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EC number: 231-492-7 | CAS number: 7585-20-8
- 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
Developmental toxicity / teratogenicity
Administrative data
- Endpoint:
- developmental toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 2012-12-06 to 2013-02-07
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study performed under Good Laboratory Practices (GLP) and according to OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test) without significant deviation.
Cross-referenceopen allclose all
- Reason / purpose for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- reference to other study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 013
- Report date:
- 2013
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Zirconium acetate
- EC Number:
- 231-492-7
- EC Name:
- Zirconium acetate
- Cas Number:
- 7585-20-8
- Molecular formula:
- C2H4O2.xZr
- IUPAC Name:
- λ²-zirconium(2+) diacetate
- Test material form:
- other: aqueous solution
- Details on test material:
- - Name of test material (as cited in study report): zirconium acetate solution
- Substance type: unknown
- Physical state: liquid
- Analytical purity: > 99% zirconium acetate anhydrous
- Composition of test material, percentage of components: aqueous solution containing 40.7% zirconium acetate anhydrous
- Lot/batch No.: 12/201
- Expiration date of the lot/batch: 2013-07-01
- Stability under test conditions: 8 days at room temperature in the concentration range of 10 to 100 mg/mL
- Storage condition of test material: room temperature
- Other: colourless, clear solution
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Italia S.p.A., Calco (Lecco), Italy
- Age at study initiation: 6 to 7 weeks
- Weight at study initiation: 204.5 to 212.8 g (males); 164.8 to 180.2 g (females)
- Fasting period before study: none
- Housing: From arrival to pairing, animals were housed up to 5 of one sex to a cage, in polisulphone solid bottomed cages measuring 59.5 x 38 x 20 cm. Nesting material was provided inside suitable bedding bags and changed at least twice a week. During mating, animals were housed one male to one female in clear polycarbonate cages measuring approximately 43 x 27 x 18 cm with a stainless steel mesh lid and floor. Each cage tray held absorbent material which was inspected and changed daily. After mating, the males were re-caged as they were before mating while females were transferred to individual solid bottomed cages for the gestation period, birth and lactation.
- Diet: ad libitum, except prior to drawing of blood for clinical chemistry examinations
- Water: ad libitum
- Acclimation period: 2 weeks
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 2
- Humidity (%): 55 +/- 15%
- Air changes (per hour): 15 to 20
- Photoperiod (hours dark / hours light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: purified water
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS
The required amount of zirconium acetate solution (containing 40.7% of zirconium acetate anhydrous) was dissolved in the vehicle (purified water) to obtain final concentrations of 10, 30 and 100 mg/mL. The formulations were prepared daily or up to 7 days before dosing according to stability data. The concentrations were calculated and expressed in terms of zirconium acetate content (40.7%).
VEHICLE
- Concentration in vehicle: 10, 30, 100 mg/L (expressed as active compound content)
- Amount of vehicle (if gavage): 10 mL/kg body weight (for males, dose volumes were adjusted once per week for each animal according to the last recorded body weight; for females, dose volumes were calculated according to individual body weight on days 0, 7, 14 and 20 post coitum and on day 1 post partum, thereafter individual dose volumes remained constant)
- Purity: not required - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Prior to commencement of treatment, analysis was performed to confirm that the proposed formulation procedure was acceptable (check of concentration) Samples of dosing formulations prepared on Weeks 1 and 5 were analysed to verify the concentrations. Samples of the formulations were collected and sent at ambient temperature to the analytical laboratory. Chemical analyses were carried out according to an Inductively Coupled Plasma-Optical Emission Spectroscopy (ICP-OES) method.
- Details on mating procedure:
- Mating was monogamous (one male to one female). A vaginal smear was taken from the day after the start of pairing until positive identification of copulation (sperm identification, vaginal plugin situor copulation plugs found in the cage tray). The female was paired with the same male until positive identification occurs or 14 days had elapsed.
