Chemical Information Review Document for Artificial Butter Flavoring

Artificial butter flavoring and two important constituents, diacetyl and acetoin, were nominated by the United Food and Commercial Workers International Union for long-term testing via inhalation for respiratory and other toxicity and for cancer-causing properties. There is growing concern that workers in the microwave popcorn manufacturing industry may be at risk of developing the lung disease bronchiolitis obliterans from exposure to vapors from artificial butter flavoring. The first case of bronchiolitis obliterans in a popcorn manufacturing worker was reported in 2000 in Missouri. Since then several devastating outbreaks of severe and even fatal lung disease, including bronchiolitis obliterans, have been documented among workers in microwave popcorn manufacturing plants who have been exposed to the vapors of butter flavoring. To date, limited toxicological studies are available for artificial butter flavoring and its constituents. Inhalation studies in male rats showed that exposure to vapors from artificial butter flavoring caused necrosis of nasal and airway epithelium. Necrotizing bronchitis was observed in the lung, and necrosuppurative rhinitis and inflammation were seen at all nasal levels. An inhalation study with diacetyl also produced significant necrosis of nasal epithelium and significant necrosis of tracheal epithelium in male rats. However, no significant effects in the lung were reported. In another inhalation study, necropsy revealed general congestion, focal hyperemia of the lungs, atelectasis and bloody edema of the lungs, bronchial edema, and intensified hydrothorax in rats that did not survive a four hour treatment with diacetyl. Histopathological examination showed emphysema, hyperemia of the lungs, peripheral or centrilobular swelling of hepatocytes, and necrosis in the proximal tubules of the kidney. In rats, [C]-diacetyl given by intragastric gavage was rapidly metabolized and excreted, primarily as carbon dioxide in the breath and in urine. Metabolism of acetoin in vivo was mainly by oxidation at low concentrations and by reduction to 2,3-butanediol at higher concentrations. Diacetyl was not a reproductive or teratological toxicant in studies with pregnant mice, rats, or hamsters. Intraperitoneal injections of diacetyl or acetoin did not induce tumors in mice. Diacetyl, but not acetoin, was mutagenic in some strains of bacteria. It was negative in a micronucleus test but induced sister chromatid exchanges in Chinese hamster ovary AUXB1 cells and unscheduled DNA synthesis in various organs of laboratory animals. Diacetyl exhibited activating and deactivating effects on several enzymes and metabolic processes. It has been postulated that oxidative stress may play a role in diacetyl-induced lung damage.