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:
0.3 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
When the starting point for the DNEL delineation is a NOAEC, the default assessment factor as a standard procedure is 1 (Guidance Document R.8, ECHA, 2012).
AF for differences in duration of exposure:
1
Justification:
The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2, but justified deviations are possible. In the case of IPDI oligomers, allophanate type, no systemic effects were observed and the observed local effects from two repeated inhalation toxicity studies with different exposure duration (pilot study 5x6h and OECD 412-study 20x6h) does not give evidence for a major time-dependent change of the response threshold, as the NOAECs were 5.5 mg/m³ for the pilot study (concentrations 5.5, 23.4, 126 mg/m³) and 4.5 mg/m³ for the OECD 412-study (concentrations 4.5, 25.8, 122 mg/m³). Moreover, there is scientific evidence that for non-volatile polyisocyanates that act predominantly as pulmonary irritants even the NOAECs from acute studies, when conducted according to the Technical Rule for Hazardous Substances 430*, does not essentially differ from NOAECs of long(er)-term repeated inhalation studies (Pauluhn, Journal of Applied Toxicology, 24, 231-247, 2004). On this basis it is not expected that a longer duration of the study would essentially change the response threshold and an AF of 1 provides sufficient safety. *TRGS 430, published by the German Federal Ministry of Labour and Social Affairs, last update in 2009; exposure 1x6 h, NOAECs based on bronchoalveolar lavage fluid analysis
AF for interspecies differences (allometric scaling):
1
Justification:
According to the Guidance Document R.8 (ECHA, 2010) allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects; therefore AF 1 is chosen.
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. For local effects on the respiratory tract it should be taken into account that rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Particular in the repeated dose 28 days-study with IPDI oligomers, allophanate type, a local irritant effect on the rat larynx was observed, which is known to be a common finding in rat inhalation studies because of the high susceptibility of the rodent larynx to any mild irritant (Kaufmann et al., Exp. Toxicol. Pathol. 61, 591 -603, 2009). Also the other effects observed for the substance were solely local or rat specific secondary effects and indicated on irritancy as the primary Mode of Action. Therefore a factor of 1 is applied.
AF for intraspecies differences:
5
Justification:
A factor 5 is suggested by Guidance Document R.8 (ECHA, 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor 3 is proposed for workers for intraspecies extrapolation of systemic effects if the point of departure is derived from animal studies. This is based on a thorough evaluation of scientific literature. Nevertheless, for a more conservative approach the ECHA default-factor 5 is applied here.
AF for the quality of the whole database:
1
Justification:
The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements, is 1.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 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:
medium hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
medium 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 workers in industrial settings, which are exposed via inhalation to the aerosolized substance, DNELs for acute and long-term inhalative effects of 3-isocyanatomethyl-3,5,5-trimethylcyclohexylisocyanate (IPDI) oligomers, allophanate type, have to be derived. Because of the known skin sensitization potential of the substance this also has to be assessed.

For repeated dose toxicity a subacute (28-days) inhalation study on rats (OECD TG 412) is available with exposure to the liquid aerosol IPDI oligomers, allophanate type (80 % in butyl acetate; Pauluhn, 2012). The NOAEC in this study was 4.5 mg/m³, based on local irritant effects on the respiratory tract at the next higher dose (25.8 mg/m³). Effects at the LOAEC were mild and could partly be ascribed to rat specific physiology (see chapter repeated dose toxicity). The large spacing between the NOAEC and LOAEC of ca. 6 - instead of typically a factor of 3, and the mild response at the LOAEC needs to be taken into consideration. With regard to extrapulmonary toxicity, no effects were found up to the maximum concentration examined.

The port-of-entry irritant toxicity is the common mode of action also for the other aliphatic isocyanates that build a group according to REACH, Annex XI, 1.5. A document that justifies the grouping and read across is attached to this endpoint summary. Based on the read across also a subchronic (90-day) study for a close structural analogue is available. As the subchronic study is the higher tier study, the NOAEC of this study, which is 2.9 mg/m³, is used as starting point for the delineation of the DNEL.

DNEL Workers, Hazard via inhalation route, local effects, long-term:

For rats exposed to the substance 6 hours/day 5 days/week for 13 weeks (subchronic study): NOAEC = 2.9 mg/m³ 

Correction of dose-descriptors (Guidance Document R.8, ECHA, 2012)

In case of workers 8 h/day exposed:

corrected NOAEC =  inhalatory NOAEC x (exp. cond. rat/exp. cond. human)

                                                             

corrected NOEAC =  inhalatory NOAEC x  (6/8) hours/day x (6.7 m³ (8 h)/10 m³ (8 h))

 

corrected NOAEC = 1.46 mg/m³

 

According to Guidance Document R.8 (ECHA, 2012) a series of assessment factors (AF) were applied to the corrected NOAEC and are summarized in the table below:

Assessment

Assessment Factor

 

 

1 Dose-response relationship  

1

 

2 Differences in duration of exposure

1

 

3 For interspecies differences rat vs.
human (allometric scaling)

5

 

4 For remaining interspecies
differences

1

 

5 For intraspecies differences
(workers)

1

 

6 Quality of whole Database

1

 

Overall Assessment Factor

5

 

 

1When the starting point for the DNEL delineation is a NOAEC, the default assessment factor as a standard procedure is 1 according to Guidance Document R.8 (ECHA, 2012). 

