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3
Brass Smoke

Background Information

Military Applications

Brass flakes are used in smoke grenades to block detection of infrared waves for thermal imaging systems. Currently, the U.S. Army uses a product called EA 5763 that contains brass flakes. Other products containing brass flakes developed by the military include EA 5763D and EA 5769, but those are not in use.

Physical and Chemical Properties

The brass flakes in EA 5763 (composed of 70% copper (Cu) and 30% zinc (Zn)) generally have a mass median aerodynamic diameter (MMAD) of 2.1 to 2.3 micrometers (µm). Sometimes the flakes are called ''dust'' or "powder," but the material is really an irregular flake with a diameter of approximately 1.7 µm and a thickness of 0.08 to 0.32 µm. To facilitate manufacture, the flakes are coated with palmitic or stearic acid or both (Wentsel 1986).

Analysis of flakes of EA 5763 generally reveals trace amounts of aluminum (0.2%), antimony (0.1%), and lead (0.1%), but other metals might be present that are below detectable limits (0.25 microgram per milliliter (µg/mL) by atomic absorption spectroscopy (Thomson et al. 1985).

Occurrence and Use

In addition to the use of brass flakes by the military, the brass-foundry



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--> 3 Brass Smoke Background Information Military Applications Brass flakes are used in smoke grenades to block detection of infrared waves for thermal imaging systems. Currently, the U.S. Army uses a product called EA 5763 that contains brass flakes. Other products containing brass flakes developed by the military include EA 5763D and EA 5769, but those are not in use. Physical and Chemical Properties The brass flakes in EA 5763 (composed of 70% copper (Cu) and 30% zinc (Zn)) generally have a mass median aerodynamic diameter (MMAD) of 2.1 to 2.3 micrometers (µm). Sometimes the flakes are called ''dust'' or "powder," but the material is really an irregular flake with a diameter of approximately 1.7 µm and a thickness of 0.08 to 0.32 µm. To facilitate manufacture, the flakes are coated with palmitic or stearic acid or both (Wentsel 1986). Analysis of flakes of EA 5763 generally reveals trace amounts of aluminum (0.2%), antimony (0.1%), and lead (0.1%), but other metals might be present that are below detectable limits (0.25 microgram per milliliter (µg/mL) by atomic absorption spectroscopy (Thomson et al. 1985). Occurrence and Use In addition to the use of brass flakes by the military, the brass-foundry

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--> industry produces small particles of brass that can be inhaled. Workers in this industry, particularly workers who polish brass pots, can be exposed to brass dust at concentrations as high as 0.19 mg/m3 (combined concentrations of Cu and Zn) (Rastogi 1992a,b). Combustion Products The smoke from the M76 grenade has the same chemical and physical properties as the bulk material. Explosion of the grenades simply releases the brass flakes that serve to block detection of infrared waves. Toxicokinetics Absorption and Distribution No studies have been published on the distribution of inhaled EA 5763. However, evaluations of absorption and distribution have been conducted on a similar material, EA 5769, that the Army investigated at one time but subsequently dropped (Muse 1983). EA 5769 flakes that were used for the study had a geometric mean diameter of 5.5 µm or 4.9 µm for two samples taken from the inhalation chamber (Feeney et al. 1983), whereas the EA 5763 flakes generally have a MMAD size of about 2 µm. The overall conclusions about the characteristics of EA 5769 should be applicable to EA 5763. A principal difference in the deposition between these two particles is that EA 5763 deposition should be greater in the lower respiratory tract because of the smaller size of those brass flakes. Fischer 344 (F344) rats (four males and four females) were exposed to EA 5769 for 15 min at a concentration of 1,000 milligrams per cubic meter (mg/m3) (Muse 1983). In an additional group, four males and four females were exposed at 2,000 mg/m3 for 30 min, but that dosage was lethal to all the animals within 24 hr. For the 1,000-mg/m 3 exposure group, tissue concentrations of Cu were determined immediately after exposure and 5, 7, and 14 days after exposure (Muse 1983). Immediate examination showed high concentrations of Cu (150 to 452 µg of Cu per gram (g) of dry weight) in the larynx, trachea, esophagus, stomach, upper right lung, lower right lung, upper left lung, and lower left lung. Of the tissues with initially high Cu concentrations, only the lung had high concentrations of Cu 5 days after exposure. By day 5, the

