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

Abstract

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.

Polyisocyanates in occupational environments: A critical review of exposure limits and metrics

“…For example, the NOEL of pMDI (0.16 mg NCO/m 3 ) is similar to that for polymeric HDI (pHDI, biuret, and isocyanurate; NOAEL $0.65 mg NCO/m 3 ) [Pauluhn and Mohr, 2001;Pauluhn, 2002]. Animal toxicity data for other polyisocyanates, such as polymeric IPDI (pIPDI) and polymeric TDI (pTDI), are limited and it is difficult to draw any general conclusions for the whole class of polyisocyanates based on toxicity data of pMDI and pHDI.…”

“…Animal data suggests that there are some differences in toxicity between various isocyanates [Pauluhn et al, 1990[Pauluhn et al, , 1995Pauluhn and Eben, 1992;Pauluhn, 2000aPauluhn, , 2000bPauluhn, , 2002Pauluhn and Mohr, 2001]. With regard to diisocyanate monomers, the largest reported differences are for HDI versus MDI.…”

Critical analysis of biomonitoring endpoints for measuring exposure to polymeric diphenyl-methane-4,4'-diisocyanate (MDI) in rats: a comparison of markers of exposure and markers of effect

“…More details of the lavage technique have been published previously Pauluhn 2000aPauluhn , 2000b. Samples of bronchoalveolar lavage¯uid (BALF) were analysed for factors indicative of early response, which have proved useful in the context of inhalation studies with polyisocyanate aerosols Pauluhn and Mohr 2001;Pauluhn 2001). In the BAL, the following indicators of pulmonary eects were addressed:…”

Pulmonary irritant potency of polyisocyanate aerosols in rats: comparative assessment of irritant threshold concentrations by bronchoalveolar lavage

“…The NOAECs of 3-and 13-week inhalation studies with either HDI biuret or HDI isocyanurate were in the range of 3-4 mg m −3 (Pauluhn & Mohr, 2001) whereas the acute NOEC and NOAEC of the HDI isocyanurate (compound IV) were Figure 10. Analysis of data of rats exposed to the aerosol of substance X (see Table 1).…”

“…3465 (1998) and that similar particle sizes were evaluated for all substances (Table 1). The comparisons included published data from single (Pauluhn 2000a(Pauluhn ,b, 2002 and repeated inhalation studies with aerosols of polymeric methylene diphenyl-4,4′-diisocyanate (MDI) and hexamethylene 1,6-diisocyanate (HDI) homopolymers in rats (Pauluhn et al, 1999;Pauluhn & Mohr, 2001). Particular attention was directed towards biomarkers in BALF that probe for changes indicative of irritant-related, functional impairments of the blood/air barrier, including an analysis of the time course of effects and their concentration dependence.…”