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Arsanilic acid
Arsanilic acid
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Arsanilic acid
Chemical structure of arsanilic acid
Chemical structure of arsanilic acid
Ball-and-stick model of the solid-state zwitterionic structure of arsanilic acid
Ball-and-stick model of the solid-state zwitterionic structure of arsanilic acid
Names
Preferred IUPAC name
(4-Aminophenyl)arsonic acid
Other names
4-Aminobenzenearsonic acid, 4-Aminophenylarsonic acid, 4-Arsanilic acid, Atoxyl
Identifiers
3D model (JSmol)
1102334
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.002.432 Edit this at Wikidata
EC Number
  • 202-674-3
406354
UNII
  • InChI=1S/C6H8AsNO3/c8-6-3-1-5(2-4-6)7(9,10)11/h1-4H,8H2,(H2,9,10,11) checkY
    Key: XKNKHVGWJDPIRJ-UHFFFAOYSA-N checkY
  • InChI=1/C6H8AsNO3/c8-6-3-1-5(2-4-6)7(9,10)11/h1-4H,8H2,(H2,9,10,11)
    Key: XKNKHVGWJDPIRJ-UHFFFAOYAQ
  • O=[As](O)(O)c1ccc(N)cc1
  • zwitterion: O=[As]([O-])(O)c1ccc([NH3+])cc1
Properties
C6H8AsNO3
Molar mass 217.054 g/mol
Appearance white solid
Density 1.957 g/cm3
Melting point 232 °C (450 °F; 505 K)
modest
Hazards
Occupational safety and health (OHS/OSH):
Main hazards
 Toxic
GHS labelling:
GHS06: ToxicGHS09: Environmental hazard
Danger
H301, H331, H410
NFPA 704 (fire diamond)
NFPA 704 four-colored diamondHealth 2: Intense or continued but not chronic exposure could cause temporary incapacitation or possible residual injury. E.g. chloroformFlammability 0: Will not burn. E.g. waterInstability 0: Normally stable, even under fire exposure conditions, and is not reactive with water. E.g. liquid nitrogenSpecial hazards (white): no code
2
0
0
Related compounds
Related compounds
 phenylarsonic acid
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 ?)

Arsanilic acid, also known as aminophenyl arsenic acid or aminophenyl arsonic acid, is an organoarsenic compound, an amino derivative of phenylarsonic acid whose amine group is in the 4-position. A crystalline powder introduced medically in the late 19th century as Atoxyl, its sodium salt was used by injection in the early 20th century as the first organic arsenical drug, but it was soon found prohibitively toxic for human use.[1]

Arsanilic acid saw long use as a veterinary feed additive promoting growth and to prevent or treat dysentery in poultry and swine.[2][3][4] In 2013, its approval by US government as an animal drug was voluntarily withdrawn by its sponsors.[5] Still sometimes used in laboratories,[6] arsanilic acid's legacy is principally through its influence on Paul Ehrlich in launching the antimicrobial chemotherapy approach to treating infectious diseases of humans.[7]

Chemistry

[edit]

Synthesis was first reported in 1863 by Antoine Béchamp and became the basis of the Bechamp reaction.[8][9] The process involves the reaction of aniline and arsenic acid via an electrophilic aromatic substitution reaction.

C6H5NH2 + H3AsO4 → H2O3AsC6H4NH2 + H2O

Arsanilic acid occurs as a zwitterion, H3N+C6H4AsO3H−,[10] yet is typically represented with the non-zwitterionic formula H2NC6H4AsO3H2.

History

[edit]

Roots and synthesis

[edit]

Since at least 2000 BC, arsenic and inorganic arsenical compounds were both medicine and poison.[11][12] In the 19th century, inorganic arsenicals became the preeminent medicines, for instance Fowler's solution, against diverse diseases.[11]

In 1859, in France, while developing aniline dyes,[13] Antoine Béchamp synthesized a chemical that he identified, if incorrectly, as arsenic acid anilide.[14] Also biologist, physician, and pharmacist, Béchamp reported it 40 to 50 times less toxic as a drug than arsenic acid, and named it Atoxyl,[14] the first organic arsenical drug.[1]

Medical influence

[edit]