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--> liver and kidney also showed increased Cu concentrations (23 and 38 µg/g of dry weight, respectively) until day 7 (the liver) and day 14 (the kidney). By day 14, no tissues had increased concentrations of Cu. Snipes et al. (1988) exposed rats to EA 5763 brass flakes at concentrations of 0.32, 1.0, 3.2, or 10 mg/m3 for 1.5 hr per day, 4 days per week for 13 weeks. The amount of Cu and Zn retained in the lungs was measured at the end of the exposure and 4 weeks later for the three highest-dose groups. The amount of the two metals combined in the lung at the end of the 13-week exposure was approximately 23 µg per animal; 4 weeks later it dropped to approximately 19 µg. The similarity in the residual amount of Cu and Zn retained in the lungs of animals from the three highest-dose groups, despite an order of magnitude difference in exposure concentrations, indicates a limit to the accumulation of the brass in the lungs. The data also indicate that the clearance time for low residual concentrations after the last dose was greater than 4 weeks. Metabolism and Excretion Feces was the primary route of elimination of Cu from an inhaled dose of EA 5769 brass flakes in a study of F344 rats (Muse 1983). Urinary content of Cu within the first day of collection after a 15-min exposure to EA 5769 at 1 mg/L was 190 mg of Cu per kilogram (kg) of dry weight (freeze-dried), and fecal content at that time was 1,165 mg/kg of dry weight. Urinary concentrations dropped to control values by day 5, and fecal concentrations never dropped below 150 mg/kg of dry weight up to 13 days after exposure. No data were presented concerning the metabolism of the brass flakes. Toxicity Summary Effects in Humans Human data are not available on the effects of brass flakes (the form to which military personnel might be exposed from launching brass grenades). However, the effects of chronic exposures to brass fumes from the brass industry in India have been published (Rastogi et al. 1991, 1992a,b). The particulate size of brass fumes is smaller than that of brass flakes, and therefore, fumes are likely to be more toxic than flakes.

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--> The studies examined the prevalence of chronic bronchitis in over 580 workers in various suboccupations in the brass industry. The findings were compared with those obtained from unexposed workers. Those studies indicated that long-term exposures (10–17 years) to fumes containing brass can be associated with increased risk of chronic bronchitis, with an odds ratio risk of 2.74. In addition, there was a direct correlation between length of exposure and risk. No effects were observed in solders chronically exposed to brass fumes at 0.001 mg/m3 (Rastogi et al. 1991), and respiratory effects were observed only in polishers chronically exposed to an average Cu-plus-Zn concentration of 0.19 mg/m3 (Rastogi et al. 1992a,b). The workers were also exposed to other toxic metals, including lead, nickel, cadmium, manganese, and chromium. Those metals might also contribute to the respiratory effects observed in the study. The risk associated with short-term exposures to brass flakes is not known for humans. Effects in Animals Inhalation Exposures One-Time Exposures Lethality. Guinea pigs are the most susceptible species to brass flakes. Exposure to EA 5763 at 100 mg/m3 for 150 min caused respiratory failure and death in 12 out of 12 animals. Pathological findings included severe edema and bronchoconstriction (Thomson et al. 1982b). Rats are less susceptible. Groups of 12 (six males and six females) F344 rats were exposed by inhalation to brass flakes (EA 5763) at 1,000 mg/m3 for 30 to 90 min (Feeney et al. 1983). The shortest exposure was not lethal to the rats. At exposure times greater than 50 min, at least 6 of the 12 animals died within 24 hr of the end of the exposure (Feeney et al. 1983). Groups of 12 (six males and six females) B6C3F 1 mice were also exposed at 1,000 mg/m3 for durations ranging from 15 min to 300 min. The mice were less susceptible than the rats (Feeney et al. 1983). The calculated lethal concentration for 50% of the test animals multiplied by exposure time (LCt50) for rats and mice were 53,538 mg • min/m3 and 199,511 mg • min/m3, respectively. Thus, acute toxicity studies show a species susceptibility that is greater in guinea pigs than rats and mice and greater in rats than mice.

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--> Pulmonary Effects. Pathological lesions in the respiratory systems of rodents exposed to high concentrations (1,000 mg/m3) of brass flakes were characterized largely by moderate necrosis of the turbinate epithelium, necrotizing bronchiolitis, moderate pneumonia, and alveolar histiocytic proliferation (Feeney et al. 1983). In rats, a lower concentration (100 mg/m3 for 4 hr) produced an acute inflammatory response and pulmonary alveolar macrophage activation (Anderson et al. 1988). The macrophages isolated from exposed animals by lavage showed morphological and functional abnormalities. Acute toxicity studies (4 hr) using F344 rats exposed at concentrations of 200, 100, 50, 10, and 1 mg/m3 showed dose-related changes in biochemical, morphological, and functional measurements (Thomson et al. 1986). Rats examined within 24 hr of exposure showed increases in lactate dehydrogenase and protein in the lung lavage fluid. In addition, the animals showed an acute inflammatory response in the terminal airways, comprising increases in macrophages and neutrophils. The rats also showed an increased pulmonary resistance. No pathological and only minimal cytological effects were observed after a 4-hr exposure at a concentration of 1-mg/m3. Gastrointestinal Effects. None of the available studies reported examination of gastrointestinal tissues after inhalation of brass flakes. Mutagenic Effects. No information was found concerning possible mutagenic effects of a single exposure to brass flakes. Reproductive and Developmental Toxicity. No information was found concerning the reproductive or developmental toxicity of a single exposure to brass flakes by the inhalation route. Repeated Exposures Lethality. Exposure of F344 rats to brass flakes at a concentration of 100 mg/m 3 produced no lethality after a single 4 hr exposure (Thomson et al. 1986). That concentration was lethal to 9 of 72 rats exposed for 15 min per day, 5 days per week for 13 weeks (Thomson et al. 1982b). Lethality was observed during the second to ninth week of the exposure. Thus, repeated exposures to 100 mg/m3 for only 15 min per day were significantly more lethal than a single exposure to the same concentration of brass flakes. Longer exposures of 150 min per day caused 23 of 72 rats to die within only 7 days; the experiment was prematurely terminated due to high lethality from repeated exposures.

