Registration Dossier

Administrative data

Endpoint:
dermal absorption
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Meets generally accepted scientific standards, well documented and acceptable for assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
In vitro permeation of nickel salts through human stratum corneum.
Author:
Tanojo, H., Hostynek, J.J., Mountford, H.S. and Maibach, H.I.
Year:
2001
Bibliographic source:
Acta Derm Venereol. Suppl 212:19-23.

Materials and methods

Principles of method if other than guideline:
Measures of the permeation of these salts through the stratum corneum (SC). No standard guideline followed. Test methods are described in the following sections.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Nickel sulphate hexahydrate
- 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 solution
- Physical state: liquid
- Composition of test material, percentage of components: 1% w/v nickel
- Other details on test material not reported or not applicable
Radiolabelling:
no

Test animals

Species:
other: human stratum corneum
Strain:
other: not applicable
Details on test animals and environmental conditions:
not applicable

Administration / exposure

Type of coverage:
other: not applicable
Vehicle:
other: not applicable
Duration of exposure:
not applicable
Doses:
not applicable
No. of animals per group:
not applicable
Control animals:
no
Remarks:
not applicable
Details on study design:
Heat-separated human stratum corneum sheets from cadavers were placed in a continuous flow-through diffusion cell system
maintained at 37 deg. C. Aqueous donor solutions of nickel salts (nitrate, sulfate, and chloride) were prepared containing 1% w/v Ni
(10 mg/ml Ni2+). HPLC-grade water was used as the receptor fluid, which was pumped at a rate of 4-5 ml/hr through the receptor side of the
diffusion cells. The receptor water was collected every 4 hours up to 96 hours. Donor solutions were collected from each diffusion cell. The
stratum corneum sheets were boiled in 10 ml of a 30% hydrogen peroxide solution for 4 hours and cooled. Analyses were conducted by ICP-MS.
The percentage of Ni compound recovered from the applied dose was determined.
The 96-h in vitro permeation profile of each nickel salt was plotted against time using Microcal Origin,
and the permeability constant of each salt was calculated from the permeation rate during steady state.
Data were analyzed using the paired Student t-test on Microcal Origin

Details on in vitro test system (if applicable):
not applicable

Results and discussion

Absorption in different matrices:
The permeation of various nickel salts across human skin was relatively minute. One percent or less of the nickel salts penetrated the stratum corneum at 96 hours, and less than 1% of the salts was retained. Retention in the stratum corneum was highest for the nitrate (0.95%) and lowest for the acetate (0.10%). Percent retentions in the stratum corneum of the chloride and sulfate salts were 0.18 and 0.56%,respectively. 
 
The highest rate of permeation for all salts tested occurred within the first 24 hours. The chloride and acetate salts reached peak penetration  
within 4 hours. Nickel nitrate peaked at ca. 8 hours, while nickel sulfate peaked after 12 hours post-application. Steady state was  
obtained after 24 hours for all the nickel salts tested. 
 
The permeability constants (standard deviation) of nickel salts across human stratum corneum in vitro were reported as: 

nickel sulfate: 8.5 (5.5) cm/h x 10e-7 
nickel chloride: 6.8 (1.2) cm/h x 10e-7 
nickel nitrate: 5.2 (1.6) cm/h x 10e-7 
nickel acetate: 5.2 (1.1) cm/h x 10e-7 
Total recovery:
not applicable
Conversion factor human vs. animal skin:
not applicable

Any other information on results incl. tables

The permeation of various nickel salts across human skin was relatively  minute. One percent or less of the nickel salts penetrated the stratum corneum at 96 hours, and less than 1% of the salts was retained. Retention in the stratum corneum was highest for the nitrate (0.95%) and lowest for the acetate (0.10%). Percent retentions in the stratum corneum of the chloride and sulfate salts were 0.18 and 0.56%,respectively.

 

The highest rate of permeation for all salts tested occurred within the first 24 hours. The chloride and acetate salts reached peak penetration

within 4 hours. Nickel nitrate peaked at ca. 8 hours, while nickel sulfate peaked after 12 hours post-application. Steady state was obtained after 24 hours for all the nickel salts tested. The permeability constants (standard deviation) of nickel salts across human stratum corneum in vitro were reported as:

nickel sulfate: 8.5 (5.5) cm/h x 10e-7

nickel chloride: 6.8 (1.2) cm/h x 10e-7

nickel nitrate: 5.2 (1.6) cm/h x 10e-7

nickel acetate: 5.2 (1.1) cm/h x 10e-7 

Applicant's summary and conclusion

Executive summary:

ROBUST SUMMARY DEVELOPED BY AN INDEPENDENT REVIEWER.

 

Human skin was obtained from cadavers and the stratum corneum was prepared using a modification of the method of Tanojo et al (1997).

Heat-separated human stratum corneum sheets were placed in a continuous flow-through diffusion cell system maintained at 37 deg. C. Aqueous donor solutions of nickel salts (nitrate, sulfate, and chloride) were prepared containing 1% w/v Ni (10 mg/ml Ni2+). HPLC-grade water was used as the receptor fluid, which was pumped at a rate of 4-5 ml/hr through the receptor side of the diffusion cells. The receptor water was collected every 4 hours up to 96 hours.

Donor solutions were collected from each diffusion cell. The stratum corneum sheets were boiled in 10 ml of a 30% hydrogen peroxide solution for 4 hours and cooled. Analyses were conducted by ICP-MS. The percentage of Ni compound recovered from the applied dose was determined. The 96-h in vitro permeation profile of each nickel salt was plotted against time using Microcal Origin, and the permeability constant of each salt was calculated from the permeation rate during steady state. Data were analyzed using the paired Student t-test on Microcal Origin. 

 

The permeation of various nickel salts across human skin was relatively minute. One percent or less of the nickel salts penetrated the stratum corneum at 96 hours, and less than 1% of the salts was retained. Retention in the stratum corneum was highest for the nitrate (0.95%) and lowest for the acetate (0.10%). Percent retentions in the stratum corneum of the chloride and sulfate salts were 0.18 and 0.56%,respectively. 

 

The highest rate of permeation for all salts tested occurred within the first 24 hours. The chloride and acetate salts reached peak penetration  

within 4 hours. Nickel nitrate peaked at ca. 8 hours, while nickel sulfate peaked after 12 hours post-application. Steady state was  

obtained after 24 hours for all the nickel salts tested. 

 

The permeability constants (standard deviation) of nickel salts across human stratum corneum in vitro were reported as: 

nickel sulfate: 8.5 (5.5) cm/h x 10e-7 

nickel chloride: 6.8 (1.2) cm/h x 10e-7 

nickel nitrate: 5.2 (1.6) cm/h x 10e-7 

nickel acetate: 5.2 (1.1) cm/h x 10e-7 

STUDY RATED BY AN INDEPENDENT REVIEWER.