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Nonoxynol-9
Nonoxynol-9
Nonoxynol-9
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Nonoxynol-9
Partially condensed skeletal formula of nonoxynol-9
Partially condensed skeletal formula of nonoxynol-9
Ball-and-stick model of a nonoxynol-9 molecule.
Ball-and-stick model of a nonoxynol-9 molecule.
Names
Preferred IUPAC name
26-(4-Nonylphenoxy)-3,6,9,12,15,18,21,24-nonaoxahexacosan-1-ol[1]
Other names
1-(4-Nonylphenyl)-1,4,7,10,13,16,19,22,25-nonaoxaheptacosan-27-ol[citation needed]
Identifiers
3D model (JSmol)
2031786
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.043.454 Edit this at Wikidata
EC Number
  • 247-816-5
KEGG
MeSH Nonoxynol
UNII
  • InChI=1S/C33H60O10/c1-2-3-4-5-6-7-8-9-32-10-12-33(13-11-32)43-31-30-42-29-28-41-27-26-40-25-24-39-23-22-38-21-20-37-19-18-36-17-16-35-15-14-34/h10-13,34H,2-9,14-31H2,1H3 checkY
    Key: FBWNMEQMRUMQSO-UHFFFAOYSA-N checkY
  • CCCCCCCCCc1ccc(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)cc1
  • CCCCCCCCCC1=CC=C(OCCOCCOCCOCCOCCOCCOCCOCCOCCO)C=C1
  • O(c1ccc(cc1)CCCCCCCCC)CCOCCOCCOCCOCCOCCOCCOCCOCCO
Properties
C33H60O10
Molar mass 616.833 g·mol−1
log P 4.02
Pharmacology
Topical
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
☒N verify (what is checkY☒N ?)

Nonoxynol-9, sometimes abbreviated as N-9, is an organic compound that is used as a surfactant. It is a member of the nonoxynol family of nonionic surfactants. N-9 and related compounds are ingredients in various cleaning and cosmetic products. It is widely used in contraceptives for its spermicidal properties.

Uses

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Spermicide

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As a spermicide, it attacks the acrosomal membranes of the sperm, causing the sperm to be immobilized. Nonoxynol-9 is the active ingredient in most spermicidal creams, jellies, foams, gel, film, and suppositories.[citation needed]

Lubricant

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Nonoxynol-9 is a common ingredient of most vaginal and anal lubricants due to its spermicidal properties.

A 2004 study found that over a six-month period, the typical-use failure rates for five nonoxynol-9 vaginal contraceptives (film, suppository, and gels at three different concentrations) ranged from 10% to 20%.[2]

Condoms

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Many models of condoms are lubricated with solutions containing nonoxynol-9. In this role, it has been promoted as a backup method for avoiding pregnancy and a microbicide for sexually transmitted diseases in the event of condom failure. However, the 2001 WHO / CONRAD Technical Consultation on Nonoxynol-9 concluded that: There is no published scientific evidence that N-9-lubricated condoms provide any additional protection against pregnancy or STDs compared with condoms lubricated with other products. Since adverse effects due to the addition of N-9 to condoms cannot be excluded, such condoms should no longer be promoted. However, it is better to use N-9-lubricated condoms than no condoms.[3]

Compared to regular lubricated condoms, condoms containing nonoxynol-9 present another disadvantage — they are limited by the shelf-life of the spermicide. [4]

Cervical barriers

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Almost all brands of diaphragm jelly contain nonoxynol-9 as the active ingredient. This jelly may also be used for a cervical cap. Most contraceptive sponges contain nonoxynol-9 as an active ingredient.

Shaving cream

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Nonoxynol-9 is sometimes included in shaving creams for its properties as a nonionic surfactant; it helps break down skin oils that normally protect hair from moisture, so that they become wet and, hence, softer and easier to shave. Gillette formerly used nonoxynol-9 for this purpose in its Foamy products, but has discontinued the practice.

Sports cream

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Nonoxynol-9 is also found in Bengay Vanishing Scent as an inactive ingredient.

Poison ivy creams

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Nonoxynol-9 is also found in Zanfel poison ivy cream. It effectively helps to break up the oil urushiol that causes the rash.

