Appendix G
Disperse Red 11

BACKGROUND

DISPERSE RED 11 is also called 1,4-diamino-2-methoxy-anthraquinone (DMA). Disperse red 11 is a component of the new red-dye mixture.

TOXICOKINETICS

No information is available on the toxicokinetics of disperse red 11 in humans. One study instilled a suspension containing disperse red 11 to determine its retention in the lungs of rats. The study determined that disperse red 11 is rapidly absorbed into the blood with only 66% of the instilled dose remaining at 5 min and 3.5% remaining at 24 hr (Henderson et al. 1988).

TOXICITY SUMMARY

Effects in Humans

One study was conducted with six females with histories of allergic contact dermatitis (Lisboa et al. 1994). The patients were patch tested with a series of 15 disperse dyes used in the textile industry. All six



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Toxicity of Military Smokes and Obscurants: Volume 3 Appendix G Disperse Red 11 BACKGROUND DISPERSE RED 11 is also called 1,4-diamino-2-methoxy-anthraquinone (DMA). Disperse red 11 is a component of the new red-dye mixture. TOXICOKINETICS No information is available on the toxicokinetics of disperse red 11 in humans. One study instilled a suspension containing disperse red 11 to determine its retention in the lungs of rats. The study determined that disperse red 11 is rapidly absorbed into the blood with only 66% of the instilled dose remaining at 5 min and 3.5% remaining at 24 hr (Henderson et al. 1988). TOXICITY SUMMARY Effects in Humans One study was conducted with six females with histories of allergic contact dermatitis (Lisboa et al. 1994). The patients were patch tested with a series of 15 disperse dyes used in the textile industry. All six

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Toxicity of Military Smokes and Obscurants: Volume 3 patients had a reaction to two or more of the disperse dyes; however, none of the patients reacted to disperse red 11. Effects in Animals A minimal battery of toxicity studies have been conducted with disperse red 11. Those studies are summarized in Table G-1. Acute-toxicity studies using two dye lots of disperse red 11 exposed female rats by either the oral or dermal routes and established the lethal dose for 50% of the animals (LD50) to be greater than 5 grams per kilogram (g/kg) of body weight (Smith et al. 1986). In contrast, for male rats, the LD50 after oral exposure was determined to be between 0.7 and 1.0 g/kg of body weight. Acute lethal doses after dermal exposure in rabbits are greater than 2 g/kg of body weight. Disperse red 11 was found to be negative in an eye irritation study conducted in rabbits (Smith et al. 1986). However, depending upon the dye lot used, disperse red 11 was found to be moderately to mildly irritating in a dermal irritation study (Smith et al. 1986). Mice studies using an ear-swelling test or a local lymphoid assay determined disperse red 11 to be negative for production of contact hypersensitivity (Sailstad et al. 1994). Mutagenicity Mutagenicity studies with disperse red 11 are summarized in Table G-2. The mutagenic effects of disperse red 11 have been investigated in three experimental systems: mouse lymphoma cells, Salmonella typhimurium bacterial assay (Ames test), and Chinese hamster ovary cells. The results of those studies are conflicting. Increased mutants and micronuclei were noted in the mouse lymphoma-cell system (Harrington-Brock et al. 1991), and an increased frequency of sister-chromatid-exchange and hypoxanthine guanine phosphoribosyl transferase (HGPRT) mutant frequency were seen in Chinese hamster ovary cells (Brooks et al. 1989). However, studies using bacterial assays have shown mixed results. The studies of Brown and Brown (1976) showed that disperse red 11 was not mutagenic, but the studies of Moore et al. (1989) showed that disperse red 11 was positive in one test strain. Brooks et al. (1989) concluded that mutagenicity of disperse red 11 was dependent upon the dye lot

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Toxicity of Military Smokes and Obscurants: Volume 3 TABLE G-1 Summary of Toxicity Studies Conducted with Disperse Red 11 Study Type Species Exposure Conditions End Points and Comments Reference Acute toxicity Rat, Fischer 344, M Oral, acute, 5 g/kg Lot 1:5/5 died, 4-6 d; Lot 2:5/5 died, 4-5 d Smith et al. 1986 Acute toxicity Rat, Fischer 344, M Oral, acute, Lot 1:0.6, 0.7, 0.9, 1.4 g/kg; Lot 2:0.5, 0.9, 1.4 g/kg Lot 1:0/5, 0/5, 4/5, 5/5 died; Lot 2:0/5, 3/5, 3/5 died; LD50 1.0 g/kg Smith et al. 1986 Acute toxicity Rat, Fischer 344, F Oral, acute, 5 g/kg Lot 1:0/10 died at 14 d; LD50 > 5 g/kg Lot 2:0/10 died at 14 d; LD50 > 5 g/kg Smith et al. 1986 Acute toxicity Rabbit, New Zealand White, M, F Dermal, acute, 2 g/kg for 24 hr Lot 1:0/10 died at 14 d; LD50 > 2 g/kg; Lot 2:0/10 died at 14 d; LD50 > 2 g/kg Smith et al. 1986 Eye irritation Rabbit, New Zealand White, M or F 0.1 g/eye Lot 1: negative; Lot 2: negative Smith et al. 1986 Dermal irritation Rabbit, New Zealand White, M, F Clipped skin, 0.5 g/kg for 24 hr Lot 1: primary irritation score 2.7; moderately irritating; Lot 2: primary irritation score 0.73; mildly irritating Smith et al. 1986 Contact hypersensitivity Mice, Balb/c, F Mouse ear-swelling test: 0.0006 g/d shaved back, 2 d; challenge on d 5 Negative Sailstead et al. 1994 Contact hypersensitivity Mice, Balb/c, F Local lymph node assay: 0.00005 g/d both ears, 3 d Negative Sailstead et al. 1994 Contact dermatitis Humans, 6 F with allergic contact dermatitis 1% solution Negative Lisboa et al. 1994 Abbreviations: M, male; F, female.

