Registration Dossier

Diss Factsheets

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
12.23 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):
12.5
Dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
152.93 mg/m³
Explanation for the modification of the dose descriptor starting point:

From prenatal development toxicity study, a NOAEL of 75mg/kg/day for maternal and development toxicity has been chosen for derivation of DNELs. The NOAEL of 75 mg/kg/day was converted to an inhalation dose using the conversion factor of 0.23 m3/kg BW/8 hours. Further adjustments are made for light work (0.67) and for 100% vs. 50% bioavailability and 1.4 for a 7 day experimental exposure to a 5 -day workweek. This results in the modified dose descriptor of 152.93 mg/m3


Corrected NOAEC = 75 mg/kg bw/day x (1/0.23 m3/ mg/kg bw/day) x 0.67 x 0.5 x 1.4 = 152.93 mg/m3

AF for dose response relationship:
1
Justification:
No uncertainties in the dose descriptor = NOAEL/NOAEC
AF for differences in duration of exposure:
1
Justification:
As the DART study duration is finite, therefore no assessment factor required
AF for interspecies differences (allometric scaling):
1
Justification:
Default for inhalation, no additional assessment factors for allometric scaling necessary. Since the interspecies differences have already been taken into account (delineation of corrected NOAEC)
AF for other interspecies differences:
2.5
Justification:
Default (a standard procedure to correct differences in metabolic rate, toxicokinetics and toxicodynamics
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers
AF for the quality of the whole database:
1
Justification:
Default - No remaining uncertainties in the derived DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties to account 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:
10.5 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):
30
Dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
315 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

From prenatal development toxicity study, a NOAEL of 75mg/kg/day for maternal and development toxicity has been chosen for derivation of DNELs. For modifying the dose descriptor, the dermal absorption of factor 100% is applied. Furthermore the NOAEL is corrected for duration of exposure (24h in rabbits Vs 8h in workers) and 7 days in rabbits vs 5 days in workers.


Corrected NOAEL = 75 mg/kg bw/day x (24h/8h) x 7d/5d = 315 mg/kg bw/day

AF for dose response relationship:
1
Justification:
No uncertainties in the dose descriptors = NAOEL/ NOAEC
AF for differences in duration of exposure:
1
Justification:
DART study duration is finite, therefore no assessment factor required
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default allometric scaling factor for systemic effects oral to dermal for rabbits
AF for other interspecies differences:
2.5
Justification:
Default (a standard procedure to correct differences in metabolic rate, toxicokinetics and toxicodynamics
AF for intraspecies differences:
5
Justification:
Default assessment factor for workers
AF for the quality of the whole database:
1
Justification:
Default - No remaining uncertainties in the derived DNEL
AF for remaining uncertainties:
1
Justification:
There are no remaining uncertainties to account 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

No oral DNEL for workers.


Worker DNEL long-term systemic for inhalation route


Start point:       NOAEL 75 mg/kg bw/day (based on oral Prenatal developmental study in rabbits)


Respiratory volume rat (sRV) (worker (8 h): 1/0.23):                                                         326.09 mg/m3


Correction for respiratory bioavailability (100%/50%):                                                      163.04 mg/m3


Corrected for 7 days of animal dosing to a 5-day work week (1.4x value):                         228.26 mg/m3


Differences in respiratory volume (default factor "light activity worker"):                         152.93 mg/m3


Corrected NOAEC:                                                                                                       152.93 mg/m3


Remaining interspecies differences:                                                                                  2.5


Intraspecies differences:                                                                                                  5


Differences in duration of exposure (Development toxicity study):                                       1


Dose response and endpoint specific/severity issues:                                                          1


Quality of database:                                                                                                         1


Overall factor (product of individual factors):                                                                     12.5


=>Worker DNEL long-term for inhalation route-systemic:                                                   12.23 mg/m3


Worker DNEL long-term systemic for dermal route


Start point:      NOAEL 75 mg/kg bw/day (based on oral Prenatal developmental study in rabbits)


Differences in absorption:           Abs (oral-rat) / Abs (dermal-human):                                 1


Correction for 7 day/week dosing in the study to a 5 day work week:                                    1.4


NOAEL is corrected for duration of exposure (24h in rabbits Vs 8h  in workers)                       3


=>Corrected NOAEL:                                                                                                  315 mg/kg bw/day


Interspecies differences:  Allometric scaling:                                                                        2.4


Remaining interspecies differences:                                                                                     2.5


Intraspecies differences:                                                                                                     5


Differences in duration of exposure (Developmental toxicity):                                                 1


Dose response and endpoint specific/severity issues:                                                             1


Quality of database:                                                                                                            1


Overall factor (product of individual factors):                                                                         30


=>Worker DNEL long-term for dermal route-systemic:                                                 10.5 mg/kg bw/day

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.17 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):
25
Dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Modified dose descriptor starting point:
NOAEC
Value:
54.35 mg/m³
Explanation for the modification of the dose descriptor starting point:

From prenatal development toxicity study, a NOAEL of 75mg/kg/day for maternal and development toxicity has been chosen for derivation of DNELs. The NOAEL of 75 mg/kg/day was converted to an inhalation dose using the conversion factor of 0.69 m3/kg BW/24 hours for rabbit. Further adjustments are made for 100% vs. 50% bioavailability. This results in the modified dose descriptor of 152.93 mg/m3


