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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
Value:
3 mg/m³
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.
AF for differences in duration of exposure:
1
Justification:
The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for duration extrapolation from subchronic to chronic should be 2, but extrapolation factors for differences in duration of exposure are not always needed. In this case no systemic effects were observed, and the observed local effects lead to LOAECs and NOAECs that does not give evidence for a major time-dependent change of the response threshold: NOAECs OECD 412 - OECD 413 - OECD 421/for general toxicity: 1 - 3 - 1 mg/m³, LOAECs OECD 412 - OECD 413 - OECD 421/for general toxicity: 6 - 18 - 6 mg/m³ (Pauluhn 2008 and 2004, Eiben 2004). On this basis it is not expected that a longer duration of the study would change the point of departure for the DNEL-delineation and therefore an AF of 1 is warranted.
AF for interspecies differences (allometric scaling):
1
Justification:
According 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.
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 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 90-days study a local irritant effect on the rat larynx was observed, which is known to be a common finding in rat inhalation studies and which is seen as an indicator of the especially 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 at the effect level 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:
For intraspecies variability, the default assessment factor for workers for local effects is 5.
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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
medium hazard (no threshold derived)

Additional information - workers

For workers in industrial settings, which are exposed to the substance via inhalation, DNELs for acute and long-term inhalation of 4,4'-methylenedicyclohexyl diisocyanate have to be derived. In addition, the possible risk of skin and respiratory sensitization has to be assessed.

For repeated inhalation toxicity a subacute (28 days, OECD 412) and a subchronic (90 days, OECD 413) rat study with aerosol exposure to 4,4´-methylenedicyclohexyl diisocyanate is available (Pauluhn, 2004 and 2008). The obtained LOAECs were 6 mg/m³ for the subacute study and 18 mg/m³ for the subchronic study for effects governed by respiratory tract irritation. Histopathological changes in the respiratory tract were related to portal-of-entry local irritant effects, i.e. squamous epithelial metaplasia and inflammatory changes in the larynx. No indications of systemic toxicity were found in either of the studies.

The NOAEC revealed from the subchronic study is 3.0 mg/m³. The result of a reproduction/­developmental toxicity screening test (OECD 421) is in line with that (NOAEC: 1 mg/m³, LOAEC: 6 mg/m³ for clinical signs like changes in breathing behaviour and/or serous nasal discharge; for reproduction/­developmental toxicity NOAEC 6 mg/m³; Eiben, 2004). Therefore 3.0 mg/m³ was set as the starting point for the delineation of the DNELlocal, long-term for workers for hazard via inhalation route.

Regarding the potential for respiratory sensitisation after inhalative exposure there is currently no validated method to determine thresholds and DNELs, therefore a qualitative hazard conclusion needs additionally to be drawn.

 

DNEL local, long-term for workers for hazard via inhalation route:

For rats exposed to the substance 6 h/d 5 d/w for 13 weeks       NOAEC = 3.0 mg/m³

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

In case of workers 8h/day exposed:

                                                              exp.cond. rat

corrected NOAEC =   inhalatory NOAEC * ————————

                                                                        exp.cond. human

 

                                                              6 h/d          6.7 m³ (8h)

corrected NOEAC =  inhalatory NOAEC *  ———— * ————

                                                              8 h/d           10 m³ (8h)

 

corrected NOAEC =  inhalatory NOAEC * 0.5025 = 1.508 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 For interspecies differences rat vs. human

(allometric scaling)  

1

2 For remaining interspecies differences

1

3 For intraspecies differences (workers)

  

4 Differences in duration of exposure

1

5 Dose-response relationship

1

6 Quality of whole Database

1

Overall Assessment Factor

5

1 According 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.

2 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 90-days study a local irritant effect on the rat larynx was observed, which is known to be a common finding in rat inhalation studies and which is seen as an indicator of the especially 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 at the effect level 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.

