Registration Dossier
Registration Dossier
Data platform availability banner - registered substances factsheets
Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.
The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 914-309-1 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic toxicity: oral
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- Not specified
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: OECD TG 451 / EPA OPPTS 870.4200 and GLP compliant study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 007
- Report date:
- 2007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 451 (Carcinogenicity studies)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.4200 (Carcinogenicity)
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- Nickel sulfate hexahydrate
- IUPAC Name:
- Nickel sulfate hexahydrate
- Reference substance name:
- 10101-97-0
- EC Number:
- 600-152-3
- Cas Number:
- 10101-97-0
- IUPAC Name:
- 10101-97-0
- Details on test material:
- - Name of test material (as cited in study report): Nickel sulfate hexahydrate
- Molecular formula (if other than submission substance): NiSO4.6H2O
- Analytical purity: 99.99%
- Provider: Sigma-Aldrich, USA
- Other: Analyses were conducted by KAR Laboratories, Inc. (Kalamazoo, Michigan) prior to study initiation, during week 51 and following study completion to confirm stability and purity of the test substance.
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Fischer 344
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Inc., Raleigh, North Carolina, USA
- Age at study initiation: Approximately 6 weeks old
- Weight at study initiation: 118-147 g (males) / 93-112 g (females)
- Fasting period before study: Not specified
- Housing: individually in suspended stainless steel cages rotated in a regular fashion
- Diet: ad libitum
- Water: ad libitum, by an automatic watering system or bottles when clinical signs warranted
- Acclimation period: Yes (duration not specified)
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-24
- Humidity (%): 29-73
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12-12
IN-LIFE DATES: Not specified
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: Reverse osmosis deionized tap water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
For each dosing group, a specified amount of test article and vehicle was mixed weekly.
The mixtures were stirred continuously throughout each exposure period.
The appearance of each test article solution was determined and documented as a clear colorless solution for 10 and 30 mg/kg groups and a clear pale blue solution for 50 mg/kg group.
VEHICLE
- Concentration in vehicle: Not specified
- Amount of vehicle (if gavage): 10 mL/kg
- Lot/batch no. (if required): Not applicable (tap water)
- Purity: Not applicable - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical concentration verification analyses conducted throughout the study demonstrated that exposure solutions were stable and prepared properly. All analyses were within +/-10% of the nominal concentration.
- Duration of treatment / exposure:
- 104 weeks minimum
- Frequency of treatment:
- Once daily
NB. Starting during week 24 and continuing through the remainder of the study, oral dosing was delayed from early morning until after 11:00 a.m. in order to allow time for gastric emptying and avoid potential pulmonary toxicity secondary to aspiration of nickel sulfate solution due to a full stomach.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 10, 30 or 50 mg/kg bw/day (corresponding to 0, 2.2, 6.7 and 11 mg nickel/kg bw/day)
Basis:
other: nominal doses
- No. of animals per sex per dose:
- 60
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: Based on the results of a 90-day range-finding study at 0, 50, 75, 100, 125 and 150 mg/kg bw/day
- Rationale for animal assignment: Computer randomization program
- Rationale for selecting satellite groups: Not applicable
- Post-exposure recovery period in satellite groups: Not applicable
- Section schedule rationale (if not random): Not applicable - Positive control:
- Not included
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly and on the day of scheduled euthanasia in week 104-105
BODY WEIGHT: Yes
- Time schedule for examinations: on days -3 and 0, weekly during first 13 weeks, once every 4 weeks thereafter, and in week 103
FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No
WATER CONSUMPTION: No
OPHTHALMOSCOPIC EXAMINATION: No
HAEMATOLOGY: Yes
- Time schedule for collection of blood: in weeks 54 and 104/105
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals/sex/group
- Parameters examined: according to OECD 451 protocol
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: in weeks 54 and 104/105
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 10 animals/sex/group
- Parameters examined: according to OECD 451 protocol
URINALYSIS: Yes
- Time schedule for collection of urine: in weeks 103, approximately 24 hrs post dosing
- Parameters examined: creatinine and albumin concentrations
NEUROBEHAVIOURAL EXAMINATION: No
OTHER:
Nickel determination in urine, feces and blood: immediately following dosing on one day during week 103, 5 animals/sex/group were placed in urine collection cages equipped with fecal collection systems and an ice bath for cooling collected urine samples. Urine and fecal samples were collected from each cage approximately 24 hrs post-exposure. Blood was collected from the orbital plexus of each animal approximately 30 min and 24 hrs post-dosing. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (at the time of death or euthanasia)
HISTOPATHOLOGY: Yes (by a board-certified veterinary pathologist followed by a peer-review and a review by a US NTP-style Pathology Working Group in order to confirm potential treatment-related effects and resolve any diagnostic discrepancies arising during initial peer-review) - Other examinations:
- No additional examinations
- Statistics:
- - In-life data (body weight, food consumption, hematology): Levene's test for equality of variance followed by Shapiro-Wilks test for normality. Single-factor ANOVA followed by Dunett's test for comparison between treated groups and respective control, or Kruskal-Wallis non-parametric ANOVA followed by Dunn's multiple comparison test if no equality or normality of variances.
