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Referenceopen allclose all

Endpoint:
dermal absorption
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2008
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Source of data is from peer reviewed literature. Acceptable well-documented study report which meets basic scientific principles: non-GLP.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
no guideline available
Principles of method if other than guideline:
A mathematical description/model was developed to describe the uptake of aromatic hydrocarbons into the stratum corneum of human skin in vivo. The dermal absorption data was gathered in a previous paper (Kim 2006).
Kim, D., Andersen, ME., Nylander-French, L.A., 2006a. Dermal absorption and penetration of jet fuel components in humans. Toxicol. Lett. 165, 11-21.
GLP compliance:
no
Radiolabelling:
no
Species:
human
Strain:
not specified
Sex:
male/female
Type of coverage:
not specified
Vehicle:
not specified
Control animals:
no
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Conclusions:
The diffusion coefficients (Dsc, cm2/min x 10^-8) of aromatic hydrocarbons were determined to be: Naphthalene 4.2+/-1.4; 1-Methyl naphthalene 4.6 +/-2.7; 2-Methyl naphthalene 4.5+/-2.6.
Executive summary:

A mathematical model was developed to describe the diffusion coefficients (Dsc) of aromatic hydrocarbons. The diffusion coefficients (Dsc, cm2/min x 10^-8) of aromatic hydrocarbons were determined to be: Naphthalene 4.2+/-1.4; 1-Methyl naphthalene 4.6 +/-2.7; 2-Methyl naphthalene 4.5+/-2.6.

Endpoint:
dermal absorption in vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2006
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Source of data is frompeer reviewed literature. Acceptable well-documented study report which meets basic scientific principles: non-GLP.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
no guideline available
Principles of method if other than guideline:
The purpose of this study was to investigate the absorption and penetration of aromatic 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 post exposure.
GLP compliance:
no
Radiolabelling:
not specified
Species:
human
Strain:
not specified
Sex:
male/female
Details on test animals or test system 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.
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
Control animals:
no
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, and 2-methyl naphthalene 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.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Conclusions:
The permeability coefficients (cm/h) of aromatic hydrocarbons were determined to be: Naphthalene 5.3E-05; 1-Methyl naphthalene 2.9E-05; 2-Methyl naphthalene 3.2E-05.
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, and 2-methyl naphthalene. It is estimated that naphthalene penetrated faster than the other aromatic components.  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 hydrocarbons were determined to be: Naphthalene 5.3E-05; 1-Methyl naphthalene 2.9E-05; 2-Methyl naphthalene 3.2E-05.

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Source of data is from peer reviewed literature. Acceptable well-documented study report which meets basic scientific principles: non-GLP.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Principles of method if other than guideline:
Two aromatic (naphthalene and 2-methylnaphthalene) chemicals, major components of JP-8, were investigated for changes in skin lipid and protein biophysics, and macroscopic barrier perturbation from dermal exposure. Percutaneous absorption was examined in vitro using porcine ears (Yorkshire marine pigs, male). Fourier transform infrared (FTIR) spectroscopy was employed to investigate the biophysical changes in stratum corneum (SC) lipid and protein. FTIR results showed that all of the above components of JP-8 significantly (P<0.05) extracted SC lipid and protein. Macroscopic barrier perturbation was determined by measuring the rate of transepidermal water loss (TEWL).
GLP compliance:
not specified
Radiolabelling:
yes
Species:
other: in vitro using porcine ears
Strain:
other: Yorkshire marine
Sex:
male
Type of coverage:
not specified
Vehicle:
not specified
Control animals:
no
Details on in vitro test system (if applicable):
MODEL SYSTEM: Porcine ears (Yorkshire marine pigs, male) were obtained. The external/dorsal skin was dermatomed to 0.5 mm thickness and used in the in vitro percutaneous absorption and TEWL studies. The method of Kligman and Christophers was used to separate epidermis from whole skin to produce the stratum corneum (SC) (Kligman and Christophers, 1963).