3 For intraspecies variability, the default assessment factor for workers for local effects is 5. 

4 The assessment factor suggested by Guidance Document R.8 (ECHA, 2012) for exposure duration from subchronic to chronic should be 2, but extrapolation factors for differences in duration of exposure are not always needed. In the depicted case no systemic effects were observed, and the observed local effects lead to LOAECs and NOAECs that does not give evidence for a major time-dependent change of the response threshold:

NOAECs OECD 412 - OECD 413 - OECD 421 (NOAEC for general toxicity): 1 - 3 - 1 mg/m³, LOAECs OECD 412 - OECD 413 - OECD 421 (LOAEC for general toxicity): 6 - 18 - 6 mg/m³ (Pauluhn 2008 and 2004, Eiben 2004).
On this basis it is not expected that a longer duration of the study would change the point of departure for the DNEL-delineation and therefore an AF of 1 is warranted. 

5 When the starting point for the DNEL delineation is a NOAEC, the default assessment factor, as a standard procedure, is 1. 

6 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.

 

Therefore the overall AF (assessment factor) is 5.

NOAEC corr.

DNEL local, long-term for workers for hazards via inhalation route=  ——————

Overall AF  

 DNEL local, long-term for workers for hazards via inhalation route = 0.302 mg/m³

 

According to the German rule for OELs (Technical Rule for Hazardous Substances 900, German Federal Ministry of Labour and Social Affairs, 2006/2009) an exposure limit for short-term ceiling concentrations 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 4,4´-methylenedicyclohexyl diisocyanate an exceeding factor of 2 is applied, leading to a short term ceiling limit or a

DNELlocal, acute for workers for hazards via inhalation route of 0.6 mg/m³.

 

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

Although data were not uniform, a dermal sensitization potential was shown for 4,4´-methylenedicyclohexyl diisocyanate. Since the substance is classified as skin sensitizer Cat.1 - without subcategorisation - it has to be allocated to the “high hazard category” for risk assessment, based on ECHA Guidance Part E (Guidance on information requirements and chemical safety assessment – Part E: Risk characterisation, ECHA 2012).

 

Furthermore, non-validated animal testing data support to some extent that respiratory hypersensitivity may be induced by the substance (Pauluhn 1995, Selgrade 2006, Farraj 2007, Plitnick 2005). There are currently no available methods to determine thresholds and DNELs for respiratory sensitizers, therefore a quantitative risk assessment for this endpoint is not possible. Based on ECHA Guidance Part E (Guidance on information requirements and chemical safety assessment – Part E: Risk characterisation, ECHA 2012) substances with R42/Cat. 1 for respiratory sensitization have also to be allocated to the high hazard category, as already concluded for skin sensitization. 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 delineation of a DNEL for skin sensitization is not indicated.

Summarising, for the hazard of sensitisation (skin and respiratory) a qualitative risk assessment has to be applied.

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 after inhalative exposure.

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

4,4´-Methylenedicyclohexyl diisocyanate has been assessed in the OECD HPV programme, 2005.


Cited from SIAR of SIAM 20 (Paris, April 19 -22, 2005): "4,4’-Methylenedicyclohexyl diisocyanate is exclusively used as an intermediate in chemical processes. A direct use of this substance is not known (...). Consistently, there is no registration of a consumer product containing 4,4’-methylenedicyclohexyl diisocyanate in the Danish, Finnish, Swedish (SPIN, 2004), and Swiss Product Register (2004). 4,4’-Methylenedicyclohexyl diisocyanate is confidentially listed in the Norwegian Product Register (SPIN, 2004), but since the main use category is “non-dispersive use”, it is assumed that the confidential registration is also for industrial use only. The exposure of consumers to 4,4’-methylenedicyclohexyl diisocyanate is unlikely to occur via consumer products, because no consumer product is known to contain 4,4’-methylenedicyclohexyl diisocyanate (...). An exposure of consumers to 4,4’-methylenedicyclohexyl diisocyanate via the environment is also unlikely to occur because there are virtually no emissions of 4,4’-methylenedicyclohexyl diisocyanate, and 4,4’-methylenedicyclohexyl diisocyanate released to environment would rapidly be degraded by photooxidants (...) and water (...)."