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Toxicological information

Dermal absorption

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Administrative data

Endpoint:
dermal absorption in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles: non-GLP. Source of data is from secondary literature.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2006

Materials and methods

Principles of method if other than guideline:
The purpose of this study was to investigate the absorption and penetration of aromatic and aliphatic components of JP-8 in humans. A surface area of 20 cm2 was delineated on the forearms of human volunteers and 1 mL of JP-8 was applied to the skin. Tape-strip samples were collected 30 min after application. Blood samples were taken before exposure (t = 0 h), after exposure (t = 0.5 h), and every 0.5 h for up to 4 h past exposure.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
human
Sex:
male/female
Details on test animals and environmental conditions:
Study volunteers
Ten healthy adult volunteers (five males and five nonpregnant females) with no occupational exposure to jet fuel were recruited for participation. No restrictions on age, race, gender, or skin type were applied other than that the group was to be equally divided between males and females. If volunteers had a history of cardiovascular disease or atopic dermatitis, were current smokers, or were on prescription medication for a current or chronic illness, they were excluded from the study. Volunteers were not permitted to drink any alcoholic beverages 24 h before or during the experiment. Individuals occupationally exposed to compounds chosen to represent JP-8 were also excluded (e.g., auto mechanics). Approval for this study was obtained from the Office of Human Research Ethics (School of Public Health, The University of North Carolina at Chapel Hill, Chapel Hill, NC). Informed consent was received from all study volunteers.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
0.5 h exposure period
Doses:
1 mL JP-8
No. of animals per group:
10 subjects; 5 males, 5 nonpregnant females
Details on study design:
The volunteer’s forearms were examined for obvious skin defects (abrasions, inflammation) that could enhance or impair the penetration of JP-8. After the volunteer was seated comfortably, one forearm was placed palm up inside the exposure chamber , and two aluminum application wells (10 cm2 per well) were pressed against the skin to prevent JP-8 from spreading during the experiment. The exposure chamber was sealed for the duration of the experiment (0.5 h).

The volume of JP-8 to be applied to the skin in order to have sufficient concentrations in blood was estimated using the limit of detection (LOD) of a published analytical method and estimates of permeability coefficients from an in vitro study (McDougal et al., 2000; Waidyanatha et al., 2003). Although the method by Waidyanatha et al. (2003) was developed for the analysis of naphthalene in urine, a similar LOD (5.0×l0−4 ng/ml) was assumed to apply for blood samples. Three times the LOD was assumed to be adequate for detection in blood.. It was determined, using a permeability coefficient of 5.1×10−4 cm/h, that 1ml of JP-8 should produce measurable blood concentrations. Neat JP-8 was applied to the volar forearm using a 0.5 ml gas-tight syringe through two openings on top of the exposure chamber; 0.5 ml was applied to each of two wells for a total of 1.0 ml JP-8 on an area of 20 cm2. Upon application, the openings were sealed to prevent loss from the chamber.

At the end of the 0.5 h exposure period, the two exposed skin sites were wiped with a gauze pad and tape-stripped as many as 10 times. Tape-stripping has also been used in dermatopharmacokinetic studies of therapeutic agents. Tape strips were placed in 10 ml of acetone containing 1 µg/ml of internal standards (naphthalene-d8). All tape-strip samples were stored in 20 ml vials and refrigerated at 4 ◦C. Blood samples were drawn from the unexposed arm at baseline, 0.5 h, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, and 3.5 h and collected in 6ml test tubes containing sodium heparin. The blood samples were stored at −80 ◦C until analysis.


Tape-strip samples were analyzed by gas chromatography mass spectrometry (GC–MS). Blood samples were analyzed using head-space solid-phase microextraction (HS-SPME) and the GC-MS system used to analyze the tape-strip samples.

Data Analysis
Exploratory analyses of skin and blood concentrations of JP-8 components were conducted using descriptive statistics. The skin and blood concentrations were plotted as functions of time. The first tape strip was not included in these plots because of potential residual contamination from the dose applied to the skin (Shah et al., 1998). The volume of blood was estimated using allometric relationships (Davies and Morris, 1993). The equation is Volume of blood (Vb) = 72.447×(body weight in kg)^1.007. Vb was used to estimate the total mass of naphthalene, 1-methyl naphthalene, 2-methyl naphthalene, decane, undecane, and dodecane in the blood of each volunteer. The steady state flux (J, µg/cm2/h) was estimated from the slope of the linear portion of the cumulative mass per cm2 versus time curve. The slope of the curve during the uptake period (i.e., exposure duration) was estimated for each subject. The permeability coefficient (Kp, cm/h) was estimated by dividing the flux by the concentration of the chemical (CJP-8, µg/cm3) in the 1ml of JP-8 that was applied to the skin (McDougal and Boeniger, 2002): Kp = J/CJP-8.

Results and discussion

Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined

Applicant's summary and conclusion

Conclusions:
The permeability coefficients (cm/h) of aromatic and aliphatic hydrocarbons were determined to be: Naphthalene 5.3E−05; 1-Methyl naphthalene 2.9E−05; 2-Methyl naphthalene 3.2E−05; Decane 6.5E−06; Undecane 4.5E−07; Dodecane 1.6E−06.
Executive summary:

Chemicals placed on the skin undergo absorption into the stratum corneum and evaporation from the surface of the skin. After absorption, the chemicals may be stored in deeper layers of the stratum corneum or in the viable epidermis, or they may penetrate into the dermis for eventual movement into the systemic circulation. Some absorbed compound may also transfer back to the skin surface and evaporate into the surrounding air.

 

The results are similar to in vitro studies that use diffusion cells and pig skin. The tape-strip data showed evidence of absorption of naphthalene, 1-methyl naphthalene, 2-methyl naphthalene, decane, undecane, and dodecane, although decane seemed to disappear faster from the surface of the stratum corneum. It is estimated that aromatic components of JP-8 penetrate faster than the aliphatic components. The flux of the aliphatic components is greater than the flux of the aromatic components because the concentration of the aliphatics in JP-8 is more than an order of magnitude greater than the concentration of the aromatics. Our overall estimates of the apparent Kp were smaller than the in vitro estimates.

 

Consequently, the study shows that permeability coefficients estimated in vitro may overestimate the internal dose of various components of JP-8. The results of the study need to be interpreted with caution because in vitro systems do not account for distribution and clearance mechanisms, i.e., processes such as uptake into peripheral tissues, binding to proteins, metabolism, and exhalation are not incorporated in diffusion-cell experiments.

 

The permeability coefficients (cm/h) of aromatic and aliphatic hydrocarbons were determined to be: Naphthalene 5.3E−05; 1-Methyl naphthalene 2.9E−05; 2-Methyl naphthalene 3.2E−05; Decane 6.5E−06; Undecane 4.5E−07; Dodecane 1.6E−06.