NTP Toxicology and Carcinogenesis Studies of o-Phenylphenol (CAS No. 90-43-7) Alone and with 7,12-Dimethylbenz(a)anthracene (CAS No. 57-97-6) in Swiss CD-1 Mice (Dermal Studies).
o-Phenylphenol is used primarily as a germicide and fungicide for citrus fruits and vegetables and was selected for carcinogenesis studies because of the potential for human exposure. Four-week studies were conducted in which groups of 10 male and 10 female Swiss Webster mice were given dermal applications to the dorsal interscapular region of 0, 6, 11, 21, 36, or 56 mg of o-phenylphenol in 0.1 ml of acetone. Doses were administered 3 days per week for 4 weeks, and animals were monitored for clinical changes. Reductions in body weights of acetone vehicle control were observed, but no compound-related changes in weight or survival occurred in male or female mice administered o-phenylphenol. o-Phenylphenol caused dose-related ulcerative lesions at the site of application. The severity of these lesions was judged not to be life threatening. Carcinogenesis studies were conducted to determine whether o-phenylphenol was a complete carcinogen for skin or a promoter in a two-stage initiation/promotion skin paint model. Groups of 50 Swiss CD-1 mice of each sex were used for up to 102 weeks. Five dose groups were used: an acetone vehicle control group; a positive control group initiated with 7,12-dimethylbenz(a)- anthracene (DMBA) and promoted with 12-O-tetradecanoylphorbol-13-acetate (TPA); an initiator control group that received DMBA plus acetone; a group that received repeated applications of o-phenylphenol. The following doses were applied dermally to a clipped area on the dorsal interscapular region 3 days per week: o-phenylphenol - 55.5 mg/0.1 ml acetone; or TPA - 0.005 mg/0.1 ml acetone. DMBA was administered as a single dose at a concentration of 0.05 mg/0.1 ml acetone to the dorsal interscapular region. In the 2-year studies, mean body weights of the o-phenylphenol, DMBA/o-phenylphenol, and DMBA/TPA groups were not markedly different from those of mice that received DMBA/acetone. Similarly, there were no significant group differences in survival except for a decrease in survival in the positive control group (DMBA/TPA). Skin neoplasms classified as squamous cell papillomas, squamous cell carcinomas, basal cell tumors, basal cell carcinomas, keratoacanthomas, or sebaceous adenomas occurred in mice dosed with DMBA/acetone, DMBA/o-phenylphenol, or DMBA/TPA alone. However, the incidence of skin neoplasms in mice dosed with DMBA/acetone (15/100) was similar to that in mice dosed with DMBA/o-phenylphenol (17/100). The incidence of skin neoplasms in male and female mice dosed with DMBA/TPA (52/100) was substantially greater than those in mice dosed with either DMBA/acetone or DMBA/o-phenylphenol. Similarly, the mean time of appearance of skin papillomas occurred much earlier in the DMBA/TPA groups than in the DMBA/acetone or DMBA/o-phenylphenol groups. All groups had nonneoplastic lesions consisting of inflammation, ulceration, hyperkeratosis, and acanthosis at the site of application. These lesions were present in the acetone vehicle control group and, to a larger extent, in the o-phenylphenol, DMBA/o-phenylphenol, and DMBA/TPA groups. No skin neoplasms were observed in male or female mice receiving o-phenylphenol or in the acetone vehicle control groups. Moreover, a complete histopathologic review revealed no other neoplasms at any other site at significantly increased incidences in the groups receiving o-phenylphenol compared with the acetone vehicle controls. There were also no tumor-enhancing (or tumor-inhibiting) effects of o-phenylphenol and DMBA given in combination. o-Phenylphenol was weakly mutagenic in strains TA1535 of Salmonella typhimurium only in the absence of rat liver S9; it was not mutagenic in strains TA1537, TA98, or TA100. It was mutagenic in the mouse lymphoma L5178/TK+/- assay in the presence or absence of Aroclor 1254-induced male F344 rat liver S9. o-Phenylphenol did not induce sex-linked recessive lethal mutations in Drosophila melanogaster. o-Phenylphenol induced sister-chromatid exchanges in Chinese hamster ovary (CHO) cells only in the absence of rat liver S9. It did not induce chromosomal aberraterrations in CHO cells in the presence or absence of Aroclor 1254-induced male Sprague-Dawley rat liver S9. An audit of the experimental data was conducted for these 2-year studies of o-phenylphenol. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year dermal application studies, there was no evidence of carcinogenicity in male or female Swiss CD-1 mice administered o-phenylphenol alone or as a promoter following initiation with DMBA. o-Phenylphenol, however, caused nonneoplastic lesions, which included ulceration, inflammation, and hyperkeratosis, at the site of application.