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EC number: 209-599-5 | CAS number: 587-26-8
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- toxicity to reproduction
- Remarks:
- other: Reproduction / Developmental Toxicity Screening Test
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- supporting study
- Study period:
- 16 July 2007 - 31 Oct 2008
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- GLP-guideline study; in accordance to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.”
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 008
- Report date:
- 2008
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)
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Dicerium tricarbonate
- EC Number:
- 208-655-6
- EC Name:
- Dicerium tricarbonate
- Cas Number:
- 537-01-9
- Molecular formula:
- CH2O3.2/3Ce
- IUPAC Name:
- dicerium tricarbonate
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approximately 10 weeks old
- Weight at study initiation: at the beginning of the treatment period, the animals had a mean body weight of 419 g (range: 392 g - 442 g) for the males and 263 g (range: 239 g - 283 g) for the females
- Fasting period before study: no
- Housing: The males were individually housed, except during pairing, in wire-mesh cages (43.0 x 21.5 x 18.0 cm). The females were individually housed, except during pairing, until late gestation in wire-mesh cages (43.0 x 21.5 x 18.0 cm). The females were individually housed from late gestation, and with their litter during lactation, in polycarbonate cages (43.0 x 21.5 x 20.0 cm).
- Diet: free access to SSNIFF R/M-H pelleted maintenance diet
- Water: free access to bottles containing tap water (filtered with a 0.22 µm filter)
- Acclimation period: the animals were acclimated to the study conditions for a period of 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 50 +/- 20
- Air changes (per hr): about 12 cycles/hour of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From 14 Aug 2007 To: 10 Oct 2007
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% aqueous methylcellulose solution
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was administered as a suspension in the vehicle. The test item was ground to fine powder using a mortar and pestle, suspended in the vehicle in order to achieve the concentrations of 30, 90 and 200 mg/mL and then homogenized using a magnetic stirrer. The test item dosage forms were prepared at a frequency based on stability data (up to 9 days) and were stored at +4 °C, protected from light, prior to use.
VEHICLE
- Justification for use and choice of vehicle (if other than water): aqueous suspension for a poorly hydrosoluble test substance, as recommended in the guideline
- Concentration in vehicle: 30, 90 and 200 mg/mL
- Amount of vehicle (if gavage): a constant volume of 5 mL/kg/day was used
- Lot/batch no. (if required): methylcellulose batch No. 017K0052, supplied by Sigma - Details on mating procedure:
- - M/F ratio per cage: one female was placed with one male
- Length of cohabitation: Each female was placed with the same male until mating occured or 14 days had elapsed. Any pairs with no evidence of mating after 14 days were separated and the female was placed for 7 days with a different male from the same dose level group who had already mated.
- Proof of pregnancy: Confirmation of mating was made in the morning, every day up to proof of mating, by checking for the presence of a vaginal plug or of sperm in a vaginal lavage.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
- Any other deviations from standard protocol: no - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- During a pre-study period, the homogeneity, stability and concentration of two dosage forms prepared at the lowest and highest concentrations of the present study (30 and 200 mg/mL) were checked using ICP-OES (Inductively Coupled Plasma/Optical Emission Spectrometry) after validation of the analytical method. The results showed acceptable homogeneity and stability of both concentrations over 9 days at +4 °C.
During the study, the concentration of the test item and homogeneity of the dosage forms was determined in samples of each control and test item dosage form prepared for use in weeks 1, 3 and 6. The results showed acceptable homogeneity and concentration of all dosage forms analyzed. Precision (RSD =< 10%) and accuracy (100 +/- 10%) of the method were found to be satisfactory. - Duration of treatment / exposure:
- - Males: 15 days before mating, during the mating period (up to 3 weeks), until sacrifice (i.e. at least 4 weeks in total)
- Females: 15 days before mating, during the mating period (up to 3 weeks), during pregnancy, during lactation until day 5 post-partum inclusive - Frequency of treatment:
- Each animal was given the appropriate dosage form once a day, at approximately the same time each day, 7 days a week.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 150, 450 and 1000 mg/kg bw/day
Basis:
nominal conc.
corrected from the water content
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: on the basis of a previous 14-day toxicity study in the rat in which the dose-levels of 150, 450 and 1000 mg/kg bw/day elicited no significant treatment-related effects.