IN VITRO PERCUTANEOUS ABSORPTION: Franz diffusion cells were used in the in vitro percutaneous absorption studies. The dermatomed skin was sandwiched between the cells with the epidermis facing the donor compartment. The maximum capacities of the donor and receiver compartments were 1 and 5 ml, respectively, and the effective diffusion area was 0.785 cm2. The donor compartment contained 4 mCi of radio labeled test chemicals in 1 ml of JP-8 and the receiver compartment was filled with 5 ml of PBS, pH 7.4 containing 0.1% formaldehyde and 0.2% Tween 80 to act as preservative and solubilizer, respectively. The donor compartment was fitted to minimize evaporation of volatile test chemical. The cells were maintained at 37oC. At appropriate times, 1 ml samples were withdrawn from the receiver compartment and transferred to scintillation vials. The samples were assayed by liquid scintillation counting. The instrument was programmed to give counts for 10 min. Net dpm was obtained by subtracting background dpm measured in the control samples. All experiments were performed in replicates of six, and the results were expressed as the mean +/- S.D. (n=6).

BINDING OF CHEMICALS:
SC was pulverized in a mortar with a pestle. Ten milligrams of pulverized SC was mixed by vortexing for 5 min with 1 ml of JP-8 containing 4 mCi of the test chemical. The mixture was shaken for 10 h at 37 oC. Since the lag time of these chemicals for attaining steady state transport was well below 2 h, 10 h contact time was considered adequate for reaching equilibrium. After 10 h of contact time, the mixture was separated by centrifugation, and the supernatant was removed. The sediment was resuspended three times in JP-8 to remove chemical adsorbed on the surface (Wester et al., 1991). The amount of radioactivity in the supernatants was determined by liquid scintillation counting. The amount of chemical that bound to the SC was obtained by subtracting the amount of chemical recovered in supernatants from the amount of chemical originally added (Menczel and Maibach, 1972; Artuc et al., 1979). Six sets of experiments were performed for each chemical.

BIOPHYSICAL PROPERTIES OF SC LIPIDS AND PROTEINS BY FTIR:
The SC samples were treated for 24 h by applying 500ml of chemical on 10 cm2 area of SC in a closed petri dish. The samples were vacuum-dried (650 mmHg) at 21oC for 3 days and stored in a desiccator to evaporate JP-8 (Yamane et al., 1995). The treated SC was then subjected to FTIR spectroscopy. Attention was focused on characterizing the occurrence of peaks near 2850 and 2920 per cm, which were due to the symmetric and asymmetric C-H stretching, respectively. Strong amide absorbance occurred in the region of 1500-1700 per cm due to C-O stretching and N-H bending (Koenig and Snively, 1998). The decrease in peak heights and areas of methylene and amide absorbancies is related to the SC lipid and protein extraction, respectively (Bhatia and Singh, 1998; Bommannan et al., 1991; Goates and Knutson, 1994; Zhao and Singh, 2000). For each SC sample, peak height and area were measured before and after the chemical treatment. This experimental strategy allowed each sample to serve as its own control.

IN VITRO TRANSEPIDERMAL WATER LOSS (TEWL) THROUGH SKIN:
Franz diffusion cells were used for in vitro TEWL studies (Kai et al., 1993). The dermatomed skin was treated with chemical in a manner similar to the SC for FTIR studies. The treated dermatomed skin was then sandwiched between the diffusion cells with the SC side up and the dermal side exposed to the receiver compartment containing isotonic saline (0.9% sodium chloride solution). Holding the probe over the donor cell opening until a stable TEWL value was achieved performed TEWL measurement. The experiments were performed in a room with an ambient temperature between 20 and 26 oC and relative humidity between 30 and 45%. In all the cases, six replicates of experiments were performed and the results expressed as the mean +/-/S.D. (n +/- 6). Experiments were performed in the same manner without chemical treatment of the dermatomed skin to serve as control.

DATA ANALYSIS:
The chemical concentration was corrected for sampling effects (Hayton and Chen, 1982): The permeability coefficient (Kp) was calculated as (Scheuplein, 1978): The binding of chemicals to the SC (P) was calculated as (Zhao and Singh, 2000). Statistical comparisons were made using the Student’s t -test and analysis of variance (ANOVA). The level of significance was taken as P<0.05.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined

RESULTS

There is an increase in binding of aromatic JP-8 components to SC with increasing Log PC values. Log PC values are Naphthalene (NAP) 3.30 and 2-Methylnaphthalene (2MN) 3.86. Bindings to SC are 8.14+/-1.02 and 8.39+/-0.77 for NAP and 2-MN, respectively. The flux (JSS), values were determined to be (mean) 10.87 and 7.59 (nmol/cm2 per h)E-2 for NAP and 2-MN, respectively.

The diffusion coefficient values were determined to be (1.30+/-/0.27)E-6 and (0.69+/-/0.16)E-6 cm2/h for NAP and 2-MN, respectively.  The lag time values were determined to be (mean) 1.19 and 1.36 hours for NAP and 2-MN, respectively.

