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IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Some Aromatic Amines, Organic Dyes, and Related Exposures. Lyon (FR): International Agency for Research on Cancer; 2010. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 99.)

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Some Aromatic Amines, Organic Dyes, and Related Exposures.

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1Exposure Data

1.1. Chemical and Physical Data

1.1.1. Nomenclature

  • Chem. Abstr. Serv. Reg. No.: 101–14–4
  • CAS Name: 4,4′-Methylenebis(2-chlorobenzenamine)
  • Synonyms: Bis(4-amino-3-chlorophenyl)methane; bis(3-chloro-4-aminophenyl)methane; 4,4'-diamino-3,3′-dichlorodiphenylmethane; di(4-amino-3-chlorophenyl)methane; di(3-chloro-4-aminophenyl)methane; 3,3′-dichloro-4,4’-diaminodiphenylmethane; 2,2’-dichloro-4,4’-methylenedianiline; 4,4'-methylenebis(2-chloroaniline); 4,4’-methylenebis(ortho-chloroaniline); methylenebis(chloraniline);methylenebis(ortho-chloroaniline);methylenebis(3-chloro-4-aminobenzene); MOCA; MBOCA

1.1.2. Structural formula, molecular formula, and relative molecular mass

Image Eq8f_01.jpg

1.1.3. Chemical and physical properties of the pure substance (OSHA, 2009)

  • Description: Colourless to yellow or light brown crystalline solid with a faint amine-like odor
  • Melting-point: 110 °C
  • Solubility: Slightly soluble in water; soluble in diluted acids, diethyl ether, benzene, ethanol, and soluble to varying degrees in most organic solvents

1.1.4. Technical products and impurities

Pure 4,4′-methylenebis(2-chloroaniline) (MOCA) is a colourless crystalline solid. Historically, the technical grade of MOCA that is available in the United States came mainly from Japan in the form of tan/yellow fused prills or pastilles. The diamine purity is 99.8%, typically with 0.2% free ortho-chloroaniline (monomer) (ATSDR, 1994).

Trade names for 4,4′-methylenebis(2-chloroaniline) include: Bisamine A; Bisamine S; CPP 100; Cuamine M; Cuamine MT; Curene 442; Diamet Kh; Ihara Cuamine MT; Isocross SM; Millionate M; Pandex E; Pandex M 3202; Quodorole; SL 4037.

1.1.5. Analysis

Analyses of 4,4′-methylenebis(2-chloroaniline) were first reported in the 1970s. Two interesting recent studies have involved the use of gas chromatography/mass spectrometry to analyse water samples for the presence of 20 carcinogenic amines, and high-performance liquid chromatography in conjunction with UV detection to determine amine levels in extracts from toys, at ppm–ppb (10−6−10−9) concentrations (Garrigös et al., 2002; Doherty, 2005). Table 1.1 presents selected recent studies of the analysis of 4,4′-methylenebis(2-chloroaniline) in various matrices.

Table 1.1.. Selected methods of analysis of 4,4′-Methylene-bis(2-chloroaniline) (MOCA) in various matrices.

Table 1.1.

Selected methods of analysis of 4,4′-Methylene-bis(2-chloroaniline) (MOCA) in various matrices.

1.2. Production and use

1.2.1. Production

MOCA is produced commercially by reacting formaldehyde with ortho-chloroaniline. By-products such as trimers and tetramers—diamines with three- and four-ring structures joined by methylene groups—constitute up to 8–10% of commercial MOCA. 4,4′-Methylenebis(2-chloroaniline) comprises up to 90–92% of the commercial MOCA produced for coatings and cast polyuremanes. There is no commercial use for pure 4,4′-methylenebis(2-chloroaniline) other than for laboratory work (ATSDR, 1994).

Reports in early 1983 indicated that US manufacturers no longer produced MOCA and that any MOCA used in the USA is imported (NTP, 2005). Since the production of MOCA in the US ceased in 1982, the amount of MOCA imported into the US has increased from 1.5 million pounds in 1983 to approximately 2.0 million pounds in 1991. Most of the MOCA used in the US is manufactured in Taiwan, China, where the annual production is about 5000 to 10 000 tonnes (Chen et al., 2005).

Although production of MOCA ceased in the United Kingdom in 1987, the amount imported has increased from 90–120 tonnes in 1995 to more than 200 tonnes in 2006 (Cocker et al., 2009).

The USEPA (2003, 2007) Inventory Update Rule regulation requires manufacturers and importers of certain chemical substances listed in the TSCA Chemical Substance Inventory to report manufacturing information (aggregate production volumes) for chemicals manufactured (including imported) in amounts of 10 000 pounds or greater (in 1986) or 25 000 pounds or greater (in 2003) at a single site. Table 1.2 presents the aggregate production volumes that were reported for MOCA.

