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ORGAN TOXICITY AND MECHANISMS Pablo Steinberg á Ingrid Zschaler á Elke Thom Manuela Kuna á GuÈnter WuÈ st Angelika SchaÈ fer-Schwebel á Rolf MuÈller Peter-JuÈ rgen Kramer á GuÈnter Weiûe The polycyclic musk 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4- tetrahydronaphthaline lacks liver tumor initiating and promoting activity in rats exposed to human-relevant doses Received: 16 May 2001 / Accepted: 14 August 2001 / Published online: 28 September 2001 Ó Springer-Verlag 2001 Abstract 7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetra- hydronaphthaline AHTN) is one of the two most widely used fragrances of a group of substances known collectively as the polycyclic musks. In the last few years evidence has been accumulating that AHTN is hepato- toxic when administered at high doses. In the present study the subchronic hepatotoxicity of AHTN admin- istered to rats at doses within the human exposure range was evaluated. For this purpose female and male juve- nile Wistar rats were exposed to AHTN 300 lg/kg body weight per day, i.p.) alone or to a single dose of diet- hylnitrosamine DEN) 100 mg/kg body weight, i.p.) followed by AHTN 1, 10, 100 or 300 lg/kg body weight per day, i.p.) for 90 days. Thereafter the liver architec- ture as well as the presence of placental glutathione S-transferase GST-P)-positive hepatic lesions was assessed. In male animals receiving AHTN alone or in combination with DEN the number of GST-P-positive single hepatocytes was similar to that in untreated rats, while GST-P-positive mini-foci and foci were not observed. In the case of female rats the number of GST- P-positive single hepatocytes and mini-foci in AHTN- treated rats was similar to that in untreated animals, whereas in those animals receiving AHTN either alone or in combination with DEN, GST-P-positive foci could not be detected or were present in a number as similar to that in untreated rats. In conclusion, in the present study it has been shown that AHTN administered over a 90-day period in concentrations similar to those taken up daily by humans does not lead to hepatotoxicity. Keywords 7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4- tetrahydronaphthaline á Hepatotoxicity á Liver tumor initiation á Liver tumor promotion Introduction 7-Acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaph- thaline AHTN) and 1,3,4,6,7,8-hexahydro-4,6,6,7,8,8- hexamethyl-cyclopenta[g]-2-benzopyran HHCB) are the two most widely used fragrances of a group of substances known collectively as the polycyclic musks. According to a survey conducted by the Research In- stitute for Fragrance Materials Hackensack, N.J., USA) the fragrance industry has been reported to use about 1,500 tons AHTN and 3,800 tons HHCB per year in the US and Europe. AHTN and HHCB are consid- ered to be essential ingredients in fragrances because of their musky scent, their ability to make a fragrance long- lasting and their positive eect on the balance of the fragrance. They are not only present in ®ne fragrances but also in cosmetics, soaps and laundry detergents. A number of recent studies show that AHTN and HHCB accumulate in river water and in ®sh Eschke et al. 1994, 1995a; Rimkus and Brunn 1996; Fromme et al. 1999) as well as in human fat and milk Eschke et al. 1995b; Hahn 1996; MuÈ ller et al. 1996; Rimkus and Brunn 1996; Rimkus and Wolf 1996; Liebl et al. 2000), which is most probably due to their high lipophilicity and chemical stability. Arch Toxicol 2001) 75: 562±568 DOI 10.1007/s002040100274 P. Steinberg &) á I. Zschaler Lehrstuhl fuÈr ErnaÈhrungstoxikologie, Institut fuÈr ErnaÈhrungswissenschaft, UniversitaÈt Potsdam, Arthur Scheunert Allee 114±116, 14558 Bergholz-RehbruÈcke, Germany E-mail: [email protected] Fax: +49-33200-88541 E. Thom á M. Kuna Max-Rubner-Laboratorium, Deutsches Institut fuÈr ErnaÈhrungsforschung, Arthur-Scheunert-Allee 114±116, 14558 Bergholz-RehbruÈcke, Germany G. WuÈst á A. SchaÈfer-Schwebel á R. MuÈller P.-J. Kramer á G. Weiûe Institut fuÈr Toxikologie, E. Merck KGaA, 64271 Darmstadt, Germany

The polycyclic musk 7-acetyl-1,1,3,4,4,6-hexamethyl-1,2,3,4-tetrahydronaphthaline lacks liver tumor initiating and promoting activity in rats exposed to human-relevant doses

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