Toxicity of Military Smokes and Obscurants: Volume 3 (1999)

SOLVENT YELLOW 33 is also known as 2-(2-quinolyl)-1,3-indandione (QID), D&C yellow no. 11, quinazoline yellow spirit soluble, and yellow no. 204. This compound is a component of the new yellow-and green-dye mixtures.

The disposition and metabolism of ¹⁴C-QID were studied in male Fischer 344 (F344) rats (Medinsky et al. 1986). Rats were exposed to solvent yellow 33 by inhalation at 0.04 grams per cubic meter (g/m³) for 6 hr. The activity median aerodynamic diameter of the particles was 3.4 micrometers (µm) with a geometric standard deviation of 1.7. At the end of exposure, greater than 90% of the radioactivity remaining in the lungs was unmetabolized solvent yellow 33. Solvent yellow 33 was rapidly cleared from the respiratory tract during and after exposure, the half-time being approximately 2 to 3 hr. Once absorbed into the blood, solvent yellow 33 was rapidly metabolized. High-pressure liquid-chromatography analysis of tissue extracts indicated that 40% to 75% of the radioactivity in liver and kidney consisted of solvent yellow 33 metabolites. The major pathway for excretion of solvent yellow 33 and solvent yellow 33 metabolites was feces, accounting for 74% of the initially

deposited material. The half-time for elimination in feces was 14 hr. Radioactivity eliminated in urine accounted for 14% of the initially deposited material, the half-time for elimination being 10 hr. Over 90% of the ¹⁴C excreted in urine was in the form of solvent yellow metabolites. Very little solvent yellow was metabolized to radiolabeled carbon dioxide and exhaled. Only 10% of the initial amount of solvent yellow deposited remained in the body 72 hr after exposure.

The disposition of solvent yellow 33 was also investigated in male F344 rats administered solvent yellow 33 intravenously or by feeding (El Dareer et al. 1988). Rats were fed food dosed with solvent yellow 33 for 7 days, followed by exposure to ¹⁴C-QID in the food on day 8. Rats were returned to feed containing unlabeled solvent yellow 33 on days 9 through 11. As calculated from feed consumption, the dose administered over the entire feeding period was 4.1 g per kilogram (kg) of body weight (0.144 microcuries per kilogram (µCi/kg) of body weight), 0.4 g/kg of body weight (0.146 µCi/kg of body weight), 0.04 g/kg of body weight (0.143 µCi/kg of body weight), or 0.004 g/kg of body weight (0.045 µCi/kg of body weight) for the 0.14%, 0.038%, 0.0037%, or 0.00044% diets, respectively. Urine and feces were collected daily on days 9 through 12. From 89% to 94% of the radiolabel was recovered in the feces of rats given solvent yellow 33 in their food; from 5% to 6% of the radioactivity was recovered in the urine. On day 12, the rats were euthanized and tissues were taken for analysis. Only trace amounts of radioactivity were present in the tissues 72 hr after dosing with radioactive solvent yellow 33.

In a separate study, rats were given ¹⁴C-QID at 0.001 g/kg of body weight (0.116 µCi/kg of body weight) by tail-vein injection. In some studies, bile was collected from intravenously dosed rats fitted with billary cannulae. Fecal excretion accounted for 89% of the administered radioactivity, and urinary excretion represented 17% 72 hr after exposure. In rats with billary cannulae, 54% of the administered radioactivity appeared in the bile within 4 hr. Analysis of the bile revealed no intact ¹⁴C-QID, but more than 10 metabolites were detected.

In summary, the results of pharmacokinetic studies of solvent yellow 33 administered to animals by inhalation, by injection, or in feed suggest that, after inhalation by humans, solvent yellow 33 will be rapidly absorbed from the respiratory tract, and extensively metabolized, with the metabolites excreted in the bile and eliminated in the feces. No tissues appear to be storage depots for significant quantities of solvent yellow 33.

There are numerous reports of contact dermatitis in humans exposed to solvent yellow 33. Some of the most recent case reports and clinical studies are presented in Table C-1. Solvent yellow 33 is used in soaps, shampoos, and other externally applied products. Case reports of allergic contact dermatitis due to exposure to solvent yellow 33 in cosmetics, such as eyeliner, rouge, and lipstick have been published (reviewed by Feinman and Doyle 1988). Weaver (1983a) reported that a soap containing solvent yellow 33 at 60 parts per million (ppm) elicited dermatitis in two consumers. Monk (1987) reported allergic contact dermatitis from exposure to solvent yellow 33 found in a hair cream. Reactivity was confirmed using a patch test. There is one report of a worker diagnosed with occupational allergic contact dermatitis (Noster and Hausen 1978). The individual was employed in a factory that manufactured colored smokes for use in detonators.