FTIR results suggest that the test chemicals significantly (P<0.05) extracted SC lipid and protein in comparison to control. There was no significant (P<0.05) difference among NAP and 2- MN with respect to their SC lipid and protein extraction.  The test chemicals caused significant (P<0.05) increase in TEWL in comparison to control. NAP produced a larger increase in TEWL (25.08+/-/0.55 g/m2 per h) then 2-MN (14.76+/-/0.42 g/m2 per h).

Conclusions:
There is an increase in binding of aromatic JP-8 components to SC with increasing Log PC values. Log PC values are Naphthalene (NAP) 3.30 and 2-Methylnaphthalene (2MN) 3.86. Bindings to SC are 8.14+/-1.02 and 8.39+/-0.77 for NAP and 2-MN, respectively. The flux (JSS), values were determined to be (mean) 10.87 and 7.59 (nmol/cm2 per h)E-2 for NAP and 2-MN, respectively.

The diffusion coefficient values were determined to be (1.30+/-/0.27)E-6 and (0.69+/-/0.16)E-6 cm2/h for NAP and 2-MN, respectively. The lag time values were determined to be (mean) 1.19 and 1.36 hours for NAP and 2-MN, respectively.

FTIR results suggest that the test chemicals significantly (P<0.05) extracted SC lipid and protein in comparison to control. There was no significant (P<0.05) difference among NAP and 2- MN with respect to their SC lipid and protein extraction. The test chemicals caused significant (P<0.05) increase in TEWL in comparison to control. NAP produced a larger increase in TEWL (25.08+/-/0.55 g/m2 per h) then 2-MN (14.76+/-/0.42 g/m2 per h).
Executive summary:

There is an increase in binding of aromatic JP-8 components to SC with increasing Log PC values. Log PC values are Naphthalene (NAP) 3.30 and 2-Methylnaphthalene (2MN) 3.86. Bindings to SC are 8.14+/-1.02 and 8.39+/-0.77 for NAP and 2-MN, respectively. The flux (JSS), values were determined to be (mean) 10.87 and 7.59 (nmol/cm2 per h)E-2 for NAP and 2-MN, respectively.

 

The diffusion coefficient values were determined to be (1.30+/-/0.27)E-6 and (0.69+/-/0.16)E-6 cm2/h for NAP and 2-MN, respectively.  The lag time values were determined to be (mean) 1.19 and 1.36 hours for NAP and 2-MN, respectively.

FTIR results suggest that the test chemicals significantly (P<0.05) extracted SC lipid and protein in comparison to control. There was no significant (P<0.05) difference among NAP and 2- MN with respect to their SC lipid and protein extraction.  The test chemicals caused significant (P<0.05) increase in TEWL in comparison to control. NAP produced a larger increase in TEWL (25.08+/-/0.55 g/m2 per h) then 2-MN (14.76+/-/0.42 g/m2 per h).

Endpoint:
dermal absorption in vitro / ex vivo
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
weight of evidence
Study period:
1999
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable well-documented study report which meets basic scientific principles.
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 428 (Skin Absorption: In Vitro Method)
Principles of method if other than guideline:
In vitro isolated perfused porcine skin flap (IPPSF) Studies.
GLP compliance:
not specified
Radiolabelling:
yes
Remarks:
14C-naphthalene, 3H-dodecane, 14C- hexadecane
Species:
pig
Strain:
not specified
Sex:
not specified
Details on test animals or test system and environmental conditions:
in vitro experiment
Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Duration of exposure:
5 hours; 4 trials
Doses:
25 uL of Jet fuel with radio labeled tracers
Control animals:
no
Details on study design:
In vitro isolated perfused porcine skin flap (IPPSF) Studies.
In these studies, jet fuel mixtures were applied non-occluded to mimic field exposure conditions, and experiments were conducted for a total of 5 h in IPPSFs with 4 replicates per treatment condition. A 1 x 5 cm dosing area was drawn on the surface of the skin flap with a surgery marker. A dose, containing 25 uLof the specified jet fuel containing approximately 2 uCi of 14C-naphthalene plus 10 uCi of 3H-dodecane and 14C- hexadecane was applied directly to the surface of the skin flap. The specific activities of the marker compounds were sufficient that the added radiolabeled compounds had little effect on the final concentration of naphthalene (1.21% instead of 1.1%) and dodecane (4.701% instead of 4.7%). Single label studies were initially conducted and compared to the dual-label results to test whether using this dual-label experimental design had any effect on marker absorption. No effect was detected.
Perfusate samples (3 ml) were collected every 5 mm for the first 40 mm. then every 10 mm until 1.5 h. and then every 15 mm until termination at 5 h. At termination, several samples were taken for mass balance of the marker compounds. The surface of the dose area was swabbed twice with a 1% soap solution and gauze, and then 12 stratum corneum tape strips were collected using cellophane tape (3M Corporation, Minneapolis. MN). The entire dose area was removed. A 1x 1 cm core of the dose area was removed and frozen for subsequent depth of penetration studies. This consisted of laying the core sample epidermal side down in an aluminum foil boat and embedding in Tissue-Tek OCT compound (Miles. Inc., Elkhart, IN), snap freezing in liquid nitrogen, followed by sectioning (40 zm) on a Reichart-Jung Model 1800 Cryocut (Warner Lambert, Buffalo, NY). The remaining dosed area as well as the surrounding skin was separated from the fat and held for analysis. All samples (including swabs, tape strips, core sections, skin, fat, mass balance samples, etc.) were dissolved separately in Soluene. A representative volume of each sample was oxidized completely via a Packard Model 307 Tissue Oxidizer. The 3H and 14C samples were counted separately on a Packard Model 1900TR TriCarb Scintillation Counter.

