NIPACIDE SOPP

NIPACIDE SOPP

Nipacide SOPP is described chemically as sodium ortho-phenyl-phenol. Nipacide SOPP is recommended for a wide range of applications including sapstain inhibitor, adhesives, textiles, paper, fruit and vegetables, hide and leather, timber and building products and as a disinfectant active.

CAS No. : 90-43-7
EC No. : 201-993-5

Synonyms:
nipasid sopp; nipaside sopp; nipacide sopp; nipacid sopp; nıpasıd sopp; ortho-phenyl-phenol; Ortho-Phenylphenol; Sodyum ortho-Phenylphenate, Toxicity; ortho-phenyl-phenol; o-Phenylphenol; phenyl phenol; orthophenyl phenol; OPP; 2-phenylphenol; 2-biphenylol; 2-hydroxybiphenyl; Dowicide 1; Topane S; Lysol®; 2-Hydroxybifenyl [Czech]; Nipacide OPP; NSC 1548; 2-Hydroxy-1,1'-biphenyl; 2-Phenylphenol [BSI:ISO]; UNII-D343Z75HT8; Phenyl-2 phenol [ISO-French]; HSDB 1753; C12H10O; EINECS 201-993-5; 2-HYDROXYBIPHENYL (2-PHENYLPHENOL); 2-Phenylphenol, 99+%; Lyorthol; Tumescal 0PE; CAS-90-43-7; OPP [pesticide]; sodium o-phenylphenoate; sodium ortho-phenylphenol; Stellisept; Manusept; Rotoline; Xenol; o-phenyl-phenol; Tetrosin OE-N; EINECS 262-974-5; Amocid (TN); Preventol 3041; (1,1'-Biphenyl)-2-ol, chlorinated; PubChem8909; 2-Phenylphenol; OPP; Phenylphenol (ortho-); 2-Phenylphenol, 99%; OPP?; Hydroxy-2-ph enylbenzene; 2-Phenylphenol, BSI, ISO; 2-Phenylphenol, >=99%, FG; 2-Phenylphenol 100 microg/mL in Acetone; Dowicide A (OPPNa); Topane WS (OPPNa); Mystox WFA (OPPNa); 2-Phenylphenol; 2-Hydroxybiphenyl; 90-43-7; Biphenyl-2-ol; O-PHENYLPHENOL; 2-Biphenylol; o-Hydroxybiphenyl; 2-Hydroxydiphenyl; o-Hydroxydiphenyl; o-Phenyl phenol; [1,1'-Biphenyl]-2-ol; Phenylphenol; Biphenylol; Orthoxenol; o-Diphenylol; Orthophenylphenol; Torsite; o-Xenol; Dowicide 1; o-Biphenylol; Orthohydroxydiphenyl; Nectryl; Tumescal OPE; ortho-Phenylphenol; Preventol O extra; Remol TRF; (1,1'-Biphenyl)-2-ol; Phenol, o-phenyl-; Tetrosin oe; 1-Hydroxy-2-phenylbenzene; 2-Fenylfenol; 2-Hydroxybifenyl; o-Xonal; 2-Phenyl phenol; Biphenyl, 2-hydroxy-; Invalon OP; Anthrapole 73; 2-hydroxy biphenyl; Usaf ek-2219; 1,1'-Biphenyl-2-ol; Dowicide; Kiwi lustr 277; Hydroxdiphenyl; (1,1-Biphenyl)-2-ol; o-phenylphenate; 2-phenyl-phenol; o-Phenylphenol, cosmetic grade; Phenyl-2 phenol; Dowicide 1 antimicrobial; Orthophenyl phenol; ortho-phenylphenate; orthohydroxydipbenyl; Biphenyl-2-o1; NCI-C50351; Hydroxybiphenyl; 2-Fenylfenol [Czech]; Hydroxy-2-phenylbenzene; Caswell No. 623AA

Nipacide SOPP

Nipacide SOPP is a low toxicity biocide specifically developed for the complete microbiological protection of water based products against bacterial and fungal spoilage in the wet state. Nipacide SOPP is a solid. Nipacide SOPP is described chemically as sodium ortho-phenyl-phenol. Nipacide SOPP is recommended for a wide range of applications including sapstain inhibitor, adhesives, textiles, paper, fruit and vegetables, hide and leather, timber and building products and as a disinfectant active.

