140. On page 47 of the TGA non-clinical report it states no unique in-vivo metabolites of ALC- 0159 were observed in the rat pharmacokinetic study, but N,N-ditetradecylamine formed by slow amide hydrolysis was identified in hepatocytes and liver S9 fractions from mouse, rat, monkey and human – Substances predicted as likely to meet criteria for category 1A or 1B carcinogenicity, mutagenicity, or reproductive toxicity, or with dispersive or diffuse use(s) where predicted likely to meet any classification criterion for health or environmental hazards, or where there is a nanoform soluble in biological and environmental media. https://echa.europa.eu/substance-information/- /substanceinfo/100.037.611 141. Why didn’t the TGA identify the accumulation of N,N-ditetradecylamine a risk from the vaccine?

Question Number: 265
PDR Number: SQ22-000636
Date Submitted: 21/11/2022
Department or Body: Department of Health

140 The primary route of metabolism identified for ALC-0159 involves amide bond hydrolysis yielding N,N-ditetradecylamine. This metabolite was only identified in vitro in isolated mouse, rat, monkey and human preparations. The metabolite was not detected in vivo in rats after an IV dose of ALC-0159. The human exposure to ALC-0159 as part of the Pfizer vaccine is 50 ?g, which is below the threshold of toxicological concern (TTC) of 120 ?g/day for substances with a dosing period of less than one month over a lifetime (ICH guideline M7: www.ema.europa.eu/en/documents/scientific-guideline/ich-guidelinem7r1-assessment-control-dna-reactive-mutagenic-impurities-pharmaceuticals-limit_en.pdf). Even if N,N-ditetradecylamine is formed from ALC-0159 in vivo, the amount of the metabolite would be much lower than the amount of ALC-0159 in the vaccine dose. Therefore, neither ALC-0159 nor N,N-ditetradecylamine from COVID-19 vaccination is considered to pose a carcinogenic risk. As per the ICH guidelines, which are used by regulators in all major developed countries, guidelines no further risk assessment was required. 141 N,N-ditetradecylamine was not detected in rats in vivo after an IV dose of ALC-0159. This means there is no accumulation of N,N-ditetradecylamine. See also the response to Question 140.