Proflavin

log Kow = 1.83 at pH 12.0

1.4

Red needles, hygroscopic. Sol in 300 parts cold water, in 1 part boiling water; slightly sol in alc. Practically insol in ether. pH of satd soln is 6-8. pH of 0.1 percent soln is 2.5 /Sulfate/

Soluble in ethanol. Practically insoluble in benzene and ether.

Soluble in water.

1.04e-01 g/L

284-286 °C

285 °C

Yellow solid; [Merck Index]

Solid

8.06 (at 20 °C)

pKa = 9.7

Warning

H302 (97.5%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 40 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Proflavine and its salts are used as topical antiseptics; No epidemiological studies available and animal data inadequate for evaluation; [IARC] Allergic contact dermatitis has been reported; [HSDB] Intraperitoneal LD50 (mouse) = 50 mg/kg; [Sax] An irritant; [MSDSonline]

The following link will take the user to the National Toxicology Program (NTP) Test Agent Search Results page, which tabulates all of the "Standard Toxicology & Carcinogenesis Studies", "Developmental Studies", and "Genetic Toxicity Studies" performed with this chemical. Clicking on the "Testing Status" link will take the user to the status (i.e., in review, in progress, in preparation, on test, completed, etc.) and results of all the studies that the NTP has done on this chemical. /Proflavin hydrochloride/ [http://ntp-apps.niehs.nih.gov/ntp_tox/index.cfm?fuseaction=ntpsearch.searchresults&searchterm=952-23-8]

/SPECIAL STUDIES/ The induction of unscheduled DNA synthesis (UDS) and the alteration of semiconservative DNA replication by the structurally related intercalating agents proflavine and 9-aminoacridine were studied in MRC-5 human fibroblasts in culture ... Proflavine affected DNA synthesis, but did not elicit any UDS.

/LABORATORY ANIMALS: Acute Exposure/ A study of the photosensitizing effects of 8-methoxypsoralen (MOP), neutral red (NR), and proflavine (PF) on the skin of female Swiss albino mice, strain 955, was carried out using fractionated exposure to long ultraviolet light (300-400 nm) and visible light (tungsten emission). The results (1) confirmed MOP photocarcinogenicity, (2) demonstrated that both NR and PF are photocarcinogens, and, further, (3) showed that the above UV light with 2.6% of fluence at 313 nm is a long-term carcinogenic agent even though the total dose of 313 nm was 100 times less than the minimal UV tumorigenic dose in mice. The tumors were mammary adenocarcinomas, carcinomas of skin appendages, carcino-mixo-sarcomas, lymphomas, and one case of thyroid adenocarcinoma. The implications of the above data regarding the controversy about oncogenic risks in photochemotherapy are discussed.

/LABORATORY ANIMALS: Subchronic or Prechronic Exposure/ In a study in which the tumor promoting effect of sclerosing agents was investigated on skin initiated with 2,10-dimethyl-1,2-benzanthracene, a control group of 20 male albino 's' strain mice were given weekly skin applications of 0.3 ml of a 1% solution of proflavine hemisulfate (B.P.) alone in 1:2 water:carbowax 300 for 24 weeks. No tumors were found in this group within 31 weeks. In addition, no tumor-promoting effet of proflavine hemisulfate was noted in this experiment. /Proflavine hemisulfate/

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Proflavine monochloride, as the hemihydrate (percentage of amine, 103.4 + or - 0.3% of the theoretical amount; minor unidentified impurities present), was administered in the diet at concentrations of 300 or 600 mg/kg diet to groups of 50 male and 50 female Fischer 344/ CR rats, 5-6 weeks of age, for 109 weeks. In male rats in the high-dose group, 3/48 leiomyosarcomas of the small intestine, 1/48 adenocarcinoma of the small intestine, 1/48 sarcoma of the large intestine and 1/49 hepatocellular carcinoma occurred; 1/50 females in the high-dose grup developed a hepatocellular carcinoma. Hepatocellular carcinomas occurred in 1/50 males and 2/50 females in the low-dose group. None of these tumors occurred in the control group. The incidences of other neoplasms in treated animals were approximately the same or lower than those reported for controls. /Proflavine monochloride hemihydrate/

