National Toxicology Program

The nomination of the methylolurea class compounds by the NIEHS for testing is based on high production volumes (including urea-formaldehyde resins which contain methylolurea or dimethylolurea as impurities), the potential for human exposure, and the lack of data on carcinogenicity.

Methylolurea monomers are available as soft pastes containing 55-65% active ingredient. Asulgan® K and Kaurit® S contain about 82% dimethylolurea and 15% methylolurea. Technical grade and photographic grade dimethylolurea is available from BASF Corp. 1,2-Dimethylol-4,5-dihydroxyethyleneurea (DMDHEU) is produced commercially in the United States by three companies. No additional data on companies producing methylolurea class compounds were found.

No production data were found on the separate methylolurea class compounds. Several sources did, however, list production volumes of urea-formaldehyde resins, some of which contain at least 10% of methylolurea or dimethylolurea as impurities. In 1994 and 1995, 1.91 and 1.84 billion lb. (866,185 and 834,440 metric tons [Mg]), respectively, of urea-formaldehyde resins were produced in the U.S. About ninety-five percent of particle board products are based on urea-formaldehyde resins while approximately 80% of the slow-release fertilizer market is based on urea-formaldehyde-containing products. The potential exists for occupational exposure to methylolurea or dimethylolurea during the production of urea-formaldehyde resins, and from the use of any products containing such resins (e.g., pressed wood products, dinnerware, foundry core binder, flexible foams, insulation materials, slow-release fertilizers).

Methylolurea is used in treating textiles and wood, and is mixed with fillers and used in molding adhesives. Dimethylolurea is currently used as a preservative in metal-working fluids (cutting fluids), as a developer of photographic film, and as a cleaning agent and disinfectant. In 1980, the main use of dimethylolurea was in textiles, with 30% of the durable press fabrics being finished with dimethylolurea. By 1990, the percentage of dimethylolurea used in durable press fabrics had dropped to 6% since this compound was found to release more formaldehyde than other durable press resins. Due to its lower release of formaldehyde, DMDHEU is the primary durable press resin currently used in cotton-containing textiles in the U.S. Human exposure to DMDHEU occurs primarily as a result of the preparation of or the wearing of DMDHEU-treated permanent-press fabrics.

DMDHEU is well absorbed by the skin and from the gastrointestinal tract. More than 90% of DMDHEU is excreted unchanged in the urine within 24 h. In rabbits receiving dermal applications of fabrics treated with DMDHEU prepared from [¹⁴C]-formaldehyde, DMDHEU had absorption, distribution and excretion characteristics similar to those of topically applied formaldehyde. In rats exposed to N-methyl-N'-(hydroxy-methyl)thiourea, a bactericide used in humans for the treatment of peritonitis and infections of the bladder and uterus, both methylolurea and dimethylolurea were identified in the urine.

In acute toxicity tests with a spray dried urea-formaldehyde powdered glue containing as much as 10% methylolurea, no deaths were recorded in rabbits dermally exposed to 2.2 g/kg (24.4 mmol/kg) of the glue. Similarly, in rats exposed for one hour via inhalation to 200 mg/L (2220 mmol/m³) of the glue, or in rats receiving a single dose of 5.2 g/kg (57.7 mmol/kg) of the glue by oral gavage, no increase in mortality was present. No irritation, injury, or ocular damage was observed among rabbits exposed in one eye to 0.1 g (1.1 mmol) of the glue.

In rats exposed via inhalation to an enriched atmosphere of DMDHEU for 8 h at room temperature, difficulty in breathing and irritation of the mucous membranes were observed. Severe skin irritation was observed in rabbits topically treated with 500 mg (2.81 mmol) DMDHEU for 24 h, and mild irritation was observed in the eyes of rabbits similarly treated. Another study, however, reported that an aqueous solution of DMDHEU was not irritating to the skin or eyes of rabbits.

The oral LD₅₀ for DMDHEU in rats was reported to be greater than 7500 mg/kg (>42.10 mmol/kg).

Male and female rats administered 1.0, 10.0, or 100.0 mg/kg (0.01, 0.08, 0.83 mmol/kg) dimethylolurea via an intragastric cannula for 14 consecutive days showed no significant exposure-related effects.

No treatment-related effects were found in mice and rats administered DMDHEU by oral gavage for 13 weeks at doses ranging from 1000 to 6000 mg/kg/day (approximately 2.32 to 13.94 mmol/kg/day of neat DMDHEU). The no observed effect level (NOEL) was 6000 mg/kg/day (13.94 mmol/kg/day of neat DMDHEU) in male and female mice and in female rats, and 1000 to 3000 mg/kg/day (2.32 to 6.97 mmol/kg/day of neat DMDHEU) in male rats.

DMDHEU, when dissolved in dimethyl sulfoxide and tested using the pre-incubation assay at doses up to 10,000 mg/plate (up to 23.24 mmol/plate of neat DMDHEU) in either the presence or absence of rat or hamster S9, was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98. However, when dissolved in water, it was mutagenic in strains TA100 (with either rat or hamster S9) and TA98 (without metabolic activation and with hamster S9). In Drosophila melanogaster, DMDHEU when administered in food at 60,000 ppm caused a significant increase in sex-linked recessive lethal mutations but not reciprocal translocations. Consistent with DNA crosslinking activity, treatment of human lymphocytes with dimethylolurea alone or in combination with methyl methanesulphonate (MMS) resulted in reduced DNA migration compared to untreated cells and MMS-treated cells, respectively, in the alkaline single cell electrophoresis (comet) assay.

Dimethylolurea and DMDHEU have been found to be causal agents in textile-related dermatitis.

No information on the methylolurea class compounds in regard to human toxicity, chronic animal toxicity, teratogenicity/embryotoxicity, carcinogenicity, or structure-activity relationships were located.