Controlled laboratory studies with human volunteers confirm the sensitizing potential of solvent yellow 33. Jordan (1981) describes contact dermatitis due to solvent yellow 33 in 11 of 149 volunteers who developed a sensitization reaction when tested with solvent yellow 33 concentrations of 16.4 ppm in a modified Draize test. Weaver (1983b) demonstrated sensitization in a repeated-insult patch test of Solvent yellow 33 at concentrations as low as 10 ppm but not at 5 ppm. Rapaport (1984) induced sensitization in 14 of 56 healthy volunteers using a solution containing 20% solvent yellow 33. Bjorkner and Magnusson (1981) and Bjorkner and Niklasson (1983) report sensitization in 4 of 88 normal volunteers exposed to 1% solvent yellow 33 in propylene glycol and in one patient exposed to 0.00001% of the dye. Kita et al. (1984) demonstrated sensitization to solvent yellow 33 in 15 of 20 subjects exposed to 0.5% solvent yellow 33 in petrolatum. All 15 allergic subjects reacted to challenge with solutions containing 1,000 ppm, and one reacted to challenges down to 1 ppm. Kita and colleagues concluded that solvent yellow 33 is a potent contact sensitizer because 15 of 20 subjects became sensitized using the maximization test, and almost half of those individuals reacted to challenge with 100 ppm. The authors also investigated the cross-reactivity to purified samples of D&C yellow

no. 10. Solutions containing 5% of that dye failed to sensitize human subjects. D&C yellow no. 10 is the sodium salt of solvent yellow 33 and is soluble and ionized in aqueous solutions. Weaver (1983b) attributes the differences in the sensitization potential of the two dyes to the ability of solvent yellow 33 to penetrate the skin more readily.

As outlined in Table C-2, numerous toxicity studies have been conducted on solvent yellow 33, most likely precipitated by its use in consumer products. The results of those investigations indicate that solvent yellow 33 is not acutely toxic. The studies of most relevance to the military for its intended use of solvent yellow 3 are reviewed in detail below.

In a repeated exposure study (Henderson et al. 1985), three male and three female F344 rats per group were exposed by inhalation to concentrations of solvent yellow 33 at 1.0 g/m³ (1 hr per day), 1.0 g/m³ (6 hr per day), and 12.1 g/m³ (6 hr per day) for 5 days. There were no overt signs of toxicity after any of the exposure regimens. Histological examination of the respiratory tract from rats exposed to the aerosol for 5 days showed globlet-cell hypertrophy and hyperplasia in the respiratory epithelium of the nasal cavity. There was mild inflammation of the respiratory epithelium and degeneration in the olfactory region. In the lung parenchyma, there were a few focal accumulations of alveolar macrophages centered on terminal airways.

In 4-week studies (Henderson et al. 1984), rats were exposed to solvent yellow 33 for 6 hr per day, 5 days per week. Concentrations of solvent yellow 33 were 0.01, 0.05, and 0.2 g/m³ with a mass median aerodynamic diameter of 3.1 to 4.1 µm and a geometric standard deviation of 2.0. Animals exposed to the highest solvent yellow 33 concentration had reduced body-weight gain (8% less than controls). Mild respiratory-function changes consisting of reduced elastic recoil, increased resting lung volumes, and reduced respiratory flow rates were found at the highest concentration. Histological lesions were not observed.

In a subchronic inhalation study (Sun et al. 1987), rats were exposed 6 hr per day, 5 days per week for 13 weeks to concentrations of solvent

yellow 33 aerosols of 0, 0.001, 0.01, and 0.1 g/m³ with particle diameters of 2.1 to 4.2 µm and a geometric standard deviation of 2.0. Animals exposed to solvent yellow 33 at 0.1 g/m³ had only a slight decrease in body-weight gain (4% less than controls) and an accumulation of foamy macrophages in the lungs. Exposure to the lower concentrations of solvent yellow 33 elicited no observed response. The no-observed-adverse-effect level (NOAEL) for these inhalation studies was 0.01 g/m³.

