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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
Toxicity to reproduction
Administrative data
- Endpoint:
- three-generation reproductive toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- key study
- Study period:
- 1960-1962 (in-life phase)
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Study in accordance with generally accepted methods, but limited level of parameters examined and data reported
Data source
Reference
- Reference Type:
- publication
- Title:
- Unnamed
- Year:
- 1 976
Materials and methods
Test guideline
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
- Deviations:
- yes
- Remarks:
- lower number of animals used and parameters examined
- GLP compliance:
- no
- Limit test:
- no
Test material
- Reference substance name:
- Nickel sulfate hexahydrate (NiS04.6H20)
- IUPAC Name:
- Nickel sulfate hexahydrate (NiS04.6H20)
- Details on test material:
- Nickel sulfate hexahydrate fines containing 22.3% nickel by analysis (theoretically 22.32%) served as the test material in this study.
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Wistar derived
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Albino Farms, Red Bank, New Jersey, USA
- Age at study initiation: (P) 4 wks
- Weight at study initiation: (P) 56-65 g
- Fasting period before study: No data
- Housing: individually caged
- Use of restrainers for preventing ingestion (if dermal): yes/no
- Diet: ad libitum, Radlston Purina, St. Louis, Missouri, USA
- Water: ad libitum
- Acclimation period: No data
ENVIRONMENTAL CONDITIONS
No details provided
IN-LIFE DATES: From: 1960 To: 1962
Administration / exposure
- Route of administration:
- oral: feed
- Vehicle:
- other: Radlston Purina feed
- Details on exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): Finely ground laboratory chow served as the basic diet. Stock aqueous solutions of nickel sulfate hexahydrate were prepared in appropriate concentrations so that the addition of 100 mL for each 6 kg of diet resulted in the desired nickel content, respectively. Additions of nickel solutions were thoroughly blended into the diet by mixing in a rotary-type blender.
- Storage temperature of food: No data - Details on mating procedure:
- - M/F ratio per cage: 1/1
- Length of cohabitation: 7 days
- Proof of pregnancy: No data
- Further matings after two unsuccessful attempts: No
- After successful mating each pregnant female was caged: individually
- Any other deviations from standard protocol: On the 20th mating day all males were removed. - Analytical verification of doses or concentrations:
- no
- Duration of treatment / exposure:
- 11 weeks prior to mating, during mating, gestation, and lactation
- Frequency of treatment:
- Daily
- Details on study schedule:
- Litters containing more than 10 offsprings were randomly reduced to 10 on day 5. All surviving F/1a siblings were sacrificed and autopsied at weaning. Approximately 10 days after weaning of F/1a litters, F/0 parent generation rats were remated for F/1b litters. Procedure and observations recorded were the same as those described for F/1a litters.
For the F/2 generation 30 male and 30 female F/1b offsprings from each diet level were continued on their respective parents' diet for 11 weeks at which time 20 of each sex within each group were mated and the same procedure followed as with the F/0 generation through production and weaning of F/2a and F/2b litters.
For the F/3 generation, the same procedure as with the previous generations was followed through the production of F/3a and F/3b litters. All matings in each generation were made with rats from different litters.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 250, 500 and 1000 ppm
Basis:
nominal in diet
equivalent to 0, 22.5, 45 and 90 mg/kg bw nickel, respectively
- No. of animals per sex per dose:
- 30
- Control animals:
- yes, plain diet
- Details on study design:
- No further details provided
- Positive control:
- Not included
Examinations
- Parental animals: Observations and examinations:
- Weekly body weight records were obtained, except during mating through weaning of litters.
Records were maintained of mating and number of pregnancies. - Oestrous cyclicity (parental animals):
- Not included
- Sperm parameters (parental animals):
- Not included
- Litter observations:
- Records were maintained of litters cast (alive and dead), pups in litter at 1, 5, and 21 days (weaning), and total weight of the litter at weaning.
- Postmortem examinations (parental animals):
- Following weaning of F/1b litters, surviving F/0 rats were sacrificed and autopsied.
- Postmortem examinations (offspring):
- At weaning of F/2b rats, F/1b parents were sacrificed and autopsied.