In 1905, in Britain, H W Thomas and A Breinl reported successful treatment of trypanosomiasis in animals by Atoxyl, and recommended high doses, given continuously, for human trypanosomiasis (sleeping sickness).[13] By 1907, more successful and less toxic than inorganic arsenicals, Atoxyl was expected to greatly aid expansion of British colonization of Africa and stem loss of cattle in Africa and India.[13] (So socioeconomically valuable was colonial medicine[15] that in 1922, German company Bayer offered to reveal the formula of Bayer 205—developed in 1917 and showing success on sleeping sickness in British and Belgian Africa—to the British government for return of German colonies lost via World War I.)[14][16]

Soon, however, Robert Koch found through an Atoxyl trial in German East Africa that some 2% of patients were blinded via atrophy of the optic nerve.[14] In Germany, Paul Ehrlich inferred Béchamp's report of Atoxyl's structure incorrectly, and Ehrlich with his chief organic chemist Alfred Bertheim found its correct structure[13]—aminophenyl arsenic acid[17] or aminophenyl arsonic acid[14]—which suggested possible derivatives.[14][17] Ehrlich asked Bertheim to synthesize two types of Atoxyl derivatives: arsenoxides and arsenobenzenes.[14]

Ehrlich and Bertheim's 606th arsenobenzene, synthesized in 1907, was arsphenamine, found ineffective against trypanosomes, but found in 1909 by Ehrlich and bacteriologist Sahachiro Hata effective against the microorganism involved in syphilis, a disease roughly equivalent then to today's AIDS.[17] The company Farbwerke Hoechst marketed arsphenamine as the drug Salvarsan, "the arsenic that saves".[14] Its specificity of action fit Ehrlich's silver bullet or magic bullet paradigm of treatment,[11] and Ehrlich won international fame while Salvarsan's success—the first particularly effective syphilis treatment—established the chemotherapy enterprise.[17][18] In the late 1940s, Salvarsan was replaced in most regions by penicillin, yet organic arsenicals remained in use for trypanosomiasis.[11]

Contemporary usage

[edit]

Arsanilic acid gained use as a feed additive for poultry and swine to promote growth and prevent or treat dysentery.[2][3][4] For poultry and swine, arsanilic acid was among four arsenical veterinary drugs, along with carbarsone, nitarsone, roxarsone, approved by the U.S. Food and Drug Administration (FDA).[19] In 2013, the FDA denied petitions by the Center for Food Safety and by the Institute for Agriculture and Trade Policy seeking revocation of approvals of the arsenical animal drugs, but the drugs' sponsors voluntarily requested the FDA to withdraw approvals of three, including arsanilic acid, leaving only nitarsone approved.[5] In 2015, the FDA withdrew nitarsone's approval.[20]

Arsanilic acid is still used in the laboratory, for instance in recent modification of nanoparticles.[6]

It is a reagent for the detection of nitrite in urinalysis dipsticks.

