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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1995
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: No guideline available for this type of special investigation using salts consisting of physiologically essential ions.

Data source

Reference
Reference Type:
publication
Title:
Penetration of selected Dead Sea Minerals through a healthy Rabbit Skin, from a sustained-release transparent Varnish, as a Prospective Treatment for Psoriasis
Author:
Shani, J. et al
Year:
1995
Bibliographic source:
Journal of the European Academy of Dermatology and Venereology 4, 267-272

Materials and methods

Test guideline
Qualifier:
no guideline available
Deviations:
not applicable
Remarks:
no guideline available for this type of special investigation
Principles of method if other than guideline:
Study was performed according to good experimental practice.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Magnesium dibromide and potassium bromide
IUPAC Name:
Magnesium dibromide and potassium bromide
Details on test material:
- Name of test material (as cited in study report): Magnesium dibromide and potassium bromide
- Purity test date: > 99%
- No further details given on test material within the publication.
Sodium bromide is an inorganic salt that dissociates to its composite ions in aqueous solutions at environmental pH and temperature. Comparison of the available data on the various bromide salts have shown that the bromide ion is the relevant ion for determination of the toxicological profile with simple cations such as potassium, sodium or ammonium, that are ubiquitous in nature, having little or no influence on the bromide ion properties. It is therefore justified to read-across data from other inorganic bromide salts to sodium bromide.
Radiolabelling:
no

Test animals

Species:
rabbit
Strain:
other: Local strain
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Not indicated
- Age at study initiation: Not indicated
- Weight at study initiation: 2.8 ± 0.2 kg

Administration / exposure

Type of coverage:
not specified
Vehicle:
other: ethyl-cellulose varnish
Duration of exposure:
Two to six applications per week for up to three weeks.
Doses:
- Dose volume: 1 mL (corresponding to 50 mg absolute)
No. of animals per group:
12/group
Control animals:
yes
Remarks:
Distilled water
Details on study design:
APPLICATION OF DOSE:

VEHICLE
- Amount(s) applied (volume or weight with unit):1 mL (corresponding to 50 mg absolute)
- Concentration (if solution): 5% (w/v) in an ethyl-cellulose varnish as the vehicle

TEST SITE
- Preparation of test site: Two days before application of test substance, an area of 5 x 4 cm of the upper back of each rabbit was shaved with an electric shaver.
- Area of exposure: 5 x 4 cm

SAMPLE COLLECTION
- Collection of blood: Blood samples were taken every morning during the three week investigation period. On the days of treatment (2 or 6 times per week), samples were taken prior to application of the test substances.

ANALYSIS
- Magnesium and potassium levels were determined in blood.

Results and discussion

Signs and symptoms of toxicity:
no effects
Dermal irritation:
no effects
Absorption in different matrices:
In the first stage of the study, the salts were applied twice weekly. For rabbits treated with dead sea salt mixture, elevation of potassium and magnesium levels in serum was recognized. Magnesium levels rose from an average of 18.91 to 22.24 µg/mL and potassium level rose from 146.29 to 162.93 µg/mL. The daily fluctuations were remarkable, due to the big time gap (72 or 96 hours) between treatments. The percentage increase in Mg and K levels were 17.6% and 11.4%, respectively.
The daily fluctuations in the groups treated at 5% MgBr2 and 5% KBr in varnish were smaller than in group 1(2 applications per week with 5% Dead Sea salt mixture), because the absolute amounts of magnesium and potassium applied were higher than those applied in the groups treated with the salt mixture. The average concentration of both cations was significantly higher after treatment than before in groups 1-3 which were treated twice per week with either 5% salt mixture, 5% MgBr2 or 5% KBr.
Magnesium and potassium levels after six applications weekly of 5% dead sea salt mixture in water or varnish resulted in percentage elevation in the average levels of the cations similar to the groups treated twice weekly, but showed much smaller daily fluctuations in the amounts due to the higher frequency of exposure. The level of significance between before and after treatment was p< 0.01.

Applicant's summary and conclusion

Conclusions:
As could be shown by increased serum levels, magnesium and potassium penetrate the skin when applied as bromide salts or within a Dead Sea salt mixture.
Executive summary:

Materials and Methods

The investigation was performed in order to establish a treatment for psoriasis with Dead Sea minerals, since bathing in dead sea is an established treatment, but clinical application with a similar solution is missing so far. Magnesium dibromide and potassium bromide are known for the relevance in psioriatic treatment and were applied via an ethyl-cellulose-based transparent varnish to rabbit skin for up to three weeks. In addition, to some rabbits Dead Sea bath salt mixture was applied in varnish or distilled water. Serum was analysed for magnesium and potassium content.

Results and Discussion

In the present study, the efficiency of a sustained-release varnish matrix to release salts into rabbit skin, as measured by the serum ion levels, was evaluated. Magnesium and potassium were chosen because of their high abundance in the dead sea brine and their possible role in psoriasis. The results of the study clearly indicate that magnesium and potassium, applied to the skin via the varnish, either as MgBr2, KBr or within the dead sea salt mixture, penetrated the skin, resulting in higher serum magnesium and potassium levels. Treatment twice weekly showed higher daily fluctuations of the cation levels than treatment for six times a week due to the more frequent exposure to the salts. Serum bromine levels was not measured in this investigation for two reasons: (1) the serum bromide levels were investigated and determined by another study, demonstrating a sharp increase in serum bromide levels after application of NaBr varnish on rabbit skin and on healthy human skin; (2) while bromine has some effect on improving the psoriatic condition due to its tranquillising ability, it would need to demonstrate such an increase in blood that could not be obtained after merely a skin application. On the other hand, the involvement of potassium and magnesium in the psoriatic proliferation is on a molecular level: via production of cyclic-AMP, and therefore even a small elevation in their serum level would account for the temporary improvement noticed in over 90% of the patients after a four-week treatment period at the dead sea. In another study diluted dead sea brine and solutions of certain of its salts were found to reversibly inhibit cell proliferation in culture. Bromides were more powerful as inhibitors than their chloride counterparts, and potassium salts were more effective than those of sodium and magnesium. KBr had the strongest inhibitory effect, which equalled that of diluted dead sea brine at the same concentration.