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A review is available summarising in vitro and in vivo data on immunotoxicity of 2-phenylphenol (OPP) (Bomhard et al., 2002). The following studies are discussed in the review:

 

In vitro

An in vitro test on antibody response of mouse spleen cells to sheep red blood cells was conducted with OPP (Luster et al., 1981). Up to 10.0 µg OPP/culture antibody response was not affected. The effect seen at 100.0 µg/culture was attributed by the authors to cell lysis rather than inhibition of lymphocytes function.

 

In vivo

Immunological responses of CBA/J mice were investigated by La Via and La Via (1979) after exposure to a cage disinfectant containing 5% OPP among other phenols or after oral administration of 1, 5 and 10 ppm OPP via drinking. Immunosuppression was observed after 14 weeks of cage exposure. Oral administration of OPP via drinking water for 3 weeks resulted in a similar immunosuppression at 10 ppm and a slight immunosuppression at 1 ppm. There was no effect on the number of lymphocytes and macrophages.

The effects of phenolic compounds (disinfectants) on immune responses were studied in BALB/c mice daily given 0.46 mg OPP/kg bw, 0.41 mg o-benzyl-p-chlorophenol/kg bw and 0.09 mg p-tert-amylphenol/kg bw) or 0.7 mg OPP/kg bw/day alone in their drinking water for 4 weeks (La Via et al., 1979). During the exposure to phenolic disinfectants, three mice were immunised with sheep erythrocytes at weekly intervals. Results similar to those described by La Via and La Via (1979) led the authors to the assumption of a significant immunosuppression after 2 and 4 weeks of treatment. Further groups of mice were exposed via their drinking water to the whole disinfectant (0.6 mg OPP/kg bw/day, 0.54 mg o-benzylp-chlorophenol/kg bw/day and 0.12 mg p-tert-amylphenol/kg bw/day) or to 0.7 mg OPP/kg bw/day. The parameters were the same as in the previous series. After 3 weeks of exposure an immunosuppression was observed in both treatment groups in comparison with control mice. Additionally, a suppression of macrophages represented as a decreased number of cells capable of phagocytosis was reported.

Luster et al. (1981) examined the effects of OPP on immunological functions and host susceptibility to infectious agents following subchronic exposure to groups of adult female B6C3F1 mice. The animals were administered 1, 10, and 200 mg OPP/kg bw/day by gavage on 10 days over a 2 week period. Exposure to OPP failed to alter any of the immune functions tested or the host susceptibility to infectious agents, whereas CP (45 mg/kg bw/day i.p.; 4 days) treatment as positive control resulted in the known marked alterations in both targets.

The long-term effects of OPP on immunobiological properties and intestinal flora were investigated in BALB/c mice (Kojima et al., 1995). OPP was given with the drinking water at concentrations of 10 or 100 µg/mL for 52 or 80 weeks. After 52 weeks, no significant changes in the lymphocyte transformation test (LTT) or the PFC assay were observed as compared to the concurrent negative control animals. After 80 weeks, spleen weights were heavier than those in the control group and there was some immunosuppression in the LTT and PFC assays in females but not in males.

 

The data provided by La Via and La Via (1979) and La Via et al. (1979) lack of detailed information on the study design, such as the number of mice used, the cage type and housing of the animals, and the statistical evaluation(s). As far as the second paper is concerned, the investigations with the mixture of phenolic compounds (disinfectant) were obviously done using only one animal at each time-point. Furthermore, the number of mice investigated in the second series of experiments remained unclear (one mice at several time-points or three mice at one time-point). The information was poorly presented in the second paper (some information is obviously missing or seems to be mixed up; occasionally tables seem to be labelled wrongly). In addition, the authors pointed out, that the data of the first study were obtained using a small number of mice and therefore are of preliminary nature only. As far as the second study is concerned, the authors again stated that future work should be directed to elucidate the nature of the effects observed, for example, including target cells, site(s) of action, effect of dose, length of exposure, etc. Owing to poor data, both studies are of limited use and of poor reliability in assessing the immunotoxicity of OPP. Information given in the abstract of Kojima et al. is also too limited and the spectrum of investigations so narrow that a sound judgement on the validity and reliability of these results is not possible. In contrast, the results from the large battery of tests (which has also been used in a collaborative investigation of over 50 selected compounds in two independent laboratories) applied to a sufficient number of animals treated with three different dose levels are well documented. As there was no indication of OPP effects whatsoever and because the large number of conventional toxicity studies with OPP gave no hint for adverse effects on the immune system, the weight of evidence suggests that the immunotoxic potential is very low.

List of original references:

- Kojima, K., Kanazawa, H. J. L., Ono, H. (1995).Long-term effects of parathion, o-phenylphenol and penicillin-g potassium on immunological properties and intestinal flora in BALB/C mice. The international congress of toxicology VII, July 2–6, 12, 1995 (abstract)

- La Via, M. F. and La Via, D. S. (1979). Phenol derivatives are immunodepressive in mice. Drug Chem. Toxicol. 2:167–177

- La Via, M. F., Loose, L. D., La Via, D. S., Silberman, M. S. (1979). The immunodepressive effect of phenol derivatives. Adv. Exp. Med. Biol. 121:523–538

- Luster, M. I., Dean, J. H., Boorman, G. A., Archer, D. L., Lauer, L., Lawson, L. D., Moore, J. A., Wilson, R. E. (1981). The effects of orthophenylphenol, tris(2,3–dichloropropyl)phosphate, and cyclophosphamide on the immune system and host susceptibility of mice following subchronic exposure. Toxicol. Appl. Pharmacol. 58:252–261

Within the US EPA’s Endocrine Disruptor Screening Program (EDSP),a series of in vitro and in vivo screening studies on endocrine activity covering mammalian and non-mammalian species were performed by industry and evaluated by the US EPA. A weight of evidence (WoE) assessment was performed by EPA and is publicly available since July 2015 (US EPA, Memorandum June 29, 2015, EDSP: Weight of evidence analysis of potential interaction with the estrogen, androgen or thyroid pathways, Chemical: o-phenylphenol (o-PP), https://www.epa.gov/sites/production/files/2015-06/documents/o-phenylphenol-064103_2015-06-29_txr0057146.pdf). In this assessment EPA concluded that OPP demonstrates no convincing evidence of a potential interaction with the estrogen, androgen or thyroid pathways in vivo in mammals (and that therefore EDSP Tier 2 testing is not recommended in mammalian species).

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