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Basic toxicokinetics

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basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment.
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
Embryotoxicity and fetal toxicity of nickel in rats.
Sunderman, F.W. et al.
Bibliographic source:
Toxicol Appl Pharmacol 43: 381-390
Reference Type:
secondary source
Nickel Chloride, CAS-No.: 7718-54-9, EINECS-No.: 231-743-0, RISK ASSESSMENT, Final version March 2008, Chapters 0, 1, 2, 4, 5, 6 & 7 –human health only
Danish Environmental Protection Agency
Bibliographic source:
European Union Risk Assessment Report

Materials and methods

Objective of study:
Principles of method if other than guideline:
Non-pregnant and pregnant rats were injected with radiolabelled NiCl2 (pregnant rats on GD8 or 18), after 24 hours the concentration of radiolabelled Ni in various tissues was measured. Additionally, three pregnant rats were injected with radiolabelled NiCl2 on GD18, and after sacrifice 24 hours later the distribution of radiolabelled Ni in the fetuses was determined by autoradiography.
GLP compliance:
not specified

Test material

Constituent 1
Reference substance name:
Nickel dichloride
EC Number:
EC Name:
Nickel dichloride
Cas Number:
nickel(2+) dichloride
Constituent 2
Reference substance name:
Nickel chloride
EC Number:
EC Name:
Nickel chloride
Cas Number:
nickel(2+) dichloride
Details on test material:
- Name of test material (as cited in study report): nickel chloride
- Molecular formula (if other than submission substance): [63Ni]Cl2
- Molecular weight (if other than submission substance): 129.60
- Analytical purity: no data
- Radiochemical purity (if radiolabelling): no data
- Specific activity (if radiolabelling): 5.8 mCi/mg of Ni
- Locations of the label (if radiolabelling): Ni
- Other: Source: New England Nuclear, Boston, Massachusetts

Test animals

Fischer 344
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratories, Inc., Wilmington, Massachusetts
- Age at study initiation: 120 - 150 days
- Housing: singly in polypropylene cages
- Diet (e.g. ad libitum): rat chow ad libitum
- Water (e.g. ad libitum): tap water ad libitum

Administration / exposure

Route of administration:
physiological saline
Details on exposure:
Injection solutions of [63Ni]Cl2 were prepared by diluting a sterile solution of [63Ni]Cl2 (specific activity, 5.8 mCi/mg of Ni) to the desired concentration by addition of sterile NaCl solution. The injection solutions were adjusted to pH 7 by addition of NaOH solution (50 mmol/liter). The nickel compound was administered by deep injection into the thigh muscles of non-pregnant rats or of pregnant rats on day 8 or 18 of gestation. The im injections were always performed at 9:00 AM.
Duration and frequency of treatment / exposure:
Single injection on GD8 or GD18
Doses / concentrations
Doses / Concentrations:
50.87 mg/kg bw (recalculated value, equivalent to 12 mg Ni/kg bw)
No. of animals per sex per dose / concentration:
4 females (3 for autoradiography of fetuses)
Control animals:
other: not necessary
Details on study design:
- Dose selection rationale: acute toxicity of NiCl2 was tested in a preliminary study by injecting five groups of 8 pregnant rats on GD8 and five groups of 8 pregnant rats on GD18 with dosages ranging from 10 to 30 mg Ni/kg bw.
Details on dosing and sampling:
PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: Liquid Scintillation Spectroscopy of blood, lung, liver, kidney, spleen, heart, skeletal muscle, ovary, uterus, adrenal, pituitary; in pregnant rats sacrificed on GD9 embryos and membranes were removed and pooled for [63Ni]-analysis; in pregnant rats sacrificed on GD19 amniotic fluid from the amniotic sacs, placentas and fetuses (serum and tissues) were analyzed separately for [63Ni]-content.
- Time and frequency of sampling: GD9 and GD19, respectively (24 h after injection)
- Other: Placentas, maternal kidneys and at least five fetuses (sagittal sections of whole fetuses) from each rat sacrificed additionally on GD19 were examined by autoradiography.
The experimental data were subjected to statistical analyses by use of the chi² test or t test (Zar, 1974). Computations of LD5, LD50, and LD95 values were performed by the graphic probit method of Miller and Tainter (1944). Slope-functions of the probit mortality curves were computed by the following formula: slope-function = [(LD84/LD50) + (LD50/LD16)]/2 (Litchfield and WiIcoxon, 1949).

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
In order of decreasing concentrations of 63Ni, the relative localization of 63Ni in organs and tissues of non-pregnant and pregnant rats was: kidneys > serum > adrenal ≈ lungs ≈ ovary > spleen ≈ heart ≈ liver > skeletal muscle. Remarkably, the mean concentrations of 63Ni in pituitaries of pregnant rats on GD9 and 19 were seven to eight times greater than those in pituitaries of non-pregnant rats. The mean concentrations of 63Ni in serum, adrenals and ovaries of pregnant rats on GD19 were significantly lower than the corresponding values in non-pregnant females.

The concentrations of 63Ni in the products of conception (embryos and membranes) on GD9 were approximately the same as those in the adrenals, lungs and ovaries from these rats and were higher than in spleen, heart, liver or skeletal muscle.

The mean concentration of 63Ni in placentas from rats on GD19 was higher than the mean concentration in all other maternal organs and tissues studied, except the maternal kidneys. Appreciable concentrations of 63Ni were also found in the fetuses and amniotic fluid from rats on GD19. Autoradiographs of sagittal sections of fetuses from rats injected 24 hours prior to sacrifice on GD19 demonstrated that 63Ni was located primarily in the urinary bladder, although faint, diffuse radioactivity was present throughout the body tissues. In the placenta, 63Ni was concentrated in yolk sac and basal lamina. Radioactivity in the maternal kidney was more intense than in the placenta and much more intense than in the fetal tissues.

These results demonstrate that nickel is able to pass the blood-placenta barrier and to accumulate in the fetus.

Metabolite characterisation studies

Metabolites identified:

Any other information on results incl. tables

Concentrations of [63]Ni in tissues of rats (µg/g wet wt; means ± SD):






16.35 ± 3.13

12.22 ± 2.65

9.64 ± 1.71**


3.67 ± 0.48

3.17 ± 0.61

1.79 ± 0.10***


2.92 ± 0.47

1.89 ± 0.39

1.49 ± 0.27***


2.32 ± 0.70

1.95 ± 0.30

2.04 ± 0.27


2.24 ± 1.07

1.97 ± 0.59

0.91 ± 0.25*


2.07 ± 0.26




0.78 ± 0.20

0.62 ± 0.26

0.70 ± 0.19


0.71 ± 0.12

0.46 ± 0.10

0.61 ± 0.19


0.57 ± 0.30

0.62 ± 0.19

0.44 ± 0.06

Skeletal muscle

0.19 ± 0.03

0.16 ± 0.03

0.13 ± 0.02


0.13 ± 0.05

1.09 ± 0.25***

0.91 ± 0.24***

Fetuses and membranes


2.00 ± 0.38





2.61 ± 0.65




1.18 ± 0.43

Amniotic fluid



0.62 ± 0.21

*p < 0.05 vs values in non-pregnant rats

**p < 0.01 vs values in non-pregnant rats

***p < 0.001 vs values in non-pregnant rats

Applicant's summary and conclusion