Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Remarks:

peer-reviewed data

Principles of method if other than guideline:

Review evaluating peer-reviewed data

Type:

absorption

Results:

PAH are absorbed through the pulmonary tract, the gastrointestinal tract, and the skin. Absorption rate from lung depends on type of PAH. Gastrointestinal absorption is rapid in rodents with metabolites returning to the intestine via biliary excretion.

Type:

distribution

Results:

PAH are widely distributed throughout the organism after administration by any route and are found in almost all internal organs, but particularly those rich in lipids.

Type:

metabolism

Results:

Metabolism is via intermediary epoxides which are further transformed by rearrangement or hydration to phenols or dihydrodiols. Secondary oxidation yield tetrols. Hydroxylated metabolites can be conjugated with sulphuric or glucuronic acid or glutathione.

Type:

excretion

Results:

PAH metabolites and their conjugates are excreted via the urine and faeces. Conjugates may be hydrolysed by gut flora after biliary excretion and be reabsorbed. With increasing size, excretion into faeces increases. PAH seem not to persist in the body.

Reference 2

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline available

Principles of method if other than guideline:

Skin model/in-vitro blood perfusion model: by de Lange et al. 1991, J. Pharmacol. Toxicol. Methods 27, 71-77

GLP compliance:

no

Specific details on test material used for the study:

- Name of test material (as cited in study report): coal tar
- Physical state: liquid, viscous

Radiolabelling:

no

Species:

pig

Strain:

other: domestic

Sex:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Slaughterhouse: no details
- Weight at study initiation: 75 – 100 kg

Type of coverage:

open

Vehicle:

unchanged (no vehicle)

Duration of exposure:

average perfusion time: 250 min

Doses:

~11 mg tar/cm² [100 %]
=================================================================
Substance: Content in coal tar [%] / Single PAH dose [µg/cm2];
fluorene: 2.1 / 230
phenanthrene: 6.8 / 750
anthracene: 3.7 / 410
fluoranthene: 4.0 / 440
pyrene: 2.1 / 230
benzo[b]fluoranthene: 0.9 / 90
benzo[k]fluoranthene: 0.4 / 44
benzo[a]pyrene: 0.9 / 90
indeno[123-cd]pyrene: 0.6 / 66
dibenz[ah]anthracene: 0.4 / 44

Total: ~22 % / ~2400 µg/cm2
===================================================================

No. of animals per group:

5 pig ears per treatment

Control animals:

no

Details on study design:

DOSE PREPARATION
not applicable, neat substance tested

APPLICATION OF DOSE: topical to the ear

VEHICLE: not applicable

TEST SITE
- Preparation of test site: no particular action
- Area of exposure: 6 x 4 cm²
- Type of cover / wrap if used: none

REMOVAL OF TEST SUBSTANCE
- Perfusion: until perfusion pressure became too high (> 70 mm Hg), max. 250 min.
- Removal of protecting device: not relevant
- Washing procedures and type of cleansing agent: not relevant, termination of test
- Time after start of exposure: max. 250 min

SAMPLE COLLECTION
- Collection of blood: 200 min, for pyrene: complete kinetics with 10 – 11 time intervals up to 200 – 250 min

ANALYSIS
- Blood samples (10 ml): Reversed-phase HPLC after 3-fold extraction with n-hexane, evaporation of the solvent and re-dissolution of the residues in methanol (2 ml)
- Limits of detection and quantification: see above under Test material
- The method for analysis of the 10 PAHs has an average coefficient of variation of 14.4 %.
- Recovery ranged from 45 % for dibenzo[a]anthracene to 97 % for anthracene.
- Limits of detection:
[pmol/ml blood]
===============================
fluorene 53.0
phenanthrene 1.7
anthracene 2.0
fluoranthene 51.0
pyrene 2.7
benzo[b]fluoranthene 7.8
benzo[k]fluoranthene 0.3
benzo[a]pyrene 6.3
indeno[123-cd]pyrene 8.3
dibenzo[ah]anthracene 16.5
===============================

STATISTICS:
Paired t-test to determine whether the dermal absorption of the various PAH was statistically different from pyrene absorption.

