Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
416 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: see discussion
Overall assessment factor (AF):
16.8
Modified dose descriptor starting point:
NOAEC
Value:
1 750 mg/m³
Explanation for the modification of the dose descriptor starting point:
The relevant oral NOAEL of 1000 mg/kg bw/d is converted into a corrected NOAEC assuming a standard 6h respiratory volume of 0.38 m³/kg for the rat, a standard 8h respiratory volume of 6.7 m³/Person for humans and a respiratory volume light activity of 10 m³/person for workers.
AF for dose response relationship:
1
Justification:
No indication for any effect level that could differ between humans and test species and which are not accounted for in the other AF.
AF for differences in duration of exposure:
1.4
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
AF for interspecies differences (allometric scaling):
4
Justification:
standard factor according to ECHA guideline.
AF for other interspecies differences:
1
Justification:
Allometric AF accounts for all interspecies differences.
AF for intraspecies differences:
3
Justification:
ECETOC assessment factor
AF for the quality of the whole database:
1
Justification:
standard factor according to ECHA guideline.
AF for remaining uncertainties:
1
Justification:
It has been shown that an additional assessment factor for remaining uncertainties is scientifically unjustified ( Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
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:
59.5 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: see discussion
Overall assessment factor (AF):
16.8
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
as a worst case, oral and dermal bioavailability is considered to be equal. Structure and molecular weight suggest that dermal penetration actually should be lower than oral uptake.
AF for dose response relationship:
1
Justification:
No indication for any effect level that could differ between humans and test species and which are not accounted for in the other AF.
AF for differences in duration of exposure:
1.4
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA standard AF
AF for other interspecies differences:
1
Justification:
Allometric AF accounts for all interspecies differences.
AF for intraspecies differences:
3
Justification:
ECETOC AF for workers.
AF for the quality of the whole database:
1
Justification:
standard factor according to ECHA guideline.
AF for remaining uncertainties:
1
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available

Workers - Hazard for the eyes

Additional information - workers

DNEL - long-term exposure - systemic effects oral:

 

The key study for DNEL derivation is a subchronic oral toxicity study in rats with the registered substance, suggesting a NOAEL of 1000 mg/kg bw/d. The following assessment factors are proposed for the oral DNEL for workers: 4 for allometric scaling, 3 for intraspecies variation, and 1.4 for exposure extrapolation (subchronic to chronic) resulting in an overall assessment factor of 16.8. An additional factor for “remaining interspecies differences” as proposed by ECHA is scientifically not justified since the allometric scaling factor fully accounts for interspecies differences. This has recently independently been confirmed by the German BAuA (BAuA Bekanntmachung 901 “Kriterien zur Ableitung von Arbeitsplatzgrenzwerten” April 2010,GMBl 2010 Nr. 32 S. 691-696) and theECETOC Assessment Factor Working Group (ECETOC Technical Report in preparation: Guidance on Assessment Factors to Derive DNELs (2010)). It had been shown recently that the assessment factor for time extrapolation from subchronic to chronic exposure actually is 1.4 (but not 2) when the statistical bias is removed from the dataset ( Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129). Based on these assessment factors, the long-term exposure DNEL for oral exposure for workers is 59.5 mg/kg bw/d. 

 

 

DNEL - long-term exposure - systemic effects dermal:

 

The key study for DNEL derivation is a subchronic oral toxicity study in rats with the registered substance, suggesting a NOAEL of 1000 mg/kg bw/d. The following assessment factors are proposed for the dermal DNEL for workers: 4 for allometric scaling, 3 for intraspecies variation because the registered substance is exclusively used in professional and industrial settings, and 1.4 for exposure extrapolation (subchronic to chronic) resulting in an overall assessment factor of 16.8. Equal absorption via the oral and dermal route is assumed based on structure considerations. An additional factor for “remaining interspecies differences” as proposed by ECHA is scientifically not justified since the allometric scaling factor fully accounts for interspecies differences. This has recently independently been confirmed by the German BAuA (BAuA Bekanntmachung 901 “Kriterien zur Ableitung von Arbeitsplatzgrenzwerten” April 2010,GMBl 2010 Nr. 32 S. 691-696) and theECETOC Assessment Factor Working Group (ECETOC Technical Report in preparation: Guidance on Assessment Factors to Derive DNELs (2010)). Furthermore, it had been shown recently that the assessment factor for time extrapolation from subchronic to chronic exposure is 1.4 (but not 2) when the statistical bias is removed from the dataset (Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129). Based on these assessment factors, the long-term exposure DNEL for dermal exposure for workers is 59.5 mg/kg bw/d. 

