N-Nitrosodimethylamine. Documentation of proposed values of occupational exposure limits (OELs)
Authors: Bruchajzer Elżbieta , Frydrych Barbara , Szymańska Jadwiga 
Published: September 2019

N-Nitrosodimethylamine is a flammable, volatile, oily liquid with a yellow color and a weak, characteristic odor. It is obtained by the nitrosation of amines and ammonium salts. It is used in many technological processes in the rubber industry (as a vulcanization accelerator and antioxidant), leather industry (for hair removing), foundry and agriculture.
N-Nitrosodimethylamine may be formed as a result of changes of nitrates added to the food products as preservatives; and endogenously in the gastrointestinal tract (in the reaction of amines and amides with nitrites formed from nitrates by denitrifying bacteria).
In Poland, in the years 2005-2016, several dozen to several hundred people per year were exposed) on N-nitrosodimethylamine (in 3-7 plants). According to the measurements made in 1990, the highest concentrations, at which rubber industry workers in Poland were exposed, were 4.5 ÷ 9.2 µg/m3.
Acute poisoning with N-nitrosodimethylamine in humans occurred as a result of accidents or criminal activities. At that time, mainly liver damage (necrosis) and hemorrhagic changes associated with a decrease in clotting time were observed. No data are available on the toxic effects of occupational exposure to N-nitrosodimethylamine.
After intragastric administration of N-nitrosodimethylamine to rats, LD50 was below
50 mg/kg bw. The sensitivity of laboratory animals (expressed in LD50) increases with their size and decreases with the relative weight of the liver. Administration of N-nitrosodimethylamine to animals at doses of 20 ÷ 40 mg/kg bw. caused hepatic necrosis, leading to death.
After a single intraperitoneally, intramuscularly or subcutaneously administration of the compound to rats in the doses of 18 ÷ 30 mg/kg a shortened lifespan and tumors, mainly of kidneys and liver were observed. In mice treated with the compound intraperitoneally or subcutaneously in doses of 0.5 ÷ 14 mg/kg primarily lung cancer was found. After doses
of 7 ÷ 15 mg/kg liver and kidney tumors have also been reported.
After 30-week exposure of rats to N-nitrosodimethylamine in drinking water in doses of 0.14 ÷ 0.82 mg/kg/day, liver tumors (at a frequency of 70% to 100%) and lung tumors (5% to 100%) was noted in animals.
Chronic orally exposure (45-52 weeks) of rats to N-nitrosodimethylamine at doses of 0.144 ÷ 3.6 mg/kg/day resulted in a dose-dependent increase in the cancer incidence of liver (from 2.7% to 83%), kidneys (in 50% of animals) and lungs (80%); and shortening of lifespan.
Increased number of liver and kidney tumors after subcutaneous administration of
N-nitrosodimethylamine to hamsters (once a week injections throughout life, at doses
of 1.4 ÷ 8.6 mg kg) was also reported.
In rats exposed on N-nitrosodimethylamine at concentrations 120, 600 or 3000 µg/m3 for 207 days, concentration-related increases in animal mortality and nasal cancers of 36%, 86% and 53% of animals were observed, respectively.
The most information about the relationship between the toxic effects and level of exposure come from an experiment performed on rats, in which N-nitrosodimethylamine was administered chronically in drinking water at doses of 0.001 ÷ 0.697 mg/kg body weight/day (male) or 0.002 ÷ 1.244 mg/kg bw./day (females). The experiment showed that for doses up to 0.2 mg/kg/day, the risk of liver cancer has been increasing (depending on the dose), and females were more sensitive than males.
Chronic exposure of laboratory animals (rats, mice, hamsters), irrespective of the route of exposure (intragastric, subcutaneous, inhalation) resulted mainly in liver damage and tumors of the liver, kidneys, lungs and nasal cavity.
N-Nitrosodimethylamine showed mutagenic and genotoxic effects in in vitro and in vivo experiments after metabolic activation. This is related to the mechanism of genotoxic and carcinogenic action of the metabolites formed in a reaction of N-nitrosodimethylamine hydroxylation followed by its demethylation.
N-Nitrosodimethylamine is a transplacental carcinogen, most pronounced when the compound has been administered to animals at the end of pregnancy.
The International Agency for Research on Cancer (IARC) has included
N-nitrosodimethylamine to 2A group (probably carcinogenic to humans), ACGIH (2001) has qualified N-nitrosodimethylamine to A3 group (proven carcinogenicity to animals and unknown human carcinogenicity), MAK-Commission - to category 2 (substances that are considered carcinogenic to humans). The European Union, according to the CLP classification, has classified the compound to the category 1B with the inscription "H350 - can cause cancer". EPA has included a compound to group B2 - probably carcinogenic to humans.
The basis for the calculation of threshold limit value-time weighted average (TLV-TWA; maximum acceptable concentration – MAC) for N-nitrosodimethylamine was the chronic exposure of rats to the compound in drinking water and observed changes in the liver. On the basis of these studies, an assessment of the risk of an additional tumor was made, which has been used to propose MAC-TWA values at 0.0025 mg/m3 (2.5 μg/m3), for which the cancer risk would be 6.15 · 10-4. There is no basis for the short-term exposure limit (STEL) and biological limit value (BLV). The notations "Carc. 1B" (carcinogenic substance Cat. 1B) and "skin" (absorption through the skin may be as important as in the case of inhalation) were proposed. This article discusses the problems of occupational safety and health, which are covered by health sciences and environmental engineering.