HDI Polyisocyanates: Toxicity and Airborne Concentration Guidelines

Painting Issues in the Aerospace Industry: RT2442000 AIHCE

Chemical Structures

Hexamethylene Diisocyanate(HDI) Monomer

HDI Biuret (Polyiso) Commercial product

contains higher mol. wt. oligomers and a small percentage of residual HDI monomer

Chemical Structure

HDI Isocyanurate Trimer (Polyiso) Commercial product

contains higher mol. wt. oligomers and a small percentage of residual HDI monomer

Molecular Weight and Vapor Pressure

HDIMonomer

HDI Biuret HDITrimer

Mol. Wt. 168 >500 >500

VP mmHg20o C

1.1x10-2 9.3x10-6 5.2x10-9

Typical 2-Component PU Paint Formulations

Highest Lowest

HDI in Polyiso 1.6% 0.2%

Polyiso inPaint

~30% ~7%

HDI in Paint 0.5% 0.014%

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

Inhalation Exposure Potential

HDI Monomer HDI Polyiso

Non-Spray,Room Temp.

Low None

Non-Spray,Oven

Mod.-High None

Spray Low-Mod. Low-High

Burning Mod.-High No Data

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

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 methodMost of isocyanate groups are on polyisoSpray painter’s most significant

isocyanate exposure potential is to polyiso aerosol

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.

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

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

Subchronic Toxicity Study Design (continued)

Exposure Atmosphere Characterization Particle Size Distribution

Laser velocimetryCascade impactor

• gravimetric

• chemical analysis

Subchronic Toxicity Study Endpoints

In-life Body weights Clinical signs Urinalysis Hematology Clinical chemistry

Post-sacrifice Gross pathology Organ weights Complete histopathology

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.

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.

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.

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)

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

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.”

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

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

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

Total Mass vs. TRIG 8 Hour Concentration Guidelines

Vol/Volppb

T. Massmg/m3

TRIGmg/m3

TRIGug/m3

HDI-TLV

5 0.034 0.017 17

HDI-UK 5.8 0.04 0.02 20

OregonPEL

Polyiso

N/A 0.5 0.11 110

Total Mass vs. TRIG STEL/C Conc. Guidelines

Vol/Volppb

T. Massmg/m3

TRIGmg/m3

TRIGug/m3

HDI-UK& MGL

20 0.14 0.07 70

UK-HDIPolyiso

N/A 0.32 0.07 70

OregonPEL

Polyiso

N/A 1.0 0.22 220

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(LC50

range) 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.

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)

Monomer vs. Polyiso Toxicity Comparison

Tox. Test HDI TRIGmg/m3

PolyisoTRIG

mg/m3

PolyisoHDI

LC50-4 hr 155-175 30-248 Similar

90 day(NOAEL)

0.017 0.71-0.73 42

“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.

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.