Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.5 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Dose descriptor:
NOAEC
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
DNEL extrapolated from long term DNEL

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

For delineating occupational exposure limits a read across to a substance with a similar composition (HDI oligomerisation product, isocyanurate type, EC 931-274-8, CAS 28182 -81 -2) is applied. The read across is based on physicochemical and toxicological similarity of the two substances. Especially a recent comparative pulmonary irritant potency study according to TRGS 430 (Technical Rule for Hazardous Substances 430; published by the German Federal Ministry of Labour and Social Affairs, 2009) confirmed for HDI oligomerisation product, allophanate-type the same toxicological mode of action (irritant portal of entry toxicity) with a similar potency (NOAECs for pulmonary irritation: 3.4 mg/m³ for HDI oligomerisation product, allophanate-type versus 3.3 mg/m³ for HDI oligomerisation product, isocyanurate type). For further justification of the grouping and read-across according to regulation (EC) No 1907/2006, Annex XI, 1.5 see document attached to chapter "Assessment Reports".

 

The most relevant route for assessing risk in humans is via inhalation for HDI oligomerisation product, allophanate-type and for the read-across substance (HDI oligomerisation product, isocyanurate type, EC No 931 -274 -8). In rats effects from repeated aerosol exposure of the substances are limited to the respiratory tract caused by local irritation (read-across data: Bayer, 1985 (OECD TG 412) and 1987 (OECD TG 413)). No indications of systemic toxicity were found in these subacute and subchronic inhalation studies. It was shown, that if a non-irritant threshold concentration is not exceeded, neither functional nor morphological indications of damage to the respiratory tract are observed.

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 assessed.

According to Guidance Document R.8 (ECHA, Nov. 2012) a national occupational exposure limit (OEL) could be used as a 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 (Technische Regel für Gefahrstoffe, TRGS) for regulating the workplace exposure of isocyanates (TRGS 430, BMAS, 2009). ”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, J. 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 the HDI oligomerisation product, isocyanurate or allophanate-type is the exposure assessment value (Expositionsbeurteilungswert, EBW). 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 (BALF) of an 1 x 6 h inhalation study (“TRGS 430 study”) or, alternatively, if available, from the NOAEC (no observed adverse effect concentration) 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 shows (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 0.035 mg/m³.
Since for HDI oligomerisation product, isocyanurate type both the pulmonary irritant threshold concentration (3 mg/m³; Bayer, 2001) and the derived no observed adverse effect concentration of the subchronic study (3.3 mg/m³; Bayer, 1987) and moreover for HDI oligomerisation product, allophanate-type the pulmonary irritant threshold concentration (3.4 mg/m³; Bayer, 2013) 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 oligomerisation product, isocyanurate type due to the reason, that for the substance data for pulmonary irritation as well as data from a subchronic inhalation study 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, 2002, 287-301).

Therefore the EBW = DNELlong-term local effectsfor inhalation is set to 0.5 mg/m³ for HDI oligomerisation product, isocyanurate type, and also for HDI oligomerisation product, allophanate-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 (TRGS 900, BMAS, 2006/2013) for short-term ceiling concentrations an exposure limit 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 effectsfor inhalation for HDI oligomerisation product, isocyanurate type, and also for HDI oligomerisation product, allophanate-type.

This procedure is in accordance to Guidance Document R.8 (ECHA, Nov. 2012), Appendix R. 8-8, Box 6.

 

No DNEL for skin sensitisation is calculated as the relationship between skin dose and response is not clear and no validated method of DNEL calculation for skin sensitisation is available. According to the potency categorization HDI oligomerisation product, allophanate-type, classified as skin sensitising 1 without sub-categorysation, has to be allocated to the high hazard category.

 

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.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population