Table 1.2.. 4,4′-methylenebis(2-chloroaniline) (MOCA) production volumes.

Table 1.2.

4,4′-methylenebis(2-chloroaniline) (MOCA) production volumes.

Available information indicates that 4,4′-methylenebis(2-chloroaniline) was produced and/or supplied in the following countries: Germany; Hong Kong Special Administrative Region; Japan; the People’s Republic of China; South Africa; Switzerland; Taiwan, China; and the USA (Chemical Sources International, 2008).

1.2.2. Use

4,4′-Methylenebis(2-chloroaniline) (MOCA) is an aromatic amine used for curing epoxy resins. It is mixed with diisocyanate-based pre-polymer resins to produce tough, resistant polyurethane products (Cocker et al., 2009). The polyurethane prepolymers are used in the manufacture of castable urethane rubber products such as shock-absorption pads and conveyor belting (IARC, 1993). In the laboratory, MOCA is used as a model compound for studying carcinogens (NTP, 2005; O’Neil, 2006).

1.3. Occurrence and exposure

1.3.1. Natural occurrence

MOCA is not known to occur as a natural product.

In MOCA-contaminated soil, the compound is rapidly adsorbed to the soil matrix and probably exists largely in a covalently bound state (Voorman & Penner, 1986).

1.3.2. Occupational exposure

Occupational exposure to MOCA can occur during its production and during its use in the polyurethane industry. Workers can be exposed to MOCA in the form of a liquid emulsion, solid pellets with dust, or solid pellets without dust. In most cases, dermal absorption after contact with contaminated surfaces is the most important occupational exposure route, with inhalation and ingestion representing minor routes of exposure (IARC, 1993).

According to Rappaport and Morales (1979), in 1972 some 10 000 persons in industrialized countries were exposed occupationally to MOCA in the context of manufacturing and processing (Will et al., 1981).

The Health and Safety Executive (HSE) in the United Kingdom estimates that in 2005–2006, 300 workers in the United Kingdom were directly exposed to MOCA during polyurethane-elastomer production, and over 1000 workers such as office staff were indirectly exposed (HSE, 2007a).

Estimates of the number of workers in the USA potentially exposed to MOCA in 1977 ranged from 2100 to 33 000. In 1979 an estimated 1400 workers in the USA were directly exposed and 7400 indirectly exposed while working in polyurethane manufacturing processes involving MOCA (Ward et al., 1987). In 1982, the EPA estimated that 1400–2720 workers were directly exposed and 7600–15200 were indirectly exposed.

(a) Exposure measurements

Concentrations of MOCA in air, blood and urine and in surface-wipe samples have been reported for workers employed in the production and use of MOCA from a range of countries, including Australia, France, Germany, Japan, Taiwan (China), the United Kingdom, and the USA. Different analytical methods have been applied, which can complicate comparisons of reported MOCA levels (see Section 1.1.5).

Monitoring of airborne MOCA alone is considered ineffective in the assessment of worker exposure (Robert et al., 1999), and post-shift urine measurement is the most-employed method to assess exposure. Concentrations of MOCA in urine reflect recent exposure, since the biological half-life of this compound is approximately 23 hours (Osorio et al., 1990).

Some studies have determined urinary concentrations of acetyl-MOCA in addition to MOCA, showing that N-acetyl-MOCA is a minor urinary metabolite compared with the elimination of the parent amine (Cocker et al., 1988; Shih et al., 2007).

An alternative to measuring MOCA in urine is to determine the concentrations of haemoglobin adducts of MOCA in blood. These adducts are stable for the lifespan of haemoglobin, which in humans is about 120 days (Vaughan & Kenyon, 1996).

(b) MOCA-production workers

Air concentrations of MOCA have been reported from two MOCA-production plants. In a study from the USA (Linch et al., 1971), the airborne concentration of MOCA was below the detection limit (< 0.01 mg/m3). In a study from Taiwan, China (Chen et al., 2005), the highest concentrations in air were measured during the purification of MOCA (0.41 mg/m3).

Urinary concentrations of MOCA in production workers have been reported from France, Taiwan (China), and the USA; they are summarized in Table 1.3.

Table 1.3.. Urinary levels of MOCA in MOCA production workers.

Table 1.3.

Urinary levels of MOCA in MOCA production workers.

In a full-scale commercial MOCA-manufacturing plant in the USA, urinary concentrations as high as 3000 µg/L were reported for the year 1969 (Linch et al., 1971). The use of gloves and protective equipment such as suits and respirators was shown to lower exposure considerably.

