The biochemistry of aromatic amines: The metabolism of 2-naphthylamine and 2-naphthylhydroxylamine derivatives

1. 2-Naphthylhydroxylamine and 2-nitrosonaphthalene were present in urine of dogs but not of guinea pigs, hamsters, rabbits or rats dosed with 2-naphthylamine. N-Acetyl-2-naphthylhydroxylamine and its O-sulphonic acid and O-glucosiduronic acid were not detected in the urine of any of these species. 2. Bile from rats dosed with 2-naphthylamine contained (2-naphthylamine N-glucosid)uronic acid and 6- and 5,6-substituted derivatives of 2-acetamidonaphthalene. 2-Amino-1-naphthyl and 2-acetamido-1-naphthyl derivatives, 2-naphthylhydroxylamine and its N-acetyl derivative or conjugates of these were not detected. Bile from a dog dosed with 2-naphthylamine contained no 2-amino-1-naphthyl derivatives. 3. 2-Naphthylhydroxylamine was metabolized by the dog, rat and guinea pig to the same products as those formed by these species from 2-naphthylamine. Rabbits formed mainly 2-amino-1-naphthyl derivatives; these are minor metabolites of 2-naphthylamine in this species. 4. (N-Acetyl-2-naphthylhydroxylamine O-glucosid)uronic acid was excreted in the urine and the bile of rats and in the urine of guinea pigs and rabbits dosed with N-acetyl-2-naphthylhydroxylamine. 5. After the administration of 2-acetamidonaphthalene, (N-acetyl-2-naphthylhydroxylamine O-glucosid)uronic acid was detected in the urine of dogs, but not in the urine of other species. The dog excreted an acid-labile cysteine derivative of 2-acetamidonaphthalene, but only traces of the corresponding mercapturic acid. 6. After dosing with N-acetyl-2-naphthylhydroxylamine-O-sulphonic acid, rats excreted derivatives of 2-amino-1-naphthol. 7. 2-Nitrosonaphthalene, N-acetyl-2-naphthylhydroxylamine, N-acetyl-2-naphthylhydroxylamine-O-sulphonic acid, 2-naphthylhydroxylamine-N-sulphonic acid, N-benzyloxycarbonyl-2-naphthylhydroxylamine and N-benzyloxycarbonyl-2-naphthylhydroxylamine-O-sulphonic acid were synthesized.     

Isolation of 2-amino-1-naphthyl hydrogen sulphate with cetylpyridinium bromide from metabolic and chemical oxidations of 2-naphthylamine

1. 2-Amino-1-naphthyl hydrogen sulphate can be rapidly isolated from the urine of dogs dosed with 2-naphthylamine by precipitation with cetylpyridinium bromide. 2. No evidence was obtained for the presence of 2-naphthylhydroxylamine-O-sulphonic acid, noteworthy as a possible source of the carcinogens, 2-naphthylhydroxylamine and 2-amino-1-naphthol. 3. Treatment of neutral persulphate oxidations of 2-naphthylamine with the reagent gave only the cetylpyridinium salt of 2-amino-1-naphthyl hydrogen sulphate.     

Carcinogenic ranking of aromatic amines and nitro compounds.

A scheme is proposed for ranking the carcinogenicity of aromatic amines and nitro compounds based on both qualitative (weight of evidence) and quantitative (carcinogenic potency, i.e. the TD50 value) factors. The scheme has been drawn up specifically with a view to linking with workplace hygiene controls. Other essential features are that a reliable database exists for the TD50 values for many compounds and that the scheme is capable of usage by non-toxicologists. Validation of the scheme using 38 aromatic amines or nitro compounds indicates that the main objectives have been met. Extension to different chemical classes should be possible but has not been attempted in this work. An example of a potential hygiene control scheme for use alongside the carcinogenicity ranking is described.