Me-@-1

Dyes based on known carcinogens such as benzidine (1) and ~-naphthylamine(2) can no longer be manufactured in the United States. In addition, numerous colorants (3, 4) have been banned from use by the food and cosmetics industries (1-3). These limitations have led us to examine structure-activity relationships that could help in the development of suitable nongenotoxic dyes and dye precursors.

00"

H2N - @ - @ -NH 2

NH 2

1

2

~-Naphthylamlne)

(Benzidine)

7). These results are generally believed to be at least partially due to the genotoxicity of the aromatic arnines that result from the metabolic reductive cleavage of the azo linkages. Formation of hydrophobic amines capable of undergoing further metabolism to N-hydroxylamines and then to arynitrenium ions (6) is believed to be an important step in the onset of mutagenesis or carcinogenesis in certain azo dyes. Gregory (7) indicated that an azo colorant exhibiting azo-hydrazone tautomerism is unlikely to undergo reductive cleavage to the corresponding aromatic amines if the colorant is an insoluble pigment. That is why pigments based on dichlorobenzidine (type 8) are commercially available (8) although the parent diarnine is mutagenic (9~ Related work (10-12) shows that certain

Me

HO

Me-@-N---c9©0 /

.

Na0 3S

S03Na

7 CI

¥

b~HN=(¥

HNMe--C)= / -N

@~H-g

0

C-Me

r-NH-@

8 4

(Pigment Yellow 12)

(A solvent dye)

A survey of the open literature (4, 5) readily shows that a hydrophobic dye of type 5 and a hydrophilic dye such as type 6 are potential human carcinogens. On the other hand, azo dyes containing at least one sodium sulfonate (-S03Na) group on each side of the azo linkage do not appear to pose a significant risk to human health (e.g., type /

Me

/

Me

@-N=N-@-NH2

molecular modifications of some known carcinogens led to significant lowering or removal of genotoxicity (Figure 1). It is believed that the increased hydrophilicity of 12, 15, and 17 (versus 1, 9, and 10) and steric inhibition of metabolism of a nitro or amino group caused by converting the parent compounds 1, 9, and 11 to the ortho, ortho' • dimethylated analogues account for the properties of 13, 16, and 18. It also has been reported (5, 13, 14) that the higher alkyl homologues of dye 9 are either nonmutagenic (ef. 19) or noncarcinogenic (ef. 20 and 21). @-N=N-@-N(R)2

5

Me-@-1 /Me

HO\

/S03Na

S03Na

6 438

CHEMTECH JULY 1991

R 19

20 21

Et n-Pr n-Bu

Let us now turn to our work (15) concerning the mutagenicity of some Widely used dyestuff intermediates and monoazo dyes derived from those intermediates. Our goal was the development of nonmutagenic azo dyes by 0009-2703/91 $2.50 © 1991 American Chemical Society

c Harold S. Freeman Michelle K. Esancy James F. Esancy Larry D. Claxton

Mutagen/carcinogen

Figure 1. Conversion of some genotoxlc compounds to nongenotoxlc analogues.

H2N - @ - @ - N H2

1

14

@-N=N-@-NMe2

9

H03S-@-N==N-@-NMe2

15 Me

©--=N~NMe' Me

18 H03S----