Ortho-phenylphenol (OPP) and its sodium (Nipacide SOPP) salt have been used world-wide for decades as fungicides and disinfectants. Nipacide SOPP is generally used as a hospital and household disinfectant, whereas Nipacide SOPP is used as a fungicide, which post-harvest treatment of citrus fruits and vegatables for the prevention of mold. Due to widespread use, including many consumer applications, the fate of OPP in the mammalian organism has been the subject of numerous investigations over many years. The aim of this review is to give information about OPP and Nipacide SOPP including metabolism, general toxicity, carcinogenicity and genotoxicity.

Ortho-phenylphenol (OPP, or 2-phenylphenol) and its water-soluble salt, sodium ortho-phenylphenate (Nipacide SOPP), are antimicrobial agents used as bacteriostats, fungicides, and sanitizers. Both have been used in agriculture to control fungal and bacterial growth on stored crops, such as fruits and vegetables. SOPP is applied topically to the crop and then rinsed off, leaving the chemical residue, Nipacide SOPP. Most agricultural food applications have been revoked, but OPP and SOPP are still used on pears and citrus (U.S.EPA, 2006).OPP is still used as a disinfectant fungicide for industrial applications, on ornamental plants and turfs, in paints, and as a wood preservative. In the past, it was used in home sanitizers for surfaces. OPP is volatile and has limited water solubility, whereas Nipacide SOPP is not volatile and is more water soluble. Both chemicals degrade within hours to weeks in the environment (U.S. EPA, 2006).

USES of Nipacide SOPP
Disinfectant

Nipacide SOPP, or o-phenylphenol, is an organic compound. In terms of structure, it is one of the monohydroxylated isomers of biphenyl. Nipacide SOPP is a white solid. Nipacide SOPP is a biocide used as a preservative with E number E231 and under the trade names Dowicide, Torsite, Fungal, Preventol, Nipacide and many others.

Uses of Nipacide SOPP
The primary use of Nipacide SOPP is as an agricultural fungicide. It is generally applied post-harvest. It is a fungicide used for waxing citrus fruits. It is no longer a permitted food additive in the European Union, but is still allowed as a post harvest treatment in 4 EU countries.

Nipacide SOPP is also used for disinfection of seed boxes. Nipacide SOPP is a general surface disinfectant, used in households, hospitals, nursing homes, farms, laundries, barber shops, and food processing plants. It can be used on fibers and other materials. It is used to disinfect hospital and veterinary equipment. Other uses are in rubber industry and as a laboratory reagent. It is also used in the manufacture of other fungicides, dye stuffs, resins and rubber chemicals.

Nipacide SOPP is found in low concentrations in some household products such as spray disinfectants and aerosol or spray underarm deodorants.

The sodium salt of orthophenyl phenol, sodium orthophenyl phenol, is a preservative, used to treat the surface of citrus fruits.

Orthophenyl phenol is also used as a fungicide in food packaging and may migrate into the contents.

Preparation of Nipacide SOPP
It is prepared by condensation of cyclohexanone to give cyclohexenylcyclohexanone. The latter undergoes dehydrogenation to give Nipacide SOPP.

A genome-wide transcriptome analysis of the cellular responses of Pseudomonas aeruginosa (P. aeruginosa) exposed to 0.82 mM Nipacide SOPP for 20 and 60 minutes was performed Ortho-phenylphenol (Nipacide SOPP) upregulated the transcription of genes encoding ribosomal, virulence and membrane transport proteins after both treatment times. After 20 minutes of exposure to 0.82 mM Nipacide SOPP, genes involved in the exhibition of swarming motility and anaerobic respiration were upregulated. After 60 minutes of Nipacide SOPP treatment, the transcription of genes involved in amino acid and lipopolysaccharide biosynthesis were upregulated. Further, the transcription of the ribosome modulation factor (rmf) and an alternative sigma factor (rpoS) of RNA polymerase were downregulated after both treatment times. Results from this study indicate that after 20 minutes of exposure to Nipacide SOPP, genes that have been linked to the exhibition of anaerobic respiration and swarming motility were upregulated. This study also suggests that the downregulation of the rmf and rpoS genes may be indicative of the mechanism by which Nipacide SOPP causes decreases in cell viability in P. aeruginosa. Consequently, a protective response involving the upregulation of translation leading to the increased synthesis of membrane related proteins and virulence proteins is possibly induced after both treatment times. In addition, cell wall modification may occur due to the increased synthesis of lipopolysaccharide after 60 minutes exposure to Nipacide SOPP. This gene expression profile can now be utilized for a better understanding of the target cellular pathways of Nipacide SOPP in P. aeruginosa and how this organism develops resistance to Nipacide SOPP.

