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Diss Factsheets

Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
publication
Title:
Dermal absorption of inorganic germanium in rats
Author:
Yokoi K, Kawaai T, Konomi A and Uchida Y
Year:
2008
Bibliographic source:
Regulatory Toxicology and Pharmacology, 52: 169-173

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Three groups of rats were treated with a 3-h topical application of hydrophilic ointment containing graded level of neutralized GeO2 (pH 7.4): 0,
0.21 and 0.42 mg GeO2/g. Germanium concentration in blood and tissues sampled from rats after topical application of inorganic germanium was measured by inductively coupled plasma-mass spectrometry
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
Germanium dioxide
EC Number:
215-180-8
EC Name:
Germanium dioxide
Cas Number:
1310-53-8
Molecular formula:
GeO2
IUPAC Name:
Germanium dioxide
Test material form:
solid

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Japan SLC Inc., Shizuoka, Japan.
- Age at study initiation: 4-week-old
- Weight at study initiation: 50–70 g (mean 56.8 g, standard deviation 3.5 g
- Fasting period before study: no
- Housing: kept individually in stainless steel cages with raised wire bottoms
- Individual metabolism cages: yes
- Diet: free access to AIN-93G diet
- Water: free access to deionized water
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS: no information

Administration / exposure

Type of coverage:
not specified
Vehicle:
other:
Duration of exposure:
3h
Doses:
0, 0.21 mg/g and 0.42 mg/g
No. of animals per group:
6
Control animals:
yes
Details on study design:
DOSE PREPARATION
- Method for preparation of dose suspensions:
Preparation of inorganic germanium ointment:
Hydrophilic ointment containing neutralized GeO2 (inorganic germanium ointment) was prepared as follows. GeO2 of 2.5 g was stirred with excess amount of sodium hydroxide in deionized water (MilliQ, Millipore Co.) for hydrolysis. The alkaline solution
containing hydrolyzed GeO2 was neutralized with hydrochloric acid to give a solution with pH 7.4. Purified water was added to obtain 2.5 g/L neutralized GeO2 solution (1.735 g of elemental germanium/L). To prepare inorganic germanium ointment containing 0.42 mg GeO2/g, 3 mL of 2.5 g/L neutralized GeO2 solution was added to 15 g of hydrophilic ointment (Yoshida Pharmaceutical Co., Saitama, Japan) concordant to Japan Pharmacopoeia that contains 250 g white petrolatum, 200 g stearylalcohol, 120 g propyleneglycol, 40 g polyoxyethylene (60) hydrogenated castor oil, 10 g monostearylglycerine, 1 g methyl p-hydroxybenzoate, 1 g propyl p-hydroxybenzoate, and 378 g purified water per 1000 g. They were thoroughly mixed with a Teflon-coated ointment spatula on a 30 cm x 30 cm square polyvinyl chloride board. Similarly, 1.5 mL of 2.5 g/L neutralized GeO2 solution, 1.5 mL purified water, and 15 g hydrophilic ointment was mixed to obtain inorganic germanium ointment containing 0.21 mg GeO2/g.

APPLICATION OF DOSE: topical; Polyvinylidene chloride food wrap (Saran Wrap, Asahi Kasei Home Products Co., Tokyo, Japan) was cut into 2 cm x 2 cm square sheets and attached on cotton gauze by adhesives (Alonalpha, Toa Gosei Chemical Industry, Tokyo, Japan). 2 g of inorganic germanium ointment or blank ointment were spread on the polyvinylidene chloride sheet attached on cotton gauze for applying to the hair-removed skin.

VEHICLE
negative control: 3 mL purified water was mixed with 15 g hydrophilic ointment to prepare blank ointment.


TEST SITE:
A patch of hair approximately 3 x 4 cm from the dorsal abdominal surface along the spinal axis was clipped with an animal hair clipper. The remaining hair was removed with a depilatory cream (Epilat, Kanebo, Tokyo, Japan). The animals were
washed by warm tap water, and their fur was wiped by a towel and dried by a hair dryer. After overnight withdrawal of diets, the hydrophilic ointment containing neutralized GeO2 (inorganic germanium ointment) spread on the polyvinylidene chloride
sheet attached on cotton gauze was applied to the rat skin re-covered with short hair (approximately 1 mm length) after hair removal.

ANALYSIS
- Method type(s) for identification : Germanium concentration in the sample solution was measured by inductively coupled argon plasma-mass spectrometry (ICPM-8500, Shimadzu, Co., Kyoto, Japan).

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Percutaneous absorptionopen allclose all
Time point:
3 h
Dose:
0.21 mg/g
Parameter:
amount
Remarks:
in plasma
Absorption:
ca. 5.5 other: ng/g
Remarks on result:
other: average value in plasma based on reported graphs
Time point:
3 h
Dose:
0.21 mg/g
Parameter:
amount
Remarks:
in liver
Absorption:
ca. 6.4 other: ng/g
Remarks on result:
other: average value in liver based on reported graphs
Time point:
3 h
Dose:
0.21 mg/g
Parameter:
amount
Remarks:
in blood
Absorption:
ca. 3.8 other: ng/g
Remarks on result:
other: average value in blood based on reported graphs
Time point:
3 h
Dose:
0.21 mg/g
Parameter:
amount
Remarks:
in kidney
Absorption:
ca. 18 other: ng/g
Remarks on result:
other: average value in kidney based on reported graphs
Time point:
3 h
Dose:
0.42 mg/g
Parameter:
amount
Remarks:
in plasma
Absorption:
ca. 8.8 other: ng/g
Remarks on result:
other: average value in plasma based on reported graphs
Time point:
3 h
Dose:
0.42 mg/g
Parameter:
amount
Remarks:
in liver
Absorption:
ca. 15 other: ng/g
Remarks on result:
other: average value in liver based on reported graphs
Time point:
3 h
Dose:
0.42 mg/g
Parameter:
amount
Remarks:
in blood
Absorption:
ca. 5.3 other: ng/g
Remarks on result:
other: average value in blood based on reported graphs
Time point:
3 h
Dose:
0.42 mg/g
Parameter:
amount
Remarks:
in kidney
Absorption:
ca. 37 other: ng/g
Remarks on result:
other: average value in kidney based on reported graphs

Applicant's summary and conclusion

Conclusions:
After 3-hour dermal exposure (depilated dorsal skin) of male F344 / N rats to a neutralized solution of sodium germanate (GeO2 dissolved in NaOH) in a hydrophilic ointment base (2 g ointment containing 0, 0.21 or 0.42 mg GeO2 / g ), the germanium content in whole blood, plasma, liver and kidney increased in a dose-dependent manner. The kidney content was about three times higher than that in the liver

Executive summary:

In this study the dermal absorption of neutralized GeO2 or germanate using male F344/N rats was investigated. Three groups of rats were treated with a 3-h topical application of hydrophilic ointment containing graded level of neutralized GeO2 (pH 7.4): 0, 0.21 and 0.42 mg GeO2/g. Germanium concentration in blood and tissues sampled from rats after topical application of inorganic germanium was measured by inductively coupled plasma-mass spectrometry. Animals topically applied 0.42 mg GeO2/g ointment had significantly higher germanium concentrations in plasma, liver, and kidney than those of rats that received no topical germanium. The results indicate that skin is permeable to inorganic germanium ion or germanate and recurrent exposure of germanium compounds may pose a potential health hazard.