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--> Pulmonary Effects. A comparison of multiple exposures (100 mg/m3 for 2.5 hr per day for 6 days) to a single exposure (100 mg/m3 for 2.5 hr) showed that multiple exposures to brass flakes were significantly more toxic than single exposures (Thomson et al. 1982a). Cytological analysis, enzyme activities, and protein contents were measured in bronchoalveolar lavage fluid as indices of damage. Multiple exposures caused an immediate increase in polymorphonuclear leukocytes along with a decrease in macrophages. After 1 week in clean air, those effects were reversed, but 4 weeks were required for those measurements to return to control values. The changes were believed to be indicative of an acute inflammatory response. The activities of enzymes, such as alkaline phosphatase, lactate dehydrogenase, and glucose-6-phosphate dehydrogenase, in the lung lavage fluid were generally not increased by a single exposure but were transiently increased for the multiple exposures (Thomson et al. 1982a). Alkaline phosphatase was markedly decreased by multiple exposures when measured from 24 hr to 2 weeks after exposure. Lactate dehydrogenase activity increased in rats exposed once or more than once and did not return to control values until 4 weeks after exposure. Protein levels in the lavage fluid of mice were much higher after multiple exposures than after a single exposure, but the single exposure did cause about a 10-fold increase in protein content. Exposures of rats at lower concentrations of brass flakes (1 and 10 mg/m3) for 6 hr per day, 5 days per week for 6 or 13 weeks, showed both enzymatic and cytological changes (Thomson et al. 1984). The high dose caused irreversible granulomatous pneumonia along with increased lung weight 3 months after the end of the exposure. The low dose caused only mild pulmonary lesions, which were reversible 30 days after exposure. Rats were exposed to EA 5763 brass flakes at concentrations of 0.32, 1.0, 3.2, or 10 mg/m3 for 1.5 hr per day, 4 days per week for 13 weeks (Snipes et al. 1988). Several end points were evaluated by bronchoalveolar lavage, immunological methods, histopathology, and respiratory function. Toxicities were observed at the three highest doses, and doseresponse effects were consistently observed. At 1.0 mg/m3, only a mild focal atrophy of olfactory epithelium was observed, and this resolved within 4 weeks of the exposure. However, the authors of this study attempted to relate human nasal exposures to rat nasal exposures. They concluded that exposure of the upper respiratory tract of rats would be

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--> approximately 20-fold higher than that exposure of humans at the same concentration of brass flakes. Thus, humans would be much less susceptible than rats to nasal toxicity from an exposure to brass flakes at a concentration of 1.0 mg/m3. Other Systemic Effects. Exposure of rats to brass flakes at 100 mg/m3 for up to 13 weeks was followed by histopathological examination (Thomson 1982b) of all major organs (heart, lung, liver, spleen, kidney, brain, eye, trachea, nasal turbinate, adrenal, stomach, urinary bladder, pancreas, thyroid, esophagus, duodenum, colon, lymph node, thymus, testes, epididymus, ovary, uterus, bone marrow, and skin). Damage was confined solely to the respiratory system. Carcinogenic and Mutagenic Effects. No information is available concerning the potential for carcinogenic effects of brass flakes. Male fruit flies (Drosophila melanogaster ) were exposed for 72 hr at concentrations of 1.0% to 25% brass flakes mixed in the food (Manthei et al. 1983). After exposed males were mated with virgin unexposed flies, the offspring were back-crossed, and third generation flies did not show any observable mutations. Reproductive and Developmental Toxicity. In a developmental toxicity study, pregnant female rats were exposed by inhalation to brass flakes at 100 mg/m3 for 15 or 150 min per day for 10 days on gestation days 6–15, and fetuses were collected and observed on gestation day 20 (Starke et al. 1987). Maternal body-weight gain was significantly reduced, as were the percentage of pregnancies, number of implantation sites, number of live fetuses, and body weights of fetuses in the group exposed for 150 min per day compared with the group exposed for 15 min per day or the control group. The data show unusual defects that the subcommittee believes can be classified as malformations (i.e., underdeveloped atria and thin-walled right cardiac ventricle). The malformations were suggestive of an effect of exposure. The disruption of implantation, in utero death, reduced maternal and fetal weight, and an increase in unusual defects indicated serious consequences of exposure to brass flakes for the longest exposure period. Thus, there is evidence of developmental toxicity in rats exposed to brass flakes at 100 mg/m3 for 150 min per day during gestation days 6–15. In a dominant lethal mutation study, male rats were exposed by inhalation to brass flakes at 100 mg/m3, for 15 or 150 min per day, 5 days per week for 10 weeks (Starke et al. 1987). Twelve males per group were exposed and then mated to unexposed females. Only three males