Details on in vitro test system (if applicable):

In-vitro blood perfusion model:
Five ears from domestic pigs were used to study the uptake of 10 PAH in blood after coal-tar application.
The treatment started after 30 min pre-perfusion with oxygenated blood. Perfusion at 30 °C with heparinized pig blood collected from the pigs.
Coal tar was applied to a skin area of 6x4 cm² with an average dose of 11 mg/cm².
Simultaneously, functional control measurements were conducted to assure the physiological integrity of the organ, including blood pressure, blood flow, and glucose uptake.

Total recovery:

see also above "Details of Study Design"
- Limit of detection (LOD): see under "Test materials"

Key result

Time point:

200 min

Dose:

11 mg coal tar (230 µg fluorene)/cm²

Parameter:

rate

Absorption:

ca. 71 other: ng/(h cm²)

Remarks on result:

other: absorption rate for fluoranthene

Key result

Time point:

200 h

Dose:

11 mg coal tar (750 µg phenanthrene)/cm²

Parameter:

rate

Absorption:

ca. 103 other: ng/(h cm²)

Remarks on result:

other: absorption rate for phenanthrene

Key result

Time point:

200 min

Dose:

11 mg coal tar (410 µg anthracene)/cm²

Parameter:

rate

Absorption:

ca. 19.5 other: ng/(h cm²)

Remarks on result:

other: absorption rate for anthracene

Key result

Time point:

200 min

Dose:

11 mg coal tar (440 µg fluoranthene)/cm²

Parameter:

rate

Absorption:

ca. 21 other: ng/(h cm²)

Remarks on result:

other: absorption rate for fluoranthene

Key result

Time point:

200 min

Dose:

11 mg coal tar (230 µg pyrene)/cm²

Parameter:

rate

Absorption:

ca. 12 other: ng/(h cm²)

Remarks on result:

other: absorption rate for pyrene

Key result

Time point:

200 min

Dose:

11 mg coal tar (90 µg benzo[a]pyrene)/cm²

Parameter:

rate

Absorption:

ca. 0.76 other: ng/(h cm²)

Remarks on result:

other: absorption rate for benzo[a]pyrene)

Key result

Time point:

200 min

Dose:

11 mg coal tar (44 µg dibenz[ah]anthracene)/cm²

Parameter:

rate

Absorption:

ca. 0.28 other: ng/(h cm²)

Remarks on result:

other: absorption rate for dibenz[ah]anthracene

Conversion factor human vs. animal skin:

not applicable

Initial absorption rates of 10 PAHs from coal tar applied to the perfused pig ear

 

	Absorption fluxes at 200 min p.a.
	pmol/(h*cm²)	ng/(h*cm²)
Fluorene	430	approx. 71
Phenanthrene	580	approx. 103
Anthracene	110	approx. 19.5
Fluoranthene	105	approx. 21
Pyrene	60	approx. 12
Benzo[b]fluoranthene	3	approx. 0.76
Benzo[k]fluoranthene	1	approx. 0.25
Benzo[a]pyrene	3	approx. 0.76
Indeno[1,2,3-cd]pyrene	1	approx. 0.28
Dibenz[a,h]anthracene	1	approx. 0.28

 

The mean absorption fluxes [pmol/(h*cm2)] at 200 min after application of coal tar varied strongly between the 10 PAH.

 

Furthermore, variation between ears was high, too: for pyrene, for example, the flux ranged between 6 and 155 pmol/(h*cm2) and the cumulative uptake after 200 min was between 26 and 193 pmol/cm2. This was not caused by differences in dosing: applied amounts were high overdoses, because 0.2 % of each PAH was absorbed through the skin after 200 min.