During a biological monitoring programme in a French factory that periodically produces MOCA, urinary concentrations were reported to range from <0.5µg/L up to 1600 µg/L (Ducos et al., 1985).

In workers from a production plant in the USA, urinary concentrations of MOCA were measured several months after production had ceased. The maximum level measured was 50 000 µg/L (Ward et al., 1990). [The Working Group noted that the high exposure levels reported may be due to continued exposure to MOCA after its production had ceased, through workplace and environmental contamination].

In 10 workers from a MOCA-manufacturing plant in Taiwan, China (Liu et al., 2005), urinary concentrations ranged between 268 and 15701 µg/g creatinine (Table 1.3).

In another study from Taiwan, China (Shih et al., 2007), 54 urine samples were collected from workers in three MOCA-manufacturing factories. MOCA and acetyl-MOCA (N-acetyl-4,4’-methylenebis(2-chloroaniline)) were measured, with median values of 38.6 and 1.8 ng/mL, respectively. MOCA concentrations correlated significantly with the corresponding acetyl-MOCA concentrations in urine.

(c) Polyurethane production workers

Concentrations of MOCA have been measured in the urine of polyurethane-production workers from Australia, Canada, France, Germany, Japan, the United Kingdom and the USA; results are summarized in Table 1.4.

Table 1.4.. Urinary levels of MOCA in polyurethane production workers.

Table 1.4.

Urinary levels of MOCA in polyurethane production workers.

Five hours after an accidental spill of hot MOCA onto the face of a worker cleaning out a MOCA-delivery line in 1976, the urinary level of the exposed worker was 1400 µg/g creatinine (Hosein & Van Roosmalen, 1978).

MOCA concentrations were measured in 49 urine specimens from MOCA-exposed personnel of a plastics manufacturing and processing plant in Germany (Will et al., 1981). The concentrations ranged between 15–100 µg/L.

During a biological monitoring programme conducted in 1978–1981 in a factory in the United Kingdom that manufactured polyurethane elastomers by use of MOCA pellets, urinary MOCA concentrations were measured before and after introduction of safety measures (ventilation, protective doming, dry-cleaning scheme for overalls) (Thomas & Wilson, 1984). Concentrations dropped from an average of 50 nmol/mmol creatinine to less than 5 nmol/mmol creatinine.

More than 340 analyses were performed on urine samples from 150 workers from 19 polyurethiane factories in France (Ducos et al., 1985). In 17 factories where MOCA was used as solid pellets or in solutions for manufacturing a variety of products by coating, moulding or foaming urethane resins, mean concentrations of excreted MOCA in the urine of exposed workers varied from undetectable to 660 µg/L, with a maximum of 1600 µg/L (1540 µg/g creatinine). Process improvements resulted in a significant reduction in urinary MOCA concentrations, to averages of 20–62 µg/L.

The Michigan Department of Public Health tested urine samples of nine manufacturing workers, and reported MOCA concentrations ranging from 13 to 458 µg/L (mean, 145 µg/L) (Keeslar, 1986).

In a NIOSH study of mixers and moulders in a polyurethiane elastomer factory, MOCA urinary concentrations were increased during the week and dropped over the weekend (NIOSH 1986).

Between 1980 and 1983, 3323 urinary samples from 54 companies in the USA were analysed: MOCA concentrations exceeded 50 µg/L in 16.9% of the samples and exceeded 100 µg/L in 9.2% (Ward et al., 1987). In 1985, the urinary concentration exceeded 50 µg/L in 12% of all samples tested. In 1990, 8% of the samples showed concentrations that were still above that level (Lowry & Clapp, 1992).

Urinary MOCA concentrations were measured on a regular basis in seven factories in Australia that used MOCA from 1984 onwards (Wan et al., 1989). The measurements were done in five factories before and after a training programme promoting the safe use of MOCA; concentrations decreased from 29.6 µg/L to 10.4 µg/L.

In a study from Japan, MOCA urinary concentrations were measured in five workers over one week (Ichikawa et al., 1990). The concentrations at the beginning and the end of the workshift were 3.1–81.5 and 2.4–96.6 µg/g creatinine, respectively. The highest concentrations were measured for workers pouring the MOCA mix.

Following the accidental spill of MOCA onto the face of a polyurethiane worker, urinary MOCA concentrations reached 1700 ppb [µg/L] 4 hours after the accident (Osorio et al., 1990).

In 1986 a study was conducted at a company in the USA that used large amounts of MOCA in manufacturing polyurethane products (Clapp et al., 1991). Sixty-six percent of the urine samples had detectable levels of MOCA, and the highest concentration measured was 159 µg/L.

