Sodium 2-biphenylate

Carcinogenicity

Justification for classification or non-classification

Classification and labelling for carcinogenicity according to Regulation (EC) No 1272/2008 is not required.

Additional information

According to the data requirements specified in Annex VIII of Regulation (EC) No 1907/2006, a study for carcinogenicity is not required for the tonnage band 10 - 100 t/a. Therefore, information related to this endpoint was not included for sodium 2-biphenylate (Na OPP, CAS 132-27-4). However, a combined chronic toxicity/carcinogenicity study conducted with the analogue substance 2-phenylphenol (OPP, CAS 90-43-7) is available (please refer to 7.5.1) and was taken into account.

In the combined chronic toxicity / carcinogenicity study conducted according to the OECD Test Guideline 453 and in compliance with GLP, rats of both sexes received OPP at dietary levels of 800, 4000, and 8000 ppm (males) or 800, 4000, and 10,000 ppm (females) for two years (Wahle, B. S. and Christenson, W. R., 1996 and Bomhard, E.M. et al., 2002, please refer to 7.5.1). The urinary bladder showed evidence of a compound-induced neoplasia in both 4000 and 8000 ppm male rats only. While this effect was unequivocal at 8000 ppm, it was considered border-line at 4000 ppm as there was only a marginal and non-statistical increase in both urinary bladder hyperplasia and transitional cell carcinoma when compared to controls or 800 ppm males. Evidence of a compound-induced neoplasia was not observed in female animals at any dose tested. The NOAEL for carcinogenicity derived from this study is therefore ≥ 10,000 ppm (647 mg/kg bw/day) for females and 4000 ppm (200 mg/kg bw/day) for males. The corresponding LOAEL for males is thus 8000 ppm (402 mg/kg bw/day), based on neoplasms (malignant and benign) in the urinary bladder.

Further studies are available for the analogue substance OPP, which were also taken into account for the evaluation of the carcinogenic potential. Bomhard, E. M. et al. (2002) reviewed and extensively discussed the carcinogenic potential available for OPP and the sodium salt Na OPP in his review. It is described that 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 tumours at high spontaneous incidences, the incidence of hepatocellular adenomas was increased. The incidence of hepatocellular carcinomas was not affected by treatment. The urothelium 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 cell carcinomas or stones in the bladder do not play a decisive role in this cascade. Na OPP 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 did 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 Na OPP but also for their metabolites on nearly all kinds of endpoints/targets. The weight of evidence suggests that genotoxicity of OPP/ Na OPP or their metabolites does not play a decisive role for the carcinogenicity at the urothelium. Among them are lack of DNA binding of OPP to the rat bladder epithelium, the differences between OPP and Na OPP, between male and female rats, between rats and mice (despite roughly comparable toxicokinetics), as well as the fact that tumours develop only at dose levels inducing hyperplasia. In addition, the strong dependence of the incidence and severity of the non-neoplastic 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 non-genotoxic mode of action. Finally, there is no correlation between the urinary concentration of OPP or its metabolites and the incidence of hyperplasia/tumours 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 non-genotoxic 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 (Bomhard, E.M. et al., 2002).

This scientific evidence on the specific susceptibility of the rat is in line with the data available with OPP. Urinary bladder tumours were observed in male rats only starting at a dose of 200 mg/kg bw/day (4000 ppm in the diet), whereas in female rats hyperplasia as precursor event and first indication of bladder toxicity, but no tumour response, was observed with 647 mg/kg bw/day (10000 ppm). In mice no bladder effects were observed up to the high dose of 1000 mg/kg bw/day. In addition, a study that specifically was designed to assess species differences of OPP Na induction of urinary bladder effects revealed no respective effect in B6C3F1 mice, Syrian golden hamsters and Hartley guinea pigs, but a clear response in rats (microvilli and simple, papillary and nodular hyperplasia). In the study male animals were fed a diet containing as much as 20000 ppm (2%) OPP Na for 4, 8, 12, 24, 36 and 48 weeks (Hasegawa et al. 1990). Also in the one year dog study there was no urinary bladder toxicity observed after treatment with up to 300 mg/kg OPP (Cosse, P.F., Stebbins, K.E., Stott, W.T., Johnson, K.A., and Atkin, L. (1990) and Bomhard, E. M. et al. (2002)).