Side effects

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From 1996 to 2000, a UN-sponsored study conducted in several locations in Africa followed nearly 1,000 sex workers who used nonoxynol-9 gels or a placebo. The HIV infection rate among those using nonoxynol-9 was about 50% higher than those who used the placebo; those using nonoxynol-9 also had a higher incidence of vaginal lesions, which may have contributed to this increased risk. Whereas these results may not be directly applicable to lower-frequency use, these findings combined with lack of any demonstrated HIV-prevention benefit from nonoxynol-9 use led the World Health Organization to recommend that it no longer be used by those at high risk of HIV infection. The WHO further notes that "Nonoxynol-9 offers no protection against sexually transmitted infections such as gonorrhoea, chlamydia."[3] A 2006 study of a nonoxynol-9 vaginal gel in female sex workers in Africa concluded that it did not prevent genital human papillomavirus (HPV) infection and could increase the virus's ability to infect or persist.[5]

References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Nonoxynol-9

View on Grokipedia
from Grokipedia
Nonoxynol-9, chemically known as nonaethylene glycol nonylphenyl ether, is a synthetic nonionic utilized as the in many over-the-counter vaginal spermicides. It acts by damaging cell membranes, leading to immobilization and death of spermatozoa, and has been employed in contraceptive products for over six decades. When used correctly and consistently as a standalone method, nonoxynol-9 provides only moderate protection against , with typical first-year failure rates ranging from 18% to 29% due to factors such as inconsistent application and rapid . Its efficacy improves substantially when combined with barrier methods like diaphragms or condoms, though formulation variations among products containing 100 mg doses show minimal differences in pregnancy risk. Despite early in vitro studies indicating potential inactivation of and other sexually transmitted pathogens, randomized controlled trials have established that nonoxynol-9 fails to reduce HIV acquisition and, with frequent use, may elevate transmission risk by causing mucosal irritation, epithelial disruption, and ulceration in the or . Health authorities, including the and Centers for Disease Control and Prevention, advise against its use for STI prevention, particularly among high-risk populations such as sex workers, and recommend limiting applications to avoid genital lesions that compromise barrier integrity. This discrepancy between laboratory promise and clinical outcomes fueled controversy in the late 1990s and early , as initial promotion of nonoxynol-9 for dual contraceptive and microbicide roles was retracted following evidence of null or adverse effects on STI rates.

Chemical Properties and Mechanism of Action

Molecular Structure and Synthesis

Nonoxynol-9, chemically designated as α-(4-nonylphenyl)-ω-hydroxynona(oxy-1,2-ethanediyl), possesses the molecular formula C33H60O10 and a of 616.8 g/mol. Its structure features a hydrophobic nonylphenyl moiety—a branched C9 alkyl chain attached to a para-position on a ring—linked via an oxygen to a hydrophilic polyoxyethylene chain consisting of nine (–CH2CH2O–) repeat units, terminating in a primary hydroxyl group. This amphiphilic architecture, with the nonpolar tail and polar head, underpins its properties. Commercial nonoxynol-9 is not a single compound but a polydisperse resulting from industrial synthesis, exhibiting a of ethoxylate chain lengths centered around an average of nine units, as confirmed by gas chromatography-mass spectrometry analysis. The synthesis of nonoxynol-9 involves the base-catalyzed of with . (C15H24O), derived from the of phenol with nonene, is reacted with approximately nine equivalents of under elevated temperature and pressure in the presence of a catalyst such as sodium or . This nucleophilic adds the oxyethylene units sequentially to the phenolic oxygen, yielding the desired average chain length; the reaction conditions control the , though variability persists due to the nature of the process. Purification typically involves removal of unreacted materials and catalysts to meet pharmaceutical standards.

Physical and Chemical Characteristics

Nonoxynol-9 is a nonionic characterized as a at room temperature, typically appearing colorless to light yellow. Its molecular formula is C₃₃H₆₀O₁₀, corresponding to the of nonaethylene glycol nonylphenyl , with a molecular weight of 616.83 g/mol. Physically, it exhibits a of 6°C and a of 250°C, with a of 197°C (closed cup), indicating combustibility but low volatility under ambient conditions. The substance has a dynamic ranging from 175 to 250 cP at 25°C, contributing to its use in formulations requiring emulsification or thickening. Its relative vapor density exceeds 1 (air = 1), and it shows moderate in , as well as miscibility with , , vegetable oils, and , reflecting its amphiphilic nature as a polyethoxylated compound. Chemically, nonoxynol-9 demonstrates stability in neutral to mildly acidic or alkaline environments typical of pharmaceutical applications, though it may degrade under extreme or oxidative conditions; it does not ionize in solution, maintaining nonionic behavior essential for its activity. No significant threshold or pH deviation from neutrality in dilute solutions is reported in standard references.