Corrected NOAEC = 75 mg/kg bw/day x (1/0.69 m3/ mg/kg bw/day) x 0.5 = 54.35 mg/m3

AF for dose response relationship:
1
Justification:
No uncertainties in the dose descriptor = NOAEL/NOAEC
AF for differences in duration of exposure:
1
Justification:
As the DART study duration is finite, therefore no assessment factor required.
AF for interspecies differences (allometric scaling):
1
Justification:
Default for inhalation, no additional assessment factors for allometric scaling necessary. Since the interspecies differences have already been taken into account (delineation of corrected NOAEC)
AF for other interspecies differences:
2.5
Justification:
Default (a standard procedure to correct differences in metabolic rate, toxicokinetics and toxicodynamics
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
Default - No remaining uncertainties in the derived DNEL
AF for remaining uncertainties:
1
Justification:
There are no additional uncertainties
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:
1.25 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):
60
Dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

From prenatal development toxicity study, a NOAEL of 75mg/kg/day for maternal and development toxicity has been chosen for derivation of DNELs. For modifying the dose descriptor, the dermal absorption of factor 100% is applied and route to route extrapolation is 100%


Corrected NOAEL = 75 mg/kg bw/day x (100%/100%) = 75 mg/kg bw/day

AF for dose response relationship:
1
Justification:
No uncertainties in the dose descriptor = NOAEL/NAOEC
AF for differences in duration of exposure:
1
Justification:
As the DART study duration is finite, therefore no assessment factor required
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default allometric scaling factor for systemic effects oral to dermal for rabbits
AF for other interspecies differences:
2.5
Justification:
Default (a standard procedure to correct differences in metabolic rate, toxicokinetics and toxico-dynamics
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
No remaining uncertainties for this derived DNEL
AF for remaining uncertainties:
1
Justification:
There are no additional uncertainties
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:
1.25 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):
60
Dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Modified dose descriptor starting point:
NOAEL
Value:
75 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:

From prenatal development toxicity study, a NOAEL of 75mg/kg/day for maternal and development toxicity has been chosen for derivation of DNELs. For modifying the dose descriptor, the factor 100% bioavailability (oral to oral) has been selected and default value for route-to-route extrapolation is 100%


Corrected NOAEL = 75 mg/kg bw/day x (100%/100%) = 75 mg/kg bw/day

AF for dose response relationship:
1
Justification:
No uncertainties in the dose descriptor = NOAEL/NAOEC
AF for differences in duration of exposure:
1
Justification:
As the DART study duration is finite, therefore no assessment factor required
AF for interspecies differences (allometric scaling):
2.4
Justification:
Default allometric scaling factor for systemic effects oral / dermal for rabbits
AF for other interspecies differences:
2.5
Justification:
Default (a standard procedure to correct differences in metabolic rate, toxicokinetics and toxico-dynamics
AF for intraspecies differences:
10
Justification:
Default assessment factor for general population
AF for the quality of the whole database:
1
Justification:
No remaining uncertainties for this derived DNEL
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties for this derived DNEL
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

General Population DNEL long-term systemic for oral route


Start point:        NOAEL:               75 mg/kg bw/day (based on oral Prenatal developmental toxicity study in rabbits).


Differences in absorption Abs (oral-rabbit) / Abs (oral-human):                                               1


=> Corrected NOAEL:    75 mg/kg bw/day


Interspecies differences: Allometric scaling:                                                                           2.4


Remaining interspecies differences:                                                                                       2.5


Intraspecies differences:                                                                                                       10


Differences in duration of exposure (DART study):                                                                   1


Dose response and endpoint specific/severity issues:                                                                1


Quality of database:                                                                                                               1


Overall factor (product of individual factors):                                                                            60


=>General Population DNEL long-term for oral route-systemic:                              1.25 mg/kg bw/day


 


General Population DNEL long-term systemic for dermal route


Start point:        NOAEL:               75 mg/kg bw/day (based on oral Prenatal developmental toxicity study in rabbits).


Differences in absorption Abs (oral-rabbit) / Abs (dermal-human):                                                   1


=> Corrected NOAEL:    75 mg/kg bw/day


Interspecies differences: Allometric scaling:                                                                                    2.4


Remaining interspecies differences:                                                                                                2.5


Intraspecies differences:                                                                                                                10


Differences in duration of exposure (DART study):                                                                            1


Dose response and endpoint specific/severity issues:                                                                        1


Quality of database:                                                                                                                       1


Overall factor (product of individual factors):                                                                                    60


=>General Population DNEL long-term for dermal route-systemic:                              1.25 mg/kg bw/day


 


General Population DNEL long-term systemic for inhalation route


Start point:                                        NOAEL 75 mg/kg bw/day (based on oral Prenatal developmental toxicity study in rabbits).


Respiratory volume of rabbit (sRV) (Rabbit - human 24h general population: 1/0.69):            108.70 mg/m3


Correction for respiratory bioavailability (100%/50%):                                                         54.35 mg/m3


Corrected NOAEC:                                                                                                             54.35 mg/m3


 


Remaining interspecies differences:                                                                                      2.5


Intraspecies differences:                                                                                                      10


Differences in duration of exposure (for DART studies):                                                           1


Dose response and endpoint specific/severity issues:                                                              1


Quality of database:                                                                                                             1


Overall factor (product of individual factors):                                                                         25


=>General Population DNEL long-term for inhalation route-systemic:                       2.17 mg/m3