 

The relative cumulative uptake (in relation to pyrene) was 0.01 for indeno[123-cd]pyrene to 12 for phenanthrene, for each PAH except fluoranthene, statistically different from pyrene uptake (p= 0.01). The inter-ear variation was relatively small when the absorbed amount was related to pyrene, indicating that the relative absorption fluxes of the various PAH were quite constant.

Reference 3

Endpoint:

dermal absorption in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 428 (Skin Absorption: In Vitro Method)

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD (1996): Dermal delivery and percutaneous absorption: in-vitro method. OECD guideline for testing chemicals – Proposal for new guideline. OECD, Paris

GLP compliance:

not specified

Specific details on test material used for the study:

Mixtuer of 13 PAH: Composition

Name CAS-No. Mol. Mass Applied dose[nmol/cm2]
=========================================================
Naphthalene 91-20-3 128.2 160.0
Acenaphthene 83-32-9 154.2 120.0
Fluorene 86-73-7 166.2 23.1
Anthracene 120-12-7 178.2 15.1
Phenanthrene 85-01-8 178.2 12.1
Pyrene 129-00-0 202.3 9.3
Benz[a]anthracene 56-55-3 228.3 8.5
Chrysene 218-01-9 228.3 6.5
Benzo[b]fluoranthene 205-99-2 252.3 16.5
Benzo[k]fluoranthene 207-08-9 252.3 6.3
Benzo(a)pyrene 50-32-8 252.3 6.1
Dibenz[a,h]anthracene 191-24-2 278.4 7.5
Benzo[ghi]perylene 53-70-3 276.3 6.9
=======================================================

Radiolabelling:

no

Species:

monkey

Strain:

other: Ceropithecus aetops

Sex:

not specified

Details on test animals or test system and environmental conditions:

Not given, from a medical facility producing poliovirus vaccine

Type of coverage:

open

Vehicle:

other: 1.) Lubricating oil: commercial lubricator for engines (PAHs below detection limits) and 2.) Artificial sweat was simulated by using 2.5 g NaH2PO4, 0.2 g triolein, 2 drops of Tween 85 per 1 litre water, pH 5.2 with HCl

Duration of exposure:

static up to 72 h

Doses:

Mixture of PAH:
==============================
Substance: applied dose [ng/cm²];

Acenaphthene: 18,505;
Fluorene: 3,840;
Anthracene: 2,691;
Phenanthrene: 2,157;
Pyrene: 1,881;
Benz[a]anthracene: 1,940;
Chrysene: 1,484;
Benzo[b]fluoranthene: 4,163;
Benzo[a]pyrene: 1,535;
Dibenz[a,h]anthracene: 2,088;
Benzo[ghi]perylene: 1,906
==============================
Note: In this study additional lower-molecular-weight PAHs have been included not relevant to CTPht, and therefore not listed.

Control animals:

no

Details on study design:

DOSE PREPARATION
- Method for preparation of dose suspensions: 13 PAH were dissolved/dispersed in either aceton or lubricating oil in concentrations that after addition to the diffusion cell, doses was as given under Test material or Doses
- Method of storage:

APPLICATION OF DOSE:
- PAH mixture: 1.) 30 µl PAH acetone solution were placed in the diffusion cell, and the acetone was allowed to evaporate. Then a few drops of artificial sweat were added.
2.) PAH mixture dispersed in lubricating oil was placed into the diffusion cell
TEST SITE
- Preparation of test site:
- Area of exposure: 1.77 cm2

REMOVAL OF TEST SUBSTANCE: diffusion cell was dismantled at the end of the test and the skin sample was disposed as waste

SAMPLE COLLECTION
- Receiving liquid from diffusion cells: ten 1 ml samples were taken after initiation of skin contact at various intervals from 20 min to 72 h (see Report Fig. 1-6)

SAMPLE PREPARATION
- Preparation details: purification of media samples with acetonitrile in the presence of NaCl,

