Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
30 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):
6
Dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
182 mg/m³
Explanation for the modification of the dose descriptor starting point:

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. Also, there is no evidence that the compound is subject to ‘first pass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. There is experimental toxico-kinetic oral absorption information available which is used for conversion. The oral absorption is 86%. The absorption via the inhalation route is chosen as 100% as mentioned in the IGHRC (2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). In the route-to-route extrapolation for the inhalation route a correction for respiratory volume is applied. The respiratory volume of rats (0.38 m³/kg bw) is multiplied by the respiratory volume of human (6.7 m³/person) and corrected for the respiratory volume for light activity to address the workers (10 m³/person). NOAECcorr = 120 mg/kg/d*(1/0.38 m3/kg/d)*(0.86*1)*0.67=182 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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic 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 NOEC mg/m3, as presented in ECHA’s guidance R.8, figure R. 8-2 (November, 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 (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:
(In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
28.7 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):
24
Dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
688 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to route extrapolation has been done because there is adequate oral toxicity data, while the dermal toxicity information was confounded by oral exposure. The critical effect is systemic. Also, there is no evidence that the compound is subject to ‘first pass’ metabolism which would lead to higher dermal compared to oral toxicity. Route-to-route extrapolation was applied using the experimental toxico-kinetic information of the oral and dermal route in line with ECHA’s Guidance R.8. The oral absorption is 86% and the dermal absorption is 15%. NOAELcorr = 120 mg/kg/d*0.86 (oral absorption) / 0.15 (dermal absorption) = 688 mg/kg bw day.

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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic 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 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.
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:
No additional assessment factor for dose response is needed because a dosing was well spaced in the study and a NOAEL in the 90-day study was derived (ECHA’s Guidance, R.8.4.3.1, November, 2012).
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
648 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
NOAEC
AF for dose response relationship:
1
Justification:
For the LLNA study an assessment factor of 1 is applicable, because 1) the NOAEC is used as a starting point; 2) the doses were well separated with a factor of 2 (2.5, 5, 10, 25, 50 %) and; 3) the dose response was 1.4, 2.4, 5.2, 28.9, and 13.5%, respectively.
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 because the experimental results are obtained from a HRIPT test.
AF for other interspecies differences:
1
Justification:
An additional assessment factor for interspecies differences is not applied because the sensitisation NOEC in mice is lower compared to those in humans: 2.5 and 40%, respectively.
AF for intraspecies differences:
1
Justification:
The healthy subjects exposed in the HRIPT study are considered to be of the same susceptebility as the worker population and therefore an intraspecies factor is not needed.
AF for the quality of the whole database:
1
Justification:
An assessment factor for the quality of the database is not needed because a well-conducted LLNA guideline study and a HRIPT study is available.
AF for remaining uncertainties:
1
Justification:
Assessment factor for remaining uncertainties is not needed. 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 skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

In deriving the DNELs for hazard identification for inhalation and the dermal route of exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors used have been adequately documented. For inter- and intraspecies assessment factors have been used which were concluded to be scientifically sound by ECETOC (TR 110, 2010) and which are based on a thorough review of the scientific literature. Therefore, the DNELs for all human health points relevant for workers are considered sufficiently conservative to be used in risk characterisation.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
9 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):
10
Dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
DNEL value:
90 mg/m³
Explanation for the modification of the dose descriptor starting point:

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. Also, there is no evidence that the compound is subject to ‘first pass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. There is experimental toxico-kinetic oral absorption information available which is used for conversion. The oral absorption is 86%. The absorption via the inhalation route is chosen as 100% as mentioned in the IGHRC (2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012). In the route-to-route extrapolation for the inhalation route a correction for respiratory volume is applied. The starting point is a NOAEL of 120 mg/kg bw. A factor 0.86 is applied for route to route extrapolation resulting in 103.2 mg/kg bw. Converting this value to inhalation NOAEL: 103.2*1/1.15=90 mg/m3 (rounded off from 89.73).

