Module 3 - Strategic case studies in practice

2.4.4.1. Discussion on exposure to N-Nitrosamines and their carcinogenic potential

Based on available data, the CHMP noted that estimates on the exogenous exposure to N- nitrosamines vary. Assessments for food-mediated intake range between average 0.5-1.7 ng NDMA + NDEA/kg food (EFSA, 2017; processed meat only) and 1 ng NDMA/kg bw (Herrman et al, 2010b; ~50-100 ng NDMA/d per adult person from across food groups) to average 2.2 µ g NDMA + 0.9 µ g NDEA/kg food across food groups (Gushgari & Halden, 2017). Some processed food types such as fried foods are likely to contain >10 µ g NDMA/kg food. Water intake is likely to represent an additional ~10-20 ng NDMA/L. Based on only NDMA measurements in urine samples, the NDMA exposure is likely to be >1-2 µ g/d for subsets of the population (which may or may not represent a large endogenous NDMA production and generation.). This does also not cover for all additional exposures that are very likely to have a far greater individual consumer and societal variability (e.g. smoking, contact exposure with rubber, personal care products etc.) and also not the total nitrosamine exposure (TNA) and non-nitrosamine exposure of relevance (e.g. all agents that generate the same DNA-lesions as pharmaceutical nitrosamines and are handled by the same cellular defence systems; see section 2.4.2.2.). Individual dietary habits are important, and it can for instance be assumed that exposure of individuals living on some types of diet (e.g. vegetarian), is significantly lower. Exposure to endogenously produced N- nitrosamines raises an equal concern as exposure to exogenous N- nitrosamines. However, the exposure to endogenously produced N- nitrosamines is hardly quantifiable. No reliable data are currently available to draw firm conclusions on the impact of endogenously produced N- nitrosamines to overall N- nitrosamine exposure. In view of the uncertainties with respect to exposure levels, additional exposure should be limited as much as possible. In conclusion, the carcinogenic potential is determined by multiple factors and depends on: • The capacity, velocity and accuracy of the different cellular repair mechanisms responsible for the repair of the different DNA-adducts in tissues • susceptibility (metabolic and proliferative) of the tissues exposed It is therefore prudent to consider all N- nitrosamines containing a α -hydrogen that can be metabolically activated as potentially mutagenic and carcinogenic to humans, however with different potencies depending on nature of the functional group, specifics of metabolic activation and repair efficiency and capacity. For NMEA, NNN, NMA, NDPA, NDBA, and NMBA, the TD 50 has been calculated from studies with one or two dose groups only and therefore the reliability of the TD 50 should be handled with caution. For NDMA and NDEA the respective harmonic mean TD 50 was used in the CHMP Art 31 referral on sartans to calculate limits. Indeed, the number and extent of rat carcinogenicity studies were considered robust enough for calculating limits based on ICH M7 principles. For NDBA and NMBA the TD 50 listed in the CPDB were not judged as robust enough because they were derived from one study with one dose group only. The study published for DIPNA was not listed in the CPDB and is assumed as not reliable enough to calculate any point of departure. CHMP has therefore recommended to use the AIs for NDMA or NDEA based on SAR considerations for NMBA and DIPNA, NDBA, respectively (EMA/351053/2019 rev 1). • The ability of the N- nitrosamine to be metabolically activated • The metabolic competence and capacity of the tissue to form diazonium/carbenium ions • The nature and stability of the diazonium/carbenium ion and the DNA-adducts formed

EMA/369136/2020

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