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--> survived 150 min per day of exposure. The three males were pooled with the surviving males from a two-generation study (see below) that delayed the mating of the males in the dominant lethal mutation study for 4 weeks longer than that of the males exposed for 15 min per day or the controls. The significant increase in resorptions in pregnancies resulted from matings with males exposed for 150 min per day compared with those exposed for 15 min per day and the controls. A limitation of the study is that the number of offspring rather than the number of males should have been the group size used in the analysis of the data. That number might have resulted in a misinterpretation of the data. The severe general toxicity to male rats exposed at 100 mg/m3 for 150 min per day, 5 days per week for 10 weeks compromises the interpretation of the data on reproductive or developmental effects in the study. There were no clear differences between the male rats exposed at 100 mg/m3 for 15 min per day, 5 days per week for 10 weeks and the controls. A third study, although called a two-generation study, was not a standard two-generation study because only the F0 males and females were exposed to brass flakes (Starke et al. 1987). F1 and F2 generations were derived from the exposed parents but were not directly exposed. Twelve males and at least 24 females per group were exposed by inhalation to brass flakes at 100 mg/m3 for 15 or 150 min per day, 5 days per week for 10 weeks (males) or 3 weeks (females) before mating. No significant difference in reproduction and body weight was observed in the groups exposed for 15 min per day and the control groups. Only 6 of the 12 males and 11 of the 24 females survived the exposure duration of 150 min per day. Because so few males and females survived, the observed effects on reproduction and body weight were difficult to interpret. Only 3 of 11 mated females gave birth, and it is not known whether the remaining females had been pregnant but had not given birth or whether they had never been pregnant. The effect of variability between mated males or litters was not addressed in this study, making it difficult to interpret the results. The authors concluded that there were no differences in viability and survival in the F1 and F2 generations; however, this conclusion is limited because the animals were only exposed in the F0 generation. Although a nonstandard study design was used, the study does have relevance to the conditions of exposure in the military. Military personnel might be exposed to brass flakes; however, it is unlikely that their offspring will be similarly exposed.

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--> Dermal, Ocular, and Oral Exposures One-Time Exposures Dermal and ocular studies of brass flakes are limited to two reports. Manthei et al. (1983) applied brass flakes suspended in corn oil to shaved adult rabbits at 2.0 g/kg. The application was allowed to remain on the skin for 24 hr. The brass-flake suspension caused mild erythema and edema, but no significant irritation. Muni et al. (1985) applied brass flakes (0.5 g) to gauze pads, moistened with saline, which were placed on two abraded and two unabraded rabbit skin sites and covered for 24 hr. The brass caused very slight edema to the unabraded site and slight edema to the abraded site; the edema resolved in both cases after 72 hr. Thus, EA 5763 appears to cause only minor skin irritation after a single dermal exposure. Ocular toxicity was evaluated by Manthei et al. (1983) in rabbits by applying 100 mg of brass flakes in one eye and observing ocular irritation for 24, 48, and 72 hr and at 7 days after application. EA 5763 was classified as a positive eye irritant in these tests, but the damage was reversible. Muni et al. (1985) applied brass flakes (80 mg) to the right eye of three rabbits. Varying degrees of corneal opacity were produced in two animals within 24 hr. It resolved in 48 hr in one rabbit and 7 days in another rabbit. The brass was considered mildly irritating to the eye. The toxicity of brass flakes by the oral route was determined by Manthei et al. (1983). EA 5763 was administered in corn oil to groups of 10 Sprague-Dawley rats (five of each gender) by gavage at doses of 5, 3.20, 2.00, 1.26, 0.79 and 0.50 g/kg. The high dose was lethal to four females and three males 48 to 144 hr after dosing. The lowest two doses were not lethal to any animals within 14 days of dosing. Toxicity was related to gastrointestinal distress and diarrhea. The 14-day lethal dose for 50% of the test animals (LD50) was determined to be 2.78 g/kg (2.00-3.84 g/kg, 95% confidence limit). An additional study by Muni et al. (1985) evaluated the oral 14-day LD50 of copper-zinc-coated powder in F344 albino rats. Range-finding studies using groups of two animals showed that oral (gavage) doses at 3,500 mg/kg were lethal to two of two males and two of two females, but doses at 1,050 mg/kg or less (315 or 94.5 mg/kg) were not lethal. When larger groups of 10 animals per group were evaluated, only two

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--> of five females and none of the males died within 14 days of administration of 3,300 mg/kg. The doses that were evaluated in the study with 10 animals per group were 3,300, 1,980, and 1,188 mg/kg, suspended in corn oil and administered by gavage. The doses lower than 3,300 mg/kg were not lethal to either gender. Thus, an approximate LD50 was determined to be greater than 3,300 mg/kg in this study. Repeated Exposures No studies are available concerning dermal, ocular, or oral toxicity of brass flakes after repeated exposures. In Vitro Studies No data are available concerning the mutagenicity of brass flakes in the Ames assay or other in vitro mutagenesis assays. A tracheal organ culture assay evaluated the cytotoxicity of brass dust to hamster upper respiratory epithelium (Placke and Fisher 1987). The brass particles caused severe degeneration and necrosis in the tracheal cultures at concentrations of 1,000 mg/L or higher. Summary of Toxicity Data Tables 3-1 to 3-3 summarize the brass-flakes toxicity studies. Table 3-1 presents some of the data on nonmammalian species and data on dermal, ocular, and oral exposures of rats. Those numbers will not be used to set guidance levels for inhalation exposures to brass. Table 3-2 presents data on single inhalation exposures to brass flakes in several species, and Table 3-3 presents data on multiple inhalation exposures to brass flakes in several species, including exposures of humans to brass dust. Noncarcinogenic Effects Acute exposure to high concentrations of brass flakes produces serious pulmonary inflammation and death in several species. The species most sensitive to the toxicity of brass flakes is the guinea pig (Thomson et al.

