Registration Dossier

Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 December 2007 - 6 January 2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline conform study, conducted and documented under the principles of GLP.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2009

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Deviations:
no
Qualifier:
according to
Guideline:
other: OECD Environmental Health and Safety Publications Series on Testing and Assessment No. 28. Guidance Document for the Conduct of Skin Absorption Studies (2004)
Deviations:
no
GLP compliance:
yes (incl. certificate)

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): sodium molybdate dihydrate
- Molecular formula (if other than submission substance): Na2MoO4 x 2 H2O
- Molecular weight (if other than submission substance): 241.95
- Substance type: inorganic metal salt, dihydrate form
- Physical state: solid, crystalline powder
- Analytical purity: 99.6 - 99.9 %
- Storage condition of test material: dry, closed container, ambient temperature
Radiolabelling:
no

Test animals

Species:
human

Administration / exposure

Type of coverage:
open
Vehicle:
water
Duration of exposure:
8 hours and 16 h post-exposure monitoring (continued collection of receptor fluid)
Doses:
- Nominal doses: 100 and 500 µg test item per cm².
- Actual doses: 105 and 542 µg sodium molybdate dihydrate per cm², corresponding to 42 and 215 µg molybdenum per cm², respectively.
- Dose volume: 10 µL/cm² (solution concentrations: 10.51 and 54.2 mg sodium molybdate dihydrate per mL).
- Rationale for dose selection: 100 and 500 µg test item per cm² cover a range of typical and rather worst case dermal loading, which could be expected during industrial handling of powders.
Details on study design:
Split-thickness human skin membranes were mounted into flow-through diffusion cells. Receptor fluid, physiological saline containing streptomycin and penicillin G, was pumped underneath the skin at a flow rate of ca 1.5 mL/h. The skin surface temperature was maintained at ca 32°C throughout the experiment. A tritiated water barrier integrity test was performed and any human skin sample exhibiting a kp value greater than 3.5 x 10-3 cm/h was excluded from subsequent absorption measurements.

Disodium molybdate dihydrate has a water solubility of ca 650 g/L. Disodium molybdate dihydrate was applied to human skin at two different application rates: ca 100 µg/cm2 and ca 500 µg/cm2 (equivalent to Molybdenum concentrations of ca 39.66 µg/cm2 and ca 198.3 µg/cm2, respectively). The two test preparations were prepared with final concentrations of Disodium molybdate dihydrate of ca 10 mg/mL and 50 mg/mL. These test preparations were applied to the skin mounted in flow through diffusion cells at an application rate of 10 µL/cm2.

Percutaneous absorption was assessed by collecting receptor fluid in 4 hourly fractions from 0 to 24 h post application. At 8 h post application, exposure was terminated by washing the skin surface with a concentrated commercial soap followed by rinsing with a dilute soap solution and drying the skin surface with tissue paper (tissue swabs). At 24 h post application (ie after a 16 h post exposure monitoring period), the underside of the skin was rinsed with receptor fluid. This rinse was added to the 20-24 h receptor fluid collection sample. The skin was then removed from the flow-through diffusion cells, dried and the stratum corneum removed with 20 successive tape strips. The tape strips were pooled in groups of 5 (1-5, 6-10, 11-15 and 16-20, respectively). These samples were despatched to the analytical laboratory Scientifics Limited where they were analysed by inductively coupled plasma-mass spectroscopy (ICP-MS). The laboratory Charles River then calculated the results from the mass of samples collected and the amount of Molybdenum in each analytical sample.

Results and discussion

Signs and symptoms of toxicity:
not specified
Dermal irritation:
not specified
Total recovery:
Recovery of applied dose acceptable: yes (>98%)
Percutaneous absorptionopen allclose all
Dose:
100 µg/cm²
Parameter:
percentage
Absorption:
0.21 %
Remarks on result:
other: 24 h (8 h exposure + 16 h post-exposure monitoring)
Remarks:
Potentially absorbable dose: includes cumulative receptor fluid, skin, and stratum corneum tape strips 6-20. The 5 outermost tape strips are excluded.
Dose:
500 µg/cm²
Parameter:
percentage
Absorption:
0.16 %
Remarks on result:
other: 24 h (8 h exposure + 16 h post-exposure monitoring)
Remarks:
Potentially absorbable dose: includes cumulative receptor fluid, skin, and stratum corneum tape strips 6-20. The 5 outermost tape strips are excluded.

Any other information on results incl. tables

Summary results table:

Test Preparation

1

2

Target Concentration of [Na2MoO4.2H2O]

10 mg/mL

50 mg/mL

Actual Concentration of [Na2MoO4.2H2O]

10.51 mg/mL

54.20 mg/mL

Target Concentration of [Molybdenum]

3.966 mg/mL

19.83 mg/mL

Actual Concentration [Molybdenum]

4.17 mg/mL

21.50 mg/mL

Application Rate of Test Preparation

10 µL/cm2(9.78 mg/cm2)

10 µL/cm2(10.34 mg/cm2)

Application Rate of Na2MoO4.2H2O

105 µg/cm2

542 µg/cm2

Target Application Rate of Molybdenum

39.66 µg/cm2

198.3 µg/cm2

Actual Application Rate of Molybdenum

42 µg/cm2

215 µg/cm2

Percentage of Target Application Rate

105.06%

108.40%

Distribution of Na2MoO4.2H2O

% Applied Dose

µg/cm2

% Applied Dose

µg/cm2

Dislodgeable Dose 8 h

98.89

103.89

98.49

533.83

Unabsorbed Dose

98.95

103.96

98.54

534.10

Absorbed Dose

0.12

0.12

0.04

0.21

Dermal Delivery

0.18

0.19

0.13

0.72

Potentially Absorbable Dose

0.21

0.22

0.16

0.85

Mass Balance

99.13

104.15

98.68

534.81

Dislodgeable dose 8 h = skin wash + tissue swab

Unabsorbed dose = dislodgeable dose 8 h + stratum corneum

Absorbed dose = cumulative receptor fluid

Dermal delivery = skin + absorbed dose

Potentially absorbable dose = dermal delivery + stratum corneum tape strips 6 to 20

Mass balance = unabsorbed dose + dermal delivery

Applicant's summary and conclusion

Conclusions:
For the purposes of risk assessment, the potentially absorbable dose (the sum of the absorbed dose, skin and stratum corneum tape strips 6 to 20) may be used. This corresponds to 0.21% for the low exposure scenarios (ca 42 µg Mo/cm2) and 0.16% for the high exposure scenarios (ca 215 µg Mo/cm2). This value also accounts for part of the material associated with the stratum corneum and the test was conducted with a highly water soluble form of Molybdenum in an aqueous solution. Thus, these values are considered to represent a conservative estimate.