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 an...

Re-evaluation of Developmental and Reproductive Toxicity of Ortho- Phenylphenol (OPP) and Sodium Ortho-Phenylphenate (SOPP)

“…Among the experimental animals tested, post-implantation loss was a common developmental effect. Published and unpublished reviews have concluded that OPP and SOPP induce developmental effects only at doses where maternal effects are observed [1,2,38]. However, our analyses indicate that fetal effects may also occur at doses where maternal toxicity is either minimal or not present (summary Table 8).…”

Induction of mitosis delay, apoptosis and aneuploidy in human cells by phenyl hydroquinone, an Ames test-negative carcinogen

“…Ortho-phenyl phenol (OPP) is an anti-microbial agent employed as disinfectant and fungicide in the preservation of wood, treatment of citrus and vegetables, and production of textile (Bomhard et al, 2002). Its widespread use means considerable potential for occupational and consumer exposure.…”

Lack of Enhanced Epithelial Cell Proliferation in the Urinary Bladder of Heterozygous p53 Knockout Mice Given Sodium <i>Ortho</i>-phenylphenate or Uracil

“…For sodium salt-induced urinary bladder carcinogenesis, changes of urinary components, with elevation of the urinary pH value and Na ion concentration, are considered essential factors for activity in male rats [25][26][27] . In fact, OPP itself does not show any modifying potential for urinary bladder carcinogenesis in rats 28,29 . It has been reported that sodium L-ascorbate and Na-OPP treated mice show elevation of urinary pH value and Na ion concentration, but no morphological changes or enhanced urinary bladder carcinogenesis 30,31 .…”