Investigation of the formation of N-nitrosodiethanolamine in B6C3F1 mice following topical administration of triethanolamine.
To determine potential nitrosation of triethanolamine (TEA) to N-nitrosodiethanolamine (NDELA) at different physiological conditions of the GI tract, in vitro NDELA formation was examined in aqueous reaction mixtures at several pHs (2-10) adjusted with acetic, sulphuric or hydrochloric acids or in cultures of mouse cecal microflora incubated. In vivo NDELA formation was also determined in blood, ingesta, and urine of female B6C3F1 mice after repeated dermal, most relevant human route, or single oral exposure to 1000 mg/kg TEA in the presence of high oral dosages of NaNO(2). Appropriate diethanolamine (DEA) controls were included to account for this impurity in the TEA used. Samples were analyzed for NDELA using GC/MS. The highest degree of nitrosation of TEA to NDELA ( approximately 3%) was observed in the in vitro cultures at pH 4 and acetic acid with lower amounts obtained using sulphuric acid ( approximately 1.3%) and hydrochloric acid ( approximately 1.2%). At pH 7, <1% of the TEA was nitrosated to NDELA and at pH 2 (HCl) or pH 10 (NaOH) no NDELA was found above the limit of detection. In incubated cultures containing cecal microflora and nutrient broth, only 0.68% of TEA was nitrosated to NDELA. No NDELA was formed in rats repeatedly dermally dosed with TEA at the limits of detection in blood (0.001 microg/ml, ppm), ingesta (0.006 microg/ml, ppm), and urine (0.47 microg/ml, ppm). Levels of NDELA measured in blood and ingesta after a single oral dose of TEA and NaNO(2) were less than those in DEA controls. These findings in toto confirm the lack of any significant formation of NDELA from TEA in vivo.
Saghir
Shakil A
SA
Toxicology and Environmental Research and Consulting, The Dow Chemical Company, Midland, MI 48642, USA. ssaghir@dow.com
Brzak
Kathy A
KA
Markham
Dan A
DA
Bartels
Michael J
MJ
Stott
William T
WT
D000042:Absorption; D000279:Administration, Cutaneous; D000284:Administration, Oral; D000818:Animals; D001419:Bacteria / Q000378:metabolism; D002432:Cecum / Q000187:drug effects / Q000382:microbiology; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000031:analogs & derivatives* / Q000032:analysis / Q000097:blood / Q000652:urine; D004983:Ethanolamines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D008297:Male; D051379:Mice; D012869:Skin Absorption; D012977:Sodium Nitrite / Q000008:administration & dosage
D004983:Ethanolamines; C014129:N-nitrosodiethanolamine; D004052:Diethylnitrosamine; C009546:triethanolamine; C020283:diethanolamine; D012977:Sodium Nitrite