Solvent yellow 33 was tested for dermal-sensitization potential in guinea pigs by Palazzolo and DiPasquale (1983). The induction regimen consisted of a single foot-pad injection of complete Freund's adjuvant diluted with antigen followed by an interdermal injection of antigen. This regimen produced delayed-type hypersensitivity. A high sensitization frequency was observed with both 50 µg of solvent yellow 33 and a positive control, dinitrochlorobenzene. The severity of reactions to solvent yellow 33 and the positive control were comparable. A dose-response profile was obtained using solvent yellow 33 at concentrations of 50, 250, and 500 micrograms per milliliter (µg/mL) and a 0.1-mL injection volume, resulting in 5, 25 and 50 µg per injection. Histological evaluation of selected skin sites demonstrated a cellular inflammatory response consistent with delayed-type hypersensitivity. On the basis of the frequency and severity of the reaction scores, the authors concluded that solvent yellow 33 could be considered a fairly potent sensitizer, with a 50-µg dose considered a strong sensitizer.

Lamson et al. (1982) investigated the sensitizing potential of solvent yellow 33 by using 1%, 3%, or 10% suspensions of the dye in alcohol for topical application. Only the 10% suspension produced a significant sensitization frequency when compared with a 95%-ethanol vehicle control.

Solvent yellow 33 is often a contaminant of dye preparations of Solvent yellow no. 10. Because solvent yellow 10 has been approved for use in food, toxicity evaluations of solvent yellow 33 administered in feed have been conducted. Solvent yellow 33 (approximately 99% pure) was

administered in feed at dietary concentrations of 1,700, 17,000, and 50,000 ppm to groups of male and female F344/N rats and B6C3F₁ mice for 14 days or 13 weeks (Eastin et al. 1996). The toxicity results were similar for rats and mice. Solvent yellow 33 caused no deaths but reduced body-weight gain slightly in rats exposed to 17,000 or 50,000 ppm. Liver weights were increased in all exposed rats and mice. There was minimum-to-mild degeneration of the periportal portion of the liver lobules in rats fed 1,700 ppm and higher and in mice fed 5,000 ppm and higher. There was an increase in the number and size of hyaline droplets in all dosed groups of male rats.

In a study to determine the reproductive and developmental toxicity of solvent yellow 33, female rats were administered diets containing solvent yellow 33 at 5,000-50,000 ppm from 4 weeks before mating to unexposed males until 4 weeks after birth of the pups (Eastin et al. 1996). The body weights of the dams were similar to those of controls at the time of mating but were lower at parturition and weaning. Fertility, gestation days, litter size, and pup birth weights were unaffected by exposure. At weaning, body weights of pups from all dose groups (5,000, 17,000, and 50,000 ppm) were lower than weights of pups from controls. After 4 weeks of exposure to solvent yellow 33 through milk and through feed containing the same dietary concentration that the dams received, weights of the pups in the 5,000-ppm group were similar to those of controls, but the weights of the pups in the 17,000- and 50,000-ppm groups remained depressed. Microscopic evaluation showed lesions in pups of all dose groups. These lesions were similar to those described in the liver and kidney of rats in the 14-day and 13-week studies.

In summary, the results of both dietary studies with solvent yellow 33 indicate that compound-related effects occurred at all concentrations, and a no-effect level was not observed.

Solvent yellow 33 has been tested for mutagenicity in a variety of assays including mouse micronucleus, L5178-Y mouse lymphoma, Salmonella reversion, and sister chromatid exchange using Chinese hamster ovary cells and the C57B1/6 mouse. Table C-3 summarizes studies testing solvent yellow 33 for mutagenicity.

When tested for mutagenicity in the mouse micronucleus assay and the

sister-chromatid-exchange assays, solvent yellow 33 gave negative results (Manthei et al. 1983; Moore et al. 1988; Brooks et al. 1989). Both positive and negative results have been reported in Salmonella reversion assays testing solvent yellow 33 for mutagenicity. The dye was nonmutagenic when assayed in Salmonella strains TA1535, TA1537, TA1538, and TA98 with and without metabolic activation (Manthei et al. 1983; Moore et al. 1988; Brooks et al. 1989). In one case, testing in identical strains gave conflicting results. When tested in strain TA100, solvent yellow 33 was reported to be nonmutagenic in studies by Manthei et al. (1983) and Brooks et al. (1989) but was found to be weakly mutagenic (with metabolic activation only) in a study by Moore et al. (1988). Moore et al. (1988) also reported that solvent yellow 33 gave positive results when tested in strains TA102 and TA104 with and without metabolic activation. However, because the rate of reversion in strain TA104 was less than double that in controls, the subcommittee concluded that the results were only weakly positive in this strain. Solvent yellow 33 produced positive results in the mouse lymphoma assay with and without metabolic activation (Moore et al. 1988).

Solvent yellow 33 is a contact allergen in some humans. Thus, even respiratory protection will not be completely effective in protecting sensitive military personnel. The respiratory sensitizing potential of solvent yellow 33 has not been adequately investigated in animals or humans. Additionally, studies testing solvent yellow 33 for mutagenicity are inconclusive.

