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EC number: 206-761-7 | CAS number: 373-02-4
- 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:
- two-generation reproductive toxicity
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 1985-1986
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Meets generally accepted scientific standards with acceptable restrictions Test animals experienced decreased water comsumption due to taste aversion; Animal room climate controls failed at one point during study
Cross-reference
- Reason / purpose for cross-reference:
- reference to same study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 988
- Report date:
- 1988
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- included F1b and F2b generations for ancillary assessments
- Principles of method if other than guideline:
- The study design exceeded the guideline through the inclusion of F1b and F2b generations for ancillary assessments. These assessments included a complete developmental toxicity assessment in the F2b generation.
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Nickel dichloride
- EC Number:
- 231-743-0
- EC Name:
- Nickel dichloride
- Cas Number:
- 7791-20-0
- Molecular formula:
- Cl2Ni
- IUPAC Name:
- Nickel (II) chloride hexahydrate
Constituent 1
- Specific details on test material used for the study:
- - Name of test material (as cited in study report): Nickel Chloride Hexahydrate (7791-20-0)
- Molecular formula (if other than submission substance): not different than submission substance
- Molecular weight (if other than submission substance): not different than submission substance
- Smiles notation (if other than submission substance): not different than submission substance
- InChl (if other than submission substance): not different than submission substance
- Structural formula attached as image file (if other than submission substance): not different than submission substance
- Substance type: pure product
- Physical state: green, deliquescent crystals or crystalline powder
- Solubility: water (20°C) 254 g/100 ml
- Other details on test material are included in the study report
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Animals and Husbandry
The experimental animals in the present study were viral antibody free (VAF/Plus) @ Crl:CD (SD)BR outbred albino rats supplied by Charles River Breeding Laboratories. Inc. (Kingston, NY). The Charles River CD rat was selected as the experimental animal assigned to this investigation. Males and females were 27-32 days old at the time of arrival at RTI.
During the quarantine period (10-14 days), animals were randomly assigned to cages. and individually coded tags were affixed to one ear of each rat. All animals were singly housed throughout the study in solid bottom polycarbonate or polypropylene cages (8" x 19" x 10 1/2") with stainless steel wire lids and molded filter tops. Ab-Sorb-Dri cage litter was used in all cages.
Purina Certified Rodent Chow (No. 5002, pelletized) was available ad libitum throughout the study. Rodent chow was stored at 55-60°F and the period of use did not exceed five months after receipt at RTI. Deionized/filtered water was available ad libitum during the quarantine period. During the exposure period animals were given ad libitum access to either control water (i.e., deioniied/filtered water with pH=4.0-6.0 adjusted with hydrochloric acid) or to an aqueous solution of nickel chloride. Clear plastic water bottles with stainless steel sipper tubes were used throughout this investigation. The animal holding room assigned for this study was equipped with individual temperature and humidity controls.
Administration / exposure
- Route of administration:
- oral: drinking water
- Vehicle:
- water
- Details on exposure:
- RTI (1988) administered nickel chloride hexahydrate to male and female CD rats (30/sex/dose) at (0, 7.3, 30.8 and 51.6 mg Ni/kg bw/day, estimated overall) in a 2-generation study. An additional dose level of 1000 ppm was eliminated after 2 weeks due to excessive toxicity. The parental animals were exposed beginning 11 weeks before cohabitation, and exposure continued for a total of 24 weeks (males) or 30 weeks (females). Groups of 10 rats/sex comprised a satellite subchronic non breeder study. The average nickel consumption reported by the authors varied by more than a factor of 2, with the highest consumption at the beginning of the premating exposure and during the latter part of the lactation period. As a conservative estimate, the average exposure during gestation, which was on the low end of overall exposure levels, was used as the dose level for each group. This choice also takes into account the possibility that gestational exposure alone could have accounted for observed the effects. Thus, the estimated doses were 0, 6.0, 25, and 42 mg Ni/kg bw/day.
- Details on mating procedure:
- 1 male and 1 female cohabited for up to 2-weeks; mating confirmed by positive spermatozoa on vaginal lavage
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- - Analytical purity: 99% as reported by vendor; >98% as reported by ICP analysis at RTI
- Stability: stability of aqueous solutions for 15 days under the anticipated conditions of use was verified by RTI for concentrations of 100 ppm Ni++ and greater
- Vehicle: Filtered/deionized water. Durham, NC city tap water was pre-filtered with 0.5 micron Nucleopore membrane filters to remove fine particulate matter. Organics were removed by charcoal adsorption. Then water was deionized by passage through two mixed-bed ion exchangers. The filtration and deionizing systems were purchased from and are routinely serviced by Hydro Ultrapure Water Systems, Inc., P. O. Box 2855, Durham, NC 27705 - Duration of treatment / exposure:
- Parental animals were exposed beginning 11 weeks before cohabitation and exposure continued for a total of 24 weeks (males) or 30 weeks (females).