- Rationale for animal assignment: during the pre-treatment period, the required number of animals (40 males and 40 females) was selected according to body weight and clinical condition and allocated to the groups (by sex), according to a computerized stratification procedure, so that the average body weight of each group was similar. - Positive control:
- not used
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: From arrival, the animals were observed once a day as part of routine examinations. From the start of treatment period, each animal was observed once a day, at approximately the same time for the recording of clinical signs.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: On all animals outside the home cage, in a standard arena, once before the beginning of the treatment period and then once a week until the end of the study.
Observations included (but were not limited to) changes in the skin, fur, eyes, mucous membranes, occurrence of secretions and excretions and autonomic activity (e.g. lachrymation, piloerection, pupil size, unusual respiratory pattern). Changes in gait, posture and response to handling as well as the presence of clonic or tonic movements, stereotypes (e.g. excessive grooming, repetitive circling) or bizarre behavior (e.g. self-mutilation, walking backwards) were also recorded.
BODY WEIGHT: Yes
- Time schedule for examinations: The body weight of each male was recorded on the first day of treatment (day 1), then once a week until sacrifice. The body weight of each female was recorded on the first day of treatment (day 1), then once a week until mated (or until sacrifice) and on days 0, 7, 14 and 20 post-coitum and days 1 and 5 post-partum.
FOOD CONSUMPTION: Yes
The quantity of food consumed by each male was recorded once a week, over a 7 day period, from the first day of treatment until sacrifice. The quantity of food consumed by each female was recorded once a week, over a 7 day period, from the first day of treatment through gestation (days 0-7, 7-14 and 14-20 post-coitum intervals) and lactation (days 1-5 post-partum intervals) until sacrifice. During the pairing period, food consumption was not recorded for males or females.
WATER CONSUMPTION: No
OTHER:
MORTALITY AND MORBIDITY: Each animal was checked for mortality or signs of morbidity at least twice a day during the treatment period.
Functional Observation Battery (FOB): On the first five males and the first five females, once at the end of the treatment period. This included a detailed clinical examination, measurement of reactivity to manipulation or to different stimuli and motor activity.
HEMATOLOGY: peripheral blood
The following parameters were determined for the last five males and females of each group on the day of sacrifice: Erythrocytes, Hemoglobin, Mean cell volume, Packed cell volum, Mean cell hemoglobin concentration, Mean cell hemoglobin, Thrombocytes, Leucocytes, Differential white cell count with cell morphology (neutrophils, eosinophils, basophils, lymphocytes and Large Unstained Cells), Monocytes, Reticulocytes, Prothrombin time, Activated partial thromboplastin time, Fibrinogen.
BLOOD BIOCHEMISTRY:
The following parameters were determined for the last five males and females of each group on the day of sacrifice: Sodium, Potassium, Chloride, Calcium, Inorganic phosphorus, Glucose, Urea, Creatinine, Total bilirubin, Total proteins, Albumin, Albumin/globulin ratio, Total cholesterol, Triglycerides, Alkaline phosphatase, Aspartate aminotransferase, Alanine aminotransferase, Lactate dehydrogenase, Bile acids.
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No data
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes - Oestrous cyclicity (parental animals):
- The pre-coital time was calculated for each female. The estrous cycle stage was determined from a fresh vaginal lavage (stained with methylene blue), each morning during the mating period, until the females were mated.
- Sperm parameters (parental animals):
- The microscopic examination made special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure.
- Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no
PARAMETERS EXAMINED
The following parameters were examined in offspring:
- Stillbirths, live births
- The total litter size and numbers of pups of each sex (sex ratio) was recorded as soon as possible after birth.
- Postnatal mortality: The litters were observed daily in order to note the number of live, dead and cannibalized pups.
- The pups were observed daily for clinical signs.
- Weight gain: The weight of each pup was recorded on days 1 and 5 post-partum.