Data analysis. Data was entered into a custom IPPSF database and the resulting analysis reported. Since all experiments were conducted using the identical marker doses across all fuels, and the absolute concentrations of these marker compounds were similar, these results are expressed as percentage applied dose to give a representative assessment of the absorption and cutaneous penetration of a complex mixture such as jet fuel. This is appropriate since the absolute concentrations of jet fuel hydrocarbons is not fixed across all fuels due to differences that arise from the natural source of the petroleum and different refining processes. Area under the curve (AUC) in the perfusate was calculated using the trapezoidal method. Peak flux was the maximum flux (% dose/mm) observed at any one time point.

The experimental compartments which were analyzed in these studies used the following definitions: (1) Surface is the residue removed by washing the surface of the IPPSF at termination of the experiment plus the residues remaining in the dosing template. (2) Stratum corneum is the residue extracted from the outermost stratum corneum via 12 tape strips at the termination of the experiment. (3) Dosed skin is the residue that remained in the dosed skin plus the depth of penetration core taken at termination. (4) Absorption is the cumulative amount of the marker compound collected in the effluent over the course of the 5-h experiment. (5) Fat is the residue remaining in the fat when it was separated from the dermis at the end of the experiment. (6) Penetration is the summation of the label in the effluent plus skin plus fat, but not stratum corneum nor surface. (7) Evaporative loss is that label which was lost to evaporation. Our previous studies in the IPPSF indicated that the penetration estimate is the best empirical correlate to predict eventual in vivo absorption in humans.

Statistical significance of absorption and penetration parameters were determined using ANOVA or by a priori-defined orthogonal contrasts where appropriate at the 0.05 level of significance. A least significance difference (LSD) procedure was used for multiple comparisons on overall tissue disposition.
Details on in vitro test system (if applicable):
A 1 x 5 cm dosing area was drawn on the surface of the skin flap with a surgery marker. A dose, containing 25 uLof the specified jet fuel containing approximately 2 uCi of 14C-naphthalene plus 10 uCi of 3H-dodecane and 14C- hexadecane was applied directly to the surface of the skin flap. Perfusate samples (3 ml) were collected every 5 mm for the first 40 mm. then every 10 mm until 1.5 h. and then every 15 mm until termination at 5 h. At termination, several samples were taken for mass balance of the marker compounds. The surface of the dose area was swabbed twice with a 1% soap solution and gauze, and then 12 stratum corneum tape strips were collected using cellophane tape (3M Corporation, Minneapolis. MN). The entire dose area was removed. A 1x 1 cm core of the dose area was removed and frozen for subsequent depth of penetration studies. This consisted of laying the core sample epidermal side down in an aluminum foil boat and embedding in Tissue-Tek OCT compound (Miles. Inc., Elkhart, IN), snap freezing in liquid nitrogen, followed by sectioning on a Reichart-Jung Model 1800 Cryocut. The remaining dosed area as well as the surrounding skin was separated from the fat and held for analysis.
Signs and symptoms of toxicity:
not examined
Dermal irritation:
not examined
Conclusions:
Within JP-8, the rank order of absorption for all marker components was (mean +/- SEM; % dose) naphthalene (1.17 +/- 0.07)> dodecane (0.63 +/- 0.04) > hexadecane (0.18 +/- 0.08).  The area under the curve (AUC) was determined to be (mean +/- SEM; % dose-h/mL): naphthalene (0.0199 +/- 0.0020)> dodecane (0.0107 +/- 0.0009) > hexadecane (0.0017 +/- 0.0003). In contrast, deposition within dosed skin showed the reverse pattern.
Executive summary:

The purpose of these studies was to assess the percutaneous absorption and cutaneous disposition of topically applied (25 uL/5 cm2) neat Jet-A, JP-8, and JP-8(100) jet fuels by monitoring the absorptive flux of the marker components 14C naphthalene and 4H dodecane simultaneously applied non-occluded to isolated perfused porcine skin flaps (IPPSF) (a = 4). Absorption of 14C hexadecane was estimated from JP-8 fuel. Absorption and disposition of naphthalene and dodecane were also monitored using a nonvolatile JP-8 fraction reflecting exposure to residual fuel that might occur 24 h after a jet fuel spill. In all studies, perfusate, stratum corneum, and skin concentrations were measured over 5 h. Naphthalene absorption had a clear peak absorptive flux at less than 1 h, while dodecane and hexadecane had prolonged, albeit significantly lower, absorption flux profiles. Within JP-8, the rank order of absorption for all marker components was (mean +/- SEM; % dose) naphthalene (1.17 +/- 0.07)> dodecane (0.63 +/- 0.04) > hexadecane (0.18 +/- 0.08).  The area under the curve (AUC) was determined to be (mean +/- SEM; % dose-h/mL): naphthalene (0.0199 +/- 0.0020)> dodecane (0.0107 +/- 0.0009) > hexadecane (0.0017 +/- 0.0003). In contrast, deposition within dosed skin showed the reverse pattern.

Endpoint:
dermal absorption in vivo
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:

Description of key information

Hydrocarbons, C9, aromatics:

Hydrocarbons, C9, Aromatics can be dermally absorbed, albeit at low levels. When dermally absorbed, C9 Aromatics are rapidly eliminated. 

 

Hydrocarbons, C10 aromatics:

C10 aromatic fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2 µg/cm2/hr or 1% of the total fluid applied. When dermally absorbed, C10 aromatics are rapidly eliminated.

Key value for chemical safety assessment

Additional information

Hydrocarbons, C9, aromatics:

ABSORPTION

 

INHALATION EXPOSURE

 

Human Data

Exposure of human volunteers to trimethylbenzene vapour concentrations ranging from 5 -150 mg/m3 resulted in pulmonary retentions between 56 -71% depending on the chemical species and the study (1, 2). Absorption into the blood stream of human volunteers exposed to a 25 ppm vapour of 1,3,5-trimethylbenzene for a period of 4 hours was rapid, and resulted in a mean steady-state blood level of 0.85 micromol/l after 1-2 hours of exposure(3). Similar results were observed in human volunteers exposed to 100 ppm (26). Likewise, rapid pulmonary absorption of

1,2,3-trimethylbenzene in human volunteers has also been demonstrated (4, 5).

 

In vitro human blood:gas partition coefficients for the trimethylbenzenes are high, ranging from 40.8 to 69.3, depending on the chemical species (6). Thus the pulmonary absorption of trimethylbenzenes is ventilation-limited.  This is consistent with the apparent high rate of uptake of the

trimethylbenzenes from the alveoli into the blood and the apparent slow rate of equilibration of 1,3,5-trimethylbenzene partial pressures in alveolar

and inspired air in man (3).

 

Animal Data:

The systemic absorption of inhaled trimethylbenzenes in rats is rapid with blood levels reaching a plateau after about 2 hours of

exposure (7, 8).   The rate of uptake of inhaled 1,2,4-trimethylbenzene rats is 13.6 nmol×kg-1×min-1×ppm-1during nose-only exposure (9, 10). As in humans, 1,2,4-trimethylbenzene has a relatively high blood:gas partition coefficient and its uptake is ventilation-limited (10).  

 

Summary: The available human and animal data imply that: a high proportion of inhaled C9 aromatic substances are available for absorption; that

rapid systemic absorption of C9 aromatics following inhalation exposure can be expected; and that pulmonary absorption of the C9 aromatic

substances is ventilation limited.

