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 HDI oligomers, isocyanurate type (EC 931 -274 -8) is applied. This substance is a close structural analogue to HDI oligomers, iminooxadiazindione type, also derived from catalytic oligomerisation of 1,6 -hexamethylene diisocyanate (HDI; CAS 822 -06 -0) and also belonging to the CAS number 28182 -81 -2 (Hexane, 1,6 -diisocyanato-, homopolymer). The read across is based on physicochemical and toxicological similarity. In fact, comparison of the toxicological endpoints, that are available for both of the two substances reveal good correlation.

 Toxicological endpoint  HDI oligomers, isocyanurate type  HDI oligomers, iminooxadiazindione type
 Acute oral toxicity  > 2000 mg/kg  > 2000 mg/kg
 Acute inhalation toxicity (pulmonary irritant study) NOAEL 3 mg/m³   NOAEL 2.1 mg/m³
 Skin Irritation/Corrosion  slight irritation/no classification required  slight irritation/no classification required
 Eye Irritation/Corrosion  very slight irritation/no classification required  very slight irritation/no classification required
 Skin Sensitisation  classification required  classification required
 Bacterial Mutagenicity (Ames)  negative  negative

With respect to Inhalation Toxicity an expert statement is available justifying the read across (Pauluhn, Comparison of pulmonary irritation potency..., Bayer HealthCare AG, 2008; attached to this endpoint summary).

Therefore, test results obtained for HDI oligomers, isocyanurate type can be transferred to HDI oligomers, iminooxadiazindione type and the DNELs delineated for HDI oligomers, isocyanurate type are also valid for HDI oligomers, iminooxadiazindione type. This approach is in accordance with Annex XI, section 1.5 of the REACH Regulation (Regulation (EC) No 1907/2006).

The most relevant route for assessing risk in humans is via inhalation for HDI oligomers, iminooxadiazindione type and also for the read-across substance HDI oligomers, isocyanurate type. In rats effects from repeated aerosol exposure to the read-across 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 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, 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 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, 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 HDI oligomers, iminooxadiazindione 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 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 0.035 mg/m³.
Since for HDI oligomers, iminooxadiazindione type the pulmonary irritant threshold concentration (2.1 mg/m³; report no. AT01058, Bayer AG, 2004) is > 10 * AGW the EBW = 10 * AGW. The data for the read-across substance support this, as for HDI oligomers, isocyanurate type both the pulmonary irritant threshold concentration as well as the derived no observed adverse effect concentration of the subchronic study are > 10 * AGW (3 mg/m³, report AT03922, Bayer AG, 2007, and 3.3 mg/m³, report 16070, Bayer AG, 1987, respectively).

According to TRGS 430 there is even an option to set the EBW > 10 * AGW. This was done for HDI oligomers, iminooxadiazindione type and also for its read-across substance HDI oligomers, isocyanurate type taking into account that there were data from the read-across substance on pulmonary irritation as well as on repeated (e.g. subchronic) inhalation exposure available, which 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 effects for inhalation is set 0.5 mg/m³.

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

For skin sensitization no DNEL is calculated as the relationsship 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, Nov. 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.

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