Registration Dossier

Administrative data

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
Not applicable
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Peer reviewed literature data
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
publication
Title:
Comparative in vitro percutaneous absorption of nonylphenol and nonylphenol ethoxylates (NPE-4 and NPE-9) through human, porcine and rat skin.
Author:
Monteiro-Riviere NA, Van Miller JP, Simon G, Joiner RL, Brooks JD and Riviere JE
Year:
2000
Bibliographic source:
Toxicology and Industrial Health, 16; 49-57

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Percutaneous absorption of ring-labelled 14C-NP (1%), 14C-NPE-4 and 14C-NPE-9 (0.1, 1.0, 10%) applied in polyethylene glycol (PEG-400) or water (NPE-9) only using in vitro flowthrough diffusion cells containing split thickness human, pig and rat skin. Absorption into perfusate, as well as disposition into stratum corneum and skin was assessed.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
See attached dosument for general structure.
The substances tested are alkyl phenols and structural analogs of the identified substance.

- Name of test material (as cited in study report): 14C-NPE-4
- Specific activity (if radiolabelling): 3.976 mCi/mmol
- Locations of the label (if radiolabelling): Ring labelled

- Name of test material (as cited in study report): 14C-NPE-9
- Specific activity (if radiolabelling): 6.179 mCi/mmol
- Locations of the label (if radiolabelling): Ring labelled

- Name of test material (as cited in study report): 14C-NP
- Specific activity (if radiolabelling): 2.214 mCi/mmol
- Locations of the label (if radiolabelling): Ring labelled
Radiolabelling:
yes

Test animals

Species:
other: Pig, rat, human
Strain:
other: Pig: 8 week old Yprkshire piglet weanling, Rat: 8-1- week old Sprague-Dawley, Human: obtained from parties undergoing abdominal plasty or breast reduction
Sex:
female
Details on test animals and environmental conditions:
Tissue Samples:
Immediately placed on large gauze strips saturated with saline and placed in zip-lock seal bags on wet ice.
Samples refridgerated for 18-20 h before use.
Skin thickness measured before use.
Human skin thickness: 1.6 - 2.0 mm
Animal tissue dermatomed to 500µm.
Circular sections prepared with 16 mm biopsy punch and mounted epidermal side up in Teflon diffusion cell blocks

Perfusion conditions
- Temperature (°C): 37
- pH: 7.4-7.5
- Humidity (%):55-65
- Perfusive flow rate: 4.0 mL/H (multi-channel peristaltic cassette pump)
- Perfusate: Krebs-Ringer bicarbonate buffer with added glucose and bovine serum albumin

Administration / exposure

Type of coverage:
open
Vehicle:
other: NP, NPE-4 and NPE-9: polyethylene glycol (PEG 400)NPE-9: water
Duration of exposure:
8 h
Doses:
14C-NP = 1%
14C-NPE-4 and 14C-NPE-9 = 0.1, 1.0, 10%
NPE-9 in water = 1%
No. of animals per group:
4 replicates per species per concentration
Control animals:
no
Details on study design:
See details on in vitro test system
Details on in vitro test system (if applicable):
Dosing area: 0.32 cm2
Total dose volume: 10 µL with target radioactivity of 0.5 - 1.0 µCi per diffusion cell
Perfusate collected at 0.25h intervals for first 2 h then at 1 h intervals up to 8 h expsoure period.
At completeion of study application site swabbed with soapy solution and six cellophane tape strips collected for estimation of stratum corneum penetration.
Upper half of teflon chamber rinsed and wash collected for mas balance determination.
Remaining skin divided into dosing site and peripheral tissue (outer ring of skin clamped in diffusion cell)
Perfusate and all tissue samples combusted in autoated tissue oxidiser and analysed in a liquid scintillation counter for total 14C determination.

Absorption defined as Total amount of radioactivity detected in the perfusate over the 8h expsore and expressed in units of mass absorbed and % applied dose (mass).
Penetration = sum of total radioactivity in the perfusate, stratum corneum and dosed skin.
Total recovery = sum of penetration + amount of radioactivity in upper Teflon cell, surface wash, and clamped skin.

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Absorption in different matrices:
See attached tables.
In all species, the fraction of the dose absorbed was dependant upon concentration of the applied dose with increased absorption efficiency seen at lower concentrations. In all dosing scenarios the bulk of the dose remained on the surface and did not penetrate the stratum corneum even after 8 h.
Total recovery:
See attached tables
Percutaneous absorptionopen allclose all
Dose:
0.1%
Parameter:
percentage
Absorption:
1 %
Remarks on result:
other: 8 h
Dose:
1%
Parameter:
percentage
Absorption:
0.1 %
Remarks on result:
other: 8h
Dose:
10%
Parameter:
percentage
Absorption:
0.01 %
Remarks on result:
other: 8h
Conversion factor human vs. animal skin:
Not applicable, human skin tested in vitro along side of animal skin

Any other information on results incl. tables

In the case of NPE, an absorbed flux of 0.1 µg/0.32 cm2/8 h or 0.3 µg/cm2/8 h is a more accurate estimate of absorption for all doses up to 10%

Applicant's summary and conclusion

Conclusions:
Exposure of human skin to concentrations of up to 10% NPE result in minimal exposure. The percentage dose absorbed was concentration dependant (ca. 1% for a 0.1% solution, 0.1% for a 1% solution and 0.01% for a 10% solution). There were no large species differences for absorption seen in the study.
Executive summary:

Test Guidance

No specific Guideline followed

Method and materials

Percutaneous absorption of ring-labelled 14C-NP (1%), 14C-NPE-4 and 14C-NPE-9 (0.1, 1.0, 10%) applied in polyethylene glycol (PEG-400) or water (NPE-9) only using in vitro flowthrough diffusion cells containing split thickness human, pig and rat skin was assessed. Absorption into perfusate, as well as disposition into stratum corneum and skin was assessed.

Results

In all species, the fraction of the dose absorbed was dependant upon concentration of the applied dose with increased absorption efficiency seen at lower concentrations. In all dosing scenarios the bulk of the dose remained on the surface and did not penetrate the stratum corneum even after 8 h.

Conclusions

Exposure of human skin to concentrations of up to 10% NPE result in minimal exposure. The percentage dose absorbed was concentration dependant (ca. 1% for a 0.1% solution, 0.1% for a 1% solution and 0.01% for a 10% solution). There were no large species differences for absorption seen in the study.

In the case of NPE, an absorbed flux of 0.1 µg/0.32 cm2/8 h or 0.3 µg/cm2/8 h is a more accurate estimate of absorption for all doses up to 10%