- Survival data: Kaplan-Meier estimates of group survival rates followed by log-rank dose response trend test and log-rank test for survival.
- Tumor analysis: Peto's mortality-prevalence method without continuity correction (incidence of tumors) / Peto's mortality-independent method (mortality-independent tumors) + One-sided trend test, pairwise comparisons with control group, exact permutation test (low tumor incidence) and trend tests for each tumor type.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- mortality only (see below)
- Mortality:
- mortality observed, treatment-related
- Description (incidence):
- mortality only (see below)
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- MORTALITY (see Table 1 below)
- Before week 24: higher rate of mortality at 10, 30 or 50 mg/kg in both males and females, considered nickel sulfate-related, likely secondary to nickel-induced pulmonary toxicity due to aspiration of test solution because of relatively full stomach at the time of dosing (rats are nocturnal feeders) as suggested by dark red areas on lungs at necropsy.
- Weeks 24-48: mortality notably reduced by shifting dosing time (after 11:00 a.m.), with only one death in females given 30 mg/kg.
- Over the entire 105-week dosing period: no apparent treatment-related effects on mortality in treated males, increasing exposure-response trend in mortality in females relative to the controls (p<0.008).
BODY WEIGHT AND WEIGHT GAIN (see Table 2 below)
Dose-related decrease in body weight, reaching biological significance (-10%) at 30 mg/kg (males) or 50 mg/kg (females), and statistical significance (p<0.01) at 30 mg/kg (males and females).
FOOD CONSUMPTION
Statistically significant variations from controls observed sporadically in nickel sulfate-treated groups, with no relationship to the decrease in body weight gains.
HAEMATOLOGY
A few statistically significant differences observed in sulfate-treated groups (e.g. increases in red blood cells, heamtocrit and/or hemoglobin at 30 and 50 mg/kg) which may be associated with dehydration or could be related to nickel effects on gene expression of erythropoietin. None of these changes considered toxicologically meaningful.
GROSS PATHOLOGY
Findings of same type and incidence between all groups including controls, consistent with findings commonly seen in aging rats in a long-term study.
HISTOPATHOLOGY: NON-NEOPLASTIC
Non-neoplastic findings considered to be secondary to toxicity or incidental background occurences rather than a direct effect of nickel sulfate.
HISTOPATHOLOGY: NEOPLASTIC (see Table 3 below)
- The pathology report, pathology peer-review and pathology working group concurred that nickel sulfate hexahydrate did not cause any carcinogenic effects.
- Analysis of tumor data revealed only onse statistically significant (p<0.001) increase in tumors corresponding to keratoacanthoma (tail) in males given 10 mg/kg. As there was no dose-response relationship, as the incidence rate in males given 10 mg/kg (15%) was only slightly higher than the upper end of Haseman's historical control incidence for this tumor type (0-14%), and as the incidence rate in the remaining control and treated groups (0-7%) was within the range of the test facility historical incidence (0-2%) and the Haseman historical incidence (0-14%), this finding was considered incidental.
OTHER FINDINGS
Toxicokinetics:
- Blood levels of nickel at the end of the study indicated that steady state levels of nickel in blood increased with exposure, in excess from the control levels by a factor of approximately 100 for 10 mg/kg group and over 350 for 30 and 50 mg/kg groups.
- 24-hour urinary nickel levels also increased with exposure and correlated with blood levels.