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--> TABLE 3-1 Summary of Effects of a Single Oral, Ocular, or Dermal Exposure to Brass Flakes Species Exposure (route) NOAEL LOAEL End Point and Comments Reference Rat 0.5-5.0 g/kg (oral) — 0.5 g/kg LD50=2,780 mg/kg oral dose of EA 5763; toxicity related to gastrointestinal distress Manthei et al. 1983 Rabbit 100 mg in cornea (ocular) — 100 mg Reversible ocular irritation Manthei et al. 1983 Rabbit 2.0 g/kg (dermal) 2.0 g/kg — Mild erythema, but not considered significant Manthei et al. 1983 Rabbit 0.5 g to abraded or unabraded skin (dermal) — — Very slight edema on unabraded skin and slight edema on abraded skin; edema resolved after 72 hr Muni et al. 1985 Rabbit 80 mg in cornea (ocular) — — Corneal opacity produced in 2 out of 3 animals, resolved in 48 hr or 7 d Muni et al. 1985 Rat 94.5-3,500 mg/kg (oral by gavage) — 94.5 mg/kg Body weight decreased at all doses; significant gastrointestinal toxicity; oral LD50 > 3,300 mg/kg; material is Cu-Zn powder, not flakes Muni et al. 1985 Abbreviations: NOAEL, no-observed-adverse-effect level; LOAEL, lowest-observed-adverse-effect level.

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--> TABLE 3-3 Summary of Effects of Multiple Inhalation Exposures to Brass Rakes Species Exposure NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Human Occupational, combined Cu + Zn; at 0.001-0.191 mg/m3; 10–17 yr 0.001 0.19 Chronic bronchitis, asthma, related to length of exposure >10 yr, some dose response evident Rastogi et al. 1991, 1992a,b Rat 100 mg/m3; 2.5 hr, 6 d — 100 BAL used, multiple exposures much more toxic than single exposure Thomson et al. 1982a Rat 100 mg/m3; 150 min/d, 5 d/wk, 6 wk — 100 Lethality: 23/72 after 7 d; 25–30% decreased body-weight gain; exposures terminated after 7 d Thomson et al. 1982b Rat 100 mg/m3; 150 min/d, 5 d/wk, 13 wk — 100 Exposures terminated after 7 d because of lethality Thomson et al. 1982b Rat 100 mg/m3; 15 min/d, 5 d/wk, 6 wk — 100 Marked pulmonary lesions in 4/12 Thomson et al. 1982b Rat 100 mg/m3; 15 min/d, 5 d/wk, 13 wk — 100 Lethality: 9/72, 2nd-9th w; decreased tidal volume and lung compliances (continued in males 30 d after exposures); mild pulmonary lesions in all 30 d after exposure Thomson et al. 1982b Mouse 100 mg/m3; 150 min/d, 5 d/wk, 6 wk — 100 Not legal, dyspnea, hypo-activity, lower body weight Thomson et al. 1982b Mouse 100 mg/m3; 150 min/d, 5 d/wk, 13 wk — 100 Respiratory lesions Thomson et al. 1982b

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--> Species Exposure NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Mouse 100 mg/m3;15 min/d, 5 d/wk, 6 wk 100 — No significant pulmonary lesions Thomson et al. 1982b Mouse 100 mg/m3; 15 min/d, 5 d/wk, 13 wk — 100 Slight damage after 13 wk Thomson et al. 1982b Guinea pig 100 mg/m3; 150 min/d, 5 d/wk, 13 wk — 100 Lethality: 12/12 after 150 min of exposure Thomson et al. 1982b Rat 1 and 10 mg/m3; 6 h/d, 5 d/wk, 6 wk and 13 wk — 1 High dose: increases respiration rate, significant lesions; low dose: mild, reversible lesions Thomson et al. 1984 Rat 0.32, 1.0, 3.2, 10 mg/m3; 1.5 h/d, 4 d/wk, 13 wk 0.32 1.0 1.0 mg/m3 mild focal atrophy olfactory epithelium (resolved in 4 wk) Snipes et al. 1988 Rat (males) 100 mg/m3; 15 or 150 min/d, 5 d/wk, 10 wk — 100 At 15 min/d, no reproductive or developmental effects observed in offspring of exposed males; at 150 min/d most exposed animals died during exposure, significant increase in resorption of pregnancies; results difficult to interpret Starke et al. 1987 Rat (pregnant females) 100 mg/m3; 15 or 150 min/d, gestation days 6–15 — 100 Evidence of developmental toxicity at 100 mg/m3, 150 min/d Starke et al. 1987

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--> Species Exposure NOAEL (mg/m3) LOAEL (mg/m3) End Point and Comments Reference Rat (males and females) F0 generation exposed at 100 mg/m3; 15 or 150 min/d, 5 d/wk, 10 wk (males) or 3 wk (females) 100 — No differences on viability and survival in F1 and F2 generations; results difficult to interpret because only rats in F0 generation exposed and few survived the exposure period Starke et al. 1987 Abbreviations: NOAEL, no-observed-adverse-effect level; LOAEL, lowest-observed-adverse-effect level; BAL, bronchoalveolar lavage.

