 | 10.0 | 11.0 | 7.3 | 3.2 | 10.2* | 11.1(6.4 – 17.1) |
Incomplete ossification of sternebra; unchanged cartilage |
92.8 | 87.5 | 94.5 | 84.4 | 90.6 | 96.3* | 84.7(69.3 – 94.7) |
Incomplete ossification of sternebra; unchanged cartilage |
36.3 | 43.7 | 39.3 | 45.0 | 36.2 | 50.7* | 52.7(29.5 – 76.9) |
HCD = Historical control data; % = per cent * = p ≤ 0.05 (Wilcoxon-test [one-sided]) ** = p ≤ 0.01 (Wilcoxon-test [one-sided])
As can be seen from the table above, the rate of incompletely ossified sternebra was statistically significantly increased and slightly outside the historical control range in the test group 5 (600 mg/kg bw/d). This minor change may represent a slight delay of ossification which did not affect morphology, as the underlying cartilage model was completely intact. As can be seen from the historical background data, increased incidences of such incomplete or nonossifications of skeletal elements are routinely quantified and are among the most frequently noted skeletal variants in control populations of this Crl:WI(Han) rat strain. This indicates that these findings reflect species-specific anatomic variation at the time around birth without any detrimental effects on further development. As the incidence in this study is still in the order of magnitude of the background rate the finding is neither considered as biologically relevant nor as adverse. Concerning the other statistically significant differences, no dose dependency was observed and all values were clearly inside the historical control range, thus, an association with the test substance and a toxicological relevance is not assumed.
Tab. 11: Total unclassified cartilage observations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter |
N | 23 | 25 | 25 | 25 | 25 | 24 |
Fetuses |
N | 119 | 132 | 122 | 130 | 136 | 134 |
Fetal incidence |
N (%) | 102 (86) | 97 (73) | 87 (71) | 106 (82) | 111 (82) | 118 (88) |
Litter incidence |
N (%) | 23 (100) | 24 (96) | 23 (92) | 23 (92) | 25 (100) | 24 (100) |
Affected fetuses/litter | Mean % | 85.4 | 74.1 | 71.0 | 79.0 | 0.0 | 0.0 |
Tab. 12: Total fetal malformations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter |
N | 23 | 25 | 25 | 25 | 25 | 24 |
Fetuses |
N | 228 | 253 | 229 | 249 | 263 | 255 |
Fetal incidence |
N (%) | 1 (0.4) | 0.0 | 2 (0.9) | 2 (0.8) | 0.0 | 0.0 |
Litter incidence |
N (%) | 1 (4.3) | 0.0 | 1 (4.0) | 2 (8.0) | 0.0 | 0.0 |
Affected fetuses/litter | Mean % | 0.4 | 0.0 | 0.7 | 0.8 | 0.0 | 0.0 |
Tab.13: Total fetal variations
group 0 - 0 mg/kg bw/d | group 1 -60 mg/kg bw/d | group 2 -200 mg/kg bw/d | group 3 -300 mg/kg bw/d | group 4 -0 mg/kg bw/d | group 5 -600 mg/kg bw/d | ||
Litter |
N | 23 | 25 | 25 | 25 | 25 | 24 |
Fetuses |
N | 228 | 253 | 229 | 249 | 263 | 255 |
Fetal incidence |
N (%) | 122 (54) | 131 (52) | 123 (54) | 130 (52) | 139 (53) | 136 (53) |
Litter incidence |
N (%) | 23 (100) | 25 (100) | 25 (100) | 25 (100) | 25 (100) | 24 (100) |
Affected fetuses/litter | Mean % | 53.4 | 52.1 | 55.3 | 52.3 | 52.7 | 53.6 |
Applicant's summary and conclusion
- Conclusions:
- Under the conditions of this prenatal developmental toxicity study, the oral administration to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 600 mg/kg bw/d caused evidence of maternal toxicity, such as reduced gross and corrected (net) body weight gain. In conclusion, the no observed adverse effect level (NOAEL) for maternal toxicity is 300 mg/kg bw/d.
The no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 600 mg/kg bw/d, the highest tested dose. - Executive summary:
In a prenatal developmental toxicity study the test substance was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential for maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. The test substance caused neither mortality nor clinical symptoms of systemic toxicity in any of the exposed groups. Two females of the high-dose group (600 mg/kg bw/d) showed transient (up to 10 minutes) salivation at two occasions during the treatment period (GD 14 and GD 17). Such transient salivation shortly after dosing most likely reflects a reaction of the animals to the taste and smell of the test substance. It is not considered to be a sign of systemic toxicity. The high-dose of the test substance (600 mg/kg bw/d) caused a decrease in body weight gain as well as a significant decrease in the corrected (net) body weight gain. These effects are considered minimal, but treatment-related and adverse. No toxicologically relevant clinical effect was noted for the animals exposed to 60, 200 or 300 mg/kg bw/d of the test substance. No differences of toxicological relevance between the control and the treated groups (60, 200, 300 or 600 mg/kg bw/d) were determined for any reproductive parameters, such as conception rate, mean number of corpora lutea, mean number of implantations, as well as pre- and postimplantation loss. Similarly, no influence of the test compound on fetal weight and sex distribution of the fetuses was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. Thus, the test item is not teratogenic in rats.
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