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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012
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:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
17.2 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
688 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to route extrapolation has been done because there is adequate oral toxicity data, while the dermal toxicity information was confounded by oral exposure. The critical effect is systemic. Also, there is no evidence that the compound is subject to ‘first pass’ metabolism which would lead to higher dermal compared to oral toxicity. Route-to-route extrapolation was applied using the experimental toxico-kinetic information of the oral and dermal route in line with ECHA’s Guidance R.8. The oral absorption is 86% and the dermal absorption is 15%. NOAECcorr = 120 mg/kg/d*0.86 (oral absorption) / 0.15 (dermal absorption) = 688 mg/kg bw day.

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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub-chronic to a chronic study as presented in R.8.4.3.1 and table R.8-5 (ECHA’s guidance, November, 2012.
AF for interspecies differences (allometric scaling):
4
Justification:
For allometric scaling a factor of 4 is applicable to convers rat to human data. ECETOC (TR110, 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.
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, and includes intraspecies differences.
AF for the quality of the whole database:
1
Justification:
In accordance with ECHA Guidance on information requirements and chemical safety assessment – Chapter 8: Characterisation of dose [concentration]-response for human health, the evaluation of the total toxicological database should include an assessment whether the available information as a whole meets the tonnage driven data requirements necessary to fulfil the REACH requirements, or whether there are data gaps (completeness of the database). Furthermore, the hazard data should be assessed for the reliability and consistency across different studies and endpoints and taking into account the quality of the testing method, size and power of the study design, biological plausibility, dose-response relationships and statistical association (adequacy of the database). When taking into account the standard information requirements and the completeness and consistency of the database the default assessment factor of 1, to be applied for good/standard quality of the database, is recommended.
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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:
380 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1.7
AF for dose response relationship:
1
Justification:
For the LLNA study an assessment factor of 1 for dose response is applicable, because 1) the NOAEC is used as a starting point; 2) the doses were well separated with a factor of 2 (2.5, 5, 10, 25, 50 %) and; 3) the dose response was (stimulation index was 2.3, 4.8, and 13.1% respectively
AF for differences in duration of exposure:
1
Justification:
An assessment factor of 1 is applicable, because the LLNA is considered to be sufficiently sensitive for assessing skin sensitization; 1) considering presence and absence of skin sensitization and; 2) determining a quantitative value for risk characterization (see note 17 in R.8, Application of AFs to the correct starting point to obtain the induction specific DNEL, page 125, 1st par.
AF for interspecies differences (allometric scaling):
1
Justification:
An assessment factor for allometric scaling is not needed because metabolic rates differences between mouse and human are not expected to be important for the skin sensitization of this substance, because the parent substance is causing the effect.
AF for other interspecies differences:
1
Justification:
An assessment factor for interspecies differences is not needed as according to ECHA Guidance R8 (2012) this applies to differences in toxicokinetic differences not related to metabolic rate and toxicodynamic differences. As skin sensitisation is a local effect caused by the parent compound differences in toxicokinetic and toxicodynamic properties are not important.

AF for intraspecies differences:
1.7
Justification:
An assessment factor of 1.7 has been used to account for the intraspecies differences. In view of skin sensitization being a systemic rather than a local effect the ECETOC assessment factor consumer /worker is used here, being a factor 1.7 (5/3) (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 for the quality of the database is not needed because well-conducted LLNA guideline studies and a well-conducted HRIPT study are available.
AF for remaining uncertainties:
1
Justification:
Assessment factor for remaining uncertainties is not needed. 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 skin of the back of the human volunteer and the skin of the mouse ear are considered sufficiently similar and more sensitive, respectively, compared to the exposed hands of the worker/consumer. Therefore an AF is not needed.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3 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):
40
Dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
DNEL value:
120 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation is not needed because the exposure in the key study is via the oral route.

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 90-day study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
2
Justification:
Since the dose descriptor is derived from a 90-day study, an additional assessment factor of 2 to take account of extrapolation of subchronic 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. ECETOC (TR110, 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 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, 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: a 90-day study according to OECD guideline (and GLP).
AF for remaining uncertainties:
1
Justification:
An assessment factor of 1 is applicable, because there are no remaining uncertainties, which have not already been accounted for.
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

In deriving the DNELs for hazard identification for inhalation, dermal route and oral exposure mostly ECHA’s guidance is used, which is generally conservative by using default values in absence of data outside the requirements of REACH regulation Annex VII to Annex XI. In addition, the used assessment factors have been adequately documented. Therefore the DNELs for all human health points relevant for the general population are considered sufficiently conservative to be used in risk characterisation.