During mating, animals were housed one male to one female in clear polycarbonate cages measuring approximately 43x27x18cm with a stainless steel mesh lid and floor (Techniplast - Gazzada S.a.r.l.). Each cage tray held absorbent material which was inspected and changed daily. - Duration of treatment / exposure:
- - Males were treated two weeks prior to pairing, throughout pairing and thereafter through the day before scheduled sacrifice (32 days of dosing).
- Females were treated two weeks prior to pairing, throughout pairing until day 3 post partum or the day before scheduled sacrifice (up to 50 days of dosing). - Frequency of treatment:
- Once daily
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
100, 300, 1000 mg/kg bw/day
Basis:
other: actual ingested (zirconium acetate anhydrous)
- Remarks:
- Doses / Concentrations:
53, 159, 530 mg/kg bw/day
Basis:
other: actual ingested (zirconium)
- No. of animals per sex per dose:
- 10
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: dose levels were selected in consultation with the sponsor based on information from a non-GLP 2 week preliminary toxicity study (RTC Study no. 94150EXT).
- Rationale for animal assignment: rats were allocated to groups by computerised stratified randomisation to give approximately equal initial group mean body weights.
- Rationale for selecting satellite groups: not applicable (satellite group not included)
- Post-exposure recovery period in satellite groups: not applicable (satellite group not included)
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were checked each morning and afternoon for mortality.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Once before commencement of treatment and at least once daily during the study, each animal was observed and any clinical sign was recorded. Observations were performed at the same time interval each day, the interval was selected taking into consideration the presence of post-dose reactions.
BODY WEIGHT: Yes
- Time schedule for examinations: Males were weighed weekly from allocation to termination. Females were weighed weekly from allocation to positive identification of mating and on Days 0, 7, 14 and 20 post coitum. Dams were also weighed on Days 1 and 4 post partum.
FOOD CONSUMPTION: Yes
- Time schedule for examinations: weekly during the pre-mating period starting from allocation. Individual food consumption for the females was measured on Days 7, 14 and 20 post coitum starting from Day 0 post coitum and on Day 4 post partum starting from Day 1 post partum.
- Parameters checked: the weight of food consumed by each cage of males and females.
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice: Females with live pups were killed on Day 4 post partum while females which did not give birth 25 days after positive identification of mating were killed shortly (Day 27 post coitum). All parental animals were killed by exsanguination under isofluorane anaesthesia.
- Organs examined: adrenal glands; bone marrow (from sternum); brain; caecum; colon; duodenum; heart; ileum; jejunum (including Peyer’s patches); kidneys; liver; lungs (including mainstem bronchi); lymph nodes - cervical ; lymph nodes - mesenteric; nasal cavity; oesophagus; pituitary gland; prostate gland; rectum; sciatic nerve; spinal column; spinal cord (cervical, thoracic, lumbar); spleen; stomach; thymus (where present); thyroid ; trachea; urinary bladder; ovaries with oviducts; uterus - cervix; vagina. - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of pre-implantations: yes
- Number of pre-birth loss: yes - Fetal examinations:
- - External examinations: Yes: all pups found dead
- Soft tissue examinations: No data
- Skeletal examinations: No data
- Head examinations: No - Statistics:
- Standard deviations were calculated as appropriate. For continuous variables the significance of the differences amongst group means was assessed by Dunnett’s test or a modified t test, depending on the homogeneity of data. Statistical analysis of histopathological findings was carried out by means of the nonparametric Kolmogorov-Smirnov test if n was more than 5. The non-parametric Kruskal-Wallis analysis of variance was used for the other parameters. Intergroup differences between the control and treated groups were assessed by the nonparametric version of the Williams test.
The criterion for statistical significance was p<0.05. - Indices:
- - The following reproductive indices were calculated: copulatory index; fertility index; pre-coital interval (mean number of days between pairing and mating); pre-implantation loss and pre-birth loss.
