Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.05 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.1 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)
Acute/short term exposure
Most sensitive endpoint:
sensitisation (respiratory tract)

Workers - Hazard for the eyes

Additional information - workers

Inhalation exposure is typically the most relevant route for assessing occupational hazard and risk in humans. Effects from repeated exposure of animals to 1,5-Naphthylene diisocyanate (NDI) are limited to effects on the respiratory tract caused by local irritation. In a subchronic (13-week) inhalation study with aerosol exposure of NDI to rats a NOAEC of 0.25 mg/m3 was determined based on histopathological effects in the upper and lower respiratory tract (Pauluhn, 2010). No indications of systemic toxicity were found in this study. It could be shown, that if a non-irritant threshold concentration was not exceeded, neither functional nor morphological indications of damage to the respiratory tract were observed. Tests assessing the mutagenic potential of NDI in vitro and in vivo provide no evidence of mutagenic or genotoxic activity.

According to the ECHA Guidance on information requirements and chemical safety assessment - chapter R.8 (May 2008) a national occupational exposure limit (OEL) was used as a surrogate for a DNEL. The German Committee on Hazardous Substances (Ausschuss für Gefahrstoffe - AGS) derived an OEL (Arbeitsplatzgrenzwert - AGW) for NDI which was listed in the Technical Rule for Hazardous Substances (TRGS) No. 900 and substantiated in a respective criteria document (published in German on the website of the Federal Institute for Occupational Safety and Health (BAuA) - www.baua.de). According to the German Hazardous Substances Ordinance (Gefahrstoffverordnung) an AGW is a time-weighted average concentration in the workplace air, referring to a given period of time. The AGW states the concentration of a substance below which acute or chronic adverse health effects are generally not expected. AGWs are thus based exclusively on available occupational medical experience and toxicological findings (= health based occupational exposure value).

For NDI the AGS established an OEL of 0.05 mg/m3 referring to an 8-hour exposure period. This OEL is used as a surrogate DNEL for long-term exposure. A ceiling limit value of 0.1 mg/m3 was set for NDI. This ceiling limit is used as a surrogate DNEL for short-term exposure. The justification of these OELs was based on evaluations of the German MAK Commission on NDI (DFG, 2004)1 and Toluene diisocyanate (TDI; DFG, 1999)2 and published in a criteria document for NDI (issue: January 2006) with the following statements (inofficial translation from German into English):

From occupational medicine perspective it is expected that the effect on the respiratory tract is the predominant effect for NDI as for other diisocyanates. So e.g. TDI leads to local irritation at eyes and respiratory tract. High concentrations lead to a decrease in respiratory rate and dyspnea. Isocyanate asthma can occur in the form of obstructive airway disease, non-specific bronchial hyperreactivity and in rare cases as allergic alveolitis (DFG, 1999)2. For the assessment of NDI data on TDI and MDI are used (DFG, 2004)1. To prevent gradual deterioration of lung function of exposed workers, it is recommended to limit the average exposure level to 0.05 mg/m3 and exposure peaks to 0.1 mg/m3 (DFG, 2004)1. Therefore, the occupational exposure limit value of 0.05 mg/m3 and the peak limit category I with exceedance factor 1 and a momentary value of 0.1 mg/m3 is established.

The German OELs for NDI are in the range of the recommended exposure limits (REL-TWA: 0.040 mg/m3; REL-Ceiling: 0.170 mg/m3) published by the National Institute for Occupational Safety and Health (NIOSH, 2004)3and no additional information became available in the meantime that would influence the respective assessment.

No comparative 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 NDI demonstrates consistently that toxicity is associated only with the portal-of-entry (respiratory tract). A plausibility check of the above mentioned national OELs revealed that the DNELs derived from animal data using assessment factors according to ECHA Guidance R.8 are in the same range and therefore in line with the OELs.

 

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 the potency categorisation approach NDI is classified at least as a strong skin sensitizer (Category 1) based on a local lymph node assay (LLNA) in mice (Vohr, 2006). In this test all test concentrations (≥ 2 %) exceeded the positive level of index 1.4.

No animal data on respiratory sensitization of NDI are available. However, due to the well known reactivity of diisocyanates, respiratory sensitization is likely to occur. Therefore, NDI was classified with R42 (Category 1). Substances with R42 (Category 1 for respiratory sensitization) have to be allocated to the high hazard category. Since there is evidence from both human and animal studies, that effective sensitization of the respiratory tract can result from dermal contact with a chemical respiratory allergen, the derivation of a DNEL for skin senzitization is not indicated (ECHA Guidance on information requirements and chemical safety assessment - Part E: Risk characterisation (May 2008)).

For NDI no repeated dose dermal toxicity studies are available. Skin penetration of NDI is considered to be low since no systemic intolerance reactions were observed in a skin irritation study after single application of 0.5 g NDI (Schüngel, 2006). As mentioned above exposure to NDI via the air does not lead to systemic toxicity, therefore taking into consideration the low dermal penetration, systemic toxicity is covered by the respective DNELs for inhalation exposure. As there is no indication 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 irritation potential (slightly to moderately irritating) as well as the sensitization potential needs to be considered in the selection of the respective risk management measures (RMMs) at the workplaces.

The DNELs acute/long-term for inhalation of workers covers also reproductive toxicity, as the local effects at the respiratory tract are the most sensitive effects and there is no indication of systemic toxicity.

1 DFG (2004): 1,5-Naphthylendiisocyanat: Gesundheitsschädliche Arbeitsstoffe - Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten. Deutsche Forschungsgemeinschaft (DFG), 38. Lieferung 2004

2 DFG (1999): Toluylendiisocyanate: Gesundheitsschädliche Arbeitsstoffe - Toxikologisch-arbeitsmedizinische Begründungen von MAK-Werten. Deutsche Forschungsgemeinschaft (DFG), 28. Lieferung 1999

3 NIOSH (2004): A Summary of Health Hazard Evaluations: Issues Related to Occupational Exposure to Isocyanates, 1989 to 2002. DHHS (NIOSH) Publication No. 2004 -116, Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, January 2004 (see also the NIOSH Web site at www.cdc.gov/niosh)

General Population - Hazard via inhalation route

Systemic effects

Acute/short term exposure
DNEL related information

Local effects

Acute/short term exposure
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard via oral route

Systemic effects

Acute/short term exposure
DNEL related information

General Population - Hazard for the eyes

Additional information - General Population

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