- Frequency of treatment:
- Daily
- Details on study schedule:
- F1b males and females of the RTI (1988) study were randomly mated on postnatal day 70 and their offspring (F2a and F2b) were evaluated through postnatal day 21. This phase included teratological evaluations of F2b fetuses.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 50, 250, or 500 ppm nickel in drinking water (0, 7.3, 30.8 and 51.6 mg Ni/kg bw/day, estimated overall)
Basis:
nominal in water
- No. of animals per sex per dose:
- 30/sex/dose
- Control animals:
- yes, concurrent no treatment
- Details on study design:
- None
- Positive control:
- None
Examinations
- Parental animals: Observations and examinations:
- Daily cage-side Morbidty/Mortality and Clinical Signs of Toxicity
- Oestrous cyclicity (parental animals):
- Not evaluated
- Sperm parameters (parental animals):
- Not evaluated
- Postmortem examinations (parental animals):
- Gross examination of all organs at necropsy. Histopathology was performed for liver, kidney, lungs, heart, pituitary, adrenals and reproductive organs.
- Postmortem examinations (offspring):
- Gross examination of all organs at necropsy. Histopathology was performed for liver, kidney, lungs, heart, pituitary, adrenals and reproductive organs.
- Statistics:
- When the data were expected to violate the assumptions of the parametric tests, then similar nonparametric tests were used. When data were continuous or approximately continuous but not normally distributed, the KruskalWallis (Siegel, 1956), Mann-Whitney U (Siegel, 1956), and Jonckheere's (Jonckheere, 1954) tests were used to examine the experiMent-wise effect of dose, the pair-wise effect of dose, and the dose response trend, respectively. For nonparametric pair-wise cOMparisons of individual groups against the controls, the following tests were used: (I) for data with a significant Kruskal-Wallis Test (p<0.05) and evidence of a trend (p<0.10, Jonckheere's Test), Shirley's multiple comparison procedure (Shirley, 1977) was used to determine the smallest dose at which there was a statistically significant effect, or (2) for data with a significant Kruskal-Wallis Test (p<0.05) and no evidence of a trend (p>O.IO, Jonckheere's Test), Dunn's Test, a nonparametric analogue to Dunnett's Test was applied (Dunn, 1964). Index (categorical) data were analyzed using the Chi-Square Test for Independence (Snedecor and Cochran, 1967), Fisher's Exact Probability Test (Snedecor and Cochran, 1967), and the Test for Linear Trend on Proportions (Snedecor and Cochran, 1967) for the detection of the experiment-wise, pair-wise, and trend effects of dose, respectively.
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- An additional dose level of 1000 ppm was eliminated after 2 weeks due to excessive toxicity.
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- At the 500 ppm (~42 mg/kg) dose level there was a statistically significant decrease in parental body weight in males and females (95% and as low as 80% of controls, respectively)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- At the 500 ppm (~42 mg/kg) dose level there was a statistically significant decrease in parental body weight in males and females (95% and as low as 80% of controls, respectively)
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- Test substance intake: Average nickel consumption varied by more than 2-fold, with the highest consumption at the beginning of the premating exposure and during the latter part of lactation. As a conservative estimate, the average exposures doses were 0, 6.0, 25, & 42 mg Ni/kg.
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Details on results (P0)
The average nickel consumption reported by the authors varied by more than a factor of 2, with the highest consumption at the beginning of the premating exposure and during the latter part of the lactation period. As a conservative estimate, the average exposure during gestation, which was on the low end of overall exposure levels, was used as the dose level for each group. This choice also takes into account the possibility that gestational exposure alone could have accounted for the observed effects. Thus, the estimated doses were 0, 6.0, 25, and 42 mg Ni/kg bw/day.
At the 500 ppm dose level there were statistically significant decreases in both parental generation body weights in males and females (95% and as low as 80%, respectively), along with decreased absolute and relative liver weights in the females (90% and 80% of controls, respectively), but not in the males. Females also show the most pronounced effects on body weight during the premating exposure period and during lactation in both breeding generations.