Citations

[edit]
  1. ^ a b Burke ET (1925). "The arseno-therapy of syphilis; stovarsol, and tryparsamide". British Journal of Venereal Diseases. 1 (4): 321–38. doi:10.1136/sti.1.4.321. PMC 1046841. PMID 21772505.
  2. ^ a b National Research Council (US) Committee on Medical Biological Effects of Environmental Pollutants (1977). "Biological effects of arsenic on plants and animals: Domestic animals: Phenylarsonic feed additives". In Levander OA (ed.). Arsenic: Medical and Biological Effects of Environmental Pollutants. Washington DC: National Academies Press. pp. 149–51. doi:10.17226/9003. ISBN 978-0-309-02604-8. PMID 25101467.
  3. ^ a b Hanson LE, Carpenter LE, Aunan WJ, Ferrin EF (1955). "The use of arsanilic acid in the production of market pigs". Journal of Animal Science. 14 (2): 513–24. doi:10.2527/jas1955.142513x.[permanent dead link]
  4. ^ a b "Arsanilic acid—MIB #4". Canadian Food Inspection Agency. Sep 2006. Archived from the original on 2012-12-13. Retrieved 3 Aug 2012.
  5. ^ a b U.S. Food and Drug Administration (1 Oct 2013). "FDA response to citizen petition on arsenic-based animal drugs". Archived from the original on October 22, 2013.
  6. ^ a b Ahn, J; Moon, DS; Lee, JK (2013). "Arsonic acid as a robust anchor group for the surface modification of Fe3O4". Langmuir. 29 (48): 14912–8. doi:10.1021/la402939r. PMID 24246012.
  7. ^ Patrick J Collard, The Development of Microbiology (Cambridge, London, New York, Melbourne: Cambridge University Press, 1976), pp 53–4.
  8. ^ M. A. Bechamp (1863). "de l'action de la chaleur sur l'arseniate d'analine et de la formation d'un anilide de l'acide arsenique". Compt. Rend. 56: 1172–1175.
  9. ^ C. S. Hamilton and J. F. Morgan (1944). "The Preparation of Aromatic Arsonic and Arsinic Acids by the Bart, Bechamp, and Rosenmund Reactions". p. 2. doi:10.1002/0471264180.or002.10. ISBN 978-0471264187. {{cite book}}: ISBN / Date incompatibility (help); |journal= ignored (help); Missing or empty |title= (help)
  10. ^ Nuttall RH, Hunter WN (1996). "P-arsanilic acid, a redetermination". Acta Crystallographica Section C. 52 (7): 1681–3. doi:10.1107/S010827019501657X.
  11. ^ a b c d Jolliffe DM (1993). "A history of the use of arsenicals in man". Journal of the Royal Society of Medicine. 86 (5): 287–9. doi:10.1177/014107689308600515. PMC 1294007. PMID 8505753.
  12. ^ Gibaud, Stéphane; Jaouen, Gérard (2010). "Arsenic-Based Drugs: From Fowler's Solution to Modern Anticancer Chemotherapy". Medicinal Organometallic Chemistry. Topics in Organometallic Chemistry. Vol. 32. pp. 1–20. Bibcode:2010moc..book....1G. doi:10.1007/978-3-642-13185-1_1. ISBN 978-3-642-13184-4.
  13. ^ a b c d Boyce R (1907). "The treatment of sleeping sickness and other trypanosomiases by the Atoxyl and mercury method". BMJ. 2 (2437): 624–5. doi:10.1136/bmj.2.2437.624. PMC 2358391. PMID 20763444.
  14. ^ a b c d e f g h Steverding D (2010). "The development of drugs for treatment of sleeping sickness: A historical review". Parasites & Vectors. 3 (1): 15. doi:10.1186/1756-3305-3-15. PMC 2848007. PMID 20219092.
  15. ^
  16. ^ Pope WJ (1924). "Synthetic therapeutic agents". BMJ. 1 (3297): 413–4. doi:10.1136/bmj.1.3297.413. PMC 2303898. PMID 20771495.
  17. ^ a b c d Bosch F, Rosich L (2008). "The contributions of Paul Ehrlich to pharmacology: A tribute on the occasion of the centenary of his Nobel Prize". Pharmacology. 82 (3): 171–9. doi:10.1159/000149583. PMC 2790789. PMID 18679046.
  18. ^ "Paul Ehrlich, the Rockefeller Institute, and the first targeted chemotherapy". Rockefeller University. Retrieved 3 Aug 2012.
  19. ^ U.S. Food and Drug Administration (8 Jun 2011). "Questions and answers regarding 3-nitro (roxarsone)". Archived from the original on June 12, 2011.
  20. ^ U.S. Food and Drug Administration (April 1, 2015). "FDA announces pending withdrawal of approval of nitarsone". Archived from the original on 2017-04-06.
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Arsanilic acid

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from Grokipedia

Arsanilic acid, systematically named 4-aminobenzenearsonic acid, is an organoarsenic compound with the molecular formula C₆H₈AsNO₃ and a zwitterionic structure in solid state.
It functions primarily as an anti-infective agent and growth promoter when added to animal feed, enhancing weight gain in poultry and swine while aiding in the prevention of dysentery and other infections.
Introduced as a veterinary additive since the mid-20th century, it contributed to advancements in organoarsenic applications in agriculture and early chemotherapy research.
Despite these benefits, arsanilic acid's arsenic content raises significant toxicity concerns, including potential carcinogenic metabolites, neurological effects like ataxia and blindness in overdosed animals, and environmental persistence leading to bioaccumulation.
Its use as a feed promoter has been voluntarily withdrawn in the United States and banned in numerous countries, including China since 2019, due to these health and ecological risks.

