Registration Dossier

Administrative data

Workers - Hazard via inhalation route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
24.5 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):
18
Modified dose descriptor starting point:
NOAEC
Value:
440.8 mg/m³
Explanation for the modification of the dose descriptor starting point:
The NOAEL from the repeated dose study was converted to an inhalatory NOAEC according to the following formula. NOAEC = NOAEL / resp. volume (rat) x (resp. volume (human) / resp. volume (human, light activity)) x (absorption (dermal) / absorption (inhal.)) = 250mg/kg b.w. / 0.38m³/kg b.w. x 0.67 x 1 = 440.8mg/m³
AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Already considered during route to route extrapolation.
AF for other interspecies differences:
1
Justification:
Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used. In the oral repeated dose study, the NOAEL is based on few changes in serum chemistry without histopathological changes. Additionally, rats were treated for almost 50 days, which is significantly longer than the 28days in a subacute study. Thus the factor of 6 for extrapolation of duration already contains an additional safety factor.
AF for intraspecies differences:
3
Justification:
Based on ECETOC guidance
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
Default factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
Acute/short term exposure
Hazard assessment conclusion:
low hazard (no threshold derived)
DNEL related information

Workers - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
2.77 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
24
Modified dose descriptor starting point:
NOAEL
Value:
66.5 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
This factor describes the differences in metabolic rate between rats and humans based on body weight and is generally applicable to renally excreted substances.
AF for other interspecies differences:
1
Justification:
Within the ERASM project, studies in rats and mice were being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a default factor (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). Additionally, effects in the high dose animals were limited to an unspecific reduction of body weightin male animals only. The NOAEL thus already represent a worst case approach, and no additional safety factor is considered necessary.
AF for intraspecies differences:
3
Justification:
Systemic toxicity is limited to reduced body weight in male rats. Since no other parameters were affected, this change is likely secondary to bad general state associated with severe irritation. No large intraspecied differences are expected an a factor of 3 is considered sufficient in this case.
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
default factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

Workers - Hazard for the eyes

Local effects

Hazard assessment conclusion:
low hazard (no threshold derived)

Additional information - workers

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:
ECHA REACH Guidance
Overall assessment factor (AF):
30
Modified dose descriptor starting point:
NOAEC
Value:
217.4 mg/m³
Explanation for the modification of the dose descriptor starting point:
The substance is not classified for acute systemic effects according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).
AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
1
Justification:
Already considered during route to route extrapolation.
AF for other interspecies differences:
1
Justification:
Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used. In the oral repeated dose study, the NOAEL is based on few changes in serum chemistry without histopathological changes. Additionally, rats were treated for almost 50 days, which is significantly longer than the 28days in a subacute study. Thus the factor of 6 for extrapolation of duration already contains an additional safety factor.
AF for intraspecies differences:
5
Justification:
Based on ECETOC guidance
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
Default factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

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

General Population - Hazard via dermal route

Systemic effects

Long term exposure
Hazard assessment conclusion:
DNEL (Derived No Effect Level)
Value:
1.66 mg/kg bw/day
Most sensitive endpoint:
repeated dose toxicity
Route of original study:
Dermal
DNEL related information
DNEL derivation method:
ECHA REACH Guidance
Overall assessment factor (AF):
40
Modified dose descriptor starting point:
NOAEL
Value:
66.7 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
2
Justification:
subchronic to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
This factor describes the differences in metabolic rate between rats and humans based on body weight and is generally applicable to renally excreted substances.
AF for other interspecies differences:
1
Justification:
Within the ERASM project, studies in rats and mice were being examined to substantiate whether the factors for allometry and 'remaining‘ differences would be appropriate for these species. The results suggest that a factor of 2.5 for 'remaining‘ interspecies differences may be questionable as a default factor (Escher and Mangelsdorf, 2009; Batke et al, 2011; Bitsch et al, 2006). Additionally, effects in the high dose animals were limited to an unspecific reduction of body weightin male animals only. The NOAEL thus already represent a worst case approach, and no additional safety factor is considered necessary.
AF for intraspecies differences:
5
Justification:
Systemic toxicity is limited to reduced body weight in male rats. Since no other parameters were affected, this change is likely secondary to bad general state associated with severe irritation. No large intraspecied differences are expected an a factor of 3 is considered sufficient in this case.
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
default factor
Acute/short term exposure
Hazard assessment conclusion:
no hazard identified
DNEL related information

Local effects

Long term exposure
Hazard assessment conclusion:
medium hazard (no threshold derived)
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:
2.1 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):
120
Modified dose descriptor starting point:
NOAEL
Value:
250 mg/kg bw/day
AF for dose response relationship:
1
Justification:
NOAEL was used as starting point
AF for differences in duration of exposure:
6
Justification:
subacute to chronic
AF for interspecies differences (allometric scaling):
4
Justification:
This factor describes the differences in metabolic rate between rats and humans based on body weight and is generally applicable to renally excreted substances.
AF for other interspecies differences:
1
Justification:
Besides the applied allometric scaling factors no additional interspecies factor for remaining differences has been used. In the oral repeated dose study, the NOAEL is based on few changes in serum chemistry without histopathological changes. Additionally, rats were treated for almost 50 days, which is significantly longer than the 28days in a subacute study. Thus the factor of 6 for extrapolation of duration already contains an additional safety factor.
AF for intraspecies differences:
5
Justification:
Based on ECETOC guidance
AF for the quality of the whole database:
1
Justification:
GLP guideline study
AF for remaining uncertainties:
1
Justification:
Default factor
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

It should be stressed that consumer DNELs were only derived for the sake of completeness. The substance is currently not used in consumer applications, and future uses are neither planned nor advised.