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-! PRIVILEGED AND CONFIDENTIAL ATTORNEYS' WORK PRODUCT Covington & Burliing Draft May 20, 199'2 SLrMMARY OF DATA ON~AMMONItrM BICARBONATE Abstract. Ammonium bicarbonate is commonly used as a leavening agent inbaking powder formulations, a fertilizer, and a flavorant in tobacco, products, and has numerous commer- cial applications. It has been recognized as GRAS by the FDA for multiple uses in food. When used as a. tobacco additive, ammoni~um bicarbon- ate increased the phenol content and decreased the amount of cresols and B(a)!P in cigarette smoke. One study reported~ an associa.tLon between the intake of cough medicine contaLning ammonium bicarbonate by pregnant women and congenital anomalies in their children. However, no such association was reported in a subsequent study. Acute doses of ammonium bfcarbonate have been associated with, weak ammonium poisoning in children, andl some deaths ~n infants. Acute doses of ammonium bicarbonate have also decreased glutamLne levels in the liver of and increased glutamine levels in. the tissue of rats. There was no evidence of tumor formation in a chronic feeding study in female rabbits, and the compound tested negatLvely in genotoxic and mutagenic studies. There are no published subchronic studies on. ammohium bicarbonate. -I. Backqround. An~nonium bicarbonate (,CHsN0~), ....... also known as anunonium hydrogen carbonate, is the monoammonium salt of carbonic acid. The compound is used commonly as a leavening, agent in baking powder formulatLons because of its complete decomposition into C02, H20, and NH3 at temperatures above 60"C. Ammonium bicarbonate is used in cooling baths (~ kg dissolved in five l~ters of water at 17°C lowers the temperature to 7"C)., fire extinguishers, and the manufacture

of porous plastics and ceramics, dyes, and pigments. Ammonium bicarbonate and ammonium salts also are used as fertil, izers (Windholz, 1976). In, fact, ammonium bicarbonate was the major fertilizer used in China in 1985 (Anonymous, 1985.). Ammonium, b~carbonate has additional applications in accelerating the decomposition in compost heaps and as an additive in defatting~ textiles, cold wave solutions for hair styling, chrome leather tanning, and removing gypsum from, heat exchanges and other processing equipment (Windholz, 1976):. A highly purified preparation of this compound is used ~n pharmaceuticals (:Snell and Hilton, 1966). Ammonium bicarbonate is one of various NH~-CO2 compounds which belong to the system NH~.-CO2-H20. The com- pou.nds include: ammonium b~carbonate (NH~HC03), ammon,ium carbonate (I(NHi.)2CO~.x H~O:), ammonium sesquicarbonate ((NH~)2CO3 x 2NH~HCO~ x H20), and ammonium carbamate (NH~CO2NH~) (iUllmann, 1974). Ammonium bicarbonate is the most stable of these compounds. During storage under ambient conditions, ammonium carbonate andl ammonium carbamate decompose to ammonium b~car- bonate, ammonium, water, and carbon dioxide (U~Imann, 1974; Windholz, 1976; List and H6rhammer, 1972; Ho~mann and Hofmann, 1945). In contrast to ammonium bicarbonate, ammonium carbon- . ate, also known as 'hartshorn' (iWindho~z, 1976), is not defined we~l and cannot be produced commercially in a pure • form. The preparation process of ammonium carbonate creates two mixed salts composed of ammonium bicarbonate and ammonium - 2 -

carbamate (NH4CO2NH2 x 2NHiHCO~. and NH4CO2NH~ x NH4HCO~). The usual commercial form of ammonium carbonate contains about 5:0 mole percent carbamate (.Snell and Hilton,, 19:66; Wilson. et al., 1968; Solar and Carrison, 1963.; DABg, 1,986). Ammonium bicarbonate has the following chem~ca~ and physical properties: O'---NH~* molecular weight: 79.06 mp: I07.5°C volatile with decomp.: 60" soluble: water insoluble: a~cohol, acetone Ammonium bicarbonate is prepared as a shiny, hard, colorless or wh,ite, prismatic or crystalline, mass (Windholz, 1976.). It is synthesized by the counter current absorption of carbon dioxide in an aqueous ammonia solution. The crystal- line salt precipitates as the saturation of the solution occurs, and the crystals are filter@d~ off. The resultant salt slurry is ~entrifuged, dried, cooled, and crystallized.(Snel, l and Hilton, 1966; U~Imann, 1974). . ~ Ammonium bicarbonate is used~ by the tobacco industry as a flavorant. During the nicotine extraction process, an aqueous solution of ammonium bicarbonate is sprayed on the tobacco. This pretreatment process makes the resu.lting tobacco less harsh, than non-pretreated ,tobacco. In this

