Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

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

Based on toxicokinetic assessment, default values of 100% are derived for both oral and respiratory absorption. A standard respiratory volume of 0.38 m3/kg/day in rat (considering 8 hours exposure) and a standard respiratory volume of 6.7 m3/person for a person at rest and 10 m3/person for a worker performing light activity (for 8 hours exposure) were considered.

AF for dose response relationship:
1
Justification:
There is no evidence of a steep dose-relationship, and a reliable NOAEL can be derived based on the dose range tested.
AF for differences in duration of exposure:
6
Justification:
The NOAEL was derived in a subacute exposure study; the extrapolation factor to the chronic exposure duration is 6.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is required for the extrapolation from an oral animal study to human inhalation exposure.
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed, as has been concluded 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:
Data from a reliable guideline study
AF for remaining uncertainties:
1
Justification:
The NOAEL is considered appropriate for the DNEL derivation.
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:
8.3 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
72
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on toxicokinetic assessment, 100% and 50% values are considered for oral and dermal absorption, respectively.

AF for dose response relationship:
1
Justification:
There is no indication of a steep dose-response, and a reliable NOAEL can be derived based on the dose range tested.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is derived in a subacute study; the extrapolation factor to the chronic exposure duration is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value for the extrapolation from an oral animal study to human dermal exposure
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed, as has been concluded 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:
The NOAEL is derived in the GLP-compliant guideline study
AF for remaining uncertainties:
1
Justification:
The NOAEL is considered appropriate for the DNEL derivation.
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:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - workers

General Population - Hazard via inhalation route

Systemic effects

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

Based on toxicokinetic assessment, default values of 100% are derived for both oral and respiratory absorption.

A standard respiratory volume of 1.15 m3/kg bw for rats (considering 24 hours exposure) was used.

AF for dose response relationship:
1
Justification:
There is no indication of a steep dose-response, and a reliable NOAEL can be derived from the dose range tested.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is derived in a subacute toxicity study; the assessment factor for the extrapolation to chronic exposure is 6.
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling is required for the extrapolation from an oral animal study to the respiratory human exposure.
AF for other interspecies differences:
1
Justification:
Additional assessment factors for interspecies differences are not needed, as has been concluded 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 concluded 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:
The NOAEL is derived in a GLP-compliant guideline study.
AF for remaining uncertainties:
1
Justification:
The NOAEL is considered appropriate for the DNEL derivation.
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:
5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
600 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

Based on the toxicokinetic assessment, values of 100% and 50% have been derived for oral and dermal absorption, respectively.

AF for dose response relationship:
1
Justification:
There is no indication of a steep dose-response, and a reliable NOAEL can be derived from the dose range tested.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is derived in a subacute study; the extrapolation factor to chronic exposure is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value
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:
The NOAEL is derived in a GLP-compliant guideline study.
AF for remaining uncertainties:
1
Justification:
The NOAEL is considered appropriate for the DNEL derivation.
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:
2.5 mg/kg bw/day
Most sensitive endpoint:
developmental toxicity / teratogenicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
120
Dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
300 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

No modification of the starting point is necessary, as the NOAEL is derived in an oral toxicity study.

AF for dose response relationship:
1
Justification:
There is no evidence of a steep dose-response, and the adequate NOAEL can be derived from the dose range tested.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is derived in a subacute study; the assessment factor for the extrapolation to chronic exposure is 6.
AF for interspecies differences (allometric scaling):
4
Justification:
Default value
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:
The NOAEL is derived in a GLP-compliant guideline study
AF for remaining uncertainties:
1
Justification:
The NOAEL is considered appropriate for the DNEL derivation.
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected

Additional information - General Population