Дифенилметандиизоцианат синоним

Uses

4,4′-Methylenediphenyl diisocyanate (MDI) is used to produce polyurethane foams.

Background Information

MDI is a light-yellow fused solid or it may occur in crystalline form.

Exposure Routes and Pathways

Inhalation and dermal exposure can occur during the manufacture and use of MDI. Workers and individuals in close proximity to the plant may inhale emissions from urethane foam production manufacturing facilities.

Acute and Short-Term Toxicity (or Exposure)

Acute inhalation exposure may result in sensitization and asthma in humans. Dermal contact with MDI resulted in dermatitis and eczema in plant workers. Animal studies revealed skin and eye irritation in rabbits, extreme toxicity by inhalation and moderate toxicity by oral ingestion in rodents.

Chronic Toxicity (or Exposure)

Chronic inhalation exposure to MDI is one of the leading causes of asthma in plant workers. In addition, chronic inhalation exposure can cause dyspnea, immune disorders as well as nasal and lung lesions. EPA has set the RfC for MDI at 0.0006 mg m⁻³ based upon irritation of nasal membranes in rodents. EPA has not established an RfD for MDI.

Reproductive Toxicity

No information is available in the reproductive or developmental effects of MDI in humans; however, some effects (decreased placental and fetal weights and increased skeletal variations) were noted in a rat study.

Carcinogenicity

No information is available on the carcinogenic effects of MDI in humans. Animals exposed to polymeric MDI were reported to increase the incidence of pulmonary adenomas. EPA has classified MDI as a group D (not classifiable as to human carcinogenicity).

Exposure Standards and Guidelines

The (US) OSHA PEL 8 h TWA is 0.02 ppm (0.2 mg m⁻³). The (US) NIOSH REL is 0.005 ppm (0.05 mg m⁻³) as a 10 h TWA, and the NIOSH IDLH value is 75 mg m⁻³.

6.7.1 Asthma

Little is known about the role of DBP in children with asthma. A small cross-sectional study showed significantly higher DBP levels in bronchoalveolar lavage fluid of children with severe therapy-resistant asthma as compared with those in moderate asthma and control individuals. DBP levels in bronchoalveolar lavage fluid correlated with asthma severity, as assessed by the asthma control test, spirometry, and usage of inhaled corticosteroids. Excessive DBP in the airway may limit vitamin D bioactivity with potential immunological consequences. Due to the stimulated chemotactic functions of monocytes and neutrophils and together with the macrophage-activating factor, DBP can drive excessive airway alveolar macrophages into a more inflammatory state, diverting them from their tolerogenic role. However, a raised airway DBP level can also be a reflection of a chronic inflammation in the airway [158].

Isocyanate-induced occupational asthma is the most frequent cause of occupational asthma worldwide. Proteomic analysis with bronchoalveolar lavage fluid showed an upregulation of DBP expression in patients with diphenyl-methane diisocyanate occupational asthma [159]. Serum DBP level may be used as a useful serological marker for the detection of isocyanate-occupational asthma among workers exposed to isocyanate and for prediction of the severity of airway hyperresponsiveness, with a sensitivity of 69% and specificity of 81% [160]. DBP is associated with immune modulation of T helper 2-mediated inflammation, influencing the susceptibility to asthma [161]. In addition, the presence of megalin in the alveolar epithelial cells may mediate the endocytic uptake of 25-hydroxyvitamin D-DBP complexes. After uptake, 25-hydroxyvitamin D dissociates from DBP and is metabolized to 1,25-dihydroxyvitamin D [162]. Exposition to toluene diisocyanate may lead to higher DBP levels in bronchoalveolar fluid by suppressing megalin expression in lung alveolar cells [160].

In a Chinese case–control cohort of asthma consisting of 467 cases and 288 unrelated healthy controls, the DBP SNPs rs4588 and rs7041 were significantly associated with the risk of asthma and the DBP1 allele might confer a protective effect (OR: 0.65). No significant association with serum 25-hydroxyvitamin D levels was found, which could be explained by the influence of several genetic loci on the 25-hydroxyvitamin D concentration [163].