Spermicidal Mechanism

Nonoxynol-9 functions as a by acting as a non-ionic that targets the lipid-rich plasma membrane of spermatozoa. Upon contact, it incorporates into the membrane's , destabilizing its structure through detergent-like solubilization of phospholipids and . This interaction compromises membrane integrity, causing rapid leakage of cellular contents, loss of osmotic balance, and ultimate cell . The process immobilizes within seconds to minutes at spermicidal concentrations (typically ≥0.05% w/v), preventing flagellar and acrosomal function essential for fertilization. Beyond initial disruption, nonoxynol-9 induces secondary damage, including generation of (ROS) and enzymatic inactivation, which exacerbate membrane breakdown and confirm sperm death rather than mere reversible immobilization. assays, such as those measuring viability via dye exclusion or electron microscopy, reveal ultrastructural changes like membrane blebbing and fragmentation as early as 5-10 minutes post-exposure. This non-specific action extends to other enveloped pathogens but is optimized in formulations for vaginal application to achieve localized at pH levels compatible with seminal fluid. Peer-reviewed studies consistently attribute the contraceptive reliability of nonoxynol-9-containing products to this membrane-lytic pathway, though diminishes with suboptimal dosing or repeated exposure due to potential dilution.

Interactions with Biological Tissues

Nonoxynol-9, a non-ionic surfactant, primarily interacts with biological tissues through disruption of cell membrane integrity, a mechanism analogous to its spermicidal action on spermatozoa. In vitro studies demonstrate that N-9 exhibits cytotoxicity toward cervical and vaginal epithelial cells by lysing lipid bilayers, leading to cell death at concentrations as low as 50 μg/mL after 6 hours of exposure in HeLa 229 and monkey cervical epithelial cell models. This membrane disruption triggers inflammatory responses, including release of interleukin-1α/β (IL-1α/β), activation of nuclear factor-kappa B (NF-κB), and upregulation of interleukin-8 (IL-8) in epithelial monolayers, contributing to localized inflammation. In vivo and ex vivo assessments reveal that repeated N-9 application damages mucosal barriers, particularly in the vaginal and rectal epithelia. Colposcopic evaluations and animal models indicate epithelial exfoliation and increased inflammatory scores with higher doses or frequencies, such as in vaginas where escalating N-9 amounts correlated with graded inflammatory changes. Rectal administration in mice has shown rapid shedding of epithelial sheets, elevating susceptibility to pathogens by compromising . Human studies link frequent use (e.g., multiple daily applications) to heightened , including disruption of the , though some long-term users experience minimal shifts in dominated by . These interactions underscore N-9's dose- and frequency-dependent , with lower sensitivity observed in passaged or immortalized epithelial cells compared to primary isolates, potentially due to adaptive changes in composition. Such effects have prompted warnings against overuse, as mucosal damage may paradoxically facilitate transmission despite microbicidal intent.

History and Development

Discovery and Early Formulation

Nonoxynol-9, a nonylphenol ethoxylate with nine ethylene oxide units, was developed as a nonionic surfactant in the mid-20th century, with its spermicidal properties identified during screening of surface-active agents for contraceptive applications in the 1950s. This compound belongs to the broader class of alkylphenol ethoxylates, which were synthesized to leverage their detergent-like ability to disrupt lipid membranes, a mechanism later confirmed effective against spermatozoa. Early research built on 19th-century efforts to test substances for sperm immobilization, transitioning to synthetic surfactants after initial reliance on quinine and other natural agents proved inconsistent. No single inventor is credited; rather, it arose from industrial chemistry advancements by firms producing ethoxylated phenols for emulsification and wetting, with spermicidal utility demonstrated through in vitro motility assays. Initial formulations emphasized vaginal delivery for localized spermicidal action, typically incorporating 2-12% nonoxynol-9 in water-based vehicles to ensure rapid dispersion and contact with ejaculated . Common early products included creams and jellies, which provided sustained release via thickening agents like glycerin or derivatives, allowing insertion 10-15 minutes prior to intercourse for optimal . Foams emerged shortly thereafter, generated from dispensers to mimic natural while achieving broad coverage; these were preferred for ease of use and lower compared to gels. By the , nonoxynol-9 spermicides became widely available over-the-counter in the United States, marking a shift toward accessible non-hormonal contraception amid growing demand post-approval of oral pills. These formulations prioritized stability and , though early studies noted potential for epithelial irritation due to the surfactant's amphiphilic nature.

