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Description of key information

Short description of key information on bioaccumulation potential result: 
Animal experiments in rats investigating toxicokinetics upon single or repeated oral dosing indicated rapid absorption, and elimination mainly via urine. Tetrahydronaphthalin is metabolized by hydroxylation at the non-aromatic portion of the molecule. The metabolites are excreted mainly (generally > 90 %) as glucuronides (cited from SIAR to SIAM 19, 2004)

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

Cited from SIAR for SIAM 19 (19-22 October 2004):

Studies in Animals

In vitro Studies

Using a homogenate of male Holtzman rat livers, Chen and Lin (1968) found out that both 1,2,3,4-

tetrahydronaphthalene and its 1-hydroperoxide were converted to tetrahydronaphthalene-1-ol by rat

liver enzymes. Both conversions required NADHP. The authors concluded that hydroxylation of

1,2,3,4-tetrahydronaphthalene probably occurs via the hydroperoxide.

In vivo Studies

The toxicokinetic behavior of 1,2,3,4-tetrahydronaphthalene in rats was studied by Hüls AG

(1995 c) using a modified version of the test method described in Directive 84/449/EEC, and part of

the results was reported by Meineke et al. (1998). Six groups each comprising five Wistar rats per

sex were assigned to the following dose levels: vehicle control (2 groups); 15; 50;

150 mg/kg bw/day; 150 mg/kg bw/day reversal group. 2 ml/kg bw of the vehicle corn oil including

the appropriate doses of 1,2,3,4-tetrahydronaphthalene were applied by gavage for 28 consecutive

days. Blood was sampled from all animals once (terminal) for serum chemical and hematological

investigations plus twice for the toxicokinetics during study (high dose group days 1 and 16;

medium and low dose groups days 3 and 18 of treatment); detailed sampling times (approximately)

were:

- 0.5; 1.5; 3.0; 6.0; 23.0 hours after treatment on days 1 and 16 from one animal per sex and

group each;

- on days 2 and 17 from control groups;

- 0.5; 1.5; 6.0 hours after treatment on days 3 and 18 from 2; 2; 1 animals per sex and group;

- additional sampling from two animals each of the high dose groups at five different times

during the 14 day reversal period (first sampling from non-reversal animals before

sacrifice); 200 - 500μl/sample.

The blood concentration maximum for 1,2,3,4-tetrahydronaphthalene was reached approximately

30 minutes after administration of the highest dose. The AUC (area under curve) of the high dose

groups was more than proportional higher than that of the lower dose groups indicating that

elimination may be saturated at this dose level. An accumulation of test substance after repeated

oral administration of up to 150 mg/kg bw/day was, however, not observed. After 23 hours, only

traces of test substance were detectable in the blood. In the low and mid dose group, elimination

was almost finished after 6 hours. The elimination half life was determined in the range of 30 to

100 minutes. The first order half-life of elimination was approximately 1.5 hours with a onecompartment model and 4.7 hours (for males) with a two-compartment model. The authors

concluded that resorption is rapid, but is probably decreased upon repeated dosing.

IN an NTP study (NTO 2005) toxicokinetic studies were conducted in F344/N rats and B6C3F1 mice to estimate toxicokinetic parameters for the elimination of tetralin from blood. Male and female rats and mice received either a single intravenous dose of 2 or 20 mg tetralin/kg body weight or a single 6‑hour inhalation exposure of 15, 60, or 120 ppm. Post‑dose blood samples were analyzed for tetralin up to 24 hours after dosing and used to estimate the toxicokinetic parameters.

When comparing the elimination kinetics of tetralin in mice to rats receiving equivalent doses by two exposure routes (inhalation and intravenous), mice eliminated tetralin more rapidly than rats. Elimination half-lives were shorter, and AUC values were lower in mice compared to rats at similar doses and exposure concentrations.

The metabolism of 1,2,3,4-tetrahydronaphthalene in Doe albino rabbits after single doses (210 -

approximately 1,000 mg/kg bw) by stomach tube was studied by Elliott and Hanam (1968) using

purified unlabeled as well as radioactive test substance. Of the radioactivity, 87 – 90 % was

excreted in the urine within two days and 0.5 - 3.7 % on the third day. The feces contained 0.6 -

1.8 %. No radioactivity was found in the breath and negligible amounts were retained in the tissue.