ANALYSIS
- Method type(s) for identification: reverse-phase HPLC; Column: LC-PAH Supelchem column (25 cm long, 4.6 mm i.d., 5 µm grain size), Eluent: acetonitrile-water gradient; Detector: programmable excitation and emission wavelength spectro-fluorimeter Shimadzu RF 551
- Limits of detection [nmol/L]: naphthalene 25.8, acenaphthene 1.67, fluorene 7.5, phenanthrene 2.80, anthracene 0.56, pyrene 0.49, benzo[a]anthracene 1.32, and chrysene 0.45.
- Coeffcient of variation of the analytical method: 10.8 %

Details on in vitro test system (if applicable):

SKIN PREPARATION
- Source and type of skin: Full-thickness skin from abdomen of Ceropithecus aetops
- Membrane integrity check: Barrier integrity of skin specimens was demonstrated by measuring 3H-H2O penetration after treatment with acetone.
- Storage conditions: Skin samples were frozen and stored for a few days.

PRINCIPLES OF ASSAY
- Diffusion cell: Static diffusion cell (FDC 400, Crown Glass, N.J. USA), exposure area 1.77 cm² (diameter 1.5 cm).
- Receptor fluid: (volume not specified): saline/bovine serum albumin solution (4 % BSA) containing gentamycin sulphate as antibiotic.
The PAH mixture was applied
1. in 30 µl acetone followed by addition of artificial sweat after solvent evaporation (6 diffusion cells)
2. in lubricating oil (7 diffusion cells)
- Static system: yes
- Test temperature: diffiusion cell kept at 37 °C resulting in a skin temperature of 32 °C
- Occlusion: no

Dermal irritation:

not examined

Absorption in different matrices:

Kinetic key data from in-vitro studies on monkey skin specimens (exposure medium lubrication oil or artificial sweat/acetone):
==============================
Average steady state absorption rate [ng/(h*cm²)]
------------------------------------------------------------
Lubricating oil / Acetone/sweat

Acenaphthene: 34 / 147;
Fluorene: 6 / 24;
Anthracene: 2.1 / 9.4;
Phenanthrene: 1.0 / 5.7;
Pyrene: 0.3 / 7.8;
Benz[a]anthracene: n.d. / 3.2;
Chrysene: 0.3 / 0.8;
Benzo[b]fluoranthene: n.d. / 0.9;
Benzo[a]pyrene: n.d. / 0.4;
Dibenzo(a,h)anthracene n.d / n.d;.
Results for the additional PAH tested in the study are not reported.
==============================
Absorption percentage of selected components is calculated from steady state absorption rate, exposure time (8 h corresponding to a work shift) and dose.

Key result

Dose:

18.5 µg/cm²

Parameter:

percentage

Absorption:

ca. 6.4 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 3 hrs

Remarks:

substance acenaphthene; absorption from artificial sweat/acetone

Key result

Dose:

3.84 µg/cm²

Parameter:

percentage

Absorption:

ca. 5 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 5 hrs

Remarks:

substance fluorene; absorption from artificial sweat/acetone

Key result

Dose:

2.69 µg/cm²

Parameter:

percentage

Absorption:

ca. 2.8 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 13 hrs

Remarks:

substance anthracene; absorption from artificial sweat/acetone

Key result

Dose:

2.16 µg/cm²

Parameter:

percentage

Absorption:

ca. 2.1 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 11 hrs

Remarks:

substance phenanthrene; absorption from artificial sweat/acetone

Key result

Dose:

1.88 µg/cm²

Parameter:

percentage

Absorption:

ca. 3.3 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 25 hrs

Remarks:

substance pyrene; absorption from artificial sweat/acetone

Key result

Dose:

1.48 µg/cm²

Parameter:

percentage

Absorption:

ca. 0.4 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 24 hrs

Remarks:

substance chrysene; absorption from artificial sweat/acetone

Key result

Dose:

1.54 µg/cm²

Parameter:

percentage

Absorption:

ca. 0.2 %

Remarks on result:

other: absorption period 8 hrs; calculated from steady-state flux after a lag phase of ca. 32 hrs

Remarks:

substance benzo[a]pyrene; absorption from artificial sweat/acetone

TEST RESULTS are expressed as

1.    specific steady-state absorption flux F [nmol/(cm²_*h)],

2.    a penetration constant Kp [cm/h], a dose-independent parameter which results from division of F by the dose and

3.    the lag time [h].

After the lag time, the increase in concentration on the receptor side were nearly linear for some 70 h except for naphthalene, which did not accumulate any more after 30 to 40 h. 

Tab. 1: Kinetic key data from in-vitro studies on monkey skin specimens: specific steady-state absorption flux F [nmol/(cm²_*h)], penetration constant Kp [cm/h],  and the lag time [h]

	Lubricating oil	Acetone/ sweat	Lubricating oil	Acetone/ sweat	Lubricating oil	Acetone/ sweat
	Average steady-state absorption rate [ng/(h*cm^2]		Average Kp [cm/h]		Average lag-time [h]
Naphthalene	35	129	1.87	6.31	4.9	1.2
Acenaphthene	34	147	1.72	7.80	8.4	2.3
Fluorene	6	24	1.64	6.56	5.7	4.2
Anthracene	2.1	9.4	0.93	3.97	17.6	12.9
Phenanthrene	1.0	5.7	0.5	2.63	15.2	11.0
Pyrene	0.3	7.8	0.17	4.13	13.4	24.5
Benz[a]anthracene	n.d.	3.2	n.d.	1.72	--	27.1
Chrysene	0.3	0.8	0.22	0.57	26.1	23.8
Benzo[b]fluoranthene	n.d.	0.9	n.d.	0.09	n.d.	22.5
Benzo[k]fluoranthene	n.d.	0.4	n.d.	0.09	n.d.	23.8
Benzo(a)pyrene	n.d.	0.4	n.d.	0.23	n.d.	31.2
Dibenzo[a,h]anthracene	n.d.	n.d.	n.d.	n.d	n.d.	n.d.
Benzo[ghi]perylene	n.d.	n.d.	n.d.	n.d	n.d.	n.d.
n.d. = not detected in receptor fluid (see Report, Tab. 2 + 3)

PASSAGES estimated from Fig. 1, 2, 4, and 6 and Tab. 1):

	OIL MATRIX	ACETONE/SWEAT
	Passage in % dose after 24 h
Naphthalene^*)	1.5	5
Acenaphthene	2.0	15.0
Fluorene	1.7	10.0
Anthracene	1.2	3.0
Phenanthrene	0.4	2.5
Pyrene	0.5	1.8
Chrysene	0.1	0.25

^*) For naphthalene after 10 h /data from Report, Fig. 1- 4, 6 and 7 and Tab. 1)

The average skin absorption of aromatic components was significantly delayed when incorporated in an oil matrix, at factors from about 3 to 7 for individual substances as compared to application in acetone-artificial sweat solution. For benz[a]anthracene, benzo[b]- and benzo[k]fluoranthene as well as benzo[a]pyrene it was possible to demonstrate a passage through the skin only when applied in acetone/sweat mixture (Report, Tab. 3, and p. 530). No passage was found for dibenz[a,h]anthracene and benzo[g,h,i]perylene.
   

Executive summary:

Materials and methods

This in-vitro diffusion system is a suitable technique to demonstrate penetration through the skin, in particular for comparative purposes (species differences and/or different exposure scenarios). In this case, reasons for selection of monkey: similarity of percutaneous penetration through human and monkey skin, based on published data.