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Björkner, B., and Magnusson, B. 1981. Patch test sensitization to D&C yellow no. 11 and simultaneous reaction to quinoline yellow. Contact Dermatitis 7(1):1-4.

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.

Eastin, W.C., M.R. Elwell, S. Grumbein, and J.H. Yuan. 1996. Effects of D&C yellow no. 11 ingestion on F344/N rats and B6C3F1 mice. J. Toxicol. Environ. Health 48(2):197-213.

el Dareer, S.M., J.R. Kalin, K.F. Tillery, and D.L. Hill. 1988. Disposition of 2-2 quinolyl-1 3-indandione (D.C. yellow no. 11) in rats dosed orally or intravenously. J. Toxicol. Environ. Health 23(3):385-393.

Feinman, S.E., and E.A. Doyle. 1988. Sensitization to dyes in textiles and other consumer products. J. Toxicol.-Cut. Ocular Toxicol. 7(3):195-222.

Henderson, R.F., J.S. Dutcher, F.F. Hahn, D.E. Bice, T.C. Marshall. 1985. Studies on the Inhalation Toxicity of Dyes Present in Colored Smoke Munitions. Final Report Phase II Studies: Range Finding and Toxicokinetics Studies of Inhaled Dye Aerosols. Final Report AD A163267. Inhalation Toxicology Research Institute, Lovelace Biomedical Research Institute, Albuquerque, NM.

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Jordan Jr., W.P. 1981. Contact dermatitis from D&C yellow 11 dye in a toilet bar soap. J. Am. Acad. Dermatol. 4(5):613-614.

Kita, S., T. Kobayashi, H. Kutsuna, and A.M. Kligman. 1984. Human maximization testing of D&C Yellow no. 10 and Yellow no. 11. Contact Dermatitis 11(4):210-213.

Krebs, J.S. 1980. Toxicity of D&C yellow 11: a literature review. SRI Project LSU-6465, Contract No. DAAK 11-17-C-0029, Chemical Systems Laboratory, Aberdeen Proving Ground, Edgewood, MD.

Lamson, S.A., B.M. Kong, and S.J. De Salva. 1982. D&C Yellow Nos. 10 and 11: delayed contact hypersensitivity in the guinea pig. Contact Dermatitis 8(3):200-203.

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Medinsky, M.A., Y.S. Cheng, S.J. Kampcik, R.F. Henderson, and J.S. Dutcher. 1986. Disposition and metabolism of ¹⁴C-solvent yellow and solvent green aerosols after inhalation. Fundam. Appl. Toxicol. 7(1):170-178.

Monk, B. 1987. Allergic contact dermatitis to D&C yellow 11 in a hair cream. Contact Dermatitis. 17(1)57-58.

Moore, M.M., J.W. Allen, L. Claxton, C. Doerr, C. Gwaltney, J.S. Dutcher, M. Kohan, B.K. Lawrence, R. Templeton, and Barbara Westbrook-Collins. 1988.

Mutagenic screening of marker grenade dyes by the Salmonella reversion assay, L5178Y/TK +/- mouse lymphoma assay, and in vivo sister chromatid exchange analysis in mice. Environ. Mol. Mutagen. 12(2):219-233.

Noster, U., and B.M. Hausen. 1978. Occupational dermatitis due to a yellow quinophthalone dye (solvent yellow 33; C.I. 47000) [in German]. Hautarzt. 29(3):153-157.

Palazzolo, M.J., and L.C. DiPasquale. 1983. The sensitization potential of D&C yellow no. 11 in guinea pigs. Contact Dermatitis 9(5):367-371.

Rapaport, M.J. 1984. Allergy to yellow dyes. Arch. Dermatol. 120(4):535-536.

Sun, J.D., R.F. Henderson, T.C. Marshall, Y.S. Cheng, J.S. Dutcher. J.A. Pickrell, J.L. Mauderly, F.F. Hahn, D.A. Banas, F.A. Seiler, and C.H. Hobbs. 1987. The inhalation toxicity of two commercial dyes: Solvent yellow 33 and solvent green 3. Fundam. Appl. Toxicol. 8(3):358-371.

Weaver, J.E. 1983a. Dose response relationships in delayed hypersensitivity to quinoline dyes . Contact Dermatitis 9(4):309-312.

Weaver, J.E. 1983b. Sensitization potentials of D&C yellow no. 10 and D&C yellow no. 11 dyes [correspondence]. J. Am. Acad. Dermatol. 9(4):605-606.