GROSS EXAMINATION OF DEAD PUPS: yes - Postmortem examinations (parental animals):
- SACRIFICE
After overnight fasting, at least 14 hours, all surviving F0 animals were deeply anesthetized by an intraperitoneal injection of sodium pentobarbital and sacrificed by exsanguination:
- males: after the end of the mating period (after at least 4 weeks of treatment),
- females: on day 6 post-partum,
GROSS NECROPSY
- A complete macroscopic post-mortem examination was performed on all animals. This included examination of the external surfaces, all orifices, the cranial cavity, the external surfaces of the brain, the thoracic, abdominal and pelvic cavities with their associated organs and tissues and the neck with its associated organs and tissues. Special attention was paid to the reproductive organs. The numbers of corpora lutea and implantation sites were also recorded.
HISTOPATHOLOGY / ORGAN WEIGHTS
A microscopic examination was performed on:
- all the tissues listed in the Table 1 for the first five males and females of the control and high-dose groups (groups 1 and 4) sacrificed as scheduled
- all macroscopic lesions
The microscopic examination made special emphasis on stages of spermatogenesis in the male gonads and histopathology of interstitial testicular cell structure. - Postmortem examinations (offspring):
- Pups found dead, prematurely sacrificed and pups sacrificed on day 5 post-partum were carefully examined externally for gross external abnormalities and a macroscopic examination was performed. There was no preservation of tissues.
- Statistics:
- Mean values were compared by one-way variance analysis and Dunnett test, (mean values being considered as normally distributed, variances being considered as homogeneous). Percentage values were compared by Fisher exact probability test.
- Reproductive indices:
- The following parameters were evaluated:
- Pre-implantation loss
- Post-implantation loss
- Mating index
- Fertility index
- Gestation index
- Number of corpora lutea
- Number of implantations
- Number of pups delivered - Offspring viability indices:
- The following parameters were evaluated:
- Live birth index
- Viability index on day 4 post-partum
- Mean litter size
- Pup sex ratios
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- findings in the stomach
- Other effects:
- no effects observed
- Description (incidence and severity):
- Test substance intake: substance administered by gavage
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- no effects observed
- Reproductive function: sperm measures:
- no effects observed
- Reproductive performance:
- no effects observed
Details on results (P0)
BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Females had lower mean body weight gains during pregnancy and lactation and lower food consumption during lactation but this may be related to the higher number of fetuses/pups in the control group. There were no effects during the pre-mating period and no effects on mean male body weight or food consumption.
HISTOPATHOLOGY (PARENTAL ANIMALS):
No microscopic treatment related changes were observed in the testes and ovaries.
REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
There were no treatment-related differences in the mating, fertiliy and gestation indices between treated and control animals (Table 2).
Effect levels (P0)
- Key result
- Dose descriptor:
- NOAEL
- Remarks:
- for reproductive performance (mating and fertility)
- Effect level:
- 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: no effects on mating and fertility in highest dose tested
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- not examined
Effect levels (F1)
- Key result
- Dose descriptor:
- NOAEL
- Generation:
- F1
- Effect level:
- >= 1 000 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: No adverse and treatment-related effects were observed up to and including the highest tested dose level.
