HDI Polyisocyanates: Toxicity
and Airborne Concentration
Guidelines
Painting Issues in the
Aerospace Industry: RT244
2000 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
HDI
HDI Biuret
Monomer
HDI
Trimer
Mol. Wt.
168
>500
>500
VP mmHg
20o 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 in
Paint
~30%
~7%
HDI in Paint
0.5%
0.014%
Volatility
HDI polyisocyanate is essentially nonvolatile 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 62500 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 method
Most of isocyanate groups are on polyiso
Spray 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 velocimetry
Cascade 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 Biurettype 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.333339
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
Total Mass vs. TRIG STEL/C Conc.
Guidelines
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 TRIG
mg/m3
Polyiso
TRIG
mg/m3
Polyiso
HDI
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 nonspecifically 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.