Introduction as a Contraceptive Agent

Nonoxynol-9, a nonionic , was developed in the as a more effective spermicidal chemical and first commercialized in contraceptive formulations during the . It rapidly became the predominant active ingredient in over-the-counter vaginal spermicides, including foams, creams, jellies, films, and suppositories, intended for intravaginal application shortly before intercourse to disrupt and viability. These products were marketed for standalone use or in combination with barrier methods like diaphragms, offering a non-hormonal alternative amid the era's expanding contraceptive options following the introduction of the oral pill in 1960. Regulatory approval in the United States occurred under less rigorous standards than today, relying primarily on laboratory demonstrations of spermicidal action—such as rapid sperm immobilization in vitro—rather than large-scale clinical trials assessing real-world pregnancy rates. Early formulations, like those in brands such as Emko foam, delivered standardized doses (typically 100-150 mg per application) to ensure sufficient concentration for efficacy, with instructions emphasizing timely insertion and avoidance of douching post-use. By the late 1960s, nonoxynol-9 spermicides were widely accessible without prescription, reflecting confidence in their safety and mechanism as a detergent-like agent that lyses sperm cell membranes. Initial adoption was driven by its perceived advantages over prior spermicides, including higher potency and compatibility with latex barriers, though long-term tissue effects were not thoroughly evaluated at launch. Usage peaked in the 1970s and 1980s, with millions of units sold annually, positioning nonoxynol-9 as a cornerstone of chemical contraception before subsequent research highlighted limitations in preventing unintended pregnancies and potential mucosal disruptions.

Evolution of Research and Applications

Nonoxynol-9 was initially developed in the as a nonionic with spermicidal properties, entering commercial use in over-the-counter contraceptive formulations such as gels, foams, creams, and suppositories by the . Early focused on its ability to disrupt cell membranes through its action, establishing it as a primary in vaginal contraceptives for over 60 years. By the 1970s, it was widely incorporated into products like lubricants, with manufacturers promoting its dual role in prevention and potential benefits. In the late 1970s and 1980s, laboratory studies demonstrated nonoxynol-9's inactivation of pathogens causing , , , , and , prompting its evaluation as a candidate microbicide for (STI) prevention. This led to its addition to condoms and sexual lubricants in the late 1980s, amid hopes it could enhance barrier methods against emerging HIV threats, particularly in high-risk populations. Initial epidemiologic data suggested possible protection against bacterial STIs when used with diaphragms, fueling further applications beyond contraception. However, these findings were preliminary and not derived from randomized controlled trials. The and early marked a shift as clinical trials revealed limitations. Randomized studies among commercial sex workers in , including a 1995-1997 trial in and a 2000 trial across multiple sites, found no reduction in or gonorrhea/ incidence with frequent nonoxynol-9 gel use; instead, infection rates were approximately 50% higher in the treatment groups due to epithelial disruption facilitating viral entry. A 2002 review of these and other trials concluded nonoxynol-9 was ineffective for prevention and contraindicated for frequent users at high STI risk, leading to its removal from many products and restrictions in by pharmaceutical firms in several European countries. Subsequent research refined its role to standalone spermicidal use with caveats, emphasizing low (around 72% typical-use prevention when used alone) and risks of vaginal , which could increase HIV susceptibility in low-mucus environments. By the mid-2000s, guidelines from bodies like the CDC and WHO advised against nonoxynol-9 for STI protection, redirecting microbicide development to less cytotoxic agents, while its contraceptive applications persisted in limited OTC contexts despite declining popularity due to hormonal alternatives. Recent studies continue to affirm its sperm-immobilizing mechanism but highlight microbiota disruption as a persistent concern, underscoring a research pivot toward safer formulations.

Primary Uses

Contraceptive Applications

Nonoxynol-9 functions as a spermicidal agent in over-the-counter vaginal contraceptives, primarily by acting as a nonionic that disrupts cell membranes, leading to immobilization and rapid inactivation of spermatozoa. These products are formulated for intravaginal insertion shortly before intercourse, with common types including water-based gels, creams, foams, suppositories, dissolvable thin films, and sponges impregnated with the at concentrations typically ranging from 2% to 12.5%. Application instructions generally require users to insert the product deep into the , allowing 5-15 minutes for dispersion and activation prior to coitus, with reapplication advised for additional acts of intercourse occurring more than one hour after initial use or after . To augment spermicidal effects, nonoxynol-9 is frequently used adjunctively with barrier methods such as diaphragms, cervical caps, or / condoms, where it provides chemical backup to mechanical blockage by coating the device or being applied separately to target in the vaginal environment. The U.S. has categorized nonoxynol-9-based vaginal contraceptives as and effective for pregnancy prevention when directions are followed, permitting their sale without prescription since their approval in the mid-20th century. However, product labeling mandates disclosure that these formulations offer no protection against sexually transmitted infections, emphasizing their limitation to fertility control.

