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EC number: 401-540-3 | CAS number: 84632-65-5
- 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:
- March to Spetember 2021
In-life phase: March 17, 2021, to April 22, 2021 - Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 022
- Report date:
- 2022
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- June 25, 2018
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- -
- EC Number:
- 401-540-3
- EC Name:
- -
- Cas Number:
- 84632-65-5
- Molecular formula:
- C18H10Cl2N2O2
- IUPAC Name:
- 3,6-bis(4-chlorophenyl)-1H,2H,4H,5H-pyrrolo[3,4-c]pyrrole-1,4-dione
- Test material form:
- solid: particulate/powder
Constituent 1
- Specific details on test material used for the study:
- SOURCE OF TEST MATERIAL
- Source (i.e. manufacturer or supplier) and lot/batch number of test material: Cinilex® DPP Red SR2P, Lot D23508919P1
- Purity, including information on contaminants, isomers, etc.: 99.6% pure
STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Room temperature (15-25ºC) protected from humidity
- Stability and homogeneity of the test material in the vehicle/solvent under test conditions (e.g. in the exposure medium) and during storage: stable
- Stability in the medium, i.e. sensitivity of the test material to hydrolysis and/or photolysis: stable
- Solubility and stability of the test material in the solvent/vehicle and the exposure medium: stable
- Reactivity of the test material with the incubation material used (e.g. plastic ware): none
TREATMENT OF TEST MATERIAL PRIOR TO TESTING: none
Test animals
- Species:
- rabbit
- Strain:
- New Zealand White
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: S & K-LAP Kft., Császár út 135, 2173 Kartal, HUNGARY
- Age at study initiation: young adults
- Weight at study initiation: 3427-4008 g (at insemination)
- Fasting period before study: none
- Housing: individually in metal cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 6 or 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16.4-21.0 °C
- Humidity (%): 30 - 64 %
- Air changes (per hr): 12 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 17 March 2021 To: 22 April 2021
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% aqueous methylcellulose
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
VEHICLE
- Justification for use and choice of vehicle (if other than water):
The test item is not soluble in water therefore 0.5% aqueous methylcellulose was used for preparing formulations. 0.5% aqueous methylcellulose has been shown to be a suitable vehicle to facilitate formulation analysis for the test item.
The test item is suitable for oral administration when suspended in methylcellulose.
- Amount of vehicle (if gavage): treatment volume: 10 mL/kg body weight - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Test substance content was determined in 0.5 % Aqueous Methylcellulose.
Five samples were analysed from each test concentration and five samples were analysed from the control two times.
Formulation samples were diluted to fit the calibration curve and analysed by a UV photometric method.
Test substance concentrations in the samples varied in the range from 95 % to 106 % in comparison to the nominal values. Test substance was not detected in the control samples. - Details on mating procedure:
- - Impregnation procedure: artificial insemination
Day of insemination was regarded as day 0 of gestation.
Synchronization of the cycle was completed 48 hours prior to insemination by administering PMSG (gonadotropin) hormone subcutaneously into the neck region. The insemination procedure was performed at the test facility by the breeder. Each female was inseminated with diluted sperm and receiveds 0.2 mL Receptal hormone preparation was given with intramuscular injection into the femur region to provoke ovulation. The sperm originated from New Zealand White male rabbits from the same source as the females. The origin and quality of the sperm were certified by the breeder. - Duration of treatment / exposure:
- 22 days (from gestation day (GD) 6 to GD 27)
- Frequency of treatment:
- daily, in the morning hours, at approximately the same time each day
- Duration of test:
- 28 days (from insemination to sacrifice)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (actual dose received)
- Remarks:
- vehicle control
- Dose / conc.:
- 100 mg/kg bw/day (actual dose received)
- Remarks:
- also refered to as low dose
- Dose / conc.:
- 300 mg/kg bw/day (actual dose received)
- Remarks:
- also refered to as mid dose
- Dose / conc.:
- 1 000 mg/kg bw/day (actual dose received)
- Remarks:
- also refered to as high dose
- No. of animals per sex per dose:
- 24 females per dose and per control
- Control animals:
- yes
- Details on study design:
- - Dose selection rationale:
The dose levels were selected by the Sponsor with the highest dose level at 1000 mg/kg b.w./day (limit dose according to OECD TG 414) based on the results of the Tolerability Study of the test susbatnce in rabbits by oral administration (Study number 678-410-5845; Toxi-Coop Zrt.).
