Health Risk Assessment for an Unregulated Neurotoxic Nicotine Analogue in Oral Pouch Products.

Background: Oral pouch products containing nicotine analogues such as 6-methyl nicotine (6MN) were recently introduced to evade federal and state regulations. Preclinical studies demonstrated that 6MN is more toxic than nicotine and binds to nicotinic receptors with higher potency. However, the nicotine analogue contents of oral pouch products and the associated health risks remain unknown. Methods: Twenty-five flavor varieties from three oral pouch product (OPP) brands (Aroma-King, Hippotine-Happy Hippo, MG-Upperdeckys) marketed to contain 6MN were purchased in 2024-25. 6MN was quantified by either GC-FID (Yale) or GC-MS (Duke) to assess the estimated exposure dose (EED) from OPP use. Health risks associated with acute 6MN exposure from a single pouch use were assessed by calculating (i) hazard quotient (HQ) for heart-rate increase, and (ii) margin of exposure (MOE) for convulsions, with HQ more than 1 considered a potential health risk and the acceptable safety threshold value of MOE for proconvulsive effects considered 10. For comparison, both risk measures were determined for Zyn nicotine pouch products. Results: 6MN contents in analyzed OPPs ranged from 2.96-14.5 mg and diverged significantly from labelled contents for some products. HQ's for 6MN OPPs for heart-rate increase ranged from 74-381, compared to 95-162 for nicotine in Zyn. MOEs for convulsion risk ranged from 0.6-2.8, indicating elevated risk. MOEs for nicotine in Zyn products were 3.2-5.4. Conclusions: 6MN contents in novel pouch products are higher than in popular nicotine pouch products. Consumers using these products are exposed to 6MN levels that may exceed safety thresholds, potentially leading to adverse health effects. Nicotine analogues should be urgently addressed by lawmakers and regulators, and FDA should be authorized to regulate products containing them.