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EC number: 266-047-6 | CAS number: 65997-18-4 Frit is a mixture of inorganic chemical substances produced by rapidly quenching a molten, complex combination of materials, confining the chemical substances thus manufactured as nonmigratory components of glassy solid flakes or granules. This category includes all of the chemical substances specified below when they are intentionally manufactured in the production of frit. The primary members of this category are oxides of some or all of the elements listed below. Fluorides of these elements may also be included in combination with these primary substances.@Aluminum@Manganese@Antimony@Molybdenum@Arsenic@Neodymium@Barium@Nickel@Bismuth@Niobium@Boron@Phosphorus@Cadmium@Potassium@Calcium@Silicon@Cerium@Silver@Chromium@Sodium@Cobalt@Strontium@Copper@Tin@Gold@Titanium@Iron@Tungsten@Lanthanum@Vanadium@Lead@Zinc@Lithium@Zirconium@Magnesium
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- repeated dose toxicity: oral
- Remarks:
- combined repeated dose and carcinogenicity
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- not reported
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Guideline study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 2 007
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: OECD 451 (Carcinogenicity Studies)
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPPTS 870.4200 (Carcinogenicity)
- GLP compliance:
- yes
- Limit test:
- no
Test material
Constituent 1
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.
- Age at study initiation: 6 weeks
- Weight at study initiation: 118 to 147 g for males and 93 to 112 g for females
- Fasting period before study: not reported
- Housing: housed individually in suspended stainless steel cages that were rotated in a regular fashion
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: acclimated to the laboratory conditions prior to in-life initiation
- Other: The results of the pretest health screen (gross necropsy and serological analyses) conducted prior to in-life initiation indicated that the population of animals was suitable for study use. Serological analyses of blood samples fromfive male and five female sentinel animals conducted by
BioReliance Corporation, Rockville, Maryland, during weeks 25, 51, 77 and 103 did not reveal the presence of any viral infections that would
negatively impact the results of this study.
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 70 to 76 °F
- Humidity (%): 29 to 73%
- Air changes (per hr): 10 to 15 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-h light/12-h dark cycle
IN-LIFE DATES: not reported
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- water
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS: a specified amount of the test article and vehicle was mixed weekly. The mixtures were stirred continuously throughout each exposure period. The appearance of each test article preparation was determined and documented as a clear colorless solution for groups 2 and 3 (10 and 30mg/kg/day) and a clear pale blue solution for group 4 (50 mg/kg/day).
DIET PREPARATION
- not applicable
VEHICLE
- water - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analyses were conducted by KAR Laboratories, Inc. (Kalamazoo, Michigan) prior to study initiation, during week 51, and following study completion
to confirm the stability and purity of the test substance. Reverse osmosis deionized tap water was used for administration to control animals and in
the preparation of the test article mixtures. Analytical concentration verification analyses conducted throughout the study demonstrated that the
exposure solutions were stable and properly prepared. All analyses were within ±10% of the nominal concentration. - Duration of treatment / exposure:
- 104 weeks
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
10, 30 and 50 mg/kg/day
Basis:
other: dose via oral gavage
- No. of animals per sex per dose:
- 60 males/60 females per dose
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- - Dose selection rationale: Exposures for the 90-day range finding study were selected based on previous gavage studies of nickel sulfate hexahydrate in rats. The 90-day range-finding study of nickel sulfate hexahydrate administered by gavage was conducted using exposures of 0, 50, 75, 100, 125, and 150 mg/kg. Findings from this study are reported in the Results section. Based on the data from the 90-day range-finding study, exposure levels of 10, 30 and 50 mg/kg/day were selected for the 2 year oral gavage carcinogenicity study.
- Rationale for animal assignment (if not random): Sixty female and sixty male animals were assigned to each exposure group using a computer randomization program. - Positive control:
- None reported
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: General health/mortality/moribundity checks were performed twice daily.
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Detailed clinical observations were performed weekly and on the day of scheduled euthanasia (weeks 104–105). Beginning on week 25, detailed clinical observations included a palpable mass examination (including the occurrence, size, location and description of any palpable masses) followed by persistence or disappearance of these masses being documented at the next weekly clinical observation.
BODY WEIGHT: Yes
- Time schedule for examinations: Individual body weights were recorded prior to randomization (day −3), on day 0 (i.e., the start of exposure), weekly during the first 13 weeks, once every 4 weeks thereafter and during week 103.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Individual food consumption (grams/animal/day) was recorded on day 0, weekly during the first 13 weeks and once every 4 weeks thereafter, with the final food consumption measurement during week 103.