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--> 1982b). However, few studies have been conducted with this species. The only available data on this species were from exposures to a single concentration (100 mg/m3) for a single duration (150 min) that was lethal to all 12 animals. Thus, results concerning the lowest dose that produces toxicity are too uncertain to permit the use of data from guinea pigs to set guidance levels. Rats are more sensitive than mice to the toxic effects of brass flakes (Feeney et al. 1983), and respiratory effects are the predominant toxic end points in this species. One-time exposure to brass flakes is lethal to rats at LCt 50 values of approximately 50,000 mg • min/m3 (Feeney et al. 1983). Functional respiratory deficits and enzymatic and cytological changes in bronchopulmonary lavage fluid were observed in rats exposed at 2,400 mg • min/m3 (Thomson et al. 1986). Exposure at 1 mg/m3 for 4 hr (CT, 240 mg • min/m3) was a NOAEL for rats, and that value can be used to calculate guidance levels for a one-time exposure to brass flakes. Multiple exposures to brass flakes significantly increased the toxicity of this material to rats and mice (Thomson et al. 1982b). Exposure of rats at 100 mg/m3 for 4 hr (CT, 24,000 mg • min/m3) produced no lethality, but the same concentration (100 mg/m3) for only 15 min per day, 5 days per week (cumulative CT, 15,000 mg • min/m3 by the end of week 2 was lethal to 9 of 72 rats during the second through the ninth week of a chronic exposure (Thomson et al. 1982b). Longer daily exposures for 150 min per day, 5 days per week (cumulative CT, 75,000 mg • min/m3 by the end of week 1) were lethal to 23 of 72 rats. A careful study (Snipes et al. 1988) with many biochemical, functional, and histological end points demonstrated a NOAEL in rats of 0.32 mg/m3 when exposures were conducted for 90 min per day, 4 days per week for 13 weeks (cumulative CT, 1,500 mg • min/m3 by the end of week 13). That value can be used to calculate guidance levels for multiple exposures to brass flakes. Carcinogenic Effects No studies have been done on the carcinogenicity of brass flakes. Previous Recommended Exposure Limits There are no current recommended exposure limits for brass flakes as

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--> used by the military in obscurant grenades. However, brass flakes are composed of approximately 70% Cu and 30% Zn, so some comparisons can be made to current standards or guidelines for exposure to Cu and Zn from various agencies. The current Occupational Safety and Health Administration (OSHA) permissible exposure limits (PELs) for Zn oxide are 5 mg/m3 for fumes and 10 mg/m3 for dusts. The OSHA PELs for Cu are 0.1 mg/m3 for fumes and 1.0 mg/m3 for dusts. The Threshold-Limit-Value-time-weighted-average (TLV-TWA) values established for Cu by the American Conference of Government Industrial Hygienists (ACGIH) are 0.2 mg/m3 for fumes and 1.0 mg/m3 for dust. The brass flakes evaluated in this chapter are not considered fumes because they are approximately 2 µm in diameter and because the oxides of fumes are chemically different from brass flakes. Cohen and Powers (1994) reported that the particle size of dusts in a nonferrous brass-casting foundry was greater than the particle size in fumes. Therefore, an appropriate comparison between the brass flakes used by the military and the OSHA PELs or ACGIH TLV-TWAs for Cu and Zn dusts cannot be made. Subcommittee Evaluation and Recommendations Using the toxicity information described above, the subcommittee recommended exposure guidance levels for military personnel exposed during an emergency release and during regular training exercises and for consideration at military-facility boundaries to protect nearby communities from emergency or repeated releases of brass flakes. Military Exposures Emergency Exposure Guidance Levels (EEGLs) Acute inhalation exposure to high concentrations of brass flakes is lethal to all animal species that have been tested. Respiratory effects are the first to appear. Pulmonary inflammation can be produced in rats with 4-hr exposures at a concentration of 10 mg/m3 (Thomson et al. 1986); however, that response is reversible, and clearance of the particulate matter appears to be fast (Muse 1983). The 4-hr NOAEL of 1 mg/m3 identified by Thomson et al. (1986) for

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--> F344 rats is used to recommend EEGLs for 15 min, 1 hr, and 6 hr. An uncertainty factor of 10 is used to extrapolate from animals to humans. Although no studies have demonstrated that Haber's rule can be applied to brass flakes, the mechanism of acute toxicity appears to be related to inflammatory responses. Acute inflammation of airways should follow Haber's rule for this material. Therefore, an increase in acceptable concentrations for shorter durations is warranted. Thus the 1-hr and 6-hr EEGLs for brass flakes are 0.4 mg/m3 and 0.07 mg/m3, respectively. Extrapolating back from the 1-hr EEGL indicates a 15-min EEGL of 1.6 mg/m3. However, on the basis of Thomson et al. (1986) data, extrapolating back from a 4-hr NOAEL to a 15-min exposure might exceed the range of exposure durations over which Haber's rule can be expected to apply. The study by Feeney et al. (1983) indicated that exposure at 1,000 mg/m3 for 30 min was not lethal to rats but did produce a variety of pathological lesions of moderate severity in the respiratory tract. That value is used to check the validity of the proposed 15-min EEGL. A LOAEL-to-NOAEL uncertainty factor of 10, a species uncertainty factor of 10, and an uncertainty factor of 10 to extrapolate from moderate toxic effects to mild reversible effects are applied to estimate a 30-min exposure guidance level of 1 mg/m3, which agrees well with the recommended 15-min EEGL of 1.6 mg/m3, assuming Haber's rule applies over the 15-min time interval. Thus, the recommendation appears to be validated by the 30-min exposure study. Repeated Exposure Guidance Level (REGL) Multiple exposures to brass flakes produce significantly more toxicity in experimental animals than single exposures that have the same cumulative exposure dose. Data are not available on the effects of human exposure to brass flakes; however, humans who were occupationally exposed to high concentrations of brass fumes exhibit an increased risk of chronic bronchitis and other severe respiratory problems. Combined Cu and Zn concentrations that were shown to be associated with chronic bronchitis were 0.19 mg/m3 over a period of at least 10 years. Concentrations that could not be associated with respiratory disease were about 0.001 mg/m3 (Rastogi et al. 1991). The human NOAEL is 0.001 mg/m3 (Rastogi et al. 1991), and the subcommittee recommends that value as the REGL. The REGL is sup-