- Rationale for animal assignment: Females were randomly assigned to dose groups on the basis of their body weight on the day of insemination in such a way that the group averages of the body weight were as similar as possible on the first day (day 0) of gestation.
- Fasting period before blood sampling for (rat) dam thyroid hormones: none
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least daily
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weight was recorded on gestation days 0, 3, 6, 9, 12, 15, 18, 21, 24, 27 and 28 (accuracy 1 g).
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 28
- Organs examined: neck, thorax and abdomen of the does were examined macroscopically, ovaries and uterus
OTHER: Blood was sampled for possible measurement one and three hours after the last treatment (GD 27), but not examined. - 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 - Blood sampling:
- Blood was sampled for possible measurement one and three hours after the last treatment (GD 27), but not examined.
- Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: all per litter
- Skeletal examinations: Yes: all per litter
- Head examinations: Yes: half per litter
- Anogenital distance of all live rodent pups: not examined - Statistics:
- Statistical analysis was performed with SPSS PC+ software.
The heterogeneity of variance between groups was checked by Bartlett's homogeneity of variance test.
Where no significant heterogeneity detected, a one-way analysis of variance (ANOVA) was carried out. If the obtained result was positive, Duncan's Multiple Range test was used to assess the significance of inter-group differences.
Where significant heterogeneity is found, the normal distribution of data will be examined by Kolmogorov-Smirnov test. In case of a none-normal distribution, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there is a positive result, the inter-group comparisons were performed using the Mann-Whitney U-test.
Chi2 test was performed if feasible. - Indices:
- Pre-implantation loss: (no. of corpora lutea - no. of implantations)/no. of implantations*100
Post-implantation loss: (no. of implantations - no. of live fetuses)/no. of live fetuses*100 - Historical control data:
- Historical control data on eight New Zealand white rabbit studies conducted between 2016 and 2020 were available. Four of those studies used water as a solvent and for sunflower oil. Five studies included visceral and skeletal examinations, comprising three studies using water as a solvent.
Results and discussion
Results: maternal animals
General toxicity (maternal animals)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- There were no clinical signs of systemic toxicity.
Red coloured faeces were observed in all test item treated animals from GD 7 during the whole in-life phase. This was not considered as adverse and attributed to the red color of the test item. Before the treatment period, one female had reddish discoloration on the underlay on GD 1 in the 300 mg/kg bw/day group. - Mortality:
- mortality observed, non-treatment-related
- Description (incidence):
- None of the pregnant females died before scheduled termination due to toxicity or was considered as moribund.
Mis-gavage caused the death of 2 does in the low dose group, 2 does in the mid dose group and 1 doe in the high dose group.
One doe of the control died due to an intercurrent disease. - Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- There were no significant differences in the mean body weight, body weight gain, corrected body weight of the dams in the experimental groups in the different time periods, except on G.D. 28 in the 1000 mg/kg bw/day dose group (p<0.05). Between G.D. 27 and 28 the mean body weight gain was lower in the 1000 mg/kg bw/day group without attaining statistical significance. The corrected body weight gain was negative in the test item treated groups and positive in the control, however the difference was not statistically significant and the values (together with the body weight on G.D. 28) were within the historical control range. Hence, the slightly lower values in the 1000 mg/kg bw/day group were neither confirmed to have a relationship with the treatment, nor could a relation be ruled out. However, these slight reductions were considered as not adverse.
