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EC number: 931-274-8
CAS number: 28182-81-2
For hexamethylene diisocyanate (HDI) oligomers, isocyanurate type,
the most relevant route for assessing risk in humans is via inhalation.
In rats effects from repeated aerosol exposure to the substance caused
by local irritation are limited to the respiratory tract (report nos
22725, 16070, and 13504, Bayer AG, 1993, 1987, and 1985, respectively).
No indications of systemic toxicity were found in these subacute and
subchronic inhalation studies. It was shown, that if a nonirritant
threshold concentration is not exceeded, neither functional nor
morphological indications of damage to the respiratory tract are
For workers in industrial settings, which are exposed via
inhalation, DNELs for local effects for acute and long-term inhalation
exposure have to be derived. In addition, sensitisation after skin
contact has to be addressed.
According to Guidance Document R.8 (ECHA, 2012) a national
occupational exposure limit (OEL) could be used as surrogate for a DNEL.
The German Federal Ministry of Labour and Social Affairs
(Bundesministerium für Arbeit und Soziales, BMAS) published the
Technical Rule for Hazardous Substances 430 (TRGS 430, last updated in
2009) for regulating the workplace exposure of isocyanates. ”This
technical rule describes procedures for the assessment and surveillance
of workplaces involved in the handling and use of polyurethanes and
requires the assessment of isocyanates present either in the form of
vapour, aerosol or both” (Pauluhn, Appl. Toxicol., 24, 2004, 231-247).
In contrast to commonly employed workplace standards that focus solely
on monomeric (di)isocyanates, the common unifying concept of TRGS 430 is
to consider separate hazard assessment for monomeric and polymeric
isocyanates, present as vapour and/or aerosol.
The surrogate now used as DNEL for HDI oligomers, isocyanurate
type, is the exposure assessment value (Expositionsbeurteilungswert,
EBW), as described in TRGS 430. The EBW is either derived from the acute
pulmonary irritant threshold concentration using a benchmark
extrapolation of the concentration dependence of protein in
bronchoalveolar lavage fluid of an 1 x 6 hours inhalation study (study
recommended in TRGS 430) or, alternatively, if available, from the NOAEC
of a subchronic (13-week) inhalation study according to OECD 413 or
OPPTS 870.3465. The approach suggested by TRGS 430 is inherently
conservative, as a comparison of the irritant threshold concentration to
the NOAEC from repeated inhalation studies show (Pauluhn, J. Appl.
Toxicol., 24, 2004, 231-247).
If the irritant threshold concentration/NOAEC of the polymeric
diisocyante from either of the two studies is ≤ 10 * AGW (Arbeitsplatzgrenzwert
= German national OEL) of the monomeric diisocyanate then EBW = AGW, if
the threshold concentration is > 10 * AGW then EBW = 10 * AGW.
For the monomeric hexamethylen-1,6-diisocyante (HDI) the AGW is
Since for HDI oligomers, isocyanurate type, both the pulmonary irritant
threshold concentration (3 mg/m³; report no. AT03922, Bayer AG, 2007)
and the derived no observed adverse effect concentration of the
subchronic study (3.3 mg/m³; report no 16070, Bayer AG, 1987) are > 10 *
AGW the EBW = 10 * AGW.
According to TRGS 430 there is even an option to set the EBW > 10
* AGW. This was done for HDI oligomers, isocyanurate type, taking into
account that for the substance data on pulmonary irritation as well as
data on repeated (e.g. subchronic) inhalation exposure are available and
the data clearly show that the respiratory damage is linked to the
inhaled irritating concentration, and does not exacerbate during
repeated exposure (Pauluhn, Inhal. Toxicol., 13, 2001, 513-532 and 14,
Therefore the EBW = DNELlong-term, local effects for
inhalation is set 0.5 mg/m³ for HDI oligomers, isocyanurate type.
This is in line with a published proposed TLV-TWA of 0.5 mg/m³
(Pauluhn and Mohr, Inhal. Toxicol., 13, 2001, 513-532). The value is
further in the same order of magnitude compared to a DNEL delineated
according to Guidance Document R.8 (ECHA, Nov. 2012).
AGWs are based on 8-hour time weighted average exposure. According
to the German rule for OELs (Technical Rule for Hazardous Substances
900, BMAS, 2006/2013) an exposure limit for short-term ceiling
concentrations could be established by multiplication to an exceeding
factor (Überschreitungsfaktor), which is set per default 1 (could be
adjusted to max. 8). Pauluhn and Mohr proposed a maximum concentration
limit of 1.0 mg/m³ (exceeding factor 2) for HDI-derived polyisocyanates.
This value was used as surrogate DNELacute, local effects for
inhalation for HDI oligomers, isocyanurate type. This procedure is in
accordance to Guidance Document R.8 (ECHA, Nov. 2012), Appendix R. 8-8,
For skin sensitization no DNEL is calculated as the relationship
between skin dose and response is not clear. Furthermore, there is no
validated method of DNEL calculation for skin sensitizers, therefore a
quantitative risk assessment for this endpoint is not possible and a
qualitative risk assessment is applied. As the substance is classified
with R43/Cat. 1 for skin sensitisation (without sub-categorisation), it
has to be allocated to the high hazard category (Guidance Document –
Part E: Risk characterization, ECHA, November 2012). Consequently, the
respective risk management measures (RMMs) at the workplaces have to be
considered for risk assessment.
The DNEL acute/long-term for inhalation for workers covers also
reproductive toxicity, as the local effects at the respiratory tract are
the most sensitive effects.
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