Pitch, coal tar, high-temp.

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

in vivo and in vitro

Type of information:

experimental study

Remarks:

information comes from a comprehensive report summarising properties, toxicological/ecotoxicological effects, and effects on humans and the environment of a variety of polycyclic aromatic hydrocarbons

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Review, peer-reviewed data

Data source

Reference

Reference Type:

review article or handbook

Title:

Selected non-heterocyclic polycyclic aromatic hydrocarbons - IPCS Environmental Health Criteria 202 (§)

Author:

WHO

Year:

1998

Bibliographic source:

International Programme on Chemical Safety (IPCS), WHO - World Health Organization, Geneva, Switzerland

Materials and methods

Objective of study:

other: various objectives

Principles of method if other than guideline:

Review on PAHs summarising data peer-reviewed by a group of international experts

GLP compliance:

no

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

Constituent 2

Reference substance name:

1-methylnaphthalene

EC Number:

201-966-8

EC Name:

1-methylnaphthalene

Cas Number:

90-12-0

Molecular formula:

C11H10

IUPAC Name:

1-methylnaphthalene

Constituent 3

Reference substance name:

Acenaphthene

EC Number:

201-469-6

EC Name:

Acenaphthene

Cas Number:

83-32-9

Molecular formula:

C12H10

IUPAC Name:

1,2-dihydroacenaphthylene

Constituent 4

Reference substance name:

Fluorene

EC Number:

201-695-5

EC Name:

Fluorene

Cas Number:

86-73-7

Molecular formula:

C13H10

IUPAC Name:

9H-fluorene

Constituent 5

Reference substance name:

Anthracene

EC Number:

204-371-1

EC Name:

Anthracene

Cas Number:

120-12-7

Molecular formula:

C14H10

IUPAC Name:

anthracene

Constituent 6

Reference substance name:

Phenanthrene

EC Number:

201-581-5

EC Name:

Phenanthrene

Cas Number:

85-01-8

Molecular formula:

C14H10

IUPAC Name:

phenanthrene

Constituent 7

Reference substance name:

Fluoranthene

EC Number:

205-912-4

EC Name:

Fluoranthene

Cas Number:

206-44-0

Molecular formula:

C16H10

IUPAC Name:

fluoranthene

Constituent 8

Reference substance name:

Pyrene

EC Number:

204-927-3

EC Name:

Pyrene

Cas Number:

129-00-0

Molecular formula:

C16H10

IUPAC Name:

pyrene

Constituent 9

Reference substance name:

Benz[a]anthracene

EC Number:

200-280-6

EC Name:

Benz[a]anthracene

Cas Number:

56-55-3

Molecular formula:

C18H12

IUPAC Name:

tetraphene

Constituent 10

Reference substance name:

7,12-dimethylbenz[a]anthracene

EC Number:

200-359-5

EC Name:

7,12-dimethylbenz[a]anthracene

Cas Number:

57-97-6

Molecular formula:

C20H16

IUPAC Name:

7,12-dimethyltetraphene

Constituent 11

Reference substance name:

Chrysene

EC Number:

205-923-4

EC Name:

Chrysene

Cas Number:

218-01-9

Molecular formula:

C18H12

IUPAC Name:

chrysene

Constituent 12

Reference substance name:

Benzo[e]acephenanthrylene

EC Number:

205-911-9

EC Name:

Benzo[e]acephenanthrylene

Cas Number:

205-99-2

Molecular formula:

C20H12

IUPAC Name:

benzo[e]acephenanthrylene

Constituent 13

Reference substance name:

Benzo[k]fluoranthene

EC Number:

205-916-6

EC Name:

Benzo[k]fluoranthene

Cas Number:

207-08-9

Molecular formula:

C20H12

IUPAC Name:

benzo[k]fluoranthene

Constituent 14

Reference substance name:

Benzo[def]chrysene

EC Number:

200-028-5

EC Name:

Benzo[def]chrysene

Cas Number:

50-32-8

Molecular formula:

C20H12

IUPAC Name:

benzo[pqr]tetraphene

Constituent 15

Reference substance name:

Dibenz[a,h]anthracene

EC Number:

200-181-8

EC Name:

Dibenz[a,h]anthracene

Cas Number:

53-70-3

Molecular formula:

C22H14

IUPAC Name:

benzo[k]tetraphene

Constituent 16

Reference substance name:

Indeno[1,2,3-cd]pyrene

EC Number:

205-893-2

EC Name:

Indeno[1,2,3-cd]pyrene

Cas Number:

193-39-5

Molecular formula:

C22H12

IUPAC Name:

indeno[1,2,3-cd]pyrene

Constituent 17

Reference substance name:

Benzo[ghi]perylene

EC Number:

205-883-8

EC Name:

Benzo[ghi]perylene

Cas Number:

191-24-2

Molecular formula:

C22H12

IUPAC Name:

benzo[ghi]perylene

Constituent 18

Reference substance name:

Benzo(r,s,t)pentaphene

EC Number:

205-877-5

EC Name:

Benzo(r,s,t)pentaphene

Cas Number:

189-55-9

Molecular formula:

C24H14

IUPAC Name:

benzo[rst]pentaphene

Test material form:

solid

Details on test material:

- Individual test substances (PAH) are reported in the specific study records.
- Substances were applied individually or combined as mixtures (for details see study record).

Specific details on test material used for the study:

PAH consisting of four and more condensed aromatic ring systems are relevant components of CTPht. Their properties and toxicokinetic behaviour are used for the characterisation of the toxicokinetic properties of CTPht.

Test animals

Species:

other: various

Administration / exposure

Route of administration:

other: oral, dermal, inhalation

Results and discussion

Main ADME results

Main ADME results 1

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.

Main ADME results 2

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 in those rich in lipids.

Main ADME results 3

Type:

metabolism

Results:

Metabolism is via intermediary epoxides that 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.

Main ADME results 4

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.

Applicant's summary and conclusion

Executive summary:

PAH are absorbed through the pulmonary tract, the gastrointestinal tract, and the skin. The rate of absorption from the lungs depends on the type of PAH, the size of the particles on which they are absorbed, and the composition of the adsorbent. PAH adsorbed onto particulate matter are cleared from the lungs more slowly than free hydrocarbons. Absorption from the gastrointestinal tract occurs rapidly in rodents, but metabolites return to the intestine via biliary excretion. Studies with 32P-postlabelling of percutaneous absorption of mixtures of PAH in rodents showed that components of the mixtures reach the lungs, where they become bound to DNA. The rate of percutaneous absorption in mice varies according to the compound.

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.

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 and - following secondary oxidation - to yield tetrols, which can themselves be conjugated with sulfuric 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.

PAH metabolites and their conjugates are excreted via the urine and faeces, but conjugates excreted in the bile can be hydrolysed by enzymes of the gut flora and 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 nucleic acids, and that are not removed by repair.