2- Naphthylamine, carcinogenicity

I-Naphthylamine readily diazotizes and couples to aromatic hydroxylic or basic compounds. It was thus used as a first component in a number of important monoazo dyes, but its use has been severely curtailed because of its potent carcinogenicity. It sulphonates to give naphthionic acid (l-naphthylamine-4-sul-phonic acid). 

Nitration. Naphthalene is easily nitrated with mixed acids, eg, nitric and sulfuric, at moderate temperatures to give mostly 1-nitronaphthalene and small quantities, 3—5%, of 2-nitronaphthalene. 2-Nitronaphthalene [581-89-5] is not made in substantial amounts by direct nitration and must be produced by indirect methods, eg, the Bucherer reaction starting with 2-naphthalenol (2-naphthol [135-19-3]). However, the 2-naphthylamine [91-59-8] made using this route is a carcinogen thus the Bucherer method is seldom used in the United States. 

Naphthylamine [134-32-7] M 143.2, m 50.8-51.2 , b 160 , pK 3.94. Sublimed at 120° in a stream of nitrogen, then crystd from pet ether (b 60-80°), or abs EtOH then diethyl ether. Dried under vacuum in an Abderhalden pistol. Has also been purified by crystn of its hydrochloride from water, followed by liberation of the free base and distn finally purified by zone melting. CARCINOGEN. 

Aldehyde-amines Aldol-naphthylamines Yes Not often used. Possibilities of carcinogenic hazard with some types. 

Carcinogens Cancer-producing agents Skin Respiratory Bladder/urinary tract Liver Nasal Bone marrow Coal tar pitch dust crude anthracene dust mineral oil mist arsenic. Asbestos polycyclic aromatic hydrocarbons nickel ore arsenic bis-(chloromethyl) ether mustard gas. p-naphthylamine benzidine 4-am i nodi pheny lam ine. Vinyl chloride monomer. Mustard gas nickel ore. Benzene. 

Discussion. General procedures for the determination of nitrites are usually based upon some form of diazotisation reaction, often involving carcinogenic materials such as the naphthylamines. In the following method these compounds are avoided. 

P-Bromonaphthalene. The preparation from p-naphthylamine, which has carcinogenic properties, is avoided by the use of 2-naphthylamine-1-sulphonic acid ( 2-amino-1-naphthalenesulphonic acid ) the latter is obtained commercially by cautious treatment of p-naphthol with sulphuric acid—the SOjH group first enters the 1-position—followed by the Bucherer reaction. Diazotisation and reaction with cuprous bromide yields 2-bromonaphthalene-l-sulphonic acid heating with sulphuric acid eliminates the sulphonic acid group to give 2-bromonaphthalene. 

The role of N-sulfonyloxy arylamines as ultimate carcinogens appears to be limited. For N-hydroxy-2-naphthylamine, conversion by rat hepatic sulfotransferase to a N-sulfonyloxy metabolite results primarily in decomposition to 2-amino-l-naphthol and 1-sulfonyloxy-2-naphthylamine which are also major urinary metabolites and reaction with added nucleophiles is very low, which suggests an overall detoxification process (9,17). However, for 4-aminoazobenzene and N-hydroxy-AAF, which are potent hepatocarcinogens in the newborn mouse, evidence has been presented that strongly implicates their N-sulfonyloxy arylamine esters as ultimate hepatocarcinogens in this species (10,104). This includes the inhibition of arylamine-DNA adduct formation and tumorigenesis by the sulfotransferase inhibitor pentachlorophenol, the reduced tumor incidence in brachymorphic mice that are deficient in PAPS biosynthesis (10,115), and the relatively low O-acetyltransferase activity of mouse liver for N-hydroxy-4-aminoazobenzene and N-OH-AF (7,114,115). 

The exceptional reactivity of DNA for protonated N-hydroxy arylamines can be rationalized by at least two mechanisms. First, intercalation of the electrophilic intermediate between DNA bases could sterically assist in desolvation and in directing the electrophilic center of the carcinogen over the nucleophilic region of the DNA base. This seems unlikely, however, as pretreatment of DNA with cis-Pt, which decreased the DNA contour length by 50%, failed to reduce the reactivity of N-hydroxy-1-naphthylamine for the DNA (137). A second possibility involves an electrostatic attraction between the electrophile and the phosphate backbone of the DNA (77). This seems more probable since eithe j +high ionic strength or stoichiometric (to DNA-P) amounts of Mg strongly inhibit DNA adduct formation (77,137). In addition, evidence has been presented that N-hydroxy arylamine-DNA/RNA phosphotriesters may be formed which induce strand breaks (137,138) and could serve as a catalyst for desolvation and subsequent adduct formation. 

Use Rat poison. Banned in Britain due to carcinogenic impurities such as p-naphthylamine (Cremlyn, 1991). 

It was claimed that these reagents lead to more stable azo colors. In addition, 1-naphthylamine was reported to have possible carcinogenic properties [47]. 

ANTU was not carcinogenic in rodent feeding studies. Cases of bladder tumors among rat catchers exposed to ANTU have been attributed to P-naphthylamine, a manufacturing impurity of ANTU. In bacterial assays ANTU induced mutations. 

ACGIH classifies (3-naphthylamine as Al, a confirmed human carcinogen, and as such, there is no threshold limit value (TLV). 

US Department of Health and Human Services (NIOSH) Occupational safety and health guidelines for chemical hazards—Supplement n—OHG (Pub No. 89-104), pp 1-6. Occupational Safety and Health Guideline for f-Naphthylamine Potential Human Carcinogen. Cincinnati, OH, 1988... 

Toxicology. AT-phenyl-P-naphthylamine (PBNA) is carcinogenic to experimental animals in some studies. 

PBNA has been tested for carcinogenicity in a number of species without conclusive results. There was no evidence of carcinogenic activity in male or female rats or in male mice fed 2500 or 5000 ppm in the diet for 2 years. The lack of carcinogenicity in rats may be related to an inability to metabolize PBNA to the known animal and human urinary bladder carcinogen P-naphthylamine. There was equivocal evidence for carcinogenicity in female mice, as indicated by the occurrence of two rare kidney tumors. Chemical-related non-neoplastic lesions, including nephropathy, karyomegaly, and hyperplasia, occurred in the kidneys of both species. 

The lARC has concluded that there is limited evidence for carcinogenicity to animals and inadequate evidence for humans. ACGIH considers PBNA to be a suspected human carcinogen because P-naphthylamine is both an impurity and a human metabolite of PBNA. ... 

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