Chemical Properties

Molecular Structure and Formula

Arsanilic acid, systematically named 4-aminobenzenearsonic acid or (4-aminophenyl)arsonic acid, possesses the molecular formula C₆H₈AsNO₃ and a molecular weight of 217.05 g/mol. Its CAS number is 98-50-0. The core molecular structure consists of a benzene ring with an amino group (-NH₂) and an arsonic acid moiety (-AsO₃H₂) attached at opposite (para) positions, enabling resonance stabilization between the electron-donating amino and electron-withdrawing arsonic groups. In the solid state, arsanilic acid primarily exists as a zwitterion, formulated as ⁺H₃N-C₆H₄-AsO₃H⁻, with the proton from the arsonic acid transferred to the amino group, as confirmed by crystallographic studies showing isostructural analogy and hydrogen bonding patterns. In aqueous solution, equilibrium exists between zwitterionic and neutral forms, influenced by pH.

Physical and Chemical Characteristics

Arsanilic acid, also known as 4-aminobenzenearsonic acid, presents as a to off-white crystalline . Its molecular formula is C₆H₈AsNO₃, with a molecular weight of 217.06 g/mol. The compound has a of 1.957 g/cm³. Key physical properties are summarized in the following table:
PropertyValue
232 °C
Solubility in Sparingly soluble (slightly soluble in cold ; more soluble in hot )
Solubility in other solventsSoluble in alkaline solutions and concentrated mineral acids
In the solid state, arsanilic acid adopts a zwitterionic form, with the amino group protonated (–NH₃⁺) and the arsonic acid group partially deprotonated (–AsO₃H⁻). This structure arises from the amphoteric nature of the molecule, combining aniline-like basicity and arsonic acid acidity. The pKa of the arsonic acid moiety is approximately 4.17. Chemically, it exhibits reactivity characteristic of aromatic amines, such as and diazotization, alongside the reducing properties of the arsonic acid group. It is incompatible with strong oxidizing agents, which can lead to decomposition or oxidation of the center.

Stability and Decomposition

Arsanilic acid exhibits good stability under standard storage and handling conditions, remaining unchanged at without hazardous . Safety data sheets indicate compatibility with most materials, though prolonged exposure to moisture or incompatible substances should be avoided. Incompatibility arises primarily with strong acids, which can reduce the moiety to generate (AsH₃), a highly toxic and flammable gas. This reaction underscores the need for careful handling to prevent reductive conditions. stability is high, with reported melting points ranging from 232 °C to ≥300 °C across sources, suggesting initiates at elevated temperatures rather than ; fire exposure yields irritating and toxic gases including oxides and nitrogen compounds. In aqueous solutions at neutral (e.g., pH 7), arsanilic acid demonstrates persistence but undergoes under UV irradiation, primarily cleaving to as the dominant byproduct, with secondary photooxidation leading to further mineralization. Oxidative , whether photochemical or via advanced processes like Fenton-like reactions, breaks the As-C bond, releasing inorganic species such as (AsV) and (AsIII), which pose environmental and toxicological risks due to their mobility and . These pathways highlight arsanilic acid's recalcitrance in natural waters absent catalysts or oxidants, yet its eventual breakdown to bioavailable arsenic.

Synthesis

Early Synthetic Methods

Arsanilic acid, chemically known as 4-aminobenzenearsonic acid, was first synthesized in 1863 by through the direct reaction of with , establishing the foundational Béchamp reaction for preparing aromatic arsonic acids. This method relies on the where acts as the , facilitated by the activating amino group of directing the arsonation primarily to the para position. The classical procedure involves heating a of excess and concentrated aqueous , typically in a ratio providing about two equivalents of aniline per arsenic acid molecule, at temperatures around 100–120°C for several hours to drive the . Excess aniline forms an aniline salt initially, which decomposes under heating to yield the arsonic acid; unreacted aniline is subsequently removed by under alkaline conditions to solubilize the product as its sodium salt. Acidification of the filtrate with acetic or then precipitates the free arsanilic acid, which is purified by recrystallization from hot water, achieving yields of approximately 60–70% based on arsenic acid consumed. Early adaptations of this synthesis, as detailed in procedures from the early 20th century, emphasized controlling reaction conditions to minimize side products like diarylarsonic acids formed from over-substitution, often by using precisely measured reagents and gradual heating. The method's simplicity made it industrially viable despite the toxicity of arsenic compounds, though it required careful handling to avoid explosive risks from concentrated acids and amines. Limitations included incomplete para selectivity, with minor ortho isomers, necessitating chromatographic or fractional crystallization for high purity in research applications.