- Food efficiency:
- no effects observed
- Description (incidence and severity):
- There were no significant differences indicated the mean food consumption of the does.
- Ophthalmological findings:
- not examined
- Haematological findings:
- not examined
- Clinical biochemistry findings:
- not examined
- Endocrine findings:
- not examined
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Description (incidence and severity):
- The findings revealed at gross pathology such as point-like haemorrhages in the lungs were not attributed to the treatment of the test item considering the similar distribution in the groups including control. One dam had double gall bladder in the 100 mg/kg bw/day and one clotted blood in the uterine horn in the 1000 mg/kg bw/day group. Considering that these findings occurred in single cases, it was not attributed to the test item.
Brick-reddish or brownish discolouration of the stomach or/and intestines’ content in all mid and high dose animals and 20 of 21 low dose animal (but none in the controls) was attributed to the red colour of the test item and considered to be without any toxicological relevance. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
Maternal developmental toxicity
- Number of abortions:
- effects observed, non-treatment-related
- Description (incidence and severity):
- One female each aborted in the control group (GD 27) and the 100 mg/kg bw/day dose group (GD 25) due to an intercurrent disease.
- Pre- and post-implantation loss:
- no effects observed
- Description (incidence and severity):
- There were no adverse effects indicated in the percentage of pre- and post- implantation loss when comparing dose group mean values to the control group mean values.
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- no effects observed
- Dead fetuses:
- no effects observed
- Description (incidence and severity):
- There were no adverse effects indicated in the number of dead fetuses, percentage of total intrauterine mortality and number of viable fetuses when comparing dose group mean values to the control group mean values.
- Changes in pregnancy duration:
- no effects observed
- Changes in number of pregnant:
- no effects observed
- Description (incidence and severity):
- There were three non pregnant females (no implantation and no corpora lutea) in the control group, a one each in the mid and high dose group.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- > 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Basis for effect level:
- other: no effects observed
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- no effects observed
- Description (incidence and severity):
- The fetal weight and crown-rump length was slightly lower in the 1000 mg/kg bw/day group, however without a statistical significance and the values were within the historical control range. The lower values were neither confirmed to have a relationship with the treatment or the slightly lower body weight values of the does on G.D. 27 and 28, nor could a relation be ruled out.. However, these slight reductions were judged as not adverse.
Relative placental weight was statistically significantly increased (p<0.01) in male fetuses of the 300 mg/kg bw/day dose group without showing any dose response and, therefore, this alteration was considered as incidental and unrelated to treatment. - Reduction in number of live offspring:
- no effects observed
- Description (incidence and severity):
- Detailed results are provided under 'Any other information on results incl. tables'.
- Changes in sex ratio:
- no effects observed
- Description (incidence and severity):
- Detailed results are provided under 'Any other information on results incl. tables'.
- Changes in litter size and weights:
- no effects observed
- Description (incidence and severity):
- Detailed results are provided under 'Any other information on results incl. tables'.
Statistical significance (p<0.01) was revealed in the higher relative placental weight only belonging to male fetuses in the 300 mg/kg bw/day dose group, but there was no dose response indicated. - Anogenital distance of all rodent fetuses:
- not examined
- Changes in postnatal survival:
- not examined
- External malformations:
- no effects observed
- Description (incidence and severity):
- There were no significant increases in the incidence of external malformations.
Two fetuses were found with malformation at external examination, one fetus with acrania in the control group and one with umbilical hernia in the 1000 mg/kg bw/day group.
Considering that umbilical hernia was found in one single fetus, the occurrence of this malformation was considered incidental.
The neck edema which was recorded for one fetus in the 300 mg/kg bw/day group was classified as a variation. Considering that this was a single case and not in the high dose group, this was judged as incidental. - Skeletal malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no significant increases in the incidence of all over skeletal variations and malformations.