Histopathologic examinations were performed on 10 male and 10 female F/3b weanlings from each diet level. Absolute and relative organ-to-body weight ratios for heart, spleen, kidneys, liver, and testes were analysed statistically. Tissues preserved in formalin for histopathologic study were in addition to the above: lung, urinary bladder, stomach, small and large intestine, skeletal muscle, brain, skin, bone marrow, pituitary, thyroid, adrenal, pancreas, and gonad. - Statistics:
- No data
- Reproductive indices:
- Fertility (F.l.) = (pregnancies/matings) x 100
Gestation (G. I.) = (litters cast/pregnancies) x 100 - Offspring viability indices:
- Viability (V.I.) = (live pups at day 5/live pups born) x 100
Lactation (L.I.) = (weaned/live pups-discards on day 5) x 100
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- decreased bodyweight at 1000 ppm (90 mg/kg)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- decreased bodyweight at 1000 ppm (90 mg/kg)
- Organ weight findings including organ / body weight ratios:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- not examined
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)
Body weights for parent generation rats on 250 and 500 ppm diets (22.5 and 45 mg/kg nickel, resp.), before mating and at weaning of respective litters, were not adversely affected, but rats on 1000 ppm (90 mg/kg nickel) exhibited slightly lower body weights. The average decrease in body weight did not exceed 8% for females and 13% for males.
OTHER FINDINGS (PARENTAL ANIMALS)
On fertility and gestation indices, no adverse effects were noted at any of the dietary levels of nickel.
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Remarks:
- reproductive toxicity
- Effect level:
- 1 000 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- not specified
- Mortality / viability:
- mortality observed, treatment-related
- Description (incidence and severity):
- higher incidence of stillborn in the first generation
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- decreased at 1000 ppm (90 mg/kg nickel)
- Sexual maturation:
- no effects observed
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- no effects observed
- Histopathological findings:
- no effects observed
Details on results (F1)
Data on the number of pups born dead showed higher incidence of stillborn in the first generation at all levels of nickel, not observed to any extent in subsequent generations. The number of siblings (alive and dead) cast per litter averaged 10.3, 10.6, 9.8, and 9.0 for 0, 250, 500, and 1000 ppm (0, 22.5, 45, and 90 mg/kg nickel, resp.) diets, respectively. The number of siblings weaned per litter were progressively fewer with increasing dietary level of nickel, averaging 8.1, 7.2, 6.8, and 6.4 for 0, 250, 500, and 1000 ppm (0, 22.5, 45, and 90 mg/kg nickel, resp.) diets, respectively.
BODY WEIGHT (OFFSPRING)
On average weaning body weight, a clear-cut adverse effect is only apparent in weanlings of females on 1000 ppm (90 mg/kg nickel) diet, averaging 73% of control. However, offsprings maintained on 1000 ppm (90 mg/kg nickel) diet from weaning to mating of succeeding generations recovered considerably from this deficit, averaging 92% of controls.
OTHER FINDINGS (OFFSPRING)
On viability and lactation indices, no adverse effects were noted at any of the dietary levels of nickel.
Effect levels (F1)
- Dose descriptor:
- LOAEL
- Generation:
- F1
- Effect level:
- 250 ppm (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: Higher incidence of stillborn
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
Summary table of reproduction data for rats fed with nickel sulfate hexahydrate through 3 generations:
Generation |
Dose (ppm) |
Number of rats |
Total number of pups |
Weanlings mean body weight (g) |
Indices (%)* |
||||||||||
Mated ** |
Pregnant *** |
Whelped§ |
Born alive |
Born dead |
Alive on day 5§§ |
Discarded§§§ |
Weaned |
F.I. |
G.I. |
V.I. |
L.I. |
||||
F0 => |
F1a |
0 |
20(1) |
15(1) |
14 |
113 |
5 |
