Biological monitoring of isocyanates and related amines. IV. 2,4- and 2,6-toluenediamine in hydrolysed plasma and urine after test-chamber exposure of humans to 2,4- and 2,6-toluene diisocyanate.

Two men were exposed to toluene diisocyanate (TDI) atmospheres at three different air concentrations (ca. 25, 50 and 70 micrograms/m3). The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The effective exposure period was 4 h. The isomeric composition of the air in the test chamber was 30% 2,4-TDI and 70% 2,6-TDI. The concentration of TDI in air of the test chamber was determined by an HPLC method using the 9-(N-methyl-amino-methyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. Following the hydrolysis of plasma and urine, the related amines, 2,4-toluenediamine (2,4-TDA) and 2,6-toluenediamine (2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas chromatography using selected ion monitoring (SIM) in the electron-impact mode. In plasma, 2,4- and 2,6-TDA showed a rapid-phase elimination half-time of ca. 2-5 h, and that for the slow phase was greater than 6 days. A connection was observed between concentrations of 2,4- and 2,6-TDI in air and the levels of 2,4- and 2,6-TDA in plasma. The cumulated amount of 2,4-TDA excreted in the urine over 24 h was ca. 15%-19% of the estimated inhaled dose of 2,4-TDI, and that of 2,6-TDA was ca. 17%-23% of the inhaled dose of 2,6-TDI. A connection was found between the cumulated (24-h) urinary excretion of 2,4- and 2,6-TDA and the air concentration of 2,4- and 2,6-TDI in the test chamber.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological monitoring of isocyanates and related amines. III. Test chamber exposure of humans to toluene diisocyanate.

Five men were exposed to toluene diisocyanate (TDI) atmospheres for 7.5 h. The TDI atmospheres were generated by a gas-phase permeation method, and the exposures were performed in an 8-m3 stainless-steel test chamber. The mean air concentration of TDI was ca. 40 micrograms/m3, which corresponds to the threshold limit value (TLV) of Sweden. The inhaled doses of 2,4- and 2,6-TDI were ca. 120 micrograms. TDI in the test chamber air was determined by an HPLC method using the 9-(N-methylaminomethyl)-anthracene reagent and by a continuous-monitoring filter-tape instrument. After hydrolysis of plasma and urine, the related amines, 2,4- and 2,6-toluenediamine 2,4-, and 2,6-TDA), were determined as pentafluoropropionic anhydride (PFPA) derivatives by capillary gas-chromatography using selected ion monitoring (SIM) in the electron-impact mode. The urinary elimination of the TDAs showed a possible biphasic pattern, with rapid first phases for 2,4-TDA (mean t1/2 for the concentration in urine, 1.9 h) and for 2,6-TDA (mean t1/2 for the concentration in urine, 1.6 h). The cumulative amount of 2,4-TDA excreted in urine within 28 h ranged from 8% to 14% of the estimated dose of 2,4-TDI, and the cumulative amount of 2,6-TDA in urine ranged from 14% to 18% of the 2,6-TDI dose. The average urinary level of 2,4-TDA was 5 micrograms/l in the 6 to 8-h sample (range 2.8-9.6 micrograms/l), and the corresponding value for 2,6-TDA was 8.6 micrograms/l (range, 5.6-16.6 micrograms/l). Biological monitoring of exposure to 2,4- and 2,6-TDI by analysis of 2,4- and 2,6-TDA in urine is feasible.

Chromatographic determination of amines in biological fluids with special reference to the biological monitoring of isocyanates and amines. IV. Determination of 1,6-hexamethylenediamine in human urine using capillary gas chromatography and selective ion monitoring.

A capillary gas chromatographic (GC) method was developed for the determination of 1,6-hexamethylenediamine (HDA) in hydrolysed human urine. The method was based on a derivatization procedure with heptafluorobutyric anhydride. The amides formed were determined using capillary GC with selected ion monitoring in the chemical ionization mode with ammonia as reagent gas. The overall recovery was 34% for a concentration of 100 micrograms/l of HDA in urine. The minimum detectable concentration in urine was below 0.5 microgram/l. The precision of the method was 5% (n = 9). Deuterium-labelled HDA [H2NC2H2(CH2)4C2H2NH2] was used as the internal standard. A male subject was exposed to hexamethylene diisocyanate (HDI) for 7.5 h in a test chamber. The average air concentration of HDI was ca. 30 micrograms/m3, which corresponds to ca. 85% of the threshold limit value in Sweden (35 micrograms/m3). The half time of urinary levels of HDA was ca. 1.4 h and more than 90% of the urinary elimination was completed within 4 h after the exposure. The amount of HDA excreted in urine was ca. 10 micrograms, corresponding to ca. 10% of the estimated inhaled dose of HDI.

Biological monitoring of isocyanates and related amines. II. Test chamber exposure of humans to 1,6-hexamethylene diisocyanate (HDI).