Together with the available genotoxicity data and the conclusion derived from the mechanistic study conducted by Christenson, W.R. and colleagues (1996), a cytotoxic mode of action together with species- and sex-specific sensitivity for urinary tract lesions is likely. Although humans may respond to chronic irritation in the bladder with tumour development, the human appears to be much less sensitive than the rat (Rodent Bladder Carcinogenesis Working Group, 1995).

Conclusion:

For OPP there is convincing evidence that the carcinogenetic effects shown in rodents are threshold effects with an indirect and non-genotoxic mechanism. Furthermore, the tumors as reported (liver tumors in mouse, urinary bladder tumors in rat) are not of relevance for humans, due to proven species differences. Therefore, the OPP findings from animal studies are not to be considered as predictive of a risk for human.

This is in general agreement with the evaluations of FAO WHO (1999), US-EPA (2005) and EU EFSA (2008) who came to a similar conclusion when deriving an ADI value using the NOEL (rat) = 39 mg/kg bw/day for systemic toxicity (Wahle, B. S. and Christenson, W. R., 1996 and Bomhard, E.M. et al., 2002, Section 7.5) as a starting point and subsequently applying the conventional margin of safety approach, as this effect level is markedly below the threshold for species specific carcinogenic effects of OPP. Taken into account the toxicokinetic behaviour of OPP and Na OPP similar effects regarding carcinogenicity can be expected for the target substance Na OPP.

References:

Brusick, D. (2005). Analysis of Genotoxicity and the Carcinogenic Mode of Action for Ortho-Ohenylphenl. Environmental and Molecular Mutagenesis 45:460 -481.

Cosse, P.F., Stebbins, K.E., Stott, W.T., Johnson, K.A., and Atkin, L. 1990: Ortho-Phenylphenol: Palatability/Probe, Four-Week and One-Year Oral Toxicity Studies in Beagle Dogs. (study report), Testing laboratory: The Toxicology Research Laboratory, Health and Environmental Sciences, Dow Chemical Company, Midland, MI, USA, Report no: K-001024-039. Owner company; Dow Chemical Company and Lanxess GmbH, Report date: Sep 24, 1990

Christenson, W.R., Wahle, B.S. and Cohen, S.M. 1996: Technical Grade ortho-Phenylphenol: A 32P-Postlabelling Study to Examine the Potential for the Formation of DNA Adducts in the Urinary Bladder of the Male Rat (study report), Testing laboratory: Bayer Corporation, Agriculture Division, Toxicology, Stilwell, KS, USA and University of Nebraska Medical Center, Dept. Pathology & Micropathology, Omaha, NE, USA, Report no: 94-972-AV. Owner company; Dow Chemical Company and Lanxess GmbH, Report date: Nov 11, 1996

ECHA (2008): Peer review of the pesticide risk assessment of the active substance 2 -phenylphenol. EFSA Scientific Report (2008) 217, 1-67

EU EFSA (2008). Conclusion on pesticide peer review regarding the risk assessment of the active substance 2-phenylphenol. EFSA Scientific Report (2008) 217, 1-67.

FAO WHO (1999): Join FAO/WHO Meeting on Pesticide Residues. Rome, 20-29 Sep 1999

Hasegawa R, Takahashi S, asamoto M, Shirai T, Fukushima S 1990: Species differences in sodium o-phenylphenate induction of urinary bladder lesions (publication), Cancer Letters 50, 87-91 (1990).

Rodent Bladder Carcinogenesis Working Group (1995). Urinary Bladder Carcinogenesis: Implications for Risk Assessment. Fd Chem. Toxic., 33:797.

US EPA (2005): Reregistration Eligibility Decision for 2-phenylphenpl and salts