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Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.67 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
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
22 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. In the route to route extrapolation for the inhalation route a correction for respiratory volume is applied. The oral rat study NOAEL is modified into a NOAEC for human inhalation using ECHA guidance: 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). In addition, the inhalation absorption is twice as high as oral absorption. Therefore, the modified dose descriptor is calculated as follows: 25 mg/kg bw NOAEL / 2 (oral versus inhalation) / 0.38 x (6.7/10) = 22 mg/m3.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because dosing is spaced well in the one generation study and a NOAEL is 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 (the-one generation study is considered to be a sub chronic study because exposure days are > 90-days) 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 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 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:
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 fulfills the REACH requirements: a one generation study in combination with a 28-day repeated dose toxicity 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

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:
1.43 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
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
34.3 mg/kg bw/day
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. 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 the route to route extrapolation for the dermal route the experimentally determined value is used which is 36.4 %.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because dosing was well spaced in the selected study and a NOAEL 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 (the one-generation study is considered to be a chronic study) to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (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:
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 selected study and a NOAEL 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:
2.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
An assessment factor of 1 is applicable the doses were well separated with a factor of 2 (0, 1, 2.5, 5, 10 and 25 %. There was dose response starting at 5 % (EC3 was 0.6, 0.7, 1.3 and 4.9, respectively).
AF for differences in duration of exposure:
1
Justification:
An assessment factor of 1 is applicable because repeated exposure is performed during testing and reflects exposure conditions of workers.
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 sensitisation 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 because a well conducted HRIPT test is available showing a NOAEL of 15 % corresponding with 8264 μg/cm2/%
AF for intraspecies differences:
1
Justification:
An intraspecies factor is not needed. This is because the well conducted HRIPT with more than 100 healthy subjects are expected to be from a similar sensitive population as the working population and therefore the intraspecies sensitivity is sufficiently covered.
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 study and a HRIPT test are available.
AF for remaining uncertainties:
1
Justification:
Vehicle effects: An assessment factor of 1 is applied as the matrices of the products compiled from thest substance are not intended to enhance penetration.
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

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. For inter and intraspecies factors the ECETOC TR 110 (2010) has been used because these assessment factors are scientifically sound, the test substance is considered to be within the applicability domain, and these assessment factors have been adequately documented. Therefore the DNELs for all human health points relevant for workers are considered sufficiently conservative to be used in risk characterization.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.09 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
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
10.9 mg/m³
Explanation for the modification of the dose descriptor starting point:

Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8. In the route to route extrapolation for the inhalation route a correction for respiratory volume is applied. The oral rat study NOAEL is modified into a NOAEC for human inhalation for the General population using ECHA guidance: Starting point is the NOAEL of 25 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: 25 mg/kg bw NOAEL / 2 (oral versus inhalation)/1.15 = 10.9 mg/m3.

AF for dose response relationship:
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 one generation 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 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 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. 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. To be conservative a factor of 5 has been chosen.
AF for the quality of the whole database:
1
Justification:
An assessment factor of 1 is applicable because the information fulfills the REACH requirements: a one generation study in combination with a 28-day repeated dose toxicity 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

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:
0.86 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
Value:
25 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
34.3 mg/kg bw/day
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. 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. For the dermal route the experimentally determined value is used which is 36.4%.

AF for dose response relationship:
1
Justification:
No additional assessment factor for dose response is needed because dosing was well spaced in the selected study and a NOAEL 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 (the one generation study is considered to be a chronic study) to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (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. The chosen factor of 5 is therefore considered to be conservative.
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 a one generation study supported by a 28-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:
1.5 mg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
1.7
Dose descriptor:
other: NOAEL
AF for dose response relationship:
1
Justification:
An assessment factor of 1 is applicable the doses were well separated with a factor of 2 (0, 1, 2.5, 5, 10 and 25%). The dose response started at 5% (EC3 was 0.6, 0.7, 1.3 and 4.9, respectively).
AF for differences in duration of exposure:
1
Justification:
An assessment factor of 1 is applicable because repeated exposure is performed during testing and reflects exposure conditions of workers.
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 because a well conducted HRIPT test is available showing a NOAEL of 15% corresponding with 8264 ug/cm2/% (=0.15 x 200 mg/3.63 cm2)
AF for intraspecies differences:
1.7
Justification:
An intraspecies factor is applied. This is because the well conducted HRIPT with more than 100 healthy subjects may be somewhat less sensitive compared to general population as the working population and therefore the intraspecies factor between workers and general population established in the ECETOC TR110 report has been used (5/3 = 1.7).
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 study and a HRIPT test are available.
AF for remaining uncertainties:
1
Justification:
Vehicle effects: An assessment factor of 1 is applied as the matrices of the products compiled from the test substancel are not intended to enhance penetration.
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:
0.63 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
Value:
25 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

The selected conservative NOAEL has been derived from an oral one generation study dose toxicity test has been performed via the oral route and therefore route to route extrapolation is not needed, because there are no indications that rat has a different oral absorption compared to humans.

AF for dose response relationship:
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 differences in duration of exposure:
2
Justification:
An assessment factor of 2 has been applied to extrapolate the NOAEL from sub chronic (the one generation study is considered to be a subchronic study because of the exposure > 90d) to a chronic study as presented in ECHA’s guidance R.8.4.3.1 and table R.8-5, (November, 2012)
AF for interspecies differences (allometric scaling):
1
Justification:
For allometric scaling a factor of 4 is applicable to convert 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:
4
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. Therefore the selected factor of 5 is considered to be sufficiently conservative
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

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. For inter and intraspecies factors the ECETOC TR 110 (2010) has been used because these assessment factors are scientifically sound, the test substance is considered to be within the applicability domain, and these assessment factors have been adequately documented. Therefore the DNELs for all human health points relevant for workers are considered sufficiently conservative to be used in risk characterisation.