Moreover, the incidence of malformations was statistically significantly lower in the 300 mg/kg bw/day group by U test (p<0.05) and by the Chi square test (p<0.01) as well as the incidence of malformed fetuses was statistically significantly lower in the 1000 mg/kg bw/day group by the Chi square test (p<0.05).
There was no statistical significance indicated in the different type of malformations which occurred with a sporadic distribution and without a dose response.
Malformation of the skull (see below) was found in one fetus in each group except the 100 mg/kg bw/day dose group where no skull malformation was observed.
A hole was observed between parietal and frontal bones in the control fetus which was observed with acrania at external examination.
The anterior fontanelle was larger and irregular ossification was recorded for one fetus in the 300 mg/kg bw/day dose group. The anterior fontanelle was markedly larger and misshapen, and the posterior fontanelle was larger in one fetus in the 1000 mg/kg bw/day group.
Sternebral malformations such as misshapen xiphoid cartilage, small or thin split in the cartilage (between 5th and 6th or in 6th), different degree of fusions or wider sternum was observed.
Ribs with fusion or disconnection to sternum (if other than 7th) were found with low incidences (one in the 100 and one in the 300 mg/kg bw/day group).
Malformed vertebrae were found in single cases.
In a few cases (three fetuses in the control and one fetus in the 100 mg/kg bw/day group) more regions (sternum, ribs and vertebrae, sternum and vertebrae or ribs and vertebrae) were affected.
The incidence of the variation 'misaligned sternebra' was statistically significantly higher (p<0.01) by Duncan’s test and (p<0.05) for the fetal and litter incidence by Chi square test in the 100 mg/kg bw/day group. However, this variation was not present in the higher dose groups, hence this was not attributed to the treatment.
There was no increase seen in the incidence of other skeletal variations. - Visceral malformations:
- no effects observed
- Description (incidence and severity):
- There were no significant increases in the incidence of visceral variations and malformations.
There was one malformed fetus (with larger peri-meningeal space and slightly pushed brain) found in the control group and none in the test item treated groups.
Fetal variations such as slightly enlarged peri-meningeal space, slightly dilated IIIrd brain ventricle, larger hole between cerebral hemisphere and thalamus, smaller lung lobes, full and distended urinary bladder, convoluted ureter/s and slightly mal-positioned kidney were found sporadically, in single cases or with a distribution similar in the experimental groups or only in the control group. - Other effects:
- no effects observed
Effect levels (fetuses)
- 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: no effects observed
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
The following table summarises detailed maternal and fetal data of the control and the three test groups:
|
| test doses |
|
|
| control | 100 mg/kg bw | 300 mg/kg bw | 1000 mg/kg bw |
number of inseminated does | 24 | 24 | 24 | 24 |
number of pregnant does | 21 | 24 | 23 | 23 |