Industrial Production Techniques

Arsanilic acid is produced industrially through the direct condensation of with via , typically employing excess to drive the reaction. The process commences by gradually introducing into a concentrated solution, which forms lumps of ; these are disrupted by vigorous agitation to ensure homogeneity before heating the mixture to 180–200°C for 2–3 hours. This thermal reaction generates arsanilic acid alongside byproducts such as di-(p-aminophenyl), the latter of which undergoes under acidic conditions (pH adjusted with ) to yield additional arsanilic acid, achieving overall yields of 45% or higher relative to consumed. Optimization in patented variants includes precise molar ratios (e.g., 3–5 moles per mole ) and post-reaction cooling to facilitate crude product isolation. Purification entails dissolving the cooled reaction mass in aqueous , steam to remove unreacted , of insolubles, and acidification (typically with ) to precipitate the zwitterionic arsanilic acid, followed by washing and drying to constant weight. This method, refined since early 20th-century developments, prioritizes efficiency over aniline due to the latter's abundance and lower cost.

Historical Development

Discovery and Initial Research

Arsanilic acid (4-aminobenzenearsonic acid) was first synthesized in by French chemist through the direct reaction of with under heating conditions, a method later termed the Béchamp reaction. This synthesis represented an early example of preparing organoarsenic compounds, though Béchamp's initial work focused on its chemical properties rather than . The sodium salt of arsanilic acid, marketed as Atoxyl, gained attention in 1905 when its trypanocidal effects were demonstrated against gambiense, the parasite responsible for African trypanosomiasis (sleeping sickness). Early trials, including those reported by researchers at the Institut Pasteur, showed partial efficacy in reducing parasitemia in infected patients, positioning it as one of the first synthetic organic arsenicals tested for parasitic infections. However, clinical observations quickly revealed significant toxicity, including damage leading to blindness in up to 1-2% of treated individuals, limiting its therapeutic utility. These findings spurred systematic derivatization efforts by and Alfred Bertheim starting in 1906, who modified arsanilic acid to improve selectivity and reduce toxicity, ultimately yielding (compound 606, or Salvarsan) in 1909. Ehrlich's approach emphasized structure-activity relationships, testing over 600 arsenic-based analogs against bacterial and spirochetal pathogens, which validated arsanilic acid as a foundational scaffold for chemotherapeutic development despite its own limitations. Initial research thus highlighted both the antimicrobial promise of organoarsenicals and the challenges of balancing efficacy with safety.

Transition to Veterinary Applications

Arsanilic acid, initially developed as the sodium salt Atoxyl for human treatment of (sleeping sickness) following its synthesis in 1859, showed limited efficacy and significant toxicity, including and blindness in patients during early 20th-century trials. These adverse effects curtailed its therapeutic promise in humans, prompting researchers to investigate alternative applications where lower doses might mitigate risks while retaining antimicrobial properties. By the 1920s, arsenic compounds, including arsanilic acid, entered veterinary practice as tonics, alteratives, and vermifuges for , capitalizing on their historical use in for purported benefits despite sparse empirical validation at the time. The transition accelerated in the 1940s when organic arsenicals like arsanilic acid were first approved by the U.S. (FDA) as feed additives, specifically for growth promotion and control of enteric diseases such as swine dysentery and avian coccidiosis in and pigs. This shift reflected post-World War II agricultural demands for efficient animal production, with arsanilic acid incorporated at subtherapeutic levels (typically 0.01–0.02% in feeds) to enhance feed efficiency and reduce mortality from bacterial infections. Initial veterinary adoption faced scrutiny over residue accumulation and potential toxicity, but studies demonstrated rapid excretion in animals when withdrawn from diets prior to slaughter, alleviating early concerns. In , the FDA affirmed the safety of four key arsenical drugs, including , for continued use in feeds after reviewing data on low tissue residues and absence of carcinogenic effects in short-term animal models. This regulatory endorsement solidified its role in , with widespread commercial formulations distributed by pharmaceutical firms for swine and operations through the late , until voluntary withdrawals in 2013 amid evolving evidence on inorganic conversion risks.

Veterinary Uses

Growth Promotion and Disease Prevention

Arsanilic acid has been incorporated into and feeds at concentrations typically ranging from 50 to 100 ppm to promote growth and enhance feed efficiency. In chicks, supplementation with arsanilic acid or sodium arsanilate has demonstrated increased body weight gain and reduced fecal counts, suggesting a role in modulating to support growth. Studies in reported average weight gains of 6.16 kg over four weeks with arsanilic acid supplementation, compared to 4.16 kg on unsupplemented basal diets, alongside improved feed conversion ratios. However, efficacy varies; some trials in s found no significant improvements in growth or feed utilization at doses up to 99 mg/kg. For disease prevention, arsanilic acid was employed primarily to control in , with feed inclusion aiding in reducing oocyst shedding and lesion scores in challenged birds. In , it helped mitigate scours and mortality when administered at 250 ppm in feed or 175 ppm sodium arsanilate in water, particularly in young pigs. Additional veterinary applications included prevention of bloody and counteraction of toxicity effects in . These uses stemmed from observed reductions in pathogenic burdens, though mechanisms beyond activity, such as improved absorption, were hypothesized in early .

