Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
18
Modified dose descriptor starting point:
NOAEC
Value:
436.2 mg/m³
Explanation for the modification of the dose descriptor starting point:
no repeated dose toxicity study via inhalation route is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
6.94 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
72
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no dermal repeated dose toxicity study is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
3
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricaboxylic acid cycle) makes a lower variability likely, hence the AF of 3 by ECETOC (2010) is sufficiently conservative for workers.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - workers

Route-to-route extrapolation:

Oral to inhalatory

Only oral studies are available.

Extrapolation oral to inhalation: AF 2

 

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD422 guideline study (dose levels: 50, 175 and 500 mg/kg bw/d). No treatment-related effects were noted -> NOAEL (repeated dose, reproduction, neurotoxicity) = 500 mg/kg bw/d

 

DNEL worker, chronic dermal systemic: 6.94 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 500 mg/kg bw/d

Overall AF: 4*1*3*6*1*1 = 72

 

DNEL worker, chronic inhalative systemic: 24.2 mg/m³

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 436.2 mg/m³

inhalatory NOEC (8 h)  = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-humanx sRVhuman/ wRV

                                 = 500 x 1/0.384 x 50/100 x 6.7/10

Overall AF: 1*1*3*6*1*1 = 18

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
7.2 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
217 mg/m³
Explanation for the modification of the dose descriptor starting point:
no repeated dose toxicity study via inhalation route is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
1
Justification:
No allometric scaling rat to humans as inhalation; differences in respiratory volume already included in route-to-route extrapolation (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown but no further hazard information necessary as no exposure expected
DNEL related information

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no dermal repeated dose toxicity study is available
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
no hazard identified
Acute/short term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
4.17 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: ECHA REACH Guidance and ECETOC 2010
Overall assessment factor (AF):
120
Modified dose descriptor starting point:
NOAEL
Value:
500 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
no route-to-route extrapolation required
AF for dose response relationship:
1
Justification:
The NOAEL is reliable. No adjustment is required.
AF for differences in duration of exposure:
6
Justification:
The NOAEL is based on a 33-40 day study. AF for extrapolation from sub-acute to chronic (ECHA 2008).
AF for interspecies differences (allometric scaling):
4
Justification:
Allometric scaling rat to humans AF 4 (ECHA 2008).
AF for other interspecies differences:
1
Justification:
The substances are metabolised via general metabolic pathways that are common and very similar to rodents and humans and the absence of any specific target organs indicating a specific MOA at high concentrations there is no reason to believe that an additional AF of 2.5 for remaining differences is justified.
AF for intraspecies differences:
5
Justification:
Known mode of action involving ubiquitous and non-specific enzyme systems (carboxylesterases, tricarboxylic acid cycle) makes a lower variability likely, hence the AF of 5 by ECETOC (2010) is sufficiently conservative for the general population.
AF for the quality of the whole database:
1
Justification:
The key study was conducted according to modern regulatory standards and was adequately reported. On this basis the quality of the database is not considered to contribute uncertainty and it is therefore not necessary to apply an additional factor.
AF for remaining uncertainties:
1
Justification:
No remaining uncertainties.
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
no hazard identified

Additional information - General Population

Route-to-route extrapolation:

Oral to inhalatory

Only oral studies are available.

Extrapolation oral to inhalation: AF 2

 

Oral to dermal

Only oral studies are available. In the absence of data on dermal uptake, 100% dermal absorption is assumed.

Extrapolation oral to dermal: AF 1

DNEL derivation is based on an OECD422 guideline study (dose levels: 50, 175 and 500 mg/kg bw/d). No treatment-related effects were noted -> NOAEL (repeated dose, reproduction, neurotoxicity) = 500 mg/kg bw/d

DNEL general population, chronic dermal systemic: 4.17 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 500 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120

 

DNEL general population, chronic inhalative systemic: 7.2 mg/m³

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point after route-to-route extrapolation: 217.0 mg/m³

inhalatory NOEC (24 h)          = oral NOAEL x 1/sRVratx ABSoral-rat/ ABSinh-human

                                              = 500 x 1/1.152 x 50/100

 

Overall AF: 1*1*5*6*1*1 = 30

 

DNEL general population, chronic oral systemic: 4.17 mg/kg bw/d

Start value: 500 mg/kg bw/d

Route of original study: oral

Dose descriptor starting point: 500 mg/kg bw/d

Overall AF: 4*1*5*6*1*1 = 120