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SOME AROMATIC AMINES AND RELATED COMPOUNDS VOLUME 127 This publication represents the views and expert opinions of an IARC Working Group on the Identification of Carcinogenic Hazards to Humans, which met remotely, 25 May–12 June 2020 LYON, FRANCE - 2021 IARC MONOGRAPHS ON THE IDENTIFICATION OF CARCINOGENIC HAZARDS TO HUMANS ANILINE AND ANILINE HYDROCHLORIDE 1. Exposure Characterization 1.1.2 Structural and molecular formulae, and relative molecular mass 1.1 Identification of the agent (a) Aniline 1.1.1 Nomenclature NH2 (a) Aniline Chem. Abstr. Serv. Reg. No.: 62-53-3 EC No.: 200-539-3 Molecular formula: C H N IUPAC systematic name: aniline 6 7 Relative molecular mass: 93.13 (NCBI, 2020a). Synonyms and abbreviations: benzenamine; phenylamine; aminobenzene; aminophen; (b) Aniline hydrochloride aniline oil. NH2 (b) Aniline hydrochloride Chem. Abstr. Serv. Reg. No.: 142-04-1 EC No.: 205-519-8 HCl IUPAC systematic name: aniline hydro - Molecular formula: C6H8ClN chloride Relative molecular mass: 129.59 (NCBI, Synonyms: aniline chloride; anilinium chlo- 2020b). ride; benzenamine hydrochloride; aniline. HCl; phenylamine hydrochloride; phenylam- monium chloride. 1.1.3 Chemical and physical properties of the pure substance Aniline is a basic compound and will undergo acid–base reactions. Aniline and its hydrochlo- ride salt will achieve a pH-dependent acid–base equilibrium in the body. 109 IARC MONOGRAPHS – 127 (a) Aniline Octanol/water partition coefficient (P): log Kow, 0.936, predicted median (US EPA, 2020b) Description: aniline appears as a yellowish Conversion factor: 1 ppm = 5.3 mg/m3 [calcu- to brownish oily liquid with a musty fishy lated from: mg/m3 = (relative molecular odour (NCBI, 2020a), detectable at 1 ppm 3 mass/24.45) × ppm, assuming temperature [3.81 mg/m ] (European Commission, 2016; (25 °C) and pressure (101 kPa)]. NIOSH, 2019) Boiling point: 184.1 °C (NCBI, 2020a) Melting point: −6 °C (NCBI, 2020a) 1.2 Production and use Flash point: 70 °C, closed cup (NCBI, 2020a) 1.2.1 Production process Density: 1.02 g/cm3 (NCBI, 2020a) Historically, aniline was produced by Otto Vapour density: 3.2 (air = 1) (NCBI, 2020a) Unverdorben in 1826 by dry distillation from Vapour pressure: 40 Pa at 20 °C; 0.67 mm Hg the leaves of the indigo plant, genus Indigofera at 25 °C (NCBI, 2020a) (most probably Indigofera tinctoria). Aniline was Solubility: 36 g/L at 25 °C in water; soluble isolated from coal tar in 1834. Aniline was first in alcohol, ether, benzene, ethyl ether, and synthesized in 1842 by reducing nitrobenzene carbon tetrachloride (NCBI, 2020a) with sodium sulfates (Zinin reaction; Zinin, Dissociation constant: pKa, 4.6 (at 25 °C; 1842) and first manufactured commercially in aniline conjugate acid) (NCBI, 2020a) 1847 (Kouris & Northcott, 1963). Aniline was Octanol/water partition coefficient (P): log made by the Bechamp process of reduction of nitrobenzene with iron and hydrochloric acid Kow, 0.9 (US EPA, 2020a) and, until 1966, by amination of chlorobenzene 3 Conversion factor: 1 ppm = 3.81 mg/m with ammonia (IARC, 1982). Presently, aniline 3 (NIOSH, 2019) [calculated from: mg/m = (rela- is produced by catalytic reduction of nitroben- tive molecular mass/24.45) × ppm, assuming zene. The process can be divided into three main temperature (25 °C) and pressure (101 kPa)]. parts: nitrobenzene hydrogenation, dehydration, (b) Aniline hydrochloride and purification. Nitrobenzene is converted to aniline (nearly 100%) in a single pass by feeding Description: aniline hydrochloride appears as it with hydrogen into a reactor containing the a white to greenish coloured crystalline solid catalyst metal. The excess hydrogen is removed, (NCBI, 2020b) and the liquid product is dehydrated. The Boiling point: 245 °C (NCBI, 2020b) crude aniline is purified by distillation. The final product obtained is aniline with a purity Melting point: 198 °C (NCBI, 2020b) of > 99.95 wt% containing less than 0.1 ppm Flash point: 193 °C, open cup (NCBI, 2020b) [0.1 mg/kg] of nitrobenzene by weight. The Density: 1.22 g/cm3 (NCBI, 2020b) conversion of nitrobenzene to aniline remains Vapour density: 4.46 (air = 1) (NCBI 2020b) the most common pathway for aniline prod- Solubility: soluble in water: 1070 g/L at 20 °C uction. An alternative production pathway for (NCBI, 2020b) aniline uses phenol and ammonia as the starting raw materials (Intratec Solutions, 2016). Dissociation constant: pKa, 4.6 (at 25 °C; aniline conjugate acid) 110 Aniline and aniline hydrochloride Aniline hydrochloride is prepared by reacting aniline vapour and hydrogen chloride gas at Table 1.1 Global production of aniline in 2006, by geographical region temperatures of > 250 °C (Holt & Daudt, 1935). Region Aniline production 1.2.2 Production volume (tonnes per year) Western Europe 1 620 000 Aniline is a High Production Volume chem- USA 1 380 000 ical (OECD, 2009; US EPA, 2020c). It is used Asia-Pacific (excluding Japan) 1 150 000 as a starting material in several industries, Japan 474 000 including for the manufacture of a variety of Eastern Europe 316 500 plastics, rubber additives, colourants, and drugs Latin America 70 000 (Käfferlein et al., 2014). Asia or Middle East 64 000 Global capacity for aniline production was Data from ICIS (2008). 