Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.47 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
8.82 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose 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 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:
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:
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 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

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:
0.42 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity 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. 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 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 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 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:
5 510 µg/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 separated with a factor of 2 (0, 25, 50 and 100%) and the dose response was shallow (EC3 was 2.69, 3.66 and 3.52, 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 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 10% corresponding with 5500 ug/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 Cashmeran are not intended to enhance penetration.
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:
low hazard (no threshold derived)

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:
0.44 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
Modified dose descriptor starting point:
NOAEC
DNEL value:
4.35 mg/m³
Explanation for the modification of the dose descriptor starting point:
No inhalation toxicity data are available. The NOAEL from the 90-day repeated-dose 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 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 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 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 fulfills 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

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:
0.25 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The NOAEL from the 90-day repeated-dose oral toxicity study is used for derivation of the DNEL long-term for the dermal route. No repeated dose dermal toxicity data are available. The NOAEL from the 90-day repeated-dose oral toxicity 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 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. 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 latter 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 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 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 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:
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 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:
3 241 µg/cm²
Most sensitive endpoint:
sensitisation (skin)
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Dose descriptor:
other: LOAEL
AF for dose response relationship:
1
Justification:
An assessment factor of 1 is applicable the doses were separated with a factor of 2 (0, 25, 50 and 100%) and the dose response was shallow (EC3 was 2.69, 3.66 and 3.52, 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 the general population.
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 10% corresponding with 5510 ug/cm2
AF for intraspecies differences:
1.7
Justification:
An intraspecies of 1.67 will be used to account for the sensitivity of the general population which may be more vulnerable compared to healthy volunteers used in the HRIPT test. The AF of 1.67 is based on the differences in sensititivity between workers and general population as has been derived in the ECETOC report for systemic toxicity based on a review of the scientific literature.
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 Cashmeran are not intended to enhance penetration.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Most sensitive endpoint:
skin irritation/corrosion

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
0.25 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
Modified dose descriptor starting point:
NOAEL
DNEL value:
10 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
The repeated 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 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 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:
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 assessment factors (ECETOC TR 110, 2010) based on 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:
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 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:
low hazard (no threshold derived)

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 workers are considered sufficiently conservative to be used in risk characterization.