- Nickel levels in feces increased in an exposure-dependent manner in treated males and females. The relatively high fecal levels compared to the blood and urinary nickel levels demonstrated that the majority of nickel was not systematically absorbed but excreted in the feces.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 2.2 mg/kg bw/day (nominal)
- Based on:
- other: nickel content
- Basis for effect level:
- other: Decreased body weights
- Dose descriptor:
- LOAEL
- Effect level:
- 6.7 mg/kg bw/day (nominal)
- Based on:
- other: nickel content
- Basis for effect level:
- other: Decreased body weights
Target system / organ toxicity
- Critical effects observed:
- not specified
Any other information on results incl. tables
Table 1: Male and female mortality during weeks 0 to 105
Dose (mg/kg/day) |
Male deaths/total (% mortality) |
Female deaths/total (% mortality)* |
0 |
36/60 (60) |
14/60 (23) |
10 |
29/60 (48) |
20/60 (33) |
30 |
30/60 (50) |
26/60 (43) |
50 |
34/60 (57) |
27/60 (45) |
* Increasing exposure-response trend in mortality relative to controls (p<0.008) |
Table 2: Summary of body weights at week 103
Dose (mg/kg/day) |
Male [grams +/- SD] (% of controls) |
Female [grams +/- SD] (% of controls) |
0 |
397 +/- 49 |
285 +/- 23 |
10 |
376 +/- 49 (95%) |
273 +/- 31 (96%) |
30 |
355 +/- 46* (89%) |
263 +/- 27* (92%) |
50 |
348 +/- 42* (88%) |
257 +/- 21* (90%) |
* p<0.01 vs. controls |
Table 3: Tumor summary table
Dose (mg/kg/day) |
Males* |
Females* |
||
Total number of malignant tumors |
Total number of malignant tumors with metastasis |
Total number of malignant tumors |
Total number of malignant tumors with metastasis |
|
0 |
28 |
23 |
15 |
11 |
10 |
21 |
11 |
14 |
9 |
30 |
20 |
9 |
11 |
6 |
50 |
17 |
11 |
13 |
7 |
* 60 animals per group |
Applicant's summary and conclusion
- Conclusions:
- - Nickel sulfate hexahydrate is not carcinogenic in rats up to the MTD (Maximum Tolerated Dose) through the oral route of exposure
- The NOAEL is set at 10 mg/kg bw/day (equivalent to 2.2 mg nickel/kg bw/day) based on significantly decreased body weight at higher dose levels. The dose of 30 mg/kg bw/day (equivalent to 6.7 mg nickel/kg bw/day) can be considered as a LOAEL. - Executive summary:
Nickel sulfate hexahydrate was administered daily to 6 -week-old Fischer 344 rats (60/sex/group) by once daily oral gavage (10 mL/kg) for 2 years (104 or 105 weeks) at exposure levels of 0 (vehicle: reverse osmosis deionized tap water), 10, 30 or 50 mg/kg bw/day in an OECD TG 451, EPA OPPTS 870.4200 and GLP-compliant study.
The administration of nickel sulfate hexahydrate produced a statistically significant reduction in body weight of male and female rats, compared to controls, in a dose -related manner at 30 and 50 mg/kg/day. An exposure-dependent increase in mortality was observed in female rats. However, the overall study survival rate (males and females) was at least 25 animals per group (compliant with OECD guidelines) in the treated animals.
Daily oral administration of nickel sulfate hexahydrate did not produce a dose-related increase in any common tumor type or an increase in any rare tumors. One tumor type was statistically increased in a nickel sulfate-treated group compared to the study controls (keratoacanthoma in males given 10 mg/kg bw/day), but there was no exposure-response relationship for this common tumor type and this was therefore considered to be incidental.
This study achieved sufficient toxicity to reach the Maximum Tolerated Dose (MTD) while maintaining a sufficiently high survival rate to allow evaluation for carcinogenicity. The present study indicated that nickel sulfate hexahydrate does not have the potential to cause carcinogenicity by the oral route of exposure in the Fischer 344 rat. The dose of 10 mg/kg bw/day (equivalent to 2.2 mg nickel/kg bw/day) was a NOAEL, based on body weight decreases, and the dose of 30 mg/kg bw/day (equivalent to 6.7 mg nickel/kg bw/day) was a LOAEL.
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.