Determination of isocyanates in working atmospheres by high speed liquid chromatography

Dunlap, Kenneth L.; Sandridge, R. L.; Keller, J. U.

doi:10.1021/ac60367a043

Cited by 92 publications

(33 citation statements)

References 3 publications

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“…Exposure atmospheres of TRIDI were characterized using the nitro-reagent derivatization technique as described by Dunlap et al (1976), which collects both the liquid and the vapor phase. Details of the analytical method have been published previously (Pauluhn 2000a).…”

Section: Characterization Of Exposure Atmospheresmentioning

confidence: 99%

Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization

Pauluhn

2004

Archives of Toxicology

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Current testing conventions for inhalation toxicity studies require that solid and non-volatile liquid compounds are converted to respirable aerosol, which is often achieved by laboratory-specific technical methodologies. So far, internationally harmonized approaches are lacking that would allow comparison of results from inhalation studies with 'contrived' test aerosols taking into account the actual particle size of the product as it might be encountered in normal handling and use. The focus of this paper is to consider aerosols of irritant substances eliciting their mode of action on sites of initial deposition within the respiratory tract of rats. Assessment is based on conventional endpoints, such as mortality (LC(50)), and sublethal endpoints that include an analysis for the concentration-effect relationship of protein in bronchoalveolar lavage fluid (BAL-protein) as a sensitive, early marker of lung edema. This retrospective analysis also addresses whether common denominators can be found for different aerosol sizes of direct and indirect irritants, such as monomeric and polymeric diphenylmethane-4,4'-diisocyanate (mMDI and pMDI), naphthylene diisocyanate (NDI), dicyclohexylmethane-4,4'-diisocyanate (HMDI), 2,4-triisopropyl-benzene-diisocyanate (TRIDI) and substances (e.g., chlorofluoroalkyl side-chain fungicides) known to decompose to irritant intermediates in the lining fluids of the airways. Collectively, this analysis shows that for irritant aerosols both the concentration and the particle size are equally important for the outcome of the test, independent of whether the endpoint chosen is lethality or BAL protein. The scientific value of 1-h exposures to high aerosol concentrations, as required by some regulations, could be challenged because high concentrations and high respirability of aerosol appear to be mutually exclusive, as shown for mMDI and NDI (LC(50 )>2000 mg/m(3)). Thus, for a meaningful risk characterization, test results from inhalation studies with 'contrived properties' due to the specific techniques employed need to be compared with the real properties of substances as marketed, handled and used.

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Section: Characterization Of Exposure Atmospheresmentioning

confidence: 99%

Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization

Pauluhn

2004

Archives of Toxicology

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“…Details of the nose-only exposure systems used have been published elsewhere (Pauluhn, 1984(Pauluhn, , 1988(Pauluhn, , 2000aPauluhn & Eidmann, 2001). Exposure atmospheres were characterized using the nitro-reagent derivatizatio n technique (Dunlap et al, 1976;Pauluhn, 2000a). Whenever technically feasible, samples were taken from the vicinity of the breathing zone of the rats one to three times per exposure day for nitro-reagent analyses.…”

Section: Experimental Design Exposure Technique Aerosol Generation mentioning

confidence: 99%

INHALATION TOXICITY OF 1,6-HEXAMETHYLENE DIISOCYANATE HOMOPOLYMERS (HDI-IC AND HDI-BT): Results of Subacute and Subchronic Repeated Inhalation Exposure Studies