Results and discussion

The penetration constant Kp values of compounds resulted in a significant slower passage from the oil matrix than from the acetone/sweat combination (p <=0.05) (although the SD was very high, see Tab. 2 and 3): for naphthalene, acenaphthene, fluorene, anthracene and phenanthrene, the penetration was about 4 to 5 times less in the oil matrix than in the solvent/sweat combination. For pyrene and chrysene the factor was on the order of 3. This is also reflected in the significant extended lag-time for the oil matrix.

After the lag-time, the increases in concentration on the receptor side were nearly linear for some 70 h except for naphthalene which did not accumulate any more after 30 to 40 h (see Report Fig. 6).

Chrysene was found to be below or at the border of detection limit, while a passage for the other PAH with >=4 rings could only be demonstrated when they were applied in acetone/sweat mixture.

Description of key information

PAH are absorbed rapidly through the pulmonary tract, the gastrointestinal tract, and to a much lesser extent through skin. Metabolism is complex resulting mostly in hydroxylated species which in part may further be conjugated. Excretion is via urine, bile and faeces. Conjugates excreted into bile can be hydrolysed in the gut and be reabsorbed.
Absorption through human skin will be not more than 2 % within and after 8 h of exposure. Permeation through rat skin is much more pronounced (ca. 8 fold) compared to human skin.
Regarding the highly inert matrix of the substance Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht), the behaviour of the substance as such will be different from the biological fate of its individual constituents (5- and 6-ring PAH).

Properties described for PAH represent a worst-case situation. The substance as such will be much less biologically available and undergo absorption, distribution and metabolism in a way much more limited than described for individual PAH.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The substance Pitch, coal tar, high-temp., < 1% 4- to 5-membered condensed ring aromatic hydrocarbons [EC no. 701-305-8] (CTPhtht), is a UVCB and consists of a complex and variable combination of polycyclic aromatic hydrocarbons (PAH). Substance matrix is composed of highly condensed ring aromatic systems because the substance is obtained as residue from a distillation process at temperatures up to > 550 °C.

The substance fraction that can be distilled from the material up to > 500 °C is only 5 - 6 %. The percentage of substances that can be identified by GC analysis is < 1 %. These components are essentially PAH consisting of 5- and 6-ring-condensed aromatic hydrocarbons (PAH). Concentrations of individual substances range from < 0.01 to ca. 0.2 % (w/w). Concentration of benzo[a]pyrene is ca. 0.04 % while EPA PAH sum up to ca. 0.4 %.

Taking into account the highly inert matrix, the low water solubility (clearly below 0.2 mg/L) and the low percentage of toxicologically relevant constituents, the toxicokinetic characteristics of the substance as such will not be very well represented by individual constituents. The substance itself is assessed as not being biologically available and not being well absorbed and metabolised. Constituents will only be released from the substance in very low amounts. These will be 5- and 6-ring PAH.

Therefore, the fate and properties of the substance as well as adverse effects in biological systems will be characterised on the one hand by the inert matrix of CTPhtht, in combination with its high carbonisation in the production process and the low solubility in aqueous and in organic media. On the other hand, PAH are present as constituents and may be released to some even if rather low extent. The poor bioavailability of the pitch matrix will reduce effects observed with neat individual PAH, hence the toxicokinetic characteristics of single PAH can be taken for granted as "worst case". In order to characterise toxicokinetics at all, some higher PAHs may be used as relevant constituents in CTPhtht.

Toxicokinetics of PAH

Toxicokinetic characteristics of PAH are reported based on a review of the WHO 1998/2003.

Absorption

PAH are absorbed through the pulmonary tract, the gastrointestinal tract, and the skin. The degree of absorption may be different for individual substances. The rate of absorption from the lungs depends on the type of PAH, the size of the particles on which they are adsorbed, and the composition of the adsorbent. PAH adsorbed onto particulate matter are cleared from the lungs more slowly than free hydrocarbons.