- Historical control data:
- No data
Results and discussion
Results: maternal animals
Maternal developmental toxicity
- Details on maternal toxic effects:
- Maternal toxic effects:no effects
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY
- No mortality occurred in the study.
- No clinical findings of toxicological significance were observed. Hair loss was occasionally recorded throughout the study including control animals. One female of the mid-dose group had salivation on Day 20 post coitum. One high dose female, that did not give birth, showed prolapse of the uterus on Day 27 post coitum. Another high dose female had rales during pairing.
BODY WEIGHT AND WEIGHT GAIN
- Body weight and body weight gain did not show relevant differences between groups. In particular, body weight gain was in some occasions higher in treated groups compared to the control group.
HAEMATOLOGY
- No changes of toxicological relevance were recorded.
- A statistically significant decrease of lymphocytes recorded in some females dosed with 300 mg/kg bw/day (42%) was not dose-related and, therefore, is considered incidental.
- No changes were observed in the coagulation test.
CLINICAL CHEMISTRY
- One animal showed high triglycerides (6.2 fold compared with controls). Due to the low incidence, this finding cannot be conclusively attributed to treatment; however, it also cannot be ruled out that it was related to treatment.
NEUROBEHAVIOUR
- Motor activity recorded at the end of treatment did not show significant differences between control and treated groups.
ORGAN WEIGHTS
- A slight significant reduction of epididymides weight occurred in the high-dose group; however, this reduction was found to be related to the higher terminal body weight in the high-dose group compared to controls. In addition, this change was minimal and no histological associated-findings were found. Therefore, it was considered of no toxicological relevance.
TERMINAL BODY WEIGHT AND ORGAN WEIGHTS
Body weight at term and organ weights did not show differences of toxicological relevance.
HISTOPATHOLOGY: NON-NEOPLASTIC
- Minimal, focal vacuolation of squamous epithelium (limiting ridge) of the non-glandular region of the stomach was observed was observed in the high and mid-dose males with an increased incidence in the high dose males and similar severity levels across treatment groups. However, as this gastric change was noted only in males, in a specific zone of the forestomach (limiting ridge) with focal and minimal severity and since humans do not have forestomach (squamous epithelium), such change could be considered toxicologically irrelevant.
- The remaining lesions reported in control and treated animals were considered to be an expression of spontaneous and/or incidental pathology, commonly seen in this species and age under our experimental conditions.
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Remarks:
- anhydrous zirconium acetate
- Basis for effect level:
- other: developmental toxicity
Results (fetuses)
- Details on embryotoxic / teratogenic effects:
- Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
CLINICAL SIGNS (OFFSPRING)
- Small pups were generally observed in all groups including the control group.
- Cold to touch and/or apparently no food intake were also occasionally recorded in all groups.
- One pup of low dose group showed absence of tail. This abnormality was considered incidental.
BODY WEIGHT (OFFSPRING)
- Mean pup weights were found comparable between groups at birth and on Day 4 post partum. Sex ratio did not differ between groups.
GROSS PATHOLOGY (OFFSPRING)
- The majority of decedent pups had autolysed organs in the abdominal cavity at necropsy.
- No abnormalities were found in pups sacrificed on Day 4 post partum with the exception of the low dose pup with the absence of tail. One pup of the mid-dose group showed no milk in stomach.
LITTER DATA AND SEX RATIOS:
Litter data including mean litter and pup weights were comparable between groups. No differences were found in sex ratio.
Fetal abnormalities
- Abnormalities:
- not specified
Overall developmental toxicity
- Developmental effects observed:
- not specified
Any other information on results incl. tables
The overall results of the test formulation analyses were within the limits of acceptance for concentration (15% of the theoretical concentration).
Applicant's summary and conclusion
- Conclusions:
- No effects on reproduction or development were observed in any dose group or in pups. Therefore, on the basis of the results obtained in the study, the No Observed Adverse Effect Level (NOAEL) for reproductive toxicity and for developmental toxicity was considered to be >=1000 mg/kg bw/day (expressed as zirconium acetate anhydrous).
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