Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
3.4 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
62 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOAEL from the oral repeated dose / reproscreen study of at least 32 days day is used for derivation of the DNEL-long-term for the inhalation route. Route-to route extrapolation can be done because there is adequate oral toxicity data, the critical effect is systemic rather than 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. To account for any uncertainties considering the toxicity potential via the oral and the inhalation route, the absorption via the inhalation route is chosen twice as high as the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012).Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8 (November, 2010). 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).
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:
6
Justification:
An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute 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:
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:
An assessment factor of 1 is applicable because the information fufils the REACH requirements a repeated dose /reproscreen study is available as well as a 28-day repeated dose toxciity study and a 14-day repeated dose dermal toxicity study similar to OECD guidelines 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 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Modified dose descriptor starting point:
NOAEL
DNEL value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only a 14-day repeated dose dermal toxicity data is available showing a higher NOAEL compared to the oral repeated dose toxicity studies. Therefore for the derivation of the NOAEL the NOAEL from the repeated dose / reproscreen study was used for derivation of the DNEL-long-term for the dermal route, being more conservative and showing a longer exposure compared to the repeated dose dermal and gavage study. 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 and there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. This is confirmed with a NOAEL from the dermal study being much higher than via the oral route. 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 some 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 key study and a NOAEL in the 32-day repeated dose / reproscreen study was derived (ECHA’s guidance, R.8.4.3.1, November 2012).
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied to extrapolate the NOAEL from sub acute 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 study and a NOAEL in the repeated dose / reproscreen 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:
no hazard 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

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 characterization.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
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):
30
Modified dose descriptor starting point:
NOAEC
DNEL value:
30 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOAEL from the repeated dose / reproscreen oral toxicity study is used for derivation of the DNEL-long-term for the inhalation route. 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 and there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher inhalation toxicity compared to oral toxicity. To account for any uncertainties considering the toxicity potential via the oral and the inhalation route, the absorption via the inhalation route is chosen twice as high as the oral route (IGHRC, 2006 as mentioned in the ECHA guidance, R.8.4.2, November, 2012) Route-to-route extrapolation was applied in accordance with ECHA’s Guidance R.8 (November, 2012). In the route to route extrapolation via the inhalation route a correction for respiratory volume is applied by using 1.15 m3/kg bw (ECHA’s guidance R.8, 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 >=32 repeated dose / reproscreen study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute 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:
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 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 for the quality of the database is not needed because well conducted repeated dose / reproscreen study and a 28-day repeated dose toxicity study are available with a reliability 1.
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:
0.6 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
Only a 14-day repeated dose dermal toxicity data is available showing a higher NOAEL compared to the oral repeated dose toxicity studies. Therefore for the derivation of the NOAEL the NOAEL from the repeated dose / reproscreen study was used for derivation of the DNEL-long-term for the dermal route. 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 and there is no evidence that the compound is subject to ‘first-pass’ metabolism which would lead to higher dermal toxicity compared to oral toxicity. This is confirmed with a NOAEL from the dermal study being much higher than via the oral route. 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 some 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 repeated dose / reproscreen study was derived (ECHA’s guidance, R.8.4.3.1, November, 2012).
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute 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. 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 for the quality of the database is not needed because two well conducted repeated dose toxicity studies with a reliability of 1 are available.
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

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.6 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
70 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
For the oral route no route to route extrapolation is needed because the oral NOAEL from the repeated / reproscreen is used for deriving the DNEL-long-term and there are no indications that oral absorption in the rat is different from humans.
AF for dose response relationship:
1
Justification:
No route to route extrapolation is needed because the route of exposure in the repeated dose toxicity study is the oral route which will also be the route for human exposure via the environment. In addition, there is no information that indicates differences in absorption via the oral route between rats and humans.
AF for differences in duration of exposure:
6
Justification:
An assessment factor of 6 has been applied to extrapolate the NOAEL from sub-acute 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 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:
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 for the quality of the database is not needed because two reliable 1 repeated dose toxicity studies are available.
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 characterization.