Non-Contraceptive Applications

Nonoxynol-9 has been explored as a topical microbicide for preventing sexually transmitted infections (STIs), including , due to its nonionic action that disrupts envelopes of viruses and in laboratory settings. experiments by the late 1980s revealed inhibitory effects against , , and HIV-1, prompting its evaluation as a female-initiated barrier method independent of contraceptive intent. , such as those in macaques exposed to , further supported potential efficacy by demonstrating pathogen inactivation without systemic toxicity. Clinical investigations advanced to randomized controlled trials in the and early , testing formulations including gels (e.g., 2% concentration applied up to four times daily), films, and sponges among high-risk groups like sex workers in and . A of five such trials involving 3,454 participants found no protective effect against acquisition (relative risk 1.12, 95% CI 0.88-1.42), with frequent use correlating to epithelial disruption and genital ulceration that paradoxically heightened susceptibility. Similar outcomes emerged for bacterial STIs, where nonoxynol-9 exhibited variable antibacterial activity but failed to reduce infection rates , often enhancing adherence to damaged mucosa. Limited applications extended to topical creams for recurrent simplex, based on early observations of virucidal potential against herpesviruses in , though controlled efficacy data remain sparse and not indicative of routine therapeutic adoption. Overall, despite initial mechanistic promise, clinical evidence established nonoxynol-9's inefficacy and risks as a microbicide, leading regulatory bodies like the to advise against its promotion for STI prevention by the mid-2000s.

Efficacy

Effectiveness as a Spermicide

Nonoxynol-9 functions as a through its properties, which disrupt cell membranes, leading to rapid immobilization and death of spermatozoa. In assessments confirm high efficacy, with concentrations as low as 0.05% immobilizing over 99% of within 30 seconds and reducing in cervical mucus by significant margins in meta-analyses of experimental data. Clinical trials evaluating nonoxynol-9 spermicides alone for prevention report modest effectiveness, primarily limited by user adherence and application errors. A multicenter study of 1,536 women using five nonoxynol-9 formulations found a 6-month cumulative probability of approximately 12-15% among modified intent-to-treat participants who continued reliance on the method. Similarly, randomized evaluations of and products yielded 6-month rates around 12% under typical trial conditions approximating real-world use. Pearl Index failure rates from aggregated clinical data indicate 18% for perfect use (correct and consistent application every time) and 21-29% for typical use over the first year, reflecting challenges like insufficient dosing or timing relative to intercourse. These rates position nonoxynol-9 spermicides below hormonal methods or intrauterine devices but above no contraception, with efficacy enhanced when combined with barriers like diaphragms, though standalone use remains suboptimal for reliable prevention.

Claims and Evidence for STI Prevention

Early claims suggested that nonoxynol-9 (N-9) could prevent sexually transmitted infections (STIs) beyond its spermicidal action, based on in vitro studies demonstrating inactivation of pathogens such as Neisseria gonorrhoeae, Chlamydia trachomatis, and HIV. However, randomized controlled trials (RCTs) have consistently failed to show clinical efficacy against HIV acquisition in women. A 2002 systematic review and meta-analysis of six RCTs involving over 2000 women found no statistically significant reduction in HIV risk with N-9 use, with confidence intervals indicating negligible or absent protection. Similarly, a phase III trial among female sex workers in South Africa and Thailand reported that frequent N-9 gel application (up to four times daily) did not reduce HIV incidence and was associated with a higher infection rate (hazard ratio 1.7) compared to placebo, attributed to epithelial disruption facilitating viral entry. Evidence for N-9 against bacterial STIs like and is also lacking. Five placebo-controlled RCTs evaluating N-9 gels, sponges, and films showed no protective effect against urogenital or chlamydial , with infection rates similar to or exceeding placebo groups in high-frequency users. A 1998 RCT of N-9 vaginal film in sex workers found no reduction in or incidence despite condom promotion. Observational studies occasionally reported associations with lower risk (e.g., 89% reduction in one cohort without condoms), but these are confounded by behavioral factors and contradicted by RCTs, which provide higher-quality causal evidence. Health authorities have issued warnings against relying on N-9 for STI prevention. The concluded in 2002 that N-9 does not protect against and may increase transmission risk with repeated use, urging development of safer microbicides. The U.S. Centers for Disease Control and Prevention (CDC) states that N-9 alone is ineffective against , , and , recommending it only as a contraceptive supplement for low-STI-risk individuals, never as a standalone STI barrier. A Cochrane review reinforced this, finding evidence that N-9 may heighten vulnerability in women via mucosal damage without conferring benefits. These findings underscore that N-9's properties disrupt cell membranes non-selectively, failing to achieve targeted inactivation while promoting irritation-linked susceptibility.

