Naphthalene

Dermal absorption

Administrative data

Endpoint:

dermal absorption in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Well performed study reported in detail, based on scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

publication

Title:

A Comparative Study of the Kinetics and Bioavailability of Pure and Soil-Adsorbed Naphthalene in Dermally Exposed Male Rats

Author:

Turkall RM, Skowronski GA, Kadry AM, Abdel-Rahman MS

Year:

1994

Bibliographic source:

Arch. Environ. Contam. Toxicol. 26, 504-509 (1994)

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 427 (Skin Absorption: In Vivo Method)

Deviations:

not specified

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Naphthalene

EC Number:

202-049-5

EC Name:

Naphthalene

Cas Number:

91-20-3

Molecular formula:

C10H8

IUPAC Name:

naphthalene

Details on test material:

- Name of test material (as cited in study report): Naphthalene (1,4,5,8-14C)
- Source: Custom synthesized by E.I. DuPont de Nemours and Co., Inc., New England Nuclear (NEN) Research Products (Boston, MA)
- Substance type: Organic, aromatic hydrocarbon
- Physical state: Solid
- Radiochemical purity (if radiolabelling): 99%.
- Specific activity (if radiolabelling): 15 mCi/mmol
- Locations of the label (if radiolabelling): C1,4,5 and 8
- Other: Prior to use, the radioisotope was diluted with pure ethyl alcohol, dehydrated U.S.P. (U.S. Industrial Chemicals Co., Division of National Distillers and Chemical Corp., NY) to reduce the specific activity to a workable range.

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Taconic Farms (Gerrnantown, NY)
- Weight at study initiation: 275-300 g
- Housing: Animals were housed three per cage
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): Ralston Purina rodent lab chow (St. Louis, MO) ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: at least 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Constant temperature (23-25°C)
- Humidity (%): Constant and humidity (50-55%)
- Photoperiod (hrs dark / hrs light): 12 h light/dark cycle

Administration / exposure

Type of coverage:

occlusive

Vehicle:

ethanol

Duration of exposure:

48 h

Doses:

225 µl of an ethanol solution of 14C-naphthalene (5 µCi). The applied chemical dose was 3.3 µg naphthalene/cm2 skin surface area.

No. of animals per group:

five to eight

Control animals:

no

Details on study design:

A shallow glass cap (Q Glass Company, Towaco, N J) circumscribing a 13-cm2 area was tightly fixed with Lang's jet liquid acrylic and powder (Lang Dental Manufacturing Co., Inc, Chicago, IL) on the lightly shaved right costoabdominal region of each ether-anesthetised animal 0.5 hour prior to the administration of naphthalene. Care was taken to prevent any abrasion of the skin during shaving and cap attachment. The glass cap was attached immediately after shaving the animal and remained on the rat for the duration of the study. Then 225 µl of an ethanol solution of 14C-naphthalene (5 µCi) was introduced by syringe through a small opening in the cap which was immediately sealed. The applied chemical dose was 3.3 µg naphthalene/cm2 skin surface area.

In the absorption and elimination studies, each treatment group contained five to eight rats. Heparinised blood samples were collected by cardiac puncture under light ether anaesthesia at selected time points up to 48 h after treatment. Samples were processed, and radioactivity was measured by liquid scintillation spectrometry.

Groups of six rats each were administered pure naphthalene as described above. Animals were housed in all-glass metabolism chambers (Bio Serv Inc, Frenchtown, NJ) for the collection of expired air, urine, and faecal samples. Expired air was passed through activated charcoal tubes (SKC Inc., Eighty Four, PA) for the collection of the parent compound, then bubbled through traps filled with ethanolamine-ethylene glycol monomethyl ether (1:2, v/v) for the collection of 14CO2. All excreta were collected up to 48 h after administration of compound. Charcoal was extracted with toluene, while faecal samples were homogenised in deionised water. Aliquots of the charcoal extracts, ethanolamine-ethylene glycol monomethyl ether mixture, faecal homogenates, and urine were dispensed directly into Aquasol-2 (NEN) for analysis. At the conclusion of the excretion studies, whole blood was collected from the rats, after which they were sacrificed by an overdose of ether. Prior to removing the glass caps from the rats, the surface of the treated skin area was washed with ethyl alcohol to determine the percentage of radioactivity remaining on the skin application sites. Two to three mL of ethyl alcohol was introduced into the glass cap, and the animals were rotated from side to side. Aliquots of ethanol wash were removed from the skin and radioactivity counted. Glass caps were removed from the skin, and the following tissues excised and weighed: brain, thymus, thyroid, esophagus, stomach, duodenum, ileum, lung, pancreas, adrenal, testes, skin, fat, carcass, bone marrow, liver, kidney, spleen, and heart. Radioactivity was determined in the skin application site and in the untreated skin of the rat (left side). Three areas of fat were examined: namely, fat beneath treated or untreated skin and subrenal fat. Samples were processed, and radioactivity was quantitated as previously reported.