- Remarks on result:
- other: based on gross necropsy of offspring on day 5 post-partum
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Table 2: Summary of reproductive data
Dose level (mg/kg/d) |
|
0 |
150 |
450 |
1000 |
Paired males + females |
n |
10 + 10 |
10 + 10 |
10 + 10 |
10 + 10 |
Pairs mated |
n |
10 |
10 |
9 (10) |
10 |
Mating index |
% |
100.0 |
100.0 |
90.0 (100.0) |
100.0 |
Mean number of days of pairing before mating |
n |
3.4 |
2.4 |
4.3 |
2.3 |
Pregnant female partners |
n |
10 |
8 |
10 |
10 |
Fertility index |
% |
100.0 |
80.0 |
100.0 |
100.0 |
Females with live concepti |
n |
10 |
8 |
10 |
10 |
Gestation index |
% |
100.0 |
100.0 |
100.0 |
100.0 |
( ): female with no evidence of mating
Summary of delivery data
Dose level (mg/kg/day) |
0 |
150 |
450 |
1000 |
Number of pregnant females |
10 |
8 |
10 |
10 |
Mean duration of gestation (days) |
21.8 |
21.9 |
22.1 |
22.0 |
Mean number of corpora lutea |
18.6 |
17.6 |
18.5 |
18.0 |
Mean number of implantations |
16.5 |
16.5 |
15.1 |
14.7 |
Mean pre-implantation loss (%) |
11.3 |
5.6 |
17.0 |
17.4 |
Mean number of pups delivered |
15.6 |
14.6 |
12.0 |
12.9 |
Mean post-implantation loss (%) |
5.7 |
11.6 |
22.2 |
12.3 |
Reproductive and litter data
Dose (mg/kg/day) |
0 |
150 |
450 |
1000 |
|
Females on Study |
N |
10 |
10 |
10 |
10 |
Females Surviving Delivery
Duration of gestation
With stillborn pups
With all stillborn
With entire liveborn litter dying and/or missing, cannibalized, culled
Days 0-4
Days 0-5 |
N
Mean S.D.
N %
N %
N %
N % |
10 f
21.8 d 0.4
0 f 0.0
0 f 0.0
0 f 0.0
0 f 0.0 |
8
21.9 0.4
0 0.0
0 0.0
0 0.0
0 0.0 |
10
22.1 0.6
0 0.0
0 0.0
1 10.0
1 10.0 |
10
22.0 0.0
0 0.0
0 0.0
0 0.0
0 0.0 |
Litters with liveborn pups |
N |
10 |
8 |
10 |
10 |
Pups Delivered (total)
Liveborn Live birth index
Stillborn
Culled (total) Cannibalized Missing Died
Liveborn, not culled Prior to day 5 |
N Mean S.D.
N %
N %
N N N N
N |
156 15.6 d 2.7
156 f 100.0
0 f 0.0
0 2 0 4
156 |
117 14.6 2.3
117 100.0
0 0.0
0 4 0 1
117 |
120 12.0 5.2
120 100.0
0 0.0
0 2 0 1
120 |
129 12.9 4.4
129 100.0
0 0.0
0 0 0 1
129 |
Pups dying, missing, and/or cannibalized Day 0
Days 1-4
Days 5-7
|
N %
N %
N % |
0 f 0.0
6 f 3.8
0 f 0.0 |
0 0.0
5 4.3
0 0.0 |
0 0.0
3 2.5
0 0.0 |
0 0.0
1 0.8
0 0.0 |
Pups surviving 4 days Viability index |
N % |
150 f 96.2 |
112 95.7 |
117 97.5 |
128 99.2 |
Pups surviving 5 days Lactation index |
N % |
150 f 100.0 |
112 100.0 |
117 100.0 |
128 100.0 |
Implantation sites per litter |
N Mean S.D. |
165 16.5 d 2.5 |
132 16.5 1.1 |
151 15.1 4.1 |
147 14.7 4.1 |
Corpora lutea |
Total Mean S.D. |
186 18.6 d 1.0 |
141 17.6 2.2 |
185 18.5 3.3 |
180 18.0 3.3 |
Preimplantation loss |
Mean% S.D. |
11.3 d 12.2 |
5.6 8.1 |
17.0 21.7 |
17.4 21.9 |
Live pups / litter Day 1
Day 4
Day 5 |
Mean S.D.
Mean S.D.
Mean S.D. |
15.3 d 2.5
15.0 d 2.3
15.0 d 2.3 |
14.5 2.2
14.0 1.9
14.0 1.9 |
11.8 5.1
13.0 3.6
13.0 3.6 |
12.8 4.3
12.8 4.3
12.8 4.3 |
Pup weight / Litter (grams) Day 1
Day 5 |
Mean S.D.
Mean S.D. |
7.3 d 0.5
12.0 d 1.5 |
7.5 0.4
12.2 1.2 |
7.6 0.9
12.6 2.1 |
7.9 0.5
12.8 1.8 |
Applicant's summary and conclusion
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.