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Groups of 50 male and 50 female B6C3F1 mice, 5-6 weeks of age, were fed diets containing 200 or 400 mg/kg diet proflavine monohydrochloride, as the hemihydrate, for up to 104 weeks. (The percentage of amine was 103.4 + or - 0.3% of the theoretical amount; minor unidentified impurities were present.) Of the treated mice, 20/49 females (p < 0.001) and 28/49 males in the low-dose groups and 22/50 females (p < 0.01) and 30/50 males (p = 0.04) in the high-dose group developed hepatocellular carcinomas, compared with 4/50 and 20/49, respectively, in the controls. Hemangiosarcomas of the liver developed in 0/49 females and 6/49 males in the low-dose group and in 2/50 females and 3/50 males in the high-dose group, compared with 1/50 and 6/49, respectively, in the controls. The overall incidence of malignant lymphomas was high: 16/50 females and 11/50 males in the low-dose group, and 20/50 and 11/50, respectively, in the controls. Because a positive control carcinogen, N-2-fluorenylacetamide, was tested in the same room with these animals, the authors questioned the validity of these bioassay results; the statistical inference was made, however, that in female mice there was a strong association of development of hepatocellular carcinomas with the dose of proflavine monohydrochloride hemihydrate administered. /Proflavine monohydrochloride hemihydrate/

For more Non-Human Toxicity Excerpts (Complete) data for PROFLAVINE (12 total), please visit the HSDB record page.

Classification of carcinogenicity: 1) evidence in humans: no data; 2) evidence in animals: limited. Overall summary evaluation of carcinogenic risk to humans is Group 3: The agent is not classifiable as to its carcinogenicity to humans. /Proflavine salts; From table/

/SRP:/ Basic treatment: Establish a patent airway. Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with normal saline during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 ml/kg up to 200 ml of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poison A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in respiratory arrest. Positive pressure ventilation techniques with a bag valve mask device may be beneficial. Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start an IV with D5W /SRP: "To keep open", minimal flow rate/. Use lactated Ringer's if signs of hypovolemia are present. Watch for signs of fluid overload. Consider drug therapy for pulmonary edema ... . For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam (Valium) ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poison A and B/

A bioassay of the carcinogenicity of proflavine monohydrochloride hemihydrate was conducted using Fischer 344/CR rats and B6C3F1 mice. The compound was administered in the diet at concentrations of 300 and 600 ppm to groups of 50 rats for 109 weeks and at concentrations of 200 and 400 ppm to groups of 50 mice for 104 weeks. The animals were subjected to necropsy and histopathologic evaluation as they died or at the end of their periods of treatment. Average weights attained by high-dose groups were consistently lower than those of control groups; weights of low-dose groups showed essentially no differences from those of the controls. Survival rates of the treated rats and mice did not differ from those of the controls except for a lower rate among the female mice. Five malignant neoplasms of the intestinal tract consisting of three leiomyosarcomas of the small intestine, a sarcoma near the colon area, and an adenocarcinoma of the small intestine were observed in five of the high-dose male rats. None were observed in other treatment or control groups. If these five intestinal neoplasms are considered together, they aresignificant at the P=0.026 level using the Fisher exact test. A positive dose-related trend (P=0.034) was also present for the three leiomyosarcomas. The observed incidence of hepatocellular carcinoma in female mice was 4/50 (8%) in the control group, 20/49 (41%) in the low-dose group, and 22/50 (44%) in the high-dose group. The test for dose-related trend showed a level of significance of P<0.001. In male mice, the observed incidence of hepatocellular carcinoma was 20/49 (41%) in the control group 28/49 (57%) in the low-dose group, and 30/50 (60%) in the high-dose group. The dose-related trend was significant at P=0.057, and the high dose was significant at P=0.044. The unusually high incidence of hepatocellular carcinomas and hemangiosarcomas in control male mice and the unusually high incidence of malignant lymphomas in all groups of female mice in conjunction with the fact that a positive-control carcinogen was tested in the same room with these animals, raises a question of the validity of these bioassay results. /Proflavine monohydrochloride hemihydrate (CAS No. 952-23-8)/

