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:
0.035 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.07 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

For derivation of DNELs a read across to 1,6-diisocyanatohexane (HDI, CAS 822-06-0) is applied. See in the following the DNEL argumentation based on HDI.

Inhalation exposure is typically the most relevant route for assessing occupational risk in humans. Effects from repeated exposure of animals to HDI are limited to effects on the respiratory tract caused by local irritation. In a 2-year chronic toxicity and carcinogenicity study with vapour exposure of HDI to rats a NOAEC of 0.035 mg/m³ (0.005 ppm) was determined (Shiotsuka 1989/2010, Foureman 1994). Neither indications of systemic toxicity nor evidence of a carcinogenic potential were found in rats. Moreover, tests assessing the mutagenic potential of HDI or PDI provide no evidence of mutagenic or genotoxic activity.

According to the Guidance Document R.8 (ECHA, Nov. 2012) a national occupational exposure limit (OEL) could be used as surrogate for a DNEL. This OEL of HDI (CAS no. 822 -06 -0) is published by the German Federal Ministry of Labour and Social Affairs in the TRGS 430 for regulating the workplace exposure of isocyanates in Germany (Technical Rule for Hazardous Substances 430, version of march 2009). It stipulates the maximum concentration in the workplace air to be 0.035 mg/m³ (0.005 ppm) for repeated exposure (taking into account an 8-hour working day under the assumption of an average 40-hour working week). This OEL of HDI is applicable also for PDI as a surrogate DNEL for long-term exposure.

For HDI an exceeding factor of 1 is specified in TRGS 430, which is the rule for substances for which local irritant effects determine the MAK value. It is further laid down in the TRGS 430 that a momentary value of 0.070 mg/m³ should not be exceeded for HDI. This momentary value of the read across substance serves as DNEL acute/short term for local effects for PDI.

The justification for the read acoss is attached at this endpoint as a separate document. For HDI the justification of the OEL is given in the published documentation for the scientific evaluation of HDI (MAK Value Documentations 2013 for 1,6- Hexamethylene diisocyanate, DFG, Deutsche Forschungsgemeinschaft, © 2013 Wiley-VCH Verlag GmbH & Co. KGaA); in excerpts:

“Both in humans and in animals, the main effects of hexamethylene diisocyanate (HDI) are irritation and sensitization of the respiratory tract. The available results with humans are however not suitable for the derivation of a MAK value, as practically always exposures to a mixture of substances with HDI prepolymers, other diisocyanates and solvents are involved and the real exposure levels have, for the most part, not been recorded quantitatively. For rats, the NOEC is 0.005 ml/m³ (0.035 mg/m³) in a subacute inhalation study. Concentrations above 0.15 ml/m³ (1.05 mg/m³) resulted in marked changes in the nasal mucosa (squamous cell metaplasia). In an investigation lasting 13 weeks, the same changes as well as first clinical signs of an irritant effect to the eyes were already observed at the lowest tested concentration of 0.011 ml/m³ (0.08 mg/m³). In a study lasting 2 years, concentrations of 0.005 ml/m³ and above produced metaplasia and/or hyperplasia with a hyaline degeneration of the respiratory epithelium and the mucus-secreting glands. At 0.025 ml/m³ (0.175 mg/m³) and above, hyperkeratosis of the respiratory epithelium and degeneration of the olfactory epithelium were additionally found. As the findings described at the concentration of 0.005 ml/m³ only increased as regards incidence but not severity, and comparable changes also occurred spontaneously, they were evaluated as an adaptive response (Foureman et al. 1994). Adaptive reactions of this kind are frequently observed in rodents after exposure to gaseous irritants (Monticello et al. 1990). Thus, for the long-term inhalation study in the rat, a NOAEC of 0.005 ml/m³ is obtained. The MAK value for HDI is thus reduced to 0.005 ml/m³ (0.035 mg/m³). Even according to the findings with humans, which must still only be interpreted with caution, irritant effects are no longer to be expected at this concentration. However, this does not apply for persons with non-specific bronchial hyperreactivity or allergic HDI hypersensitivity, as minimal HDI concentrations are already able to provoke bronchospastic conditions in these persons. The peak limitation Category I is retained. A classification of HDI in a pregnancy risk group is not possible due to the lack of data. HDI is thus listed in Section IIc of the List of MAK and BAT Values. No specific reproduction toxicity potential can be derived for the class of diisocyanates from investigations with MDI and TDI as well as with HDA, the HDI metabolite. In humans, HDI is able to induce allergies in most cases by inhalation. The designation with “S” is retained.”

The German OEL for HDI is in agreement with the threshold limit value (TLV-TWA: 0.005 ppm (0.034 mg/m³)) recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2004).

No DNELs for systemic effects (short-term and long-term exposure) are calculated since no indications of systemic toxicity were observed in the repeated dose toxicity studies by the inhalation route. The toxicological database for inhaled PDI and HDI demonstrates consistently that toxicity is associated only with the portal of entry (respiratory tract).

No DNEL for skin sensitization is calculated as the relationship between skin dose and response is not clear. There is no validated method of DNEL calculation for skin sensitization. According to Guidance document Part E: Risk characterization (ECHA, November 2012) the substance has to be allocated to the high hazard category due to its classification as skin sensitization Category 1, and with that a qualitative risk assessment for this endpoint is applied.

Concluding from the read across substance HDI also PDI has a potential for respiratory sensitization. The classification as respiratory sensitization Category 1 triggers also the high hazard category for the qualitative risk assessment (Guidance document Part E: Risk characterization; ECHA, November 2012). Anyway, the risks of skin and respiratory sensitization cannot be assessed separately, since there is evidence from both human and animal studies, which indicate, that effective sensitization of the respiratory tract can result from dermal contact with a chemical respiratory allergen.

As there is no indication for PDI or the read across substance HDI that dermal contact could lead to principally different and more severe systemic effects compared to inhalation exposure, a DNEL for systemic toxicity (short-term and long-term) after dermal contact is not required. Regarding local effects the corrosive potential as well as the sensitization potential needs to be considered in the selection of the respective risk management measures (RMMs) at the workplaces.

Based on the read across the DNEL for long-term exposure covers also reproductive toxicity, as HDI has shown no reproductive toxicant properties and the local effects at the respiratory tract covered by the DNEL for long-term exposure 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