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Acute Toxicity: other routes

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Administrative data

Endpoint:
acute toxicity: other routes
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for publication.
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Physicochemical characteristics and biological effects of nickel oxides
Author:
Sunderman FW, Hopfer SM, Knight JA, McCully KS, Cecutti AG, Thornhil PG, Conway K, Miller C, Patierno SR, Costa M
Year:
1987
Bibliographic source:
Carcinogenesis. 8: 305-313

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
F344 rats were administered 14 mg Ni/rat via intrarenal injection. Histopathology was assessed at 12 weeks post-injection.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): NiO
- Substance type: black NiO calcined at < 650 °C; ) grey-black NiO calcined at 735 C; two grey NiO calcined at 800 and 850 C; dark green calcined at 918 C; green NiO calcined at 1045 C


Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: (Harland-Sprague Farms, Madison, WI
- Weight at study initiation: 135-184 g
- Housing: housed in stainless-steel mesh cages
- Diet (e.g. ad libitum): Ralston Purina rat chow ad libitum
- Water (e.g. ad libitum): tap water ad libitum.

Administration / exposure

Route of administration:
other: intrarenal
Vehicle:
physiological saline
Details on exposure:
The rats were anesthetized with ether and the test compounds were administered by i.r. injection into both poles of the right kidney (14 mg Ni/rat), as previously described
Doses:
14 mg Ni/rat
No. of animals per sex per dose:
10 males
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 13 weeks
- Frequency of observations and weighing: biweekly
- Necropsy of survivors performed: yes
- Other examinations performed: renal pathology, hematocrit
Statistics:
Statistical computations means, standard deviations, Student's t test, Fisher's
exact test, Mann- Whitney test, Spearman's rank correlation test and Kendall's
coefficient of concordance.

Results and discussion

Effect levels
Sex:
male
Dose descriptor:
other: dose
Effect level:
14 other: mg/rat
Remarks on result:
other: 12 weeks post injection, a slight but statistically significant reduction in bodyweight and peak hematocrit levels were significantly elevated.
Mortality:
Not applicable.
Clinical signs:
Not reported.
Body weight:
At 13 weeks post injection, there was a slight but statistically significant reduction in bodyweight in rats exposed to the two lowest calcined NiO compounds, as well as the NiO calcined at 850°C.
Gross pathology:
Not applicable.
Other findings:
- Histopathology:
Renal pathological responses were most evident in the rats exposed to black NiO.

Any other information on results incl. tables

   Means (SD) Bodyweight (g)  Mean (SD) Peak Hematocrit (%)  Range
 A  279 (30)*  73 (7)**  57 -80
 B  279 (24)*  55 (2)  52 -58
 295 (21)  53 (1)  51 -55
 D  278 (16)**  54 (2)  51 -56
 E  297 (27)  53 (1)  51 -55
 F  289 (27)  55 (2)  51 -57
 vehicle  308 (23)  54 (4)  51 -56
 alphaNi3S2  290 (23)  78 (2)  76 -81
 NiO  284 (10)  75 (2)  72 -78

*, P < 0.05

**, P < 0.01

Applicant's summary and conclusion

Conclusions:
The presence of high surface area and demonstrable Ni(lll) were two physicochemical characteristics that were associated with the greatest biological effects of nickel oxides.The authors reported a strong paired ranking correlation between erythrocytosis and in vitro cell transformation. These study results were used to design further studies on the carcinogenesis of Ni compounds in animal bioassays (see Sunderman et al. 1990).
Executive summary:

Sunderman et al. (1987) examined the physicochemical properties of various nickel compounds with both in vitro and in vivo measures of biological responses in order to examine whether there are any relationships between these properties and responses to the carcinogenic potential of these nickel compounds. Because carcinogenic forms of nickel had previously been reported to, among other things, induce erythrocytosis following intrarenal administration, Sunderman et al. (1987) examined the correlation of physicochemical properties of NiO compounds with erythropoietic responses. Thus, F344 rats were administered 14 mg Ni/rat via a single intrarenal injection of black NiO (INCO black NiO calcined at < 650 °C), as well as a number of other NiO compounds described as grey-black, grey, grey, dark green, and green which were calcined at 735, 800, 850, 918, and 1045 °C, respectively (note: other nickel compounds were also evaluated). Blood samples were then drawn 2, 4, 6, 8, 10, and 12 weeks thereafter. Data provided in tabular form at 12 weeks post injection indicated a slight but statistically significant reduction in bodyweight in rats exposed to NiO calcined at <650, 735 and 850 °C. Similarly, peak hematocrit levels were only significantly elevated in animals exposed to black NiO (calcined at < 650 °C). The authors reported a strong paired ranking correlation between erythrocytosis and in vitro cell transformation. Pathological responses in the rat kidney were also scored and were generally more pronounced in rats receiving black NiO relative to the other NiO compounds evaluated. Given the route of exposure, the significance of these findings are unclear. Given the effects on erythropoiesis, the authors predicted that the carcinogenicity of black NiO would be greater than NiO compounds calcined at higher temperatures. These study results were used to design further studies on the carcinogenesis of nickel compounds in animal bioassays (see Sunderman et al. 1990 in the Carcinogenicity section). STUDY RATED BY AN INDEPENDENT REVIEWER