 

DERMAL EXPOSURE

 

Human Data

Attempts at dermal absorption determinations in humans with trimethylbenzenes has been difficult due to their acute primary skin irritancy (3). Slow, low-level skin penetration of 1,2,4-trimethylbenzene through excised human skin in vitro, as measured using Franz static diffusion cells, can occur although steady state absorption conditions were not established following an 8 hour exposure period (11).

 

Animal Data:

The mean in vitro rat dermal absorption flux of trimethylbenzenes present in a kerosene-based fuel (JP-8), was 1.25 micrograms/cm2/hour

with a breakthrough time of 1 hour, as determined in Franz static diffusion cells.12 Similarly, in a study in which pigs were treated dermally with jet

fuel for 1-4 days, and then skin removed and tested for dermal penetration under in vitro conditions, values of 0.49-1.01 micrograms/cm2/hour were reported for trimethylbenzene (27).

 

Summary: The available in vitro and animal data imply that C9 aromatics will be systemically absorbed following dermal exposure, albeit at low levels.

Hydrocarbons, C10 aromatics:

Discussion on absorption rate:

There have not been any dermal absorption studies of C10 aromatics, but there have been studies of some of the constituents, particularly naphthalene and methyl naphthalenes.  Due to the structural similarity of these molecules to other constituents of the C10 aromatics, it seems reasonable to assume that the solvents would have toxicokinetic properties similar to those of these constituents.  

 

ANIMAL DERMAL ABSORPTION DATA - IN VITRO DATA

 

Perfused porcine skin flaps were used to determine the absorption and disposition of naphthalene. Naphthalene absorption had a clear peak absorptive flux at less than 1h and the absorption was (mean +/- SEM; % dose) naphthalene (1.17 +/-0.07).  The area under the curve (AUC) was determined to be (mean +/- SEM; % dose-h/mL): naphthalene (0.0199 +/- 0.0020). In contrast, deposition within dosed skin showed the reverse pattern.

 

HUMAN DERMAL ABSORPTION DATA

 

SKIN PENETRATION: The slopes of the curves for aromatic compounds began to decrease at 120 min but did not reach zero. The apparent Kp was calculated for each volunteer and component of JP-8, assuming the absorbed compounds were restricted to the blood compartment in the body. The mean apparent Kp in decreasing order is naphthalene > 1-methyl naphthalene = 2-methyl naphthalene. A Student's t- test for comparison of the apparent Kp estimates for 1-methyl naphthalene and 2-methyl naphthalene showed no statistically significant difference (p > 0.05).  The apparent permeability coefficients (cm/h) of aromatic hydrocarbons were determined to be: Naphthalene 5.3E-05; 1-Methyl naphthalene 2.9E-05; 2-Methyl naphthalene 3.2 E-05.

 

COMPARISON TO IN VITRO STUDIES: This study, conducted with human subjects, indicates that permeability coefficients estimated in vitro may overestimate the internal dose of various components of JP-8. To illustrate, the Kp values determined from rat skin, pig skin, and this study to estimate the internal dose of naphthalene: Mrat = 1.29 mg, Mpig = 0.53 mg, and Mhuman = 0.13 mg.  The Kp from rat skin overestimates human internal dose by a factor of 10, and the Kp from pig skin by a factor of 4.

 

MODEL: A mathematical model was developed to describe the diffusion coefficients (Dsc) of aromatic hydrocarbons. The diffusion coefficients (Dsc, cm2/min x 10^-8) of aromatic hydrocarbons were determined to be: Naphthalene 4.2+/-1.4; 1-Methyl naphthalene 4.6 +/-2.7; 2-Methyl naphthalene 4.5+/-2.6.

 

OVERVIEW OF PERCUTANEOUS ABSORPTION OF HYDROCARBON SOLVENTS

 

There are no studies of repeated dose toxicity of hydrocarbon solvents using the dermal route of administration. Accordingly, where it is necessary to calculate dermal DNELs, systemic data from studies utilizing other routes of administration, normally inhalation but also oral data, can be used in some situations. In accordance with ECHA guidance, read across from oral or inhalation data to dermal should account for differences in absorption where these exist (R8, example B.6). In fact, hydrocarbon solvents are poorly absorbed in most situations, in part because some are volatile and do not remain in contact with the skin for long periods of time and also because, due to their hydrophobic natures, do not partition well into aqueous environments and are poorly absorbed into the blood. 

