Azo dyes, Hormones, Indigo, Male, Paracetamol, Sexology
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Aniline, through its conversion into antiandrogenic paracetamol (acetaminophen, tylenol), impairs male reproductive development

Industrial use of aniline is increasing worldwide with production estimated to surpass 5.6 million metric tons in 2016. Exposure to aniline occurs via air, diet, and water augmenting the risk of exposing a large number of individuals. Early observations suggest that aniline is metabolized to paracetamol/acetaminophen, likely explaining the omnipresence of low concentrations of paracetamol in European populations. This is of concern as recent studies implicate paracetamol as a disrupter of reproduction. Here, we show through steroidogenic profiling that exposure to aniline led to increased levels of the Δ4 steroids, suggesting that the activity of CYP21 was decreased. By contrast, paracetamol decreased levels of androgens likely through inhibition of CYP17A1 activity. We confirm that aniline in vivo is rapidly converted to paracetamol by the liver. Intrauterine exposure to aniline and paracetamol in environmental and pharmaceutical relevant doses resulted in shortening of the anogenital distance in mice, a sensitive marker of fetal androgen levels that in humans is associated with reproductive malformations and later life reproductive disorders. In conclusion, our results provide evidence for a scenario where aniline, through its conversion into antiandrogenic paracetamol, impairs male reproductive development.

Holm JB, Chalmey C, Modick H, Jensen LS, Dierkes G, Weiss T, Jensen BA, Nørregård MM, Borkowski K, Styrishave B, Martin Koch H, Mazaud-Guittot S, Jegou B, Kristiansen K, Kristensen DM. Aniline Is Rapidly Converted Into Paracetamol Impairing Male Reproductive Development. Toxicol Sci. 2015 Nov;148(1):288-98. doi: 10.1093/toxsci/kfv179. Epub 2015 Aug 10. PMID: 26259604.

Aniline (Wikipedia)

Aniline (from Portugueseanil ‘indigo shrub’, and -ine indicating a derived substance) is an organic compound with the formula C6H5NH2. Consisting of a phenyl group (−C6H5) attached to an amino group (−NH2), aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starting material for fine chemical synthesis. Its main use is in the manufacture of precursors to polyurethane, dyes, and other industrial chemicals. Like most volatile amines, it has the odor of rotten fish. It ignites readily, burning with a smoky flame characteristic of aromatic compounds. It is toxic to humans.

Aniline is predominantly used for the preparation of methylenedianiline and related compounds by condensation with formaldehyde. The diamines are condensed with phosgene to give methylene diphenyl diisocyanate, a precursor to urethane polymers.

Most aniline is consumed in the production of methylenedianiline, a precursor to polyurethanes.

Other uses include rubber processing chemicals (9%), herbicides (2%), and dyes and pigments (2%). As additives to rubber, aniline derivatives such as phenylenediamines and diphenylamine, are antioxidants. Illustrative of the drugs prepared from aniline is paracetamol (acetaminophen, Tylenol). The principal use of aniline in the dye industry is as a precursor to indigo, the blue of blue jeans.

Cake of indigo dye, which is prepared from aniline.

History

Aniline was first isolated in 1826 by Otto Unverdorben by destructive distillation of indigo. He called it Crystallin. In 1834, Friedlieb Runge isolated a substance from coal tar that turned a beautiful blue color when treated with chloride of lime. He named it kyanol or cyanol. In 1840, Carl Julius Fritzsche (1808–1871) treated indigo with caustic potash and obtained an oil that he named aniline, after an indigo-yielding plant, anil (Indigofera suffruticosa). In 1842, Nikolay Nikolaevich Zinin reduced nitrobenzene and obtained a base that he named benzidam. In 1843, August Wilhelm von Hofmann showed that these were all the same substance, known thereafter as phenylamine or aniline.