number of does with no corpora lutea | 3 | 0 | 1 | 1 |
number of females with no implantation but corpora lutea (100% preimplantation loss) | 0 | 0 | 0 | 0 |
number of does dead due to misgavage | 0 | 2 | 2 | 1 |
Number of does dead due to an intercurrent disease | 1 | 0 | 0 | 0 |
number of does with abortions | 2 | 1 | 0 | 0 |
number of evaluated does and litters | 18 | 21 | 21 | 22 |
number of dams with early deliveries | 0 | 0 | 0 | 0 |
number of dams with early embryonic death | 15 | 20 | 10 | 11 |
number of dams with late embryonic death | 5 | 4 | 10 | 3 |
number of dams with dead featuses | 1 | 0 | 0 | 1 |
corpora Lutea | 251 | 281 | 283 | 290 |
preimplantation loss (% as compared to no. of corpora lutea) | 39 (16%) | 24 (9%) | 24 (8%) | 33 (11%) |
postimplantation loss (% as compared to no. of corpora lutea) | 21 (10%) | 24 (9%) | 19 (7%) | 15 (6%) |
Implantations | 212 | 257 | 259 | 258 |
mean number of implantations | 11.8 | 12.2 | 12.3 | 11.7 |
early embryonic death (% as compared to no. of implantations) | 15 (7%) | 20 (8%) | 10 (4%) | 11 (4%) |
late embryonic death (% as compared to no. of implantations) | 5 (2%) | 4 (2%) | 10 (4%) | 3 (1%) |
dead fetuses | 1 | 0 | 0 | 1 |
total intrauterine mortality (% as compared to no. of corpora lutea) | 60 (24%) | 48 (17%) | 44 (16%) | 48 (17%) |
clinical signs: red coloured faeces (no. of does) | 0 | 21 | 21 | 22 |
clinical signs: reddish discolouration of the underlay (no. of does) | 0 | 0 | 1 | 0 |
clinical signs: reduced activity | 0 | 0 | 0 | 0 |
clinical signs: dyspnoea | 0 | 0 | 0 | 0 |
body weight (in g): gestational day 0 (mean +/- standard deviation) | 3691.9 +/- 159.45 | 3695.1 +/- 162.92 | 3690.7 +/- 155.70 | 3681.0 +/- 124.33 |
body weight (in g): gestational day 28 | 4734.7 +/- 193.98 | 4652.5 +/- 180.64 | 4732.8 +/- 209.09 | 4592.0 +/- 184.58 |
body weight gain (in g): from gestational day 0 to day 28 | 1042.8 +/- 186.60 | 957.4 +/- 206.23 | 1042.10 +/- 184.70 | 911.1 +/- 202.85 |
gravid uterine weight (in g) (mean +/- standard deviation) | 632.7 +/- 165.66 | 657.7 +/- 93.23 | 672.4 +/- 188.34 | 616.6 +/- 150.36 |
corrected body weight (in g) | 4102.1 +/- 256.66 | 3994.8 +/- 214.34 | 4060.4 +/- 281.25 | 3975.5 +/- 242.94 |
corrected body weight gain (in g) | 22.8 +/- 222.84 | -71.7 +/- 169.13 | -45.0 +/- 220.20 | -42.6 +/- 235.57 |
necropsy findings: no. of does with no macroscopic alterations (disclouration of digestive system excluded) | 16 | 17 | 18 | 18 |
necropsy findings: no. of does with discoloration (brick-reddish or brownish) | 0 | 20 | 21 | 22 |
necropsy findings: no. of does with point-like haemorrhages in the lungs | 2 | 3 | 2 | 2 |
necropsy findings: no. of does with dark red liver | 0 | 0 | 0 | 1 |
necropsy findings: no. of does with double gall bladder | 0 | 1 | 0 | 0 |
necropsy findings: no. of does with clotted blood in the uterine horn | 0 | 0 | 0 | 1 |
viable fetuses (total) | 191 | 233 | 239 | 243 |
viable fetuses (% as compared to no. of corpora lutea) | 76.1 | 82.9 | 84.5 | 83.8 |
sex ratio (male/female) | 89/102 = 0.87 | 108/125 = 0.86 | 114/125 = 0.91 | 102/141 = 0,72 |
viable fetuses (mean) | 10.6 | 11.1 | 11.4 | 11.0 |
