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EC number: 919-284-0 | CAS number: -
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
Administrative data
Link to relevant study record(s)
- Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- 2009
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Acceptable well-documented study reports which meet 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
- Objective of study:
- metabolism
- Principles of method if other than guideline:
- This is a review article that compiles data from many studies.
- GLP compliance:
- not specified
- Species:
- other: various
- Strain:
- not specified
- Sex:
- not specified
- Route of administration:
- other: various
- Vehicle:
- not specified
- Control animals:
- not specified
- Metabolites identified:
- not specified
- Conclusions:
- Interpretation of results: low bioaccumulation potential based on study results
- Executive summary:
The first step in the metabolism of methylnaphthalenes can occur either via ring epoxidation or via oxidation of the methyl side chain to generate an alcohol. Both processes are catalyzed by the cytochrome P450 monooxygenases. Investigators showed that the most catalytically active proteins involved in naphthalene metabolism (as assessed by Vmax/Km) were CYP1A2 and CYP2E1. CYP1A2 is localized primarily in the liver whereas CYP2E1 is found in a number of organs including respiratory tissue. More recent investigations have shown that CYP2A13 metabolizes naphthalene with relatively high turnover and low Km. Since this protein is expressed in human lung, albeit with a high degree of variability, it is a potential candidate for catalyzing the initial metabolism of naphthalene in human respiratory tissue.
Other data available come from work conducted with a single recombinant protein, CYP2F2. Although this protein appears to be abundant in airways of the mouse, available evidence suggests that the rat and Rhesus macaque orthologues are present in far smaller amounts in the lung. This protein metabolizes naphthalene, 2-methylnaphthalene and 1-nitronaphthalene, all with relatively low Km and high Vmax, and, based on inhibition studies with 5-phenyl-1-pentyne, appears to play a major role in the epoxidation of closely related substrates, i.e. styrene. These data suggest that this protein plays a quantitatively important role in the metabolic activation of these substrates at least in the mouse. The presence of large quantities of this protein in target cells may explain the species differences in susceptibility to naphthalene and 2-methylnaphthalene in mouse but not in rat.
Urinary Metabolites. The most prominent metabolites isolated in rat urine after treatment with low doses of 2-methylnaphthalene originated from initial oxidation of the parent hydrocarbon on the methyl moiety. Thirty to thirty-five percent of a dose of 14C-2-methylnaphthalene was recovered as a glycine conjugate of 2-naphthoic acid. Six to eight percent of the dose was represented by dihydrodiols and 3-5% of the dose was recovered as parent hydrocarbon. Other polar metabolites appeared to account for 35-45% of the radioactivity in the urine. Later work, showed that approximately 75% of the radioactive metabolites eliminated in the urine of guinea pigs administered a low dose of 3H-2-methylnaphthalene resulted from oxidation of the methyl group. These metabolites included free naphthoic acid, the glucuronide of naphthoic acid as well as the glycine conjugate. In these studies, a cysteine derivative, accounting for approximately 10% of the total urinary radioactivity, was reported in the urine. Finally, small percentages of sulfate and glucuronide conjugates of 8-hydroxy-2-methylnaphthalene (<10% of total urinary radioactivity) were measured.
More recent studies on the disposition and metabolism of 3H-1,2-dimethylnaphthalene (28 mg/kg) in rats showed that the radioactive parent compound was rapidly absorbed after ip administration, reaching peak levels within 4 h. Sixty-five percent of the administered radioactivity was recovered in the excreta within 24 h, with roughly equal amounts eliminated in the urine and feces. Greater than 95% of the administered radioactivity was recovered in the excreta within 72 h of administration. The highest tissue concentrations of radioactivity were observed in fat, but these fell rapidly to very low levels within 48 h. This compound apparently distributes rapidly to the fat but redistributes easily due to the rapid clearance of the compound. Urinary metabolites were identified in ether extracts of acidified (pH 1) urine. The parent compound (representing roughly 30% of the ether-extractable metabolites from urine), several dimethylthionaphthols, at least 2 dimethylmethylthionaphthalene derivatives as well as several derivatives generated from oxidation of the methyl groups to the alcohol and subsequently to the acid were measured in the urine following dimethylnaphthalene administration. The most prominent metabolites were the dimethylthionaphthol derivatives and the metabolites generated from side chain oxidation. It is noted that the 30% of the radioactivity unextracted by ether at pH 1may include a number of conjugated metabolites including glucuronides, sulfates and mercapturic acids. The results from more recent studies of the metabolism and distribution of radioactivity from 3H-1,4-dimethylnaphthalene and 1,6-dimethylnaphthalene are nearly identical to those with the 1,2-dimethylnaphthalene derivative. Again, radioactivity is rapidly absorbed reaching peak plasma concentrations within 4 h of administration. Metabolites which were derived from both oxidation of the methyl groups and the aromatic nucleus were isolated from the urine of treated rats.
