title: O-phenylphenol and its sodium and potassium salts: a toxicological assessment.
abstract: Ortho-phenylphenol (OPP) and its sodium (SOPP) and potassium (POPP) salts are used as fungicides and disinfectants. Due to the widespread use of especially OPP and SOPP, the potential for consumer exposure and some "critical" findings the toxicological database is quite extensive and complex. In experimental animals toxicity after single oral and dermal administration of these compounds is low. For the skin and mucous membranes, OPP has to be considered as irritating, and SOPP and POPP as corrosive. A large number of chronic toxicity and reproduction studies did not show any indication of oestrogen-like or other endocrine effects of OPP in the mammalian organism. No teratogenic effects were observed after the administration of OPP or SOPP in rats, mice, and rabbits. In two-generation studies in rats, OPP did not affect reproduction. The available data do not suggest a relevant potential for immunotoxic properties. The administration of high dietary concentrations of OPP to mice up to 2 years induced hepatocellular changes indicative of adaptations to metabolic demands, zonal degeneration, focal hepatocellular necrosis, and/or pigmentation of the liver. Only in male mice of one study, using a strain prone to develop hepatocellular tumors at high spontaneous incidences, the incidence of hepatocellular adenomas was increased. The incidence of hepatocellular carcinomas was not affected by treatment. The urothel of the urinary bladder (at very high doses also of the renal pelvis and the papilla) is the main target tissue after the repeated oral exposure of rats. The changes initially consist of increased mitosis, followed by simple epithelial hyperplasia, developing to a papillary and/or nodular form, later on to papillomas and transitional carcinomas. Crystals or stones in the bladder do not play a decisive role in this cascade. SOPP is more effective than OPP in this respect. Male rats are much more sensitive than females. In mice, hamsters, guinea pigs, and dogs, urothelial lesions do not develop even at very high oral dose levels. The findings in rats explain why there is a large genotoxicity/mutagenicity data base not only for OPP and SOPP but also for their metabolites on nearly all kinds of endpoints/targets. The weight of evidence suggests that genotoxicity of OPP/SOPP or their metabolites does not play a decisive role for the carcinogenicity at the urothel. Among them are lack of DNA binding of OPP to the rat bladder epithelium, the differences between OPP and SOPP, between male and female rats, between rats and mice (despite roughly comparable toxicokinetics), as well as the fact that tumors develop only at dose levels inducing hyperplasias. In addition, the strong dependence of the incidence and severity of the nonneoplastic and neoplastic bladder changes on urinary pH values (modified by feeding of ammonium chloride or sodium hydrogen carbonate) is consistent with the hypothesis of a nongenotoxic mode of action. Finally, there is no correlation between the urinary concentration of OPP or its metabolites and the incidence of hyperplasias/tumors in the urinary bladder. Both tumorigenic effects in rats and male mice are considered to represent high-dose, sex- and/or species-specific phenomena, based on nongenotoxic mechanisms of action and therefore allow the conclusion that the conventional margin of safety approaches are appropriate when assessing the risk of applications of OPP and its salts.
authors.affiliation: Bayer AG, Institute of Toxicology, D-42096 Wuppertal, Germany. ernst.bomhard.eb@bayer-ag.de
authors.forename: E M
authors.initials: EM
authors.lastname: Bomhard
authors.forename: S Y
authors.initials: SY
authors.lastname: Brendler-Schwaab
authors.forename: A
authors.initials: A
authors.lastname: Freyberger
authors.forename: B A
authors.initials: BA
authors.lastname: Herbold
authors.forename: K H
authors.initials: KH
authors.lastname: Leser
authors.forename: M
authors.initials: M
authors.lastname: Richter
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000493:pharmacokinetics / Q000633:toxicity*; D015197:Carcinogenicity Tests; D004202:Disinfectants / Q000493:pharmacokinetics / Q000633:toxicity*; D005260:Female; D005659:Fungicides, Industrial / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D009152:Mutagenicity Tests; D023422:Skin Irritancy Tests; D013045:Species Specificity; D036401:Toxicity Tests, Chronic
chemical_list: D001713:Biphenyl Compounds; D004202:Disinfectants; D005659:Fungicides, Industrial; C004369:2-phenylphenol