Urine samples were obtained from five workers involved in the production of polyurethane elastomers in Australia (Vaughan & Kenyon, 1996). The urine contained MOCA at 4.5–2390 nmol/L. Blood samples contained MOCA at 0.13–17.37 nmol/L.

In another study from Australia (Murray & Edwards, 1999), 12 workers in the manufacture of polyurethiane showed a median MOCA urinary concentration of 6.5 <mol/mol creatinine (range, 0.4–48.6 <mol/mol creatinine). MOCA was not detected in the urine of control workers.

In a study from France (Robert et al., 1999), postshift urinary MOCA concentrations were determined in 40 workers from four factories producing polyurethane resin. Workers exposed directly to crystallized MOCA on a daily basis had the highest concentration of MOCA in their urine, with a median value of 84 µg/L (49 µg/g creatinine). Concentrations by job category and trends between 1982 and 1996 were also reported (see Table 1.4).

In a small company manufacturing pliable polyurethane, urinary MOCA concentrations were determined (Fairfax & Porter, 2006). None of the 13 employees had detectable amounts of MOCA except the one who performed the urethane casting (15 µg/L total MOCA in urine). Personal air samples collected from the location where the urethane caster worked contained no detectable amounts of MOCA.

A survey of occupational exposure to MOCA in the polyurethane-elastomer industry in Great Britain conducted in 2005–2006 (HSE, 2007a) included 20 polyurethane elastomer manufacturers and two suppliers of MOCA. Urinary concentrations ranged between 1.3–25.0 µmol/mol creatinine.

(d) Occupational surface contamination

Studies from the United Kingdom and USA reported work-surface contamination in the polyurethane industry by determining MOCA concentrations in surface-wipe samples (Table 1.5).

Table 1.5.. MOCA levels in workplace surface wipe samples.

Table 1.5.

MOCA levels in workplace surface wipe samples.

Data from occupational health and safety inspections from 41 polyurethane-production facilities in the USA were assembled (PEDCo Environmental, 1984) and reported surface contamination at facilities using solid and liquid MOCA.

In 1986 a study was conducted at a company in the USA that manufactured polyurethane products and was a large user of MOCA (Clapp et al., 1991). Wipe sampling indicated moderate contamination of the workplace by MOCA dust, with averages up to 19 µg/100 cm2. The average MOCA concentration found on skin pads worn on workers’ hands was generally less than 10 µg/set, with a high of 25 µg/set.

In a small company manufacturing pliable polyurethane (Fairfax & Porter, 2006), the presence of MOCA on work surfaces was reported. Nine locations had non-detectable amounts of MOCA, including a desktop 15 feet from the urethane-casting area; the door handles of the mould oven, respirator locker, gloves locker and restroom; the top of an oven; the handle of the water dispenser in the breakroom; and the handle of a coffee mug. The top of a metal scale table had the highest amount, at 209.7 µg/m2.

In an occupational exposure survey conducted in 2005–2006 in the polyurethane-elastomer industry in Great Britain, contamination of various surfaces with MOCA was reported (HSE, 2007a). The amounts detected were similar for most surfaces. Contamination around the hopper was generally above that at the other sites, which was thought to be due to excess spillage of MOCA during hopper filling and failure to clean it up immediately.

1.3.3. Exposure to the general population

The general population can be exposed to MOCA in an area that has been contaminated with MOCA or upon consumption of certain types of plants (e.g. root crops) grown in MOCA-contaminated soil. Also, immediate family members of workers exposed to MOCA can be affected. Concentrations of MOCA in urine of up to 15 µg/L have been reported (Keeslar, 1986).

1.3.4. Accidental release of MOCA in the environment

Extensive environmental contamination with MOCA on several hundred hectares of land surrounding a MOCA plant occurred in 1979 in Adrian, MI, USA (Keeslar, 1986). Levels up to several milligrams per kilogram were found in gardens and community recreation areas. Of 12 selected children, aged 2 to 16 years, half were found to have detectable concentrations of MOCA ranging from 0.3 to 1.0 ppb [µg/L] in the urine. These children were all under the age of six years. Contact with contaminated soil during playing and going barefoot was considered the most likely route of exposure. The general adult population living within the MOCA-contaminated area had no detectable levels of MOCA in the urine samples tested.