 

If these differences in relative absorption are introduced into the DNEL calculations to calculate external doses, the DNELs based on systemic effects are highly inflated. This seems potentially misleading as it implies that substances have different intrinsic hazards when encountered by different routes whereas in fact the differences are due ultimately to differences in absorbed dose. Accordingly, it is our opinion that it would be more transparent if the differences in absorption were taken into account in the exposure equations rather than in DNEL derivation. 

 

Shown below is a compilation of percutaneous absorption information for a number of hydrocarbon solvent constituents covering carbon numbers ranging from C5 to C14 as well as examples of both aliphatic and aromatic constituents. The low molecular weight aliphatic hydrocarbons (n-pentane, 2-methylpentane, n-hexane, n-heptane, and n-octane) were tested by Tsuruta (1982) using rat skin in an in vitro model system. As shown (Table 1), the highest percutaneous absorption value was 2 ug/cm2/hr for pentane. Lower values (< ~ 1 ug/cm2/hr) were reported for aliphatic hydrocarbons ranging from hexane to octane. Several authors have assessed the percutaneous absorption of higher molecular weight aliphatic constituents including Baynes et al. (2000), Singh and Singh (2003), Muhammad et al. (2005), and Kim et al., (2006). The first three of these authors used porcine skin models and reported that, except for one anomalous result with tridecane, the percutaneous absorption values for aliphatic constituents ranging from nonane to tetradecane were well below 1 ug/cm2/hr. Rat and human skin are considered to be more permeable than human skin (Kim et al., 2006), so these numbers can be considered conservative. 

 

Kim et al. (2006) reported results of percutaneous absorption studies with human skin under in vivo conditions. In this case, the assessment method was based on tape stripping. The authors reported percutaneous absorption values ranging from 1 – 2 ug/kg/day for decane, undecane and dodecane. These values are higher than those reported by other authors, most likely because this technique measures absorption into the skin but not through the skin as was done in the studies listed above. Accordingly, it seems likely that these numbers are conservative as well.

 

With respect to aromatic hydrocarbons, most of the reported percutaneous absorption values [Baynes et al. (2000); Singh and Singh (2003); Mohammad et al. (2005); and Kim et al. (2006)] are less than 2 ug/cm2/day. The only exceptions are the values for naphthalene from Mohammad et al. (2005) which range from 4.2-6.6 ug/cm2/hr. 

 

After considering all of the above, it seems reasonable to assume apparent that across the entire range of hydrocarbon solvent constituents, percutaneous absorption values are less than 2 ug/cm2/day. Accordingly, when systemic dermal DNELs are calculated using route to route extrapolations, the values will not be corrected for differences in absorption. Rather, 2 ug/cm2/hr will be used as a common percutaneous absorption rate for all hydrocarbon solvents for which dermal exposure estimates are provided. 

           

Table 1: Summarized information on percutaneous absorption of hydrocarbon solvent constituents (C5-C16). 

Constituent

Molecular Weight

nmol/min/cm2

nmol/hr/cm2

µg/cm2/hr

Reference

Aliphatic Constituents

Pentane

72

0.52

31.2

2.2

Tsuruta et al. 1982

 

2-methyl pentane

86

0.02

1.2

0.1

Tsuruta et al. 1982

 

n-hexane

86

0.02

0.6

0.5

Tsuruta et al. 1982

 

n-heptane

100

0.02

1.2

0.1

Tsuruta et al. 1982

 

n-octane

114

0.08 x 10-3

0.005

0.0005

Tsuruta et al. 1982

 

Nonane

128

 

 

0.03

Muhammad et al., 2005

 

Nonane

 

 

 

0.38

McDougal et al., 1999

 

Decane

142

 

 

2

Kim et al., 2006

 

Decane

 

 

 

1.65

McDougal et al., 1999

 

Undecane

156

 

 

0.06-0.07

 

Muhammad et al., 2005

 

Undecane

 

 

 

1.0

Kim et al., 2006

 

Undecane

 

 

 

1.22

McDougal et al., 1999

 

Dodecane

170

 

 

0.02-0.04

Muhammad et al., 2005

 

Dodecane

 

 

 

2

Kim et al., 2006

 

Dodecane

 

 

 

0.3

Singh and Singh, 2003

 

Dodecane

 

 

 

0.51

McDougal et al., 1999

 

Dodecane

 

 

 

0.1

Baynes et al. 2000

 

Tridecane

184

 

 

0.00-0.02

Muhammad et al., 2005

 

Tridecane

 

 

 

2.5

Singh and Singh, 2003

 

Tridecane

 

 

 

0.33

McDougal et al., 1999

 

