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:
0.045 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
NOAEC
Value:
0.136 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 the ECHA TGD 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 for comparison:
NOAEC(subacute) = 0.24 mg/m3 (Bayer AG, 2003) versus NOAEC(subchronic) = 0.27 mg/m3 (Pauluhn, 2008) and
LOAEC (subacute) = 1.05mg/m3 (Bayer AG, 2003) versus LOAEC (subchronic) = 1.1 mg/m3 (Pauluhn, 2008)
On this basis it is not expected that a longer duration of the study would change the outcome and an AF of 1 is warranted.
AF for interspecies differences (allometric scaling):
1
Justification:
According to the ECHA TGD allometric scaling should not be applied for local effects, since local effects are independent of the basal metabolic rate, therefore AF 1 is chosen.
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences, but justified deviations are possible. Rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.
AF for intraspecies differences:
3
Justification:
As a conclusion the remaining relevant differences between individuals which should be represented by the intraspecies assessment factor are non-metabolic differences and most of these non-metabolic differences should
be rather small due to the homogeneousness of the workers sub-population. Furthermore in general for the workers sub-population metabolic differences should contribute much more to such a intraspecies assessment
factor than non-metabilic differences, but the local toxic effect of the substance Isophorone diisocyanate is not related to metabolic mechanisms, because it is a simple destruction of membranes due to corrosivity of the
substance. Therefore a reduced assessent factor of 3 for remaining intraspecies differences within the workers sub-population provides sufficient protection. The possibility to reduce the default assessment factor is in line
with the statement of the TGD that default assessment factors represent a fall back position rather than the starting point (see R.8.4.3).
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:
0.045 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
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:
high hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

For workers, which are exposed via inhalation, relevant DNELs for acute and long-term inhalation effects of 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate (syn. isophorone diisocyanate) have to be derived. Additionally, the sensitization potential after skin contact to 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanate has to be assessed.

For repeated dose toxicity a subacute and a subchronic inhalation study with aerosol exposure of 3-Isocyanatomethyl-3.5.5-trimethylcyclohexyl isocyanat to rats are available (Bayer AG, 2003 and Pauluhn, 2008). The obtained LOAECs were 1.05 mg/m³ (subacute study) and 1.1 mg/m³ (subchronic study), respectively, for effects governed by irritation of the respiratory tract. No indications of systemic toxicity effects were found within the studies.

Histopathological changes in the respiratory tract were related to portal-of-entry, local irritant effects, i. e. epithelial metaplasia and inflammatory changes predominantly in the upper respiratory tract (larynx). For the subchronic study the NOAEC relating to these changes was set 0.27 mg/m³ (Pauluhn, 2008). The result of a developmental toxicity test (NOAEC: 0.929 mg/m³ analytical concentration for developmental and maternal toxicity; developmental toxicity considered to be a secondary effect as a result of maternal toxicity; maternal toxicity predominantly caused by irritative effects on respiratory tract; Klaus, 2004) is in line with the NOAEC of 0.27 mg/m³ based on the subchronic inhalation study. Therefore 0.27 mg/m³ was used as a starting point for the derivation of a DNELlong-term for long-term local effects for inhalation.

 

DNELlong-termfor workers for inhalation route (local effects):

For rats exposed to the substance 6 h/d 5 d/w for 13 weeks      NOAEC = 0.27 mg/m³

 

Correction of dose-descriptors (ECHA Guidance, part B, chapter R.8.4):

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  

      

corrected NOAEC = 0.136 mg/m³

 

According to ECHA Guidance "Guidance on information requirements and chemical safety assessment; Chapter R.8: Characterisation of dose [concentration]-response for human health" chapter R.8.4 a series of assessment factors (AF) were applied to the NOAEC from rats and are summarized in the table below. 


 

Assessment

Assessment Factor

 

1For interspecies differences rat vs. human (allometric scaling)  

1

2For remaining interspecies differences

1

3For intraspecies differences in workers                               

3

4Differences in duration of exposure

1

5Dose-response relationship

1

6Quality of whole Database

1

Overall Assessment Factor

3

 

1According to the ECHA TGD allometric scaling should not be applied for local effects, since local effects are independent of the basal metabolic rate, therefore AF 1 is chosen.

 2A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences, but justified deviations are possible. Rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.

3For intraspecies variability, the default assessment factor of 5 is recommended for workers for effects on respiratory tract (see Appendix R. 8 -9 of TGD). Furthermore chapter R.8.4.3.1 of the TDG states that in general the assessment factor for local (concentration-dependent) effects is very scarce and no attempt has therefore been made to refine the default intraspecies factors already used for systemic effects. So TGD proposes to use the same assessment factor (5 in case of workers sub-population) for local as well as for systemic effects as generic step but justified deviations are possible.

In general the assessment factor should cover intraspecies differences which are a result of biological factors such as genetic polymorphism affecting e.g. toxicokinetic/metabolism, age, gender, health status and nutritional status as well as environmental influences as described in TGD. Regarding Isophorone diisocyanate the mechanism of toxicity at the port of entry is still a mechanical destruction of membranes because of the corrosive effects of the substance. Metabolic activities are not involved in this mechanism. Hence intraspecies differences should not be related to metabolic differences between the individuals und thus these differences could be caused only by non-metabolic differences. The workers sub-population is more homogeneous than other populations also for non-metabolic effects like e.g. good health status, restricted age range, good nutrition status.