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--> ported by two experimental animal studies. Snipes et al. (1988) exposed rats to brass flakes at concentrations of 0.32, 1.0, 3.2, or 10 mg/m 3 for 1.5 hr per day, 4 days per week for 13 weeks and identified a NOAEL of 0.32 mg/m3. Applying a time extrapolation of 6 hr/40 hr to that concentration, a species uncertainty factor of 10, and a 10-fold uncertainty factor to extrapolate from a 13-week subchronic exposure to a chronic exposure, a REGL of 0.0005 mg/m3 is obtained. That value is lower than the recommended REGL of 0.001 mg/m3 by only a factor of 2. Thomson et al. (1984) exposed rats to brass flakes at 1.0 or 10 mg/m3 for 6 hr per day, 5 days per week for 13 weeks and identified a LOAEL of 1.0 mg/m3. Applying a time extrapolation of 30 hr/40 hr for that concentration, a species uncertainty factor of 10, a 10-fold uncertainty factor to extrapolate from a 13-week subchronic exposure to a chronic exposure, and a 10-fold uncertainty factor to extrapolate from a LOAEL to a NOAEL, a REGL of 0.0008 is obtained. That value is lower than the recommended REGL by only a factor of 1.25. Therefore, the subcommittee concludes that the data from the two experimental animal studies provide justification for the use of the human NOAEL value in the derivation of the REGL. Public Exposures Short-Term Public Emergency Guidance Levels (SPEGLs) The subcommittee assumes that more inherent susceptibility to the respiratory effects of brass flakes will be found in the general population than in healthy adult military personnel. Thus, an additional uncertainly factor of 10 is used to extrapolate from the recommended EEGLs to levels that protect the general public. Therefore, the SPEGLs for a single emergency exposure to brass flakes are 0.16, 0.04, and 0.007 mg/m3 for 15 min, 1 hr, and 6 hr, respectively. Repeated Public Exposure Guidance Level (RPEGL) A RPEGL is estimated from the REGL by incorporating an additional uncertainty factor of 10 to protect susceptible individuals in the general population. Thus, the RPEGL is 0.0001 mg/m3.

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--> Summary of Subcommittee Recommendations The subcommittee's recommendations for exposure limits for military personnel exposed to brass flakes are listed in Table 3-4. Table 3-5 summarizes the subcommittee's recommendations for exposure limits for the general public. The subcommittee recommends that the Army's use of brass flakes be limited to minimize the potential for increasing toxicity with repeated exposures. Research Needs The subcommittee recommends that long-term, chronic inhalation studies in experimental animals be conducted to characterize the precise toxic effects due to chronic exposure. Additionally, reproductive and developmental studies using standard testing protocols should be considered. TABLE 3-4 EEGLs and REGL for Brass Smoke for Military Personnel Exposure Guideline Exposure Duration Exposure Guidance Level (mg/m3) EEGL 15 min 1.6   1 hr 0.4   6 hr 0.07 REGL 8 hr/d, 5 d/wk 0.001 Abbreviations: EEGL emergency exposure guidance levels; REGL, repeated exposure guidance level. TABLE 3-5 SPEGLs and RPEGL for Brass Smoke for the Boundaries at Military-Training Facilities Exposure Guideline Exposure Duration Exposure Guidance Level (mg/m3) SPEGL 15 min 0.16   1 hr 0.04   6 hr 0.007 RPEGL 8 hr/d, 5 d/wk 0.0001 Abbreviations: SPEGL, short-term public emergency guidance level; RPEGL, repeated public exposure guidance levels.