The Agency has completed its assessment of the dietary, occupational, drinking water, and ecological risks associated with the use of pesticide products containing the active ingredient Nipacide SOPP and salts. The Agency has determined that Nipacide SOPP containing products are eligible for reregistration provided that: (i) current data gaps and confirmatory data needs are addressed; (ii) the risk mitigation measures outlined in this document are adopted; and (iii) label amendments are made to reflect these measures where necessary. ... Based on its evaluation of Nipacide SOPP and salts, the Agency has determined that Nipacide SOPP products, unless formulated and used as specified in this document, would present risks inconsistent with FIFRA. Accordingly, should a registrant fail to implement any of the risk mitigation measures identified in this document, the Agency may take regulatory action to address the risk concerns from the use of Nipacide SOPP. If all changes outlined in this document are incorporated into the product formulations, then all current risks for Nipacide SOPP and its salts will be substantially mitigated for the purposes of this determination. Once an Endangered Species assessment is completed, further changes to these registrations may be necessary as explained in Section III of this document.

Risks of Nipacide SOPP
Ingestion is toxic, expecially to small mammals (e.g., cats) and aquatic organisms. LD50 = 2480 mg/kg
Inhalation and contact may cause irritation and redness. Combustible. Flash point = 124 C (255 F)
May discolor textiles, especially silk.

Description of Nipacide SOPP
A Fungicide and Bactericide. Ortho-phenyl phenol (OPP) inhibits the growth of fungi and bacteria. Nipacide SOPP is effective at concentrations as low as 0.05% by weight. Nipacide SOPP is an ingredient in Lysol® and has been used as a fungicides in Starch, Glue, and Polyvinyl acetate emulsions. Dilute solutions have also been used for removing lichens from Granite. OPPNa, the sodium salt of ortho-phenyl phenol, is more soluble.

The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (Nipacide SOPP) were followed in six human male volunteers given a single 8 hr dermal dose of 6 ug Nipacide SOPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 hr post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). Following dermal application, peak plasma levels of radioactivity were obtained within 4 hr post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 hr post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of Nipacide SOPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 hr. Once absorbed the renal clearance of Nipacide SOPP was rapid with an average half-life of 0.8 hr. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of Nipacide SOPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. Approximately 73% of the total urinary radioactivity was accounted for as free Nipacide SOPP, Nipacide SOPP-sulfate and Nipacide SOPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary Nipacide SOPP equivalents (acid-labile conjugates+free Nipacide SOPP) can be used to estimate the systemically absorbed dose of Nipacide SOPP. The rapid excretion of Nipacide SOPP and metabolites into the urine following dermal exposure indicates that Nipacide SOPP is unlikely to accumulate in humans upon repeated exposure.

The relationship between the metabolism and the cytotoxicity of ortho-phenylphenol (Nipacide SOPP) was investigated using isolated rat hepatocytes. Addition of Nipacide SOPP (0.5-1.0 mM) to the hepatocytes caused a dose-dependent toxicity; 1.0 mM Nipacide SOPP caused acute cell death. Pretreatment of hepatocytes with SKF-525A (50 microM, a non-toxic level) enhanced the cytotoxicity of Nipacide SOPP (0.5-1.0 mM). This was accompanied by inhibition of Nipacide SOPP metabolism. Conversely, Nipacide SOPP at low concentrations (0.5 or 0.75 mM) was converted sequentially to phenyl-hydroquinol (PHQ) and then to glutathione (GSH) conjugate in the cells. The concentrations of both metabolites, especially PHQ-GSH conjugate, were very low in hepatocytes exposed to 1.0 mM Nipacide SOPP alone as well as with SKF-525A. The cytotoxicity induced by 0.5 mM Nipacide SOPP was enhanced by the addition of diethylmaleate (1.25 mM) which continuously depletes cellular GSH. In contrast, additions to hepatocytes of 5 mM of dithiothreitol, cysteine, N-acetyl-L-cysteine or ascorbic acid significantly inhibited the cytotoxicity induced by 0.5 mM PHQ; GSH, protein thiols and ATP losses were also prevented. Further, these compounds depressed the rate of PHQ loss in hepatocyte suspensions. These results indicate that the acute cytotoxicity caused by the high dose (1.0 mM) of Nipacide SOPP is associated with direct action by the parent compound; at low doses (0.5-0.75 mM) of Nipacide SOPP, the prolonged depletion of GSH in hepatocytes enhances the cytotoxicity induced by PHQ.