Evidence of Efficacy

Studies from the mid-20th century indicated that arsanilic acid supplementation at levels of 0.01% improved growth rates in by approximately 5% compared to unsupplemented controls. In , additions of arsanilic acid or sodium arsanilate to feed at 50–100 ppm enhanced and feed efficiency, with reported reductions in fecal counts correlating to improved chick growth. Similar effects were observed in , where 50–100 mg/kg dietary arsanilic acid significantly boosted feed utilization and egg production performance. However, a in chickens found arsanilic acid supplementation ineffective for enhancing biological metrics such as growth rate or feed conversion, nor did it improve economic outcomes like cost per unit of . Regulatory approvals for growth promotion in feeds reflected dose ranges (e.g., up to 90 g/) based on earlier demonstrations of feed gains, though quantitative efficacy data in approval summaries emphasized combined uses rather than standalone effects. For disease prevention, arsanilic acid exhibited efficacy against swine dysentery (caused by Brachyspira hyodysenteriae), with early reports confirming control of natural outbreaks when combined with bacitracin, and standalone arsenicals like arsanilic acid noted as among the first effective compounds. In some field applications, arsenicals including arsanilic acid successfully mitigated dysentery symptoms, though outcomes varied by dosage and disease severity. Evidence for coccidiosis prevention in is more limited for arsanilic acid specifically, with organoarsenicals generally approved as aids in prevention and layer treatment at 0.01% levels, but primarily supported by broader aryl arsonic acid data showing reduced clinical symptoms in cecal models. Overall, while historical use relied on modest, species-specific benefits, later assessments highlighted inconsistent growth responses, prompting shifts away from routine application.

Mechanism of Action

Arsanilic acid functions primarily as a subtherapeutic agent in veterinary feed additives, exerting bacteriostatic effects that modulate the to enhance growth performance and mitigate certain infections in and . At concentrations typically used (e.g., 0.01–0.05% in feed), it inhibits the proliferation of such as species, reducing their fecal counts by up to several log units in , which correlates with improved feed efficiency and . This microbial modulation likely facilitates better nutrient absorption by decreasing competition from gut pathogens and altering patterns, though direct causation remains correlative rather than definitively proven. The compound's anti-infective properties stem from its organoarsenic structure, which disrupts bacterial metabolism, potentially through interference with sulfhydryl-dependent enzymes essential for microbial growth, akin to historical arsenical therapeutics. However, the precise biochemical targets in veterinary contexts are not fully elucidated, with evidence suggesting weak but selective activity against anaerobes like rather than broad-spectrum killing. For disease prevention, such as swine dysentery or avian coccidiosis adjunct therapy, it complements other agents by suppressing secondary bacterial overgrowth, but lacks direct efficacy. Experimental data from chick trials indicate no significant promotion of antibiotic resistance genes at these doses, underscoring a targeted rather than indiscriminate profile. Overall, while empirical observations confirm growth promotion (e.g., 5–10% body weight increase in broilers) and reduced incidence, the mechanism's uncertainty highlights reliance on microbiota-mediated indirect effects over direct metabolic stimulation in host tissues. Peer-reviewed studies emphasize that efficacy diminishes without adequate baseline , implying an auxiliary role in optimizing microbial ecology rather than a standalone metabolic enhancer.