Thus, 250 ppm (25 mg Ni/kg bw/day) was a NOAEL for breeders. Histopathology was performed for liver, kidney, lungs, heart, pituitary, adrenals and reproductive organs to make this assessment. There was no treatment-related effect on reproductive performance indices (mating success, rate of impregnation), reproductive organ weights or histopatholgy of reproductive organs. Therefore, the NOAEL for fertility in this study is 42 mg Ni/kg bw/day and a LOAEL was not identified. However, it should be noticed that effects on sperm quality and oestrus cyclicity were not investigated in this study.
Effect levels (P0)
- Dose descriptor:
- LOAEL
- Effect level:
- ca. 42 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: perinatal lethality/fertility
- Remarks on result:
- other: NOAEL 25 mg/kg bw/day (parental animals)
Target system / organ toxicity (P0)
- Critical effects observed:
- not specified
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- increased perinatal mortality in the high exposure group
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- decreased weight in the high exposure group
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Effect levels (F1)
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- 500 ppm
- Sex:
- not specified
- Basis for effect level:
- mortality
- Remarks on result:
- other: F1a generation
Results: F2 generation
Target system / organ toxicity (F2)
- Critical effects observed:
- not specified
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
RTI (1988) administered nickel chloride hexahydrate to male and female CD rats (30/sex/dose) at 0, 50, 250, or 500 ppm nickel in drinking water in a 2-generation study. An additional dose level of 1000 ppm was eliminated after 2 weeks due to excessive toxicity. The parental animals were exposed beginning 11 weeks before cohabitation, and exposure continued for a total of 24 weeks (males) or 30 weeks (females). Groups of 10 rats/sex comprised a satellite subchronic non breeder study. The average nickel consumption reported by the authors varied by more than a factor of 2, with the highest consumption at the beginning of the premating exposure and during the latter part of the lactation period. As a conservative estimate, the average exposure during gestation, which was on the low end of overall exposure levels, was used as the dose level for each group. This choice also takes into account the possibility that gestational exposure alone could have accounted for observed the effects. Thus, the estimated doses were 0, 6.0, 25, and 42 mg Ni/kg bw/day.
At the 500 ppm dose level there was a statistically significant decrease in the Po body weight in males and females (95% and 90% of controls, respectively), along with decreased absolute and relative liver weights in the females (90% and 89% of controls, respectively), but not in the males. Thus, 250 ppm (25 mg Ni/kg bw/day) was a NOAEL forbreeders. There was no treatment-related effect on reproductive performance indices (mating success, rate of impregnation), reproductive organ weights or histopatholgy of reproductive organs. Therefore, the NOAEL for fertility in this study is 42 mg Ni/kg bw/day and a LOAEL was not identified. However, it should be noticed that effects on sperm quality and oestrus cyclicity were not investigated in this study.
In the F1a generation at the 500 ppm dose level, the number of live pups/litter was significantly decreased, pup mortality was significantly increased, and average pup body weight was significantly decreased in comparison with controls. Although there was no statistically significant effect at 250 ppm, there was some indication of decreased number of live pups/litter. Similar effects were seen with FIb litters ofdams exposed to 500 ppm nickel. In the 50 and 250 ppm dose groups, increased pup mortality and decreased live litter size was observed in the F1b litters. However, these effects seen in the F1b litters are somewhat questionable because the room temperature was 3-5° C higher than normal at certain times (gestation-postnatal days) along with lower levels of humidity. Therefore, the above results seen at 50 and 250 ppm may not be adverse effects of nickel only.
F1b males and females were randomly mated (19-30/sex/group) on postnatal day 70 and their offspring (F2a and F2b) were evaluated through postnatal day 21 or on gestational day 21. This phase included teratological evaluations of F2b foetuses. The average gestational nickel consumption of F1b dams was 0, 6.2, 23, and 42 mg Ni/kg. Evaluation of the data indicated that the 500 ppm dose caused significant body weight depression of both mothers and pups and increased neonatal mortality during the postnatal development period. No effects on prenatal growth or viability were observed in F2b. The percent foetuses malformed per litter were significantly increased at 50 ppm, due primarily to a higher incidence of short rib in that group. In the absence of similar effects at higher doses, the increased incidence at 50 ppm is probably not due to exposure to nickel.
Overall, the study shows that exposure to nickel can cause increased neonatal mortality at 42 mg Ni/kg bw/day and possibly at lower doses of 6 and 25 mg Ni/kg bw/day, but a reliable developmental NOAEL cannot be identified in this study.