Results and discussion

Signs and symptoms of toxicity:

not examined

Remarks:

not relevant

Dermal irritation:

not examined

Remarks:

not relevant

Absorption in different matrices:

after 48 h:
- Skin test site
- Skin, untreated site:
- Blood:
- Urine: 70.3%
- Faeces: 3.7%
- Expired air (if applicable): 13.6%

Total recovery:

- Total recovery: 87% after 48 hours

Percutaneous absorption

Percutaneous absorption 1

Dose:

43 µg

Parameter:

percentage

Absorption:

87.6 %

Remarks on result:

other: 48 h

Remarks:

Basis for absorption is excretion during 48 hours after start of exposure

Percutaneous absorption 2

Dose:

43 µg

Parameter:

percentage

Absorption:

78 %

Remarks on result:

other: 24

Remarks:

Basis for absorption is excretion during 24 hours after start of exposure

Conversion factor human vs. animal skin:

not applicable

Any other information on results incl. tables

Plasma half-lives of radioactivity in male rats following dermal exposure to ¹⁴C-naphthalene were 2.1 h for absorption and 12.8 h for elimination. The major excretion route of radioactivity in male rats dermally exposed to naphthalene was via the urine. Approximately 50% of the radioisotope was recovered in the urine within 12 h of dosing. Another 20-25% of the dose was collected between 12 and 24 h (urinary excretion during the 0-24 h collection period 63%). Expired air was the secondary route of excretion (13.6% of the initial dose). The percentage of the administered dose expired as CO₂ was less than 0.02%. Tissue distribution studies 48 h post-administration of naphthalene revealed that skin application sites contained the highest tissue concentrations of radioactivity with lesser concentrations determined in ileum, duodenum, and kidney. The major metabolite found in the urine of all naphthalene treated groups was 2,7-dihydroxynaphthalene followed by 1,2- dihydroxynaphthalene. Lower concentrations of 1,2-naphthoquinone, 1- and 2-naphthol, and two undetermined compounds were observed. Less than 0.5% of the parent compound was identified.

Applicant's summary and conclusion

Conclusions:

Results demonstrate that pure naphthalene applied dermally is absorbed relatively quickly into the plasma and is rapidly excreted into the urine.

Executive summary:

Turkall et al. (1994) utilised pharmacokinetic techniques to assess the bioavailability of naphthalene following dermal

treatment of male Sprague Dawley rats. Animals were exposed to 43 µg total of ¹⁴C-naphthalene introduced into a shallow glass cap covering a 13-cm² area on the skin of each rat. Plasma half-lives of radioactivity in male rats following dermal exposure to ¹⁴C-naphthalene were 2.1 h for absorption and 12.8 h for elimination. Plasma concentration reached a maximum 4 hours after start of exposure. The major excretion route of radioactivity in male rats dermally exposed to naphthalene was via the urine. Approximately 50% of the radioisotope was recovered in the urine within 12 h of dosing. Another 20-25% of the dose was collected between 12 and 24 h (urinary excretion during the 0-24 h collection period 63%). Expired air was the secondary route of excretion (13.6% of the initial dose). However, the percentage of the administered dose expired as CO₂ was less than 0.02%. Tissue distribution studies 48 h post-administration of naphthalene revealed that skin application sites contained the highest tissue concentrations of radioactivity with lesser concentrations determined in ileum, duodenum, and kidney. The major metabolite found in the urine of all naphthalene treated groups was 2,7-dihydroxynaphthalene followed by 1,2- dihydroxynaphthalene. Lower concentrations of 1,2-naphthoquinone, 1- and 2-naphthol, and two undetermined compounds were observed. Less than 0.5% of the parent compound was identified.

Results demonstrate that pure naphthalene applied dermally absorbs relatively quickly into plasma. Naphthalene-derived radioactivity was rapidly excreted in urine. Between 70% and 87% of absorbed radioactivity was excreted as urinary metabolites, but another 6-14% was exhaled as parent compound.