fetal weight (in g) (mean +/- standard deviation) | 38.5 +/- 7.70 | 38.0 +/- 7.25 | 37.2 +/- 7.26 | 35.9 +/- 7.58 |
fetal weight (in g): male (mean +/- standard deviation) | 38.5 +/- 7.79 | 39.0 +/- 6.73 | 38.1 +/- 6.84 | 36.2 +/- 7.33 |
fetal weight (in g): female (mean +/- standard deviation) | 38.6 +/- 7.66 | 37.1 +/- 7.59 | 36.3 +/- 7.55 | 35.7 +/- 7.78 |
crown-rump length (in mm) (mean +/- standard deviation) | 90.7 +/- 7.40 | 90.6 +/- 6.64 | 90.2 +/- 6.46 | 89.0 +/- 7.11 |
crown-rump length (in mm): male (mean +/- standard deviation) | 90.4 +/- 7.78 | 91.3 +/- 6.12 | 91.2 +/- 6.04 | 89.8 +/- 6.74 |
crown-rump length (in mm): female (mean +/- standard deviation) | 90.9 +/- 7.08 | 90.0 +/- 7.02 | 89.3 +/- 6.72 | 88.5 +/- 7.35 |
fetuses with malformations (total number): external/visceral/skeletal | 1/1/12 | 0/0/11 | 0/0/2 | 1/0/6 |
type of malformation: external/visceral/skeletal | arcrania/enlarged perimeningeal space and brain slightly pushed /skull, sternebra, vertebrae | -/-/sternebra, ribs, vertebrae | -/-/skull, sternebra, ribs | umbilicial hernia/-/skull, sternebra, ribs |
fetuses with malformations (%): external/visceral/skeletal | 1/1/6 | 0/0/5 | 0/0/1 | 0.5/0/2 |
litters with malformations (total number): external/visceral/skeletal | 1/1/7 | 0/0/9 | 0/0/2 | 1/0/4 |
litters with malformations (%): external/visceral/skeletal | 6/6/39 | 0/0/43 | 0/0/10 | 5/0/18 |
fetuses with variations (total number) | 11/10/27 | 7/6/39 | 7/5/38 | 12/14/37 |
fetuses with variations (%) | 6/5/14 | 3/3/17 | 3/2/16 | 5/6/15 |
External variation: fetuses with retarded body weight (total number/%) | 7/4 | 5/2 | 6/3 | 8/3 |
External variation: litters with retarded body weight (total number/%) | 3/17 | 4/19 | 3/14 | 5/23 |
External variation: fetuses retarded in crown-rump length (total number/%) | 8/4 | 6/3 | 2/1 | 11/5 |
External variation: litters with retarded crown-rump length (total number/%) | 4/22 | 5/24 | 2/10 | 6/27 |
External variation: fetuses with neck edema (total number/%) | 0/0 | 0/0 | 1/0 | 0/0 |
Visceral variations: fetuses with slightly enlarged perimeningal space (total number/%) | 1/1 | 0/0 | 0/0 | 2/1 (two litters) |
Visceral variations: fetuses with dilated 3rd ventricle (total number/%) | 1/1 | 0/0 | 0/0 | 0/0 |
Visceral variations: fetuses with slightly larger hole between cerebral hemisphere and thalamus (total number/%) | 1/1 | 0/0 | 0/0 | 0/0 |
Visceral variations: fetuses with smaller lung lobes (total number/%) | 0/0 | 0/0 | 1/0.5 | 0/0 |
Visceral variations: fetuses with urinary bladder distended (total number/%) | 0/0 | 1/0.5 | 0/0 | 0/0 |
Visceral variations: fetuses with ureter convoluted (total number/%) | 7/4 (from 5 litters) | 5/2 (from 5 litters) | 3/1 (from 3 litters) | 12/5 (from 9 litters) |
Visceral variations: fetuses with slightly malpositioned kidney (total number/%) | 0/0 | 0/0 | 1/0.5 | 0/0 |
Skeletal variations: fetuses with slightly larger anterior or posterior fontanelle (total number/%/no. of litters) | 2/1/2 | 9/4/3 | 5/2/5 | 8/3/3 |
Skeletal variations: fetuses with slightly larger anterior and posterior fontanelle (total number/%/no. of litters) | 2/1/2 | 3/1/2 | 0/0/0 | 2/1/1 |
Skeletal variations: fetuses with less than 5 sternebrae ossified total (number/%/no. of litters) | 1/1/1 | 0/0/0 | 0/0/0 | 1/0.5/1 |