The main metabolites in the urine were:

glucuronide of 1,2,3,4-tetrahydro-1-naphthol [1]: 52.4 %

glucuronide of 1,2,3,4-tetrahydro-2-naphthol [2]: 25.3 %

1,2,3,4-tetrahydro-1-oxo-4-naphthol [3] (conjugated): 6.1 %

trans-1,2,3,4-tetrahydronaphthalene-1,2-diol [4] (conjugated): 0.6 %

cis-1,2,3,4-tetrahydronaphthalene-1,2-diol [5] (conjugated): 0.4 %

Previously reported as metabolites, but now identified to be artefacts, were: 1,2,3,4-tetrahydro-2-

oxonaphthalene, 1-naphthol, 1,2-dihydronaphthalene, and naphthalene. The substances 1,2,3,4-

tetrahydronaphthalene (= test substance itself), 1,2,3,4-tetrahydro-1-oxonaphthalene, 2-naphthol,

5,6,7,8-tetrahydro-1-naphthol, and 5,6,7,8-tetrahydro-2-naphthol also could not be found.

Upon treatment of male and female Fischer 344 rats with 0.5 ml 1,2,3,4-tetrahydronaphthalene/kg

bw = 485 mg/kg bw intragastrically on alternate days over a 14 day period, the following

metabolites were found (Servé, 1989; Servé et al., 1989):

1,2,3,4-tetrahydro-1-naphthol [1]: 29 %

1,2,3,4-tetrahydro-2-naphthol [2]: 7 %

1,2,3,4-tetrahydro-1-oxo-2-naphthol [6]: 33 %

1,2,3,4-tetrahydro-1-oxo-4-naphthol [3]: 25 %

1,2,3,4-tetrahydronaphthalene-1,4-diol [7]: 1 %

1,2,3,4-tetrahydronaphthalene-1,2-diol [4] and [5]: traces

The findings of Röckemann (1922) can, due to lacking documentation, only indicate that 1,2,3,4-

tetrahydronaphthalene is metabolized in different ways by rabbits on one hand and by dogs and

humans on the other hand. The main metabolite in rabbits is 1,2,3,4-tetrahydro-1-naphthol [1],

which is excreted as glucuronate. The main metabolite in dogs is 1,2,3,4-tetrahydro-2-naphthol [2],

also excreted as glucuronate. Both main metabolites ([1] more rapidly than [2]) are further

converted into dihydronaphthalene and subsequently into naphthalene. Considering the conflicting

statements of Elliott and Hanam (1968) cited above, who identified 1,2-dihydronaphthalene and

naphthalene as artefacts, one may conclude that there are certainly quantitative and maybe also

qualitative differences between different mammals in their metabolism of 1,2,3,4-tetrahydronaphthalene.

Considering the purity of the test substances and the analytical tools available in the

two studies, the data of Elliott and Hanam (1968) have a much higher reliability than those of

Röckemann (1922). However, the studies of Servé (1989) and co-workers confirm that there are at

least two metabolic pathways in competition with each other.

 

Studies in Humans

In vitro Studies

There were no studies available

 

In vivo Studies

Pohl and Rawicz (1919) exposed volunteers through the food to doses of 5 or 7 g 1,2,3,4-tetrahydronaphthalene

and performed various analyses with the urine collected thereafter. Dark green

colored urine was observed, in which an unidentified pigment, naphthalene, and 1,2-dihydronaphthalene

were found.

A woman was admitted to a hospital 48 hours after she had drunk about 250 ml (1/2 - 3/4 pint) of

Cuprex (1,2,3,4-tetrahydronaphthalene 31.5 %, copper oleate 0.03 %, paraffin oil 52.7 %, acetone

15.7 %) in an episode of self-poisoning. A total of 1900 ml of green-grey urine was collected

during the 24 hour period after admission and analyzed for metabolites, which were identified by

comparison of GC retention times and mass spectra with reference compounds. The following

substances were found in the urine beside unchanged 1,2,3,4-tetrahydronaphthalene:

A = 1,2,3,4-tetrahydro-1-naphthol [1]

B = not identified

C = glucuronide of A

D = glucuronide of 1,2,3,4-tetrahydro-2-naphthol [2]

The predominant metabolite was A. The concentration ratios A:B and C:D were approximately

84:16 and 1:2, respectively (Drayer and Reidenberg, 1973).

As mentioned earlier in this chapter, findings of Röckemann (1922) and others give evidence,

however unreliable, that metabolism of 1,2,3,4-tetrahydronaphthalene in humans may be somewhat

different from that in rabbits and rodents in quantitative, but possibly also in qualitative terms.

Conclusion

1,2,3,4-Tetrahydronaphthalene is rapidly absorbed when ingested or inhaled. The chemical is metabolized

by hydroxylation at the non-aromatic portion of the molecule. The metabolites are excreted

mainly (generally > 90 %) as glucuronides with the urine, but elimination with the feces was also

observed. Dark green colored urine, which is observed as a typical symptom in humans, indicates

metabolization to a pigment.