Pauluhn¹,

Möhr²

2001

Inhalation Toxicology

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This article addresses results of two 13-wk inhalation toxicity studies in Wistar rats with aerosolized 1,6-hexamethylene diisocyanate (HDI) homopolymers using either the isocyanurate (HDI-IC) type or biuret (HDI-BT) type. Groups of 10 rats/sex/level were exposed nose-only to breathing zone concentrations of 0.5, 3.3, and 26.4 mg HDI-IC/m(3) or 0.4, 3.4, and 21.0 mg HDI-BT/m(3) (MMAD = 1.4-3.3 microm). The exposure regimen was 6 h/day, 5 days/wk for 13 wk. Two control groups were used in each study; one was exposed to filtered air, and the other to the vehicle acetone. In subacute pilot studies, groups of rats were exposed under identical conditions for 3 consecutive weeks using concentrations of approximately 4, 15-18, and 77-90 mg homopolymer/m(3). All studies demonstrated that adverse effects were caused by irritation-related responses occurring predominantly in the lower respiratory tract. Following subchronic exposure, compound-related effects were found only at the highest concentrations used and were confined to mild respiratory distress, marginally decreased body weights, and increased lung weights. Hematological evaluation showed a marginal increase in leukocyte counts. Pulmonary function testing revealed minimal changes indicative of increases in functional residual capacity and total lung capacity but without evidence of increased bronchial hyperreactivity to acetylcholine aerosol. Histopathology demonstrated an increased recruitment of alveolar macrophages, focal interstitial fibrosis with round-cell infiltrations, and bronchiolo-alveolar proliferations at the high-level exposure groups. The no-observable-adverse-effect levels (NOAELs) of both the 3- and 13-wk studies were in the range of 3-4 mg/m(3). Appreciable differences between the two types of polyisocyanates were not observed.

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“…For gravimetric determinations, glass-fiber filters were used (SM 13400, Sartorius, Göttingen, Germany). For isocyanate-specific determinations, two in-line connected tubes packed with glass-powder-filled sampling tubes containing the derivatizing agent N-4-nitrobenzyl-N-n-propylamine were used, according to the method published by Dunlap et al (1976). The resultant urea derivative was subsequently extracted using acetonitrile (Baker, HPLC gradient grade) and analyzed by high-performance liquid chromatography (HPLC).…”

Section: Inhalation Exposure Techniquementioning

confidence: 99%

Respiratory Hypersensitivity to Diphenylmethane4,4'-Diisocyanate in Guinea Pigs:comparison With Trimellitic Anhydride

Pauluhn

Dearman²,

Doe³

et al. 1999

Inhalation Toxicology

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Published evidence demonstrates successful induction and elicitation of respiratory hypersensitivity in guinea pigs by the known human respiratory allergens trimellitic anhydride (TMA) and diphenylmethane-4,4'-diisocyanate (MDI). From these data it is apparent that TMA-related respiratory hyperresponsiveness can be elicited readily in guinea pigs upon inhalation challenge with the free chemical. Despite the interlaboratory variability in methodological procedures used for the sensitization as well as elicitation of response and the wide range of concentrations of TMA employed for challenge exposures (6-57 mg/m(3) air), TMA had been unequivocally identified as a benchmark respiratory sensitizer by measurements of the respiratory rate during challenge. The protocols were duplicated to examine the respiratory sensitizer MDI. In intradermally sensitized guinea pigs, changes in immediate-onset-like respiratory response were observed when MDI challenge concentrations exceeded approximately 30 mg MDI/m(3) air. Collective experimental evidence suggests that the respiratory responses observed upon challenge with TMA were markedly more pronounced and easier to identify than those recorded following challenge with MDI or MDI conjugate. In contrast to TMA, irritant concentrations of MDI had to be used to elicit any respiratory response and the differentiation of irritant and allergic responsiveness became increasingly difficult. Despite the absence of unequivocal changes in breathing patterns upon MDI challenge, MDI-sensitized animals displayed elevated anti-MDI immunoglobulin G1 (IgG1) antibodies, and a significant influx of eosinophilic granulocytes in the bronchial wall and lung-associated lymph nodes. Therefore, it is believed that the robustness of this animal model to identify low-molecular-weight agents as respiratory sensitizer is increased when several endpoints are considered. These are (1) positive respiratory response upon challenge with the hapten, and if negative, also challenge with the conjugate of the hapten; (2) an influx of eosinophilic granulocytes; and (3) increased specific IgG1 response. Furthermore, it appears that particles in the range of approximately 2-6 microm evoke more consistent respiratory response upon challenge exposure than particles in the 1-2 microm range.

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Determination of isocyanates in working atmospheres by high speed liquid chromatography

Cited by 92 publications

References 3 publications

Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization

Acute inhalation studies with irritant aerosols: technical issues and relevance for risk characterization

INHALATION TOXICITY OF 1,6-HEXAMETHYLENE DIISOCYANATE HOMOPOLYMERS (HDI-IC AND HDI-BT): Results of Subacute and Subchronic Repeated Inhalation Exposure Studies

Respiratory Hypersensitivity to Diphenylmethane4,4'-Diisocyanate in Guinea Pigs:comparison With Trimellitic Anhydride

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