Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.1 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
18
Dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
73 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point us the oral NOAEL 0f 83 mg/kg bw. A factor of 2 is applied for route to route extrapolation: oral to inhalation. For animal versus human exposure the following formula is applied: 41.5*(1/0.38)*6.7/10) = 73 mg/m3.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECD TG 422 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from a OECD TG 422 study, an additional assessment factor of 6 is used to take the extrapolation of subacute data to chronic exposure into account (ECHA 2012, Chapter R8, p 29)
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for intraspecies differences:
3
Justification:
An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR110, 2010). The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients; this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 422 study according to OECD guideline (and GLP) (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 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):
72
Dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on the toxico-kinetic information it can be anticipated that dermal absorption is expected to be lower than dermal absorption and will not exceed oral absorption. Therefore the starting dose descriptor is the same: 83 mg/kg bw.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECD TG 422 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from an OECD TG 422 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convers rat to human data, as determined by ECHA (Table R.8-3, 2012)
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
3
Justification:
An assessment factor of 3 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, and includes intraspecies differences
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 422 study according to OECD guideline (and GLP) (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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:
784 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
3
Dose descriptor:
other: NOAEC: 2351 µg/cm2
AF for dose response relationship:
1
Justification:
As the NOAEC was taken as the dose descriptor starting point no (additional) assessment factor is needed (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
1
Justification:
Repeated exposure is taken into account in the exposure assessment by using events/day.
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not needed since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1) ECHA, 2012, Chapter R8.
AF for other interspecies differences:
1
Justification:
The assessment factor for remaining uncertainties can be 1. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the human skin (exposed hands) to be similarly or less sensitive compared to the skin of the mouse ear. The LLNA is selected as a model because the mouse ear is considered very thin with high blood flow and as such reflect a similar thickness and integrity compared to human skin in general.
AF for intraspecies differences:
3
Justification:
ECETOC TR No. 110 (2010) The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC, an AF of 3 for workers is advised after a detailed review of the literature. The ECETOC review is based on systemic effect. Sensitisation results from systemic exposure and therefore these ECETOC AFs can be applied here.
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: a LLNA study according to OECD guideline was used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were identified.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
36.09 mg/m³
Explanation for the modification of the dose descriptor starting point:

Starting point is the NOAEL of 83 mg/kg bw. A factor of 2 is applied for route-to-route extrapolation: oral to inhalation. In addition, for rat to human extrapolation the following formula is used: 41.5 mg/kg bw /1.15 = 36.09 mg/m3.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECD TG 422 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from a OECD TG 422 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29).
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor of 1 has been used because the difference in metabolic rate between rat and humans has been accounted for in the conversion of NOAEL in mg/kg bw to the NOAEC in mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 2012).
AF for other interspecies differences:
1
Justification:
An assessment factor of 1 has been applied because besides allometric differences no other interspecies differences need to be accounted for which has been shown by ECETOC TR 110 (2010) after a review of the scientific literature. ECETOC concludes that adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. The application the ‘remaining’ AF of 2.5 for interspecies variability would mean an unjustified compilation of AF. The ‘residual’ interspecies variability may remain following allometric scaling, but this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences as has been derived by ECETOC (TR110, 2010) based on a review of the scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.)
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 422 (2017 under GLP) is available (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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:
DNEL (Derived No Effect Level)
Value:
0.7 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):
120
Dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with ECHA guidance R.7.5-7.7. The NOAEL from the >=28-day repeated-dose oral toxicity study with reproduction/developmental toxicity screening is used for derivation of the DNEL long-term for the dermal route because no long-term dermal information is available. Route-to route extrapolation can be done because there is adequate oral toxicity data; the critical effect is systemic rather than at the site of contact. There here is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the dermal route, the absorption via the dermal route is the same as for the oral route, though higher absorption is expected for the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). In absence of dermal absorption information a factor of 1 for oral versus dermal absorption is applicable as proposed in ECHA guidance, Chapter R.8.4.2 (November, 2012).