Tetradecane

198

 

 

0.3

Singh and Singh, 2003

 

Hexadecane

 

 

7.02 x 10E-3

0.00004

 

Singh and Singh, 2002

Aromatic Constituents

Trimethyl benzene

120

 

 

0.49-1.01

Muhammad et al., 2005

 

Trimethyl benzene

 

 

 

1.25

McDougal et al., 1999

 

Naphthalene

 

128

 

 

6.6-4.2

Muhammad et al., 2005

 

Naphthalene

 

 

 

0.5

Kim et al., 2006

 

Naphthalene

 

 

 

1.4

Singh and Singh 2002

 

Naphthalene

 

 

 

1.8

Baynes et al. (2000)

 

Naphthalene

 

 

 

1.0

McDougal et al., 1999

 

1 methyl naphthalene

142

 

 

0.5

Kim et al., 2006

 

Methyl naphthalene

 

 

 

1.55

McDougal et al., 1999

 

2-methyl naphthalene

 

 

 

0.5

Kim et al., 2006

 

2-methyl naphthalene

 

 

 

1.1

Singh and Singh, 2002

 

Dimethyl naphthalene

156

 

 

0.62-0.67

Muhammad et al., 2005

 

Dimethyl naphthalene

 

 

 

0.59

McDougal et al. 1999

 

Table 2. Estimated percentages of various hydrocarbon solvent constituents absorbed

 

Based on the information provided below, an overall estimate of 1% for all hydrocarbon solvents seems reasonable. 

 

Category

Representative Substance

Estimate of Percent absorption

Proposal for category

Reference for percent value

 

1

 

Trimethyl benzene

0.2%

0.2%

Based on data in Muhammad et al. (2005)

 

2

Naphthalene

1.2%

1.2%

Riviere et al. 1999

 

3

Dodecane (75%)

0.63%

0.5%

Riviere et al., 1999

 

TMB (25%)

0.2%

 

Muhammad et al., 2005

 

4

Hexadecane (70%)

0.18%

0.5%

Riviere et al., 1999

 

Naphthalene (30%)

1.2%

 

Riviere et al., 1999

 

5

Pentane

?

 

 

 

6

Hexane

?

 

 

 

7

Heptane

0.14%

0.14%

Singh et al. 2003

 

8

Dodecane

0.63%

0.63%

Riviere et al. 1999

 

 

 

 

 

9

Hexadecane

0.18%

0.18%

Riviere et al., 1999

 

Kim, D., Andersen, M., and Nylander-French (2006). Dermal absorption and penetration of jet fuel components in humans. Toxicology Letters 165:11-21.

 

Muhammad, F., N. Monteiro-Riviere, R. Baynes, and J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. Journal of Toxicology and Environmental Health Part A. 68:719-737.

 

Singh Somnath, Zhao Kaidi, Singh Jagdish. (2002). In vitro permeability and binding of hydrocarbons in pig ear and human abdominal skin. Drug and chemical toxicology, (2002 Feb) Vol. 25, No. 1, pp. 83-92.

 

Singh, S. and Singh, J. (2003). Percutaneous absorption, biophysical and macroscopic barrier properties of porcine skin exposed to major components of JP-8 jet fuel. Environmental Toxicology and Pharmacology 14:77-85.

 

Singh, S., Zhao, K., Singh, J. (2003). In vivo percutaneous absorption, skin barrier perturbation and irritation from JP-8 jet fuel components. Drug Chem. Toxicol 26:135-146.

 

McDougal, J., Pollard, D., Weisman, W., Garrett, C., and Miller, T. (2000). Assessment of skin absorption and penetration of JP-8 jet fuel and its components. Toxicological Sciences 25:247-255.

 

Muhammad, F., N. Monteiro-Riviere, R. Baynes, and J. Riviere (2005). Effect of in vivo jet fuel exposure on subsequent in vitro dermal absorption of individual aromatic and aliphatic hydrocarbon fuel constituents. Journal of Toxicology and Environmental Health Part A. 68:719-737.

 

Riviere, J., Brooks, J., Monteiro-Riviere, N., Budsaba, K., and Smith, C. (1999). Dermal absorption and distribution of topically dosed jet fuels jet A, JP-8 andJP-8(100). Toxicology and Applied Pharmacology 160:60-75.

 

Tsuruta, H. et al. (1982). Percutaneous absorption of organic solvents III. On the penetration rates of hydrophobic solvents through the excised rat skin. Industrial Health 20:335-345.