Safety Profile and Adverse Effects

Local Genital Irritation and Tissue Damage

Nonoxynol-9, functioning as a , disrupts epithelial cell membranes in vaginal and cervical tissues, leading to cytotoxic effects that manifest as irritation and damage, with severity correlated to dosage and frequency of application. In controlled dosing trials, subjective symptoms such as vaginal burning or itching showed no significant elevation over with any frequency of use, but objective colposcopic assessments consistently identified heightened epithelial disruption. Epithelial damage rates escalated markedly with repeated exposure: application every other day yielded disruption comparable to , while once- or twice-daily use increased rates 2.5-fold, and four-times-daily application produced a five-fold elevation. Such disruptions, observed via as , petechiae, and sloughing primarily on vaginal and cervical surfaces, were absent or minimal after isolated low-dose exposures but accumulated with daily regimens, including ulceration in 2 of 31 participants using 100 mg gel for seven days. In a 1998 randomized among female sex workers applying nonoxynol-9 film before each intercourse (often multiple times daily), genital incidence reached 42.2 cases per 100 woman-years, compared to 33.5 in the arm (rate ratio 1.3, 95% CI 1.0-1.6), with colposcopies revealing microulcerations, excoriations, and fissures predominantly on vulvar and vaginal tissues. FDA analyses of supporting studies corroborated these risks, noting epithelial disruption and/or in 6 of 15 women using 150 mg suppositories hourly over 14 days, alongside vulvar irritation, burning, or ulceration complaints in 47% of nonoxynol-9 users versus 7% in controls. These findings underscore nonoxynol-9's potential to erode mucosal integrity, particularly under frequent-use scenarios mimicking high-risk contraceptive or microbicide applications.

Disruption of Vaginal Microbiota

Nonoxynol-9, a nonionic used in spermicidal formulations, exerts cytotoxic effects on vaginal epithelial cells and microorganisms through membrane disruption, which can alter the composition of the -dominated vaginal . This selectively depletes protective species, particularly hydrogen peroxide-producing strains, while promoting by opportunistic pathogens such as and anaerobic gram-negative rods. In a 1999 clinical study involving single applications of three nonoxynol-9 preparations (4% gel, 3.5% gel, and 28% film), transient decreases in Lactobacillus concentrations were observed, alongside increases in E. coli proportions and anaerobic gram-negative rod numbers, though epithelial damage remained minimal and symptoms rare. These shifts recovered within 72 hours post-application, suggesting short-term reversibility, but the authors noted potential exacerbation with repeated or chronic exposure. Similarly, in vitro assessments confirmed nonoxynol-9's suppression of Lactobacillus growth within hours, leading to broader bacterial inhibition by 24 hours. A 2006 randomized trial of 235 women using various nonoxynol-9 formulations over seven months reported minimal overall disruptions to vaginal flora for most participants, with no significant differences across formulations. However, higher exposure levels correlated with dose-dependent increases in anaerobic gram-negative rods (odds ratio 2.4, 95% CI 1.1-5.3), hydrogen peroxide-negative lactobacilli (odds ratio 2.0, 95% CI 1.0-4.1), and bacterial vaginosis (odds ratio 2.3, 95% CI 1.1-4.7). Reviews of multiple studies affirm that such dysbiosis, characterized by reduced Lactobacillus dominance, heightens risks of bacterial vaginosis and urinary tract infections, particularly in frequent users.

Broader Health Risks

Nonoxynol-9 exhibits minimal systemic absorption following vaginal or topical application, with studies in animal models demonstrating poor penetration across mucosal or barriers and rapid unmetabolized excretion via liver and kidneys. Human data on systemic disposition remain limited, but the compound's properties and low suggest negligible plasma concentrations and no significant accumulation with typical contraceptive dosing. Carcinogenicity assessments, including lifetime exposure studies in rats, have shown no evidence of tumor induction or genotoxic potential for nonoxynol-9. Similarly, long-term vaginal use does not appear to elevate risks of systemic conditions such as vulvovaginal candidiasis or bacterial vaginosis beyond baseline rates, based on longitudinal monitoring of vaginal ecology. Rare but serious broader risks include (TSS), a potentially life-threatening condition linked to bacterial overgrowth in disrupted tissues, though incidence remains exceedingly low with proper use. No adverse systemic effects have been observed in breastfed infants of users, indicating compatibility during . Overall, empirical indicate that broader health risks are constrained by nonoxynol-9's localized action and pharmacokinetic profile, with no substantiated links to chronic systemic toxicities in clinical or preclinical evaluations.