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECD TG 422 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from a OECD TG 422 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29)
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convers rat to human data, as determined by ECHA (Table R.8-3, 2012)
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.)
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: an OECD TG 422 (2017 under GLP) is available (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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:
470 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
5
Dose descriptor:
other: NOAEC: 2351 µg/cm2
AF for dose response relationship:
1
Justification:
As the NOAEC was taken as the dose descriptor starting point no (additional) assessment factor is needed (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
1
Justification:
Repeated exposure is taken into account in the exposure assessment by using events/day.
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not needed since local effects are independent of the basal metabolic rate, allometric scaling should not be applied (allometric scaling factor of 1) ECHA, 2012, Chapter R8.
AF for other interspecies differences:
1
Justification:
The assessment factor for remaining uncertainties can be 1. For vehicle effects: an assessment factor of 1 is applied as the matrices of the products compiled from the substance are not intended to enhance penetration. For type of skin (skin thickness and skin integrity) it can be seen that the human skin (exposed hands) to be similarly or less sensitive compared to the skin of the mouse ear. The LLNA is selected as a model because the mouse ear is considered very thin with high blood flow and as such reflect a similar thickness and integrity compared to human skin in general.
AF for intraspecies differences:
5
Justification:
ECETOC TR No. 110 (2010). The intraspecies variation in humans is greater than that in the more homogenous experimental animal population. Based on an evaluation of the scientific literature by ECETOC, an AF of 5 for the general population is advised, after a detailed review of the literature for systemic effects. Sensitisation is a result from systemic effects and therefore the ECETOC systemic AFs can be applied here.
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: a LLNA study according to OECD guideline was used.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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:
DNEL (Derived No Effect Level)
Value:
0.7 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):
120
Dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
83 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The substance fulfils the REACH Annex VII to Annex XI information requirements in accordance with R.7.5-7.7 for assessing long-term systemic toxicity. The NOAEL from a >28-day repeated dose /reproscreen toxicity study is used to derive a DNEL. A DNEL derivation for the oral route is considered necessary, because oral exposure via the environment cannot be excluded.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because the dosing was well spaced in the study and a NOAEL in the OECD TG 422 study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
Since the dose descriptor is derived from a OECD TG 422 study, an additional assessment factor of 6 to take account of extrapolation of sub-acute data to chronic exposure (ECHA 2012, Chapter R8, p 29)
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convers rat to human data (ECHA guidance, 2012 Table R.8-3).
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed as has been derived in the ECETOC report (TR 110, 2010) based on a review of the scientific literature. The concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans (see below at intraspecies differences).
AF for intraspecies differences:
5
Justification:
An assessment factor of 5 has been used to account for the intraspecies differences. This factor has been retrieved by ECETOC (TR 110, 2010) based on scientific literature. The ECETOC analysis has been based on a comparison between animal and actual human data that per se includes intraspecies variability in humans. In addition, the human population under investigation comprised cancer patients, which represents a very sensitive subpopulation. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. Thus, this standard deviation represented by the GSD of 2.5-2.6 is probably due to potential differences in biological sensitivity between species, but includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfils the REACH requirements: ian OECD TG 422 (with CLP) is available (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties were 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

The DNELs for long term exposure (systemic effects) were derived in accordance with the Guidance on Information Requirements and Chemical Safety Assessment, Chapter R.8: Characterisation of dose [concentration]-response for human health with the exception of two assessment factors:

1.        Interspecies differences, remaining differences. For remaining differences it is considered that those already have been taken into account when applying an assessment factor for allometric scaling. The argumentation for this can be found in the ECETOC Guidance on Assessment Factors to Derive a DNEL (Technical Report No. 110, 2010). It is concluded that the concept of adjusting animal dose by allometric scaling predicts reasonably well the appropriate dose in humans. A Geometric Standard Deviation (GSD) of 2.5-2.6 suggests the likelihood of some variability or additional uncertainty around the predicted NOAEL in humans. This analysis is based on a comparison of animal to actual human data that per se includes intraspecies variability in humans. As the human population under investigation comprised cancer patients, this represents a very sensitive subpopulation. Thus, this additional’ variability represented by the GSD of 2.5-2.6 is probably due to not only potential differences in biological sensitivity between species, but also intraspecies differences. The intraspecies variability in humans is taken into account by the specific Assessment Factors for workers (3) and the general population (5). The introduction of the ‘remaining’ AF of 2.5 for interspecies variability would therefore mean an unjustified compilation of AF. Therefore, although ‘residual’ interspecies variability may remain following allometric scaling, this is largely accounted for in the default AF proposed for intraspecies variability, i.e. reflecting the interdependency of inter- and intraspecies AF.

2.        Intraspecies differences. The current proposed AF for intraspecies extrapolation of systemic effects for workers and the general population in the ECHA guidance differ from those proposed in the ECETOC guidance (2010). After studying both guidances it is concluded that the AF proposed by ECETOC are based on an evaluation of the scientific literature while the REACH TGD refers to standard default procedures. Therefore, the ECETOC guideline will be followed until the scientific basis for using an alternative approach has been established. This means that for workers instead of an AF of 5 as proposed in the ECHA guidance an AF of 3 will be used and for the general population instead of an AF of 10 and AF of 5.

 

ECETOC, 2010,http://www.ecetoc.org/wp-content/uploads/2014/08/ECETOC-TR-110-Guidance-on-assessment-factors-to-derive-a-DNEL.pdf