2The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2, but justified deviations are possible. In the case of IPDI oligomers, allophanate type, no systemic effects were observed and the observed local effects from two repeated inhalation toxicity studies with different exposure duration (pilot study 5x6 h and OECD 412-study 20x6 h) does not give evidence for a major time-dependent change of the response threshold, as the NOAECs were 5.5 mg/m³ for the pilot study (concentrations 5.5, 23.4, 126 mg/m³) and 4.5 mg/m³ for the OECD 412-study (concentrations 4.5, 25.8, 122 mg/m³). Moreover, there is scientific evidence that for non-volatile polyisocyanates that act predominantly as pulmonary irritants even the NOAECs from acute studies, when conducted according to Technical Rule for Hazardous Substances 430*, does not essentially differ from NOAECs of long(er)-term repeated inhalation studies (Pauluhn, Journal of Applied Toxicology, 24, 231-247, 2004). On this basis it is not expected that a longer duration of the study would change the response threshold and an AF of 1 provides sufficient safety.

*TRGS 430 published by the German Federal Ministry of Labour and Social Affairs, 2009: exposure 1x6 h, NOAECs based on bronchoalveolar lavage fluid analysis

3According to the Guidance Document R.8 (ECHA, 2012) allometric scaling should not be applied if the effects are not dependent on metabolic rate or systemic absorption, e.g. in the case of local effects; therefore AF 1 is chosen.

4 A factor 2.5 is suggested by Guidance Document R.8 (ECHA, 2012) for remaining interspecies differences, but justified deviations are possible. For local effects on respiratory tract it should be taken into account that rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Particular in the repeated dose 28 days-study with IPDI oligomers, allophanate type, a local irritant effect on the rat larynx was observed, which is known to be a common finding in rat inhalation studies because of the high susceptibility of the rodent larynx to any mild irritant (Kaufmann et al., Exp. Toxicol. Pathol. 61, 591 -603, 2009). Also the other effects observed for the substance were solely local or rat specific secondary effects and indicated on irritancy as the primary Mode of Action. Therefore a factor of 1 is applied.

5A factor 5 is suggested by Guidance Document R.8 (ECHA, 2012) for intraspecies differences in workers, but justified deviations are possible. According to ECETOC (Technical Report No. 110, 2010) a factor 3 is proposed for workers for intraspecies extrapolation of systemic effects if the POD is derived from animal studies. This is based on a thorough evaluation of scientific literature.

Nevertheless, for a more conservative approach the ECHA default-factor 5 is applied here.

6The default assessment factor to be applied for good/standard quality of the database, taking into account completeness, consistency and the standard information requirements is 1.

 

Therefore the overall AF (assessment factor) is 5.

NOAEC corr.

DNELlong-term for workers for inhalation route – local effects=NOAEC corr. /Overall AF  

 
DNELlong-term for workers for inhalation route – local effects = 0.29 ~ 0.3 mg/m³

 

This DNEL is expected to ensure enough safety with regard to the local irritant effects to the respiratory tract. In addition, applying this limit value will also protect against potential unspecific effects of the substance in the lung (e.g. particle related toxicity), since it is the same as the general threshold limit value for the respirable fraction of insoluble dusts* (0.3 mg/m³) and more than 10 times lower than the general threshold limit value for the inhalable fraction of insoluble dusts* (4 mg/m³), as set by the German MAK Commission (see List of MAK and BAT Values 2012, DFG; * related to insoluble dusts with density 1 g/cm³).

 

According to the German rule for OELs (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs, 2006/2009) for short-term ceiling concentrations an exposure limit could be established by multiplication of an occupational exposure limit (Arbeitsplatzgrenzwert) to an exceeding factor (Überschreitungsfaktor), which is set per default 1 (could be adjusted to max. 8) . For the substance an exceeding factor of 2 is applied, since the most prominent effect of the substance is the local “port-of-entry” irritation both for the acute and for the long-term toxicity, leading to a short term ceiling limit or a

 

DNELacute for workers for inhalation route – local effects of 0.6 mg/m³.

 

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

 

There are currently no available methods to determine thresholds and DNELs for skin sensitizers, therefore a quantitative risk assessment for this endpoint is not possible. According to Guidance Document Part E (ECHA, 2012) substances classified for skin senisitization with R43/Cat. 1B have to be allocated to the moderate/medium hazard category.

 

The DNEL acute/long-term for inhalation for workers covers also reproductive/developmental 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