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Toxicity of Military Smokes and Obscurants: Volume 3 TABLE G-2 Summary of Mutagenicity Studies Conducted with Disperse Red 11 Experimental System Exposure Conditions End Points and Comments Reference Mouse lymphoma cells 0-40 µg/mL, 4 hr 264 thymidine kinase mutants per 106 survivors; 109 micronuclei per 1,000 cells at 15% survival Harrington-Brock et al. 1991 Salmonella typhimurium (strains TA1535, TA1537, TA1538, TA98, TA100, TA1978) ± S9 Not specified Not mutagenic Brown and Brown 1976 Salmonella typhimurium (strains TA1537, TA1538, TA98, TA100, TA102, TA104) ± S9 0-7, 500 µg/plate Positive in TA102 +S9 Moore et al. 1989 Salmonella typhimurium (strains TA1535, TA1538, TA98, TA100) ± S9 0-1,000 µg/plate, Lot 1: not mutagenic; Lot 2: mutagenic activity in TA98 and TA1538 +S9 Brooks et al. 1989 Chinese hamster ovary cells 0-40 µg/mL, 3 hr Lot 1 and 2: increased frequency of sister chromatid exchange; delay in cell growth; no increase in chromosomal aberrations; Lot 2: increase in HGPRT mutant frequency Brooks et al. 1989 Abbreviations: HGPRT, hypoxanthine guanine phosphoribosyl transferase.

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Toxicity of Military Smokes and Obscurants: Volume 3 type, suggesting that the observed mutagenicity might be due to a contaminant in the dye lot. SUBCOMMITTEE EVALUATION OF DYE TOXICITY The experimental data are insufficient to assess the toxic effects of disperse red 11. REFERENCES Brooks, A.L., F.A. Seiler, R.L. Hanson, and R.F. Henderson. 1989. In vitro genotoxicity of dyes present in colored smoke munitions. Environ. Mol. Mutagen. 13(4):304-313. Brown, J.P., and R.J. Brown. 1976. Mutagenesis by 9-10-anthraquinone derivatives and related compounds in Salmonella typhimurium. Mutat. Res. 40(3):203-224. Harrington-Brock, K., L. Parker, C. Doerr, M.C. Cimino, and M.M. Moore . 1991. Analysis of the genotoxicity of anthraquinone dyes in the mouse lymphoma assay. Mutagenesis 6(1):35-46. Henderson, R.F., W.E. Bechtold, M.A. Medinsky, J. P. Fischer, and T.T. Lee. 1988. The effect of molecular weight/lipophilicity on clearance of organic compounds from lungs. Toxicol. Appl. Pharmacol. 95(3):515-521. Lisboa, C., M.A. Barros, and A. Azenha. 1994. Contact dermatitis from textile dyes. Contact Dermatitis 31(1):9-10. Moore, M.M., L. Claxton, V. Houk, G.M. Nelson, and K. Harrington-Brock. 1989. Toxicity of Red and Violet Dyes in M18 Grenades: Mutagenic Screening of Three Dyes for Marker Grenades in the Salmonella Reversion Assay and the L5178Y/TK +/- Mouse Lymphoma Assay. Final Report. AD A229021. U.S. Environmental Protection Agency, Health Effects Research Laboratory, Research Triangle Park, NC. Sailstad, D.M., J.S. Tepper, D.L. Doerfler, M. Qasim, and M.K. Selgrade. 1994. Evaluation of an azo and two anthraquinone dyes for allergic potential. Fundam. Appl. Toxicol. 23(4):569-577. Smith, S.H., G.L. Doyle, J.C. Kreuger, K.A. Mellon, D.A. Mayhew. 1986. Dermal, Eye, and Oral Toxicological Evaluations, Phase IV Report with Disperse Red 11, Disperse Blue 3, Solvent Red 1, and Red and Violet Mixtures. AD A172-758. Bioassay Systems Corporation, Woburn, MA.