 

 

DNEL - long-term exposure - systemic effects inhalation:

 

For inhalation the relevant oral NOAEL of 1000 mg/kg bw/d is converted into a corrected NOAEC assuming a standard 6h respiratory volume of 0.38 m³/kg for the rat, a standard 8h respiratory volume of 6.7 m³/Person for humans, a body weight of 70 kg and a respiratory volume light activity of 10 m³/person for workers. This results in a corrected NOAEC of 1750 mg/m³. Taking in account assessment factors of 1 for interspecies differences (inhalation), 3 for intraspecies variation (worker), and 1.4 for exposure time extrapolation (subchronic to chronic) the long-term exposure DNEL for inhalation is 416 mg/m³.Equal absorption via both routes is assumed.

Local Effects

 

Local effects were not observed in any investigation, therefore local DNELs may not be derived.

Acute/short term exposure

 

The registered substance is neither irritating to the skin or the eyes and it is not a sensitizer. Therefore, acute DNELs may not be derived.

General Population - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
125 mg/m³
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: see discussion
Overall assessment factor (AF):
28
Modified dose descriptor starting point:
NOAEC
Value:
875 mg/m³
Explanation for the modification of the dose descriptor starting point:
For inhalation the relevant oral NOAEL of 1000 mg/kg bw/d is converted into a corrected NOAEC assuming a standard body weight of 70 kg, an allometric scaling factor (rat-human) of 4 and a respiratory volume of 20 m³/person for the general population.
AF for dose response relationship:
1
Justification:
ECHA guidance default. No indication for any effect level that could differ between humans and test species and which are not accounted for in the other AF.
AF for differences in duration of exposure:
1.4
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA guidance default.
AF for other interspecies differences:
1
Justification:
Allometric AF accounts for all interspecies differences.
AF for intraspecies differences:
5
Justification:
ECETOC default for general population.
AF for the quality of the whole database:
1
Justification:
ECHA guidance default.
AF for remaining uncertainties:
1
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: see discussion
Overall assessment factor (AF):
28
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
As a worst case, oral and dermal bioavailability is considered to be equal. Structure and molecular weight suggest that dermal penetration actually should be lower than oral uptake.
AF for dose response relationship:
1
Justification:
ECHA guidance default. No indication for any effect level that could differ between humans and test species and which are not accounted for in the other AF.
AF for differences in duration of exposure:
1.4
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default AF.
AF for other interspecies differences:
1
Justification:
Allometric AF accounts for all interspecies differences.
AF for intraspecies differences:
5
Justification:
ECETOC default AF for the general population.
AF for the quality of the whole database:
1
Justification:
ECHA default AF.
AF for remaining uncertainties:
1
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
Acute/short term exposure
Hazard assessment conclusion:
no-threshold effect and/or no dose-response information available
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)

General Population - Hazard via oral route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
35.7 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Oral
DNEL related information
DNEL derivation method:
other: see discussion
Overall assessment factor (AF):
28
Modified dose descriptor starting point:
NOAEL
Value:
1 000 mg/kg bw/day
Explanation for the modification of the dose descriptor starting point:
not necessary.
AF for dose response relationship:
1
Justification:
ECHA guidance default. No indication for any effect level that could differ between humans and test species and which are not accounted for in the other AF.
AF for differences in duration of exposure:
1.4
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
AF for interspecies differences (allometric scaling):
4
Justification:
ECHA default AF.
AF for other interspecies differences:
1
Justification:
Allometric AF accounts for all interspecies differences.
AF for intraspecies differences:
5
Justification:
ECETOC default AF.
AF for the quality of the whole database:
1
Justification:
ECHA default AF.
AF for remaining uncertainties:
1
Justification:
Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129
Acute/short term exposure
Hazard assessment conclusion:
hazard unknown (no further information necessary)
DNEL related information

General Population - Hazard for the eyes

Local effects

Hazard assessment conclusion:
hazard unknown (no further information necessary)

Additional information - General Population

Acute/short term exposure

 

The registered substance is neither irritating to the skin or the eyes and it is not a sensitizer. Therefore, acute DNELs may not be derived.