So as a conclusion the remaining relevant differences between individuals which should be represented by the intraspecies assessment factor are non-metabolic differences and most of these non-metabolic differences should be rather small due to the homogeneousness of the workers sub-population. Furthermore in general for the workers sub-population metabolic differences should contribute much more to such a intraspecies assessment factor than non-metabilic differences, but the local toxic effect of the substance Isophorone diisocyanate is not related to metabolic mechanisms, because it is a simple destruction of membranes due to corrosivity of the substance. Therefore a reduced assessent factor of 3 for remaining intraspecies differences within the workers sub-population provides sufficient protection. The possibility to reduce the default assessment factor is in line with the statement of the TGD that default assessment factors represent a fall back position rather than the starting point (see R.8.4.3).  

4The assessment factor suggested by the ECHA TGD 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 for comparison: NOAECsubacute= 0.24 mg/m3 (Bayer AG, 2003) versus NOAEC subchronic = 0.27 mg/m3 (Pauluhn, 2008)

and LOAEC subacute= 1.05mg/m3 (Bayer AG, 2003) versus LOAEC subchronic = 1.1 mg/m3 (Pauluhn, 2008)

On this basis it is not expected that a longer duration of the study would change the outcome and an AF of 1 is warranted.  

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

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 3.

                                 

DNELlong-termfor workers for inhalation route – local effects = (NOAEC corr.) : (Overall AF)

         

                                      

 

 DNELlong-termfor workers for inhalation route – local effects = 0.045 mg/m³

This derived long term DNEL for workers for inhalation route (local effects) is in line with the German Occupational Limit Value (= Arbeitsplatzgrenzwert (AGW) =0.046 mg/m3) as listed in Technical Rule for Hazardous Substances (TRGS) No. 900 (Joint Ministerial Gazette (GMBI) 2010 Nr. 5-6 S. 111 (04.02.2010).

According to the TRGS No. 900 the AGW multiplied by an exceeding factor results in a 15 minutes average value. The exceeding factor(Überschreitungsfaktor), which is set per default 1 when the deviation of the limit value is governed by local effects or by the respiratory sensitization potential of the substance (could be adjusted to max. 8 on a case by case decision). For Isophorone diisocyanate an exceeding factor of 1 is

applied, since the most prominent effect of the substance is the portal-of-entry dependent local irritation both for the acute and for the long-term

toxicity, leading to the 15 minutes average value or

DNELacutefor workers for inhalation route – local effects of 0.045 mg/m³.

This procedure is in accordance to ECHA Guidance, Chapter R.8., Appendix R. 8-8,Box 6 and is in line with the German15 minutes average value.(=

0.046 mg/m³). In addition a ceiling limit value of 0.092 mg/m³ is stated (using an exceeding factor of 2) which may be exceeded at no time (Joint

Ministerial Gazette (GMBl) 2010 Nr. 5-6 S. 111 (04.02.2010).

In animal studies as well as in occupational health reports a dermal sensitization potential was shown for isophorone diisocyanate. According to the potency categorisation approach isophorone diisocyanate is classified as a moderate skin sensitizer based on a Guinea Pig Maximization Test (10 % induction conc., 85 % incidence of sensitization; Hüls/IBR, 1983).

At present no validated animal model is available to assess the potential for respiratory sensitization or asthma in humans, and one animal study did not show respiratory tract sensitization when exposed by inhalation (challenge) following intradermal induction. However, due to the well known reactivity of diisocyanates, respiratory sensitization is likely to occur. Althrough some of the results of the following studies are ambiginous and still under discussion this hypothesis will be supported by further investigations (Plitnick 2005, De Jong et al. 2009, Arts et al. 2008, Farraj et al. 2007, Selgrade et al. 2006) leading to the conclusion that Isophorone diisocyanate appears to have some potential to induce respiratory hypersensitivity.

Because 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. Substances with R42/Cat. 1 for respiratory sensitization have to be allocated to the high hazard category (ECHA Guidance on information requirements and chemical safety assessment – Part E: Risk characterisation (May 2008)). 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.

Corrosive effect to the skin and irritant properties on eye and mucosa are also reflected in studies investigating effects on skin (Krötlinger 1994) and eye (Mobay Chemical 1987, Schreiber 1981).Qualitative assessement: Substance is considered to be corrosive to the skin and irritant to eyes and mucosa. No DNEL can be derived from the data of the studies because no dose response information is available.

 

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

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

Cited from SIAR for SIAM 23 (Korea, October 17 -20, 2006): "In order to avoid harm that may be caused when 3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate is used by private consumers, the producers have agreed to recommend in their safety data sheets that handling the substance “requires appropriate protective measures. These products may therefore be used only in industrial or trade applications. They are not suitable for use in homeworker (DIY) applications.” Because Isophorone diisocyanate (3-isocyanatomethyl-3,5,5-trimethylcyclohexyl isocyanate) is used only in industrial and professional applications there is no need to derive DNEL´s for consumers.