6.7.2 Chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is associated with low serum levels of 25-hydroxyvitamin D, which are correlated with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) [164,165]. Genetic association studies have demonstrated a link between the DBP gene and COPD-related phenotypes [166]. DBP has the potential to influence the respiratory function by determining vitamin D bioavailability and via direct effects on innate cell function (neutrophil chemotaxis and macrophage activation). More specifically in the presence of high serum DBP levels, a decreased lung function, expressed as a lower FEV1, has been observed (which is in contrast to the vitamin D status) and high airway DBP concentrations are associated with an increased macrophage activation [167].

Differences in vitamin D level are determined by the underlying DBP genotypes and subjects with a DBP2 allele exhibit a decreased risk of COPD. Although the DBP1F allele has no effect on the age of onset of COPD, the annual decline in FEV1 is significantly higher in Asian subjects [168,169]. The DBP1S variant is not associated with COPD in any racial population [170]. Although variants in the sugar structure of DBP have been proposed to explain the observed differences between the DBP phenotypes, differences in conversion to the macrophage-activating factor are probably much more important [171]. DBP2 is less able to be converted to DBP-MAF, resulting in a reduced macrophage driven parenchymal inflammation and destruction [167]. The protective effect of DBP2 has been confirmed in the Han population of north-east China [172]. However, α1-antitrypsin deficiency patients carrying a DBP2 allele have an increased risk of bronchiectasis, which could be explained by a reduced ability to defend the airway against pathogens [167]. Significant associations have been seen between SNPs rs17467825 and rs1155563 of the DBP gene and FEV1% predicted and FEV1/FVC [166].

6.7.3 Cystic fibrosis

Cystic fibrosis is an autosomal recessive condition, characterized by a vicious circle of progressive inflammation of lung and pancreas, leading to malnutrition and early death. DBP has been proposed as a sensitive marker (T½ = 2.5 days) for nutritional status (especially for lipids), being an integral part of an overall assessment program in cystic fibrosis [173]. Significantly lower mean DBP concentrations have been reported in the sera of cystic fibrosis patients, compared with heterozygotes and controls [173,174]. Lower serum DBP values may point toward a lower lipid absorption or hypolipoproteinemia. In cohort study of 116 cystic fibrosis patients, a strong correlation between serum DBP concentration and lipid parameters [serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, triglycerides, and leptin concentration] was demonstrated. This finding was supported by precipitation experiments of VLDL and LDL, which showed a partial coprecipitation of DBP, VLDL, and LDL particles. This suggests a partial presence of DBP as an LDL- and VLDL-bound plasma protein. In a similar way, serum DBP concentration correlated with serum α-tocopherol concentration. Decreased vitamin E levels and a disturbed fat malabsorption are observed in cystic fibrosis. Serum α-tocopherol strongly correlated with total lipids and serum β-lipoprotein concentrations, as it is mainly transported through VLDL and LDL particles [175].

6.7.4 Tuberculosis

In a case–control study (544 adult tuberculosis patients, 400 controls), the DBP2-2 phenotype was strongly associated with susceptibility to active tuberculosis in Gujarati Asians, compared with the DBP1-1 group (OR 2.81, 95% CI: 1.19–6.66; p = 0.009). However, this association was only observed in patients with profound vitamin D deficiency and was lost when the serum 25-hydroxyvitamin D concentration was > 20 nmol/L [176]. Vitamin D deficiency decreases antimycobacterial immunity [177] and vitamin D-deficient carriers of the DBP2 allele may have particularly low circulating concentrations of the 25-hydroxyvitamin D–DBP complex [2]. Carriage of the DBP2 allele was also associated with increased purified protein derivate of tuberculin-stimulated IFN-γ release in Gujarati Asian tuberculosis contacts. This finding suggests that in comparison with DBP2 allele carriers, DBP1 homozygotes are relatively resistant to acquisition of latent tuberculosis infection. The association might be consistent with the reduced ability of DBP2 to convert DBP to DBP-MAF. No association between the DBP phenotype and susceptibility to tuberculosis was observed in the other studied populations in Rio de Janeiro, Cape Town [176], Kuwait [211], India [212], which had a lower DBP2 frequency and a low prevalence of vitamin D deficiency [176].