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--> References Anderson, R.S., L.L. Gutshall, and S.A. Thomson. 1988. Responses of rat alveolar macrophages to inhaled brass powder. J. Appl. Toxicol. 8:389–393. Cohen, H.J., and B.J. Powers. 1994. A study of respirable versus nonrespirable copper and zinc oxide exposures at a nonferrous foundry. Am. Ind. Hyg. Assoc. J. 55:1047–1050. Feeney, J.J., P. Hott, R.L. Farrand, and J.T. Weimer. 1983. Acute Inhalation Toxicity of EA 5769 in Rats and Mice Comparison of Toxicity with EA 5763. ARCSL-TR-82069. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Grose, E.C., and J.A. Graham. 1987. Short-term In Vitro Screening Studies Related to the Inhalation Toxicology of Potentially Toxic Aerosols. Procurement No. 84PP4850. Prepared by U.S. Environmental Protection Agency, Health Effects Research Laboratory, Research Triangle Park, N.C., for U.S. Army Medical Bioengineering Research and Development Laboratory, Fort Detrick, Md. Haley, M.V., and C.W. Kurnas. 1993. Toxicity and Fate Comparison Between Several Brass and Titanium Dioxide Powders. ERDEC-TR-094. Edgewood Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Manthei, J.H., F.K. Lee, Jr., M. Donnelly, and J.T. Weimer. 1980. Preliminary Toxicity Screening Studies of 11 Smoke Candidate Compounds. ARCSL-TR-79056. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Manthei, J.H., F.K. Lee, D.H. Heitkamp, and W.C. Heyl. 1983. Preliminary and Acute Toxicological Evaluation of Five Candidate Smoke Compounds. ARCSL-TR-82066. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Muni, I.A, E.B. Gordon, and J.B. Goodband. 1985. Dermal, Eye, and Oral Toxicological Evaluations. Phase II Report. DAMD17-82-C-2301. Prepared by Bioassay Systems Corp., Woburn, Mass., for U.S. Army Research and Development Command, Fort Detrick, Frederick, Md. Muse, W.T. 1983. A Pilot Study to Determine the Biological Fate of Inhaled EA 5769 in Rats. ARCSL-TR-82067. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Placke, M.E., and G.L. Fisher. 1987. In Vitro Toxicity Evaluation of Ten Particulate Materials in Tracheal Organ Culture. CRDEC-TR-88010. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Rastogi, S.K., B.N. Gupta, T.H. Husain, B.S. Pangtey, S. Srivastava, and N. Garg.

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--> 1991. Long-term effects of soldering fumes upon respiratory symptoms and pulmonary function. Am. Occup. Hyg. 35:299–307. Rastogi, S.K, B.N. Gupta, N. Mathur, T. Husain, P.N. Mahendra, B.S. Pangtey, and S. Srivastava. 1992a. A survey of chronic bronchitis among brassware workers. Am. Occup. Hyg. 36:283–294. Rastogi, S.K., B.N. Gupta, T. Husain, N. Mathur, B.S. Pangtey, and N. Garg. 1992b. Respiratory symptoms and ventilatory capacity in metal polishers. Hum. Exp. Toxicol. 11:466–472. Snipes, M.B., D.E. Bice, D.G. Burt, E.G. Damon, A.F. Eidson, F.F. Hahn, B.R. Harkema, R.F. Henderson, J.L. Mauderly, J.A. Pickrell, F.A. Seiler, and H.C. Yeh. 1988. Comparative Inhalation Toxicology of Selected Materials—Phase III Studies. Procurement No. 85PP5805. Prepared by Inhalation Toxciology Research Institute, Lovelace Biological and Environmental Research Institute, Albuquerque, N.M., for U.S. Army Biomedical Research and Development Laboratory, Fort Detrick, Frederick, Md. Starke, W.C., R.J. Pellerin, D.C. Burnett, C.J. Richmond, J.H. Manthei, and D.H. Heitkamp. 1987. Inhalation of Brass Flakes, Effects on Reproduction in Rats. CRDEC-TR-88035. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S., J. Height, P. Lee, A. Cooper, and L. Buettner. 1982a. Enzymatic and Cytological Changes in Lung Lavage Fluid from Rats Exposed to Inhaled EA 5763 Flakes. ARCSL-TR-81049. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S.M., J. Callahan, C. Crouse, D. Burnett, R. Pellerin, J. Height, R. Farrand, and D. Heitkamp. 1982b. The Effects of Subchronic Toxicity in Rats and Mice Exposed by Inhalation to EA 5763 (100 mg/cu m). ARCSL-TR-82026. Chemical Systems Laboratory, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S.M., D.C. Burnett, J.F. Callahan, C. Crouse, A. Cooper, J.J. Height, D.H. Heitkamp, R.L. Farrand, W. Muse, and R.J. Pellerin. 1984. Subchronic Inhalation Toxicity of EA 5763 (1 and 10 mg/m3) in Rats. CRDC-TR-84027. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S.M., D. Burnett, J. Bergmann, M. Lamb, J. James, A. Cooper, and L. Yellets. 1985. A study of the Acute Inhalation Hazards of EA 5752, EA 5763, and EA 5763 (Dedusted) Using Bronchopulmonary Lavage in the Rat. CRDC-TR-84122. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Thomson, S.M., D.C. Burnett, J.D. Bergmann, and C.J. Hixon. 1986. Comparative inhalation hazards of aluminum and brass powders using bronchopul-

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--> monary lavage as an indicator of lung damage. J. Appl. Toxicol. 6:197–209. Wentsel, R.S. 1986. Fate and Effects of Brass Powder on the Environment. CRDEC-TR-86044. Chemical Research, Development and Engineering Center, U.S. Army Armament, Munitions and Chemical Command, Aberdeen Proving Ground, Edgewood, Md. Yeh, H.C., M.B. Snipes, A.F. Eidson, C.H. Hobbs, and M.C. Henry. 1990. Comparative evaluation of nose-only versus whole-body inhalation exposures for rats—Aerosol characteristics and lung deposition. Inhalation Toxicol. 2:205–221.