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)
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

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

The most relevant route for assessing risk for Hexamethylene diisocyanate, oligomers (biuret) in humans is via inhalation. In rats effects from repeated aerosol exposure are limited to the respiratory tract caused by local irritation (Bayer AG, 1985 (OECD TG 412) and 1988 (OECD TG 413)). No indications of systemic toxicity were found in the named subacute and subchronic inhalation studies, respectively. 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 of HDI diisocyanate, oligomers (biuret) have to be derived. In addition, sensitisation after skin contact has to be assessed.

According to REACH (ECHA Guidance, chapter R.8-13) 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 HDI, oligomers (biuret) is the exposure assessment value (Expositionsbeurteilungswert, EBW). This value for polyisocyanate-aerosols is taking into account the lower irritant potential to the respiratory tract in comparison to the monomeric Diisocyanate, respectively. 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 (OECD, 1981) or OPPTS 870.3465 (1998).

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, respectively.

This means: For the monomeric hexamethylen-1,6-diisocyante (HDI) the AGW is 0.035 mg/m³.

 

For HDI, oligomers (biuret) the derived no observed adverse effect concentration identified in a subchronic study (3.4 mg/m³; Bayer AG, 1988) is >10 * AGW for HDI (0.035). Therefore 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 (biuret), since data from subacute and subchronic inhalation studies are available. Both studies are resulting in almost identical no observed adverse effect concentrations (NOAEC 3.7 mg/m³ from subacute study, Bayer 1985; NOAEC 3.4 mg/m³ from subchronic study, Bayer 1988). It can therefore reliably be demonstrated, 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. 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 ECHA guidance, chapter R.8.4.

 

AGWs are based on 8-hour time weighted average exposure. According to the German rule for OELs (TRGS 900, BMAS, 2006/2009) 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 could be used as surrogate DNELacute local effectsfor inhalation for HDI trimer.

This procedure is in accordance to ECHA Guidance, Chapter R.8., Appendix R. 8-8, Box 6.

No DNEL for skin sensitization is calculated as the relationsship between skin dose and response is not clear. There is no validated method of DNEL calculation for skin sensitization. According to the potency categorization approach HDI Trimer is classified as a moderate skin sensitizer (see EPS skin sensitization).

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
Explanation for the modification of the dose descriptor starting point:

The substance is not used in the public domain and exposure of consumers is thus not to be expected.

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
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is not used in the public domain and exposure of consumers is thus not to be expected.

Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information
Explanation for the modification of the dose descriptor starting point:

The substance is not used in the public domain and exposure of consumers is thus not to be expected.

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

The substance is not used in the public domain and exposure of consumers is thus not to be expected.