6.7.5 Acute lung injury

Diffuse alveolar damage with neutrophils, macrophages, and protein-rich edema fluid in the alveolar spaces, together with capillary injury and disruption of the alveolar epithelium are the pathological characteristics of acute lung injury [171,178]. Although there is a lack of candidate gene studies relating to the vitamin D axis, patients with adult respiratory distress syndrome exhibited decreased serum DBP concentrations [179]. The massive cellular injury is associated with the liberation of large amounts of actin in the extravascular space and with an increased formation of DBP–actin complexes [171].

2.06.4.2.5(i) Polyester urethane

Shown in Figure 40 are two 2D ¹H–¹H slices from 3D TOCSY-HSQC spectrum at different ¹³C chemical shift of 63.2 (Figure 40(a)) and 60.2 ppm (Figure 40(b)). The former corresponds to a segment from the TOCSY plane at the chemical shift of ¹³C attributed to e-e CH₂O groups, and the latter corresponds to a segment from the TOCSY plane at the chemical shift of ¹³C from e CH₂OH groups. Ordinarily, the 3D-TOCSY-HSQC spectrum will contain TOCSY planes at the shifts of each proton-bearing carbon. These TOCSY planes will contain a diagonal peak in which the proton chemical shifts correspond to the shift of the ¹H attached to that ¹³C, and off-diagonal crosspeaks from other ¹H atoms that are part of the same ¹H spin system. In the case of symmetric structures such as butanediol, it becomes impossible to distinguish a diagonal peak as the original source of magnetization for TOCSY transfer, from a crosspeak arising because the spin is the destination of TOCSY transfer down the chain of coupled spins.

In the version of the 3D TOCSY-HSQC experiment used by LeMaster and co-workers, they suppress the signals from the source ¹H–¹³C pair, which usually produces diagonal peaks in the ¹H–¹H TOCSY dimension. Since they did not decouple ¹³C in the f₁ dimension, the trace doublet flanking the intense crosspeak (at 4.0/4.0 ppm) at the bottom of Figure 40(a) is the residual signal from incomplete suppression of magnetization derived from e-e ¹³CH₂O groups. The doublet confirms the identity of this signal component in the 3D-NMR spectrum. The strong signal at 4.0/4.0 ppm is the consequence of signal initially derived from e-e CH₂O– groups, and ultimately transferred through TOCSY mixing to e-e ¹³CH₂O– groups at the other end of the internal butanediol unit (symmetric in all respects except for isotopic distribution). The strong crosspeak at (4.0, 1.6) ppm in Figure 40(a) is a signal produced by the magnetization transfer from two equivalent central methylene units of the internal butanediol to methylene group of –CH₂–OR of the butanediol unit.

The much weaker crosspeaks in Figure 40(b) were attributed to the lower occurrence of unsymmetrical CO₂CH₂CH₂CH₂CH₂OH chain-end groups. This region of the TOCSY plane was taken from the 3D spectrum, at the ¹³C chemical shift (60.2 ppm) of the terminal e –¹³CH₂OH group. The residual doublet from incomplete suppression of ¹³CH₂OH source magnetization (3.4/3.4 ppm) is not detected in this plot due to its much weaker intensity (lower occurrence of chain-end vs. backbone butanediol units). At the ¹H chemical shift of 3.4 ppm, crosspeaks are observed to 4.0, 1.6, and 1.45 ppm. These were attributed to TOCSY transfer to CH₂ groups α, β, and γ to the ester group, respectively.