The concentrations in sediment samples collected from the lagoon used by the MOCA plant mentioned above ranged from 1600 to 3800 ppm [mg/kg dry weight]. Effluent water from the lagoon had a concentration of 250 ppb [µg/L], deep-well water from under the plant had a concentration of 1.5 ppb [µg/L], and surface runoff water contained 1 ppb [µg/L]. Activated sludge from the sewage-treatment plant contained an estimated 18 ppm [mg/kg]. MOCA was not detected in sewage treatment-plant influent or effluent water (detection limit 0.5 µg/L) or in the water of a river located near the plant (detection limit 0.1 µg/L.) (Parris et al., 1980).

1.4. Regulations and guidelines

1.4.1. Europe

(a) Directive 97/56/EC

According to Directive 97/56/EC on the restrictions on the marketing and use of certain dangerous substances and preparations, the packaging of 4,4′-methylenebis(2-chloroaniline) and preparations containing this compound must be marked legibly and indelibly as follows: “Restricted to professional users” (European Commission, 1997).

(b) Directive 2002/61/EC

Directive 2002/61/EC restricts the marketing and use of azocolourants (European Commission, 2002). In this Directive, Annex I to Directive 76/769/EEC is amended. Azodyes which, by reductive cleavage of one or more azo groups, may release 4,4′-methylenebis(2-chloroaniline) (MOCA) in detectable concentrations, i.e. above 30 ppm in the finished articles or in the dyed parts thereof, according to the testing method established in accordance with Article 2a of this Directive, may not be used in textile and learner articles that may come into direct and prolonged contact with the human skin or oral cavity.

(c) Directive 2004/37/EC

4,4′-Methylenebis(2-chloroaniline) (MOCA) is regulated by the Directive 2004/37/EC (European Commission, 2004), which applies to activities in which workers are exposed to carcinogens or mutagens of Category 1 and 2. Rules are fixed regarding the employers’ obligations of reduction and replacement, prevention and reduction of exposure, unforeseen exposure, foreseeable exposure, access to risk areas, hygiene and individual protection, information for the competent authority, information and training of workers, consultation and participation of workers, health surveillance, record keeping and limit values.

1.4.2. Japan

The Japan Society for Occupational Health (JSOH; 2007) has reported an occupational exposure limit (OEL) value of 0.005 mg/m3 with a skin notation for 3,3′-dichloro-4,4′-diaminodiphenylmethane [MOCA]. An Occupational Exposure Limit based on Biological Monitoring (OEL-B) was mentioned of 50 µg/g-creatinine (total MOCA) in urine sampled at the end of the shift at the end of the work week. The JSOH follows the classification by IARC of 3,3′-dichloro-4,4′-diaminodiphenylmethane in Group 2A.

1.4.3. Germany

4,4′-Methylenebis(2-chloroaniline) (MOCA) is classified as a Category-2 carcinogen by the MAK Commission. The MAK Commission listed 4,4′-methylenebis(2-chloroaniline) as a substance where percutaneous absorption may significantly contribute to systemic exposure. A MAK value was not set (MAK, 2007).

1.4.4. USA

(a) ACGIH

4,4′-Methylenebis(2-chloroaniline) (MOCA) has been assigned an A2 notation, suspected human carcinogen (ACGIH, 2001). A TLV-TWA (threshold limit value-time-weighted average) of 0.01 ppm (0.11 mg/m3) is recommended. A skin notation is assigned (potentially significant contribution to the overall exposure by the cutaneous route) in recognition of the consensus that skin absorption from direct contact is the major source of occupational exposure. Implementation of a urine-monitoring programme to ensure the effectiveness of dermal exposure control is encouraged.

(b) NIOSH

4,4′-Methylenebis(2-chloroaniline) is listed with a TWA of 0.02 ppm (0.22 mg/m3) [skin] as a recommended exposure limit (REL) not in effect (NIOSH, 1989).

(c) NTP

4,4′-Methylenebis(2-chloroaniline) is listed in the NTP Report on Carcinogens as reasonably anticipated to be a human carcinogen (NTP, 2005).

1.4.5. United Kingdom

The Health and Safety Commission (HSE, 2007b) has set an 8-hour time-weighted average Workplace Exposure Limit (WEL) of 0.005 mg/m3 for 2,2′-dichloro-4,4′-methylenedianiline (MOCA), with a skin notation. HSE also lists MOCA as capable of causing cancer and/or heritable genetic damage, and has defined a Biological Monitoring Guidance Value (BMGV) of 15 µmol total MOCA/mol creatinine in urine sampled after the work-shift.

1.4.6. Other

(a) GESTIS

Table 1.6 presents some international limit values for MOCA (GESTIS, 2007).

Table 1.6.. International limit values (2007) for MOCA.

Table 1.6.

International limit values (2007) for MOCA.

©International Agency for Research on Cancer, 2010.
Bookshelf ID: NBK385412

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