These metabolites included methylnaphthoic acid as well as the intermediates leading to this derivative (methylhydroxymethyl, methylnaphthaldehyde). Trace quantities of a methylthio metabolite were observed; these metabolites have been measured in the urine of naphthalene-treated rodents as well.
- Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Study period:
- N/A
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: The documentation is from secondary literature.
- 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
- Objective of study:
- toxicokinetics
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 417 (Toxicokinetics)
- Principles of method if other than guideline:
- Biotransformation of 1,4-diethenylbenzene in rat was studied.
- GLP compliance:
- not specified
- Radiolabelling:
- not specified
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Control animals:
- no
- Metabolites identified:
- yes
- Details on metabolites:
- Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol
- Conclusions:
- Interpretation of results: low bioaccumulation potential based on study results
- Executive summary:
Biotransformation of 1,4-diethenylbenzene in rat was studied. Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol, were isolated and identified by n.m.r. and mass spectrometry. GC-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid, 4-ethenylphenylacetylglycine, 4-ethenylmandelic acid, and 4-ethenylphenylglyoxylic acid. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1,4-diethenylbenzene is 4-ethenylphenyloxirane. The first step in the biotransformation of 1,4-diethenylbenzene is the formation of an oxirane. Subsequent steps lead to oxidation of the second ethenyl group leading to the aldehyde N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine metabolite. Rats dosed with a single i.p. dose excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).
- Endpoint:
- basic toxicokinetics
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 4 (not assignable)
- Rationale for reliability incl. deficiencies:
- other: The documentation is from secondary literature.
- 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 417 (Toxicokinetics)
- Principles of method if other than guideline:
- The metabolism of p-tert-butyltoluene (TBT) was studied in the rat and guinea pig.
- GLP compliance:
- not specified
- Radiolabelling:
- not specified
- Species:
- rat
- Strain:
- not specified
- Sex:
- not specified
- Route of administration:
- oral: gavage
- Vehicle:
- not specified
- Control animals:
- no
- Metabolites identified:
- yes
- Details on metabolites:
- The major urinary metabolites in rats were p-tert-butylbenzoic acid and its alcohol derivative 2-(p-carboxyphenyl)-2-methylpropan-1-ol whereas p-tert-butylbenzoylglycine was the most prominent metabolite in guinea pig urine.
- Conclusions:
- Interpretation of results: low bioaccumulation potential based on study results
- Executive summary:
The metabolism of p-tert-butyltoluene (TBT) was studied in the rat and guinea pig. Both the methyl and the tert.-butyl group were oxidized to alcohol and carboxylic acid derivatives in these species. The major urinary metabolites in rats were p-tert-butylbenzoic acid and its alcohol derivative 2-(p-carboxyphenyl)-2-methylpropan-1-ol whereas p-tert-butylbenzoylglycine was the most prominent metabolite in guinea pig urine. No significant differences in metabolism were found when TBT was given intragastrically or by inhalation. The intragastric administration of 14C-TBT to rats showed that the bulk of the excretion of radioactivity occurred within three days. A recovery of 83% was achieved and the ratio of urinary/faecal radioactivity was roughly 3.5:1.
- Endpoint:
- basic toxicokinetics in vivo
- Data waiving:
- study scientifically not necessary / other information available
- Justification for data waiving:
- other:
- Endpoint:
- dermal absorption
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- 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 vitro / ex vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- 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
- 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:
- read-across from supporting substance (structural analogue or surrogate)
- 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:
- Endpoint:
- dermal absorption in vivo
- Type of information:
- read-across from supporting substance (structural analogue or surrogate)
- 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.
Referenceopen allclose all
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).
Description of key information
Short description of key information on
bioaccumulation potential result:
C10-C12 Aromatic hydrocarbon fluids can be absorbed when inhaled or
ingested. C10-C12 Aromatic hydrocarbon fluids are poorly absorbed
dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total applied fluid. Regardless of exposure route, C10-C12 Aromatic hydrocarbon fluids are typically metabolized by side chain oxidation to alcohol and carboxylic acid derivatives. These metabolites can be glucuronidated and excreted in the urine or further metabolized before being excreted. The majority of the metabolites are excreted in the urine and to a lower extent, in the feces. Excretion is rapid with the majority of the elimination occurring within the first 24 hours of exposure. Due to the rapid excretion, bioaccumulation of the test substance in the tissues is not likely to occur.
Short description of key
information on absorption rate:
C10-C12 Aromatic fluids are poorly absorbed dermally with an estimated
overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1%
of the total fluid applied. When dermally absorbed, C10-C12 Aromatics
are rapidly eliminated.
Key value for chemical safety assessment
Additional information
C10-C12 Aromatic fluids are readily absorbed when inhaled or ingested. C10-C12 Aromatic fluids are poorly absorbed dermally with an estimated overall percutaneous absorption rate of approximately 2ug/cm2/hr or 1% of the total fluid volume. Bioaccumulation of C10-C12 Aromatic fluids is not expected.