The metabolites of o-phenylphenol (Nipacide SOPP) /were identified/ in the urine of male and female rats dosed with 2% sodium o-phenylphenate (Nipacide SOPP-Na) in food from the age of 5 wk for 136 days. The urinary metabolites of Nipacide SOPP-Na produced during the 24 hr after Nipacide SOPP-Na feeding accounted for 55% of the dose in male rats and 40% in females. The main metabolites were Nipacide SOPP-glucuronide and 2,5-dihydroxybiphenyl (2,5-DHBP)-glucuronide. Nipacide SOPP metabolites in the free form accounted for only 1% of the total phenolic metabolites excreted. 2,5-DHBP was rapidly converted to the corresponding quinone in aqueous solvents but not in organic solvents. There was a clear sex difference in the proportions of urinary metabolites; the amount of 2,5-DHBP excreted by male rats in 24-hr urine was more than seven times that excreted by females.

The validity of in vitro and in vivo methods for the prediction of percutaneous penetration in humans was assessed using the fungicide ortho-phenylphenol (Nipacide SOPP) (log Po/w 3.28, MW 170.8, solubility in water 0.7 g/L). In vivo studies were performed in rats and human volunteers, applying the test compound to the dorsal skin and the volar aspect of the forearm, respectively. In vitro studies were performed using static diffusion cells with viable full-thickness skin membranes (rat and human), nonviable epidermal membranes (rat and human), and a perfused pig ear model. For the purpose of conducting in vitro/in vivo comparisons, standardized experimental conditions were used with respect to dose (120 ug Nipacide SOPP/sq cm), vehicle (60% aqueous ethanol), and exposure duration (4 hr). In human volunteers, the potentially absorbed dose (amount applied minus dislodged) was 105 ug/sq cm, while approximately 27% of the applied dose was excreted with urine within 48 hr. In rats these values were 67 ug/sq cm and 40%, respectively. In vitro methods accurately predicted human in vivo percutaneous absorption of Nipacide SOPP on the basis of the potential absorbed dose. With respect to the other parameters studied (amount systemically available, maximal flux), considerable differences were observed between the various in vitro models.

The pharmacokinetics and metabolism of uniformly labeled 14C/13C-ortho-phenylphenol (Nipacide SOPP) were followed in six human male volunteers given a single 8 h dermal dose of 6 microg Nipacide SOPP/kg body weight formulated as a 0.4% (w/v) solution in isopropyl alcohol. The application site was covered with a non-occlusive dome allowing free movement of air, but preventing the loss of radioactivity due to physical contact. At 8 h post-exposure the non-occlusive dome was removed, the dose site was wiped with isopropyl alcohol containing swabs and the skin surface repeatedly stripped with tape. Blood specimens, urine, and feces were collected from each volunteer over a 5 day post-exposure period and were analyzed for radioactivity and metabolites (urine only). 2. Following dermal application, peak plasma levels of radioactivity were obtained within 4 h post-exposure and rapidly declined with virtually all of the absorbed dose rapidly excreted into the urine within 24 h post-exposure. A one-compartment pharmacokinetic model was used to describe the time-course of Nipacide SOPP absorption and clearance in male human volunteers. Approximately 43% of the dermally applied dose was absorbed through the skin with an average absorption half-life of 10 h. Once absorbed the renal clearance of Nipacide SOPP was rapid with an average half-life of 0.8 h. The rate limiting step for renal clearance was the relatively slower rate of dermal absorption; therefore the pharmacokinetics of Nipacide SOPP in humans was described by a 'flip-flop' single compartment model. Overall, the pharmacokinetics were similar between individuals, and the model parameters were in excellent agreement with the experimental data. 3. Approximately 73% of the total urinary radioactivity was accounted for as free Nipacide SOPP, Nipacide SOPP-sulfate and Nipacide SOPP-glucuronide conjugates. The sulfate conjugate was the major metabolite (approximately 69%). Therefore, total urinary Nipacide SOPP equivalents (acid-labile conjugates+free Nipacide SOPP) can be used to estimate the systemically absorbed dose of Nipacide SOPP. 4. The rapid excretion of Nipacide SOPP and metabolites into the urine following dermal exposure indicates that Nipacide SOPP is unlikely to accumulate in humans upon repeated exposure. Based on these data, blood and/or urinary Nipacide SOPP concentration (acid-labile conjugates) could be utilized to quantify the amount of Nipacide SOPP absorbed by humans under actual use conditions.