Health and Safety Assessments

Acute and Chronic Toxicity in Animals

Arsanilic acid demonstrates relatively low acute oral in , with overdosage primarily occurring from excessive feed supplementation. In pigs, administration at 15 times the recommended therapeutic level (approximately 675 ppm) for one week elicited toxic symptoms such as , , and diarrhea, yet even doses up to 8000 ppm proved non-fatal over short periods. and turkeys exhibit greater susceptibility to these effects compared to chickens, with potential exacerbation of under conditions of or concurrent stressors. Organic arsenical toxicosis, including from arsanilic acid, manifests in pigs and diets exceeding normal levels, featuring dose-dependent gastrointestinal distress, neurological signs, and rapid onset proportional to exposure magnitude. Chronic toxicity from arsanilic acid in animals is minimal at growth-promotion dosages, with long-term feeding studies indicating no significant adverse effects in rats administered the compound as a dietary additive. In rats fed 100 to 1000 ppm arsanilic acid continuously for 106 to 116 weeks, no overt chronic pathologies were reported sufficient to contraindicate veterinary use at lower levels, though higher inorganic equivalents from pose risks of liver and strain over extended exposure. Unlike inorganic arsenicals, where chronic effects are rare in animals due to rapid elimination, arsanilic acid's partial to more toxic or forms may contribute to subacute accumulative damage in sensitive species like during prolonged high-level intake, but therapeutic regimens (typically 45-90 ppm) remain below thresholds for observable harm.

Risks to Human Consumers

Arsanilic acid, when used as a veterinary feed additive in and swine, leaves residues in edible tissues such as muscle and liver, potentially exposing consumers to through consumption. These residues primarily consist of organic forms, but studies indicate partial to inorganic , a known associated with , , and cancers. In from markets where arsanilic acid was used, total levels were elevated, with arsanilic acid contributing more than other arsenicals like roxarsone, heightening dietary exposure risks. Regulatory concerns prompted the U.S. (FDA) to withdraw approval for arsanilic acid-containing new animal drug applications in 2013, citing potential risks from inorganic accumulation in products. This action followed evidence that organic arsenicals like arsanilic acid could convert to toxic inorganic forms under certain conditions, including in animal and environmental persistence, exceeding safe thresholds in tissues. Levels above 0.13 µg/g total in muscle have been linked to concerns for humans. Chronic low-level exposure via consumption contributes to overall intake, which epidemiological data correlates with increased cancer incidence and non-carcinogenic effects like . While acute toxicity from single servings is unlikely, cumulative dietary from multiple sources, including arsanilic acid residues, amplifies long-term health risks, particularly for frequent consumers of products. Arsanilic acid use remains banned as a growth promoter in many countries due to these persistent safety issues.

Arsenic Metabolism and Residue Concerns

Arsanilic acid demonstrates high metabolic stability in target species, including chickens and . In chickens, administration of doubly labeled arsanilic acid revealed that less than 1% of the dose undergoes degradation, with over 90% recovered unchanged in excreta, primarily feces, indicating minimal absorption from the . Similar patterns occur in , where low limits systemic uptake, favoring fecal elimination over tissue incorporation or to inorganic forms. This stability contrasts with related compounds like roxarsone, which partially metabolize to other arsenicals, though arsanilic acid's inertness reduces immediate conversion risks during animal exposure. Arsenic residues from arsanilic acid supplementation accumulate unevenly in animal tissues, concentrating in liver and while remaining low in muscle. In , hepatic and renal levels can reach 3–5 ppm following chronic feeding, whereas muscle typically stays below 1 ppm; U.S. regulatory tolerances set limits at 2 ppm for uncooked liver and and 0.5 ppm for muscle and other by-products. studies confirm analogous distribution, with organ residues declining rapidly post-withdrawal—often to negligible levels in edible within days—due to the compound's poor retention. These patterns underscore the importance of adherence to withdrawal periods to minimize carryover into products. Residue concerns center on potential exposure via consumption of treated products, particularly if organoarsenic forms degrade to carcinogenic inorganic under physiological or environmental conditions. Although residues exhibit low —as shown by chickens failing to retain from swine liver fed arsanilic acid—trace metabolites like N-acetyl-4-hydroxy-m-arsanilic acid (3–12% of total in some analyses) raise questions about cumulative toxicity. Chronic low-level has been linked to -related effects, including cancer, prompting FDA evaluations that highlighted risks despite tolerances; this contributed to phased withdrawals of arsenicals in feeds by 2015, prioritizing empirical residue data over assumed margins. Global monitoring in markets like detects arsanilic acid as a notable contributor to total in , amplifying calls for stricter controls.