Skeletal variations: fetuses with dumb-bell shaped ossified sternebrae (number/%/no. of litters) | 8/4/6 | 7/3/5 | 8/3/5 | 8/3/5 |
Skeletal variations: fetuses with bipartite ossified sternebrae (number/%/no. of litters) | 3/2/3 | 9/4/7 | 3/1/3 | 6/2/5 |
Skeletal variations: fetuses with hole in xiphoid cartilage (number/%/no. of litters) | 6/3/3 | 6/3/5 | 7/3/5 | 7/3/4 |
Skeletal variations: fetuses misshapen ossification of sternebrae (number/%/no. of litters) | 2/1/1 | 3/1/2 | 0/0/0 | 1/0.51 |
Skeletal variations: fetuses with misalinged sternebae (number/%/no. of litters) | 0/0/0 | 5/2/5 | 0/0/0 | 0/0/0 |
Skeletal variations: fetuses with sternebrae with fusing tendency (number/%/no. of litters) | 1/1/1 | 0/0/0 | 0/0/0 | 0/0/0 |
Skeletal variations: fetuses with slightly wider sternebrae (number/%/no. of litters) | 4/2/1 | 0/0/0 | 0/0/0 | 2/1/2 |
Skeletal variations: fetuses with 7th rib not connected to sternum (number/%/no. of litters) | 2/1/1 | 1/0.5/1 | 6/3/4 | 3/1/2 |
Skeletal variations: fetuses with dumb-bell shaped vertebrae (number/%/no. of litters) | 4/2/3 | 5/2/4 | 4/2/3 | 5/2/4 |
Skeletal variations: fetuses with assymetric vertebrae (number/%/no. of litters) | 0/0/0 | 0/0/0 | 1/0.5/1 | 0/0/0 |
Skeletal variations: fetuses with pubis not ossified (number/%/no. of litters) | 0/0/0 | 1/0.5/1 | 0/0/0 | 3/1/3 |
Skeletal variations (limbs): fetuses with pollex not ossified (number/%/no. of litters) | 2/1/1 | 1/0.5/1 | 0/0/0 | 3/1/3 |
Skeletal variations (limbs): fetuses with talus not ossified (number/%/no. of litters) | 4/2/3 | 0/0/0 | 0/0/0 | 5/2/4 |
Skeletal variations (limbs): fetuses with small pubic (number/%/no. of litters) | 3/2/2 | 0/0/0 | 0/0/0 | 0/0/0 |
Skeletal variations: fetuses with less ossified phalanges (number/%/no. of litters) | 1/1/1 | 2/1/2 | 2/1/1 | 4/2/4 |
Skeletal variations: fetuses with asymmetrically ossified phalanges (number/%/no. of litters) | 2/1/2 | 7/3/6 | 6/3/5 | 5/2/5 |
Applicant's summary and conclusion
- Conclusions:
- In a GLP-study according to OECD test guideline 414 with rabbits, the substance, orally applied, did not reveal any adverse effects on the pregnancy, body weight, food consumption data of the does and on the intrauterine development of the fetuses. Therefore, both the NOAEL maternal toxicity and the NOAEL developmental toxicity were 1000mg/kg bw/day.
- Executive summary:
The developmental toxicity of the substance was investigated in a GLP-study according to OECD test guideline 414. Oral treatment of pregnant New Zealand white rabbit does from gestation day 6 up to the day before Caesarean section on gestation day 28 with the substance at the dose levels of 100, 300 and 1000 mg/kg bw/day did not reveal any adverse effects on the pregnancy, body weight, food consumption data of the dams and on the intrauterine development of the fetuses.
Under the conditions applied in this study and from the observations made in the does and their fetuses the following no-observable-adverse-effect levels were derived:NOAELmaternal toxicity:1000mg/kg bw/day
NOAELdevelopmental toxicity:1000mg/kg bw/day
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