2,2’-dichloro-4,4’-methylenedianiline – inhalable fraction and vapours. Documentation of proposed values of occupational exposure limits (OELs)
Authors: Kilanowicz Anna , Skrzypińska-Gawrysiak Małgorzata 
Published: September 2019

2,2'-Dichloro-4,4'-methylenedianiline (MOCA) is an aromatic amine. It is produced commercially by the reaction of formaldehyde and 2-chloroaniline. It is not produced in Europe and its import to Europe is estimated at 1000-10000 t/year. MOCA is mainly used as a curing agent in the production of polyurethane elastomers. Occupational exposure to MOCA occurs during production, distribution and use of this compound. In Poland in 2016, 14 people were exposed to this compound, including 10 women.
Under occupational exposure conditions, MOCA is mainly absorbed through the skin; absorption in the respiratory tract is of secondary importance. Available literature does not provide data on chronic MOCA poisoning under occupational conditions. No methemoglobinogenic effect typical for aromatic amines was found in exposed subjects.
MOCA has a moderate toxic effect on animals; median lethal doses after oral administration to rodents are 400 ÷ 1140 mg/kg of body weight. It also has a moderate irritant effect on the skin and eyes, but no allergenic effect. Data on subchronic and chronic animal toxicity indicate multiorgan toxicity.
MOCA shows mutagenic and genotoxic potential, both in vivo and in vitro. In bacterial tests, it requires the presence of metabolic activation. It causes DNA damage and formes DNA adducts both in vitro and in vivo. MOCA also forms adducts with other macromolecules such as haemoglobin, globin or plasma albumin.
No data are available on the effects of MOCA on human reproduction or on the embryotoxicity and teratogenicity of this compound. The only rat experiment showed that MOCA has no influence on the reproductive potential of parents and the growth and of pre- and postnatal development of offspring.
There are no epidemiological studies in the literature that clearly indicate that occupational exposure to MOCA is the cause of cancer in workers. However, there are reports of bladder cancer, usually found in cystoscopic examination in young men occupationally exposed to MOCA.
Animal studies have provided sufficient evidence for the carcinogenic effects of MOCA. It was shown that this compound administered to rats in the diet induces a dose-dependent increase in the number of lung cancer, hepatocellular carcinomas, hemangiosarcomas, mammary gland adenomas and Zymbal gland carcinomas. MOCA administered in capsules to dogs induced tumors of the bladder and urethra. The mechanism of carcinogenic action of MOCA is related to the potential of this compound and/or its metabolites to bind with macromolecules, mainly DNA.
MOCA has a harmonised classification as Carc.1B. IARC considered that there was insufficient evidence of MOCA carcinogenicity in humans and that there was sufficient evidence of carcinogenicity in animals. In the overall assessment IARC classified MOCA into group 1 – compound carcinogenic to humans. SCOEL (2010) included MOCA to genotoxic carcinogens with non-threshold effect (group A).
MOCA is absorbed into the body by inhalation, ingestion and dermal routes, the latter is the main route of absorption under occupational exposure conditions. There is no quantitative data on efficiency or absorption rate. In animals, regardless of the route of administration, the highest MOCA concentrations are in the liver, lower in the lungs, kidneys, adipose tissue and blood.
MOCA is metabolized mainly in the liver by CYP3A4. Metabolism may proceed along the pathways of N-acetylation, N-hydroxylation/N-oxidation and ring hydroxylation. The main and the most reactive and directly carcinogenic metabolite is N-hydroxy-MOCA.
MOCA is excreted from the body with urine and faeces. The relative share of these excretion routes in animals depends on both the species and the route of administration. Based on the MOCA measurement in the urine of an employee who accidentally sprayed with molten MOCA, the biological half-life was set at 23 hours.
Since the main route of absorption of MOCA in occupational exposure conditions is the dermal route, biological monitoring, usually based on measurement of the total MOCA concentration in urine, is necessary for the assessment of total exposure. Modern monitoring studies have found that although the MOCA concentration in air was low, a significant percentage of urine samples exceeded the detection limit of the method, which for most methods is 0.5 µmol MOCA/mol creatinine. In addition, some studies have shown that the MOCA level in urine correlated with the amount of glove contamination, not the working surfaces.
The values of the current hygiene standards in the various countries range from 0.22 mg/m3 to 0.005 mg/m3 and are usually labelled "skin" and "carcinogen". Furthermore, in many countries, no limit values have been set for MOCA due to its carcinogenic effects. Also in the EU, SCOEL did not set a standard value for MOCA.
In 2018. The European Commission has proposed to include a limit value of 0.01 mg/m3 as a binding value (BOELV) with the simultaneous notation of 'skin' in Annex III to the proposal for a Directive of the European Parliament and of the Council amending Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens or mutagens at work.
At the same time, it was proposed to set the urinary MOCA concentration at 5 µmol MOCA/mol creatinine as the Biological Guidance Value (BGV), in line with the list of recommended values of the Biological Exposure Limits (BEIs) based on the health effects and Biological Guidance Values (BGVs) provided by SCOEL, which however takes the detection limit of the method as the BGV without giving a specific numerical value for this indicator.
The basis for proposing a MAC value was the carcinogenic effect of MOCA. Since MOCA is a genotoxic carcinogen with non-threshold effect, the values of hygiene standards should be based on the cancer risk assessment for this compound. All existing risk assessments are based on the results of an experiment on rats receiving MOCA in the diet under chronic exposure conditions.
The MAC value currently in force in Poland of 0.02 mg/m3 was derived on the basis of the linear model with the assumed risk of 10-4. The cancer risk assessment using the two-step model gave the risk values accordingly: 4.6 - 10-4 for MOCA concentration 0.02 mg/m3 and 1.7 - 10-4 for 0.01 mg/m3. A similar risk value of 9.65 - 10-5 (≈ 1 - 10-4) for inhalation exposure to 0.01 mg/m3 was assigned by RAC using a linear model.
In view of the fact that the risk assessments presented above gave compatible values for 0.01 mg/m3 and that the European Union proposed this value as a binding concentration, it was proposed to use a MOCA concentration in air of 0.01 mg/m3 as the MAC value in Poland.
The main route of exposure to MOCA at occupational condition is the dermal route. MOCA levels in workers' urine samples are a better indicator for overall exposure assessment than measuring MOCA concentrations in air.
MOCA is not detected in the urine of subjects not occupationally exposed, i.e. it remains below the detection limit of the method. Therefore, the Biological Guidance Value (BGV) for MOCA should correspond to the detection limit of the biomonitoring method.
However, for practical reasons, it was proposed to use 5 µmol MOCA/mole creatinine in urine collected at the end of the shift as an equivalent to BEI. Under industrial conditions, total MOCA concentrations below 5 µmol/mol creatinine can be achieved under appropriate hygienic working conditions. Moreover, according to the risk assessment presented by SCOEL, this MOCA concentration in urine leads to a cancer risk of 3 ÷ 4 - 10-6.
Biomonitoring should be supplemented by air monitoring and, where appropriate, measurements of dermal contamination, gloves and work surfaces contamination to identify sources of exposure.
Since dermal exposure accounts for a significant proportion of the MOCA taken by workers, a 'skin' notation is required.
This article discusses the problems of occupational safety and health, which are covered by health sciences and environmental engineering.