The urinary metabolites from repeated oral doses of 3.7 mg o-phenylphenol (Nipacide SOPP) to mature and immature dogs and cats were studied. At both age levels, dogs excreted significantly more Nipacide SOPP as sulfate and glucuronide than did cats. Puppies produced 4 times the level of glucuronides than mature dogs. No such age differences were seen with glucuronide formation by cats, nor were there any age differences in either group of animals for sulfate formation. Some sex differences were observed in conjugation of Nipacide SOPP in cats and dogs. The dominant urinary excretion product of oral Nipacide SOPP administration was the unchanged Nipacide SOPP.

Ortho-phenylphenol (Nipacide SOPP) was well absorbed in the male B6C3F1 mouse, with 84 and 98% of the administered radioactivity recovered in the 0-48-hr urine of animals administered a single oral dose of 15 or 800 mg/kg respectively. High absorption and rapid elimination were also seen in the female and male F344 rat with 86 and 89% respectively of a single oral dose (27-28 mg/kg) found in the urine in 24 hr. Nipacide SOPP was also rapidly eliminated from human volunteers following dermal exposure for 8 hr (0.006 mg/kg), with 99% of the absorbed dose in the urine in 48 hr.. Sulfation of Nipacide SOPP was found to be the major metabolic pathway at low doses in all three species, accounting for 57, 82 and 69% of the urinary radioactivity in the male mouse (15 mg/kg, po), male rat (28 mg/kg, po) and male human volunteers (0.006 mg/kg, dermal). Nipacide SOPP-glucuronide was also present in all species, representing 29, 7 and 4% of the total urinary metabolites in the low dose groups of mouse, rat and human volunteers respectively. Conjugates of 2-phenylhydroquinone (PHQ) in these single-dose studies accounted for 12, 5 and 15% of the dose in mouse, rat and human, respectively. Little or no free Nipacide SOPP was found in any species. No free PHQ or PBQ was found in the mouse, rat or human (LOD = 0.1-0.6%). A novel metabolite, the sulfate conjugate of 2,4'-dihydroxybiphenyl, was identified in rat and man, comprising 3 and 13% of the low dose respectively. Dose-dependent shifts in metabolism were seen in the mouse for conjugation of parent Nipacide SOPP, indicating saturation of the sulfation pathway. Dose-dependent increases in total PHQ were also observed in mouse. This study was initiated to elucidate a mechanistic basis for the difference in carcinogenic potential for Nipacide SOPP between rat and mouse. However, the minor differences seen in the metabolism of Nipacide SOPP in these two species do not appear to account for the differences in urinary bladder toxicity and tumor response between mouse and rat.

Chronic administration of o-phenylphenol (Nipacide SOPP) is known to induce urinary bladder tumours in the Fischer rat. The underlying toxic mechanism is poorly understood. Recently, arachidonic acid (ARA)-dependent, prostaglandin-H-synthase (PHS)-catalysed metabolic activation of the Nipacide SOPP metabolite phenylhydroquinone (PHQ) to a genotoxic species was suggested to be involved in Nipacide SOPP toxicity. To investigate this hypothesis in more detail, we have studied the effects of Nipacide SOPP and its metabolites on PHS. When microsomal PHS from ovine seminal vesicles (OSV) was used as enzyme source, both Nipacide SOPP, PHQ, and 2-phenyl-1,4-benzoquinone (PBQ) inhibited PHS-cyclooxygenase. The inhibitory potency was inversely related to the ARA concentration in the assay; at 7 microM ARA IC50-values were: 13 microM (Nipacide SOPP), 17 microM (PHQ), and 190 microM (PBQ). In cells cultured from OSV, which express high PHS activity, 40 microM Nipacide SOPP almost completely suppressed prostaglandin formation. Studies with microsomal PHS demonstrated that PHQ was an excellent substrate for PHS-peroxidase; both ARA and hydrogen peroxide supported oxidation to PBQ. Nipacide SOPP was only a poor substrate for PHS, but inhibited the ARA-mediated and to a lesser extent also the hydrogen peroxide-mediated in vitro oxidation of PHQ. Moreover, PHQ at up to moderately cytotoxic concentrations (50 microM) did not induce micronuclei in OSV cell cultures. Taken together, our findings do not provide evidence for an ARA-dependent, PHS-catalysed formation of genotoxic species from PHQ. Moreover, it seems to be questionable whether such activation can effectively occur in vivo, since Nipacide SOPP and PHQ turned out to be efficient cyclooxygenase inhibitors, and high levels of Nipacide SOPP and PHQ were found at least in the urine of Nipacide SOPP-treated rats. On the other hand, inhibition of the formation of cytoprotective prostaglandins in the urogenital tract may play a crucial role in Nipacide SOPP-induced bladder carcinogenesis.