Environmental and Regulatory Impacts

Ecological Effects and Persistence

Arsanilic acid demonstrates moderate in , where it undergoes slow degradation and binds to soil components, with studies reporting fractional remaining concentrations of 0.78 and 0.28 after one year at unit application, corresponding to of 34.3 months and 6.6 months, respectively, varying by soil properties. In contrast, aqueous proceeds rapidly under , exhibiting a of 11.82 ± 0.19 minutes at neutral , primarily yielding inorganic through oxidative cleavage of the As-C bond. in increases with initial concentration, as higher doses extend degradation timelines due to saturation effects in microbial or photolytic processes. Ecological impacts stem largely from arsanilic acid's transformation into more bioavailable and toxic inorganic , released via excretion in manure applied to fields, leading to and runoff contamination. This inorganic exhibits , inhibiting plant growth in contaminated soils, and facilitates uptake into crops like , where total arsenic concentrations elevate in edible tissues. Aquatic ecosystems face acute risks, as arsanilic acid is classified as very toxic to organisms, with potential for chronic adverse effects including bioaccumulation of arsenic derivatives in food webs, disrupting microbial communities and higher trophic levels. Such transformations amplify environmental toxicity beyond the parent compound's lower inherent risks.

Regulatory Approvals and Withdrawals

In the United States, arsanilic acid received approval from the Food and Drug Administration (FDA) for incorporation into animal feeds as a growth promotant and coccidiostat for poultry and swine, with specific new animal drug applications (NADAs) such as those for Type A medicated articles permitting up to 0.05% arsanilic acid in complete feeds. These approvals dated back to the mid-20th century but faced increasing scrutiny over arsenic residues and potential metabolism into carcinogenic inorganic forms. In October 2013, manufacturers including Huvepharma voluntarily requested withdrawal of NADAs for arsanilic acid, roxarsone, and carbarsone, prompting the FDA to phase out their use; existing stocks were permitted until depleted, but no new approvals followed. The FDA formalized this via amendments to 21 CFR parts 556 and 558, effective November 26, 2013, codifying the withdrawal and eliminating regulatory provisions for arsanilic acid residues in edible tissues. In the , arsanilic acid was never authorized as a feed additive for ; Directive 70/524/EEC and subsequent regulations explicitly prohibited compounds in animal nutrition due to risks, with a full ban on such substances implemented in 1999 under Council Directive 96/25/EC targeting antimicrobial growth promoters. This stance extended to all phenylarsonic acids, reflecting precautionary principles amid evidence of environmental persistence and . similarly withheld approval for arsanilic acid in animal feeds, aligning with restrictions on organoarsenicals. Globally, regulatory withdrawals accelerated in the 2010s; China prohibited phenylarsonic additives like arsanilic acid in poultry and swine feeds effective October 1, 2017, with studies estimating resultant reductions in human cancer cases from lowered dietary arsenic exposure. Despite these actions, arsanilic acid persists in veterinary applications in certain developing regions where regulatory oversight is limited, though international bodies like the Codex Alimentarius have not endorsed its use in food-producing animals. Withdrawals were driven by empirical data on arsenic's carcinogenicity rather than manufacturer incentives alone, as petitions from public health groups highlighted residue violations exceeding safe limits in prior monitoring.

Global Usage and Bans

Arsanilic acid, a phenylarsonic compound, was historically incorporated into poultry and swine feeds worldwide to enhance growth rates and control diseases such as coccidiosis, with usage peaking in the mid-20th century in regions like North America and Asia. By the late 1990s, accumulating evidence of inorganic arsenic residues in animal tissues prompted regulatory scrutiny, leading to phased restrictions amid concerns over carcinogenic risks to humans and environmental contamination. The prohibited the use of arsanilic acid and other phenylarsonic feed additives in 1999, citing insufficient safety data and potential for ; this ban encompassed all organoarsenicals for prophylactic or growth-promoting purposes in . In the United States, the (FDA) rescinded approvals for arsanilic acid in November 2013, following voluntary withdrawals by manufacturers Alpharma and , which affected 101 associated new animal drug applications primarily for and feeds. This action aligned with prior FDA findings on roxarsone, another arsenical, revealing up to 5% conversion to toxic inorganic under anaerobic conditions in animal intestines. China, a major producer of compounds, extended the global trend by banning phenylarsonic feed additives including arsanilic acid on May 1, 2019, as part of broader efforts to mitigate human cancer risks estimated at 1,160 fewer cases annually from reduced dietary exposure. This prohibition targeted additives used in over 70% of Chinese and production prior to the cutoff. As of 2025, no major agricultural economies report active approvals for arsanilic acid in feeds, reflecting a near-universal phase-out driven by international pressure and domestic assessments, though sporadic veterinary applications may persist in unregulated markets without verified data.

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