process, ammonium bicarbonate can. be applied at 1:-3 percent of the dry weight of tobacco (.mass/mass)(Grubbs et al., 198:7)i. An aqueous solution of about 5. percent ammonium bicarbonate is used!in the production of smoking material made of expanded carboxymethyl starch and powdered tobacco (Battard, 1985), and there is a patent for its use in the tobacco swel~ing process (.Armstrong et al., 1972). Ammonium bicarbonate was recognized by the FDA as GRAS in the 1950,'s. FDA has since affirmed the ingredient's GRAS status for mul~tipl~e uses as a food ingredient, dough streng%hener, leavening agent, pH control agent, and texturiz- er to be used at levels not to exceed~ good manufacturing practice (,21C.F.R. § ~84.1135 (1991); 48 Fed:. Reg. 52438, 52439 (198:3); Kilgore and Li, 1980'). Ammonium bicarbonete also is permitted~ for use in cocoa products (2'1 CFR Part 163). The cocoa fraction maximum u.se level for the manufacture o~ cocoa and chocolate products is 50 g/kg, when used alone or with hydroxides, other hydrogen carbonaZes, or carbonates (Codex Alilmentariu.s)~. Ammonium carbamate, which decomposes below pH 10 to ammonium carbonate and ammon.ium, bicarbonate (Wilson et al., 1968), is permitted for use a~s an additive for snuff and. for white snuff powder under the German. Tobacco Ordinance (.Tabakverodnungi, 1990). Ammonium carbonate, which in usual commercial form consists of about 50 mole percent carbamate and 50 mole percent bicarbonate, is approved for use as a - 4 -

tobacco additive at a 4 percent maximum inclusion level in the United Kingdom (Fourth Report of the Independent Scientific Committee on Smoking~ & Hea~th, 1988). In addition, carbonates are permitted for use in tobacco in Spain (Codigo Alimentario, 1985). Ammonium salts are approved for use in foods by many countries. ~n Belgium and France, ammonium salts of carbonic acid are permitted substa~nces for tobacco and a~l tobacco products (Arr~te Royal of December 28, 1979 and Decree of November 23, 1978, respectively). ~I. Use in. Tobacco. A. Function. Ammonium bicarbonate is used by the tobacco industry as a flavorant during the nicotine extraction process, making: the resulting tobacco, less harsh than non- treated tobacco.. B. Use Level. Information. on. the levels of ammonium bicarbonate in commercially available tobacco prod- ucts was not found in the available literature. The Industry maximum use level for ammon.ium bicarbonate is less than 1 ppm. III. Chemistry & Pyrolysis. Ammonium bicarb0nate was tested at a 5. percent leve~ in IRI tobacco for its ability to alter the chemical composition of cigarette smoke. The concentrations of selected smoke components were compared with smoke components from untreated IRI cigarettes. The results for TPM and tar were reported~ on a per gram of tobacco burned

basis. Resul.ts for other smoke components were presented as the change in percent composition of the treated tobacco smoke components as compared to the untreated tobacco smoke components. For TPM, tar, and nicotine, no slgnificant changes were observed. The phenol content of smoke was 16 percent higher, while the content of o-cresol, m- and p- cresol, and B(a)P were reduced to. 57 percent, 89 percent, and 62 percent, respectively, compared to the smoke composition of untreated IRI cigarettes (Burton and Benner, 1972).. ~V. Toxicology A. Metabolism. Ammonia and ammonium ion are integra~ components of normal metabolic processes and~ play an essential role in the physiollogy of man and other species (Windholz, ~9'76; Coulson and Hernandez, 1955). B. Acute Human. Toxicity. In a study by Moeschlin (19'80), a 1-2 percent aqueous solution of ammonium carbona~te led to. weak ammonium poisoning in children (30 g for a two- year old child) and to some fatalities in infants. Single cases a~so were reported in which unknown oral doses of ammonium, carbonate led to severe poisoning or fatality, even in adults (Wirth et al., 1967; Lewin, 196.2)i. C. Chronic Animal Studies. No published studies on the chronic toxLcity of ammonium bicarbonate were found. Pursuant to the FDA's review of food ingredients classified as GRAS, however, the Select Committee on GRAS Substances - 6 -