Synthetic dye industry

In 1856, while trying to synthesise quinine, von Hofmann‘s student William Henry Perkin discovered mauveine. Mauveine quickly became a commercial dye. Other synthetic dyes followed, such as fuchsin, safranin, and induline. At the time of mauveine’s discovery, aniline was expensive. Soon thereafter, applying a method reported in 1854 by Antoine Béchamp, it was prepared “by the ton”. The Béchamp reduction enabled the evolution of a massive dye industry in Germany. Today, the name of BASF, originally Badische Anilin- und Soda-Fabrik (English: Baden Aniline and Soda Factory), now the largest chemical supplier, echoes the legacy of the synthetic dye industry, built via aniline dyes and extended via the related azo dyes. The first azo dye was aniline yellow.

Developments in medicine

In the late 19th century, derivatives of aniline such as acetanilide and phenacetin emerged as analgesic drugs, with their cardiac-suppressive side effects often countered with caffeine.[32] During the first decade of the 20th century, while trying to modify synthetic dyes to treat African sleeping sickness, Paul Ehrlich – who had coined the term chemotherapy for his magic bullet approach to medicine – failed and switched to modifying Béchamp‘s atoxyl, the first organic arsenical drug, and serendipitously obtained a treatment for syphilis – salvarsan – the first successful chemotherapy agent. Salvarsan’s targeted microorganism, not yet recognized as a bacterium, was still thought to be a parasite, and medical bacteriologists, believing that bacteria were not susceptible to the chemotherapeutic approach, overlooked Alexander Fleming‘s report in 1928 on the effects of penicillin.

In 1932, Bayer sought medical applications of its dyes. Gerhard Domagk identified as an antibacterial a red azo dye, introduced in 1935 as the first antibacterial drug, prontosil, soon found at Pasteur Institute to be a prodrug degraded in vivo into sulfanilamide – a colorless intermediate for many, highly colorfast azo dyes – already with an expired patent, synthesized in 1908 in Vienna by the researcher Paul Gelmo for his doctoral research. By the 1940s, over 500 related sulfa drugs were produced. Medications in high demand during World War II (1939–45), these first miracle drugs, chemotherapy of wide effectiveness, propelled the American pharmaceutics industry. In 1939, at Oxford University, seeking an alternative to sulfa drugs, Howard Florey developed Fleming’s penicillin into the first systemic antibiotic drug, penicillin G. (Gramicidin, developed by René Dubos at Rockefeller Institute in 1939, was the first antibiotic, yet its toxicity restricted it to topical use.) After World War II, Cornelius P. Rhoads introduced the chemotherapeutic approach to cancer treatment.

Rocket fuel

Some early American rockets, such as the Aerobee and WAC Corporal, used a mixture of aniline and furfuryl alcohol as a fuel, with nitric acid as an oxidizer. The combination is hypergolic, igniting on contact between fuel and oxidizer. It is also dense, and can be stored for extended periods. Aniline was later replaced by hydrazine.

Toxicology and testing

Aniline is toxic by inhalation of the vapour, ingestion, or percutaneous absorption. The IARC lists it in Group 3 (not classifiable as to its carcinogenicity to humans) due to the limited and contradictory data available. The early manufacture of aniline resulted in increased incidents of bladder cancer, but these effects are now attributed to naphthylamines, not anilines.

Aniline has been implicated as one possible cause of forest dieback.

Many methods exist for the detection of aniline.

Oxidative DNA damage

Exposure of rats to aniline can elicit a response that is toxic to the spleen, including a tumorigenic response. Rats exposed to aniline in drinking water, showed a significant increase in oxidative DNA damage to the spleen, detected as a 2.8-fold increase in 8-hydroxy-2′-deoxyguanosine (8-OHdG) in their DNA. Although the base excision repair pathway was also activated, its activity was not sufficient to prevent the accumulation of 8-OHdG. The accumulation of oxidative DNA damages in the spleen following exposure to aniline may increase mutagenic events that underlie tumorigenesis.

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