4.98 million tonnes per year in 2006, with the major producers being in western Europe, the pounds [887 000 tonnes], whereas in 2012–2015, USA, and the Asia-Pacific region ICIS,( 2008; it was between 1000 million and 5000 million see Table 1.1). Total volume for manufacture pounds [450 000–2 300 000 tonnes] (ChemView, and use in the European Union is 1 million to 2016). According to another source, annual 10 million tonnes per year (ECHA, 2020a). In an aniline production in the USA since 1990 has updated assessment report on aniline under the varied between 449 000 and 1 065 000 tonnes; Canadian Environmental Protection Act of 1999 in 2019, it was 845 000 tonnes (Statista, 2020a). (Health Canada, 2011), Health Canada reported The production volume of aniline in India that more than 28 tonnes of aniline and its salts during 2013–2019 varied between 34 470 and were synthesized as a by-product of chemical 48 230 tonnes (Statista, 2020b). manufacturing in Canada in 2007. Additionally, between 13 and 48 tonnes of aniline and aniline 1.2.3 Uses salts were imported into Canada in 2000–2007 In the chemical industry, aniline is used as (Health Canada, 2011). During 2014–2019, glob - a parent substance for the synthesis of many al consumption of aniline grew at an average compounds, including isocyanates, dyes and annual rate of 4.8%, reaching more than pigments, antioxidants, and accelerators in 6.7 million tonnes in 2019 (IHS Markit, 2020). rubber processing, pharmaceuticals, varnishes, North-eastern Asia was the largest producer perfumes, photographic chemicals, herbicides, of aniline during 2013–2018, accounting for and fungicides (aniline is no longer approved more than half of the global production of for pesticide use in the European Union) (ICIS, aniline. Western Europe and the USA were 2008; European Commission, 2016; see Fig. 1.1). the next-largest suppliers. Most increases in China is the world’s largest consumer of production capacity for aniline were in China aniline and accounted for 37% of global demand during 2013–2018, along with expansions in the in 2018. Western Europe is the second-largest Middle East and western Europe. In 2018, China consumer of aniline, accounting for 23% of accounted for almost 50% of the world’s aniline global aniline demand in 2018. The USA follows production capacity, followed by western Europe as the third-largest consumer, accounting for and the USA (IHS Markit, 2019). 17% of global aniline consumption (IHS Markit, The national aggregate production volume in 2019). [The Working Group noted that, despite the USA in 2011 was approximately 1956 million the major demand for aniline in Asia, few data 111 IARC MONOGRAPHS – 127 Fig. 1.1 Global consumption of aniline, by industry 4,4-Methylene diphenyl diisocyanate (MDI) Construction Rubber products Transportation Consumer Adhesives/sealants Packaging Agriculture Textiles Coatings Manufacturing Photography Pharmaceuticals Electronics Pulp and paper From Independent Commodity Intelligence Service (ICIS, 2008). Reproduced with permission from www.icis.com. on uses and exposure levels were available for polyurethane foam. Rigid polyurethane is used this region.] in walls and roofs of new residential and commer- cial constructions as well as in the renovation of (a) 4,4-Methylene diphenyl diisocyanate older buildings for insulating purposes. Flexible Production of 4,4-methylene diphenyl diiso- polyurethane foam is primarily used in furniture cyanate (MDI) accounts for more than 90% of and transportation (IHS Markit, 2019; American aniline use (IHS Markit, 2019). Aniline and Chemistry Council, 2020; GlobeNewswire, formaldehyde react in an acid-catalysed reac- 2020). tion, which is followed by liquid-phase phos- genation of diphenylmethane diamine to MDI (Lynch & Ryan, 2012). MDI is used to produce 112 Aniline and aniline hydrochloride (b) Rubber processing exposure levels related to production and use of Production of chemicals used in rubber denim garments.] processing is the second largest sector of aniline (d) Pharmaceutical products use (Amini & Lowenkron, 2003). Among the rubber-processing agents made from aniline Aniline is used as an intermediate in the are several important vulcanization accelerators production of a variety of pharmaceutical prod- and antioxidants, including aldehyde–aniline ucts. A major derivative is acetanilide, which is condensates (e.g. N-butyraldehyde conden- used in the production of phenazopyridine and sate), guanidines (e.g. 1,3-diphenylguanidine), several sulfa drugs, including sulfafurazole and N-phenyl-2-naphthylamine (IARC, 1978), thia- sulfamethoxazole (previously evaluated as IARC zoles (e.g. 2,2′-dithiobisbenzothiazole and other Group 3, not classifiable as to its carcinogenicity to derivatives of 2-mercaptobenzothiazole, MBT), humans, by the IARC Monographs programme; and a variety of derivatives of diphenylamine IARC, 1980), and also as a precursor in the (which is made from aniline) (IARC, 1982).
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