Discussion on bioaccumulation potential result:
There have not been any toxicokinetic studies of C10-C12 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-C12 Aromatics, it seems reasonable to assume that the solvents would have toxicokinetic properties similar to those of these constituents.
Biotransformation of 1,4-diethenylbenzene in rat was studied. Nine urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine, N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine, 1-(4-ethenylphenyl)ethane-1,2-diol, 4-ethenylbenzoic acid, 4-ethenylbenzoyl-glycine, 1-ethenyl-4-(1-hydroxyethyl)benzene, 4-(1,2-dihydroxyethyl)benzoic acid, (4-carboxymethylphenyl)acetylglycine, N-acetyl-S-[2-carboxy-1-(4-ethenylphenyl)ethyl]-L-cysteine, and two isomeric beta-D-glucosiduronates derived from 1-(4-ethenylphenyl)ethane-1,2-diol, were isolated and identified by n.m.r. and mass spectrometry. GC-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid, 4-ethenylphenylacetylglycine, 4-ethenylmandelic acid, and 4-ethenylphenylglyoxylic acid. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1,4-diethenylbenzene is 4-ethenylphenyloxirane. The first step in the biotransformation of 1,4-diethenylbenzene is the formation of an oxirane. Subsequent steps lead to oxidation of the second ethenyl group leading to the aldehyde N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine metabolite. Rats dosed with a single i.p. dose excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).
The metabolism of p-tert-butyltoluene (TBT) was studied in the rat and guinea pig. Both the methyl and the tert.-butyl group were oxidized to alcohol and carboxylic acid derivatives in these species. The major urinary metabolites in rats were p-tert-butylbenzoic acid and its alcohol derivative 2-(p-carboxyphenyl)-2-methylpropan-1-ol whereas p-tert-butylbenzoylglycine was the most prominent metabolite in guinea pig urine. No significant differences in metabolism were found when TBT was given intragastrically or by inhalation. The intragastric administration of 14C-TBT to rats showed that the bulk of the excretion of radioactivity occurred within three days. A recovery of 83% was achieved and the ratio of urinary/faecal radioactivity was roughly 3.5:1.
As summarized in the ATSDR toxicological profile, naphthalene (NAP), 1-methylnaphthalene (1-MN) and 2-methylnaphthalene (2-MN) are well absorbed if ingested. As one example, at least 80% of an oral dose of 2-MN was absorbed within 24 hours of oral administration to guinea pigs (Teshima et al., 1983). Conversely, it is believed that only limited absorption occurs following dermal contact. Riviere et al. (1999) for example, reported that 1.17 + 0.07% of the naphthalene content of a sample of jet fuel A (Jet-A) was percutaneously absorbed in a porcine skin flap model. Further studies by the same group (Baynes, et al., 2000) reported flux values ranging from approximately 1-2 ug/cm2/hr. Subsequent work by Singh and Singh (2003) reported a value of approximately 1 nmol/cm2/hr or approximately 0.1 ug/cm2/hr. Kim et al. (2006) reported values of approximately 300-500 ng/cm2/hr for NAP, 1-MN and 2-MN from a study utilizing human volunteers. Of these, the report by Kim et al. (2006) is probably the most reliable as it came from direct human measurements; reassurance is provided by the similar estimates obtained by other experimental techniques. The potential for systemic doses from inhalation exposures is unknown.
Once absorbed, naphthalenes are distributed to the principal organs.
Naphthalene is metabolized by side chain oxidation, leading to the formation of mono- or di-alcohols. These can be glucuronidated and excreted in the urine or further metabolized to quinones which are then further metabolized before being excreted. The methyl naphthalenes are preferentially metabolized by side chain oxidation to form naphthoic acids although ring oxidation can also occur. As with naphthalene, these species or their subsequent metabolites are generally glucuronidated and excreted in the urine. The majority of administered material is excreted within about 24 hours, principally as urinary metabolites.
Teshima R, Nagamatsu K, Ikebuchi H, et al. 1983. In vivo and in vitro metabolism of 2-methylnaphthalene in the guinea pig. Drug Metab Dispos 11(2):152-157.
Kim, D., Andersen, M., and Nylander-French, L. (2006). Dermal absorption and penetration of jet fuel components in humans. Toxicology Letters 165:11-21.
Baynes, R., Brooks, J., and Riviere, J. (2000). Membrane transport of naphthalene and dodecane in jet fuel mixtures. Toxicology and Industrial Health 16:225-238.
Riviere, J., Brooks, J., Monteiro-Riviere, N., Budsaba, K., and Smith, C. (1999). Dermal absorption and distribution of topically dosed jet fuelsJet-A, JP-8 and JP-8(100). Toxicology and Applied Pharmacology 160:60-75.
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.
Discussion on absorption rate:
There have not been any dermal absorption studies of C10-C12 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-C12 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 coefficient (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 |
ug/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.
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