Controversies

HIV Transmission Risk and Microbicide Trials

Nonoxynol-9 was evaluated in multiple clinical trials as a candidate microbicide for preventing heterosexual transmission in women, motivated by laboratory evidence of its virucidal effects against . However, randomized controlled trials consistently failed to demonstrate protective efficacy, with some indicating heightened transmission risk due to mucosal disruption from repeated exposure. The primary mechanism implicated is N-9-induced epithelial damage, including ulceration and inflammation in the vaginal and cervical mucosa, which compromises barrier integrity and facilitates viral entry during high-frequency use, such as in sex workers or frequent intercourse scenarios. A pivotal phase III trial published in 1998 enrolled 974 female sex workers in and , randomizing participants to nonoxynol-9 vaginal film or alongside use. rates were 6.7 cases per 100 woman-years in the N-9 group versus 6.6 in the group, yielding a rate of 1.0 (95% CI 0.7-1.5), indicating no reduction in acquisition risk. Subgroup analysis among high-frequency users (over 6 applications daily) suggested a trend toward increased incidence, though not statistically significant in this study. Subsequent trials reinforced these findings. A 2000 multicenter study in involving nonoxynol-9 gel reported HIV infection rates approximately 50% higher in the active arm compared to , prompting early termination due to futility and potential harm. A Cochrane and of five randomized trials (n=2144 women) found an overall of HIV infection of 1.12 (95% CI 0.88-1.42) with N-9 versus , excluding benefit, and a of 1.7 (95% CI 1.21-2.36) among women applying N-9 more than three times daily. No trials showed statistically significant protection, and the review concluded N-9 lacks efficacy as an HIV microbicide while posing risks in vulnerable populations. In response to these results, the issued a 2002 statement deeming nonoxynol-9 ineffective for prevention and advising against its promotion for this purpose, particularly in high-risk groups where frequent dosing exacerbates genital lesions. The U.S. Centers for Disease Control and Prevention echoed this, noting that N-9 alone does not prevent and may elevate susceptibility via tissue disruption. These outcomes shifted microbicide research toward less cytotoxic agents, highlighting N-9's failure to translate preclinical promise into clinical utility.

Discrepancies in Early vs. Modern Studies

Early research on nonoxynol-9 (N-9) in the late and 1990s, primarily through experiments, indicated potential microbicidal activity against HIV-1 by disrupting viral lipid envelopes, similar to its spermicidal mechanism targeting cell membranes. These preclinical findings fueled optimism for N-9 as a topical microbicide, prompting its incorporation into condoms and early clinical testing as a dual contraceptive and STI preventive agent. However, phase II and III clinical trials conducted from 1998 onward in high-risk populations, such as female sex workers with frequent vaginal intercourse (often 10–20 times daily), revealed no protective effect against -1 acquisition and, in some cases, elevated infection rates compared to . For instance, a 1998 randomized trial in involving 377 sex workers found that daily use of N-9 vaginal film did not reduce , , or incidence over 16 months. A larger 2000–2002 multinational phase III trial of COL-1492 (a 3.5% N-9 ) in 991 sex workers across and the reported a 50% higher -1 rate in the N-9 group versus , with hazard ratios rising to 1.7 for frequent users (over six applications daily). The divergence stems from early studies' limitations: assays and animal models overlooked cumulative epithelial damage from repeated exposure, which disrupts vaginal mucosa and lactobacilli barriers, facilitating entry —effects absent or minimal in single-dose lab settings. Modern meta-analyses, including Cochrane reviews up to 2021, synthesize these trials to conclude no evidence of prevention and moderate evidence of for frequent use, contrasting initial preclinical promise. Similar patterns hold for other STIs like , where early virucidal claims failed to translate clinically due to overriding any direct inactivation.

Ethical and Promotional Issues

The promotion of nonoxynol-9 as a with potential benefits against sexually transmitted infections, including , has drawn scrutiny for overstating efficacy amid emerging evidence of harm, particularly in high-frequency use scenarios among vulnerable populations. Early studies suggested antiviral activity, leading to its inclusion in some condoms and lubricants marketed as enhanced protection, yet phase III clinical s from the late 1990s demonstrated no reduction in acquisition and a dose-dependent increase in risk due to epithelial disruption. A multicenter involving 974 female sex workers in and found that daily use of nonoxynol-9 film resulted in a of 1.7 for infection compared to , alongside elevated rates of genital lesions that could facilitate entry. Ethical challenges in nonoxynol-9 microbicide trials centered on equipoise, , and participant selection, as studies proceeded in resource-limited settings with women at elevated risk, such as sex workers, despite preclinical signals of mucosal . designs often prioritized endpoints over interim monitoring for irritation-induced vulnerability, raising questions about whether true uncertainty of benefit justified exposing participants to a product already in widespread use as a . Post-trial obligations remain contentious, with calls for compensation or access to alternatives for harmed individuals in developing countries, where nonoxynol-9 was sometimes distributed via programs without updated risk disclosures following 2002 World Health Organization advisories against its use for prevention. Regulatory responses highlighted promotional shortcomings, as initial over-the-counter labeling failed to emphasize nonoxynol-9's inefficacy against or its risk amplification with repeated application, prompting the U.S. in 2007 to mandate warnings on products stating that frequent use may increase transmission odds. Advocacy groups, including those focused on prevention, urged manufacturers to phase out nonoxynol-9 from condoms and lubricants by 2002, citing its rectal and lack of added value beyond contraception, though some products persisted in markets with lax oversight. These issues underscore tensions between commercial interests in positioning nonoxynol-9 as a multifaceted barrier and the imperative for evidence-based messaging, particularly in populations reliant on non-prescription options.