 

Local effects

Local effects were not observed in any investigation, therefore local DNELs may not be derived.

DNEL - long-term exposure - systemic effects oral:

 

The key study for DNEL derivation is a subchronic oral toxicity study in rats with the registered substance, suggesting a NOAEL of 1000 mg/kg bw/d. The following assessment factors are proposed for the oral DNEL for workers: 4 for allometric scaling, 5 for intraspecies variation (general population), and 1.4 for exposure extrapolation (subchronic to chronic) resulting in an overall assessment factor of 28. An additional factor for “remaining interspecies differences” as proposed by ECHA is scientifically not justified since the allometric scaling factor fully accounts for interspecies differences. This has recently independently been confirmed by the German BAuA (BAuA Bekanntmachung 901 “Kriterien zur Ableitung von Arbeitsplatzgrenzwerten” April 2010,GMBl 2010 Nr. 32 S. 691-696) and theECETOC Assessment Factor Working Group (ECETOC Technical Report in preparation: Guidance on Assessment Factors to Derive DNELs (2010)). It had been shown recently that the assessment factor for time extrapolation from subchronic to chronic exposure actually is 1.4 (but not 2) when the statistical bias is removed from the dataset (Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129). Based on these assessment factors, the long-term exposure DNEL for oral exposure for workers is 35.7 mg/kg bw/d. 

 

DNEL - long-term exposure - systemic effects inhalation:

 

For inhalation the relevant oral NOAEL of 1000 mg/kg bw/d is converted into a corrected NOAEC assuming a standard body weight of 70 kg, an allometric scaling factor (rat-human) of 4 and a respiratory volume of 20 m³/person for the general population. This results in a corrected NOAEC of 875 mg/m³. Taking in account assessment factors of 1 for interspecies differences (inhalation), 5 for intraspecies variation (general population), and 1.4 for exposure time extrapolation (subchronic to chronic) the long-term exposure DNEL for inhalation is 125 mg/m³.Equal absorption via both routes is assumed.

 

 

DNEL - long-term exposure - systemic effects dermal:

 

The key study for DNEL derivation is a subchronic oral toxicity study in rats with the registered substance, suggesting a NOAEL of 1000 mg/kg bw/d. The following assessment factors are proposed for the dermal DNEL for workers: 4 for allometric scaling, 5 for intraspecies variation because the registered substance is exclusively used in professional and industrial settings, and 1.4 for exposure extrapolation (subchronic to chronic) resulting in an overall assessment factor of 28. Equal absorption via the oral and dermal route is assumed based on structure considerations. An additional factor for “remaining interspecies differences” as proposed by ECHA is scientifically not justified since the allometric scaling factor fully accounts for interspecies differences. This has recently independently been confirmed by the German BAuA (BAuA Bekanntmachung 901 “Kriterien zur Ableitung von Arbeitsplatzgrenzwerten” April 2010,GMBl 2010 Nr. 32 S. 691-696) and theECETOC Assessment Factor Working Group (ECETOC Technical Report in preparation: Guidance on Assessment Factors to Derive DNELs (2010)). Furthermore, it had been shown recently that the assessment factor for time extrapolation from subchronic to chronic exposure is 1.4 (but not 2) when the statistical bias is removed from the dataset (Batke et al., Derivation of sound time extrapolation factors for repeated dose toxicity studies using RepDose. Toxicology Letters 205 (2011) 122– 129). Based on these assessment factors, the long-term exposure DNEL for dermal exposure for workers is 35.7 mg/kg bw/d