Module 3 - Strategic case studies in practice

the formation of ENOCs from exposure to nitrite or nitrate under normal diet conditions so far. In addition, the impact of potential formation of ENOCs in the body under inflammatory conditions and the amounts found in urine is currently unclear. There are no data available re the metabolic activation of NOCs outside the liver in humans. Surrogate models have so far been used mainly evaluating NDMA and NDEA formation in the upper gastrointestinal tract (see table 2.4.1.2-1). Table 2.4.1.2-1 Some estimates on endogenous nitrosamine exposure using artificial in vitro models.

Source

Range detected

Endogenous generation from nitrites.

Artificial stomach models (static and dynamic) [at low pH, defined levels of nitrite or nitrate, amine rich foods]:

Krul et al (2004)

Groenen et al (1980)

Zeilmaker et al. (2010)

# Static model (2h, pH2) :): 6-18ug NDMA

# Dynamic model (rapid pH shift 2.5->1.7, 3h) – cumulative mean 2.3–422ug NDMA. # Dynamic model (slow pH shift 3->1.7, 3h) – cumulative mean 1.8–42.7ug NDMA. # Extrapolation model based on Dutch food consumption data - 4ng/kg BW NDMA in young children and 0.4ng/kg BW NDMA in adults.

Zeilmaker et al. (2010) estimated the NDMA exposure of adults to NDMA formed after ingesting fish and nitrate rich vegetables to be 0.4 ng/kg bw/day. This has already been summarized and critically discussed in the CHMP Art 31 referral on sartans. The EFSA panel used the model described in the Guideline for Canadian Drinking Water Quality (Health Canada 2013) to calculate potential exposure by formation of ENOCs using NDMA as representative. The calculated NDMA exposure from endogenous formation was calculated by 0.064 ng/kg bw/day at the acceptable daily intake of nitrite ion of 0.07 mg/kg bw/d (EFSA 2017). The Panel also noted that this calculation included conservative assumptions like the availability of sufficient amounts of nitrosatable substrates and complete reaction of all nitrite with only these substrates at all time to produce only carcinogenic ENOCs. Most N- nitrosamines are considered to be mutagenic and carcinogenic, at least in animals, and with extensive difference in potency between the most and least potent nitrosamines. IARC has classified those with animal data available as class 2A or 2B. Currently, only some tobacco-related N- nitrosamines are classified as class 1 (e.g. NNN, NNK) although sufficient substance specific human data are lacking. Those with insufficient data from animals are classified as class 3. As outlined already in the Art 31 referral on sartans, the mechanistic principles of N- nitrosamine mutagenicity and carcinogenicity are also considered relevant in humans. Of highest concern with respect to mutagenic and carcinogenic potential are some of the so called volatile N- nitrosamines potentially formed in food (EFSA, 2017) such as N- nitrosodimethylamine NDMA, N- nitrosodiethylamine (NDEA), N- nitrosopyrrolidine (NPYR), N- nitrosopiperidine (NPIP) Nitroso- N- methyl- N- (2-phenyl)ethylamine (NMPEA), N- nitrosodibutylamine (NDBA), N- nitrosomorpholine (NMOR), N- nitrosomethylethylamine (NMEA) and N- nitroso-di-n-propylamine (NDPA). 2.4.2. Mutagenicity and carcinogenicity of N- nitrosamines

EMA/369136/2020

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