Five male subjects were exposed to 1,6-hexamethylene diisocyanate (HDI) atmospheres for 7.5 h. The exposures were performed in an 8 m3 stainless steel test chamber, and the HDI atmospheres were generated by a gas-phase permeation method. HDI in air was determined by an HPLC method utilizing the 9-(N-methylaminomethyl)-anthracene reagent, and by a continuous monitoring device (MDA 7100). The average air concentration was ca 25 micrograms/m3, and the inhaled dose of HDI for the different subjects was estimated at ca 100 micrograms. The related amine 1,6-hexamethylene diamine (HDA) was after acid hydrolysis of urine and plasma, determined as a heptafluorobutyric derivative, by glass capillary gas-chromatography and selected ion monitoring (SIM), in a chemical ionization mode using ammonia as reagent gas. The cumulated urinary excretion of HDA during 28 h was 8.0 to 14 micrograms, which corresponds to ca 11 to 21% of the inhaled dose of HDI. The urinary level of HDA, in samples collected immediately after the end of the exposures, was on average 0.02 mmol/mol creatinine (range 0.01-0.03 mmol/mol creatinine). The urinary elimination was rapid, and half-time (t 1/2), for the concentration of HDA in urine, showed an average of 1.2 h (range 1.1-1.4 h). No specific IgE and IgG antibodies to HDI were detected before and after provocation; nor were spirometry or bronchial reactivity changed immediately and 15 h after provocation. Analysis of HDA in hydrolysed urine, as a marker of short-time exposure to HDI, is proposed.

Biological monitoring of isocyanates and related amines. I. Determination of 1,6-hexamethylene diamine (HDA) in hydrolysed human urine after oral administration of HDA.

1,6-Hexamethylene diamine (HDA), used as raw material in industrial manufacturing operations, was orally administered to six healthy volunteers. After acid hydrolysis of the urine by hydrochloric acid, HDA and the metabolite 6-aminohexanoic acid were quantified. HDA was determined as an ethyl-chloroformate derivative by capillary gas chromatography using thermionic specific detection (TSD), and 6-aminohexanoic acid was quantified by ion chromatography using the ninhydrin reaction. In nonhydrolysed urine, monoacetylated HDA (N-acetyl-1,6-hexamethylene diamine) and HDA, were verified as heptafluorobutyric anhydride derivatives by gas chromatography-mass spectrometry (GC-MS), in a chemical ionization mode using isobutane and ammonia as reagent gases. In hydrolysed urine, a mean of 0.28 mg (range 1-6%) of the administered dose (8.2 mg) was recovered as HDA, and a mean of 0.8 mg (range less than 1-27%) as 6-aminohexanoic acid. The urinary excretion of both the determined compounds was rapid, and the principal part (greater than 90%) of the elimination was completed within 10 h. There was a considerable inter-individual variation in the excreted amounts, but the intra-individual variation in the excretion of HDA was limited. The subjects N-acetylator phenotype was determined by a dapsone test. Three slow acetylators excreted lower amounts (mean 2% of given dose) of HDA than three rapid ones (mean 5%).

Test atmospheres of diisocyanates with special reference to controlled exposure of humans.

An all glass apparatus for the generation of air concentrations of 2,4-toluene diisocyanate (2,4-TDI), 2,6-toluene diisocyanate (2,6-TDI) and 1,6-hexamethylene diisocyanate (HDI) was developed. The generation principle was based on gas-phase permeation with permeation membranes of silicon rubber. In an 8 m3 stainless steel test chamber, low and steady TDI-and HDI atmospheres (1-100 micrograms/m3) could be maintained. The diisocyanate concentrations were determined by an HPLC method, using the 9-(N-methylaminomethyl)-anthracene reagent utilizing UV detection. The sum of diisocyanates and their related amines were determined by sampling in 0.4 M hydrochloric acid solution, and analysis by capillary gas chromatography with thermionic specific detection. Related amines were determined by sampling in ethanol - 0.2% KOH and analysis on GC-TSD. A continuous band-tape monitor was used for the determination of diisocyanates. Losses of diisocyanates in the test chamber were evaluated by measuring the TDI and HDI concentrations at the inlet respectively the outlet of the test chamber. At the outlet of the test chamber, ca 25% of the TDI respectively HDI concentrations were recovered. With a male subject in the test chamber ca 15% of the HDI concentration was recovered. The air flow through the test chamber was ca 10 m3/h. The changes in isomeric composition of airborne TDI, at stopped flow conditions, showed that the decay of the 2,4-isomer was faster than of the 2,6-isomer. No trace of the related amine toluene diamine (TDA) was detected in the test chamber, at TDI concentrations ranging from 20 to 50 micrograms/m3. Sampling losses due to sampling connections were evaluated.(ABSTRACT TRUNCATED AT 250 WORDS)