Regulatory Status and Recommendations

FDA and International Agency Positions

The U.S. (FDA) classifies nonoxynol-9 (N-9) spermicides as over-the-counter vaginal contraceptives, approving their use for prevention when applied correctly, typically achieving a of around 18-28% with typical use. However, since 2007, FDA regulations mandate specific labeling warnings on N-9 products, stating that frequent use (more than three times daily) can cause vaginal irritation, potentially increasing susceptibility to transmission from an infected partner, and that N-9 offers no protection against or other sexually transmitted infections (STIs). The agency has not banned N-9 but requires manufacturers to include these disclosures based on clinical data showing epithelial disruption and lack of efficacy against pathogens. The Centers for Control and Prevention (CDC), aligning with FDA assessments, advises against N-9 use for individuals at high risk of acquisition, citing evidence from repeated high-dose applications that genital lesions may heighten transmission risk, while affirming limited contraceptive efficacy only in low-STI-risk scenarios. In 2002, CDC recommended discontinuing procurement of N-9-lubricated condoms for distribution due to inefficacy against /STIs, though existing stocks were permissible if unexpired. Internationally, the (WHO) explicitly discourages N-9 for or STI prevention, following a 2002 technical consultation that reviewed trials showing no protective benefit and potential harm via mucosal disruption, particularly in high-frequency use among sex workers. For contraception, WHO permits N-9 as a secondary option solely for women at negligible risk, emphasizing condoms as the preferred barrier method and noting N-9's suboptimal standalone efficacy. The (EMA) has not issued a unified contraindication but defers to member state approvals with similar irritation and non-protection warnings, consistent with broader EU on spermicides lacking antiviral substantiation.

Current Usage Guidelines and Alternatives

Health authorities, including the U.S. Centers for Disease Control and Prevention (CDC) and the (WHO), advise against the use of nonoxynol-9 (N-9) spermicides for preventing sexually transmitted infections (STIs), including , due to evidence of mucosal disruption and potential increased susceptibility with frequent or high-dose application. The CDC's U.S. Medical Eligibility Criteria for Contraceptive Use (updated 2024) classifies spermicides, including N-9, as category 4 (unacceptable health risk) in contexts involving risk or certain comorbidities, citing associations with genital lesions that may heighten vulnerability. The WHO similarly states that N-9 provides no protection against or other STIs like and , and recommends discontinuing promotion of N-9-lubricated condoms due to adverse effects observed in trials. For pregnancy prevention in low-STI-risk scenarios, N-9 remains available over-the-counter (OTC) in the U.S. as creams, foams, gels, films, or suppositories, per (FDA) classification, but labeling mandates warnings about vaginal or rectal irritation, lack of STI protection, and elevated HIV transmission risk with use exceeding three times daily. Application guidelines specify insertion into the 10-15 minutes before intercourse (up to 1 hour for efficacy), with reapplication per act, but not exceeding once daily to minimize irritation; rectal use is contraindicated. Providers should counsel users on these limitations, emphasizing combination with mechanical barriers like diaphragms or condoms for enhanced efficacy, though N-9 adds minimal contraceptive benefit beyond barriers alone. Alternatives to N-9 spermicides include non-spermicidal barrier methods (e.g., condoms, diaphragms, or cervical caps without chemical agents) and hormone-free options like Phexxi (, , and gel), FDA-approved in 2020 as a vaginal regulator that immobilizes without surfactants, showing comparable typical-use rates (around 14-21%) but lower irritation profiles in trials. Diaphragm-compatible gels such as Contragel or Caya gel, formulated without N-9, offer spermicide-free lubrication and acidification for barrier enhancement. Broader contraceptive choices encompass hormonal methods (pills, patches, rings), intrauterine devices, or sterilization, which provide superior efficacy ( rates <1% with perfect use) and STI protection when paired with condoms, bypassing N-9's risks entirely.

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