HAEMATOLOGY: Yes
- Selected hematological parameters were measured in blood samples collected from 10 animals/sex/group during week 54 (via tail vein) and prior to scheduled euthanasia during week 104/105 (via orbital plexus). Hematology and clinical chemistry parameters were measured according to the OECD 451 protocol. - Sacrifice and pathology:
- GROSS PATHOLOGY/HISTOPATHOLOGY:
All animals were subjected to a complete gross necropsy examination at the time of death or euthanasia. Tissues collected at necropsy from all
animals were processed for histopathological evaluation. Slides were prepared by Histo Techniques (Powell, Ohio) and Charles River Laboratories-
Pathology Associates (Frederick, Maryland) and were examined microscopically by a Charles River Laboratories board-certified veterinary
pathologist. - Other examinations:
- Near the end of the study (week 103), additional biological sampling was performed to provide data on nickel in urine, feces and blood. Immediately
following exposure on 1 day during week 103, five females and five males from each exposure group were placed in urine collection cages equipped with fecal collection screens, and an ice bath for cooling collected urine samples. Blood was collected from the orbital plexus of each animal
approximately 30 min and 24 h post-exposure and sent to WIL Research Laboratories, Inc. (Ashland, Ohio) for analysis of blood nickel
concentration. Urine and fecal samples were collected from each cage approximately 24 h post-exposure and sent to KAR Laboratories, Inc. for
urine and fecal analysis of nickel concentrations. Urine was analyzed also for creatinine and albumin concentrations. Other standard hematology
and clinical chemistry parameters for blood as well as other standard urinalysis parameters for urine were measured by Charles River Laboratories. - Statistics:
- In-life data: The data were initially tested for normality using Levene's test for equality of variance followed by the Shapiro–Wilks test for normality.
A p≤0.001 level of significance was required for either test to reject the assumptions. If both assumptions were fulfilled, a singlefactor
ANOVA was applied, with animal grouping as the factor, utilizing a p≤0.05 level of significance. If the parametric ANOVA was significant at p≤0.05,
Dunnett's test was used to identify statistically significant differences between the control group and each nickel sulfate-treated group at the 0.05,
0.01 and 0.001 levels of significance. If either of the parametric assumptions was not satisfied, then the Kruskal–Wallis nonparametric ANOVA
procedure was used to evaluate intergroup differences (p≤0.05). The Dunn's multiple comparison test was applied if this ANOVA was significant,
again utilizing significance levels of p≤0.05, 0.01 and 0.001.
Survival Data: Kaplan–Meier estimates of group survival rates were calculated, by sex, and shown graphically. A log-rank dose response trend test
of survival rates was performed utilizing dose coefficients. In addition, a log-rank test for survival was used to make pairwise comparisons of each
treated group with the control group. Both the trend test and pairwise comparisons were conducted at the 0.05 significance level.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- 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):
- no effects observed
- 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:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- MORTALITY:
Group (Dose) Males (deaths/N, % mortality) Females(deaths/N, % mortality)
1 (0 mg/kg/day) 36/60 (60) 14/60 (23)
2 (10 mg/kg/day) 29/60 (48) 20/60 (33)
3 (30 mg/kg/day) 30/60 (50) 26/60 (43)
4 (50 mg/kg/day) 34/60 (57) 27/60 (45)
BODY WEIGHT AND WEIGHT GAIN:
Body weights decreased in a exposure-dependent manner, with significantly decreased body weights observed in the two highest exposure groups for males and females. Reductions in weight gain relative to controls at study week 103 reached the level of biological significance (i.e., >10% decrease) in the group 3 and 4 males and the group 4 females. This significant weight reduction indicates that the Maximum Tolerated Dose was reached in this study for both males and females.
HAEMATOLOGY:
A few statistically significant differences in the hematology data were observed in the nickel sulfate-treated males and females. However, none of these differences was suggestive of a hyperplastic (i.e., leukemia) response and none of these changes was considered toxicologically meaningful since they were small and did not follow a consistent exposure-related pattern.
GROSS PATHOLOGY/HISTOPATHOLOGY:
Gross necropsy and histopathology observations: Numerous gross necropsy findings were observed for animals in the control and nickel
sulfate-treated groups but the type and incidence of these findings observed for the treated animals were comparable to those observed in the
control group, and were consistent with findings commonly seen in aging rats in a longterm study. None of the neoplastic or non-neoplastic
microscopic findings was considered to be related to the experimental exposures. The non-neoplastic findings were either considered to
be secondary to toxicity or incidental background occurrences rather than a direct effect of nickel sulfate.
The pathology report, pathology peer-review and the pathology working group concurred that nickel sulfate hexahydrate did not
cause any carcinogenic effects in this study. Analysis of the tumor data revealed only one statistically significant (p<0.001) increase in tumors
corresponding to keratoacanthoma (tail) in the group 2 males. However, this finding is of questionable toxicologic significance since there was no
exposure–response relationship, the incidence rate in the group 2 males (15%) was only slightly higher than the upper end of Haseman's historical
control incidence for this tumor type (0–14%) and the incidence rate in the remaining control and treated groups (0–7%) was within the range of the
CRL-Ohio historical incidence (0–2%) and the Haseman historical incidence (0–14%). No other tumor finding in this study was statistically significant.
No notable differences were observed between controls and treated animals for the hematology, biochemistry and urinalysis parameters measured
during the toxicokinetic satellite study.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- 2.2 other: mg Ni/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: significant decrease in body weight
- Dose descriptor:
- LOAEL
- Effect level:
- 6.7 other: mg Ni/kg bw/day
- Sex:
- male/female
- Basis for effect level:
- other: significant decrease in body weight
Target system / organ toxicity
- Critical effects observed:
- not specified
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.
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