LD50 mouse intraperitoneal 50 mg/kg

LD50 mouse subcutaneous 140 mg/kg

Proflavine is an acriflavine derivative which is a disinfectant bacteriostatic against many gram-positive bacteria. Proflavine is toxic and carcinogenic in mammals and so it is used only as a surface disinfectant or for treating superficial wounds.

Proflavine acts by interchelating DNA (intercalation), thereby disrupting DNA synthesis and leading to high levels of mutation in the copied DNA strands. This prevents bacterial reproduction.

The ability of proflavine (3,6-diaminoacridine) and its 2,7-dimethyl, 2,7-diethyl, 2,7-diisopropyl and 2,7-di-tert.-butyl derivatives to induce the 'petite' mutation in Saccharomyces cerevisiae has been studied in relation to the DNA-binding properties of the compounds. The nature of the binding has been investigated by nuclear magnetic resonance techniques, and the results support and clarify earlier suggestions that the first 3 members of the series intercalate into DNA while the diisopropyl and di-tert.-butyl compounds do not. Toxicity of the drugs was primarily associated with their mode of DNA binding, but lipophilicity had an important secondary effect. It seems likely that the toxic properties of the more lipophilic DNA-intercalating members of the series mask their potential for 'petite' mutagenesis.

The toxicities of several aminoacridines were measured against pathogenic strains of both Gram-positive (Staphylococcus aureus, Enterococcus faecalis, Bacillus cereus) and Gram-negative (Escherichia coli, Pseudomonas aeruginosa) organisms. In several cases, illumination at a light dose of 6.3 J/cm2 resulted in considerable decreases in the minimum lethal drug concentrations required, giving up to 50-fold increases in bactericidal activity. Derivatives of 9-aminoacridine (aminacrine) exhibited phototoxicity against one or more of the test organisms, but the established photosensitizing acridines proflavine and acridine orange were photobactericidal against all strains.

Proflavine (3,6-diaminoacridine) has potential for use as an antiinfective in fish, and its metabolism by rainbow trout was therefore studied. Fourteen hours after intraarterial bolus administration of 10 mg/kg of proflavine, three metabolites were found in liver and bile, and one metabolite was found in plasma using reversed-phase HPLC with UV detection at 262 nm. Treatment with hydrochloric acid converted the three metabolites to proflavine, which suggested that the metabolites were proflavine conjugates. Treatment with beta-glucuronidase and saccharic acid 1,4-lactone, a specific beta-glucuronidase inhibitor, revealed that two metabolites were proflavine glucuronides. For determination of UV-VIS absorption and mass spectra, HPLC-purified metabolites were isolated from liver. Data from these experiments suggested that the proflavine metabolites were 3-N-glucuronosyl proflavine (PG), 3-N-glucuronosyl,6-N-acetyl proflavine (APG), and 3-N-acetylproflavine (AP). The identities of the metabolites were verified by chemical synthesis. When synthetic PG and AP were compared with the two metabolites isolated from trout, they had the same molecular weight as determined by matrix-assisted, laser desorption ionization, time-of-flight MS. In addition, they coeluted on HPLC under different mobile phase conditions. Finally, the in vitro incubation with liver subcellular preparations confirmed this characterization and provided the evidence that APG can be formed by glucuronidation of AP or acetylation of PG.

