Module 3 - Strategic case studies in practice

very low dose (see sections 2.4.5. and 2.5 of the report). An additional factor is that most of the lifetime bioassays have been performed in rats and mice. However, laboratory rodent strains used were different. It is well known that various strains often display different sensitivities even to the same chemical. The most comprehensive source for animal carcinogenicity data is the Carcinogenic Potency Database (CPDB, 2007). For this database, 6540 long-term animal cancer studies of 1547 chemicals were evaluated and the dose causing cancer in 50 percent of the animals (TD 50 ) was calculated by a mathematical model. For N- nitrosamines mentioned in this report, the TD 50 values found in CPDB are listed in table 2.4.3-1. sorted by their descending carcinogenic potency (harmonic mean TD 50 ). Table 2.4.3-1 TD 50 values found in the CPDB for some N- nitrosamines considered of relevance (EFSA 2017, IARC)

Abbre- viation

IARC Group

TD 50 [mg/kg/ day] harmonic mean rat, CPDB

TD 50 [mg/kg/day] other species, CPDB

TD 50 [mg/kg/day] most relevant study, sensitive species (tissue), CPDB

Agent

Mutagenicity

Nitroso- N- methyl- N- (2- phenyl)ethylamine

0.00998

0.00788, rat (ugi), Lijinsky et al 1982

Ames test positive (CPDB)

NMPEA

male only

0.00725, cynomolgus; 0.012 bush babies; 0.054, rhesus (harmonic means)

0.05, rat (liv), Peto et al 1991b; 0.026, rat (eso), Lijinsky et al 1981

N- Nitrosodiethylamine

DENA, NDEA

Ames test positive (CPDB)

2A

0.026

0.053

N- Nitrosomethylethyla mine

Ames test positive (CPDB)

2B

(1 dose group)

NMEA

0.04 rat (liv), Peto et al 1991b; 0.06, rat (liv), Lijinsky et al 1984

N- Nitrosodimethylami ne

0.189, mouse (harmonic mean)

Ames test positive (CPDB)

DMN, NDMA

2A

0.096

0.096

Ames test positive, Padma et al 1989

N- Nitrosonornicotine

10.8, hamster (harmonic mean)

NNN

1

(1 dose group)

4-( N- Nitrosomethylamino ) -1-(3-pyridyl)-1- butanone

0.182, rat (lun), Rivenson et al 1988

NNK

1

0.0999

EMA/369136/2020

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