113(10) |
2 |
89 |
37.5 |
79 |
93 |
100 |
87 |
250 |
20(1) |
11 |
11(1) |
72 |
17 |
69 |
5 |
60 |
40.1 |
58 |
100 |
96 |
94 |
||
500 |
19 |
14 |
14(1) |
96 |
13 |
95 |
5 |
72 |
34.4 |
74 |
100 |
99 |
80 |
||
1000 |
20 |
12 |
12(1) |
93 |
16 |
91 |
5 |
83 |
27.8 |
60 |
100 |
98 |
97 |
||
F1b |
0 |
17 |
14 |
14 |
143 |
3 |
139 |
0(8) |
137 |
33.8 |
82 |
100 |
97 |
99 |
|
250 |
19 |
16 |
16 |
164 |
6 |
150 |
0(12) |
134 |
31.6 |
84 |
100 |
91 |
89 |
||
500 |
19 |
14 |
14(3) |
109 |
27 |
106 |
0(9) |
98 |
28.1 |
74 |
100 |
97 |
93 |
||
1000 |
20(1) |
15 |
15 |
93 |
31 |
77 |
0(3) |
67 |
25.1 |
79 |
100 |
83 |
87 |
||
F1b => |
F2a |
0 |
20 |
15 |
15 |
142 |
0 |
138 |
13 |
115 |
35.9 |
75 |
100 |
97 |
92 |
250 |
20 |
18 |
18(1) |
188 |
2 |
181 |
30 |
119 |
31.1 |
90 |
100 |
96 |
79 |
||
500 |
20 |
17 |
17 |
171 |
0 |
141 |
10 |
129 |
34.6 |
85 |
100 |
82 |
98 |
||
1000 |
20 |
16(2) |
14 |
127 |
6 |
120 |
8 |
96 |
25.9 |
80 |
88 |
94 |
86 |
||
F2b |
0 |
20 |
14 |
14(1) |
149 |
1 |
146 |
30 |
116 |
37.9 |
70 |
100 |
98 |
100 |
|
250 |
20 |
17 |
17(1) |
181 |
16 |
177 |
39 |
130 |
35.7 |
85 |
100 |
98 |
94 |
||
500 |
20 |
16(1) |
15 |
166 |
0 |
160 |
22 |
131 |
36.9 |
80 |
94 |
96 |
95 |
||
1000 |
18 |
11 |
11(1) |
109 |
3 |
103 |
10 |
90 |
26.9 |
61 |
100 |
94 |
97 |
||
F2b => |
F3a |
0 |
20 |
18(1) |
17 |
180 |
5 |
175 |
20 |
125 |
36.7 |
90 |
94 |
97 |
81 |
250 |
20 |
19 |
19 |
207 |
4 |
201 |
21 |
121 |
34.5 |
95 |
100 |
97 |
67 |
||
500 |
20 |
19(1) |
18(1) |
184 |
5 |
172 |
20 |
102 |
35.6 |
95 |
95 |
93 |
67 |
||
1000 |
20 |
20(1) |
19 |
168 |
7 |
162(10) |
6 |
107 |
280. |
100 |
95 |
96 |
73 |
||
F3b |
0 |
18 |
18 |
18 |
216 |
0 |
206 |
38 |
158 |
41.9 |
100 |
100 |
95 |
94 |
|
250 |
20 |
18 |
18 |
204 |
2 |
198 |
32 |
161 |
41.4 |
90 |
100 |
97 |
97 |
||
500 |
18 |
16 |
16(1) |
142 |
6 |
138 |
22 |
102 |
41.2 |
89 |
100 |
97 |
88 |
||
1000 |
17 |
17 |
17 |
139 |
7 |
138 |
13 |
114 |
29.7 |
100 |
100 |
99 |
91 |
* Indices: F.I., G.I., V.I., and L.I. refer to Fertility, Gestation, Viability, and Lactation Index, respectively.
** Numbers within parentheses refers to non-pregnant dams found dead during mating period, not included in calculation of F.I.
*** Within parentheses, dams found dead and autopsied to confirm pregnancies.
§ Numbers within parentheses refers to litters born dead
§§ Numbers within parentheses refers to number of siblings sacrificed after day 5 and before weaning due to death of dam, not used in calculation of L.I.
§§§ To reduce litter size to 10 on day 5; and within parentheses are totals in excess of 10/litter not discarded as planned, due to oversight, and carried to weaning.
Applicant's summary and conclusion
- Conclusions:
- Based on the only occurrence of slightly decreased body weight at 1000 ppm (90 mg/kg nickel) in the parental generation, the NOAEL for parental reproductive toxicity can be set at 90 mg nickel/kg/day.
Based on increased lethality in F1 pups, the low dose of 250 ppm (22.5 mg/kg nickel) can be considered as a LOAEL. - Executive summary:
In a 3-generation study, Wistar-derived rats were fed with 0, 250, 500, or 1000 ppm of nickel sulfate hexahydrate (equivalent to 0, 22.5, 45, or 90 mg/kg of nickel, respectively).
In the parental generation, body weights for rats on 250 and 500 ppm diets (22.5 and 45 mg/kg nickel, resp.), before mating and at weaning of respective litters, were not adversely affected, but rats on 1000 ppm (90 mg/kg nickel) exhibited slightly lower body weights. The average decrease in body weight did not exceed 8% for females and 13% for males. On fertility and gestation indices, no adverse effects were noted at any of the dietary levels of nickel.
A higher incidence of stillborn was observed only in the first generation at all dietary levels of nickel and decreased body weights of weanings on 1000 ppm diet in all generations. On viability and lactation indices, no adverse effects were noted at any of the dietary levels of nickel.
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