A liquid chromatographic (LC) method was developed for determination of acriflavine (ACR) and proflavine (PRO) residues in channel catfish muscle. Residues were extracted with acidified methanol solution, and extracts were cleaned up with C18 solid-phase extraction columns. Residue concentrations were determined on an LC cyano column, with spectrophotometric detection at 454 nm. Catfish muscle was individually fortified with ACR (purified from commercial product) and PRO at concentrations of 5, 10, 20, 40, and 80 ppb (5 replicates per level). Mean recoveries from fortified muscle at each level ranged from 86 to 95%, with relative standard deviations (RSDs) of 2.5 to 5.7%. The method was applied to incurred residues of ACR and PRO in muscle after waterborne exposure of channel catfish to commercial acriflavine (10 ppm total dye for 4 h). RSDs for incurred residues of ACR and PRO were in the same range as those for fortified muscle. Low residue concentrations (< 1% of exposure water concentration) suggested poor absorption of ACR and PRO in catfish.

The uptake of the fluorescent drug proflavine was measured in suspensions of hepatocytes from normal and carcinogen (2-acetylaminofluorine, AAF)-fed rats by flow cytometry. Drug uptake into hepatocytes from carcinogen-fed animals was consistently lower than that into hepatocytes from normal animals. Isolated nuclei, prepared from the livers of normal and AAF-fed rats showed similar proflavine uptake. Drug uptake into hepatocytes from AAF-fed animals, however, was increased by prior exposure to a metabolic inhibitor. Thus, differences in drug uptake may reflect changes in the cell membrane, together with an alteration in the metabolic integrity of the cells. The uptake of drug in hepatocytes from AAF-fed rats was uniformly low within each cell preparation. However, drug uptake varied not only between tumours arising in the livers of these animals but also within each tumour cell preparation. This study indicates that flow cytometry can provide an effective means for analysing drug uptake into cell populations arising during hepatocarcinogenesis.

1. The disposition of proflavine (PRO) and acriflavine (ACR) were examined in channel catfish after intravascular (i.v.) dosing (1 mg/kg) or waterborne exposure (10 mg/l for 4 h). 2. After i.v. dosing, plasma concentration-time profiles of parent PRO and ACR were best described by two- and three-compartment pharmacokinetic models respectively. Terminal elimination half-lives of PRO and ACR in plasma were 8.7 and 11.4 h respectively. 3. In animals dosed with 14C-PRO or 14C-ACR, total drug equivalent concentrations were highest in the excretory organs and lowest in muscle, fat and plasma. In PRO-dosed animals, residues in the liver and trunk kidney were composed primarily of glucuronosyl and acetyl conjugates of PRO; residues in muscle were composed mostly (> 95%) of the parent drug. In ACR-dosed animals, the parent compound comprised > 90% of the total residues in all tissues examined. 4. PRO and ACR were poorly absorbed in catfish during waterborne exposure. At the end of a 4-h exposure, parent PRO and ACR concentrations in muscle were 0.064 and 0.020 microgram/g respectively. Levels in muscle declined below the limit of determination (0.005 microgram/g) within 1-2 weeks.

Used as a topical antiseptic; [Merck Index] Proflavine impregnated wool is used by some UK plastic surgeons; [HSDB] Used in the treatment of psoriasis and herpesvirus infections; [NTP]

Using Disinfectants or Biocides [Category: Clean]

The survival of Salmonella dublin exposed to visible sunlight, and heterotrophic bacteria in freshwater microcosms in the presence and absence of the photosensitizer proflavine, was studied. Enumeration of S. dublin and the heterotrophic bacteria showed that in both illuminated and nonilluminated systems (without proflavine) the bacteria remained viable and culturable for at least 6 days. The optimal proflavine concentration (no effect in the dark and a maximal photoinactivation of salmonellae after irradiation) was 2 mg l(-1). In contrast to S. dublin, the heterotrophic bacteria overcame the initial inhibitory effect of proflavine. The possible use of photosterilization against contamination with pathogenic bacteria in water model ecosystems, is discussed.