Environmental fate and toxicity testing typically requires knowledge of the water solubility of the test substances. Determining the solubility of aromatic diisocyanates in water poses great challenges because of their hydrophobic nature and water-reactivity. The reactive dissolution process is dynamic and the establishment of a steady-state equilibrium cannot readily be observed. In preparation of experimental work, computer simulation was used to derive and evaluate criteria that enable distinguishing homogeneous (i.e., substances would be fully dissolved in water) from heterogeneous (i.e., a separate organic phase would be present) conditions. The simulation utilized available kinetic information and models representing the main physical and chemical processes taking place. It was found that the transition to heterogeneous conditions (i.e., the exceedance of the solubility limit with increasing loading) can be identified by observing either a rapid decline in ultimate yield of the diamine hydrolysis product from near-stoichiometric to much lower values, or a decrease in rate of formation of the diamine hydrolysis product relative to its ultimate yield. The latter criterion is expected to be the more powerful indicator. These criteria can be used in future work to define and interpret an experimental program for determining solubility limits for aromatic diisocyanates or other poorly-soluble, water-reactive substances.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Performing risk assessments (RA) on household use of flexible polyurethane (PU) foams requires access to reliable data about emission and migration of potential diamine impurities. A toluene diisocyanate (TDI) and a methylene diphenyl diisocyanate (MDI) based foam were thermally treated to enable measurements on samples with defined concentrations of the corresponding diamines, toluene diamine (TDA), and methylene dianiline (MDA). The thermally treated foams used for emission testing contained up to 15 mg.kg^-1 of TDA and 27 mg.kg^-1 of MDA. Those used for migration testing contained 5.1 mg.kg^-1 of TDA and 14.1 mg.kg^-1 of MDA. Stability of the thermally generated diamines was sufficient for testing over a 37-day period. Analytical techniques that did not decompose the polymer matrix were applied. Emission rates for TDA and MDA isomers were less than the limit of quantitation (LOQ) of 0.008-0.07 μg.m^-2.h^-1. Migration was studied using samples of the same thermally treated foams over a 35-day period. Quantifiable migration of MDA from the MDI-based foam was only observed on Days 1 and 2. From Day 3 onward, migration rates were less than the LOQ. Quantifiable migration of TDA from the TDI-based foam rapidly decreased with time and was only observed on Days 1 thru 3. From Day 4 onward, migration rates were less than the LOQ. Theoretically, the migration rate should be inversely proportional to the square root of time (t) as t^-0.5. This relationship was confirmed by the experimental data and enables extrapolating migration values to more extended time periods to conduct RAs.

Isocyanates such as 1,6-hexamethylene diisocyanate (HDI), 4,4'-methylenediphenyl diisocyanate, and toluene diisocyanate are highly reactive compounds that have a variety of commercial applications, including manufacturing polyurethane foam, elastomers, paints, adhesives, coatings, insecticides, and many other products. Their primary route of occupational exposure is through inhalation. Due to their high chemical reactivity, they are toxic and have adverse effects at the cellular and subcellular levels, leading to irritative and immunological reactions associated with lung disease. High concentrations of isocyanates are strong respiratory irritants. Bronchial sensitization and asthma are among the major adverse clinical reactions associated with low-level chronic exposure to isocyanates. Albumin adducts have been linked to the mechanism of occupational asthma caused by isocyanates. Isocyanates react in vivo with albumin, which is recognized by the immune system. Albumin adducts of isocyanates trigger immune responses and are probably the antigenic basis for isocyanate asthma. Sensitization to isocyanates is the main pathway for adverse health effects. Therefore, markers for the biologically effective dose such as albumin adducts of HDI are needed. A new isocyanate adduct of HDI with lysine─N^ε-[(6-amino-hexyl-amino)carbonyl]-lysine (HDI-Lys)─was synthesized and characterized by ¹H-NMR, ¹³C-NMR, and mass spectrometry (MS). Appropriate internal standards─HDI-Lys-4,4'-5,5'-d₄ (HDI-d₄-Lys) and N^ε-[(7-amino-heptyl-amino)carbonyl]-lysine (Hep-Lys)─were synthesized to establish a LC-MS/MS method for the analysis of HDI adducts in in vitro modified albumin and in workers. The presence of HDI-Lys was found after pronase digestion of albumin and confirmed by two independent chromatographic approaches: with a C8 reversed-phase column and with a hydrophilic interaction liquid chromatography column. Quantification was performed with positive electrospray ionization (ESI)-MS. The adduct peak found in vivo was confirmed with the less sensitive negative ESI-MS. In summary, these are new compounds and methods to determine isocyanate-specific adducts with albumin in workers exposed to HDI.

The sensitization potencies of twenty custom-designed monomer-depleted polymeric polyisocyanate prepolymer substances and their associated toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI), and isophorone diisocyanate (IPDI) monomer precursors were investigated by means of the mouse Local Lymph Node Assay (LLNA). These polymeric prepolymers were designed to represent the structural features and physical-chemical properties exhibited by a broad range of commercial polymeric polyisocyanate prepolymers that are produced from the reaction of aromatic and aliphatic diisocyanate monomers with aliphatic polyether and polyester polyols. The normalization of LLNA responses to the applied (15-45-135 mM) concentrations showed that the skin sensitization potency of polymeric polyisocyanate prepolymers is at least 300 times less than that of the diisocyanate monomers from which they are derived. The sensitization potency of the prepolymers was shown to be mainly governed by their hydrophobicity (as expressed by the calculated octanol-water partition coefficient, log K_ow) and surfactant properties. Neither hydrophilic (log K_ow <0) nor very hydrophobic (log K_ow >25) prepolymers stimulated lymphocyte proliferation beyond that of the dosing vehicle control. The findings of this investigation challenge the generally held assumption that all isocyanate (-N=C=O) bearing substances are potential skin (and respiratory) sensitizers. Further, these findings can guide the future development of isocyanate chemistries and associated polyurethane applications toward reduced exposure and health hazard potentials.