HDI Polyisocyanates: Toxicity and Airborne Concentration Guidelines

1. HDI Polyisocyanates: Toxicity and Airborne Concentration Guidelines Painting Issues in the Aerospace Industry: RT244 2000 AIHCE

2. Chemical Structures • Hexamethylene Diisocyanate(HDI) Monomer • HDI Biuret (Polyiso) • Commercial product contains higher mol. wt. oligomers and a small percentage of residual HDI monomer

3. Chemical Structure • HDI Isocyanurate Trimer (Polyiso) • Commercial product contains higher mol. wt. oligomers and a small percentage of residual HDI monomer

4. Molecular Weight and Vapor Pressure

5. Typical 2-Component PU Paint Formulations

6. Volatility • HDI polyisocyanate is essentially non-volatile at room temperature • Even at oven temperatures up to 300 F no airborne polyisocyanate was found • Airborne HDI polyisocyanate found only during spray application

7. Inhalation Exposure Potential

8. During Paint Application • Potential for inhalation of HDI monomer is low (spray or non-spray) • Potential for inhalation of HDI polyiso can be high during spray application • Not surprising since there is typically 62-500 times more polyiso than monomer in the mixed paint

9. Why Study Polyisocyanate Toxicity and Exposure? • In 2-component (2K) PU paints used as topcoats in the aerospace industry, there is isocyanate present during application • Spraying is most common method • Most of isocyanate groups are on polyiso • Spray painter’s most significant isocyanate exposure potential is to polyiso aerosol

10. Purpose • To describe the selection criteria for toxicity studies to be used in this evaluation and • To provide a brief description of the studies and the biologic endpoint selected.

11. Selection Criteria for Toxicity Studies • Test substance is HDI monomer or HDI polyisocyanate and not paint formulations • Common test species across studies • Route of exposure is inhalation • Repeated exposure designs preferred to acute exposure • Comparable duration of exposure with analytically determined exposure concentrations • Multiple concentrations (dose response) • Studies with No-Observed-Adverse-Effect-Level • Relevance to potential worker exposures

12. Subchronic Toxicity Study Design • Exposure Regimen: • 6h/day, 5d/wk for 13 wks • Exposure Atmosphere Characterization • Air Concentration • Vapor: N-4-nitrobenzyl-N-n-propylamine in midget impingers in series; HPLC quantification • Aerosol: Filtration; nitro-reagent reaction and HPLC quantification

13. Subchronic Toxicity Study Design (continued) • Exposure Atmosphere Characterization • Particle Size Distribution • Laser velocimetry • Cascade impactor • gravimetric • chemical analysis

14. Subchronic Toxicity Study Endpoints • In-life • Body weights • Clinical signs • Urinalysis • Hematology • Clinical chemistry • Post-sacrifice • Gross pathology • Organ weights • Complete histopathology

15. Subchronic Inhalation Toxicity Study with HDI Monomer • Test species: Fischer 344 rats • Exposure regimen: 0, 0.01, 0.04 & 0.14 ppm vapor • Findings: Ocular irritation only during exposure; histopathologic lesions of nasal cavity • Target organ: Respiratory tract • NOAEL: *0.005 ppm or 0.034 mg/m3 (*Estimated from subacute and chronic studies) • Source: Shiotsuka, R.N., 90-day inhalation toxicity study with 1,6-hexamethylene diisocyanate (HDI) in rats, Bayer Corp., 1988.

16. Subchronic Inhalation Toxicity Study with Biuret-type HDI Polyisocyanate • Test species: Wistar rats • Exposure regimen: 0, 0.4, 3.5 & 21 mg/m3; aerosol • Particle size distribution: 1.4 - 3.3 um MMAD • Findings: increased lung wts; proliferative lesions in lower lung with septal thickening • Target organ: Respiratory tract • NOAEL: 3.4 mg/m3 • Source: Pauluhn, J., Desmodur N 3200, Untersuchsungen zur subchronischen inhalationstoxizitat an der ratte nach OECD-richtline No. 413, Bayer AG, 1988.

17. Subchronic Inhalation Toxicity Study with Isocyanurate Polyisocyanate • Test species: Wistar rats • Exposure regimen: 0, 0.5, 3.3 & 26.4mg/m3; aerosol • Particle size distribution: 1.5 um MMAD • Findings: clinical signs, increased lung wts, flow obstruction in pulmonary function tests, pulmonary fibrosis • Target organ: Respiratory tract • NOAEL: 3.3 mg/m3 • Source: Pauluhn, J., Desmodur N 3300, Study of the subchronic inhalation toxicity to rats in accordance with OECD Guideline No. 413, Bayer AG, 1987.

