Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.073 mg/m³
Most sensitive endpoint:
irritation (respiratory tract)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor:
LOAEC
AF for dose response relationship:
10
Justification:
An assessment factor of 10 is assumed to be sufficient as corrosive properties are usually steep effects
AF for differences in duration of exposure:
1
Justification:
A factor of 1 is used, because for local effects in the respiratory tract there is no substancial difference in LOAEC following acute and subacute exposure by inhalation; ECHA Guidance R8 Chapter 8.4.3.1.
AF for interspecies differences (allometric scaling):
1
Justification:
No factor for allometric scaling is needed in case of inhalation exposure. Furthermore, the factor for remaining uncertainties is not needed as the rat is a more sensitive species for inhalation exposure and an obligatory nose breather and as the rat’s ventilation frequency is higher
AF for other interspecies differences:
1
Justification:
No factor for other interspecies differencs was given, because the local effect in the respiratory tract is not triggered by other toxikokinetic or toxikodynamic differences.
AF for intraspecies differences:
3
Justification:
Using a reduced factor of 3 is justified because the critical effect is a local effect that is hardly, if at all, determined by toxicodynamics and kinetics. Absorption,distribution and elimination play no or only a minor role. Local effects are largely concentration-dependent whereas exposure time and enzyme polymorphisms are of minor importance in such cases.Due to the fact that the local effects are driven by local exposure peaks and are not supposed to worsen with time and considering the rat is over-predictive in this case, a joint assessment factor of 3 is applied for intraspecies differences and exposure duration correction.
AF for the quality of the whole database:
1
Justification:
The data are based on a good/standard quality database, which is complete, consistent contains standard information.
AF for remaining uncertainties:
1
Justification:
There are no other differences between species to be considered for the observed local effects in the respiratory tract.
Acute/short term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.073 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:
high hazard (no threshold derived)
Most sensitive endpoint:
sensitisation (skin)
Acute/short term exposure
Hazard assessment conclusion:
high hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
high hazard (no threshold derived)

Additional information - workers

Derivation of corrected starting points, overall assessment factors and DNEL´s for workers:

Oral exposure for workers is not considered to be a relevant exposure pathway. Hence DNEL´s for oral exposure of workers are not derived.

As the derivation of DNEL is not possible, because of the corrosive and skin sensitizing properties of the substance a qualitative assessment is needed for dermal exposure (short-term and long-term).

Furthermore a qualitative assessment is needed for short and long-term inhalation exposure as the derivation of DNEL is not possible because of the irritant properties to respiratory tract.

As the substance is corrosive the caustic properties represent the primary effect. Thus delineation of a dermal or inhalation DNEL after long-term inhalation exposure is not warranted because the local effects occur already at lower concentrations than systemic 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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.526 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
80
Modified dose descriptor starting point:
NOAEL
DNEL value:
42 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
assumptions: - absorptionrat = absorptionhuman) - frequency of exposure of rat (5d/wk) ≠ frequency of exposure of general population (7d/wk) corrected NOAEL oral; rep. dose = rat NOAEL oral; rep. dose * (exp. cond. rat / exp. cond. human) = rat NOAEL oral; rep. dose * (5d/wk / 7 d/wk) * (ABSrat/ ABShuman) = 59 mg/kg bw day * 0.714 * 1 = 42.1 mg/kg bw day
AF for dose response relationship:
1
Justification:
Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
AF for other interspecies differences:
1
Justification:
A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences which are not releated to differences in basal metabolic rate, but justified deviations are possible. Regarding exposure by inhalation rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Furthermore the substance is corrosive to the skin, eye and mucosa. Organ specific effects shown e. g in the repeated dose 90 day toxicity study (tubular nephrosis) are considered to be effects due to the high pH. It is assmued that animals and human will respond in the same way. Thus no differences in susceptibility which are not releated to differences in basal metabolic rate are expected between rats an humans after dermal or oral exposition or after inhalation of the substance. Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.
AF for intraspecies differences:
10
AF for the quality of the whole database:
1
Justification:
Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD
AF for remaining uncertainties:
1
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

The use of the substance isophorone diamine is restricted only to industrial and professional applications. Hence there is no need to derive DNEL´s for general population (consumers).

An indirect exposure of man via the environment might occur through ingestion of foodstuff or drinking water. Therefore, a systemic oral long-term DNEL for general population is derived and will be used to assess any possible risk that could result from indirect exposure of man via the environment .

Conversion of an rat NOAEL oral; rep. dose from 90 day rat oral repeated dose toxicity study into an corrected NOAEL oral; rep. dose (derived from example A.1; Appendix R 8-2 of TGD “Chapter R.8: Characterisation of dose [concentration]-response for human health” called only “TGD” in this text) and derivation of an systemic oral long-term DNEL for general population which will be used to assess any possible risk that could result from indirect exposure of man via the environment:

For general population:

assumptions:

- absorptionrat = absorptionhuman)

- frequency of exposure of rat (5d/wk) ≠ frequency of exposure of general population (7d/wk)

corrected NOAEL oral; rep.dose = rat NOAEL oral; rep. dose * (exp. cond.rat / exp. cond.human)

= rat NOAEL oral; rep. dose * (5d/wk / 7 d/wk) * (ABSrat/ ABShuman)

= 59 mg/kg bw day * 0.714 * 1

= 42.1 mg/kg bw day

Selected assessment factors (according to Table R 8-6 of the TGD):

- Interspecies: factor for allometric scaling (systemic) 4

- Interspecies: remaining differences (systemic) 1***

- Intraspecies (systemic) 10

- Exposure duration (systemic; subchronic to chronic) 2

- Dose-response (systemic) 1*

- Quality of the database (systemic; overall) 1**

overall Assessment Factor (overall AF) 80

* Starting point is a NOAEL. Thus standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

**Because of good/standard quality of the database the standard assessment factor 1 is used as described in chapter R 8.4.3.1 of TGD

***A factor 2.5 is suggested by the ECHA TGD for remaining interspecies differences which are not releated to differences in basal metabolic rate, but justified deviations are possible. Regarding exposure by inhalation rodents like the rat are in general more sensitive compared to humans as the rat’s ventilation frequency is higher. Furthermore the substance is corrosive to the skin, eye and mucosa. Organ specific effects shown e.g in the repeated dose 90 day toxicity study (tubular nephrosis) are considered to be effects due to the high pH. It is assmued that animals and human will respond in the same way. Thus no differences in susceptibility which are not releated to differences in basal metabolic rate are expected between rats an humans after dermal or oral exposition or after inhalation of the substance.Therefore, as a general rule a factor of 1 for remaining interspecies differences provides sufficient protection.

Calculation of systemic DNELoral; long-term :

DNELoral; long-term = corrected NOAELoral; rep. dose / overall AF

DNELoral; long-term = 42.1 mg/kg bw day / 80

DNELoral; long-term = 0.526 mg/kg bw day