Gastrointestinal absorption in rodents has been reported to be high. Fractional absorption of lower-molecular-weight PAHs, e.g. two-ring aromatics such as naphthalene, may be more complete than that of higher-molecular-weight PAHs, e.g. five-ring aromatics such as benzo[a]pyrene. Effective absorption by the different routes is also evidenced by observation of systemic toxicity following exposure by the different routes. Absorption from the gastrointestinal tract occurs rapidly in rodents, but metabolites return to the intestine via biliary excretion.

Distribution

PAH are widely distributed throughout the organism after administration by any route and are found in almost all internal organs, but particularly those rich in lipids. Intravenously injected PAH are cleared rapidly from the bloodstream of rodents but can cross the placental barrier and have been detected in foetal tissues.

Studies with 32P-postlabelling for the detection of DNA-adducts after percutaneous absorption of mixtures of PAH in rodents showed that components of the mixtures reach the lungs, where they became bound to DNA.

Metabolism

The metabolism of PAH to more water-soluble derivatives, which is a prerequisite for their excretion, is complex. In general, parent compounds are converted into intermediate epoxides (a reaction catalysed by cytochrome P450-dependent mono-oxygenases), which are further transformed by rearrangement or hydration to yield phenols or diols. In following steps conjugation by glutathione, sulphate or glucuronic acid may occur. Alternatively or in addition, a second oxidation at another position of the aromatic system is possible to yield tetrols, which can themselves be conjugated with sulphuric or glucuronic acids or with glutathione. Most metabolism results in detoxification, but some PAH are activated to DNA-binding species, principally diol epoxides, which can initiate tumours.

Excretion

PAH metabolites and their conjugates are excreted via the urine and faeces, but conjugates excreted into the bile can be hydrolysed by enzymes of the gut flora and be reabsorbed. It can be inferred from the available information on the total human body burden that PAH do not persist in the body and that turnover is rapid. This inference excludes those PAH moieties that become covalently bound to tissue constituents, in particular to nucleic acids, and are not removed by repair.

References

WHO (1998). Selected non-heterocyclic polycyclic aromatic hydrocarbons. Environmental Health Criteria 202, Geneva, Switzerland, WHO (World Health Organisation) 1998

WHO (2003). HEALTH RISKS OF PERSISTENT ORGANIC POLLUTANTS FROM LONG-RANGE TRANSBOUNDARY AIR POLLUTION, JOINT WHO/CONVENTION TASK FORCE ON THE HEALTH ASPECTS OF AIR POLLUTION. WHO Regional Office for Europe, World Health Organization 2003

It should be kept in mind that the properties described above relate to individual PAH. CTPhtht, as such will behave quite differently and will show a highly inert behaviour.

Dermal absorption

Studies of Van Rooij 1995 and Sartorelli 1999 show that higher molecular weight PAH are absorbed at a much lesser rate than lower molecular weight PAH. For absorption through pig ear (Van Rooij) [1] and full thickness skin from the abdomen of monkeys (Ceropithecus aetops) (application in artificial sweat) (Sartorelli) [2], differences in absorption rates from 0.8 ng/(h*cm²) [1] and 0.9 ng/(h*cm²) [2] for benzo[b]fluoranthene to not detectable [1] and [2] for dibenzo[a,h]anthracene and benzo[ghi]perylene were observed. In comparison, pyrene showed considerable higher absorption rates of 12 [1] and 7.8 [2] ng/(h*cm²).

In addition, observations from comparative in-vivo and in-vitro studies (human vs. rodent) on spiked creosote demonstrate that not more than 2 % of a dermal dose of a tar oil (creosote) will be absorbed through human skin within and after 8 hours of exposure (Fasano 2007). This will be a worst-case situation compared to dermal absorption of CTPhtht.

This indicates that absorption of CTPhtht through skin is highly limited. Single components (5- and 6-membered PAHJ) are absorbed very slowly. CTPhtht as such is composed of a highly inert matrix and will be absorbed through skin to a considerably lower extent.