18. Discussion/Summary of Toxicity Studies • All subchronic studies showed compound-related effects due to sequalae of repeated acute irritation • Respiratory tract was the target organ • Based on mass concentration, the NOAELs for the HDI monomer (0.034 mg/m3) was approximately two orders of magnitude lower than that for the polyisocyanates of HDI (range: 3.3 to 3.4 mg/m3)

19. History of Polyiso Tox. And Exp. Studies by Producers • Acute inhalation toxicity tests first run in the mid 1970s • 21 day and 90 day inhalation toxicity tests run in the mid 1980s • Workplace air monitoring ongoing since the late 1970s, both monomer and polyiso

20. UK Isocyanate Control Limits • 1983, Silk and Hardy paper, “Control Limits for Isocyanates”,Ann. Occup. Hyg. Vol. 27,pp.333-339 • Basic Hypothesis: • Inhalation of aerosols containing polyisocyanates “…is no different from the inhalation of monomer vapours as regards their ability to cause adverse respiratory effects and sensitization.”

21. UK Isocyanate Control Limits • Control Limits • 8 hr TWA -- 20ug NCO/m3 • 10 min TWA(STEL) -- 70ug NCO/m3 • We would now refer to this as a TRIG limit as it is based on the airborne concentration of Total Reactive Isocyanate Groups

22. Total Mass vs. TRIG • HDI Diisocyanate Monomer • Total Molecular Mass/Wt. = 168 • Mass or wt. Of 2 N, 2 C and 2 O found in the two isocyanate functional groups = 84 • Therefore, 50% of the mass/wt. is reactive isocyanate groups (TRIG) • Thus a Total Mass Concentration of 0.034 mg/m3 = a TRIG Conc. of 0.017 mg/m3

23. Total Mass vs. TRIG • HDI Polyisocyanate • Since the commercial product is a mixture of oligomers of varying molecular mass/wt., the conversion must be done using a measured NCO (TRIG) percentage • A major HDI polyiso product currently in use has an NCO (TRIG) percentage of 21.6 • Therefore, a Total Mass conc. of 0.5 mg/m3 = a TRIG conc. of 0.11 mg/m3

24. Total Mass vs. TRIG 8 Hour Concentration Guidelines T. Mass Vol/ Vol TRIG TRIG 3 3 3 ppb mg/m mg/m ug/m HDI- 5 0.034 0.017 17 TLV HDI-UK 5.8 0.04 0.02 20 Oregon N/A 0.5 0.11 110 PEL Polyiso

25. Total Mass vs. TRIG STEL/C Conc. Guidelines Vol/ Vol T. Mass TRIG TRIG 3 3 3 ppb mg/m ug/m mg/m HDI-UK 20 0.14 0.07 70 & MGL UK-HDI N/A 0.32 0.07 70 Polyiso Oregon N/A 1.0 0.22 220 PEL Polyiso

26. Why Not Accept Silk & Hardy Hypothesis? • At the time (1983) only acute LC50 data was available and monomer and polyiso results were quite similar • BUT, workers are not exposed to hundreds of mg/m3(LC50range) • Janko (AIHAJ 1992) and Myer (AIHAJ 1993) reported workplace ranges of <1 to 30mg/m3 (or <1 to 6.5 mgTRIG/m3) of airborne HDI polyisocyanate.

27. Why Not Accept Silk & Hardy Hypothesis • Subchronic inhalation toxicity tests were run on HDI monomer, HDI biuret and HDI trimer in the mid ‘80s. • These studies exposed the animals to polyisocyanate concentrations in the same range as was found in field survey studies (Janko and Myer)

28. Monomer vs. Polyiso Toxicity Comparison

29. “No Difference” Hypothesis Wrong • At concentrations and exposure patterns like those found in the workplace, the rat studies showed that NCO groups found on HDI polyisocyanate molecules were clearly much less toxic than an equal number of diisocyanate monomer NCO groups. • In other words, in this case, the Silk and Hardy “no difference” hypothesis is clearly wrong.

30. Conclusion • Measuring airborne TRIG concentrations non-specifically in an HDI polyisocyanate spray painting operation and comparing the results to the UK-HSE control limits would greatly overestimate the risk (~42 fold). • On the other hand, a good TRIG method may be useful for thermal decomposition situations.