Evidence for magnetization transfer within symmetric and asymmetric butanediol units are shown in Figure 41, where two ¹H–¹H TOCSY slices at different ¹³C chemical shifts were overlaid. The peaks in blue are from the f₂ plane at δ_C = 63.61 ppm and are attributed to urethane linked CH₂O groups; while those in green are from the f₂ plane at δ_C = 63.24 ppm and are attributed to ester linked CH₂O groups. The crosspeaks at (4.01, 4.01) and (4.09, 4.09) are derived from symmetric diester and diurethane-linked butanediol units, respectively, as the ¹H chemical shifts are the same in both the f₁ and f₃ dimensions. The crosspeaks at (4.04, 4.07) and (4.07, 4.04) are derived from asymmetric ester-urethane linked butanediol units.

The ultimate objective of the project was to measure the composition of 42 and to study the reaction kinetics of its hydrolysis. Since all of the resonances of this complex polymer were not resolved in the 1D-NMR spectra, these researchers resorted to integration of the crosspeak volumes in the 2D-HSQC spectra. They noted that a number of factors normally impede the use of 2D-NMR data for quantitative analysis. These included (1) variable polarization transfer efficiency due to a range of J couplings used for INEPT polarization transfer in the various stages of the HSQC pulse sequence; (2) resonance offset effects; (3) a range of ¹H T₁ causing differential saturation during the relaxation delay between transients; and (4) differential polarization transfer efficiencies due to variations in ¹H and ¹³C T₂’s. To this list, the effects of limited digital resolution on the accuracy of peak volume measurement must also be considered. The effects of digital resolution can easily be dealt with by increasing the number of sampled data points in the f₁ and f₂ dimensions, and extending the data set using numerical methods such as linear prediction and by zero filling.

The authors dealt with J coupling issue by comparing crosspeak intensities for CH₂ groups, which have a narrow range of couplings. They also noted that for this polymer, the range of chemical shifts was small 1.5 kHz for ¹³C, compared to an 18.5 kHz for the B₁ field created by the pulse. Thus, resonance offset errors were insignificant for this system. To correct for shorter ¹H T₁’s of the backbone relative to the chain-end groups, they collected two HSQC spectra with different relaxation delays. Based on the changes of the intensity ratios for the CH₂OR/CH₂OH they derived a 1.2 s difference in T₁’s and calculated a corrected intensity ratio, from volume integrals of peaks similar to those seen in Figure 39. They were less successful in deriving T₂ values and their influence on 2D-NMR peak volumes, but did estimate a small signal loss from T₂ relaxation of the backbone and chain-end groups. They estimated less than 10% error in their calculations.

Using the 2D-HSQC peak volumes from backbone e-e, e-u, u-e, and u-u –CH₂–OR correlations in Figure 39(a) and from chain-end e– and u–CH₂–OH correlations in Figure 39(b), they derived an internal –CH₂–OR/terminal –CH–OH peak volume ratio of 203:1. Similarly, the direct integration of crosspeak volumes in the spectrum shown in Figure 39(a) gave the monomer distribution ratio of 4.76:3.76:1.00 for butanediol:adipate:diphenylmethane units.

Arylamine chain-end groups were quantified by direct integration of the well-resolved ¹H 1D-NMR resonances from arylamine end groups. The resonances from –CH₂–COOH methylene chain-end groups were found to overlap with the tail of large –CH₂–COOR resonances in both the 1D- and 2D-NMR spectra (spectra not shown); the content of free acid end groups in the unhydrolyzed sample could not be determined independently from the NMR data. Ideally, the intensity increase between time points in the hydrolysis series should be identical for both the butanediol –CH₂OH group and –CH₂COOH group during solid-state hydrolysis of the polymer; the free –CH₂COOH end group in the unhydrolyzed sample was estimated as 10% of total end groups. From this, they were able to determine the ratio of hydroxyl/acid/arylamine end groups as 86.3/10/3.7. Having all these data, in hand, the M¯n of the starting polymer was estimated to be 40.2 kDa.

By measuring volume integrals from 2D-HSQC solution spectra of reaction aliquots, collected over a reaction time of 49 days, they were able to do an impressive job of monitoring the reaction kinetics for solid-phase hydrolysis of 42 at elevated temperature.