Table Litter size and pup mortality in RTI (1988) study
Dose (ppm Ni) |
Live pups per litter, |
Live pups per litter, |
% mortality per litter, |
F1a litters |
|||
0 |
13.3 (26) |
13.0 |
2.1% |
50 |
14.0 (25) |
13.8 |
1.2% |
250 |
11.5 (23) |
11.3 |
1.7% |
500 |
10.9* (27) |
8.8** |
18.4%** |
F1b litters |
|||
0 |
15.3 (15) |
15.1 |
0.9% |
50 |
11.8* (19) |
11.4* |
7.2% |
250 |
11.5* (19) |
11.3* |
8.6% |
500 |
9.5** (15) |
5.3** |
53.3%** |
F2a litters |
|||
0 |
13.6 (24) |
12.3 |
12.9% |
50 |
14.2 (28) |
13.5 |
4.4% |
250 |
12.4 (25) |
11.7 |
9.8% |
500 |
11.4* (15) |
8.3* |
28.6% |
* P < 0.05; ** P < 0.01
Applicant's summary and conclusion
- Executive summary:
RTI (1988) administered nickel chloride hexahydrate to male and female CD rats (30/sex/dose) at 0, 50, 250, or 500 ppm nickel in drinking water(0, 7.3, 30.8 and 51.6 mg Ni/kg bw/day, estimated overall)in a 2-generation study. An additional dose level of 1000 ppm was eliminated after 2 weeks due to excessive toxicity. The parental animals were exposed beginning 11 weeks before cohabitation, and exposure continued for a total of 24 weeks (males) or 30 weeks (females). Groups of 10 rats/sex comprised a satellite subchronic non-breeder study.
The average nickel consumption reported by the authors varied by more than a factor of 2, with the highest consumption at the beginning of the premating exposure and during the latter part of the lactation period. As a conservative estimate, the average exposure during gestation, which was on the low end of overall exposure levels, was used as the dose level for each group. This choice also takes into account the possibility that gestational exposure alone could have accounted for the observed effects. Thus, the estimated doses were 0, 6.0, 25, and 42 mg Ni/kg bw/day.
At the 500 ppm dose level there were statistically significant decreases in both parental generation body weights in males and females (95% and as low as 80%, respectively), along with decreased absolute and relative liver weights in the females (90% and 80% of controls, respectively), but not in the males. Females also show the most pronounced effects on body weight during the premating exposure period and during lactation in both breeding generations.
Thus, 250 ppm (25 mg Ni/kg bw/day) was a NOAEL for breeders.Histopathology was performed for liver, kidney, lungs, heart, pituitary, adrenals and reproductive organs to make this assessment.There was no treatment-related effect on reproductive performance indices (mating success, rate of impregnation), reproductive organ weights or histopatholgy of reproductive organs. Therefore, the NOAEL for fertility in this study is 42 mg Ni/kg bw/day and a LOAEL was not identified. However, it should be noticed that effects on sperm quality and oestrus cyclicity were not investigated in this study.
In the F1a generation at the 500 ppm dose level, the number of live pups/litter was significantly decreased, pup mortality was significantly increased, and average pup body weight was significantly decreased in comparison with controls. Although there was no statistically significant effect at 250 ppm, there was some indication of decreased number of live pups/litter. Similar effects were seen with F1b litters of dams exposed to 500 ppm nickel. In the 50 and 250 ppm dose groups, increased pup mortality and decreased live litter size was observed in the F1b litters. However, these effects seen in the F1b litters are somewhat questionable because the room temperature was 3-5° C higher than normal at certain times (gestation-postnatal days) along with lower levels of humidity. Therefore, the above results seen at 50 and 250 ppm may not be adverse effects of nickel only.
F1b males and females were randomly mated (19-30/sex/group) on postnatal day 70 and their offspring (F2a and F2b) were evaluated through postnatal day 21 or on gestational day 21. This phase included teratological evaluations of F2b foetuses. The average gestational nickel consumption of F1b dams was 0, 6.2, 23, and 42 mg Ni/kg. Evaluation of the data indicated that the 500 ppm dose caused significant body weight depression of both mothers and pups and increased neonatal mortality during the postnatal development period. No effects on prenatal growth or viability were observed in F2b. The percent foetuses malformed per litter were significantly increased at 50 ppm, due primarily to a higher incidence of short rib in that group. In the absence of similar effects at higher doses, the increased incidence at 50 ppm is probably not due to exposure to nickel.
Overall, the study shows that exposure to nickel can cause increased neonatal mortality at 42 mg Ni/kg bw/day and possibly at lower doses of 6 and 25 mg Ni/kg bw/day, but a reliable developmental NOAEL cannot be identified in this study.
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