reviewed those studies relevant to the oral toxicity .of ammonium compounds. According to a summary of the information from the Select Committee report, no evidence of tumor formation was found after feedilng female rabbits ammon,ium carbonate, chloride, hydroxide, a~nd sulfate iln doses up to 700 mg/kg body weight for 5 to 16 months. 43 Fed. Reg. 14064, 14066 (1978)i. D. Acute & Subchroni~c Animal Studies. In mice, the LDs0 of intrav.enously ~njected ammonium bicarbonate was 3..10 ± 0.2 mmol/kg (approx. 245 mg/kg) (~Wilson e__t al., 1968),. ~n rats, intraperitoneal injectilon of 110.6 mmol (approx. 838 mg/kg) ammonium, bicarbonate led to a more than 130 percent increase of glutaminase I and a more than 50 percent decrease of glutamine in the liver (.Petit et al., 1974).. In freeze- clamped kidneys of fasted rats, a single intraperitoneal injection of 2.5 mmol of NH~HCO3/kg (:approx. 19'8 mg/kg) body weilght resulted i~n a 29 percent decrease in the tissue concentration of 2-oxog~utarate and a slight increase in the tissue concentration of glutamine. A constant infusion of NH~HCO~ over 60 minutes at a rate of 15 mmol/mi.n (approx. 1.2 mg/min) produced a simil~ar result, with a significant increase in tissue glutamine content and renal vein, gl~utamine concentration (Vinay et al., 1978). In cats, an intravenous injection of 0.8 mmol/kg (approx. 63 mg)ammonium bicarbonate produced electro- encephalographic changes, which were reversible within 30

minutes (Watanabe, 1978). In anesthetized dogs with a mean weight of 17.5 kg, a 15 minute infusion of 13 mmol (approx. 1.03 g) ammonium bicarbonate slightly increased the oxygen consumption by the brain, which persisted during the foll~owing 30 minutes, and largely increased glucose utilization by the brain, which returned to control values after the infusion was turned off (~James e__%t al., 1,9'74). In. the previously cited Wilson study, the LDs0 of intravenouslly administered ammonium carbonate ((NH~),2C03) for mice was 0:.99' ±' 0.1~4 mmol/kg (approx. 95 mg/kg). The LDs0 of ammonium carbamate (NH~CO2NH~.), administered by the same route, was determined to be 1.02-0.11 mmol/kg (approx. 80 mg/kg) for m~ce, dogs, and sheep. One mole of ammonium carbamate contained two mol~es of ammonia,, whereas one mole of ammonium bicarbonate contained only one mole of ammonium. It was concluded that the ammonium carbonate would be at l~east twice as toxic as ammonium bilcarbonate (Wilson et al., 1968).. No. published studies on the subchronic toxicity of ammonium bicarbonate were fou.nd. However, up to 3 g/100, g basal diet of ammonium carbonate was given to male chicks in a 14-day feeding study without any effect. The same study found that ammonihm, was more toaic as the sulphate thah~as the carbonate salt (Sibbald and Cave, 1976). I.t is not known. whether there is any difference in subchronlc toxicity between ammonium as the carbonate salt or bicarbonate salt; moreover, - 8 -

the amount of carbonate converted or previously converted to bicarbonate before feeding is not known. E. Genotoxicit¥ & Mutaqenicity. Ammonium bicarbonate was evaluated~ in Salmonella typhimurium strains TAg'2, TA1535, TAI00, TAI~5.37, TA94, and TA98 with and~ without metabolic activation; no mutagenic activity was observed. I'n vitro chromosomal~ aberration tests using a Chinese hamster fibroblast cell l~ine, without any metabolic activation system were also negative for mutagenic activity (Ish,idate e__%t a__~l., 1984). In another study, ammonium bicarbonate toxilcity was assessed in Saccharom¥ces cerevisiae (,straiin-D4)and in ~. typhimurium (,strains TA1535., TA1537, TAI~538, TA98, and TAI00), with and without microsomes from the liver and lungs o.f the mouse, rat, and monkey. Ammonium bicarbonate was not active in any assay (~Litton Bionetics, 1977). F. Reproductive Toxilcitv& Teratoloqy. Ammonium bicarbona:te is one of the most common ingredients in cough mixtures. In Australila, cough, medicine was suspected to be associated with a higher rate of congenital anomalies when used by women during their entire pregnancy (Nelson and ~F~far, i971i). However, another study reexamined £he-use of- cough mixtures containing ammonium bicarbonate by pregnant women and did not find any statistically significant association, between the maternal use and adverse neonatal outcomes (Collley et el., 1982).

No published animal studies on the reproductive/ teratologic toxicity of ammonium bicarbonate were found. - I0 -